General Principles

Anatomy

FOOSH injury (fall onto an outstretched, dorsiflexed hand) (1682)

Distal complications are the most common and include scaphoid fracture, lunate dislocation, and distal radius fracture.
The lunate is one of the proximal carpal bones. It can be identified on x-ray of the hand as the more medial of the 2
bones that articulate with the radius. The scaphoid is the other (more lateral bone that articulates with the radius, and
injuries that cause lunate dislocation often also cause fracture of the scaphoid.

Trendelenburg sign (1639)

The superior gluteal nerve innervates the gluteus medius, gluteus minimus, and tensor fasciae latae muscles. Theses
muscles fx to stabilize the pelvis and abduct the thigh. Weakness of the gluteus medius and gluteus minimus muscles
will cause the pelvis to sag toward the unaffected (contralateral) side when the patient stands on the affected leg
(positive Trendelenburg sign). When walking, the px will lean toward the affected (ipsilateral) side to compensate for the
hip drop (gluteus medius lurch).

VS. the inferior gluteal nerve innervates the gluteus maximus muscle, which is responsible for extension and external
rotation of the thigh at the hip. Inferior gluteal nerve injury typically causes difficulty in rising from a seated position and
climbing stairs.

VS. injury of the obturator nerve causes impaired thigh adduction and medial thigh sensory loss

VS. The sciatic nerve innervates the muscles in the posterior compartment of the thigh (ie, hamstrings). It subsequently
divides into the tibial and common fibular/common peroneal nerves, which provide motor and sensory innervation to
the leg and foot.

VS. the femoral nerve innervates the muscles responsbiel for flexion of the thigh at the hip (eg, iliacus and sarotorius
muscle) and extension of the leg at the knee (Eg, quadriceps femoris). It also supplies sensory innervation to the skin on
the anterior thigh and medial leg. Injury results in knee buckling and loss of the patellar reflex.

Psoas abscess (1885)

The psoas muscle originates from the anterior surface of the transverse processes and lateral surface of the vertebral
bodies and functions primarily as a hip flexor and contributes to external rotation of the thigh. Psoas abscess may form
due to direct spread of infection from an adjacent structure (eg, vertebral bodies, appendix, hip joint) or from
hematogenous seeding from a distant site.

Brachial plexus (1812)

Dissection of the axillary lymph nodes can injure the long thoracic nerve. This results in weakness of the serratus
anterior with winging of the scapula and impaired abduction of the shoulder past the horizontal

VS. anterior dislocation of the shoulder or fracture of the neck of the humerus can injure the axillary nerve. This causes
paralysis of the deltoid and teres minor muscles and localized sensory loss in the upper arm

VS. clavicular fracture only occasionally causes neurovascular compromise, usually involving the subclavian vessels and
supraclavicular nerve
VS. thyroidectomy may cause injury to the recurrently laryngeal nerve. Injury causes weakness of the posterior
cricoarytenoid muscles, with hoarseness and impaired breathing

VS. injury to the upper brachial plexus (musculocutaneous and suprascapular nerves) can occur due to traction between
the head and shoulder. This can occur in the neonate due to dystocia or in the adult from violent injury. The resulting
palsy is characterized by shoulder adduction, elbow extension and forearm pronation

(1930)

The radial nerve (receives fibers from C5-T1) provides sensory innervation to the skin of the posterior arm, forearm and
dorsal lateral hand and provides motor innervation to all the extensor muscles of the upper limb below the shoulder.
Dmg to the proximal radial nerve (eg, at the axilla or midshaft humerus) may result in wrist drop.

Sciatic neuropathy (15705)

Sciatic neuropathy is a common complication of hip fracture and/or arthroplasty because of the proximity fo the sciatic
nerve to the hip joint. Injury to the sciatic nerve in the pelvis causes neurological deficits across the sciatic nerve (knee
flexion), common peroneal nerve (dorsiflexion, numbness of the calf and dorsal foot), and tibial nerve (plantar flexion,
ankle reflex).
Rotator cuff muscles (11776)

Facial nerve (12025)

The extracranial portion of the facial nerve (CN VII) carries motor innervation to the muscles of facial expression. This
nerve exits the skull through the stylomastoid foramen and courses within the substance of the parotid gland. Within
this gland, the facial nerve divides into its 5 terminal branches (temporal, zyogmatic, buccal, mandibular and cervical).
Parotid gland tumors can compress and disrupt the ipsilateral facial nerve and its branches, causing facial droop. In fact,
most parotid gland tumors causing facial nerve paralysis are malignant neoplasms.

Reflexes (11779)

Tibial nerve injury (1638)

The tibial nerve may be injured at the level of the popliteal fossa due to deep penetrating trauma or knee surgery. Px
typically have weakness on foot plantarflexion, foot inversion and toe flexion with sensory loss over the sole.

Sciatic neuropathy (11727)

The priiformis passes through the greater sciatic foramen and is involved with external hip rotation. Muscle injury or
hypetrophy can compress the sciatic nerve in the foramen, causing piriformis syndrome

Major muscles responsible for motion at the hip (7621)

Flexion Extension Abduction Adduction
- Iliopsoas - Gluteus maximus - Gluteus medius - Adductor brevis
- Rectus femoris - Semitendinosus - Gluteus minimus - Adductor longus
- Tensor fascia lata - Semiemmbranosus - Adductor magnus
- Biceps femoris – long
head

Muscles used when sitting up from the supine position include the external abdominal obliques, the rectus abdominis
and the hip flexors. The iliopsoas muscle is the most important of the hip flexors and includes the psoas major, psoas
minor and iliacus. The rectus femoris, Sartorius, tensor fascia lata, and the medial compartment of the thigh also
contribute to hip flexion.
Broad ligament (1632)

Is a sheet of peritoneum that extends from the lateral uterine body and upper cervix to the pelvic sidewall. It is
subdivided according to the following associated reproductive structures:

- The mesosalpinx (descends from the fallopian tube)

- The messovarium (inferior to the mesosalpinx, convers the ovarian hilum)
- The mesometrium (inferior to the messovarium, extends from the lateral uterine body to the external iliac vessls
and the proximal part of the round ligament)

The ovaries, located posterolaterally to the uterus, are suspended by the messovarium superiorly, the ovarian ligament
medially and the suspensory ligament of the ovary (also known as the infundibulopelvic ligament) laterally. The
suspensory ligmanet of the ovary is a fold of peritoneum that attahes the ovary to the pelvic sidewall and contains the
ovarian artery (major ovarian blood supply arising from the abdominal aorta entering the ovary at the hilum), vein
lymphatics, and nerves. The suspensory ligament of the ovary must be ligated to prevent heavy ovarian bleeding in an
oophorectomy

The ureter is in close proximity to the suspensory ligament of the ovary (medial at the level of the bifurcation of the
common iliac artery). The ureter must be identified prior to ligation to avoid anadvertent ureteral transection

Inferior epigastric artery (11831)

The inferior epigastric artery is 1 of 2 branches of the external iliac artery and takes off immediately proximal to the
inguinal ligament. It provides blood supply to the lower anterior abd wall as it runs superiorly and medially up the abd.

Femoral nerve block (11777)

The optimal site for femoral nerve block is in the inguinal crease at the lateral border of the femoral artery. Injecting at
this site anesthetizes the skin and muscles of the anterior thigh, femur, and knee. The block also anesthetizes the
saphenous nerve (terminal extension of the femoral nerve) to decrease sensation in the medial leg below the knee.

Obturator nerve (1802)

The obturator nerve is the only major nerve that exits the pelvis through the obturator foramen. Nerve injury typically
results from compression (eg, due to pelvic trauma, surgery or tumor) and presents with weakness on thigh adduction
and sensory loss over the distal medial thigh

Midshaft humerus fracture (1704)

Should raise concern for an associated injury to the deep brachial artery, branches off the brachial artery high in the
arm, passes inferior to the teres major muscle and courses posteriorly along the humerus in close association with the
radial nerve

Radial nerve injury (eg, wrist drop), innervates most of the forearm extensors at the elbow (Eg, triceps) and most of the
hand extensors at the wrist. It also innervates the extrinsic extensors of the digits and the brachioradialis and supinator
muscles. The radial nerve also provides cutaneous sensory innvervation to the dorsal hand, forearm, and upper arm.

(1695)

CN XI innervates the sternocleidomastoid and trapezius muscles. This nerve may be injured during surgery involving the
posterior triangle of the neck (a region bounded by the sternocleidomastoid muscle, trapezius muscle and clavicle)
The ansa cervicalis arises from the C1, C2, and C3 nerve roots and innervates the sternohyoid, ternothyroid, and
omohyoid muscles of the anterior neck. Penetrating trauma to the neck above the cricoid cartilage can injure this nerve.

The inferior thyroid artery arises from the thyrocervical trunk and courses posterior to the carotid artery and jugular vein
to supply the inferior pole of the thyroid gland. Injury to the inferior thyroid artery is commonly associated with
hoarseness because it runs adjacent to the recurrent laryngeal nerve.

Biochemistry

Cellular phases/replication (1717)

1. Gap phase 0 (G0 phase) is the stage in which the cell cycle is suspended. The cells are resting and do not divide
2. Interphase comprises 90% of the cell cycle and is the stage in which the cell prepares for division. Interphase is
subdivided into the G1 phase (ie, synthesis of RNA, protein, lipid and CHO), S phase (ie, DNA replication, and the
G2 phase (ie, ATP synthesis)
3. Mitosis (M) is the stage in which the cell divides into two daughter cells

At both the G1 to S phase transition and the G2 to M phase transition and the G2 to M phase transition, the cell cycle
can be stopped. These stages are called “checkpoints” and are regulated by cyclins and cyclin-dependent kinases that
screen for DNA dmg or abnormalities. Cells with normal DNA are allowed to proceed through the checkpoint, while cells
with dmged DNA trigger DNA repair mechanisms. If the DNA dmg is too substantial to be repaired, the cell undergoes
apoptosis.

The Rb (retinoblastoma) tumor suppressor gene located on chromosome 13q14 encodes a nuclear phosphoprotein that
regulates the G1->S checkpoint. Rb point can be in an active (hypophosphorylated) state or an inactive
(hyperphosphorylated) state. The inactivated Rb protein allows the cell to proceed through the G1->2 checkpoint. The
activated Rb protein, in contrast, stops the cell cyle. Abnormal phosphorylation of Rb protein results in its inactivation,
thereby allowing cells with dmged DNA to proceed through the G1->S checkpoint and then divide.

Mutations of the Rb protein have been linked to retinoblastoma, osteosarcoma, breast adenocarcinoma, small cell
carcinoma of the lung and bladder carcinoma.

Releasing factors (2029)

Releasing factors recognize stop codons (eg, UAA, UAG, and UGA) and terminate protein synthesis. They facilitate
release of the polypeptide chain from the ribosome and dissolution of the ribosome-mRNA complex

Ubiquitin proteasome pathway (11674)

A key step in the ubiquitin proteasome pathway is controlled by ubiquitin ligases, which recognize specific protein
substrates and attach a ubiquitin tag. The proteins are then degraded to an appropriate size and coupled with the major
histocompatibility I protein complex in the endoplasmic reticulum. Finally, they are presented on the cell surface for
recognition by cytotoxic CD8+ lymphocytes

Eukaryotic DNA replication (1437)

The key steps of DNA replication are similar in eukaryotes and prokaryotes (eg, E. Coli), and are as follows:

1. Unwinding of double-stranded DNA by helicase to produce single-stranded DNA

2. Formation of a replication fork
3. Synthesis of RNA primers by the enzyme primase
 4. Synthesis and concurrent proofreading of daughter DNA strands by DNA polymerases
5. Removal and replacement of RNA primers with DNA
6. Ligation of Okazaki fragments on lagging strands by the enzyme ligase

Despite the similarities of prokaryotic and eukaryotic DNA replication, there are important differences between these
processes. Prokaryotes possess 3 major DNA polymerases (I, II and III), whereas eukaryotes have 5 major DNA
polymerases (alpha, beta, gamma, delta and episilun). The eukaryotic genome is also much larger and more complex
than the prokaryotic genome, which can be partly explained by the abundance of noncoding DNA regions (introns)
located between coding regions (exons). In addition, prokaryotes typically have circular DNA with a single origin of
replication, whereas eukaryotes have linear DNA with multiple origins of replication. This feature allows the eukaryotic
genome to be copied in a quick and effective manner despite its large size.

Eukaryotic RNA polymerase Major RNA product

RNA polymerase I Ribosomal RNA
RNA polymerase II Messenger RNA
RNA polymerase III Transfer RNA

Internal ribosome entry site (6462)

Eukaryotic translation is initiated when the small ribosomal subunit binds the 5’cap of mRNA and scans for the
methionine start codon (AUG) within the kozak consensus sequence. Ribosomal binding to the 5’ cap is facilitated by a
family of proteins known as eukaryotic initiation factors (eIFs).

During apoptosis, the activation of caspases resultsin eIF degradation, leading to interruption of translation. As a result,
many of the proteins necessary for apoptosis are translated using an alternative method known as internal ribosome
entry. With this method, a distinct nucleotide sequence called the internal ribosome entry site (IRES) attracts the
eukaryotic ribosome to mRNA and allows translation to the begin in the middle of the mRNA sequence. IRESs are usually
located in the 5’ untranslated region, the segment of mRNA located directly upstream from the translation start codon.

tRNA (2037)

Is a small, noncoding form of RNA that contains chemically modified bases (eg, dihydrouridine, ribothymidine,
pseudouridine). tRNA has a CCA sequence at its 3’-end that is used as a recognition sequence by proteins. The 3’
terminal hydroxyl group of the CCA tail serves as the aa binding site.

RNA structure and function (1428)

The 3’ CCA tail of tRNA serves as the aa binding site. Aminoacyl tRNA synthetase is the enzyme responsible for “loading’
the appropriate AA to the 3’ terminal hydroxyl group of the CCA tail

snRNPs (361)

Smith protein normally complexes with small nuclear RNA (snRNA) in the cytoplasm, forming small nuclear
ribonucleoproteins (snRNPs).

Transcription occurs in the nucleus and is catalyzed by 3 types of RNA polymerases, leading to the formation of
messenger RNA (mRNA), ribosomal RNA (rRNA), transport RNA (tRNA), and snRNA. RNA polymerase II synthesizes both
mRNA and snRNA, the latter of which combines with specific proteins to form snRNPs. mRNA synthesis occurs in 2
stages. During the first, the DNA template is transcribed into a complementary strand of pre-mRNA. In the second, pre-
mRNA is processed into mature mRNA through the following steps:

1. RNA capping: addition of a methylated guanine nucleotide to the 5’ end.

2. RNA polyadenylation: Addition of several denine nucleotides to the 3’ end (poly-A tail).
3. RNA splicing: Removal of introns (noncoding regions) by spliceosomes, which consist of snRNPs and other
proteins.

Mature mRNA then transfers the genetic code to the cytoplasm and serves as a template for protein synthesis
(translation)

RNA splicing (6503)

Newly transcribed mRNA (pre-mRNA) undergoes splicing (removal of introns) to form mature mRNA before leaving the
nucleus. If a gene sequence is hybridized with its complementary mature mRNA, loops of unbound DNA will appear,
representing regions of the gene that code ofr introns. These DNA loops form because their complementary mRNA
sequences (introns) have been spliced out posttranscriptionally. mRNA processing (posttranscriptional modification)
involves 3 main steps:

1. 5’ capping: 7-methylguanosine is added to the 5’ end of the primary mRNA transcript via a 5’-5’ triphosphate
linkage. This modification helps stabilize mRNA in the cytosol
 2. Poly(A) tail addition: following transcription, a tail rich in adenine residues is added to the mRNA transcript by
poly(A) polymerase. The poly(A) tail stabilizes the 3’ end of mRNA in the cytosol
3. Splicing out introns: introns are noncoding segments of a gene that are transcribed with exons into the primary
mRNA transcript (pre-mRNA). Introns must be removed from pre-mRNA for protein translation to occur. This
energy-dependent process is facilitated by small nuclear ribonucleoproteins (snRNPs).

DNA structure & function

Nucleosomes are composed of DNA wrapped around a core of 8 histone proteins (2 molecules each of H2A, H2B, H3,
and H4). H1 histone is located outside of this histone core and helps package nucleosomes into more compact structures
by binding and linking the DNA btween adjacent nucleosomes.

DNA replication (1419)

DNA replication occurs in the 5’->3’ direction on both strands. In contrast to the continuous synthesis of the leading
strand, lagging strand synthesis occurs discontinuously and is composed of short stretches of RNA primer plus newly
synthesized DNA segments (Okazaki fragments). As a result, lagging strand synthesis requires the repetitive action of
DNA primase and DNA ligase.

(1435) DNA replication is coordinated by the actions of multiple enzymes and proteins and requires a high degree of
fidelity to ensure preservation of the genetic code in daughter cells.

DNA polymerases are the primary enzymes responsible for DNA synthesis. Prokaryotes such as E. Coli have 3 major
types of DNA polymerase: I, II, and III. All 3 prokaryotic DNA polymerases are capable of removing mismatched
nucleotides via their 3’ to 5’ exonuclease (“proofreading”) activity. Only DNA polymerase I has 5’ to 3’ exonuclease
activity, which is used to remove the RNA primer synthesized by RNA primase.

Proteins & their fx in prokaryotic DNA replication (1435)

Helicase Unwinding of double helix
Topisomerase II (DNA gyrase) Removal of supercoils
Single-stranded DNA-binding protein Stabilization of unwound template strands
Primase (RNA polymerase) Synthesis of RNA primer
DNA polymerase III 5’ to 3’ DNA synthesis & 3’ to 5’ exonuclease (“proofreading”) activity
DNA polymerase I Same as DNA polymerase III
Also removes RNA primer (5’ to 3’ exonuclease activity) & replaces it with DNA
DNA ligase Joining of Okazaki fragments (lagging strand)

(1436)

Bloom syndrome, a rare AR disorder caused by mutations in the BLM gene. This gene encodes DNA helicase, an enzyme
resposbiel for unwinding of the double helix during DNA replication and repair. Helicase dysfunction results in
chromosomal instability and breakage and manifests clinically with growth retardation, facial anomalies (Eg,
microcephaly), photosensitive rash and immunodeficiency (eg, recurrent infections).

Translation of the mRNA (1420)

Translation of the mRNA template proceeds in the 5’ to 3’ direction. Because complementary sequences align in
antiparallel fashion, during translation tRNA anticodons will be oriented in the opposite 3’ to 5’ direction. Stop codons
(USS, UAG, and UGA) halt protein synthesis by binding a release factor; they do not add AA to the polypeptide chain.
(1471) during bacterial DNA replicaion, DNA polymerase I functioncs to remove RNA primers (via 5’ to 3’ exonuclease
activity) and replace them with DNA (via 5’ to 3’ polymerase activity). DNA polymerase I is the only bacterial DNA
polymerase that possesses 5’ to 3’ exonuclease activity.

Principles of cell biology (1119)

Cellular compartmentalization allows multiple biochemical processes to occur simultaneously at maximum efficiency.
Beta-oxidaton of fatty acids, the TCA cycle, and the carboxylation of pyruvate (gluconeogenesis) all occur within the
mitochondria. The enzymes responsible for glycolysis, fatty acid synthesis, and the pentose phosphate pathway reside in
the cytosol.

Transcription (11913)

Alternative splicing is a process by which a single gene can code for various unique proteins by selectively including or
excluding different DNA coding regions (exons) into mature mRNA. CA in particular can use alternative splicing to evade
innate defense mechanisms. The Fas receptor-Fas ligand interaction drives programmed cell death via the cytotoxic T-
cell mediated extrinsic pathway. CA cells may develop the ability to splice out a particular exon that codes for the
transmembrane domain of the Fas receptor (FasR), converting it to a soluble form that is not expressed on the cell
surface, which allows the cells to evade apoptosis.

(2015) Homeobox genes encode DNA-binding transcription factors that play an important role in the segmental
organization of the embryo along the cranio-caudal axis.

(6543) HOXA13 is a homeobox gene mutated in hand-foot-genital syndrome, a rare, dominantly inherited condition
characterized by malformations of the distal limbs, such as hypoplastic first digits, and Mullerian fusion abnormalities
(eg, uterus didelphys), which can cause miscarriages.

(2017) in prokaryotic DNA replication, primase (an RNA polymerase) is responsible for synthesizing a short RNA primer
using the separated strands of DNA at the replication fork as templates. DNA replication then proceeds, with DNA
polymerase using the 3’ hydroxyl group of the RNA primer as a starting point for synthesis. Primase is a crucial enzyme
for bacterial replication as DNA polymerase cannot initiate DNA synthesis without this short nucleic sequence primer.

(11950) zinc-finger motifs are composed of chains of AA bound together around a zinc atom via linkages with cysteine
and histidine residues. They recognize specific DNA sequences are are used by many transcription factors to bind DNA
and alter activity of target genes. Intracellular receptors that bind steroids, thyroid hormone, and fat soluble vitamins act
directly as transcription factors and contain zinc-finger binding domains.

mRNA processing and regulation (2035)

After transcription, the preliminary, unprocessed mRNA is known as precursor for mRNA, or hnRNA. Eukaryotic pre-
mRNA undergoes significant posttranscriptional processing before leaving the nucleus, including 5’-capping, poly A tail
addition, and intron splicing

Once mRNA is finalized, it leaves the nucleus bound to specific packaging proteins. Upon entering the cytoplasm, these
mRNA complexes often associated with ribosomes to undergo translation. However, certain mRNA sequences instead
associate with proteins that are found in P bodies. P bodies are distinct foci found within eukaryotic cells that are
involved in mRNA decay, and contain numerous proteins including RNA exonucleases, mRNA decapping enzymes, and
constituents involved in mRNA quality control and microRNA-induced mRNA silencing. P bodies also seem to function as
a form of mRNA storage, as certain mRNAs are incorporated into P bodies only to be lated released and utilized for
protein translation.
Transcription (12263)

CAAT box, a highly conserved (consensus) sequence that fx as a promoter of transcription in the eukaryotic genome. It is
typically located 70-80 bases upstream from the transcription start site. The Hogness (TATA) box is a second promoter
region in the eukaryotic genome. The TATA box is generally located 25 bases upstream from the transcription start site.
Both the CAAT box and the TATA box promote initiation of transcription by acting as binding sites for general
transcription factors and RNA polymerase II

Transcription termination in prokaryotes, a palindromic code in the DNA template causes formation of a “hairpin” turn
in the newly synthesized mRNA, which facilitates detachment of RNA polymerase from the DNA template.

Initiation of translation (2086)

The kozak consensus sequence occurs on eukaryotic mRNA and is defined by the following sequence: (gcc)gccRccAUGG,
in which R is either adenine or guanine. This sequence helps initiate translation at the methionine start codon (AUG)

Translation (11595)

Short non-coding RNA sequences (eg, microRNA and small interfering RNA) induce posttranscriptional gene silencing by
base-pairing with complementary sequences within target mRNA molecules

DNA repair

Disorders caused by deficient DNA-repair enzymes (673)

1. Ataxia telangiectasia is characterized by DNA hypersensitivity to ionizing radiation.

2. In xeroderma pigmentosum, DNA is hypersensitive to UV radiation, causing premature skin aging and increased
risk of skin cancer (malignang melanoma and squamous cell carcinoma).
3. Fanconi anemia is caused by hypersensitivity of DNA to cross-linking agents
4. Bloom syndrome is characterized by generalized chromosomall instability. Increased susceptibility to neoplasms
is present
5. Hereditary nonpolyposis colorectal cancer (HNPCC) occurs due to a defect in DNA mismatch-repair enzymes. It
leads to increased susceptibility to colon cancer.

Xeroderma pigmentosum (1476)

- AR
- Defects in nucleotide excision repair
- DNA can be dmged by UV rays, leading to formation of thymine dimers between 2 adjacent thymine residues.
These thymine dimers are repaired by UV-specific endonuclease, an enzyme that is frequently deficient

Mismatch repair (2028)

Mismatch repair begins with MutS homolog detecting a mismatch on the newly created daughter strand, which is
distinguished from the parent strand by occasional nicks in the phosphodiester bonds. MutL homolog is then recruited,
and the resulting complex slides along the DNA molecule until 1 of the daughter strand nicks is encountered. At this
point, exonuclease 1 is loaded onto and activated by the repair complex. The daughter strand is then degraded
backward past the initial mismatch point, leaving a variable gap of single-stranded DNA that is stabilized by ssDNA-
binding protein. The complex then dissociates while DNA polymerase delta loads at the 3’end of the discontinuity and
begins synthesizing a new daughter strand segment. Finally, DNA ligase I seals the remaining nick to complete the repair
process.
Exonuclease (1434)

DNA polymerases are the primary enzymes responsible for DNA synthesis, which occurs in the 5’ to 3’ direction.
Prokaryotes such as E. coli have 3 major DNA polymerases: I, II, and III. DNA replication requires at high degree of fidelity
to preserve the genetic code in daughter cells and prevent potentially lethal mutations. This high-fidelity replication is
accomplished by the 3’ to 5’ “proofreading” exonuclease activity of all 3 DNA polymerases

DNA polymerase I is unique as it is the only prokaryotic polymerase that also has 5’ to 3’ exonuclease activity. This
activity functions to remove the RNA primer created by RNA primase and repair damaged DNA sequences.

Vs. DNA polymerase III has 5’ to 3’ polymerase and 3’ to 5’ exonuclease activity; however, it does not possess 5’ to 3’
exonuclease activity

Vs. topoisomerase II, also known as DNA gyrase in prokaryotes, relieves tension created during DNA strand unwinding
by introducing negative supercoils into the circular DNA. Fluoroquinolones (eg, ciprofloxacin) are a class of antibiotics
that work by inh DNA gyrase.

Vs. DNA polymerases cannot begin synthesizing complementary DNA on a single-stranded template without an RNA
primer. Primase is an RNA polymerase that synthesizes this primer, which is made up of short stretches of RNA base
paired to the DNA template.

Enhancer sequence (2025)

Enhancers and silencers may be located upstream, downstream or within a transcribed gene; these gene sequences
function to increase and decrease the rate of transcription, respectively. In contrast, promoter regions are typically
located 25 or 75 bases upstream from their associated genes and function to initiate transcription

Mitochondrial DNA (1473)

Is the most common non-nuclear DNA found in eukaryotic cells. It resembles prokaryotic DNA and is maternally derived.
Mutations involving mtDNA or nuclear DNA that codes for mitochondrial proteins can cause a variety of mitochondrial
disorders, including Leigh syndrome and MELAS

Collagen structure (1248)

Glycine is the most abundant amino acid in collagen. The triple helical conformation of collagen molecules occurs due to
the repetitive amino acid sequence within each alpha chain, in which glycine (gly) occupies every third amino acid
position (Gly-X-Y)

Collagen synthesis (1245)

Each collagen consists of 3 polypeptide alpha chains held together by hydrogen bonds, forming a triple helix. Collagen
assumes this conformation because each of the alpha chains has a simple, repetitive AA sequence represented as (Gly-X-
Y). The smallest AA, glycine (Gly), is necessary at every third position to ensure compact coiling of the helix. Many of the
AA represented by X and Y are proline residues, which kink the polypeptide chain and enhance the rigidity of the helical
structure due to their ring configuration.

Steps:

1. As translation begins in the cytoplasm, an AA signal sequence at the N-terminus of the alpha-chain facilitates
ribosomal binding to the RER and passage of the growing polypeptide chain (pre-pro-alpha-chain) into the RER
 2. Inside the RER, the hydrophobic signal sequence is cleaved to yield the pro-alpha-chain. Proline and lysine at the
Y positions of the pro-alpha-chain are hydroxylated to hydroxyproline and hydroxylysine, respectively.
Glycosylation of select hydroxyllysine residues also occurs within the RER
3. The central helical region of the pro-alpha-chain is flanked by N- and C-terminal propeptides. Disulfide bond
formation between the C-terminal propeptide rigeion of 3 alpha-chains brings the chains into an alignment
favorable for assembly into a tripl helix (procollagen molecule)
4. Procollagen molecules are then transported through the Golgi apparatus into the extracellular space. The N- and
C-terminal propeptides are cleaved by procollagen peptidases, converting procollagen into less soluble
tropocollagen
5. Tropocollagen monomers self-assemble into collagen fibrils. Finally, lysyl oxidase helps create covalent crosslinks
between collagen fibrils to form strong collagen fibers.

Apoptosis (1756)

Steps:

1. Initiation:
- Intrinsic, mitochondria-mediated pathway (phosphatidylserine or thrombospondin)
- Extrinsic, receptor-initiated pathway (induced by TNF + TNFR1 or Fas ligand when bound to receptor Fas)
2. Control:
- Intrinsic: mediated by a group of bcl-2 proteins
Pro-apoptotic (eg, Bak, Bax and Bim proteins)
Anti-apoptotic (eg, Bcl-x and Bcl-2 proteins)
 Mitochondrial permeability transition (MPT) and the release of cytochrome C and other pro-apoptotic
proteins into the cytoplasm -> activate caspases
- Extrinsic: the binding of the death ligand and the death receptor allows for pro-caspase molecules to be
brought into close proximity
3. Destruction: caspase activation. They are proteolytic enzymes that destroy cell components. They contain
cysteine and are able to cleave aspartic acid residues (cysteine-aspartic-acid-proteases).

(298) apoptosis can be triggered by a number of mechanisms, including deprivation of growth factors, DNA dmg,
intracellular accumulation of misfolded proteins, mediation by cytotoxic T lymph, and activation of receptors in the TNF
receptor family (such as Fas). Fas receptors initiate the extrinsinc pathway of apoptosis through a cytoplasmic
component known as the death domain. Upon biding Fas ligand (FasL), the receptors trimerize allowing their death
domains to form a binding site for an adapter protein called Fas-associated death domain (FADD). Receptor-bound FADD
then stimulates the activation of initiator caspases (8&10) that begin an activation cascade culminating in the activation
of executioner caspases (3&6). These initiate the terminal processes of apoptosis, including cleavage of DNA,
fragmentation of the nucleus, organelle autodigestion and plasma membrane blebbing.

The Fas receptor is expressed on T-lymph and plays an important role in the pathogenesis of numerous diseases,
including caner and autoimmune disorders. Once activated T-lymphocytes begin to express FasL, which can bind to Fs on
the same cell or adjacent lymphocytes. During initial clonal expansion, activated T lymph are resistant to Fas-induced
apoptosis in a process known as activation-induced cell death. Mutations involving Fas or FasL impair this process,
resulting in excessive accumulation of autoreactive T-cells and the development of autoimmune diseases such as lupus.

PCR (12278)

Reverse transcription polymerase chain reaction (RT-PCR) is used to detect and quantify levels of mRNA in a sample. It
uses reverse transcription to create a complementary DNA template that is then amplified using the standard PCR
procedure. RT-PCR can be used to dx chronic myelogenous leukemia by identifying an mRNA transcript containing both
BCR and ABL exons in affected cells.

F2, 6BP (1031)

F2,6BP activates PFK-1 (increasing glycolysis) and inhibits fructose 1,6-bisphosphatase (decreasing gluconeogenesis). F2,
6BP concentration is regulated by a bifunctional enzyme complex: PFK-2 increases F2, 6BP levels in response to insulin
and fructose 2,6-bisphosphatase decreases F2, 6BP levels in response to glucagon

Maple syrup urine disease (1336)

Branched-chain alpha-ketoacid dehydrogenase requires several coenzymes: Thiamine, Lipoate, Coenzyme A, FAD, NAD.
Some px with MSUD improve with high-dose thiamine tx, but most require lifelong restriction of leucine, isoleucine and
valine.

Hartnup disease (1334)

Hartnup disease is caused by impaired transport of neutral amino acids in the small intestine and proximal tubule of the
kidney. Symptoms include pellagra-like skin eruptions and cerebellar ataxia, which occur as a result of niacin deficiency.
The dx can be confirmed through detection of excessive amounts of neutral aa in the urine.

*neutral aa: alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine and tryptophan

Lysosomal storage disorder (11930)

Inclusion cell (I-cell) disease

AR disease, due to defects in protein targeting, a process by which proteins are transported to their appropriate intra- or
extracellular location. Post translational modifications (eg, folding, glycosylation, and phosphorylation) often function as
markers that help guide the protein to its final destination.

Proteins targeted for lysosomes are modified differently than those destined for extracellular secretion. A golgik body
phosphotransferase enzyme catalyzes the phosphorylation of mannose residues on lysosome-bound proteins, allowing
them to traverse the golgi network and ultimately be transported to the lysosome, where they serve as catalysts for
degradation of cellular components.

A defective phosphotransferase enzyme causes extracellular secretion of these proteins and accumulation of cellular
debris in the lysosome, forming the characteristic inclusion bodies seen in I-cell disease. Px with this disorder typically
present with failure to thrive and cognitive deficits in the first year of life along with characteristic physical features (eg,
coarse facial features, corneal clouding).

Lactic acidosis (996)

During glycolysis, the concentration of oxygen in the tissues affects the metabolic fate of pyruvate. In the presence of
oxygen, pyruvate is preferentially converted to acetyl coenzyme A by pyruvate dehydrogenase in the mitochondrial
matrix. Acetyl coenzyme A then undergoes oxidation in the TCA cycle. However, under hypoxic conditions, intracellular
accumulation of NADH inh pyruvate dehydrogenase. As a result, increased amounts of pyruvate are converted to lactate
by lactate dehydrogenase, which regenerates NAD+ from NADH (allowing for limitedis_. With significant tissue ischemia,
ATP production via anaerobic glycolysis). With significant tissue ischemia, lactate begins to accumulate in the circulation
and can lead to lactic acidosis. Px with lactic (or other metabolic) acidosis will typically hyperventilate to eliminate CO2
and induce a compensatory respiratory alkalosis
Urea cycle

(1336) Most disorder of the urea cycle require arginine as an essential aa. When px with urea cycle disorders develop
hyperammonemia, arginine is admn for production of downstream water-soluble intermediates (eg, ornithine, citrulline)
that lead to nitrogen disposal and decreased plasma ammonia levels.

Ornithine translocase deficiency (1372)

Ornithine transport into mitochondria is necessary for proper function of the urea cycle, which is the major disposal
pathway for waste nitrogen generated by catabolism of amino acids. Urea cycle defects typically cause neurological dmg
due to the accumulation of ammonia (progressive lethargy, vomiting, seizures and cerebral edema (may cause
hyperreflexia and abnormal posturing when severe) in infancy and early childhood; milder defects caused by partial
enzyme deficiencies may not manifest until adulthood). Tx: protein restriction improves this condition by reducing the
amount of aa turnover. Also medications (eg, phenylacetate) helps remove the ammonia from the blood.

Ubiquitin proteasome pathway (8385)

Ubiquitin is a protein that undergoes ATP-dependent attachment to other proteins, labeling them for degradation.
These modified proteins enter the proteasome and are degraded into small peptides. Impairment of the ubiquitin-
proteasome system can contribute to the development of neurodegenerative disorders, including Parkinson’s and
Alzheimer’s diseases.

Transmination (1482)

Transamination reactions typically occur between an AA and an alpha-keto acid. The amino group from the amino acid is
transferred to the alpha-keto acid, and the alpha-keto acid in turn becomes an AA. Pyridoxal phosphate (active vit B6)
serves as a cofactor in AA transamination and decarboxylation reactions

Methylmalonic acidemia (1341)

AR organic acidemia resulting from complete or partial def of the enzyme methylmalonyl-CoA mutase

Catabolism of isoleucine, valine, threonine, methionine and odd-chain fatty acids normally leads to formation of
propionyl CoA, which is then converted to methylmalonyl CoA by biotin dependent carboxylation. Isomerization of
methylmalonyl CoA through a vit B12-dependent reaction forms succinyl CoA, which subsequently enters the TCA cycle.
Mutations in methylmalonyl-CoA mutase result in buildup of methylmalonic acid and propionic acid, leading to a
metabolic acidosis. Hypoglycemia results from overall increased metabolic rate leading to increased glucose utilization
and direct toxic inh of gluconeogenesis by the organic acids. The presence of hypoglycemia leads to increased free fatty
acid metabolism that produces ketones, resulting in a further anion gap metabolic acidosis, finally, organic acids also
directly inh the urea cycle, leading to hyperammonemia.

Complete def of methlmalonyl-CoA mutase results in an anion gap metabolic acidosis, hypoglycemia, ketosis and
hyperammonemia. These metabolic derangements manifest as hypotonia, lethargy, vomiting and respiratory distress
(tachypnea due to acidosis) in the neonatal period. Dx is confirmed by the presence of elevated urine methylmalonic
acid and propionic acid.

Propionic acidemia, deficiency in propionyl-CoA carboxylase, also results in hyperammonemia, hypoglycemia, and
metabolic acidosis, although it does not display elevated levels of urine methlmalonic acid.

LDC and glycolysis (1019)

In glycolysis, glucose is metabolized to pyruvate. Under aerobic conditions, pyruvate is converted to acetyl-CoA to enter
the tricarboxylic acid (TCA) cycle. When oxygen is depleted (eg, in exercising muscle), pyruvate is converted to lactate
(anaerobic glycolysis).

During glycolysis, glyceraldehyde-3-phosphate (G3P) is converted to 1-3-bisphosphoglycerate (BPG) by the enzyme G3P
dehydrogenase. This enzyme reduces NAD+ to NADH. NAD+ is present in limited amounts in most cells, and it must be
regenerated from NADH for glycolysis to continue. Under aerobic conditions, NAD+ is converted to NADH in the TCA
cycle. NADH is then reconverted to NAD+ in the electron transport chain as the energy in NADH is utilized to synthesie
ATP.

In anaerobic glycolysis, NAD+ is regenerated from NADH when pyruvate is converted to lactate via lactate
dehydrogenase. In px with lactate dehydrogenase def, glycolysis is inh in strenuously exercising muscle as muscle cells
cannot regenerate NAD+. Consequently, high-intensity physical activity leads to muscle breakdown, pain, and fatigue as
insufficient amounts of energy are being produced in the exercising muscle.

Ornithine transcarbamyalse deficiency (OTC) (1370)

Ammonia generated from the metabolism of AA is converted into urea by the urea cycle. The combination of
bicarbonate (HCO3-), ammonia and ATP is catalyzed by carbamoyl phosphate synthetase (rate-limiting enzyme in the
urea cycle) to yield carbamoyl phosphate. Carbamoyl phosphate combines with ornithine to form citrulline in a reaction
catalyzed by ornithine transcarbamylase. Citrulline enters the cytosol and is converted to argininosuccinate, which is
then converted to arginine. The conversion of arginine to ornithine by arginase completes the urea cycle by releasing a
urea molecule. N-acetylglutamate serves as a regulator of the urea cycle through activation of carbamoyl phosphate
synthetase I.

OTC deficiency is the most common urea cycle disorder. It results in excess carbamoyl phosphate, which stimulates
pyrimidine synthesis. As an intermediate product in this pathway, orotic acid accumulates and results in increased
urinary orotic acid.

Px also have hyperammonemia due to impaired ammonia excretion, which is a metabolic emergency. Ammonia is
neurotoxic and causes episodes of vomiting and confusion/coma. Tachypnea also occurs due to cerebral edema from
ammonia buildup, resulting in central hyperventilation and respiratory alkalosis. Metabolic decompensation is often
triggered by illness (eg, viral upper respiratory infection, acute otitis media), fasting or increased protein intake.

Arginase deficiency (1480)

Progressive development of

- Spastic diplegia
- Abnormal movment
- Growth delay
- Elevated arginine levels

Arginase is a urea cycle enzyme that produces urea and ornithine from arginine. Dx is based on elevated arginine levels
of plasma aa testing. Tx of arginase deficiency consists of low-protein diet devoid of arginine. Admn of a synthetic
protein made of essential amino acids usually results in a dramatic decrease in plasma arginine concentration and an
improvement in neurological abnormalities. Unlike other urea cycle disorders, px with arginase deficiency have mild or
no hyperammonemia.

RER protein synthesis (757)

Ribosomes are cellular organelles that synthesize proteins. Each ribosome consists of 2 subunits. The small ribosomal
40s subunit is responsible for binding mRNA (the protein synthesis template) and tRNA (carries AAs). The larger 60s
subunit contains peptidyl transferase, the enzyme that catalyzes peptide bond formation between aas. All ribosomes
begin protein translation in the cytoplasm, but some translocate to the RER during protein synthesis depending on the
protein’s target destination.

- Free ribosomes remain flating in the cytosol throughout protein synthesis. They are responsible for translating
proteins found within the cytosol, nucleosol, peroxisome matrix, and nuclear-encoded mitochondrial proteins
- Attached ribosomes bind to the RER after protein translation begins. They synthesize most secretory proteins,
the integral membrane proteins of the nucleus and cell membrane, and proteins within the ER, Golgi network
and lysosomes.

The RER is particularly well developed in protein-secreting cells (eg, pancreatic and plasma cells). Ribosomes attach to
the RER via the translocon, a protein complex containing ribophorins that bind the large 60s subunit.

Aging (1438)

Critical shortening in telomere length can signal for programmed cell death. Telomerase is a reverse transcriptase (RNA-
dependent DNA polymerase) that lengthens telomeres by adding TTAGGG repeats to the 3’ end of chromosomes. Stem
cells have long telomeres due to high telomerase activity, allowing them to proliferate indefinitely in a controlled
manner.

Fructose metabolism (1067)

(1073) aldolase B def, or hereditary fructose intolerance, leads to accumulation of the toxic metabolite fructose-1-
phosphate. Px have hypoglycemia and vomiting when fructose or sucrose is consumed. Tx involves strict removal of both
CHO from the diet.
Gluconeogenesis

(1034) during gluconeogenesis, substances such as lactate and alanine are converted to pyruvate. However, pyruvate
cannot be converted to phosphoenolpyruvate directly as pyruvate kinase is unidirectional. To convert pyruvate to
phosphoenolpyruvate, pyruvate first undergoes biotin-dependent carboxylation to oxaloacetate in the mitochondria.
This reaction is catalyzed by pyruvate carboxylase. The activity of pyruvate carboxylase is increased yb acetyl-CoA. This
critical regulatory step diverts pyruvate to pyruvate dehydrogenase when acetyl-CoA levels are too low, preventing the
cell from becoming energy starved. When acetyl-CoA levels are high (as with increased beta oxidation of fatty acids
during fasting), pyruvate carboxylase can operate at full capacity and convert most of the pyruvate into oxaloacetate for
use in gluconeogenesis.

(1866)

The metabolism of ethanol by alcohol dehydrogenase and aldehyde dehydrogenase reduces NAD to NADH and increases
the NADH/NAD ratio. This inh all other pathways requiring NAD, including reactions required for gluconeogenesis.
(lactate cannot be converted to pyruvate and instead the reaction is driven from pyruvate toward lactate + excess NADH
inh the conversion of malate to oxaloacetate -> pyruvate and oxaloacetate are intermediates in gluconeogenesis)

Pentose phosphate pathway (1035)

The pentose phosphate pathway consists of an oxidative (irreversible) branch and a nonoxidative (reversible) branch,
and each can function independently based on cellular requirements. Transkletolase, an enzyme of the nonoxidative
branch, is responsible in part for the interconversion of ribose-5-phosphate (nucleotide precursor) and fructose-6-
phospahte (glycolytic intermediate)

G6PD def (1036)

X-linked recessive disorder -> hemolysis when RBC experience increased oxidative stress

G6PD is the rate-limiting enzyme of the pentose phosphate pathway (PPP). This enzyme catalyzes the conversion of G6P
to 6-phosphogluconolactone, which is subsequently converted to 6-phosphogluconate. The PPP serves to generate both
NADPH and ribose-5-phosphate, a precursor for nucleotide synthesis. As PPP is the only mechanism for RBC to generate
NADPH, enzymatic defects in the pathway increase their susceptibility to oxidative dmg.

(1037) G6PD deficiency causes hemolytic anemia and jaundice secondary to increased oxidative stress due to the lack of
NADPH. Glutathione reductase deficiency has a similar clinical consequence as its absence results in an inability tutilized
NADPH to reduce glutathione

(1066)

G6PD is the rate-limiting enzyme in the pentose phosphate pathway, the major source of cellular NADPH. This molecule
is necessary for reducing glutathione (protects RBC from oxidative dmg) and for the biosynthesis of cholesterol, FA and
steroids.

Calcium and glycogen phosphorylase (1028)

Synchronization of glycogen degradation with skeletal muscle contraction occurs due to release of sarcoplasmic calcium
following neuromuscular stimulation. Increased intracellular calcium causes activation of phosphorylase kinase,
stimulating glycogen phosphorylase to increase glycogenolysis.

Beta oxidation

(1888)

Medium chain acyl-CoA dehydrogenase def: most common impaired beta-oxidation enzymatic defect. Remains
asymptomatic until experiences a significant fast (unable to oxidize fatty acids to maintain glucose and ketone body
production)

Deficiency: Acyl-CoA dehydrogenase

Pyruvate dehydrogenase deficiency (998)

- Results from: deficient activity of the pyruvate dehydrogenase complex, a multi-enzyme complex generating
acetyl-CoA from pyruvate, thereby linking glycolysis and the TCA cycle. Dietary CHO are broken down into
pyruvate via glycolysis; in px with pyruvate dehydrogenase def, the lack of enzymatic activity leads to a buildup
of pyruvate, which is shunted to lactate via lactate dehydrogenase, generating a potentially life-threatening
lactic acidosis
- Disease management: ketogenic diet; a high-fat, low-carb diet with moderate levls of protein
- AA catabolism results in formation of intermediates that are referred to as glucogenic, ketogenic, or both.
Glucogenic aa metabolism produces pyruvate or TCA cycle intermediates, which can be converted to glucose via
gluconeogenesis. Ketogenic AA metabolism generates the ketone body precursor acetyl-CoA. Lysine and leucine
are exclusively ketogenic aa; they cannot be metabolized to pyruvate and consumption will not lead to increased
production of lactic acid.
Primary carnitine deficiency (1886)

This px’s myopathy (eg, elevated creatine kinase, weakness), cardiomyopathy (eg, S3 gallop), and hypoketotic
hypoglycemia (eg, absence of ketones in the urine) in the setting of decreased muscle carnitine content is consistent
with primary carnitine deficiency. The condition is caused by a defect in the protein responsible for canitine transport
across the mitochondrial membrane. Without sufficient carnitine, fatty acids cannot be transported from the cytoplasm
into the mitochondria as acyl-carnitine (carnitine shuttle). The mitochondria therefore cannot beta oxidize the fatty acids
into acetyl CoA, the carbon substrate for the citric acid cycle. As a result, cardiac and skeletal myocytes cannot generate
ATP from fatty acids (leading to muscle weakness, cardiomyopathy) and the liver is unable to synthesize ketone bodies
(manifests as hypoketotic hypoglycemia).

Deficiency: Acyl CoA synthase

Clinical findings:

- Hypoketotic hypoglycemia (eg, undetectable acetoacetate level)

- Mild hepatomegaly
- Liver dysfunction

Consequences:

- Seizures
- Sudden infant death

Citric Acid cycle (1022)

GTP is synthesized by succinyl-CoA synthetase during the conversion of succinyl-CoA to succinate in the citric acid cycle.
During gluconeogenesis, phosphoenolpyruvate carboxykinase uses GTP to synthesize phosphoenolpyruvate from
oxaloacetate.

Porphyria cutanea tarda (1337)

The most common disorder of porphyrin (eg, heme) synthesis. Enzyme deficiencies in the early steps in porphyrin
synthesis cause abdominal pain and neuropsychiatric manifestations (due to metabolite buildup) without
photosensitivity. Late step (ie, following porphobilinogen conversion) derangements (eg, PCT) cause photosensitivity,
which is thought to be due to the accumulation of porphyrinogens that react with oxygen on excitation by uv light.

PCT is caused by uroporhyrynogen decarboxylase deficiency, which is either inherited or (more commonly) acquired,
manifesting in the presence of iron and of susceptibility factosr (eg, alcohol, smoking, halogenated hydrocarbons, hep C,
HIV). Photosensitivity presents as vesicle and blister formation on sun-exposed areas as well as edema, pruritus, pain,
and erythema. Deficiencies in coproporphyrinogen oxidase, protoporphyrinogen oxidase, or ferrochelatase can also
result in photosensitivity.

Acute intermittent porphyria (1338)

AD characterized by porphobilinogen (PBG) deaminase deficiency

Factors:

- PBG deaminase deficiency (inherited)

 - ALA synthase induction, typically precipitated by certain medications (eg, phenobarbital, griseofulvin,
phenytoin), alcohol use, smoking, progesterone (eg, puberty), or a low-calorie diet

Clinical findings: (due to accumulation of ALA and PBG)

- Neurologic symptoms: (eg, tingling, difficulty concentrating)

- Recurrent episodes of nonspecific abd pain

Tx:

- Infusion of hemin, which downregulates hepatic aminolevulinate (ALA) synthase (rate-limiting enzyme in hepatic
pathway of heme synthesis

(1339) tx and prevention of AP is directed at inhibiting ALA synthase (the rate-limiting enzyme of heme synthesis) to
reduce formation fo the toxic intermediate metabolites. ALA synthase is upregulated by CYP450 inducers (eg, most
antiepileptics, griseofulvin, rifampin) and downregulated by heme and glucose. As such, avoidance of alcohol, smoking
and other CYP450-inducing drugs is important for preventing acute attacks. Likewise, IV heme admn and CHO loading
(such as with dextrose infusion) are useful for ameliorating acute symptoms

Vs. Lead poisoning

- Deficiencies of ALA dehydratase and ferrochelatase

Vs. Erythropoietic protoporphyria

- Deficiency of ferrochelatase, characterized by cutaneous photosensitivity beginning in early childhood

Homocysteine (1332)

Homocystinuria is most commonly caused by a defect in cystathionine synthase, resulting in an inability to form cysteine
from homocysteine. Cysteine becomes essential in affected px, and homocysteine buildup leads to elevated methionine.
Homocysteine is prothrombotic, resulting in premature thromboembolic events (eg, atherosclerosis, acute coronary
syndrome) in these patients

(1504) The most common inborn error of methionine metabolism. Most px present at age 3-10 with ectopia lentis
(dislocated lens). About half of px have intellectual disability. Other clinical manifestations include a Marfanoid habitus
(eg, elongated limbs, arachnodactyly, scoliosis). Px are at high risk fo thromboembolic occlusion of both large and small
vessels, especially those of the brain, heart and kidneys. Thromboembolic complications are the major cause of
morbidity and mortality in these px

Homocystinuria is most frequently caused by an AR deficiency of cystathionine beta-synthase, an enzyme that requires
pyridoxine (vit B6) as a cofactor. Approximately 50% of affected px respond with high doses of pyridoxine, which
improves residual enzymatic activity and reduces plasma homocysteine levels. Additional tx includes dietary restriction
of methionine.

Phenylketonuria (1500)
Most cases of phenylketonuria are due to phenylalanine hydroxylase deficiency. Less commonly, the etiology is due to
BH4 def secondary to dihydropteridine reductase deficiency. The consequences of defective phnylalanine and
tryptophan metabolism are phenylalanine accumulation and low levels of serotonin and other neurotransmitters,
respectively.

The combination of high phenylalanine levels, which may disrupt neuronal and glial development, and low serotonin and
other neurotransmitters results in progressive neurologic deterioration in untreated px. Manifestations include
developmental delay, hypotonia, dystonia, and seizures. Tx: low phenylalanine diet and BH4 supplementation.

(1501) deficiency of dihydrobiopterin reducase based on the combination of hyperphenylalanemia and elevated
prolactin.

In classic PKU, supplementation of tyrosine allows for normal catecholamine production due to intact function of
tyrosine hydroxylase. Def of dihydrobiopterin reductase, however, leads to hyperphenylalanemia from impaired
phenylalanine hydroxlase activity and low dopamine lvls from impaired tyrosine hydroxylase activity.

Disorders involving impaired BH4 levels account for 2% of hyperphenylalanemia cases, and the most common cause is
deficiency of dihydrobipterin reductase, the enzyme responsible for reduction of BH2 to BH4. Although phenylalanine
levels can be controlled by dietary restriction, downstream deficiencies of neurotransmitters (eg, dopamine, NE, epi,
sero) lead to progressive neurologic deterioration in these px. Normally, dopa from the tuberinfundibular system
tonically inh prolactin release. Decreased BH4 causes lower levels of dopamine, which lead to increased prolactin levels.
This pathophysiology is similar to the effects of bromocriptine, a dopa agonist that is used to treat hyperprolactinemia.

(1336) Tetrahydrobiopterin def results in phenylketonuria, as tetrahydrobiopterin is a cofactor for phenylalanine

hydroxylase. Phenylalanine levels can be reduced by tetrahydrobiopterin supplementation in px with
tetrahydrobiopterin def.

(1483) deficiency of the enzyme phenylalanine hydroxylase or its cofactor tetrahydrobiopterin causes accumulation of
phenylalanine in body fluids and the CNS. Homozygous infants are normal at birth but gradually develop severe
intellectual disability and seizures if left untreated. Hypopigmentation of the skin, hair, eyes and catecholaminergic brain
nuclei is also frequently seen

(1484) the excess phenylalanine inh tyrosinase, which normally results in the downstream production of melanin

Hereditary fructose intolerance (1069)

Px typically present with fructose-containing foods are introduced into the diet. The primary manifestations are vomiting
and hypoglycemia about 20-30 min after fructose ingestion. Hypoglycemia results from intracellular accumulation of
fructose-1-phosphate and depletion of inorganic phosphate, which inh glycogenolysis and gluconeogenesis. Failure to
thrive, hepatomegaly and jaundice can also occur. Undiagnosed individuals may eventually develop liver and renal
failure. Elimination of dietary fructose is the mainstay of tx and results in symptoms improvement with a good long-term
prognosis.

Gluconeogenesis (997)

The 2 major processes that maintain plasma glucose between meals are glycogenolysis and gluconeogenesis.
Glycogenolysis is the primary source of glucose for the first 12-18 hrs of fasting. Once hepatic glycogen stores become
depleted, gluconeogenesis becomes the major process used by the body to keep blood glucose levels within the normal
range. During gluconeogenesis, glucose is formed from lactate, glycerol and glucogenic amino acids. This process uses
many of the enzymes involved in glycolysis. However, hexokinase, phosphfructokinase, and pyruvate kinase are
unidirectional and must be bypassed by distinct gluconeogenic enzymes.

The first committed step of gluconeogenesis is the biotin-dependent carboxylation of pyruvate to oxaloacetate by
mitochondrial pyruvate carboxylase. Oxaloacetate is subsequently converted to malate by malate dehydrogenase to
facilitate exit from the mitochondria, and then is converted back to oxaloacetate by cytosolic malate dehydrogenase
(malate shuttle). In the cytosol, PEPCK converts oxaloacetate to phosphoenolpyruvate. Therefore, pyruvate carboxylase
and PEPCK work together to bypass pyruvate kinase. The 2 other unique gluconeogenic enzymes are fructose 1, 6-
bisphosphatase (bypasses phosphofructokinase) and glucose-6-phosphatase (bypasses hexokinase)

Glycogen storage disease

Pompe disease type II (1023)

- Deficiency of acid alpha-glucosidase (acid maltase), an enzyme responsbiel for breaking down glycogen within
the acidic environment of lysosomes
- Most glycogen is degraded in the cytoplasm, a small amount is inadvertently engulfed by lysosomes, especially
in cells containing high amounts of glycogen such as hepatocytes and myocytes
- Cardiac and skeletal muscle are particularly susceptible, as the ballooning lysosomes interfere with contractile
function
- Classic form of the disease presents in early infancy with marked:
Cardiomegaly
Severe generalized hypotonia
Macroglossia
Hepatomegaly
Blood glucose levels are normal (unlike von gierke)
A KEY DISTINGUISHING FEATURE IS THAT MUSCLE BIOPSY WILL SHOW ACCUMULATION OF GLYCOGEN IN
LYSOSOMES

(1030)
Debranching enzyme deficiency (Cori disease): leads to accumulation of glycogen with abnormally short outer chains
(limit dextrins) due to the inability to degrade alpha-1, 6- glycosidic branch points. Px present with hypoglycemia,
ketoacidosis, hepatomegaly and muscle weakness and hypotonia.

McArdle disease (1032)

Glycogen serves as a source of glucose during fasting and as an energy store that can be mobilized quickly during
strenuous muscle contraction. Myophosphorylase def (McArdle disease or glycogen storage disease type V) causes
failure of muscle glycogenolysis, resulting in decreased exercise tolerance, muscle pain and cramping, and myoglobinuria
with physical activity.

Organic acidemias

Deficiency of propionyl-CoA carboxylase (1340)

Propionyl-CoA is derived from the metabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids.
Congenital deficiency of propionyl-CoA carboxylase, the enzyme responsible for the conversion of propionyl-CoA to
methylmalonyl-CoA, leads to the development of propionic academia. The condition presents with lethargy, poor
feeding, vomiting and hypotonia 1-2 weeks after birth.

Laboratory techniques

PCR (2043)

PCR is used to amplify small fragments of DNA (e,g genes, exons, noncoding regions) by repeated replication. It requires
primers that are complementary to the regions of DNA flanking the segment of interest. Thermostable DNA polymerase,
deoxynucleotide triphospahtes, and a source DNA template strand are also necessary.
Replication of the DNA template from a pool of supplied deoxynucleotide triphosphates using the following 3 steps:

1. Denaturing: thermal separation of the DNA template is accomplished by exposing the sample to high
temperatures
2. Annealing: primers combine with the denatured, single-stranded flanking ends of the target region when the
temperature is lowered
3. Elongation: DNA polymerase forms new daughter DNA strands in the 5’ to 3’ direction, starting from the 3’ end
of each primer.

ELISA (6522)

Is a serologic test that ID the presence of serum antibody directed against a known target antigen

Steps:

1. A known antigen is fixed to the surface of a well

2. Px serum is added. If present, antigen-specific antibodies bind the antigen and remain fixed to the well. The
plate is then washed to remove unbound px antibodies
3. Anti-human IG antibody coupled to a substrate-modifying enzyme (eg, peroxidase) is then added. This antibody
enzyme conjugate binds to antigen-bound antibodies in the wells. The plate is again washed.
4. Finally, a substrate, which is modified by the enzyme to elicit a detectable signal such as a color change, is
added. If the assay is quantitative, the intensity of the color change is proportional to the amount of antibody
present in the px’s serum.

Blotting

Western blot (2041)

Used to detect a target polypeptide or protein from within a mixed sample

Northern blot – analyze mRNA

Southern blot – analyze DNA sequences

Southwestern blot (2044)

C-Jun and c-Fos are nuclear transcription factors that directly bind DNA via a leucine zipper motif. The genes that code
for c-Jun and c-Fos are proto-oncogenes, genes that can become oncogenes following a mutation or with constitutive
expression.

Ras is a proto-oncogene that codes for a memebrane-bound G-protein. This G-protein acts as a secondary mediator for
several hormones and cytokines that act on cell memebrane receptors. Ras activation activates the MAP kinase pathway
and ultimately affects transcription. However, Ras itself does not bind directly to DNA

The beta 1-adrenergic receptor is a classic Gs-protein-coupled receptor located in the cell membrane. It does not
interact directly with DNA. Adenylyl cyclase is the enzyme that cleaves ATP to form cAMP, the second messenger
associated with Gs-protein-coupled receptors. cAMP activates protein kinase A for further downstream signaling.

S-100 proteins are homodimeric calcium-binding proteins, similar in structure to calmodulin and important in
intracellular fx such as protein phosphorylation and cell growth and differentiation. S-100 is a marker for cells of neural
crest derivation (melanocytes and schwann cells), as well as Langerhans cells and other dendritic cells.

(2034)

Southern blotting is a technique used to ID DNA mutations. It involves restriction endonuclease digestion of sample DNA,
gel electrophoresis, and gene identification with a labeled DNA probe.

FISH (15301)

Is highly sensitive cytogenetic test that can id the presence of chromosomal duplications and large deletions and
translocations. FISH probes are single-stranded DNA segments that are a few hundred kilobases in length; they are
added to the cell of interest and anneal to complementary regions of the cell chromosome, which allows the area of
interest to be ID visually.

FISH is far more sensitive than traditional karyotyping (chromosome banding) and can be applied to both dividing
(metaphase) and nondividing (interphase) cells. It is often used to ID large structural chromosomal abnormalities such as
the BCR-ABL1 fusion of t(9;22) in CML. However, small chromosomal insertions and deletions cannot be ID by FISH
(because the probe size is somewhat large) and chromosomal inversions will be missed because FISH can only ID the
presence or absence of a chromosomal segment, not the order in which it is coded.
Vitamin A toxicities (1048)

- Acute: nausea, vomiting, vertigo and blurred vision

- Chronic: alopecia, dry skin, hyperlipidemia, hepatotoxicity, hepatosplenomegaly and visual difficulties.
Papilledema, when present, is suggestive of cerebral edema in the setting of benign intracranial HTA
(pseudotumor cerebri)
- Teroatogenic: microcephaly, cardiac anomalies, and fetal death (especially in the first trimester of pregnancy)

Vitamin deficiencies

Water soluble vitamins (1047)

Vitamin Primary function Deficiency
B1 (thiamine) Dearboxylation of alpha-keto acids - Beriberi (peripheral
(carbohydrate metabolism) neuropathy, heart failure)
- Wernicke-korsakoff syndrome
B2 (riboflavin) Mitochondrial electron carrier (FMN, - Angular cheilosis, stomatitis,
FAD) glossitis
- Normocytic anemia
B3 (niacin) Electron transfer reactions - Pellagra (dermatitis,
(NAD/NADP) dementia, diarrhea)
- Peripheral neuropathy
B6 (Pyridoxine) Transamination of AAs (AA synthesis) - Cheilosis, stomatitis, glossitis
B9 (folate, folic acid) Hydroxymethyl/fomyl carrier (purine& - Megaloblastic anemia
thymine synthesis) - Neural tube defects (fetus)
B12 (cobalamin) Isomerase & methyltransferase - Megaloblastic anemia
cofactor (DNA & methionine - Neurologic deficits
synthesis)
C (ascorbic acid) Hydroxylation of proline & lysine - Scurvy
(collagen synthesis)

Manifestations of infantile beriberi

- Appear at age 2-3 months

- Include fulminant cardiac syndrome with cardiomegaly, tachycardia, cyanosis, dyspnea and vomiting

Vitamin C deficiency (1247)

The hydroxylation of proline and lysine residues in collagen helps it attain its maximum tensile strength. This process
occus in the rough endoplasmic reticulum and requires vitamin C as a cofactor. Impaired collagen synthesis resulting
from vitamin C deficiency (scurvy) can lead to fragile vessels, predisposing to gingival bleeding, ecchymosis and petechia.

Vitamin D deficiency (630)

(990) Sunlight exposure catalyzes conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) in the skin.
Subsequent 25-hydroxylation in the liver and 1-hydroxylation in the kidneys produce 1, 25-dihydroxyvitamin D, the
active form. Inadequate exposure to sunlight can lead to vit D deficiency.

Vitamin D toxicity (1065)

Excessive vit D intake can lead to hypercalcemia and cause mental status changes, muscle weakness, constipation and
polyuria/polydipsia. Activated macropahges in sarcoidosis and other granulomatous diseases express 1-alpha-
hydroxylase, leading to excess production of 1, 25-dihydroxyvitamin D and hypercalcemia.

Vitamin E def (1806)

the most common clinical manifestations of Vit E deficiency are neuromuscular disease (Eg, skeletal myopathy,
spinocerebellar ataxia, polyneuropathy) and hemolytic anemia. Involvement of the dorsal column in the spinal cord is
associated with the loss of proprioception and vibratory sense. Spinocerebellar tract involvement causes ataxia, and
peripheral nerve dysfunction results in hyporeflexia.

(671) Vit E deficiency is rare but may occur in px with fat malabsorption and abetalipoproteinemia. The most notable
manifestations include hemolysis and neurologic dysfunction (due to free radical dmg of cell membranes)

Neurologic symptoms of vit E deficiency closely mimic Friedreich ataxia (and AR degenerative condition) as many of the
same areas in the nervous system are affected. Specifically, px with either condition may have ataxia (due to
degeneration of spinocerebellar tracts), loss of position and vibration sense (due to degeneration of the dorsal columns),
and loss of deep tendon reflexes (due to peripheral nerve degeneration). Vit B12 deficiency may also present similarly
due to subacute combined degeneration of the dorsal and lateral spinal columns.

Neonatal vitamin K deficiency (1062)

Biotin deficiency

Biotin (B7) as cofactor

Enzyme Reaction
Pyruvate carboxylase Pyruvate to oxaloacetate (gluconeogenesis)
Acetyl-CoA carboxylase Acetyl-CoA to malynyl-CoA (FA synthesis)
Propionyl-CoA carboxylase Propionyl-CoA to methylmalonyl-CoA (FA oxidation)

Biotin acts as CO2 carrier on the surface of carboxylase enzymes and is an essential cofactor for numerous reactions,
including the conversion of pyruvate to oxaloacetate and fatty acid metabolism. Excess ingestion of avidin, found in egg
whites, has been associated with biotin deficiency. This condition presents with mental status changes, myalgias,
anorexia, macular dermatitis and lactic acidosis.

Riboflavin deficiency B2 (1807)

Symptomatic riboflavin deficiency is rare in the US but can be seen in chronic alcoholics and the severely malnourished.
Clinical manifestations include angular stomatitis, cheilitis, glossitis, seborrheic dermatitis, eye changes (eg, keratitis,
corneal neovascularization) and anemia.

Riboflavin is a precursor of the coenzymes FMN and FAD. FAD participates in the tricarboxylic acid cycle and electron
transport chain by acting as an electron acceptor for succinate dehydrogenase (complex II), which converts succinate
into fumarate.

Niacin deficiency B3 (1064)

Can be synthesized endogenously from tryptophan and is an essential component of NAD and NADP. A deficiency of this
vitamin results in pellagra, which is characterized by dermatitis, diarrhea and dementia. In developing countries, niacin
deficiency is seen in populations that subsist primarily on corn products (niacin in corn occurs in a bound, unabsorbable
form). In developed countries, it is primarily seen in px with impaired nutritional intake (eg, alcoholism, chronic illness).
Pellagra can also be seen occasionally in those with carcinoid syndrome, prolonged isoniazid therapy, or Hartnup
disease.

(12276) nicin is a precursor for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide
phosphate (NADP), two important cofactors for many dehydrogenase and reductase enzymes. NAD is required for
catabolic reactions (eg, glycolysis, beta-oxidation) as well as cell signaling and DNA repair, whereas NADP is necessary for
many anabolic reactions such as fatty acid and cholesterol synthesis. NAD is a key constituent for the citric acid cycle; it
serves as a cofactor for isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and malate dehydrogenase
Pyridoxine B6 (1336)

Is involved in the transamination and decarboxylation steps in AA metabolism, as well as heme and neurotransmitter
synthesis. Pyridoxine supplementation is also used in the tx of hyperhomocysteinemia.

Cobalamin B12 deficiency (1336)

Leads to megaloblastic anemia, neurologic changes including peripheral neuropathy, and elevated plasma levels of
homocysteine (a prothrombotic substance), supplementation of cobalamin is recommended to lower homocysteine
levels in px with hyperhomocysteinemia.

(64) B12 serves as a cofactor for methylmalonyl-CoA mutase (converts methylmalonyl-CoA to succinyl-CoA) and
methionine synthase (converts homocysteine and folic acid to methionine). B12 deficinecy consequently results in
elevated levels of serum methylmalonic acid and homocysteine

Increased methylmalonic acid levels can disrupt myelin synthesis and result in

- Subacute combined degeneration of the dorsal columns

Loss of proprioception/vibration
Romberg sign
- Lateral corticospinal tract
Spastic muscle weakness
Hyperreflexia

(1792) moderate improvement in the hb lvl often occurs when a deficiency in vit B12 is treated with folate, or vice versa.
Tx of vit B12 def. with folate alone can actually worsen neurologic dysfunction.

Lysosomal disease

Gauchers disease (11864)

Gaucher disease is an AR lysosomal storage disorder that is characterized by beta-glucocerebrosidase deficiency and
presents with pancytopenia and hepatosplenomegaly. Glucocerebroside accumulation leads to distended macrophages
with a “wrinkled tissue paper” appearance, also known as Gaucher cells.

Genetics

Linkage disequilibrium (8283)

Two allele loci are said to be in linkage disequilibrium when a pair of alleles are inherited together in the same gamete
(haplotype) more often or less often than would be expected given random pairing. This most often occurs when the
genes are in close physical proximity on the same chromosome

Knudson’s 2-Hit hypothesis (6607)

Example: retinoblastoma is a childhood tumor that results from separate mutagenic events that inactivate both copies
of the RB1 tumor suppressor gene (one copy on each chromosome 13). Germline mutations in one of the RB1 gene
cause “hereditary” retinoblastoma, which is associated with the development of other primary tumors (such as
osteosarcoma) later in life.

Allelic heterogeneity (6506)

Describes instances when different mutations at the same genetic locus cause similar phenotypes. The underlying
concept is that more than one type of mutation is possible in a given gene, and different mutations can cause protein
alterations or loss of function, resulting in disease.

Allelic heterogeneity is not to be confused with genetic heterogeneity, where mutations of different genes cause similar
phenotypes, or phenotypic heterogeneity, where mutations in the same gene result in markedly different phenotypes.

Mutations

Frameshift (1412)

Deletion or addition of a number of bases that is not divisible by 3 in the coding region of a gene will cause a frameshift
mutation. Frameshift mutations alter the reading frame of the genetic code, resulting in the formation of nonfunctional
proteins

Nondisjunction (8328)

Nondisjunction is the failure of chromosome pairs to separate properly during cell division. This could be due to a failure
of homologous chromosomes to separate in meiosis I or a failure of sister chromatids to separate during meiosis II or
mitosis. In fact, the vas majority of Down syndrome cases arise due to nondisjunction during maternal meiosis I.

Genomic imprinting (7791)

Genomic imprinting refers to the phenomenom in which an offspring’s genes are expressed in a parent-specific manner.
Genomic imprinting is caused by DNA methylation, an epigenetic process in which genes can be silenced by attaching
methyl groups to cytosine residues in the DNA molecule

Mosaicism (12225)

Defined as the presence of multiple, genetically different cell lines within the body. It can result from several processes,
including chromosomal nondisjunction and mutations during the first stages of embryonic development. The earlier the
error happens, the more daughter cells are affected

Mosaicism can be classified as germline, somatic or both:

- Somatic: affets the cells forming the body, causing disease manifestations to develop in affected individuals. 45,
X/46, XX is the most commonly dx mosaicism affecting sex chromosomes. These px typically have a milder form
of Turner syndrome or can be asymptomatic, depending on the ratio of abnormal to normal cells
- Germline: affects the cells that give rise to gametes, allowing the affected genes to pass to the offspring. The
chance of a child being affected depends on the proportion of gametes that carry the mutation. When
mosaicism is limited to the germline, the affected parent does not develop clinical manifestations

(6457)

Penetrance: describes the probability that a person with a given mutant genotype will exhibit the corresponding
phenotype. Highly penetrant genes very commonly produce clinical signs and ysmptoms in individuals, whereas genes
with incomplete penetrance only sometimes produce the associated trait or condition. Achondroplasia demonstrates
complete penetrance.

Pleiotropy: describes the occurrence of multiple, seemingly unrelated phenotypic manifestations, often in different
organ systems, as a result of a single genetic defect. The genes responsbiel for most inherited diseases are pleiotropic in
that they have numerous and varied clinical manifestation.

(1970) dominant negative mutations occur when an abnormal gene negatively affects the product of the wild-type gene
in the same cell

VS. locus heterogeneity refers to the ability of one disease or trait to be caused by mutations in multiple different genes

VS. polyploidy occurs when more than 2 complete sets of homologous chromosomes exist within an organism or cell

Autosomal recessive inheritance (1790)

The probability that an autosomal recessive disease will be transmitted to a child can be calculated based on the
maternal and paternal pedigrees. An unaffected individual (with unaffected parents) who has a sibling affected by an AR
condition has a 2/3 chance of being a carrier for that condition.

Down syndrome (1610)

- Meiotic nondisjunction accounts for nearly 95% of DS cases. Failure of homologous chromosomes or sister
chromatids to separate during meiosis can result in the inheritance of 3 copies of chromosome 21 in on
daughter cell (trisomy) and 1 copy in the other daughter cell (monosomy). Non disjunction during meiosis is
almost always of maternal origin
 - Unbalanced translocations account for 2-3% of DS cases. Theses individuals have 46 chromosomes, but have
extra genetic material (consisting of duplicate chromosome 21 genes) attached to one of their chromosomes.
Approximately one third of these cases are due to a balanced translocation in one parent, which confers a high
recurrence risk
(1825) inherited from an unaffected parent with balanced translocation. Robertsonian translocations occur
between 2 acrocentric, nonhomologous chromosomes (eg, 14 and 21). The resultant translocated chromosomes
are the fusion of 2 long arms and the fusion of 2 short arms. The affected parent is asymptomatic because they
have a normal genetic complement. However, when an ovum containing the translocated chromosome and a
normal chromosome 21 is fertilized with a sperm containing a normal set of chromosomes (ie, 1 copy of
chromosome 21), the resultant fetus has an unbalanced Robertsonian translocation with 46 chromosomes and 3
effective copies of chromosome 21.
- Mosaicism accounts for <2% of DS cases. Affected individuals have 2 distinct cell lines as a result of
nondisjunction during mitosis: one with a normal genotype and one with trisomy 21. The proportion of affected
cells determines the severity of DS features.

Fragile x syndrome (344)

x-linked disorder, is the most common inherited cause of intellectual disability. The defect is an unstable expansion of
trinucleotide repeats (CGG) in the fragile X mental retardation 1 (FMR1) gene, located on the long arm of X
chromosome. Cytogenetic studies (chromosomal analysis) typically show a small gap near the tip of the long arm of X
chromosome

The earliest manifestations of fragile X syndrome involve developmental delay, including delayed attainment of motor
and language milestones. Mild to moderate intellectual disability is common. Classic physical features in fragile X
syndrome include macrocephaly, a long narrow face, and a prominent forehead, jaw, chin, and ears. Macroorchidism
(testicular enlargement) is also a key finding.

(1421) FXS is caused by a mutation f the fragile X mental retardation 1 (FMR1) gene on the long arm of the X
chromosome. FMR1 normally has 5 to 55 CGG trinucleotide repeats and can potentially expand during meiosis in
oocytes. “Full mutation” is characterized by >200 CGG trinucleotide repeats, which causes FMR1 hypermethylation. DNA
methylation inactivates FMR1, preventing transcription and production of fragile X mental retardation protein, thereby
impairing neural development. Southern blot analysis is used to measure the degree of methylation and determine the
number of CGG repeats.

Duchenne (1487)

Duchenne muscular dystrophy presents with progressive proximal muscle weakness in young boys due to increased
muscle fiber degeneration. It is caused by frameshift mutations (most common) or nonsense mutations in the
dystrophin gene that lead to the formation of a truncated, defective protein. Nonsense mutations introduce premature
stop codons (eg, UAA, UAG, UGA) in the coding sequence of mRNA.

(1265) deletions of the dystrophin gene that encodes the dystrophin protein on X chromosome p21 are the most
common mutation in Duchenne and Becker. Deletions that are not a multiple of 3 change the reading frame, causing a
frameshift mutation, which results in a nonfunctional protein and severe clinical manifestations (DMD). In contrast,
deletions that are a multiple of 3 base pairs preserve the reading frame, resulting in a truncated but functional protein
and a milder clinical phenotype BMD

Dystrophin is a structural component of skeletal muscle fibers that provides mechanical stability to the sarcolemma. It
links a component of the cytoskeleton (actin) to transmembrane proteins (alpha- and beta0 dystrophiglycans) that are
connected to the extracellular matrix. Loss of dystrophin results in cellular injury (myonecrosis). On light microscopy,
there is segmental degeneration and regeneration of the myofibers with marked variation in size (both atrophic and
hypertrophic fibers). Over time, the muscle tissue undergoes progressive fatty replacement.

Galactosemia (1074)

Galactokinase (GALK) deficiency causes galactose buildup and this excess is converted to galactitol, an osmotic agent
that causes cataracts. Excess galactose also spills into the urine and cuases it to test positive for a reducing substance.
Serious systemic manifestations are not seen in GALK deficiency, and cataracts may be the only manifestation.

Vs galactose-1-phosphate uridyl transferase defiency (GALT), is related to the accumulation of galactose-1-phosphate,

toxic metabolite that causes hepatic and renal dysfunction. Consequently, patients with GALT deficiency present early, in
the neonatal period, with vomiting, lethargy and failure to thrive.

Classic galactosemia (1728)

Most common and most severe of galactosemic disorders, it is AR, due to absence of galactose-1-phosphate uridyl
transferase. Newborns present within days of birgh with jaundice, vomiting and hepatomegaly

(1071) Galactose is phosphorylated to galactose-1-phosphate by the enzyme galactokinase (GALK). Galactose-1-

phosphate is converted to glucose-1-phosphate by epimerization with transfer of uridine diphosphate (UDP) from UDP-
gluse to UDP-galactose. This reaction is catalyzed by galactose-1-phosphate uridyl transferase (GALT). UDP-galactose is
then epimerized to UDP-glucose by UDP-galactose-4-epimerase. Although GALT deficiency is the most common form, a
defect in any of these 3 enzymes can cause galactosemia.

Clinically relevant disorders of galactose metabolism

Enzyme Clinical features
Galactose-1-phosphate uridyl transferase Jaundice, vomiting, hepatomegaly, renal dysfunction (aminoaciduria,
hyperchloremic metabolic acidosis) E. Coli sepsis, cataract, hemolytic
anemia.
Galactokinase Cataracts, rarely pseudotumor cerebri (galactitol accumulation)

Friedreich ataxia (672)

- AR disease
- Mutation of the frataxin (FXN) gene
- This gene codes for an essential mitochondrial protein involved in the assembly of iron-sulfur enzymes
- Increased number of GAA -> decreased FXN expression
- This leads to decreased mitochondrial energy production and increased oxidative stress, resulting in
degeneration of neural tracts and peripheral nerves

Characteristics:

1. Spinocerebellar and lateral corticospinal tract degeneration causes gait ataxia and spastic muscle weakness,
respectively
2. Degeneration of the dorsal columns and dorsal root ganglia causes loss of position and vibration sensation
3. Kyphoscoliosis and foot abnormalities (pes cavus) are characteristic skeletal deformities
4. Heart involvement includes hypertrophic cardiomyopathy and CHF
5. DM develops in about 10% of px with Friedreich ataxia
(636) Friedreich ataxia presents with progressive gait ataxia (due to degeneration of the spinocerebellar tracts) and
impaired joint and vibration sense (due to degeneration of the posterior columns and dorsal root ganglia). Other
features include hypertrophic cardiomyopathy (most common cause of death), skeletal abnormalities (eg,
kyphoscoliosis, pes cavus) and DM

Duchenne (1268)

Myotonic dystrophy is an AD disorder. It is caused by an increased number of trinucleotide repeats on myotonia-protein

kinase gene. Sustained muscle contraction (myotonia), along with weakness and atrophy, is common. Cataracts are seen
in almost all px. Frontal balding and gonadal atrophy are other common features.

Huntington disease

AD, causes progressive neurodegeneration of the caudate and putamen, leading to chorea, dementia and death

Rett syndrome:

X-linked dominant disorder, affecting females (affected males die in utero) that presents in early childhood with
progressive neurodegeneration and stereotypical hand movements. X-linked dominant conditions are characterized by a
lack of father-son transmission whereas all daughters of an affected father are affected. Half of the offspring of an
affected mother are also affected.

Mitochondrial diseases

(357) the most important mitochondrial myopathies are myoclonic epilepsy with ragged red fibers (MERRF), Leber optic
neuropathy (blindness), and mitochondrial encephalopathy with stroke-like episodes and lactic acidosis (MELAS)

(11914) mitochondrial dysfunction frequently presents with myopathy, nervous system dysfunction, lactic acidosis, and
ragged red fibers on muscle biopsy. Mitochondrial myopathies due to mtDNA mutations are inherited solely in a
maternal fashion (ie, maternal inheritance). Therefore, transmission occurs only through affected females and never
through males.

(596) Mitochondrial diseases affect both male and female offspring with equal frequency (100. The variable severity of
these disease is explained by the random distribution of normal and mutated mitochondria between daughter cells
during mitosis; as a result, some cells may have completely healthy mitochondria, while other cells contain mitochondria
affected by genetic mutation (heteroplasmy).

Leber hereditary optic neuropathy -> bilateral vision loss

Myoclonic epilepsy with ragged-red fibers myoclonic seizures and myopathy associatd with exercise. Skeletal muscle
biopsy shows irregularly shaped muscle fibers (ragged red fibers)

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) hx of seizures +muscle weakness
+ ↑ lactate levels both post-exercise and at rest

Duchenne dystrophy (1266)

Cause: deletion of dystrophin gene (DMD)

x-linked recessive (affects primarily boys)

Disease onset is age 2-5

Muscles of proximal lower extremities, back and pelvic and shoulder girdles are affected fist

Symptoms:

- Ambulation difficulties
- Gower sign
- Calf pseudophypertrophy: calf muscles hypertrophy initially in response to proximal muscle weakness and are
later replaced by fat and connective tissue
- Asymmetric weakening of the paraspinal muscles, leading to kyphoscoliosis

Lesch Nyhan Syndrome (2067)

is an X-linked recessive disorder caused by a defect in hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This

results in failure of the purine salvage pathway, leading to increased degradation of hypoxanthine and guanine to uric
acid. De novo purine synthesis must increase to replace the lost bases, necessitating in increase in phosphoribosyl
pyrophosphate (PRPP) amidotransferase activity

Immunology

Class I vs Class II HLA proteins (752)

Class I HLA proteins (eg, HLA B27) are expressed by all nucleated cells and present endogenous antigens to CD8+
cytotoxic T cells. By contrast, HLA class II proteins (eg, DR, DP, DQ alleles) are expressed by antigen-presenting cells (eg,
macrophages, dendritic cells) and present predominantly foreign antigens to CD4+ helper T cells. Conditions associated
with HLA class II genotypes include rheumatoid arthritis, type I DB, and celiac disease.

Humoral immunity (1614)

The primary immune response to a new antigen results in a plasma cells that only produce IgM. Isotype switching alter
occurs in the germinal centers of lymph nodes and requires interaction of the CD40 receptor on B-cells with the CD40
ligand (CD154) expressed by activated T-cells. IgG is the main serum ig of the secondary response.

Ig (540)
The classical complement cascade beings with binding of the C1 complement component to either 2 molecules of IgG or
to two molecules of IgM. Because IgM circulates in pentameric form, it is a much better activator of the complement
system. The C1 molecule binds to the Fc region of the heavy ig chain in the region near the hinge point.

Inflammatory & anti inflammatory cytokines (1597)

IL-10: attenuates the immune response through

- inhibition of TH1 cytokines

- reduction of major histocompatibility complex class II expression
- suppression of activated macrophages and dendritic cells

IL-1: produced by macrophages and epithelial cells, proinflammatory properites

- endothelium activation
- increased chemokine expression (promoting leukocyte recruitement
- induction of fever
- IL-1beta is important for differentiation of TH17 cells

IL-5: secreted by TH2 cells and promotes humoral response

- stimulating differentiation of B cells and increasing IgA production

- promotes the growth and differentiation of eosinophils
- implicated in the pathogenesis of many allergic diseases

IL-12: secreted by macrophages

 - induces differentiation of TH1 cells
- activation of natural killer cells

Interferon gamma: secreted by TH1 cells and promotes proinflammatory pathways

- activating macrophages
- increasing antigen presentation
- including death of epithelial cells

TNF-alpha: produced by macrophages, NK cells and T cells (proinflammatory mediator)

- promotes leukocyte recruitment

- activates endothelium (increases expression of adhesion molecules)

(759)

IL-1:

- Produced by macrophages
- Activates naïve TH0 lymphocytes and promotes their differentiation into TH1 and TH2 subpopulations
- Also an endogenous pyrogen

IL-2:

- First IL produced by T-cells after contact with antigen

- Secreted mainly by TH1 cells
- Stimulates development of CD4+ T-helper cells, CD8+ cytotoxic cells, and B cells

(8530) IL-2 is produced by helper T cells and stimulates the growth of CD4+ and CD8+ T cells and B cells. IL-2 also
activates natural killer cells and monocytes. The increased activity of T cells and natural killer cells is thought to be
responsible fir IL-2’s anti-cancer effect on metastatic melanoma and renal cell carcinoma.

IL-2 (aldesleukin) is currently used as immunotherapy for metastatic melanoma and renal cell carcinoma.

IL-3

- Stimulates growth and differentiation of bone marrow stem cells

- produced by T-helper cells

IL-4:

- responsible for B-cell growth and isotype switching

- stimulates secretion of IgE and predisposes to type I hypersensitivity reactions
- stimulates differentiation of TH0 naïve T-helper cells into TH2 helpers, thus increasing the TH2 subpopulation
and the stimulus for the humoral immune response

IL-5:

- responsible for B-cell differentiation

- stimulates IgA production and eosinophil activity and is important for host defense against parasitic infections

IL-10:
 - helps regulate the balance between TH1 and TH2
- produced by TH2 lymphocytes
- inh synthesis of interferon-g-> decrease in the TH1

IL-12:

- synthesized by macrophages
- stimulates growth and development of the TH1

(11677) the most important opsonins (coating proteins) are IgG and complement C3b, but manose-binding lectin and C-
reactive protein can also opsonize cells. After opsonins are bound to the cell surface, they act as a handle for receptors
on phagocytes (eg, Fc receptors, C3b receptors) to grasp, allowing the phagocytes to more easily engulf the foreign cell.
The importance of C3 is demonstrated by the fact that all 3 complement pathways (lectin, classical and alternative)
converge on it, resulting in cleavage into C3a and C3b. C3a helps recruit phagocytic cells and induce inflammation. C3b,
in addition to acting as an opsonin, can bind to C3b convertase and form C5 convertase, ultimately triggering the
membrane attack complex.

Eosinophils (750)

- parasitic defense: stimulated by IL-5 produced by TH2 and mast cells. When a parasite invades the mucosa or
enters the bloodstream, it is coated by IgG and IgE antibodies that bind the Fc receptors located on the
eosinophil cell surface. This triggers eosinophil degranulation and release of cytotoxic proteins (eg, major basic
protein) and reactive oxygen intermediates, substances that dmg and destroy antibody-bound parasites. This
mechanism is an example of antibody-dependent cell-mediated cytotoxicity (ADCC), which is also used by
macrophages, neutrophils and natural killer cells.

Inflammation (8539)

Pus consists of a thin, protein-rich fluid, known as liquor puris, and dead leukocytes, primarily neutrophils. During
infection, macrophages and surrounding endothelial cells release cyotkines such as IL-8 that trigger neutrophils to enter
the site of infection via chemotaxis. Il-8 also induces phagocytosis in neutrophils once they have arrived.

MHC (746)

Features MHC class I MHC class II

Structure Heavy chain and beta2-microglobulin Alpha and beta polypeptide chains
Location All nucleated cells Antigen-presenting cells (b-cells,
macrophages, dendritic cells,
langerhans cells)
Fx Present antigen to CD8+ cytotoxic T- Present antigen to CD4+ T-helper
cells lymphocytes
Type of antigen Viruses, tumor proteins; antigens are Bacterial; antigens are phagocytosed
processed in the cytoplasm and digested by lysosomes within
which antigen binds to MHC II
Antigen presentation results in Apoptosis of the presenting cell Activation of TH cells which stimulate
the humoral and cell-mediated
immune response.
(542)

MHC I
Most nucleated cells of the human body express MHC I molecules on their surfaces. MHC I molecules present either self
antigen, tumor antigen or antigen synthesized by the cell due to viral infection of that cell. This pathway of antigen
presentation is referred to as endogenous pathway. Proteins in the cytoplasm are degraded by a proteasome and then
transported into the rough endoplasmic reticulum where they are loaded onto MHC cI molecules and subsequently
routed to the cell surface via the Golgi apparatus. They are never processed within acidified lysosomes.

MHC II

Is expressed on the surface of APC and fx by presenting antigen that is foreign to the body. This antigen is taken into the
APC by phagocytosis or endocytosis and is loaded onto MHC Class II within acidified endosomes, and the MHC Class II
protein-antigen complex is then expressed on the cell surface for subsequent interaction with T-lymphocytes. Failure to
acidify lysosomes would lead to deficient expression of MHC Class II bound to foreign antigen and subsequent lack of
interaction between APCs and T-cells.

T-cell receptor

Is a membrane-bound protein on T-lymph that carries binding sites for both self MHC molecules as well as specific
protein antigen. They are unable to bind self MHC or circulating antigen alone; the antigen must be bound to a self MHC
for the TCR to bind. Initiation of T-cell activation also requires co-stimulatory binding of T-cell bound CD-28 to APC-
bound B7.

(6598) during antigen processing in macrophages, the invariant chain is removed from the MHC-invariant complex and
replaced by an external protein. This MHC-peptide complex (containing an alpha-chain, beta-chain, and external protein)
is then expressed at the cell surface.

NK cells (745)

NK cells recognize and kill cells with decreased MHC class I antigen cell surface expression, such as virus-infected cells
and tumor cells. They are large lymphocytes that contain perforins and granzymes in cytoplasmic granules. NK cells kill
target cells by inducing apoptosis.

- Do not express CD4, CD8, or CD3. Do exrpress CD16 or CD56

- Do not require the thymus for maturation and are present in athymic px
- Have no antigen-specific activites, do not require exposure to antigen for activation and do not possess antigen
memory ability
- Are activated by IF-gamma and IL-12

Goodpasture (7)

- Autoantibodies against the alpha 3 chain of type IV collagen found in the GBM and pulmonary capillary
membrane (anti-GBM antibodies)
- Rapidly progressive glomerulonephritis results in nephritic syndrome, characterized by HTA, edema, acute renal
failure, hematuria (eg, dysmorphic red cells and red cell casts), and proteinuria
- Light microscopy: glomerular crescent formation
- Immunofluorescence: linear deposition of IgG and C3 on the GBM
- Alveolar hemorrhage manifests with dyspnea
- Hb in the alveoli leads to increased alveolar oxygen absorption and high CO diffusing capacity (DLCO)

Anaphylaxis (2068)
Is the result of widespread mast cell and basophil degranulation and the release of preformed inflammatory mediators,
including histamine and tryptase. Tryptase is relatively specific to mast cells and can be used as a marker for mast cell
activation

Vs. myeloperoxidase is found predominantly in neutrophils. Serum levels of myeloperoxidase can increase following
inflammation and infection but would not rise in response to an acute allergic reaction.

(2069) the high-affinity IgE receptor (Fc3RI) is found on the surface of mast cells and basophils and normally binds the Fc
portion of circulating IgE antibodies. Cross-linking of multiple membrane-bound IgE antibodies by a multivalent antigen
results in aggregation of the FceRI receptors, causing degranulation and the release of preformed mediators (eg,
histamine, tryptase) that initiate an allergic response

Process of T-cell maturation (558)

Transplant rejection (569)

Immediate (type I)

Occur in sensitized individuals following exposure to an antigen that binds to preexisting IgE present on mast cells. Mast
cell activation leads to release of vasoactive mediators (eg, histamine, leukotrines) that cause vasodilation, vascular
leakage, and edema

(1131) type I hypersensitivity reactions are mediated by the interaction of allergen with preexisting IgE bound to
basophils and mast cells. this facilitates cross-linking of the surface IgE molecules that signals the cell to degranulate
releasing chemical mediators (eg, histamine, heparin). These agents are responsible for the immediate signs and
symptoms of allergy, from a local wheal and flare to life threatening anaphylaxis.

Examples: anaphylaxis, urticaria, some forms of asthma, and seasonal allergies

Hyperacute rejection (type II)

Caused by preformed IgG antibodies within the recipient that are directed against donor antigens

Example: anti ABO blood group

Acute hemolytic transfusion (747)

Anti-ABO antibodies (mainly IgM) in the recipient bind the corresponding antigens on transfused donor erythrocytes,
leading to complement activation. Anaphylatoxins (C3a and C5a) causes vasodilation and symptoms of shock, while
formation of membrane attack complex (C5b-C9) leads to complement-mediated cell lysis. Hemolytic disesase of the
newborn due to Rh-incompatibility is another example of type II hypersensitivity
(740) MG results from from an autimmune type II (antibody-mediated) hypersensitivity reaction against skeletal
myocyte surface acetylcholine receptors. Goodpasture syndrome similarly involves autoantibodies against basement
membrane collagen in the renal glomeruli and lung alveoli.

Immune complex-mediated (type III) (569)

Results from deposition of circulating antigen-antibody complexes in the small vessels of various tissues (eg, glomeruli,
joints), once depositd, these complexes cause complement activation and release of chemotactic mediators that attract
neutrophils, leading to inflammation and tissue damage

Examples: SLE, post-streptococcal glomerulonephritis and serum sickness

Serum sickness (741)

Serum sickness is a reaction to nonhuman proteins characterized by vasculitis resulting from tissue deposition of
circulating immune complexes. Histologic examination of affected tissues typically shows small vessel vasculitis with
fibrinoid necrosis and intense neutrophil infiltration. Deposition of IgG and/or IgM complement-fixing antibodies results
in localized complement consumption and hypocomplementemia (decreased serum C3 levels).

Occurs 7-14 days after exposure following admn of antigenic heterologous proteins such as chimeric monoclonal
antibodies (eg, rituximab and infliximab) or nonhuman immunoglobulins (eg, venom antitoxins. A serum sickness – like
reaction is also associated with the use of certain nonprotein drugs (eg, penicillin, cefaclor and TMX-SULFA)

Delayed-type hypersensitivity (type IV)

Cell-mediated hypersensitivity can cause acute or chronic solid organ transplant rejection

Examples: tuberculin skin test, the Candida antigen skin test, and contact dermatitis

Contact dermatitis (544)

Contact dermatitis, granulomatous inflammation, the tb skin test and the Candida extract skin reaction are all examples
of DTH. The cells that mediate DTH reactions are TH1-lymphocytes that release interferon-g to cause recruitement and
stimulation of macrophages. DTH reactions take days to reach their peak activity; this is in contrast to the other
hypersensitivity reactions which cause clinical effects within minutes of antigen exposure.

(1133)

Poison ivy, poison oak, and poison sumac all produce urushiol, a small allergenic substance that causes an immune
response when attached to proteins (ie, a hapten). The rash often forms linear streaks

Contact dermatitis is a type IV (delayed-type) hypersensitivity reaction that occurs in 2 distinct phases:

1. The sensitization phase leads to the creation of hapten specific T cells and takes 10-14 days. Cutaneous dendritic
cells take up the haptens and express them on MHC-I and MCH-II molecules as hapten-conjugated peptides.
These dendritic cells travel to the draining lymph nodes and interact with hapten-sensitive CD4+ and CD8+ T
cells, causing activation and clonal expansion
2. The elicitation phase occurs within 2-3 days following re-exposure to the same antigen (or following
sensitization after first exposure to a highly antigenic antigen such as urushiol). In this phase, the hapten is taken
up by skin cells and causes activation of hapten-sensitized T cells in the dermis and epidermis. This results in an
inflammatory response and the clinical manifestations of contact dermatitis.
Depending on the etiologic agent, contact dermatitis can be mediated primarily by cytotoxic CD8+ T cells or CD4+ TH1
cells (that cause indirect dmg by activating macrophages). In urushiol-induced contact dermatitis, CD8+ T cells are the
primary effector cells and directly destroy keratinocytes expressing haptenated proteins.

Graft versus host

Most commonly seen following bone marrow transplantation. The condition occurs when competent donor T-cells are
transplanted into an immunecompromised patient and subsequently attack the recipient’s organs (eg, skin, liver, GI
tract). Most patients initially have a diffuse maculopapular eruption that beings w/ the palms, soles, back and neck.

Acute rejection (546)

Mediated by host T-lymphocyte sensitization against graft (foreign) MHC antigens, and it is characterized by a dense
infiltrate of mononuclear cells (eg, lymphocytes) affecting the renal interstitium, tubules, and arterial intima.

Tx: calcineurin inh (cyclosporine or tacrolimus) + corticosteroids

Calcineurin inh (1155)

In normal T cells, calcineurin is a protein phosphatase that is activated upon stimulation of the appropriate cell receptor.
Once activated, calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), which allows NFAT to enter the
nucleus and bind to an IL-2 promotr. IL-2 stimualtes the growth and differentiation of T cells and is an important
component of the immune response. Cyclosporine and tacrolimus, 2 of the more commonly used immunosuppressants
in transplant px, inh calcineurin activation

Heart transplantation (568)

Acute rejection occurs in approximately 2 of every 5 hearts transplanted and in the large majority of cases occurs by the
cell-mediated pathway. In rare cases, cardiac rejection is due to anti-donor host antibodies, and cases of humoral
rejection are dx by direct immunofluorescence. The histopathology most consistent with acute rejection on
endomyocardial biopsy is a dense infiltrate of mononuclear cells usually composed primarily of T-lymphocytes. Acute
cellular recjection of a transplanted organ is mediated by host T-lymphocytes sensitization against graft (foreign) MHC
antigens.

VS. scant inflammatory cells and interstitial fibrosis is most characteristic of chronic rejection. Chronic rejection is a
process mediated by host T-lymph and B-lymph as well as antibodies and classically occurs months to years following
solid organ transplantation.

Lung transplantation/Chronic rejection (535)

Chronic rejection affects the small bronchiole producing the obstructive lung disease known as bronchiolitis obliterans.
Initially, histopathology shows lymphocytic inflammation and destruction of the epithelium of the small airways.
Subsequently, fibrinopurulent exudate and granulation tissue are found in the lumen of the bronchiole, which ultimately
results in fibrosis, scarring and the progressive obliteration of small airways.

Mechanism of action of common immunosuppressants (11786)

 - Sirolimus: binds to the immunophilin FK-506 binding protein (FKBP) in the cytoplasm, forming a complex that
binds and inh mTOR. Inhibition of mTOR signaling blocks IL-2 signal transduction and prevents cell cycle
progression and lymphocyte proliferation
- Bortezomib: binds and inh the 26S proteasome. In MM, botezomib can facilitate apoptosis of neoplastic cells by
preventing degradation of pro-apoptotic factors
- Mycophenolate: reversibly inh a critical step in de novo purine nucleotide synthesis (inosine monophosphate
dehydrogenase), which is required for proliferation of activated lymphocytes. It selectively targets lymphocytes,
reducing B cell and T cell proliferation and antibody production while promoting T cell apoptosis.
- Prednisone and other glucocorticoids bind with cytoplasmic receptors that then translocate to the nucleus,
where they interact with glucocorticoid receptor elements to decrease production of inflammatory cytokines
and adhesion proteins
- Rituximab: chimeric antibody directed against the CD20 antigen (specific to B lymphocytes). It depletes B cells
(and abnormal antibody production) through multiple pathways, including complement-mediated lysis,
antibody-dependent cytotoxicity (via NK cells0, and induction of lymphocyte apoptosis.

Selective IgA deficiency (1130)

Recurrent pneumonia + dx of celiac disease + anaphylactic reaction during blood transfusion -> selective IgA deficiency

- The most common primary immunodeficiency

- Mostly asymptomatic
- Some may have recurrent sinopulmonary (eg, sinusitis, pneumonia) and GI infections (eg, Giardia) due to
absence of secretory IgA
- Concomitant autoimmune disorders (eg, celiac disease) are also common

Hyper-IgM syndrome (541)

Chronic granulomatous disease (1441)

Chronic granulomatous disease

Pathogenesis: - Inactivating mutation affecting NADPH oxidase
- Impaired respiratory burst inhibits phagocytic intracellular killing
Clinical manifestations - Recurrent infections with catalase-positive bacteria & fungi; (eg, s. aureus,
burkholderia cepacia, serratia marcescens, nocardia and aspergillus)
- Lungs, skin, lymph nodes & liver most commonly involved
- Diffuse granuloma formation
Diagnosis Measurement of neutrophil superoxide production
- DHR flow cytometry (preferred)
- NBT testing

Distinctive features of selected primary immunodeficiency disorders (1995)

Conditions Characteristic features
Ataxia-telangiectasia - Ataxia
- Telangiectasias
- Sinopulmonary infections
Chediak-Higashi syndrome - Oculocutaneous albinism
- Pyogenic infections
- Progressive neurologic dysfunction
Chronic granulomatous disease - Severe bacterial & fungal infections
- Granuloma formation
DiGeorge syndrome - Congenital heart disease
- Dysmorphic facies
- Hypocalcemia
Severe combined immunodeficiency - Severe bacterial & viral infections in infancy
- Chronic diarrhea
- Mucocutaneous candidiasis
Terminal complement deficiency - Recurrent Neisseria infection
Wiskott-Aldrich syndrome - Recurrent infections that worsen with age
- Easy bleeding
- eczema
Wiskott-aldrich syndrome (537)

Three cardinal findings:

- eczema
- recurrent infections
- thrombocytopenia

Mutation on X-chromosome (only present in males as an X-linked disorder)

Is a combined B-lymphocyte and T-lymphocyte disorder

Px are at increased risk of pyogenic infections particularly due to an inability to mount a humoral immune response
against organisms with a polysaccharide capsule such as Neisseria meningitidis, H. Influenzae and S. pneumo. The T-cell
defect leads to infections with opportunistic pathogens such as p. jiroveci and herpesviridae

Severe combined immunodeficiency disease (561)

The second most common cause of severe combined immunodeficiency (SCID) is autosomal recessive deficiency of
adenosine deaminase, an enzyme necessary for the elimination of excess adenosine within cells. Toxic levels of
adenosine accumulate within lymphocytes in this condition, leading to lymphocyte cell death and resultant cellular and
humoral immune deficiency. Tx is presently being researched using retroviral vectors to “infect” patient stem cells with
the gene coding for adenosine deaminase

x-linked agammaglobulinemia (1134)

- mutation in the Bruton tyrosine kinase gene -> failure of bone marrow pre-B cells to develop into mature B
lymphocytes -> low or absent numbers of B lymphocytes
- recurrent infections in the setting of intact T lymphocyte fx (positive response to Candida antigens)
- very low immunoglobulin levels
- germinal centers and primary lymphoid follicles do not form due to an absence of B cells

(1763) is characterized by low or absent circulating CD19+ and CD20+ B cells and pan-hypogammaglobulinemia. Affected
px have increased susceptibility to pyogenic bacteria, enteroviruses and Giardia Lamblia due to the absence of
opsonizing and neutralizing antibodies.

VS. CD15 is a cell surface marker present on granulocytes. It is also present on nearly all Reed-Sternberg cells and is
therefore a cytologic marker useful in the dx of Hodgkin lymphoma

VS. CD16 is a low-affinity Fc receptor found on the surface of NK cells, neutrophils and macrophages.

C1 inh deficiency (11667)

Recurrent episodes of abd pain and an episode of facial swelling likely has angioedema due to C1 inh def. C1INH
prevents C1-mediated cleavage of C2 and C4, thereby limiting activation of the complement cascade. It also blocks
kallikrein-induced conversion of kinogen to bradykinin, a potent vasodilator that also causes increased vascular
permeability.

Acquired or hereditary C1INH def (due to the complete absence of C1INH or the presence of a dysfunctional variant or
an anti-C1INH antibody) leads to elevated levels of bradykinin, and px can develop bradykinin-associated angioedema.
Symptoms include facila swelling (without urticarial), life-threatening laryngeal edema, and GI manifestation (eg,
nausea/vomiting, colicky pain, diarrhea). Management of acute attacks involves supportive care and the admn of C1INH
concentrate or a kallkrein inh.

Chediak higashi syndrome (1132)

- AR
- Results from a defect in neutrophil phagosome lysosome fusion
- Causes abnormal giant lysosomal inclusions that are visible on light microscopy of a peripheral blood smear
- The immunodeficiency leads to recurrent pyogenic infections most commonly caused by staph and strep
- Abnormal storage in melanocytes causes partial oculocutaneous albinism

Asplenic sepsis (732)

Carries a 50% mortality risk

The spleen is a part of systemic lymphoid system and receives roughly 6% of cardiac output. Many of the splenic
capillaries are open-ended and sinusoidal, permitting whole blood to flow into the red pulp cords. These cords form a
reticular meshwork that acts as a fine sieve with spaces as small as 1 micron in diameter. Large numbers of macrophages
line the red pulp cords and sinusoids and ingest any particulate matter that becomes trapped. The splenic red pulp is
important for:

1. destroying aged and abnormal erythrocytes (eg, spherocytes) and serving as an emergency store of blood cells
and platelets that can be delivered into the circulation when needed
2. clearance of circulating bacteria that become lodged in the cords. Macrophages then presents captured antigens
to the B- and T-cells residing in the splenic white pulp to generate an active immune response.

Nearly half of the body’s total ig are produced by splenic B-lymph. Splenic opsonizing antibody is of particular
importance in the clearance of encapsulated species, as the capsule allows them to resist innate phagocytosis.
Vaccination against encapsulated bacteria such as s. pneumo, h. influenzae and Neisseria meningitidis is recommended
for all asplenic px.
Sjogren syndrome (15557)

Saliva has numerous antibacterial and antifungal proteins, along with organic and inorganic components which protect
tooth enamel. Px with SS have a higher rate of thrush, dental caries, and other complications of odontogenic infections
(eg, osteomyelitis of the mandible) because of the loss of these protective factors in saliva.

(15596) biopsy of the labial salivary glands shows periductal lymphocytic infiltrates (focal lymphocytic sialadenitis), often
with germinal centers; the glandular tissue is typically atrophic and fibrotic
Hereditary angioedema (1612)

- AD
- Episodes of painless, non-pitting, well-circumscribed edema (most affected: face, neck lips and tongue, but alsot
internal organs)
- Angioedema affecting the tracheobronchial tree can cause respiratory obstruction and is potentially fatal
- Angioedema of the GI manifests with abd pain, vomiting and diarrhea
- Low C1 esterase inh activity leads to increases in bradykinin activity
- ACE normally catalyzes the conversion of angiotensin I into angiotensin II
- ACE also converts bradykinin into inactive metabolites therefore ACE inh -> bradykinin accumulation

Immunizations

Hep B (15177)

Immunization against hepatitis B virus uses recombinant HBsAg to generate anti-HBs antibodies. These antibodies
prevent infection by binding to the envelope of circulating virus and inhibiting viral entry

H. influenzae (965)

Bacteria with polysaccharide capsules (eg, Hib, S. pneumoniae, N. meningitidis) are antiphagocytic. The polysaccharide
capsule provokes an antibody-mediated (B cell) immune response and is the primary antigenic constituent of vaccines
against encapsulated bacteria. However, vaccines containing the polysaccharide antigen alone are ineffective in children
age <2 years due to their immature humoral immunity. Therefore, the polysaccharide is conjugated with a carrier
protein to amplify the px’s humoral response against the polysaccharide through T cell recruitment. The Hib conjugate
vaccine contains a carrier proein that is derived from either a tetanus toxid protein or an outer memebrane protein of N.
meningitidis. The polysaccharide-protein conjugate then becomes a T cell dependent antigen. Immunogenicity is
increased as a result of T cell-dependent stimulation of B lymphocytes and the production of memory B lymphocytes.

Pneumococcal conjugate (11872)

Are strongly immunogenic in infancy due to both B and T cell recruitment. They provide higher, longer-lasting antibody
titers relative to pneumococcal polysaccharide vaccines. The pneumococcal polysaccharide vaccine is poorly
immunogenic in infants due to their relatively immature humoral antibody response.

Vaccine types (1853)

Live attenuated Non-live (toxoid, subunit, conjugate, inactivated vaccines
- polio (oral)* - influenza (IM) - HPV
- measles/mumps/rubella - pneumococcus - minongococcus
- rotavirus - diphtheria/tetanus/pertussis
- influenza (intranasal) - polio (inactivated)
- yellow fever - hep A
- varicella, zoster - Hep B
- H. influenzae type b

Meningococcal vaccines (1183)

Antibodies against the polysaccharide capsule of N. meningitidis provide immunity against this pathogen. Quadrivalent
meningococcal vaccines contain capsular polysaccharides from major serotypes (A, C, Y and W) of N meningitidis.
Serotype B vaccinations use recombinant proteins.

Microbiology

Microbiological laboratory id of streptococci (11812)

Enterococcus UTI (11812)

Morphology:

- gram (+) cocci in pairs and chains

- no hemolysis (gamma hemolysis)
- PYR positivity
- Ability to grow in bile
- Ability to grow in 6.5% sodium chloride
- Unable to convert nitrates to nitrites
- Part of the normal intestinal flora of humans and animals.
- E. Faecalis and E. faecium are the most prevalent species
- Causes: UTI, bacteremia/endocarditis, wound infection or intraabdominal or pelvic infection in the nosocomial
setting
- Both intrinsic (beta lactams, macrolides, aminoglycosides, TMP-SULFA and acquired (vancomycin) resistance
(makes them important nosocomial pathogens)

Mechanism of action of selected bacterial exotoxins (1101)

Organism Toxin Mechanism & effects
Bacillus Anthrax Edema factor: increases cyclic AMP concentration by acting as an adenylate
anthracis exotoxin cyclase, causing edema & phagocyte dysfunction
Lethal factor: zinc-dependent protease that inh mitogen-activated protein kinase
signaling, causing apoptosis & multisystem physiologic disruption
Polypeptide capsule: composed of poly-gamma-D-glutamic acid, which inh
phagocytosis
Bordetella Pertussis toxin Disinhibits adenylate cyclase through Gi ADP-ribosylation, increasing cAMP elvels;
pertussis causes edema & phagocyte dysfunction

Adenylate Fx as an adenylate cyclase, increasing cAMP levels; causes edema & phagocyte
cyclase toxin dysfunction
Clostridium Botulinum toxin Blocks presynaptic release of acetylcholine at the NMJ, resulting in flaccid
botulinum paralysis
Clostridium Toxin A Recruits & activates neutrophils, leading to release of cytokines that cause
difficile mucosal inflammation, fluid loss & diarrhea
Toxin B Induces actin depolymerization, leading to mucosal cell death, bowel wall necrosis
& pseudombrane formation
Shigella Shiga toxin Halts protein synthesis by disabling the 60S ribosomal subunit, leading to
dysenteriae intestinal epithelial cell death & diarrhea
Streptococcus Pyrogenic Acts as superantigen, inducing fever & shock; associated with scarlet fever &
pyogenes exotoxin streptococcal toxic shock syndrome
Streptolysin Damages erythrocyte membranes, causing beta hemolysis
O&S

Toxic shock syndrome (676)

s. aureus strains producing TSST are responsible for most cases of TSS. TSST acts as superantigen that activates large
numbers of helper T cells (compared to regular antigen, which activates few helper T cells). superantigens interact with
major histocompatibility complex molecules on antigen-presenting cells (eg, macrophages) and with the variable region
of the T lymphocyte receptor to cause a nonspecific, widespread activation of T lymph. Activation of T cells is responsible
for the release of IL-2 from the T cells and IL-1 and TNF from macropahges. These ILs cause capillary leakage, circulatory
collapse, hypotension, shock, fever, skin findings and multiorgan failure.
(15509)

Pyrogenic toxic superantigens are generated by strains of S aureus (and Strep. Pyogenes) that have acquired an
underlying mobile genetic element via bacteriophage or plasmid. These exotoxins are called superantigens because they
bind to the invariant region of the MHC-II complex of antigen-presenting cells without first being internalized and
processed (MHC-II antigens are normally processed by the phagolysosome). The superantigen/MHC-II complex
subsequently interacts with the variable part of the T-cell receptor beta chain, which results in the nonspecific
stimulation of a large percentage (>20%) of total T cells and the massive release of inflammatory cytokines (eg, IL-1, IL-2,
TNF-alpha & beta, interferon-gamma). Cytokine release mediates the major manifestations of TSS including fever,
increased capillary permeability and hypotension.

Polysaccharide capsule (730)

The primary virulence factor of s. pneumonia is a polysaccharide capsule that inh opsonization and phagocytosis. The
polysaccharide capsule of the most virulent strains is targeted by the pneumococcal vaccine, which confers immunity
against those subtypes.

Exfoliative toxin A (15361)

The blistering in BI is caused by production of exfoliative toxin A, a serine protease that targets desmoglein 1 in the
superficial epidermis, by some strains of S. aureus. Desmoglein is a cadherin component of desmosomes in epidermal
cellular junctions; disruption by exfoliative toxin A causes a loss of cell adhesion and leads to formation of flaccid bullae.
Exfoliative toxin A is also responsible for staphylococcal scalded skin syndrome, which presents with generalized
erythema and flaccid bullae in flexural areas.

(680) staphylococcal scalded skin syndrome SSSS, occurs in infants and children due to the production of the exotoxin
exfoliatin by Staph species. It causes widespread epidermal sloughing, especially with gentle pressure (Nikolsky’s sign)

Bacterial gene transfer (736)

S pneumonia is able to obtain new gentic material from the environment that is released following the death and lysis of
neighboring bacterial cells. This process, known as transformation, allows the bacterium to take up exogenous DNA
fragments, integrate the DNA into its genome and express the encoded proteins. Bacteria that have the innate capacity
to undergo transformation are said to be naturally competent and include Haemophilus, streptococcus, Bacillus and
Neisseria species.

Septic shock (1141)

Gram (-) sepsis is caused by the release of LPS from bacterial cells during division or by bacteriolysis; LPS is not actively
secreted by bacteria. Lipid A is the toxic component of LPS; it causes activation of macrophages leading to the
widespread release of IL-1 and TNF-alpha, which cause the signs and symptoms of septic shock: fever, hypotension,
diarrhea, oliguria, vascular compromise and DIC.

Listeria (1391) )

- Facultative intracellular
- Gram-positive rod
- Produces a very narrow zone of beta hemolysis on blood agar
- Is immotile at body temperature but demonstrates tumbling motility at room temperature
- The elimination of intracellular pathogens is largely reliant on the cell-mediated immune response
 - Px with impaired cell-mediated immunity are at risk for invasive Listeria infections

C. diffile

(1397)

Both toxins inactivate Rho-regulatory proteins involved in signal transduction and actin cytoskeletal structure
maintenance. As a result, the toxins can cause disruption of intercellular tight junctions leading to cell
rounding/retraction as well as increased (paracellular) intestinal fluid secretion. Both toxins have inflammatory effects
(including neutrophil recruitment) and can induce apoptosis. Although these toxins have overlapping activity, toxin A
appears to be more enterotoxic and toxin B more cytotoxic.

(15049)

Dx test:

- Nucleic acid amplification test (NAAT): uses a PCR to detect genes present in toxigenic strains (eg, toxin B-
encoding gene). This test is highly sensitive and specific for toxigenic strains but does not distinguish active toxin
production and may lead to overdiagnosis in asymptomatic carriers.
- Enzyme immunoassays (EIA): uses antibodies to detect C. difficile antigens or toxins. EIA for bacterial toxins is
highly specific but has poor sensitivity as large amounts of toxin are required. In contrast, EIA for glutamate
dehydrogenase (a bacterial antigen expressed by all C. difficile isolates) has better sensitivity but cannot
distinguish toxin-producing strains.

NAAT is considered the most sensitive method for dx of CDI in px with clinical symptoms. EIA for bacterial toxins can be
added as part of multistep algorithm to increase specificity of active disease; however, it is not recommended for use
alone.

Lyme disease (1897)

Phases:

1. Early localized phase: days to weeks following exposure, px experience flu-like symptoms and the characteristic
cutaneous eruption, erythema chronicum migrans
2. Early disseminated phase: weeks or months later, there may be CNS (eg, facial palsy) and/or cardiac involvement
(eg, AV nodal block)
3. Late Lyme disease: this phase, which occurs months to years post-exposure, is rare given the frequency with
which px receive antibiotics for other indications. Px may experience asymmetric arthritis (most often involving a
single knee joint, as in this px) and/or subacute encephalopathy with decreased memory, somnolence, and
mood changes.

Tx: doxycycline or penicillin-type antibiotics (eg, ceftriaxone)

(1677) the enzyme glycosyltransferase is a crucial component of peptidoglycan synthesis; it adds glycan molecules to the
growing peptidoglycan chain. Inhibition of this enzyme would result in gaps in the bacterial cell wall, with subsequent
loss of bacterial shape and cell lysis from osmotic stress.

All organisms in the mycoplasma genus, including ureaplasma urealyticum, lack peptidoglycan cell walls and are
therefore resistant to agents that target the cell wall such as penicillins, cephalosporins, carbapenems and vancomycin.
Mycoplasma infections can be treated with antiribosomal agents (eg, tetracyclines, macrolides)
Gonococcal infection (560)

IgA protease is produced by N. meningitidis, N. gonorrhoeae, S. pneumo and H. influenza. This enzyme cleaves secretory
IgA at its hinge region, rendering it ineffective. Secretory IgA exists on mucosal surfaces and in secretions and acts to
bind and inh the action of pili as well as other cell surface antigens that normally mediate mucosal adherence and
subsequent penetration. But IgA proteases facilitates bacterial adherence to mucosa

(1005)

The pili on the capsular surface of N. meningitidis are primarily responsible for attachment to and colonization of the
nasopharyngeal epithelium. Pili also play a role in bacterial movement and epithelial penetration during invasion.

Pili undergo high rates of antigenic variation (due to on-off gene switching and horizontal gene transfer), which limits the
effectiveness of vaccines against this target. Other prominent N meningitidis virulence factors include IgA protease
(destroys mucosal antibodies that would otherwise inhibit epithelial colonization), capsular polysaccharides (prevent
phagocytosis and phagolysosome destruction), lipo-oligosaccharide (an endotoxin that is the major source of toxicity),
and Opa-proteins (aid in endothelial attachment and invasion).

(1912) n. gonorrhoeae can be cultured on Thayer-Martin VCN selective medium, which contains vancomycin, colistin,
nystatin and trimethoprim. These antibiotics kill potential contaminants such as gram-positive organisms (vancomycin),
gram negative organisms other than Neisseria (colistin and trimethoprim), fungi (nystatin)

Pertussis (11630)

Pertussis should be considered in any adult who has not had updated vaccination boosters. The clinical presentation is a
paroxysmal cough lasting >2 weeks that is associated with post-tussive emesis or inspiratory whoop after a severe
coughing episode.

Phases:

1. Catarrhal phase – similar to many routine upper respiratory infections (eg, malaise, mild fever, rhinorrhea)
2. Paroxysmal phase – marked by severe coughing spells with the classic inspiratory whoop or post-tussive emesis
3. Covalescent phase – ruing which the cough improves

Pertussis is caused by the gram-negative coccobacillus Bordetella pertussis, which produces virulence factors that
include adhesins and toxins. Pertactin, which forms the basis of the acellular pertussis vaccine, promotes B pertussis
adherence to the ciliated upper respiratory epithelium. Tracheal cytotoxin subsequently promotes local tissue
destruction, resulting in cough. Pertussis toxin causes excessive adenylate cyclase activity, which prevents effective
phagocytosis and allows the organism to persist in alveolar macrophages and ciliated epithelial cells, leading to a
prllonged disease course. Lymphocytosis, induced by pertussis toxin is also common.

Vibrio vulnificus (15255)

Lung abscesses (533)

Peptostreptococcus and FUsobacterium are anaerobic bacteria that are part of normal mout flora. The presence of thse
organisms in this px’s lung lesion is highly suggestive of a developing lung abscess. As an abscess evolves, it typically
forms a cavitary lesion with an identifiable air-fluid level on imaging. Symptoms are often indolent and include fever,
night sweats, weight loss and a cough producing foul-smelling sputum (indicating anaerobes)

Causes of lung abscesses:

- Aspiration of oral bacteria into the lower airways (most common) – these abscesses are usually composed of a
combination of anaerobic oral flora (eg, peptostreptococcus, prevotella, bacteroides, fusobacterium) and
aerobic organisms (eg, streptococcus). Risk is greatest in those who have conditions associated with loss of
consciousness or impaired swallowing, such as alcoholism, drug abuse, neurologic disease (eg, seizures, stroke),
or anatomic abnormalities (eg, esophageal stricutres or diverticula)
- Bacterial pneumonia – lung abscess can occur in the setting of certain bacterial pneumonias such as those due to
s. aureus, e. coli, klebsiella pneumonia or pseudomonas aeruginosa. Most cases arise in the hosp setting and
occur in px with immunosuppression, older age, or underlying lung disase.
- Bacteremia and/or infectious endocarditis – hematogenous spread of an infection to the lung usually causes
multiple, monomicrobial lung abscesses. The most common causative agents are staph and strep species.

Pseudomona (8858)

P. aeruginosa is the major pathogen in burn px. Only a few specific penicillins (eg, ticarcillin, piperacillin) and
cephalosporins (eg, ceftazidime, cefepime) have activity against it. Certain aminoglycosides, fluroquinolones (eg,
ciprofloxacin, levofloxacin), and carbapenems (eg, imipenem, meropenem) are also effective.
(973) with neutropenia (ANC <500/mm^3) there is increased susceptibility to infections with gram (-) such as P.
aeruginosa which causes ecthyma gangrenosum, strongly associated with p. aeruginosa bacteremia.

Perivascular bacterial invasion of arteries and veins in the dermis and subcutaneous tissue, with subsequent release of
exotoxins destructive to human tissue, leads to characteristic skin patches exhibiting necrosis and ulceration as a result
of insufficient blood flow. P. aeruginosa virulence factors that may contribute to EG include exotoxin A (protein synthesis
inh.), elastase (degrades elastin – important for blood vessel destruction), phospholipase C (degrades cellular
membranes), and pyocyanin (generates ROS)

E. Coli vs. Enterobacter (11766)

The indole positivity (ability to convert tryptophan to indole) of E coli distinguishes it from Enterobacter cloacae, another
lactose-fermenting gram-negative rod that is a common cause of UTIs in women.

E. coli (1139)
Enterohemorrhagic E. coli (EHEC) O157:H7 (1100)

Following ingestion of inadequately cooked hamburger meat. In contrast to most E. coli strains, O157:H7 E coli does not
ferment sorbitol during overnight incubation. E. Coli O157:H7 does not produce glucuronidase

EHEC elaborates a shiga-like toxin virtually identical to the shiga toxin. The siga and the shiga like toxins inactivate the
60s ribosomal subunit in human cells, leading to an inhibition of protein synthesis and eventual cell death. Infection with
EHEC can also lead to hemolytic-uremic syndrome, characterized by thrombocytopenia, microangiopathic hemolytic
anemia, and renal insufficiency (sometimes with uremia)

Unlike enteroinvasive E. Coli, EHEC does not invate the intestinal mucosa. Unlike enterotoxigenic E Coli (ETEC), EHEC
does not produce heat-labile toxin (LT) or heat-stable toxin (ST).

Lac operon (1485)

Is the sequence of the E. coli genome which is required for the metabolism of lactose. The lac operon consists of a
regulatory gene (i), promoter region (p), operator region (o), and three structural genes (z, y and a). The z gene codes for
beta-galactosidase (beta-gal), which is primarily responsible for the hydrolysis of lactose to glucose and galactose. The y
gene codes for permease, a transmembrane enzyme that increases the permeability of the cell to lactose. The a gene
encodes a beta-galactoside transacetylase, which transfers acetyl groups to beta-galactosides and is unnecessary for
lactose metabolism by E. coli. Bacterial mRNA can be polycistronic, meaning that one mRNA codes for several proteins.
An example of polycistronic mRNA is the bacterial lac operon, which codes for the proteins necessary for lactose
metabolism by E. coli; the transcription and translation of these bacterial proteins is regulated by a single promoter,
operator and set of regulatory elements.

(1479) Is regulated in 2 distinct mechanisms:

1. Negatively by binding of the repressor protein to the operator locus

 2. Positively by cAMP-CAP binding upstream from the promoter region

Mutations impairing the binding of the repressor protein to its binding site at the operator region will prevent repression
of the genes of the lac operon in the absence of lactose. This results in increased transcription of the genes of the lac
operon in lactose-deficient media, although the presence of glucose will prevent maximal transcriptional activity.

Viridans (1003)

Viridans produces extracellular polysaccharides (dextrans) using sucrose as a substrate. Dextrans facilitate streptococcal
adherence to fibrin. Fibrin and platelets are deposited at sites of endothelial trauma, providing a site for bacterial
adherence and colonization during bacteremia. In px with pre-existing valvular lesions, viridans can adhere to the
affected valve and establish infection leading to endocarditis.

ETEC (1099)

ETEC colonizes and adhreres to small intestine enterocytes (mediated by pili). The subsequent elaboration of plasmid-
encoded heat-labile (LT) and/or heat-stable (ST) enterotoxin results in the typical manifestations of abd cramping,
nausea/vomiting and occasionally low fever. The LT enterotoxin, which resembles cholera toxin in the structure and
mode of action, increases intracellular cyclic AMP in gut mucosal cells by activating the stimulatory Gs memebrane G
protein, thereby activating adenylate cyclase. The ST enterotoxin is not inactivated by heat (likely due to its small
molecular size); it causes an increase in cyclic GMP in the host cell cytoplasm by activating guanylate cyclase located on
th apical membranes of host gut mucosal cells. as a result of both these enterotoxins, there is decreased reabsorption
and increased secretion of sodium, water and electrolytes resulting in watery diarrhea.

Cholera (976)

V. cholera and enterotoxigenic E. coli cause a purely toxin-mediated watery diarrhea. The toxins secreted by these
organisms modify electrolyte handling by enterocytes but do not cause cell death; therefore, no erythrocytes or
leukocytes are typically noted on stool microscopy.

Stool findings in acute diarrhea (976)

Mechanism Stool findings Examples of pathogens
Watery diarrhea Noninflammatory No fecal leukocytes V. cholera, Enterotoxigenic E. coli,
(enterotoxin) No red cells Bacillus cereus, S. aureus, some viruses,
giardia, cryptosporidium species,
cyclospora species, microsporidia
Dysentery or Inflammatory (invasion Fecal polymorphonuclear Shigella species, salmonella species, c.
inflammatory or cytotoxin) leukocytes jejuni, enteroinvasive E. coli, Yersinia
diarrhea With or without red cells enterocolitica, C. difficile, Entomoeba
histolytica
Enteric fever Penetration & possible Fecal mononuclear leukocytes Salmonella typhi
dissemination

Typhoid (1137)

Non typhoidal salmonella Typhoidal salmonella

Epidemiology - S. enterica - S. typhi, s. paratyphi
- Poultry/eggs, exotic pets - Humans only
- Foodborne (primarily) - Water/food contamination
- Industrialized countries - Developing countries
Pathophysio Invasion of enterocytes -> massive Invasion of enterocytes -> blunted
neutrophil-mediated inflammatory neutrophil response due to capsular
response in lamina propria/Peyer’s antigen Vi -> extensive intracellular
patches -> control of infection replication in macrophages -> spread
(usually) through lymphatics and RES
Manifestations Gastroenteritis Typhoid fever
- Self-limited watery diarrhea - Progressive fever (pulse-
- Rarely invasive (<5%): temperature dissociation)
osteomyelitis, mycotic - Rose spots, abd pain
aneurysm, endocarditis - HSM, GI bleed, perforation

Clostridium difficil infection (6510)

Is associated with white, patchy pseudomembranes on the bowel mucosa. These pseudomembranes consist of a
neutrophil-predonminat inflammatory infiltrate, fibrin, bacteria and necrotic epithelium. Px may develop a
nonobstructive colonic dilation known as toxic megacolon, which can lead to colonic perforation.

Tx (10401)

Typically include oral vancomycin or fidaxomicin

Fidaxomicin is a macrocyclic antibiotic (related to macrolides) that inh the sigma subunit of RNA polymerase, leading to
protein synthesis impairment and cell death (bactericidal activity against C difficile). It is admn orally and has minimal
systemic absorption, resulting in high fecal concentrations. It also has a narrow spectrum of activity with a lesser effect
on normal colonic flora than vancomycin.

Clostridial myonecrosis (15027)

c. septicum is a spore-forming, exotoxin-producing, gram-positive organism that is the most common cause of
spontaneous gas gangrene (eg, rapid-onset pain, hemorrhagic bullae, tissue crepitus). Underlying colonic malignancy is
the greatest risk factor for infection.

HUS (1851)

HUS (1097)
Shiga toxin enters the cytosol of host cells and cleaves a protein motif off the 60S ribosomal mucosa and the colonic
capillaries causes abd pain and bloody diarrhea. The absorption of Shiga toxin into the systemic circulation causes
glomerular (renal insufficiency) and vascular (thrombocytopenia, microangiopathic hemolytic anemia).

The primary reservoir for EHEC is the GI tract of healthy cattle. Humans primarily acquire the organism after consuming
contaminated, undercooked beef. Low infectious doses (10-100 organisms).

Children age <10 are the greatest risk

Nocardiosis (11638)
Microbiology - Gram (+) rod (beaded or branching
- Partially acid-fast
- Aerobic
Epidemiology - Endemic in soil
- Disease from spore inhalation or traumatic inoculation into skin
- Immunocompromised or elderly px
Clinical features - Pneumonia – similar to TB
- CNS involvement – brain abscess
- Cutaneous involvement
Tx - TMP-SULFA
- Surgical drainage of abscesses

Shigellosis (1143)

S sonnei is the most common cause of shigellosis in industrialized nations. Shigella invades the GI mucosa by gaining
access to microfold cells in ileal Peyer patches through endocytosis. Shigella subsequently lyses the endosome and
spreads laterally into other epithelial cells, causing cell death and ulceration with hemorrhage and diarrhea.

(1135) shigella is a non-motile, non-lactose fermenting organism that does not produce H2S when grown on triple sugar
iron agar. Mucosal invasion of the M cells that overlie Peyers patches is an essential pathogenic mechanism for Shigella
infection. Shigella then escapes the phagosome and spreads laterally to other epithelial cells via actin polymerization

Virion to cellular receptor (8324)

Virion Cellular receptor

CMV Cellular integrins
Epstein-Barr virus CR2 (CD21)
HIV CD4 and CXCR4/CCR5
Rabies virus Nicotinic acetylcholine receptor
Rhinovirus ICAM1 (CD54)

H. influezae (963)

Haemophilus requires both X factor (hematin) and V factor (NAD+) to support growth. Sheep blood agar does not allow
Haemophilus growth due to insufficient nutrients and the V factor-inactivating enzymes in the medium.

(1102) Nontypeable strains of H. influenza are part of the normal upper respiratory tract flora and are a common cause
of acute otitis media, sinusitis and bronchitis. Because nontypeable strains do not form a polysaccharide capsule,
immunity is not conferred by vaccination with the H. influenza type b vaccine.
Growth of Haemophilus species on sheep blood agar can be achieved by cross-streaking the medium with S. aureus. H.
influezae colonies will grow around the streaks of beta-hemolytic S. aureus colonies because the latter actively secrete V
factor (NAD+) into the medium and facilitate release of additional X factor (hematin) from beta-hemolysis-induced
erythrocyte lysis. This is known as the “satellite” phenomenon

(962) the major virulence factor of Hib is its polysaccharide capsule, which is composed of the polymer polyribosylribitol
phosphate (PRP). The PRP capsule protects the bacterium against phagocytosis and complement-mediated lysis by
binding factor H, a circulating regulator protein that normally prevents complement (C3b) deposition on host cells.

The conjugate Hib vaccine is composed of PRP conjugated to a protein toxoid. Immunization results in host development
of anti-PRP antibody, which leads to improved opsonization and complement-mediated phagocytosis. Invasive Hib
disease is rare in immunized px, but it still occurs regularly in unimmunized children

VS. lecithinase (toxin A) is produced by Clostridium perfringens, and hydrolyzes lecithin in cell membranes. This results in
cell lysis and the development of gas gangrene.

VS. M protein is found in the cell wall of streptococcus pyogenes. It binds factor H to prevent opsonization and
destruction of streptococci by the alternative complement pathway

VS. protein A in the cell wall of s. aureus helps prevent opsonization by finding the Fc region of ig. S aureus is a common
cause of tracheitis, which presents similarly to epiglottitis (eg, stridor, fever, respiratory distress) but does not cause a
swollen epiglottis

VS. trehalose dimycolate is a cell wall component and major virulence factor of TB. It protects TB from being killed by
macrophages and stimulates granuloma formation

(1649) major adaptive immune mechanisms that prevent reinfection with the influenza virus include anti-hemagglutinin
antibodies.

(1466) inactivated versions of the influenza vaccine stimulate the formation of neutralizing antibodies against the
hemagglutinin antigen of included strains. Subsequent exposure to a strain of influenza included in the vaccine will not
result in infection because the antibodies bind to hemagglutinin, thereby preventing hemagglutinin from attaching to
the sialic acid receptor on host respiratory epithelial cells (preventing viral entry)

M protein (723)

Group A strep is studded with M protein, a virulence factor that inh phagocytosis, prevents complement binding, and
aids in the epithelial attachment.

M protein is an alpha-helical coiled-coil protein that shares epitopes and structural homology with other alpha-helical
coiled-coil proteins such as tropomyosin and myosin. In some px, the protective antibodies against M protein that
develop in S pyogenes acute infection may cross-react with myosin epitopes in the heart and cause rheumatic carditis

Skin and soft tissue infections (727)

S. aureus is the most common cause of skin and soft-tissue abscess (eg, furuncle). Tx of the abscess with incision and
drainage and antibiotics can eliminate the local infection but does not eliminate colonization of the anterior nares and
skin. Therefore, recurrent infections are common.

(974)
Hot tub folliculitis, is a superficial pseudomonal infection of the hair follicle. This condition, characterized by a pruritic,
papulopustular rash, is most commonly seen with outbreaks from public or hotel swimming pools or hot tubs where the
chemicals in the pool water have not been maintained at appropriate concentrations, thereby allowing P. aeuruginosa
proliferation

Diphteria (1093)
Epidemiology Endemic in developing countries due to inadequate vaccination but rare in developed
countries
Microbiology/pathogenesis - Corynebacterium diphteriae colonize respiratory tract & secrete diphtheria toxin,
the primary virulence factor
- Diphtheria toxin is an AB exotoxin that inhibits protein synthesis by ADP-
ribosylation of EF-2
- Toxin acts locally, causing respiratory cell necrosis with formation of fibrinous,
coagulative exudates
Clinical symptoms - Sore throat
- Fever
- Cervical adenopathy
- Pharyngeal exudates/coalescing pseudomembrane
Complications - Submucosal edema & pseudomembrane aspiration can obstruct respiratory tract,
causing suffocation
- Systemically absorbed diphtheria toxin has predilection for brain and heart tissue
. Myocarditis/HF
. Nerologic toxicity

C diphteriae produce classic 2-subunit AB exotoxin. The B(binding) subunit binds specifically to the heparin-binding
epidermal growth factor receptor on cardiac and neural cells, which explains the toxin’s affinity for heart and brain
tissue.

(1092) toxigenic strains of C. diphteriae produce diphtheria toxin, which irreversibly inh host protein synthesis due to
ADP-ribosylation of elongation factor-2. Local effects include pseudomembranous pharyngitis; systemic effects include
potentially life-threatening myocarditis and neuritis. Immunization with diphtheria toxoid generates protective
circulating IgG against the exotoxin B subunit.

(1388) the primary tx for diphtheria is diphtheria antitoxin (passive immunization), which inactivates circulating toxin.
Antibiotics should also be admn to reduce continued production of toxin

(1389) conversion from nontoxigenic to toxigenic C. diphtheria occurs due to infection with a lysogenic bacteriophage
called Corynephage beta. This phage inserts the tox gene into the C diphtheria genome, which results in the bacterial
expression of the diphtheria AB toxin. Diphtheria toxin irreversibly halts protein synthesis due to ADP-ribosylation of
elongation factor-2 and causes severe local (eg, pseudo membranous pharyngitis) and systemic (eg, myocarditis,
neuritis) effects.

(1390)

Diphtheria toxin acts in a similar manner to exotoxin A, which is produced by P. aeruginosa

P. aeruginosa produces several extracellular products, including exotoxin A, collagenase, elastase, fibrinolysin,
phospholipase C and DNAse. Both diphtheria toxin and exotoxin A ribosylate and inactivates EF-2, halting human cell
protein synthesis and causing cell death. Exotoxin A is a major virulence factor and is responsible for high mortality
associated with P. aeruginosa septicemia.

Acute parotitis (11596)

Suppurative parotitis in adults

Risk factors Decreased salivary flow
- Medications (eg, anticholinergics)
- Obstruction (eg, calculi, neoplasm)
- Dehydration, postsurgical/intubation
Microbiology - S. aureus, anaerobes
Clinical presentation - Firm, erythematous pre/postauricular swelling
- Trismus, dysphagia, systemic findings (fever, chills)
Dx - Imaging (Ultrasound/CT): ductal
inflammation/obstruction, frank abscess
- Laboratory: elevated serum amylase without
pancreatitis

Rocky mountain spotted fever (15075)

- Rickettsia rickettsia (gram -, obligate intracellular)

- Transmission: tickbite from: american dog tick), present in the eastern and south-central US and mountainous
regions west of the Mississippi River
- R rickettsia moves from the tick salivary glands to the human host after 6-12 hrs of attachment. The pathogen
enters vascular endothelial cells via endocytosis and subsequently lyses the endosome using specific virulence
factors. It then replicates in the cytosol and nucleus of the host cell and spreads rapidly to adjacent cells via
filopodia, leading to a lymphohistiocytic vasculitis
- Manifestations: fever, headache, myalgia, and malaise followed 3-5 days later by a characteristic macular rash
that becomes petechial over time. The rash typically begins on the ankles or wrists and spreads toward the
center of the body (centripetally) as well as to the palms and soles. Thrombocytopenia freuqnetly occurs as
platelets are consumed due to widespread vascular injury. Antibiotic therapy is required to prevent progression
and, potentially, death.
- First line tx: doxycycline, inh protein synthesis by binding the 30s bacterial ribosomal subunit

Necrotizing Fasciitis (8857)

Necrotizing fasciitis is a severe infection of the subcutaneous tissue and deep fascia that is a surgical emergency. The
infection is often polymicrobial, but monomicrobial cases due to S. pyogenes can also occur. S. pyogenes is a PYR-
positive, beta-hemolytic, Gram (+) cocci that grows in chains.

Neisseria (1026)

Has high antigenic variability of its surface molecules (eg, prions, Opa proteins), which prevents the formation of
protective immunity and leads to susceptibility to repeat infection.

Aspergillus fumigatus

(57) high levels of dietary aflatoxin exposure is associated with a G:C -> T:A transversion in codon 249 of the p53 gene, a
mutation thought to greatly increase the risk of developing hepatocellular carcinoma.
Allergic bronchopulmonary aspergillosis (665)
Hx - Asthma
- CF
Chest imaging - Recurrent fleeting infiltrates
- Bronchiectasis (on CT scan)
Dx - Eosinophilia
- Positive skin test for Aspergillus
- Positive Aspergillus-specific IgG
- Elevated Aspergillus-specific & total IgE

(11637) px with febrile neutropenia are at increased risk for severe infection. Broad-spectrum antibiotic therapy is
indicated. Gram-positive organisms are now the most commonly identified pathogens in FN. However, px with profound
and prolonged neutropenia (several days) are at especially high risk for viral and fungal infections.

Mycoplasma pneumoniae (958)

Is common in adolescents and usually presents with tracheobronchitis or walking pneumonia. The pathogen attaches to
the respiratory epithelium using surface antigens (I-antigen) that are also present on the plasma membrane of
erythrocytes. Therefore, px with M penumoniae typically develop cross-reactive IgM antibodies that can attach to RBC,
activate the complement system and cause erythrocyte lysis. These corss-reacting antibodies are called cold agglutinins
because they bind to erytrhocytes most strongly at temperatures below core body temperature. Testing for cold
agglutinins can be done at the bedside by drawing blood into an edetate disodium-containing tube and placing it in a
cup of ice. Removing the tube after several seconds will reveal clumping/agglutination that resolves as the tube warms.

Cold agglutinins are often asymptomatic, but some px develop mild IV hemolytic anemia that usually resolves after 6-8
weeks (when IgM antibody titers fall). Px who have infectious mononucleosis and certain hematologic malignancies also
commonly develop cold agglutinins.

(957) M. pneumonia binds an oligosaccharide on the respiratory epithelium that is also present on erythrocytes, leading
to the generation of cross-reacting IgM antibodies (cold agglutinins). Px with M pneumoniae infections often develop
mild, transient hemolytic anemia that resolves as IgM antibody titers decline (6-8 weeks after infection begins)

(1679) a classic sign is a chest x-ray revealing findings that are much worse than the clinical appearance of the px.
Another clue for M pneumoanie infection is that the organisms require cholesterol to grow because their cell membrane
is composed of a single cholesterol-rich phospholipid bilayer.

(6781) tx: protein synthesis inh (eg, macrolides, tetracycline)

Ehrlichiosis & anaplasmosis (15543)

Ehrlichia chaffeensis is harbored by white-tailed deer in the southwestern, southeastern, and mid Atlantic US. It is
transmitted to humans by tick bite (eg, lone star tick) and subsequently spreads to tissue rich in mononuclear cells (eg,
bone marrow, lymph nodes, liver, spleen), leading to non specific symptoms (eg, fever, chills, myalgia, headache),
maculopapular rash and significant laboratory abnormalities (eg, lymphopenia, thrombocytopenia, elevated
aminotranserases)

E chaffeensis replicates in membrane-bound vacuoles within the cytoplasm of monocytes and can be visualized on
peripheral blood or buffy coat examination as mul-berry-shaped, intraleukocytic inclusions (morulae). Tx: doxycycline

Leprosy (1314)
Leprosy is a chronic, slowly progressive, communicable disease caused by Mycobacterium leprae that typically involves
thte skin and peripheral nerves. Clinical manifestations are widely variable depending on the strength of the TH1 cell
mediated immune response to the organism. Disease is classified along a spectrum between tuberculoid (mild) to
lepromatous (severe) forms. Px with tb leprosy develop a strong TH1-mediated response (IL-2, IFN-gamma, and IL-12) in
affected tissues, leading to the activation of macrophages that kill M leprae organisms, thereby limiting disease extent.
However, this localized inflammation dmgs the skin and cutaneous nerves, leading to the development of a small
number of hypopigmented, well demarcated plaque with decreased sensation.

Lepromatous leprosy is a more disseminated form of the disease characterized by an innate inability to recognize and
mount a cellular immune response against M leprae antigens. Affected tisusues show extensive accumulation of acid-
fast bacilli within macrophages and often a TH2 cytokine profile (IL-4, IL-5, and IL-10). Px with lepromatous leprosy
develop more numerous, poorly demarcated palques that are widespread across the boyd. Over time, the bacterial load
increases and the nodular lesions coalesce, causing the development of leonine facies and degeneration and loss of the
nose and digits

The lepromin skin test (in which M leprae antigens are injected intradermally) can be used to distinguish between tb and
lepromatous leprosy. Px with tb leprosy will develop an indurated nodule at the site of the injection (much like a positive
PPD test for M tb). In contrast, the test is usually nonreactive in px with lepromatous leprosy due to their weak TH1 cell
mediated immune response.

Tuberculosis (1598)

The caseating granulomas of tuberculosis almost always contain large epithelioid macrophages with pale pink granular
cytoplasm and surface CD14 at the periphery. CD14 is a surface marker of the monocyte-macrophage cell lineage. CD4
and CD8 are surface markers of T-helper and T-killer cells, respectively.

Vs. CD4 transmembrane proteins recognize antigens presented by MHC class II molecules. CD4 is thus found on the
surface of MHC II-restricted T-helper cells. Although including CD4+ T-cells) and some plasma cells, these are distinct
from the large epithelioid macrophages that are almost always present in granulomas
Vs. CD7 is a multi-chain complex T-cell marker

Vs. CD8 is a transmembrane protein associated with T-cell receptors. Together these proteins recognize antigenic
peptides presented by MHC class I molecules. Thus, CD8 is found on the surface of MHC I-restricted cytotoxic T-cells.

Vs. CD20 is a B-cell surface marker. Monoclonal antibodies against the CD-20 antigen (Rituximab) have been successful
in the tx of lymphomas.

Pathogenesis of TB (1218)

(1216) TB grows in long, serpentine cords due to the presence of cord factor, a surface glycolipid, on the cell wall.
Cordfactor is a primary virulence factor of M. TB; it prevents macrophages from being bactericidal due to the inhibition
of phagolysosome acidification and also leads to the formation of caseating granulomas

(1219) primary tb causes the formation of Ghon foci in the lower lungs. Secondary (reactivation) tb occurs in px with
prior tb infection that never cleared completely. Reactivation tb occurs most often in immunosuppressed px and is
characterized by apical cavitary lesions and hemoptysis.

Syphilis (1316)
Autosomal recessive deficiencies of the IFN-gamma receptor (8384)

Results in disseminated mycobacterial disease in infancy or early childhood, including disseminated infection by the BCG
vaccine strain if admn. Once identified, these px require lifelong tx, with continuous antimycobacterial antibiotics.

Chloramphenicol (359)

Suppresses bacterial protein synthesis by binding to the ribosomal 50S subunit and inhibiting the peptidyl transferase
enzyme. Its hematologic side effects include dose-related anemia, leukopenia and/or thrombocytopenia that are
reversible by withdrawing the medication. Chloramphenicol also causes dose-independent (idiosyncratic) aplastic
anemia, which is usually severe and fatal without treatment (eg, bone marrow transplantation).

Parasitology

Babesiosis (11524)

Primary amoebic encephalitis (15077)

Pathophysiolog - Infection with Naegleria fowleri (free-living, motile protozoan)
y - Exposure during recreational water activities (eg, boating, diving)
- Mucosal invasion -> penetration of cribriform plate -> meningoencephalitis
Presentation - Acute fever, confusion, headache, photophobia, CN palsies
- CSF – increase protein, neutrophils; motile trophozoites on wet mount
Management - Nearly all cases are fatal
- Antibiotics (Eg, amphotericin B) administered but usually insufficient
Intestinal helminth parasites (8538)

Enterobius vermicularis infection (enterobiasis) occurs most frequently in school-age children and presents with perianal
pruritus. Dx is made by the scotch tape test. Albendazole is the first-line treatment, with pyrantel pamoate as an
alternate agent preferred in pregnant px.

Vs. diethylcarbamazine is indicated for Loa loa (loiasis) and Wuchereria bancrofti (lymphatic filariasis) infections

Vs. ivermectin is used to tx infections caused by strongyloides stercoralis (strongyloidiasis) and onchocerca volvulus
(onchocerciasis)

Vs. nifurtimox is used to tx diseases caused by trypanosomes, including chagas disease (trypanosome cruzi)

Vs. infections caused by schistosoma (schistosomiasis), clonorchis sinensis (clonorchiasis) and paragonimus westermani
(paragonimiasis) are tx with praziquantel.

Leishmaniasis (15448)

Microscopy of skin lesion reveals intracellular protozoa with rod-shaped kinetoplasts, raising strong suspicion of
cutaneous leishmaniasis, a parasitic disease endemic to the Middle East and Central and South America. Leishmania
species are harbored by small mammals and transmitted to humans via bites from tinfected sand flies. The parasite
subsequently matures within mammalian macrophages and can be visualized on biopsy as intracellular, round-oval
amastigotes with rod-shaped kinetoplasts.

Cutaneous leishmaniasis is characterized by a chronic, enlarging, pinkish papule at the site of the bite that eventually
develops into a nodule or plaque and ulcerates. Most cases occur on exposed areas of skin because sand fly bites cannot
penetrate clothing. More serious mucosal or lymphatic Leishmania infections can also occur.

Giardiasis (1596)

The major immune mechanisms against Giardia involve CD4+ T helper cells and secretory IgA production. Secretory IgA
helps prevent and clear infection by binding to trophozoites and impairing their adherence to the upper small-bowel
mucosa. Children with IgA deficiency, X-linked agammaglobulinemia, and common variable immune deficiency have a
predisposition to developing chronic giardiasis.

(1574) is the most common enteric parasite in the US and Canada and is a common cause of diarrhea in campers/hikers.
Iodine-stained stool smear classically shows pear-shaped, flagellated trophozoites or ellipsoidal cysts with smooth well-
defined walls and 2+ nuclei. Metronidazole is the tx of choice.

Neurocysticercosis (11670)
Malaria

(15325) female Anopheles mosquitos injects Plasmodium sporozoites into subcutaneous capillaries during feeding.
Within hrs, sporozoites attach to and enter hepatocytes and undergo asexual reproduction. This results in the
production of tens of thousands of daughter cells (merozoites) that eventually rupture the hepatocyte and spread to
erythrocytes, where another asexual reproduction cycle occurs.

Dx is confirmed when trophozoites (intraerythrocytic, ringed inclusions) are seen on peripheral blood smear using
Giemsa stain.

2 dominant organisms are P falciparum (in Africa) and P vivax (in non-African countries). This px who traveled to India
was likely infected with P vivax. Unlike P falciparum, P vivax (and P ovale) sporozoites can undergo a dormant hepatic
phase (hypnozoite stage) that may cause recurrent parasitemia and symptoms weeks or months after initial infection.
Individuals with these strains of malaria must be treated with a combination of drugs that target both the erythrocyte
phase (eg, chloroquine) and the dormant hepatic phase (ie, primaquine) to ensure clearance.

(1965)

Chloroquine is the tx of choice for uncomplicated malaria contracted in a cloroquine-sensitive geographic region. It
eliminates susceptible erythrocytic forms of all Plasmodium species. Primaquine is added in the tx of infections with P
vivax and P ovale to eradicate the intrahepatic stages (hypnozoites) of these malarial species, which are responsible for
relapses.

(15453)

Common chemoprophylaxis regimens include atovaquoene-proguanil, doxycycline and mefloquine. Mefloquine is a

schizonticide that actively destroys replicating parasites within RBCs. However, it is inactivated in the liver and has no
efficacy against hepatic schizonts. Therefore, px must receive mefloquine chemoprophylaxis for 4 weeks upon return to
ensure that parasites released from the liver are destroyed when they infect RBC (liver schizonts rupture over 8-30
days). Individuals who do not take mefloquine upon return (as in this case) are at risk for hepatic schizont release and
subsequent red cell infection, leading to symptomatic malaria.

Babeosis (11540)

Schistosomiasis (8541)

Echinococcosis (61)

- The most common cause of hydatid cysts

- Spilling of cyst contents can cause anaphylactic shock
- Surgical manipulation should be performed with caution
- Endemic regions: eastern Mediterranean, Middle East, South Amerca, sub-Saharan Africa, former Soviet Union,
western China) or those residing in the southwestern US with sheep and dog (participate in the tapeworm life
cycle) exposure.
 - Microscopic examination: encapsulated and calcified cyst (“eggshell calcification”) containing fluid and budding
cells that will eventually become daughter cysts. The outer wall is composed of gelatinous sheets surrounded by
a thick fibrous capsule.

Strongyloides (8873)

Strongyloides stercoralis infection begins following skin penetration by filariform (infectious) larva and can be dx by
finding rhabditiform (noninfectious) larvae in the stool. Rhabditidiform larvae can mature into filariform larva in the
human GI, precipitating an autoinfection cycle that occurs entirely within the affected individual. This can result in a
hyperinfection syndrome characterized by massive dissemination of the organism, leading to multiorgan dysfunction
and septic shock.

Virology

Viral replication (6523)

DNA viruses (except for poxviruses) replicate in the nucleus, and RNA virsues (except for orthomyxoviruses and
retrovirsues) replicate in the cytoplasm. The RNA in positive-sense, single-stranded RNA virsuses can directly translated
into viral protein. In contrast, negative-sense RNA viruses must provide their own RNA-dependent RNA polymerase as
negative-sense RNA cannot be used as a translation template.

Viral genetics (1461)

Recombination refers to gene exchange that occurs through the crossing over of 2 double-stranded DNA molecules.
Reassortment describes the mixing of genome segments in segmented viruses that infect the same host cell.
Common features of dengue fever (11395)
Classic dengue fever - Flu-like febrile illness with marked myalgias & joint
pains (“break-bone fever”)
- Retro-orbital pain
- Rash (“white islands in sea of red”)
Dengue hemorrhagic fever - Increased vascular permeability
- Thrombocytopenia (<100,000/mm^3)
- Spontaneous bleeding -> shock
- Positive tourniquet test (petechiae after
sphygmomanometer cuff inflation for 5 min)
Management - Supportive care

Dengue viruses are transmitted by the Aedes mosquito and are single-stranded RNA viruses (genus Flavivirus) with 4
different serotypes (DENV1-4). Primary (first) infection can be asymptomatic or cause a self-limited disease in most
adults. Symptomatic disase can cause high-grade fever, headache, retro-orbital pain, bleeding (eg, epistaxis,
petechiae/purpura), diffuse macular rash, muscle and joint pain (“break-bone fever”), leukopenia, thrombocytopenia
and elevated liver enzymes

Primary infection leads to lifelong immunity against the same serotype, but individuals can be infected with a different
serotype. Secondary infection with a different viral serotype can cause a more severe illness, possibly due to antibody-
dependent enhancement of infection, enhanced immune complex formation, and/or accelerated (not blunted) T-
lymphocyte responses.
Zika virus (15034)

Molluscum contagiosum (6507)

- Caused by poxvirus (MC virus)

- Transmitted through direct contact or fomites
- Microscopic assessment: epidermal hyperplasia along with molluscum bodies
Large eosinophilic cytoplasmic inclusions made of virus particles

Roseola infantum (11822)

Microbiology - HHV-6 most common
Epidemiology - Age <2 years
Clinical features - 3-5 days of high fever followed by blanching maculopapular rash
- Usually starts on the trunk and spreads to the face and
extremities
Treatment - Supportive care
Vs. rubella and measles, typically present with a maculopapular rash on the face that then spreads to the trunk and
extremities. In addition, px with rubella often have Forchheimer spots on the soft palate, and measles is characterized by
pathognomonic Koplik spots on buccal mucosa.

Enterovirus
Epidemiology - Infants & young children
- Summer season
- Fecal-oral transmission
Clinical features - Herpangina (oral ulcerations)
- Hand-foot and mouth disease (oral & extremity
ulcerations
- Aseptic meningitis
- myocarditis

Aseptic meningitis (1966)

Most common causative in vaccinated children: enteroviruses (eg, coxsackievirus, echovirus, poliovirus)
Erythematous childhood rashes (8565)
Disease Agent Clinical presentation Important complications
Chickenpox Varicella-zoster virus - Pruritic, vesicular Shingles (in adulthood)
rash on face, trunk
& extremities
- Lesions in different
stages of
development
Erythema infectiosum Parvovirus B19 - Malar rash with Aplastic crisis in sickle cell
“slapped cheek” and immunocompromised
px
German measles (rubella) Rubella virus - Maculopapular rash Congenital rubella
starting on head, syndrome
progressing to trunk
& extremities
- Occipital and
postaruicular
lymphadenopathy
Measles (rubeola) Measles virus - Maculopapular rash Bronchopneumonia,
starting on head encephalitis
that progresses to
trunk & extremities
- Rash preceded by
cough, coryza,
conjunctivitis &
Koplik spots
(pathognomonic
Roseola infantum HHV6 - High fever for 3-5 Self-limited
days with rash
appearing once
fever subsides
- Macules & papules
initially on trunk
that spread to
extremities
Scarlet fever Streptococcus pyogenes - Sandpaper-like rash Rheumatic fever,
that begins on the glomerulonephritis
neck & upper trunk
& then generalized
- Associated with
fever & sore throat
Scarlet fever is characterized by fever, pharyngitis, sandpaper-like rash, circumoral pallor and a strawberry tongue. It is
caused by strains of Group A streptococcus that produce pyrogenic exotoxins. Scarlet fever can predispose to acute
rheumatic fever and glomerulonephritis.

1-5 days of incubation. After 1-2 days, a rash appears on the neck, armpits and groin that subsequently generalizes to
the rest of the body the rash begins as scarlet spots or blotche,s giving a boiled lobster appearance. As the rash
progresses and becomes more widespread, it begins to resemble a sunburn with goose pimples (“sandpaper-like” rash).
The cheeks commonly appear flushed, giving the area around the mouth a pale appearance in comparison (circumoral
pallor). Toward the end of the first week, desquamation begins and is most pronounced in the armpits, groin and tips of
the fingers and toes.
Measles virus (rubeola) (1670)
Clinical px - Prodrome (eg, cough, coryza, conjunctivitis, fever, Koplik spots)
Koplik spots: on the buccal mucosa are a pathognomonic finding and consist of small white,
blue, or gray specks on an erythematous base
- Maculopapular exanthema
Cephalocaudal & centrifugal spread
Spares palms/soles
Complications - Primary measles pneumonia
- Secondary bacterial infections (pneumonia & otitis media)
- Neurologic
Encephalitis (within days)
Acute disseminated encephalomyelitis (within weeks)
Subacute sclerosing panencephalitis (within years)
Prevention - Live attenuated measles vaccine

West Nile virus (15587)

Clinical syndrome - (1906) Most WNV infections are asymptomatic or present with a flu-like
illness (ie, West Nile fever: fever, headache, myalgias)
- West Nile fever: fever, headache, rash (maculopapular/morbilliform)
- Neuroinvasive: meningitis, encephalitis, acute asymmetric flaccid paralysis
Parkinsonian symptoms (eg, rigidity, bradykinesia, tremor)
Transmission -Mosquitoes (culex spp.)
-More common in summer/fall
-Warm climate (southern US, LA, Africa)
Risk Factors -Older age
-Malignancy/organ transplant
- Enveloped RNA virus
- Replicates extensively within birds and is passed to mosquitos
- (1906) Neuroinvasive infection is an uncommon complication of WNV but has a 10% fatality rate. It occurs most
commonly in older px and those with hx of malignancy or organ transplant and is characterized by meningitis (ie,
headache, meningisums) and/or encephalitis (altered mental status). The presence of acute-onset asymmetric
flaccid paralysis is highly suggestive of WNV, particularly if the px demonstrates concurrent parkinsonian ft (eg,
rigidity, bradykinesia, tremor, postural instability). Dx can be made when compatible clinical findings are
associated with positive cerebrospinal fluid anti-WNV antibodies (polymerase chain reaction testing often not
needed).

Double-stranded DNA viruses (1409)

Enveloped - Hepadna (eg, hep B)
- Herpes (eg, varicella, HSV-1 & HSV-2)
- Pox (eg, smallpox)
Non-enveloped - Adenovirus
- Papova (eg, HPV)
- Polyoma (eg, JC & BK)

Viral genetics (1469)

Viruses with segmented genomes (rotavirus, orthomyxoviruses, reoviruses, bunyaviruses and arenaviruses) are capable
of genetic shifts through reassortment. Reassortment (genetic shift) involves exchange of entire genomic segments, a far
more dramatic process than the point mutations responsible for genetic drift.
Rotavirus (15215)

Is a segmented, nonenveloped, double-stranded RNA

Invades the villous epithelium of the duodenum and proximal jejunum

Mechanisms:

- Villous blunting (loss of absorptive capacity)

- Proliferation of secretory crypt cells (secretory diarrhea)
- Reduced brush border enzymes (accumulation of unmetabolizaed disaccharides in the small intestine lumen)

Enteroviruses (6593)

Are members of the picornaviridae family, are the most common cause of viral meningitis. All viruses in Picornaviridae
have a positive-sense, single-stranded RNA genome.

Hepatitis A (373)

Hep A virus infection is most commonly silent or subclinical (“anicteric”) in young children but can also present as an
acute, self-limited illness characterized by jaundice, malaise, fatigue, anorexia, nausea, vomiting, right upper-quadrant
pain or an aversion to smoking.

(366) Characterized histologically by the presence of “spotty necrosis” with ballooning degeneration (hepatocyte
swelling with wispy/clear cytoplasm), Councilman bodies (eosinophilic apoptotic hepatocytes), and mononuclear cell
infiltrates.

Hepatitis B

(374) HBV is a hepadnavirus composed of:

- an outer lipid envelope that contains viral-encoded proteins (HBsAg) and host lipid components
- an icosahedral nucleocapside core that contains a circular, partially double-strnaded DNA genome and a DNA
polymerase with reverse transcriptase activity

HBV binds to a bile salt transporter on the surface of hepatocytes and enters the cell. After the virus is uncoated in the
host cytoplasm, the single-stranded DNA portion of the viral genome is completed (repaired) by cellular DNA
polymerases. This generates double-stranded viral DNA, which is subsequently transcribed by host RNA polymerase into
a +single-stranded RNA pregenome. The +RNA template is then translated inot the proteins that compose the virus (eg,
envelope, core, polymerase); it is also converted by viral DNA polymerase/reverse transcriptase into the partially
double-stranded DNA progeny of developing viral particles.

(378) vertical transmission of hep B from pregnant females to the unborn child can occur in women with active hep B
infection (especially third trimester). The presence of HBeAg (a marker of viral replication and increased infectivity) in
the mother greatly increases the risk of vertical transmission of the virus. Because of this concern, the newborns of all
mothers with active hep B are passively immunized at birth with hep B immune globulin (HBIG), followed by active
immunization with recombinant HBV vaccine.
Importance of hepatitis B serological markers (380)

(379) If HBeAg persists for several months and host anti-HBeAG remain at low or undetectable levels, suspect chronic
hep B infection with high infectivity

(375) Hep B virus infection progresses through 2 phases:

- Proliferative phase: the entire virion and all related antigens of the episomal HBV DNA are present. On the
hepatocyte cell surface, viral HBsAg and HBcAg are expressed in conjunction with the MHC I molecules. This
expression serves to activate cytotoxic CD8+ T lymphocytes, which respond by destroying the infected
hepatocytes. Note that the virion itself does not have a cytopathic effect.
- Integrative phase: the HBV DNA is incorporated into the host genome of those hepatocytes that survived the
immune response. Infectivity ceases and liver dmg tapers off when the antiviral antibodes appear and viral
replications tops. The risk of hepatocellular carcinoma, however, remains elevated because of the HBV DNA that
has been integrated into the host genome.

(365) Acute HBV is characterized by significant elevations in aspartate aminotransferase and alanine aminotransferase,
often >10 times the upper limit of normal. Most px will have nonicteric hepatitis, but icteric hepatitis with jaundice and
elevated bilirubin is also common. Impaired hepatic synthetic function, as indicated by a prolonged PT, confers a poor
prognosis.

(58) ongoing infection with either virus leads to increased hepatocyte turnover and the generation of local inflammatory
cytokines, which can result in genetic mutations that lead to malignant transformation. However, HBV has several
additional mechanisms that promote HCC, including the following:

- Integration into the host genome – Nearly 90% of px with chronic HBV who develop HCC have evidence of HBV
DNA in the chromosome of tumor cells. HBV is a partially double stranded DNA virus that is repaired by host cell
machinery into a covalently closed circular DNA stand. Although it is not required for viral replication (unlike
HIV), HBV DNA is often inserted into the cellular genome by host topoisomerase I. integration into regions that
control cell growth and differentiation can result in insertional mutagenesis.
 - Production of oncogenic viral proteins – HBV produces viral protein called HBx that is a transcriptional activator
of several genes associated with cellular growth. It also interferes with the fx of p53, an important tumor-
suppressor protein.

(374)

HBV is a hepadnavirus composed of:

- An outer lipid envelope that contains viral-encoded proteins (HBsAg) and host lipid components
- An icosahedral nucleocapside core that contains a circular, partially double-stranded DNA genome and a DNA
polymerase with reverse transcriptase activity.

HBV binds to bile salt transporter on the surface of hepatocytes and enters the cell. After the virus is uncoated in the
host cytoplasm, the single-stranded DNA portion of the viral genome is completed (repaired) by the cellular DNA
polymerases. This generates double-stranded viral DNA, which is subsequently transcribed by host RNA polymerase into
a +single-stranded RNA pregenome. The +RNA template is then translated into the proteins that compose the virus (Eg,
envelope, core, polymerase); it is also converted by viral DNA polymerase/reverse transcriptase into the partially
double-stranded DNA progeny of developing viral particles

Perinatal hep B infection (46)

Hepatitis C

(388) HCV has >6 genotypes and multiple subgenotypes. These variant strains differ primarily at hypervariable genomic
regions, such as those found in the sequences encoding its 2 envelope glycoproteins. Moreeve,r there is no proofreadin
g3’-> 5’ exonuclease activity built into the virion-enconded RNA polymerase. As a result, the RNA polymerase makes
many errors during replication, and several dozen subspecies of HCV are typically present in the blood of an infected
individual at any one time.

(15144)
Tx: direct-acting antiviral agents, which target specific enzymes in the HCV life cycle to inhibit viral replication and
assembly:

- RNA-dependent RNA polymerase inh – HCV binds to and enters host cells, uncoats, and subsequently replicates
its genome using HCV-encoded RNA-dependent RNA polymerase. Nucleotide/non-nucleoside RNA polymerase
inh such as sofosbuvir target this step
 - Protease inhibitors – HCV mRNA is translated by host ribosomes into a polyprotein, which is cleaved by HCV
protease into the individual proteins that compose the virus. HCV protease inhibitors such as simeprevir target
this step
- NS5A inh – the HCV protein NS4A is crucial for viral replication and assembly (through unclear mechanisms) and
is targeted by HCV medications such as ledivaspir.

Hepatitis D: (47)

Circular molecule of single stranded RNA

Considered replication defective as it must be coated by the external coat hep B surface antigen of HBV to penetrate the
hepatocyte. HDV infection can arise either as an actue coinfection with HBV or as a superinfection of a chronic HBV
carrier

Hepatitis E (48)

Hepatitis E virus is an unenveloped, single stranded RNA virus spread through the fecal-oral route. Infection with HEV
occurs primarily in young and middle-aged adults living in Asia, sub-Saharan Africa, and Mexico with an average
incubation period of six weeks. While the virus is shed in the stool during the acute illness, the disease is typically self-
limited and not associated with either chronic liver disease or carrier state. HEV Ag or HEV RNA can be detected in the
stool or liver in the earliest stages of infection (when the px is asymptomatic). Later, serum transaminases and IgM anti-
HEV titers rise in association with clinical illness. The most concerning feature of hepatitis E is the high mortality rate
observed in infected pregnant women.

Acute viral hepatitis (1927)

Is marked by panlobular inflammation and hepatocyte necrosis and ballooning (which may “bridge” into adjacent
hepatic lobules due to collapse of the reticulin framework. Spotty areas of hepatocyte injury are typically seen. Necrotic
hepatocytes appear ballooned with pale cytoplasm (ballooning degeneration)). Cytotoxic T-cell-mediated signals also
cause hepatocyte apoptosis with the formation of intensely eosinophilic Councilman bodies.

HSV infection (1550)

Recurrence of genital HSV can be suppressed or minimized with daily oral valacyclovir (preferred as it is dosed once daily
and has good bioavailability), acyclovir, or famciclovir. Although the antiviral agents may not be active against latent
virus forms, they can suppress further multiplication as soon as reactivation occurs. Condom use can help prevent a
primary genital HSV infection but does not prevent reactivation of latent infection.

(1499) herpetic gingivostomatitis is a severe vesicular or ulcerative disease following primary infection with HS1.
Involvement of the gingiva, tongue, palate, and pharynx along with systemic symptoms (eg, fever, malaise) is common.
In contrast, reactivation of a latent herpes infection in the trigeminal ganglia generally results in mild perioral vesicles.

Acyclovir (1645)

A guanosine analog. HSV-infected host cell, it is phosphorylated to acyclovir monophosphate, principally via a virally-
encoded thymidine kinase (TK). This is the rate-limiting step in acyclovir activation. Acyclovir monophosphate is then
phosphorylated by cellular enzymes into the active triphosphate form, which impairs DNA polymerase-mediated
replication of HSV.

Acyclovir-resistant HSV (1641)

The absence of viral thymidine kinase in a herpesvirus train confers resistance to nucleoside analog antiviral drugs.

Thymidine kinase-deficient (and therefore acyclovir-resistant) varicella zoster virus isolates tend to be obtained almost
exclusively from AIDS px. These immunocomproimsed px are best tx with either foscarnet (a pyrophosphate analog viral
DNA polymerase inh that does not require viral kinase activation) or with cidofovir. Cidofovir is a broad-spectrum
antiviral nucleotide analogue of cytidine monophosphate. Cidofovir can be converted to the active triphosphate moiety
solely by cellular kinases, thus its efficacy does not depend on the presence of a virally encoded kinase.

HPV (1992)

Individuals with HIV are unable to mount an immune response against HPV due to immunosuppression from T cell
deficiency. Therefore, px with HIV infection commonly have persistent HPV infection, which allows HPV DNA to become
incorporated into the epithelial cells. HIV coinfection may also enhance expression of HPV viral oncogenes E6 and E7,
leading to cervical dysplasia/cancer.

(1015) pap smear shows a koilocyte, a sign of HPV. A koilocyte is an immature squamous cell with dense, irregularly
staining cytoplasm and perinuclear clearing, resulting in a halo. It also has an enlarged pyknotic nucleus where the
chromatin has condensed as part of the apoptosis process, giving it a “raisinoid” appearance.

(483) tropism for stratified squamous epithelium, which protectively lines anatomical areas that undergo frequent
friction and abrasion, including the true vocal cords, cervix and anus. Infants can acquire respiratory papillomatosis via
passage through an HPV-infected birth canal.

(11858)

Progressive multifocal leukoencephalopathy (15068)

Epidemiology:

- JC virus reactivation (latent infection of the kidney and lymphoid organs)

- Untreated AIDS

Manifestations:

- Slowly progressive
- Confusion, paresis, ataxia, seizure
Diagnosis:

- CT brain – white matter lesions with no enhancement/edema(virus attacks oligodentrocytes)

- Lumbar puncture – CSF PCR for JC virus (diagnostic test)
- Brain biopsy (rarely needed)

Tx:

- Often fatal
- If HIV – antiretroviral therapy (helps stabilize neurologic symptoms

Infectious mononucleosis

(7643) IM is a disease characterized by sore throat, malaise, lymphadenopathy, myalgias, splenomegaly and fever. The
causative agent in IM is the EBV. After infecting the pharyngeal mucosa and tonsillar crypts, the virus gains access to the
bloodstream where it preferentially infects B cells by binding to the CD21 cell surface receptor. Cytotoxic T cells (CD8+)
clonally expand in response to the EBV infected B-lymphocytes in an effort to destroy the virally-infected cells. these
reactive (atypical) CD8+ T-lymphocytes may be seen on peripheral blood smear in IM. They classically appear as cells
much larger than quiescent lymphocytes with abundant cytoplasm, an eccentrically-placed nucleus, and a cell
membrane that appears to conform to the borders of neighboring cells.

CMV

(1593) in immunocompetent px with a heterophile antibody-negative mononucleosis-like syndrome, the most likely dx is
CMV infection. CMV can be acquired during the transfusion of leukocyte-laden blood products, as the virus infects
leukocytes of granulocyte-macrophage lineage. Irradiation helps reduce this risk.

Other causes of heterophile antibody-negative mononucleosis-like syndromes: human herpesvirus-6, HIV, and
toxoplasmosis.

Tx (1644) Foscarnet is a pyrophosphate analog that does not require intracellular activation. It directly inh both DNA
polymerase in herpesvirus and reverse transcriptase in HIV. Foscarnet must be administered IV. In addition to tx
ganciclovir-resistant CMV infections, foscarnet is useful in px who have acyclovir-resistant herpesvirus infections.

(1643) Foscarnet can chelate Ca2+. Moreover, foscarnet-induced renal wasting of Mg may lead to hypomagnesemia and
a reduction in the release of parathyroid hormone, which contributes to the hypocalcemic state. Both hypocalcemia and
hypomagnesemia can promote seizures.

(1576) In transplant px, pneumonia with intranuclear and cytoplasmic inclusion bodies histologically points to
opportunistic infection with CMV, an enveloped virus that contains a double-stranded DNA genome. Transplant centers
practice universal prophylaxis for lung transplant recipients (eg, valganciclovir)

CMV encephalitis (15068):

- Rapidly progressive altered mental state and focal neurologic deficits

- Highly inflammatory -> enhancing lesions

EBV

(15490)
Reactive lymphocytes are activated, pathogen-specific cytotoxic T cells and natural killer cells that form in response to
certain intracellular infections (eg, HIV, CMV, toxo); they are particularly linked to infectious mononucleosis, EBV
characterized by fever, pharyngitis, adenopathy, splenomegaly and severe fatigue.

Reactive lymphocytes are large, scalloped and have abundant cytoplasm

Reactive lymphocytes are effector cells that contain cytotoxic granules composed of perforin (creates holes in the
infected cell’s membrane) and granzymes (enter the cytoplasm of infected cells and trigger cell death), which are
released in response to foreign antigens on the surface (MHC class I receptors) of infected host cells.

(1593) Most cases of infectious mononucleosis (IM), caused by EBV, are associated with serum heterophile antibodies
that agglutinate with erytrhocytes from unrelated species (eg, horse erythrocytes in the Monospot test, sheep
erythrocytes in the classic Paul-Bunnell test). The agglutination test may be negative at the beginning of the infection
and can be repeated later for confirmation. May present sore throat + lymphadenopathy

EBV reactivation (15068):

- -> primary CNS lymphoma (1260) these tumors arise from B cells and are universally associated with EBV. They
are high-grade tumors with a poor prognosis. Microscopically appear as dense, cellular aggregates of uniform,
atypical lymphoid cells. Commonly positive for the B-cell markers CD20 and CD79a.
- (2083) primary central nervous system lymphoma is the second most common cause of ring-enhancing lesions
with mass effect in HIV. Classically, large, solitary lesions are more likely to suggest PCNSL rather than toxo;
however, multiple lesions are also common in PCNSCL
PCNSL is a diffuse, large-cell non-Hodgkin lymphoma of B-cell origin that usually occurs as a late complication of
HIV infection. EBV is IDed in almost all cases.
- Focal neurologic symptoms and altered mental state
- MRI: single enhancing lesion with mass effect
 - (1630) EBV is the etiologic agent most strongly associated with Burkitt lymphoma, with infection being present
in 40% of immunodeficiency-associated Burkitt lymphoma and nearly all cases of endemic Burkitt lymphoma. A
crucial step in the transformation of infected cells is the balanced t(8;14) translocation, which causes
overexpression of c-MYC, a transcriptional regulator that controls cell proliferation. Chronic EBV infection
increases B-cell proliferation and is thought to increase the risk of c-MYC translocation. Pre-existing
immunodeficiency secondary to HIV infection can potentiate EBV antigen-induced B-cell proliferation. The
histology described is classic of Burkitt lymphoma: diffuse medium-sized lymphocytes and a high proliferation
index represented by the high Ki-67 fraction (approaching 100%). The classic “starry-sky” appearance is usually
seen, and is due to the presence of benign macrophages.

Herpes simplex virus encephalitis:

- Causes focal neurologic deficits and altered mental status

- Symptom onset is usually rapid (<1week)
- Brain imaging: enhancing temporal lobe lesion w/ mass effect

Tx

(11729) the tx for HSV encephalitis is IV acyclovir, a nucleoside analog that, once activated, competes with
deoxyguanosine triphosphate for viral DNA polymerase; when acyclovir triphosphate becomes incorporated into the
replicating viral DNA chain, viral DNA synthesis is terminated.

(1642) IV acyclovir can cause crystalline nephropathy if adequate hydration is not also provided

Toxo

- Reactivation -> meningoencephalitis (eg, headache, confusion, fever)

- Brain imaging: several ring-enhancing lesions w/ surrounding edema

Toxoplasmosis encephalitis (14905)

Setting - Exposure to cat feces with subsequent inguestion
of Toxo
- Reactivation in setting of immunosuppression
- Primarily AIDS with CD4 count <100/mm3
Clinical - Headache
- Confusion
- Fever
- Focal neurologic deficits/seizures
Dx - Positive Toxoplasma gondii IgG
- Multiple ring-enhancing brain lesions
Therapeutic - Sulfadiazine & pyrimethamine (leucovorin)
- Antiretroviral initiation
- Prophylaxis: tmp-smx (CD4 count <100/mm3)

(1722) HIV pol gene mutations are responsible for acquired resistance to reverse transcriptase inhibitors, protease inh,
and integrase strand transfer inhibitors. Mutations of the env gene enable escape from host-neutralizing antibodies.

Measles -> subacute, sclerosing panencephalitis

- Fatal, progressive disease characterized by slowly worsening neurologic symptoms

- Multifocal enhancing, white matter lesions
Norovirus (1498)

*linear, nonenveloped, single-stranded RNA genome, resistant to inactivation by acid, bile, and pancreatic enzymes

Parvovirus (1495)

Erythema infectiosum (5th disease) is caused by parvovirus B19 and presents with a nonspecific prodrome (eg, malaise,
fever, congestion) followed by a classic “slapped cheek” facial rash and a lacy, reticular body rash. Parvovirus highly
tropic for erythroid precursor cells and replicates predominantly in the bone marrow

(1374)

Is a nonenveloped single-stranded (ss) DNA virus with an increased incidence in children and teachers, as most
individuals are infected during school outbreaks. Infection in adults can present with an acute, symmetric
arthralgia/arthritis involving hands, wrists, knees and/or feet, with or without rash.

Fetal infection with parvovirus can lead to interruption of erythropoiesis, causing profound anemia and CHF. Fetal
congestive heart failures can cause pleural effusions, pericardial effusions and ascites. The findings on fetal autopsy
(pleural effusion with secondary pulmonary hypoplasia and ascites) represent fetal hydrops.

Influenza (1377)

Is an enveloped orthomyxovirus with a segmented, negative-sense, single-stranded RNA genome. Alcohol-based

disinfectants, which are composed of ethyl or isopropyl alcohol (at concentrations of 60-90%) in water, are often used
for hand hygiene. These solutions kill vegetative bacteria (but not spores), fungus and enveloped viruses (eg, influenza,
HIV, herpes) by dissolving their lipid bilayer membranes and subsequently denaturing their proteins. Nonenveloped
viruses such as adenovirus, rhinovirus, enterovirus and poliovirus are less susceptible to some alcohol-based
desinfectants due to not having lipid bilayer envelope.

(12708)

Influenza epidemics and pandemics are typically caused by reassortment of the RNA segments coding for hemagglutinin
or neuraminidase proteins (major antigenic shifts). This process can occur between human and animal strains of
influenza A virus in avian or swine hosts.

Vs antigenic drift: refers to point mutations in HA and NA genes that slightly alter the product proteins, allowing them to
evade immune recognition and possibly increasing infectivity of the virus.

Tx: olsetamivir (6456)

Is a sialic acid analogue that inh the neuraminidases of the influenza viruses. Newly formed virus particles initially remain
attached to cells and respiratory tract mucins through hemagglutinin binding of glycoconjugate receptors.
Neuraminidase cleaves the terminal sialic acid residues on these receptors, allowing for the release of attached virions
from infected cells and subsequent viral spread. Neuraminidase inh force the newly synthesized virions to remain
adherent to the host cell surface, ultimately forming viral aggregates that are unable to infect new host cells. Through
this mechanism of action, oseltamivir can shorten the course of influenza A and B infections when taken within 48 hrs of
symptom onset.

(1648) oseltamivir is a neuraminidase inh useful in the tx and prevention of both influenza A and B virus infections. This
medication impairs the release of newly formed virions from infected host cells and impairs viral penetration of mucous
secretions that overlie the respiratory epithelium

VZV (1552)

Primary varicella-zoster virus infection (chickenpox) occurs most commonly in childhood. Subsequently, the virus
migrates to the sensory ganglia, where it lies dormant for decades. Over time, waning cell-mediated immunity allows
reactivation of the virus, which spreads down a single nerve to cause a painful, erythematous, vesicular rash in a
dermatomal distribution

AIDS

(15107)

HIV binds to host cells using the host CD4 receptor and a chemokine coreceptor (either CCR5 or CXCR4). The virus
preferentially targets T lymphocytes, dendritic cells, and macrophages because these cells contain high surface
ocncentrations of CD4. Thowever, each of these cell types contains different surface concentrations of the 2 chemokine
receptors. HIV is considered tropic for a certain cell type, depending on whether it preferentially binds to CCR5 or CXCR4
for viral entry, as follows:

- R5 virus uses CCR5 for viral entry and is considered macrophage-tropic because CCR5 is expressed in high
concentrations on both macropahges and lymphocytes. R5 is the predominant HIV type
- X4 virus uses CXCR4 for viral entry and is considered T ymphotropic because CXCR4 is expressed primarily on T
lymphocytes but only minimally on macrophages.

HIV trophism is determined by a gene sequence in the variable (V3) region of the env gene, which encodes for the HIV
surface glycoprotein 120. This glycoprotein mediates viral attachment to the CD4 receptor and chemokine coreceptor.

The laboratory results in this case indicate an X4 virus (T lymphotropic with minimal macrophage invasion). Px with X4
virus cannot be treated with HIV medications that target CCR5 (eg, maraviroc) because the X4 virus uses CXCR4, not
CCR5, to enter cells.

HIV-2 (15125)

Is endemic to West Africa (eg, Senegal)

Px infected with HIV 2 have much lower levels of viremia than those infected with HIV-1. Because viremia is directly
correlated with transmission risk, rate of CD4 count decline and progression to AIDS, individuals with HIV-2 are usually
less infectious and have longer asymptomatic periods than px with HIV-1. The dx of HIV-2 is often suspected when HIV
test results are incongruent; most px will have the following lab results
 - + fourth generation HIV testing (HIV antigen/antibody test)- this test evaluates for the presence of p24 antigen
and HIV-1 and HIV-2 antibodies but does not usually differentiate between HIV-1 and HIV-2
- Indeterminate or negative HIV-1 confirmatory testing – HIV-1 western blot evaluates for proteins in HIV-1 and is
usually indeterminate in the setting of HIV-2 infection. Plasma HIV-1 RNA testing will be negative.

Confirmation of HIV-2 infection can be made using an HIV-1/HIV-2 differentiation immunoassay. Tx with antiretroviral
therapy is required to prevent HIV-2 disease progression. However, nonnucloside reverse transcriptase inh and fusion
inh must be avoided because HIV-2 is intrinsically resistant to these HIV medications.

HIV regulatory & accessory proteins

Tat Promotes transcription of viral genes
Rev Enhances export of unspliced viral transcript from nucleus to cytoplasm
Nef Downregulates host CD4 & MHC I proteins (inhibits immune recognition)
Vpu Aids viral assembly & release
Vpr Facilitates nuclear entry & inh host cell division
Vif Increases infectivity & viral yield

Common opportunistic causes of diarrhea in HIV px (7228)

Pathogen Histopathologic findings
CMV - Multiple ulcers & mucosal erosions
- Large cells with basophilic intranuclear & intracytoplasmic inclusions
Cryptosporidium - Nonulcerative inflammation
- Basophilic clusters seen on the surface of intestinal mucosal cells
Microsporidium - Distortion of villus architecture without inflammation
- Small spores with a diagonal or equatorial belt-like structure
Mycobacterium avium complex - Necrotizing & non-necrotizing granulomas
- Acid-fast staining bacilli are present.

CMV colitis is the second most common reactivation syndrome after CMV retinitis. Px with CMV colitis have fever,
anorexia, weight loss, and abd pain. The pain may be vague initially but becomes more localized as the disease
progresses. Colonoscopy shows mucosal erythema, erosions and ulcerations. Histologic examination of biopsy
specimens will reveal acute and crhonic inflammatory changes, vasculitis and giant cells with large, ovoid nuclei
containing centralized intranuclear basophilic inclusions (owl’s eye appearance).

(7642) cryptosporidium is a common cause of self-limited diarrhea in immunocompetent hosts, but may cause life-
threatening diarra in immunocompromized px (eg, advanced AIDs). Dx is usually made when oocysts are visualized with
modified acid-fast stain in stool or biopsy (oocysts lining the brush-border).

HIV associated dementia (11568)

Should be suspected in px with AIDS who have progressive cognitive decline. The characteristic histopathologic finding is
microglial nodules (groups of activated microglia/macrophages around small areas of necrosis) and multinucleated giant
cells.

Kaposi (1761)

KS presents as multiple blue-violet or brownish dermal plaques that first appear on the feet and legs before spreading
proximally. KS lesions can also develop on the mucosal membranes of the face and genitals. In px with late-stage
disease, the lesions spread to the lungs and GI tract. Histologic examination of skin afflicted with Kaposi’s sarcoma shows
spindle and endothelial cell proliferation, RBC extravasation, and inflammation

KS is strongly associated with both HIV and the HHV-8; HHV-8 DNA has been isolated in the neoplastic cells of KS. HHV-8
infects vascular and lymphatic endothelial cells, causing their differentiation into a mixed phenotype that is thought to
increase oncogenic potential. The HHV-8 genome also contains several viral oncogenes that inh both cell cycle regulation
and apoptosis, thus promoting tumorigenesis.

Mycoses

Pneumocystis pneumonia (14840)

Pneumocystis pneumonia is common in px with advanced HIV and usually presents with slowly worsening cough and
dyspnea, hypoxia and bilateral interstitial infiltrates. Dx requires visualizing the organism in respiratory secretions using
special stains (eg, silver stain). First-line tx is TMP-SULFA
Blastomycosis (103)

Fungal species Epidemiology Clinical presentation Lab dx

Sporothrix schenckii Associated with gadening; Pustules, ulcers, and Culture (25C): branching
often transmitted via a subcutaneous nodules hyphae
thorn prick along the lymphatics Biopsy: round or cigar-
shaped budding yeasts
Coccidioides immitis Southwestern states (desert Pulmonary form: flu-like Culture (25C): forms
areas). Mold form is present illness, cough, erythema hyphae.
in soil nodosum. Disseminated Biopsy: at 37 forms thick
form: affects skin, bones walled spherules filled with
and lungs endospores
Histoplasma capsulatum Ohio and Mississippi River Pulmonary: similar to tb Culture (25C): branching
valleys. Soil, bird and bat (lung granulomas with hyphae.
droppings (chicken coops, calcifications). Biopsy: oval yeast cells
caves). Disseminated: lungs, within macrophages.
spleen, liver
Blastomyces dermatitis Ohio and Mississipi River Pulmonary pneumonia: Culture (25C): branching
valleys, Great Lakes region. Disseminated form is hyphae.
Found in Soil common and severe Biopsy: large, round yeasts
with doubly refractile wall
and single broad-based bud.
Paracoccidioides brasiliensis Central and South America Mucocutaneous: chronic Culture (25C): multiple
mucocutaneous or blastoconidia.
cutaneous ulcers, can Biopsy: cells covered in
progress to lymph nodes budding blastoconidia.
and lungs

Coccidioidomycosis (269)

Is a dimorphic fungus endemic to the southwestern US. It exists in the environment as a mold (with hyphae) that forms
spores. These spores are inhaled and turn into spherules in the lungs.

Histoplasmosis (267)

Dimorphic fungus, in light microscopy reveals several small, ovoid bodies within a macrophage

Impaired immunity are at risk for dissemination through the reticuloendothelial system due to the organism’s affinity for
mononuclear phagocytic cells. Common manifestations include hepatosplenomegaly, lymphadenopathy and
pancytopenia. Ulcerated lesions on the tongue are very characteristic of disseminated histoplasmosis

Dx: histopathology shows oval or round yeasts within macrophages; culture on Sabouraud agar grows hyphae
(Histoplasma is a mold at cooler temperatures); histoplasma antigen in blod and urine

(15061) macrophages cannot initially eliminate the organism due to microbial virulence factors that prevent
phagolysosome formation and acidification. Therefore, H capsulatum is able to replicate within the macrophage and
spread through the draining lymphatic system and (often) into the reticuloendothelial system (eg, spleen, liver). Most
healthy individuals quickly contain the infection within granulomas and do not become ill; a minority develop self-
limited pneumonia. Over time, the granulomas at the initial sites of infection calcify and may be seen incidentally on
radiographic imaging.
Cryptococcal infections

(114) meningoencephalitis is the most common presentation of Cryptococcus infection. It occurs in immunosuppressed
px and can be dx by India ink staining of the cerebrospinal fluid. Cryptococcal pneumonia is dx by mucicarmine staining
of lung tissue and bronchoalveolar washings

(117)

Cryptococcus neoformans is the only pathogenic fungus that has a polysaccharide capsule. The capsule appears red on
mucicarmine stain and as a clear unstained zone with india ink.

Candida vs C. neoformans (109)

Cryptococcus is an oval budding yeast with a thick capsule that can mimic the appearance of Candida species, although
Cryptococcus typically does not form hyphae or pseudohyphae. India ink stain of the CSF reveals a wide clear zone
around the nucleus (corresponds to unstained capsule).

(11633) the presence of a central vascular catheter and receipt of parenteral nutrition are risk factors for candidemia.
Candida play a morphology of branching pseudohyphae with blastoconidia.

(112)

Host defense of Candida:

1. T lymphocytes (in particular Th cells) are important for prevention of superficial Candida infection (Eg,
oral/esophageal candidiasis, cutaneous candidiasis, candida vulvovagitinis). Conditions such as HIV (low T-cell
count) increase the risk fo superficial candidiasis
2. Neutrophils prevent the hematogenous spread of Candida. Disseminated candidiasis (eg, candidemia,
endocarditis) is more likely in px who are neutropenic or otherwise immunocompromised (eg, cancer with
chemotherapy) and in those with inherited impairments of phagocytosis.

Coccidioides immitis (

Is a dimorphic fungus that grows as a mold in the environment but converts to spherule form within host organisms. It is
classically contracted by people in the San Joaquin Valley in California (“Valley Fever”), but it is also endemic in southern
Arizona, New Mexico, and Texas, as well as parts of Mexico and South America. Infection occurs when a host inhales
arthroconidia from the soil. Once within the host, the arthroconidia convert to multinucleate spherules (sporangia),
which produce numerous endospores capable of forming new spherules. Coccidioidomycosis most commonly causes
asymptomatic infection or mild pneumonia with pleural effusion. A rash and symmetric arthralgias can develop. Rarely,
C immitis infection can cause formation of a thin-walled cavity in the lung; in such a case, the px may have hemoptysis in
addition to fever and cough.

HIV-associated esophagitis (283)

Pathogen Endoscopic findings Microscopic findings
Candida albicans Patches of adherent, grey/white Yeast cells & pseudohyphae invading
pseudomembranes on erythematous mucosal cells
mucosa
HSV-1 Small vesicles -> “punched-out” ulcers Eosinophilic intranuclear inclusions
(cowdry type A) in multinuclear
squamous cells at ulcer margins
CMV Linear ulcerations Intranuclear & cytoplasmic inclusions

Mucormycosis (107)

The increased incidence of mucormycosis in diabetics could be due to the ketone reductase activity of Rhizopus
(allowing it to survive in an acidotic, hyperglycemic environment) and possibley to the release of iron from binding
proteins during ketoacidosis.

Histologic: appears as broad ribbon-like nonseptate hyphae with right-angle branching

VS. aspergillosis causing rhinosinusitis (commonly seen in neutropenic px. On light microscopy, Aspergillus is seen as
septate narrow hyphae with sharp-angle branching.

Pharmacology

Common antibiotic resistance mechanisms

Penicillins - Beta-lactamase, ESBL
- Mutated PBP
- Mutated porin protein
Vancomycin - Mutated peptidoglycan cell wall
- Impaired influx/increased efflux
Quinolones - Mutated DNA gyrase
- Impaired influx/increased efflux
Aminoglycosides - Aminoglycoside-modifying enzymes
- Mutated ribosomal subunit protein
- Mutated porin protein
Tetracyclines - Impaired influx/increased efflux
- Inactivated enzyme
Rifamycins - Mutated RNA polymerase

(1000) Aminoglycoside (eg, gentamicin) resistance is most commonly due to antibiotic-modifying enzymes. These
enzymes add chemical groups to the antibiotic, which diminishes its ability to bind to the 16S ribosomal RNA within the
30s ribosomal subunit.

(1310) streptomycin works by interfering with the 16s rRNA of the bacterial 30S ribosomal subunit, thereby preventing
bacterial protein synthesis. Mutations of the genes that encode ribosomal proteins are responsible for aminoglycoside
resistance because they lead to modifications in the ribosomal binding sites for these drugs. Other resistance
mechanisms to aminoglycosides include aminoglycoside-modifying enzymes (eg, transferases) and mutated porins.

(11709) other mechanism of resistance towards aminoglycosides is the methylation of the aminoglycoside-binding
portin of the ribosome, which inh the ability of aminoglycoside to interfere with protein translation

(277) echinocandins (eg, caspofungin, micafungin) are antifungal medications that inh synthesis of the polysaccharide
glucan, an assential component of the fungal cell wall

(6526) Efflux pumps are transport proteins that excrete toxic substances (eg, antibiotics) from the cytoplasm/periplasm
of bacteria into the external environment. They are common cause of drug (or multidrug) resistance. Efflux pumps are
energy dependent and operate using ATP, sodium gradients, or proton electrochemical gradients.

Antifungals resistance (271)

Main classes:

- Polyenes (eg, amphotericin B, nystatin): bind to ergosterol molecules in fungal cell membranes, creating pores
and causing cell lysis
Forming pores in the membrane and allowing leakage of ions (especially K+) from the cells
An organism that decreases the amount of ergosterol in its cell membrane would likely become resistant to
polyenes
- Triazoles (eg, ketoconazole, fluconazole, itraconazle, voriconazole): inh the synthesis of ergosterol
- Echinocandins (eg, caspofungin, micafungin): inh the synthesis of glucan, a component of the fungal cell wall
- Pyrimidines: flucytosine, the only agent in this class of antifungals, is converted to 5-fluorouracil within the
fungal cell and interferes with fungal RNA and protein synthesis.

Cephalosporin-resistant organisms (1393)

*coverage for Listeria: ampicillin (beta lactam antibiotic with a specialized side-group that allows it to bind to and
inactivate the penicillin binding proteins of Listeria

Antibiotics for methicillin-resistant s. aureus (8288)

Drugs for tx of TB (1228)

Drug Mechanism of action Side effects
(R)ifampin Inh of bacterial DNA-dependent RNA GI side effects, rash, red-orange body
polymerase fluids, cytopenias
(I)soniazid Inh of mycolic acid synthesis Neurotoxicity (give vitamin
B6/pyridoxine), hepatotoxicity
(P)yrazinamide Unclear Hepatotoxicity, hyperuricemia
(E)thambutol Inh of arabinosyl transferase (?) Optic neuropathy

(1223) The mechanism of action of isoniazid (INH) is the inh of mycolic acid synthesis by M. tb. INH accomplishes this
through an incompletely understood method. However, it is known that INH must be processed by mycobacterial
catalase peroxidase for the drug to be activated within the bacteria, and that INH requires a specific protein sequence in
its enzyme target (necessary for mycolic acid synthesis). For this reason, mycobacterial resistance to INH could be
accomplished through non-expression of the catalase-peroxidase enzyme or through genetic modification of the INH
binding site on the mycolic acid synthesis enzyme.

(11816) Isoniazid inh pyridoxine phosphokinase, leading to pyridoxine B6 def. Pyridoxine’s active form is the cofactor for
gamma-aminolevulinate synthase, the enzyme that catalyzes the rate-limiting step of heme synthesis. Inh of this step
can result in sideroblastic anemia.

(1225) resistance to isoniazid

- Decrease in bacterial expression of the catalase-peroxidase enzyme that is required for isoniazid activation once
the drug enters the bacterial cell
- Modification of the protein target binding site for isoniazid
- Isoniazid monotherapy may be used for px who have positive PPD and a negative chest x-ray

(1308)

Isoniazid is chemically similar to pyridoxine (vit B6). Because of this similarity, isoniazid can compete with vit B6 in the
synthesis of multiple neurotransmitters (including GABA), resulting in defective end products. Isoniazid also
increases the urinary excretion of pyridoxine, and a frank deficiency of this vitamin can eventually develop.
Usually clinically manifests as peripheral neuropathy.

(1226) Rifamycins block the action of the bacterial DNA-dependent RNA polymerase, thereby inh transcription.
Resistance is acquired by modification of the rifampin binding site on the bacterial DNA-dependent RNA polymerase.
Common side effects include hepatotoxicity, blood dyscrasias, and harmless red-orange discoloration of body fluids.

Clavulanic acid (1959)

Clavulanic acid, sulbactam and tazobactam are beta-lactamase inh. Concurrent admn of clavulanate with amoxicillin
expands amoxicillin’s spectrum of activity to include strains of beta-lactamase synthesizing bacteria that are resistant to
amoxicillin alone.

(11626)

Extended-spectrum beta-lactamases can be produced by gram-negative bacteria, rendering cephalosporins and other
beta-lactam antibiotics inactive. These genes can be transmitted between organisms through plasmid conjugation.

Tx of choice: carbapenems

Amphotericin B (273)
It binds cholesterol in human cell membranes to a degree, which explains the following adverse effects

- Acute infusion-related reactions, such as fever, chills, rigors, and hypotension, can occur. These are common and
are seen most frequently during initial infusions (often diminish with subsequent infusions). Premedication with
antipyretics and antihistamines can lessen the severity of these effects.
- Dose dependent nephrotoxicity can result from a drug-induced decrease in the glomerular filtration rate.
Permanent loss of renal fx is thought to be related to the cumulative total dose. Renal fx (eg, creatinine) should
be closely monitored in px undergoing tx with amphotericin. Concomitant admn of other nephrotoxic drugs (eg,
amino, cyclosporine) should be avoided
- (274) Significant electrolyte abnormalities (hypomagnesemia and hypokalemia) can develop. These effects occur
in the majority of x within the first week of therapy. Electrolytes should be monitored daily and replaced as
needed
- Anemia occurs due to suppression of renal erythropoietin synthesis. This effect may be severe in px with HIV
who are taking zidovudine (which also suppresses bone marrow fx)
- Thrombophlebitis can be seen at the site of injection
- Px who respond to initial amphotericin therapy may be switched to posaconazole

Cephalosporins (2110)

Penicillins and cephalosporins function by irreversibly binding to penicillin-binding proteins. Transpeptidases are one
form of penicillin-binding protein that functions to cross-link peptidoglycan in the bacterial cell wall. Inh of
transpeptidase (which occurs with the use of the cephalosporin ceftriaxone) leads to cell wall instability and
bacteriolysis. Many bacterial species synthesize multiple different penicillin-binding proteins; the lab study described in
this question stem identifies 5 such proteins that are produced by this isolate of S. pneumoniae

Mechanism of action of HIV antiretroviral medication(819)

HIV antiviral drugs (1674)

NNRTIs adverse effects:

- Abrupt-onset flulike symptoms

- Abd pain
- Jaundice
- Fever
- Life-threatening hepatic failure (most like to occur within the first 6 weeks)
- Life-threatening skin reactions (eg, Steven-Johnson syndrome, toxic epidermal necrolysis)

Antiretroviral therapy (1675)

Env gene encodes the polyprotein gp160, which is glycosylated in the ER and golgi body and subsequently cleaved into
the mature envelope proteins gp120 and gp41. These envelope proteins remain associated by noncovalent attachments
and form the glycoprotein spikes that pepper the surface of the HIV virus

Gp120 forms the outside surface of the glycoprotein spike and mediates viral attachment to the host cell by binding with
the CD4 receptor and a chemokine coreceptor (CXCR4, CCR5). Binding of gp120 to these host receptors induces a
conformational change in the structure of the glycoprotein spike that exposes the underlying transmembrane
glycoprotein gp41.

Gp41 mediates fusion of the viral cell membrane with the host cell membrane, thereby allowing the viral core to enter
the cell.
Fusion inh (eg, enfuvirtide) bind the HIV transmembrane glycoprotein gp41 and prevent it from approximating the viral
and host cellular membranes, which prevents HIV penetration into new host cells.

(953) The chemokine receptor CCR5 is a coreceptor that enables the HIV virus to enter cells. Blockade of CCR5 by
chemokine receptor antagonists prevents viral entry into host cells.

Ex of chemokine receptor antagonists: maraviroc

Fusion inh: enfuvirtide

(7229)

The HIV genome contains 3 major genes (env, gag and pol) that are transcribed as polycistronic mRNA and translated
into polyproteins in the ER. The gag and pol polyprotein products (gag-pol) are cleaved by HIV protease into individual
HIV enzymes and structural proteins.

Protein inhibitors inh HIV protease from cleaving the gag-pol polyproteins, which results in the formation of immature,
noninfectious virions. They’re common first like HIV antiretroviral therapy and ends in “navir” (eg, darunavir, atazanavir,
ritonavir)

Vs. Reverse transcriptase

The pol gene encodes the major HIV enzymes: reverse transcriptase (RT), integrase and protease. RT converts the HIV
RNA genome into complementary double-stranded DNA; it also destroys the HIV RNA genomic template during
transcription (ribunuclease H activity). RT is inhibited by nucleoside/nonnucleoside reverse transcriptase inhibitors.
Integrase inserts complementary viral DNA into the host chromosome. Integrase strand transfer inh block the fx of this
enzyme. Both RT and integrase inh block viral replication, but neither are associated with immature virions containing
polyproteins.

Abacavir hypersensitivity reaction (11590)

Is an allergic reaction that develops in 2%-8% of px and is strongly associated with the HLA-B*57:01 allele of the human
leukocyte antigen (HLA) system. AHR occurs due to direct binding of abacavir to a segment on the HLA-B*57:01
molecule, which alters the presentation of self-peptides to the immune system and results in a delayed hypersensitivity
reaction (type IV). A negative test for the HLA-B*57:01 allele has almost a 100% negative predictive value for AHR.

Tenofovir induced nephrotoxicity (15113)

Tenofovir is an adenosine analogue that is a member of the nucleotide reverse transcriptase inhibitors (NRTIs). NRTIs
prevent reverse transcriptase from converting the HIV RNA genome into complementary double-stranded DNA, which
inh viral replication.

Tenofovir is primarily eliminated via the proximal tubule cells of the kidney. High concentrations of tenofovir in these
cells can interfere with mitochondrial DNA synthesis and result in cellular dmg. This typically manifests with acute kidney
injury (eg, elevated creatinine, water retention) and/or signs of proximal tubule dysfunction (eg, phosphaturia,
glucosuria, proteinuria). Histopathology may show dmg to the proximal tubule cells (eg, loss of brush border, basement
membrane denudation) and evidence of giant mitochondria (eg, large eosinophilic inclusions). Renal abnormalities
typically improve once tenofovir is discontinued.

VS TMX-SULFA induced toxicity, it can cause interstitial nephritis and acute kidney injury but does not usually cause focal
dmg to the proximal tubule.
HAART (1673)

Causes medication induced body fat redistribution (sometimes called lipoatrophy or lipodystrophy) is a common adverse
effect of highly-active antiretroviral therapy and can be considered a product of 2 independent processes: wasting of fat
from the face and extremities and deposition of fat in the trunk and viscera.

1. Lipoatrophy refers to loss of subcutaneous fat, especially from the face, extremities, and buttocks. It is primarily
seen in px taking nucleoside reverse transcriptase inh (mainly stavudine and zidovudine) and is also associated
with protease inh use.
2. Central fat deposition also occurs in some px and causes increased abdominal girth and a buffalo hump
(dorsocervical fat accumulation) that is similar to cushing syndrome. Central fat deposition may be seen with any
HIV treatment regimen and may be a result of tx HIV rather than a specific medication adverse effect.

Both syndromes have been associated with metabolic abnormalities including insulin resistance, hypertriglyceridemia,
and reduced HDL cholesterol levels.

Patho

Reperfusion injury (293)

Mechanisms:

1. Oxygen free radical generation by parenchymal cells, endothelial cells and leukocytes
2. Severe, irreversible mitochondrial dmg described as “mitochondrial permeability transition”
3. Inflammation, which attracts circulating neutrophils that cause additional injury
4. Activation of the complement pathway, causing cell injury and further inflammation

*when the cells within heart, brain or skeletal muscle are injured, the enzyme creatine kinase leaks across the dmged
cell membrane and into circulation

Cell adhesion molecules (6502)

Cadherins are calcium-dependent adhesion molecules that bind epithelial cells together within tissues. Cadherin
molecules on epithelial cells bind to cadherin molecules on adjacent cells to form adherens junctions and desmosomes.

Vs: fibronctin and laminins are extracellular matrix glycoproteins that bind cell surface integrins, facilitating cell binding
to the extracellular matrix

Vs: hemidesmosomes: cell adhesion to the basement membrane. These structures rely on integrins, which are not
calcium-dependent, rather than cadherins.

(176) the appearance of vacuoles and phospholipid-containing amourphous densities within mitochondria generally
signifies irreversible injury and imples a permanent inability to generate further ATP via oxidative phosphorylation.
When the mitochondria are injured irreversibly, the cell cannot recover. Simple mitochondrial swelling may be
associated with reversible cellular injury, however.

Inflammation (8480)

Steps of inflammatory leukocyte accumulation:

1. Margination: increased vascular leakage in the microvasculature leads to hemoconcentration and decreased
wall shear stress, improving the contact of neutrophils with the endothelial lining.
 2. Rolling: neutrophils roll on the endothelium via the loose binding of sialylated carbohydrate groups such as Sialyl
Lews X or PSGL-1, to L-selectin on neutrophils or E-selectin/P-selectin on endothelial cells. Cytokine stimulation
greatly increases expression of endothelial selectins.
3. Activation: slow rolling allows the leukocytes to sample the chemokines secreted by the inflamed tissue. This
activates integrins by inducing a signaling cascade that results in a conformational change in the integrins
necessary for binding
4. Tight adhesion and crawling: neutrophils become firmly attached to the endothelium via the binding of CD 18
beta 2 integrins (Mac-1 and LFA-1) to intercellular adhesion molecule-1 (ICAM-1) on endothelial cells
5. Transmigration: after crawling to the endothelial cell periphery, neutrophils eventually migrate out of the
vasculature by squeezing in between the cells via integrin attachments and adherence to platelet endothelial
cell adhesion molecule 1 (PECAM-1). This protein is found primarily at the peripheral intercellular junctions of
endothelial cells.

Leukocyte Adhesion Deficiency (LAD) syndromes: (AR)

- Type 1: results from the absence of CD18 -> inability to synthesize the beta-2 integrins Mac-1 and LFA1, affecting
tight adhesion, crawling and transmigration. Clinical manifestation: recurrent skin infections without pus
formation, delayed detachment of the umbilical cord, and poor wound healing
- Type 2: milder condition, with no delay in the separation of the umbilical cord and less severe and fewer
infections
- Type 3: is similar to type 1 and causes severe, recurrent bacterial infections, delayed separation of the umbilical
cord, and bleeding complications (due to affected beta-3 integrins on platelets)

(538) LAD is an AR disorder characterized by absence of CD18 antigens, which are necessary for the formation of
integrins. Integrins are essential for leukocyte adhesion to endothelial surfaces and migration to peripheral tissues in
response to infection or inflammation.

Necrosis (177)

Patterns of tissue necrosis

Type Etiology Morphology
Liquefactive necrosis - Severe bacterial infections - Necrotic tissue is digested by
(eg, gangrene) hydrolytic enzymes into a
- CNS infracts viscous fluid:
Infected abscess fluid is
creamy yellow due to dead
leukocytes (pus)
Brain infarcts resolve into CSF-
filled spaces
Fibrinoid necrosis - HTA - Dmged vessels leak
- Vasculitis fibrin/immune complexes
- Eosinophilic layer of
proteinaceous material in
vessel walls
Fat necrosis - Acute pancreatitis - Free FA released by active
- Trauma (subcutaneous enzymes (eg, lipases) or
adipose tissue) mechanical dmg
- FA combine with Ca, forming
chalky-white deposits
(saponification)
Caseous necrosis - Mycobacterial infections - Friable, cheeselike material
- Fungal infections (eg, composed of cell fragments &
histoplasma, cryptococcus, amorphous proteinaceous
coccidioides) debris
- Surrounded by epithelioid
macrophages & giant cells
(granuloma)
Coagtulative necrosis - Irreversible ischemic injury - Tissue architecture is
outside CNS preserved due to
denaturation oflytic enzymes:
Cells are anucleate with
eosinophilic cytoplasm
Leukocytes eventually
infiltrate & digest necrotic
tissue

Anaplasia (1759)

Undifferentiated (anaplastic) tumors bear no resemblance to the tissue of origin. They are composed of pleomorphic
cells with large, hyperchromatic nuclei that grow in a disorganized fashion. Anaplastic tumors may also contain
numerous, abnormal mitoses and giant tumor cells.

Cell junctions (11888)

Both adherens junctions and desmosomes are composed of cadherins and are involved in intercellular adhesion. The
cytoplasmic anchor of adherens junctions is the actin filament, whereas the cytoplasmic anchor of desmosomes is the
intermediate filament. Autoantibodies against desmoglein, a cadherin protein for desmosomes, are found in pemphigus
vulgaris

Swollen fenestrae in renal glomerular capillary endothelial cells are implicated in preeclampsia (presents with new-onset
HTA and proteinuria or end-organ dysfunction at >20w of gestation

Hemidesmosomes link cells to the basement membrane via integrins, the transmembrane anchor proteins.
Autoantibodies to these proteins cause bullous pemphigoid and pemphigoid gestationis.
Tight junctions are comprised of claudins and occluding and serve as paracellular barriers to water and solutes. The
enterotoxin from C. perfringens, a common cause of food poisoning, binds claudin and interferes with tight junctions in
the intestinal barrier. Water loss from the tissue to the intestinal lumen results in watery diarrhea.

Normal wound healing (874)

(1874) secreted by several different cell types (eg, fibroblasts, macrophages, neutrophils, synovial cells, some epithelial
cells), matrix metalloproteinases (MMPs) primarily function in the degradation of collagen and other proteins in the
extracellular matrix. MMP activity is important in would healing, as it encourages both myofibroblast accumulation at
the wound edges and scar tissue remodeling. The amassed myofibroblasts initiate wound contraction during healing by
second intention. Contractures may occur when unusually pronounced MMP activity results in excessive wound
contraction.

Inflammation (1800)

Arachidonic acid metabolic pathways

Compartment syndrome (11916)

Acute compartment syndrome secondary to reperfusion injury

Restoration of arterial blood flow to an affected limb floods ischemic tissue with oxygen. Molecular oxygen reacts with
xanthine oxidase, NADPH oxidase and NO synthase to form ROS such as superoxide, hydroxyl radicals and singlet
oxygen. ROS disrupt cellular fx leading to DNA mutations, protein synthesis disruption and membrane lipid peroxidation

Antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase and catalase, convert ROS to oxygen and
water, neutralizing their capacity for cellular dmg. ROS generated during cellular respiration are typically neutralized by
antioxidants before they become problematic. However, in the postischemic state, the production of ROS exceeds the
neutralizing capabilities of antioxidant enzymes (high oxidative stress), leading to increased cell injury and death.

Pharmacology

Pharmacokinetics (1715)

Drugs with high intrinsic hepatic clearance tend to have high lipophilicity and a high volume of distribution. Highly
lipophilic drugs tend to be poorly eliminated in the kidney as these agents rapidly cross tubular cell membranes after
filtration to reenter the tissues

High lipophilicity (lipid solubility) allows the drug to cross cellular barriers more easily and enter hepatocytes. It can then
be excreted in the bile or through other methods of elimination. In addition, high lipid solubility assures a wide
distribution to many different tissues including the brain, liver and adipose tissue.

Volume of Distribution (1710)

Characteristics of a durg such as high molecular weight, high plasma protein binding, high charge, and hydrophilicity
tend to trap the drug in the plasma compartment resulting in a low VD (3-5L)
ANS

(1360) utilizes 3 types of signal pathways: cAMP, IP3, and ion channels. Nicotinic receptors are ligand-gated ion channels
that open after binding ACh. This results in an immediate influx of Na+ and Ca2+ into the cell and an outflux of K+ from
the cell.

(1121)

Janus kinase (JAK) is a component of the second messenger system for various peptide hormones (eg, GH, prolactin) and
cytokines (Eg, interferon, interleukin). JAK has tyrosine kinase activity; however, it is a cytoplasmic enzyme that is not
part of a cell surface receptor (non-receptor tyrosine kinase).

Lipoxigenase is an enzyme involved in arachidonic acid metabolism and is responsible for the arm of that pathway that
synthesizes leukotrienes

Phospholipase C is activated in the G-protein/inositol triphosphate (IP3)/calcium second messenger system. Hormone-
receptor binding activates a G-protein that in turn activates phospholipase C to degrade phospholipids into IP3 and
diacylglycerol. Both diacylglycerol and the increased intracellular calcium caused by IP3 lead to protein kinase C
activation.

Protein kinase A is the primary intracellular effector enzyme in the G-protein/adenylate cyclase second messenger
system. Glucagon acts through this pathway to stimulate glycogen breakdown. Protein kinase A activates glycogen
phosphorylase via activation of glycogen phosphorylase kinase.

(994)

Glucagon exerts its effects through G protein-coupled receptors using the adenylate cyclase and second messenger
system. G protein is a heterotrimer consisting of alpha, beta and gamma subunits associated with the intracellular
domain of these transmembrane receptors. The alpha subunit of the inactivated G protein is bound to GDP. On receptor
activation, the alpha subunit undergoes a conformational change, which releases GDP and binds GTP. GTP binding
allows the alpha subunit to dissociate from the remainder of the G protein complex.

There are multiple subtypes of alpha G proteins, each with different secondary effects. A specific alpha subunit known as
Gs (present in glucagon, TSH, and PTH receptor complexes) activates adenylate cyclase when released from the G
protein complex. Adenylate cyclase converts ATP to cAMP, which activates protein kinase A. Protein kinase A
phosphorylates specific serine/threonine residues in various enzymes, leading to their activation or deactivation. Protein
kinase A also phosphorylates proteins that bind to the regulatory regions of genes on DNA.

Adrenergic drugs (1836)

Isopoproterenol (1836)

A non selective beta adrenergic agonist. Isoproterenol increases cardiac contractility (positive inotropic effect) by acting
on myocardial beta-1 adrenergic receptors. It also binds to beta 2 adrenergic receptors and causes vasodilation by
relaxation of vascular smooth muscle, leading to decreased vascular resistance and mean arterial blood pressure.
Isoproterenol has negligible effects on alpha-1 adrenergic receptors.

Vs clonidine

Stimulates alpha 2 adrenoreceptors in the brainstem, resulting in reduced sympathetic outflow from the central nervous
system, leading to a decrease in peripheral vascular resistance, HR, and BP

Vs esmolol

Selective Beta-1 adrenergic blocking agent with negative inotropic and chronotropic effects (it would cause a decrease in
cardiac contractility)

Vs. NE that acts on alpha 1 receptors, causing vasoconstriction and an increase in systemic vascular resistance. NE also
acts as a weak agonist at beta-1 receptors, with a modest increase in myocardial contractility
Vs phenylephrine is a sympathomimetic drug with pure alpha adrenergic agonist activity. Infusion of this drug causes
vasoconstriction with an increase in systemic vascular resistance.

Second messengers (995)

G protein-coupled receptors have a characteristic structure with 7 transmembrane regions, an extracellular domain, and
an intracellular domain coupled with a G protein. In their inactivated state, G proteins exist as heterotrimers consisting
of alpha, beta, and gamma subunits with GDP tightly bound to the alpha subunit. G proteins are activated after ligand
binding to the extracellular domain of the receptor. The first step in activation occurs when GDP is exchanged for GTP on
the alpha subunit. Once bound to GTP, the alpha subunit dissociates from the beta and gamma subunits and activates
either adenylate cyclase or phospholipase C, depending on the ligand.

When phenylephrine binds to an alpha-1 receptor on vascular smooth muscle cells, the alpha subunit of the G protein
(Gq) activates phospholipase C, which breaks down phosphatidylinositol bisphosphate into inositol triphosphate (IP3)
and diacylglycerl (DAG). DAG stimulates protein kinase C, which phosphorylates downstream intracellular proteins to
produce its physiologic effects (eg, smooth muscle contraction). IP3 produces most of its effects by increasing
intracellular calcium, which also activates protein kinase C. in the study described above, protein kinase C activity would
be reduced in the experimental group compared to the control group as calcium release from the endoplasmic reticulum
is interrupted.

(1164) blanching of vein into which NE is being infused together with induration and pallor of the tissues surroundings
the IV site are signs of NE extravasation and resulting vasoconstriction. Tissue necrosis is best prevented by local
injection of an alpha 1 blocking drug, such as phentolamine.

GH (1720)

Promotes growth by acting on the cell surface receptors that stimulate production of insulin-like growth factor-1 (IGF-1),
primarily in the liver. On GH molecule binds to 2 receptors on the cell surface, leading to activation of the GH receptor.
These phosphorylated tyrosine residues function as docking sites for STAT. Once STAT is recruited to the receptor, it is
also phosphyrlated by JAK. STAT then dimerizes and translocates to the nucleus, where it induces IGF-1 gene
transcription by binding to the promoter region. Other molecules that use the JAK-STAT pathway include cytokines (eg,
interferon) and hematopoietic growth factors (eg, erythropoietin, G-CSF)

Muscarinic receptors (8249)

Blockers of catecholamine neurotransmitter release (2001)

CYP450 inducers/inh (161)

Drug metabolism (1711)

CYP450 are a group of heme-containing proteins that are responsible for the majority of drug metabolism, which occurs
predominately in the liver. Various CYP subtypes exist, with CYP3A, CYP2D, and CYP2C as the most active subtypes
involved in drug metabolism. These enzymes generally function to deactivate drugs and facilitate excretion from the
body by improving water solubility. However, they also metabolize certain compounds to their active fomrs.

Polymorphisms may occur in the genes coding for these enzymes, altering their expression or activity. Three important
phenotypes exist: poor, intermediate, and rapid metabolizer. Identifying these variations on an individual basis provides
a framework for optimizing therapy, predicting tx efficacy, and minimizing toxicity

Tamoxifen, a selective estrogen receptor modulater used in the tx of estrogen receptor-positive breast cancer, is a
prodrug metabolized by CYP2D to its active metabolite, endoxifen. Px with genetic polymorphisms resulting in poor
CYP2D activity are exposed to decreased levels of the active metaboliate and have a higher risk of disease relapse.

Anesthesia

Mnimal alveolar concentration (851) is a measure of potency of an inhaled anesthetic. It is the concentration of the
anesthetic in the alveoli that renders 50% of px unresponsive to painful stimuli (ED50). Potency is inversely proportional
to the MAC: the lower the MAC, the more potent the anesthetic.

Factors influencing anesthetic concentration (660)

Types of adverse drug reactions (11740)
Type Mechanism Examples
Type A Predictable reaction due to known - Gastritis associated with NSAID use
pharmacologic properties of the drug - Nephrotoxicity due to aminoglycosides
Type B Exaggerated sensitivity: predictable - Tinnitus after single aspirin dose
reaction occurring at lower than
expected exposure
Idiosyncratic: unpredictable reaction in - Nonimmune hemolytic anemia with primaquine in G6PD
certain px deficiency
Immunologic (drug allergy): - Rapid urticarial or anaphylaxis (Type I)
unpredictable, specific immunologic - Drug-induced hemolysis (Type II)
reaction - Serum sickness (Type III)
- Contact dermatitis (Type IV)

Public Health Science

Power and sample size

(1204) The power of a study is the ability of a study to detect a difference between groups when such a difference truly
exists. Power is related to type II error (beta), which is the probability of concluding there is no difference between
grousp when truly exists. Mathematically, power is given by:

Power = 1- beta
VS. type I error (alpha) describes the probability of seeing a difference when there is no difference in reality. The value of
alpha is generally compared to the probability that the observed difference is due to chance alone (a simplified
explanation of the p-value).

Correlation coefficient (1210)

Scatter plots are useful for crude data analysis. If a linear association is present between 2 variables, a correlation
coefficient (r) mathematically describes how well a “line of best fit”. The value of r ranges from -1 to +1 and describes 2
important characteristics of an association: the strength and the polarity. The closer the r vlue is to its margins [-1, 1],
the stronger the association

Normal distribution (1172)

A normal (Gaussian) distribution is defined as a symmetrical, bell-shaped distribution curve. One of the most important
attributes of the normal distribution is the “68/95/99” rule, which states that 68% of all observations lie within 1 DS of
the mean, 95% within 2 Sds of the mean, and 99.7% within 3 SDs of the mean. The SD is a measure of dispersion of
variance (how far the measurements are from one another)

Statistical tests (1184)

(8519) A t-test is used to compre the difference between the means of 2 groups. Analysis of variance (ANOVA) compares
the difference between the menas of 2 or more groups. Results from a t-test and ANOVA test will be equivalent when
comparing the difference between the means of 2 groups.

Common measures of therapeutic efficacy (1174)

Term Definition Calculation
Absolute risk reduction Percentage indicating the actual difference in ARR=control rate – treatment rate
event rate between control & tx groups
Relative risk reduction Percentage indicating relative reduction in the tx RRR=ARR/control rate
(RRR) event rate compared to the control group
Relative risk (RR) Ratio of the probability of an event occurring in RR=tx rate/control rate
the tx group compared to the control group
Number needed to tx (NNT) Number of individuals that need to be tx to NNT=1/ARR
prevent a negative outcome in 1 px

Relative risk (1274)

Is used in cohort studies to determine how strongly a risk factor (ie, exposure) is associated with an outcome. RR is the
risk of an outcome (eg, breast cancer) in the exposed group (eg, individuals who consume alcohol daily) divided by the
risk of that outcome in the unexposed group (eg, individuals who do not consume alcohol daily). If the RR = 1.0 (null
value), then there is no association between the exposure and the disease. An RR > 1.0 indicates that the exposure is
associated with increased risk of disease. An RR <1.0 means that the exposure is associated with decreased risk of
disease.

For a result to be considered statistically siginificant, its corresponding CI must NOT contain the null value. When the
95% CI does not include the null value, this gives a corresponding p-value < 0.05 and the association between exposure
and outcome is considered statistically significant. A p-value <0.05 reflects that there is a very low probability that the
result was due to chance alone; formally, the p-value is the probability of observing a given (or more extreme) result due
to chance alone assuming that the null hypothesis is true.

(1171) incident cases represent new cases dx in a given period of time. Prevalent cases are the total number of cases
(both old and new) at a particular point in time. Any tx that prolongs survival but does not cure the disease will increase
prevalence due to an increase in the number of afflicted (but still living) individuals over time.

Risk, rate prevalence and incidence (1187)

Prevalence equals the incidence rate multiplied by the average disease duration. Changing disease prevalence in a
steady-state population with a constant incidence rate means that there is an additional factor affecting the duration of
the condition. A factor that prolongs disease duration (Eg, improved quality of care) will increase disease prevalence, as
affected px survive longer.

Number needed to tx (6589)

Is the number of px who need to be tx with a medication to avoid an additional negative outcome. NNT is the inverse of
absolute risk reduction. Lower NNT values represent more beneficial tx.

(1231) the number needed to harm (NNH) represents the number of people who must be treated before 1 additonal
adverse event occurs. In order to calculate NNH, the absolute risk increase between the tx and control groups must be
known: NNH = 1/Absolute risk increase

Power and sample size (1272)

Statistical power, (1-beta), represents a study’s ability to detect a difference when one exists. It is the probability of
rejecting the null hypothesis when it is truly false 0i, the probability of finding a true relationship. Power depends on
sample size and the difference in outcome between the groups being tested. In this study, the researches want to detect
a difference between drug B and standard of care if one exists; they want to maximize power

Beta is the probability of committing a type II error

Type II error occurs when researchers fail to reject the null hypothesis when it is truly false. This causes investigators to
miss true relationships.

Type I error occurs when researchers reject the null hypothesis when the null hypothesis is really true. That is, a study
finds a statistically significant difference between 2 groups when one does not truly exist.

Accuracy and precision

(1278)

- Precision (reliability) is the ability of a test to reproduce identical or similar results with repeated measurements
(bottom half of figure)
- Accuracy (validity) is the ability of a test to measure what it is supposed to measure. For a new test to be
accurate, its results should be equivalent to the results obtained with a “gold standard” (eg, best convenitional
test available) on the same individual (right half of figure)

(1765)
Hospice care (10290)

- Focuse on quality of life, not cure or life prolongation

- Symptom control (pain, nausea, dyspnea, agitation, anxiety, depression)
- Interdisciplinary team (medical, nursing, psychosocial, spiritual, bereavement care)
- Services provided at home, assisted living facility, or dedicated facility
- Requires survival prognosis of <6 months

Risk (1186)

The attributable risk percent (ARP) in the exposed represents the excess risk in the exposed population that can be
attributed to the risk factor. It can be easily derived from the relative risk (RR) using the formula: ARP exposed =
100*[(RR-1)/RR]

Relative risk reduction (1176)

Effect modification (1279)

Effect modification is present when the effect of the main exposure on the outcome is modified by the presence of
another variable. Effect modification is not a bias.
Effect modification is most easily confused with confounding, but stradified analysis can help distinguish between these
2 scenarios. With effect modification, the different strata will have different measures of association. In contrast, with
confounding, stratification usually reveals no significant difference between the strata.

Bias

Hawthorne effect (1302)

Is the tendency of study subjects to change their behavior as a result of their awareness that they are being studied.

Cofounding (1173)

Occurs when the exposure-disease relationship is muddled by the effect of an extraneous factor associated with both
exposure and disease. Confounding bias can result in the false association of an exposure with a disease

(1189) matching is a method used in case-control studies to control confounding. Matching variables should always be
the potential confounders of the study (eg, age, race). Cases and controls are then selected based on the matching
variables so that both groups have a similar distribution in accordance with the variables.

Observer bias (1275)

Occurs when investigators misclassify data due to preconceived expectations or prior knowledge concerning the study
or its participants

(1301) blinding technique is commonly used in clinical trials. The blinding can involve px exclusively or both px and
physicians (double blinding). The main purpose of blinding is to prevent px or researcher expectancy from interfering
with the determination of an outcome.

Recall bias: results from inaccurate recall of past exposure by people in a study

Selection bias: occurs with inappropriate (ie, nonrandom) selection methods or through selective attrition of the study
participants.

Lead-time bias (1170)

Occurs when a new test dx a condition earlier than conventional studies, causing an apparent increase in survival time
despite no improvement in overall mortality. Long-term mortality rates, not survival times, should be considered for
measuring the effect of early screening and tx.

Study designs (1276)

Standard error (6590)

Standard error is a measure of variability around the mean. The larger the sample size, the smaller the SE.

SE=standard deviation /n (sample size)

Study designs

Ecological study (10570)

Observational study analyzing population-level data to evaluate the association between a potential exposure (eg, low
socioeconomic status population) and a given outcome (eg, increased cancer mortality). Using population-level (rather
than individual-level) data as a unit of analysis. Ecological studies are useful for generating hypotheses but should not be
used to draw conclusions regarding individuals within these populations (ecological fallacy).

Nested case-control studies start with cohort studies in which participants are followed over time; those participants
who develop an outcome of interest become cases for a case-control study.

Cross over study (8422)

Subjects are randomly allocated to sequence of 2 or more tx given consecutively.

The principal drawback of crossover trials is that the effects of one treatment may carry over and alter the response to a
subsequent tx. To avoid this, a washout phase (no tx) is often added between tx.

Vs. case control study: designed by selecting px with a particular disease (cases) and without that disease (controls),
then determining their past exposure status to >1 risk factors believed to be associated with the disease of interest.

(1202) case and controls should be selected based on disease status, not exposure status

(1277) a case control study is used to compare the exposure status of people with the disease (ie, cases) to the exposure
status of people without the disease (ie, controls). The main measure of association is the odds ratio

Vs. case series: descriptive study that tracts px with a known condition (eg, a particular exposure, risk factor or disease)
to document the natural history or response to tx. Unlike case-control study, a case series is a descriptive study that
cannot quantify statistical significance

Vs. cross sectional study: is also known as prevalence study. It is characterized by the simultaneous measurement of
exposure and outcome. It is a snapshot study design that frequently uses surveys. These studies are relatively
inexpensive and easy to perform.

Vs. prospective cohort studies: identify 2 groups of individuals (ie, cohorts), based on their exposure status to risk factor.
These 2 cohorts are then followed over time to assess development of the disease of interest. Sometimes the exposure
status is determined retrospectively, typically using medical records, and px are tracked from the point of exposure
onward.

Prospective cohort study (1203)

Prospective cohort studies are organized by selecting a group of individuals (i.e., cohort), determining their exposure
status, and then following them over time for development of the disease of interest.

Odds ratio (1205)

Is a measure of association that compares the odds of an outcome occurring based on exposure status.in this case, it
represents the odds that the outcome (eg, major arrhythmia) occurred in the presence of the exposure (eg, beta blocker
use) compared with the odds that the outcome occurred in the absence of that exposure.
In standard contingency table, OR = ad/bc

Two sample t-test (1283)

Is a statistical method commonly employed to compare the means of 2 groups of subjects. If p<0.05, the null hypothesis
(which assumes that there is no difference between 2 groups) is rejected and the 2 means are assumed to be statistically
different.

Normal distribution (1282)

The symmetrical bell-shaped curve is usually cited as the prototypical curve describing the distribution of a continuous
variable. However, in actual research scenarios, continuous variables often have asymmetrical distributions. When a
distribution curve is asymmetric, it is either positivtely or negatively skewed:

- Positively skewed distribution, there is an increased number of observations with larger than expected
magnitudes (ie, extreme values) that shift the mean toward the right, producing a longer slope of the curve
(“tail”) on the positive side of the distribution
- Negatively skewed distribution, there is an increased number of observations with smaller-than expected
magnitudes that shift the mean toward the left, producing a longer slope of the curve (“tail”) on the negative
side of distribution.

In general, in a positively skewed distribution, the mean is the most shifted to the positive direction, followed by the
median and then the mode (mode < median <mean). In such a situation, the median often reflects a central tendency
better than the mean dos.

Predictive values (1233)

Negative predictive value (NPV) represents the probability of not having a disease given a negative test result. NPV is
inversely proportional to the prevalence of a disease. When a px has characteristics similar to the overall population (eg,
age, sex, risk factor status), the disease prevalence is a valid estimate of the pretest probability of disease. The NPV is
inversely proportional to the prevalence of disease. For the NPV to be applicable to an individual px, that px’s pretest
probability must be similar to the prevalence of disease in the population

NPV= d / (c + d)

False positive rate (6586)

FPR = (1 – specificity) and is independent of disease prevalence

Sensitivity and specificity (1229)

The sensitivity of a test determines the proportion of px that are correctly classified:

TP = (sensitivity) * (number of px with the disease)

FN = (1 – sensitivity ) * (number of px with the disease)

NPV (1190)

Is the probability of not having a disease when the test result is negative. The NPV will vary with the pretest probability
of a disease. A px with a high probability of having a disease will have a low NPV with a negative test, but a px with a low
probability of having a disease will have a high NPV with a negative test.

(1271) various parameters are used to evaluate the accuracy and usefulness of dx tests. Positive and negative predictive
values are influenced by disease prevalence in the target population; sensitivity, specificity, and likelihood ratios are not
prevalence dependent.

Organ Systems
Cardiovascular

CO and Venous Return (1625)

A chronic arteriovenous shunt would increase CO because of increased sympathetic stimualation to the heart, decreased
total peripheral resistance, and increased venous return. It would also cause the venous return curve to shift to the right
because the circulating blood volume is increased through renal retention of fluids and because venous pooling is
reduced by the increased sympathetic tone.

Long QT syndrome (84)

Sudden onset syncopal episode suggests a sudden cardiac arrhythmia. QT prolongation in an otherwise healthy young
individual is usually congenital. The mutation most likely to cause QT-interval prolongation can be determined based on
an understanding of cardiac electrophysiology. On an ECG tracing, the QT interval begins at the start of the QRS complex
and ends at the end of the T wave. Thus, the QT-interval reflects the cardiac myocyte action potential duration, which is
determined in part by K+ currents through channel proteins.

There are 2 important congential syndromes that cause QT prolongation: Jervell and Lange-Nielsen syndrome (AR, with
neurosensory deafness) and the more common Romano-Ward syndrome (AD, no deafness). Both may predispose to
torsades the points (a ventricular tachyarrhythmia) at a young age, causing syncopal episodes and possible sudden
cardiac death.

(86) There are several genetic mutations described in px with congenital LQTS. The 2 most common forms (LQT type 1
and LQT type 2( are due to genetic mutations in K+ channel proteins that contribute to the outward-rectifying potassium
current.

Phase 3 (repolarization) of the myocardial action potential occurs due to time-dependent inactivation of the L-type
(long-lasting, large-conductance) Ca2+ channels (which reduces inward current) along with activation of the voltage-
gated delayed rectifier K+ channels (which increases outward current). This net increase in outward transmembrane
current is responsible for ventricular repolarization. Decreased outward potassium flow due to K+ channel mutations
leads to prolongation of action potential duration and QT interval. Prolongation of QT interval predisposes to the
development of life-threatening ventricular arrhythmias (eg, torsades de points), which can present as recurrent
palpitations, syncope, seizures or sudden cardiac death.

Jervell and Lange-Neilsen syndrome (91)

- AR
- Profund bilateral sensorineurla hearing loss and congenital long QT syndrome
- Predisposes individuals to syncope and sudden cardiac death
- Mutations in genes (eg, KCNQ1, KCNE1) that encode the alpha and beta subunits of voltage-gated potassium
channels
- These subunits contribute to the slow-acting component of the outward-rectifying potassium current, which is
responsible for ventricular repolarization during phase 3 of the cardiac action potential
- Mutations in the K channel lead to a decrease in K current with prolongation of action potential duration and the
QT interval
- QT interval prolongation predisposes to the development of life-threatening ventricular arrhythmias (torsades
de pointes and ventricular fibrillation)

Causes of QT prolongation (15693)

Acquired Medications
- Macrolides & fluoroquinolones
- Antiemetics (eg, ondansetron)
- Azoles (eg, fluconazole)
- Antipsychotics & tricyclic antidepressants
- Class IA antiarrhythmics (eg, quinidine)
- Class III antiarrhythmics (eg, dofetilide)
Electrolyte abnormalities (eg, hypomagnesemia
Congenital - Romano-ward syndrome
- Jervell & lange-nielson syndrome (associated with
 deafness

Long QT + torsades de pointes (7640)

TdP is a form of polymorphic ventricular tachycardia characterized by QRS complexes of varying amplitude and cycle
length giving the appearance that the tip of the QRS complex is “twisting” around the ECG baseline. TdP is differentiated
from other forms of polymorphic ventricular tachycardia because it is always associated with a prolonged QT interval. It
may terminate spontaneously or can degenerate into ventricular fibrillation and sudden cardiac death.

Acquired QT prolongation is most frequently caused by electrolyte imbalances (hypokalemia, hypomagnesemia) and
pharmacologic agents such as class IA and III antiarrhythmics (eg, quinidine, stoalol), antibiotics (eg, macrolides,
fluoroquinolones), methadone, and antipsychotics (eg, haloperidol). Sotalol is a class III antiarrhythmic agent (K+ channel
blocking) used for treatment of atrial fibrillation. It prolongs action potential duration, resulting in QT interval
prolongation.

Sick sinus syndrome (15574)

Sick sinus syndrome results from degeneration (usually age-related) of this sinoatrial node, leading to impaired
conduction and reduced CO with symptoms of dyspnea, fatigue, lightheadedness, presyncope and syncope. ECG
typically demonstrates bradycardia with sinus pauses (delayed P waves), sinus arrest (dropped P waves), and junctional
escape beats.

Left atrial enlargement (1623)

Cardiovascular dysphagia can result from external compression of the esophagus by a dilated and posteriorly displaced
left atrium in px with rheumatic heart disease and mitral stenosis/regurgitation. On rare occasions, left atrial
enlargement can also cause compression of the left recurrent laryngeal nerve, leading to voice hoarseness and chronic
cough.

Cardiac tamponade

(96)

Inspiration causes an increase in systemic venous return, resulting in increased right heart volumes. Under normal
conditions, this results in expansion of the right ventricle into the pericardial space with little impact on the left side of
the heart. However, in conditions that impair expansion into the pericardial space (eg, cardiac tamponade), the
increased right ventricular volume that occurs with inspiration leads to bowing of the intervetnricular septum toward
the left ventricle. This leads to a decrease in LV end-diastolic volume and forward SV, with a resultant decrease in
systolic pressure during inspiration

(1782)

Pulsus paradoxus is an important physical finding in cardiac tamponade and refers to an exaggerated drop in systolic
blood pressure (>10mmHg) during inspiration. Fluid accumulation in the pericardium causes limitation of right
ventricular expansion that is exacerbated during inspiration by the increase in venous return. This leads to bowing of the
interventricular septum towards the left ventricle, decreasing left ventricular (LV) end-diastolic volume and stroke
volume. The result is decreased systolic pulse pressure during inspiration.

Differential diagnosis & features of chest pain (11640)

Tetraology of fallot

(1705)

Abnormal neural crest cell migration leads to anterior and cephalad deviation of the infundibular septum during
embryologic development, resulting in a malaligned VSD and an overriding aorta.

(204)

- VSD
- Overriding aorta
- Right ventricular outflow tract obstruction
- RV hypertrophy

The VSD generally is large, which allows for equal pressure in the right and left ventricles. Therefore, it is the amount of
RVOT obstruction that determines how much deoxygenated blood is delivered to the systemic circulation. Infants with
significant RVOT obstruction shunt more deoxygenated blood across the VSD to the aorta and are more cyanotic. Infants
with no or minimal RVOT obstruction, such as this patient, deliver more deoxygenated blood to the lungs and appear
acyanotic. The degree of RVOT obstruction is dynamic and can increase suddenly, leading to proound cyanosis (“tet
spells”). These can be caused by dehydration or hyperventilation but are usually idiopathic

Sinoatrial node (11730)

The SA node consist of specialized pacemaker cells located at the junction of the right atrium and superior vena cava. It
is the site of earliest electrical activation in px with sinus rhythm

Echocardiography (8332)

The LA forms the majority of the posterior surface of the heart and resides adjacent to the esophagus. Enlargement of
the left atrium can compress the esophagus and cause dysphagia.

(8333)

The ascending aorta lies posterior and to the right of the main pulmonary artery. The aortic arch travels above the right
pulmonary artery and the left bronchus. The brachiocephalic, left common carotid and left subclavian arteries originate
(in that order) from its superior aspect. The descending thoracic aorta abuts the left anterior surface of the vertebral
column and lies posterior to the esophagus and the left atrium. This permits clear visualization of the descending aorta
during transesophageal echocardiography, allowing for the detection of abnormalities such as dissection or aneurysm.
The descending thoracic aorta continues to travel down the left anterior surface of the vertebral column, becoming the
abd aorta as it crosses the diaphragm and eventuallhy branching into common iliac arteries.

Aging (180)

Normal morphological changes in the aging heart include a decrease in LV chamber apex-to-base dimension,
development of a sigmoid-shaped ventricular septum, myocardial atrophy with increased collagen deposition, and
accumulation of cytoplasmic lipofuscin pigment within cardiomyocytes.

Dystrophic calcification (296)

Dystrophic calcification is considered a hallmark of cell injury and death, occurring in all types of necrosis (eg,
coagulative, fat, caseous, liquefactive) in the setting of normal calcium levels. Grossly, dystrophic calcium deposits are
seen as fine, gritty, white granules or clumps. On hematoxylin and eosin staining, these deposits typically appear as dark-
purple, sharp-edged aggregates. Deposits that develop lamellated outer layers are described as psammoma bodies.

Dystrophic calcification in aged (or damaged) cardiac valves is thought to be the result of endothelial and fibroblast
death secondary to chronic hemodynamic stress (can be accentuated by valvular abnormalities) or atherosclerotic
inflammation. Subsequent release of cellular degradation products into the valvular interstitium then promotes
calcification and thickening of the valve leaflets and annulus. These changes are often benign in elderly adults (aortic
sclerosis); however, over time, progressive valvular stiffening can lead to outflow obstruction (calcific aortic stenosis)

(300) an insoluble pigment composed of lipid polymers and protein-complexed phospholipids, lipofuscin is considered a
sign of “wear and tear” or aging. This yellow-brown, finely granular perinuclear pigment is the product of free radical
injury and lipid peroxidation. It is commonly seen in the heart and liver of aging or cachectic, malnourished patients.

Cardiac physiology

Cardiac output (1529)

CO=SV*HR

Or determined with pulmonary artery (Swan-Ganz) catheter by applying the Fick principle

CO=Rate of O2 consumption / arteriovenous O2 content difference

(1531)
SV and EF (15526)

SV is the absolute volume of blood ejected from the LV with each contraction and is calculated by subtracting LVESV
from LVEDV. Ejection fraction is the relative volume of blood ejected from the LV with each contraction; it is calculated
by diving stroke volume by LVEDV. CO, the volume of blood ejected into the aorta per unit time, is estimated by
multiplying stroke volume by HR.

Embryologic derivatives (1750)

Selected inherited disorders & associated cardiovascular developmental defects (30)
Disease CV abnormalities
Down syndrome - Endocardial cushion defects (eg, ostium primum atrial septal defects, regurgitant AV
valves)
DiGeorge syndrome - Tetraology of Fallot
- Interrupted aortic arch
Friedreich ataxia - Hypertrophic cardiomyopathy
Kartagener syndrome - Situs inversus
Marfan syndrome - Cystic medial necrosis (eg, aortic dissection & aneurysm)
- Mitral valve prolapse
Tuberous sclerosis - Valvular obstruction due to cardiac rhabdomyomas
Turner syndrome - Aortic coarctation
- Bicuspid aortic valve

Congenital coarctation of the aorta:

- Typically affects the region of the aorta just distal to the left subclavian artery
- Classified into preductal and postductal types
- Severe coarctation usually presents in infancy with differential cyanosis affecting the lower extremities as long as
the ductus arteriosus remains patent, may develop signs of HF and shock
- Moderate stenosis often presents in childhood or adolescence with symptoms of lower-extremity claudication
(Eg, pain and cramping with exercise), BP discrepancy between the upper and lower extremities, and delayed or
diminished femoral pulses. Continuous murmurs and pulsatile intercostal collaterals can also develop secondary
to restricted circulation

Atrioventricular canal defect (188)

A complete AV canal defect is comprised of an atrial septal defect, a ventricular septal defect and a common AV valve. It
is most common congenital cardiac anomaly associated with Down syndrome. Auscultatory findings of AV valve
regurgitation (holosystolic, best heard at apex) and increased pulmonary venous return (mid-diastolic rumble) are
characteristic.
Transposition of the great vessels (35)

The etiology of TGA is due to linear (rather than spiral) development of the aorticopulmonary septum in utero, resulting
in an anteriorly positioned aorta connected to the right ventricle and a posteriorly positioned pulmonary artery
connected to the left ventricle.

Cardiac pressure range (1653)

LV pressure & volume during cardiac cycle (1530)

Cardiovascular effects of adrenergic drugs (1342)
Amyloid angiopathy (499)

Is a consequence of beta-amyloid deposition in the walls of small- to medium-sized cerebral arteries, resulting in vessel
wall weakening and predisposition to rupture. Amyloid angiopathy is the most common cause of spontaneous lobar
hemorrhage, particularly in adults age >60. Hemorrhage tends to be recurrent and most often involves the occipital and
parietal lobes. Occipital lobe hemorrhage is typically associated with homonymous hemianopsia; parietal hemorrhages
can cause contralateral hemisensory loss. Frontal lobe hemorrhage is less common but may result in contralateral
hemiparesis.

Hemorrhagic stroke (498)

Charcot-Bouchard aneurysms Saccular (Berry) aneurysms

Associated conditions HTA ADPKD
Ehlers-Danlos
HTA
Location Basal ganglia Circle of willis
Cerebellum
Thalamus
Pons
Size <1mm Variable, 2-25 mm
Result of rupture Intracerebral hemorrhage Subarachnoid hemorrhage
Symptoms of rupture Progressive neurologic deficits Sudden severe headache
Headache may follow Focal neurologic deficits uncommon

Subarachnoid hemorrhage (497)

Clinically, the abrupt onset of a severe headache is very characteristic of subarachnoid hemorrhage. Confirmed through
non-contrast CT scan. Is often described as “the worst headache of my life”. Fever and nuchal rigidity may also be
present. Focal neurological deficits are usually not present

Saccular (berry) aneurysms are the most common cause of SAH. These aneurysms usually occur at the circle of Willis,
with the anterior communicating artery being the most common site. Berry aneurysms are associated with Ehlers-
Danlos syndrome and autosomal dominant polycystic kidney disease. Arteriovenous malformations also predispose
certain individuals to SAH.

In SAH, blood accumulates between the arachnoid and pia mater. Lumbar puncture reveals gross blood or
xanthochromia

(146) delayed cerebral ischemia due to cerebral vasospasm usually presents 3-12 days after the initial subarachnoid
hemorrhage (SAH) with an acute change in mental status and/or new focal neurological deficits. Nimodipine, a selective
calcium channel blocker, improves outcomes in px with cerebral vasospasm by inducing cerebral vasodilation and
decreasing calcium dependent excitotoxicity.

Basal ganglia (putaminal) hemorrhage (12007)

Putaminal hemorrhage almost always involves the adjacent internal capsule, leading to contralateral hemiparesis and
hemianesthesia due to disruption of the corticospinal and somatosensory fibers in the posterior limb. As the
hemorrhage expands, headache, nausea/vomiting, and altered mental status can develop due to elevated intracranial
pressure.
Hypertensive vasculopathy involving the small penetrating branches of the major erebral arteries is the most common
cause of spontaneous deep intracerebral hemorrhage. Chronic hypertension leads to the formation of Charcot-Bouchard
aneurysms, which may ultimately rupture and bleed within the deep brain structures. The most frequently affected
locations include the basal ganglia (putamen), cerebellar nuclei, thalamus and pons. The basal ganglia are supplied by
the lenticuostriate arteries, which are small vessel branches off the middle cerebral artery.

VS. pontine artries, arise off the basilar artery to supply the pons and can rupture in the setting of poorly controlled
chronic HTA. Bilateral pontine hemorrhage typically presents with coma (due to disruption of the reticular activating
system), total paralysis (corticospinal and corticobulbar tracts) and pinpoint pupils (descending sympathetic tract).

Coronary Artery Bypass Grafting (CABG) (1967)

the great saphenous vein is a superficial vein of the leg that originates on the medial side of the foot, courses anterior to
the medial malleolus, and then travels up the medial aspect of the leg and thigh. It drains into the femoral vein within
the region of the femoral triangle, a few centimeters inferolateral to the pubic tubercle.

Central venous catheter (2023)

The catheter is usually inserted into the neck (internal jugular vein) or chest (subclavian vein), and is advanced until the
catheter tip enters the superior vena cava (SVC). The SVC is derived from the common cardinal veins.

Cardiac catheterization (15197)

To access the left side of the heart, cardiac venous catehters must cross the interatrial septum at the site of the foramen
ovale. Entry into the left atrium allows for direct measurement of left atrial pressure and for acess to arrhythmogenic
foci on the left atrial myocardium or pulmonary veins

Natriuretic peptides (157)

Both ANP and BNP activate guanylate cyclase, which increases intracellular cyclic GMP, and leads to downstream
physiologic effects in various tissues. In the kidney, natriuretic peptides promote afferent glomerular arteriolar
vasodilation and efferent arteriolar constriction, causing increased GFR; this leads to increased natriuresis (sodium
excretion) and diuresis (fluid excretion). Natriuretic peptides also directly inh proximal tubular sodium reabsorption and
renin secretion. Decreased renin secretion results in reduced angiotensin II and aldosterone levels, further promoting
natriuresis and diuresis.

Rheumatic fever (240)

Interstitial myocardial granulomas (Aschoff bodies) are found in carditis due to acute rheumatic fever, which develops
after an untreated group A streptococcal pharyngeal infection. Aschoff bodies contain plump macrophages with
abundant cytoplasm and central, slender ribbons of chromatin (Anitschkow, or caterpillar, cells). Over subsequent years,
Aschoff bodies are replaced by fibrous scar tissue, leading to chronic mitral valve stenosis and regurgitation

(241)
Sydenham chorea px with involuntary, rapid, irregular jerking movements involving the face, arms ad legs. It occurs
months after group A streptococcal infection and is one of the major clinical manifestations of acute rheumatic fever. Px
with this condition carry a high risk of chronic valvular disease.

(726)

Empiric therapy for a condition must be considered in the context of the host characteristics, pretest probability of the
disease, benefits/risks of waiting for a definitive dx, and cost of therapy vs its potential complications. If all cases of
acute streptococcal pharyngitis were tx empirically, the incidence of rheumatic heart disease and associated cardiac
procedures would likely decrease.

Blunt aortic injury (2130)

Traumatic aortic rupture is most often caused by the rapid deceleration that occurs in motor vehicle collisions. The most
common site of injury is the aortic isthmus, which is tethered by the ligamentum arteriosum and is relatively fixed and
immobile compared to the adjacent descending aorta.

Pacemaker potential (1976)

AV nodal cells can become pacemakers when conduction between the SA and AV nodes is impaired. This can occur in
complete (third-degree) AV block, in which SA node impulses cause atrial contraction while impulses generated by the
AV node cause ventricular contraction. On ECG, the atria and ventricles depolarize independently of each other (AV
dissociation). QRS complexes are narrow since ventricular depolarization proceeds normally. The AV node produces a HR
of 45-55 bpm.

Atrial septal defect (202)

Cryptogenic stroke, which is evaluated with echocardiography with a “bubble study” to ID right-to-left intracardiac
shunts. This study is performed by injecting agitated normal saline IV and observing for microbubbles in the left heart.
Shunt detection is improved by having the px release a sustained Vasalva maneuver, which increases right atrial
pressure. Crptogenic stroke is frequently associated with atrial septal abnormalities such as patent foramen ovale and
atrial septal defect.

During fetal development, the foramen ovale shunts oxygenated fetal blood across from the right to the left atrium.
After delivery, umbilical cord clamping and decreased pulmonary vascular resistance lower right atrial pressure and raise
left atrial pressure. This pushes the septum primum against the septum secundum, closing the foramen ovale. Over
time, fibrosis and tissue remodeling fuse the flap closed. Incomplete fusion occurs in approximately 25% of normal
adults, resulting in a PFO

PFO usually remains functionally closed and asymptomatic after birth as left atrial pressure is greater than right atrial
pressure. However, conditions that raise right atrial pressure above left atrial pressure (eg, Valsalva release) produce a
transient right-to-left shunt across the PFO. This is particularly concerning in px with hypercoabulability (eg, OCP) as they
are increased risk for venous thrombosis and paradoxical brain embolism. Chronically elevated right heart pressure (eg,
Eisenmenger syndrome) is not necessary for paradoxical embolism.

VSD

(203) px with small VSDs typically have a loud, “blowing,” holosystolic murmur at the mid to lower left sternal border
and no symptoms. the murmur is not usually detectable at birth, but becomes audible around age 4-10 days as
pulmonary vascular resistance (PVR) continues to decline, permitting significant L-R shunting. Most small VSDs are
hemodynamically insignificant and close spontaneously

(187)

Increased blood oxygen saturation between 2 right-sided vessels or chambers indicates the presence of the left to right
shunt. If the abnormal oxygen increase occurs between the right atrium and the right ventricle, a ventricular septal
defect (VSD) is likely present. Small VSDs produce a holosystolic murmur that is loudest over the lower left sternal
border.

VS. a bifid carotid pulse with brisk upstroke (“spike and dome”) is characteristic of hypertrophic cardiomyopathy, a
condition with dynamic left ventricular outflow tract obstruction during systole. SpO2 in the cardiac remains normal

VS precordial continuous, machine-like murmur indicates patent ductus arteriosus, which prodces isolated pulmonary
artery SpO2 elevation

VS. a decreased femoral to brachial bp ratio is found coarctation of the aorta, which does not alter right ventricular SpO2

Patent ductus arteriosus (1751)

The ductus arteriosus is derived from the sixth embryonic aortic arch. A patent ductus arteriosus (PDA) causes L-R
shunting of blood that can be heard as a continuous murmur over the left infraclavicular region. Indomethacin (a PGE2
inh) can be used to close a PDA in premature infants, but surgical ligation is often necessary in older px

Atheletes heart (15269)

Athlete’s heart refers to physiologic cardiac adaptations that improve cardiac function in response to high-level
endurance training. There is predominant eccentric hypertrophy with a smaller component of concentric hypertrophy,
leading to an overall increase in LV mass, enlarged LV cavity size, increased LV wall thickness, and decreased resting
heart rate.

Dilated cardiomyopathy

(92)

LV cavity enlargement consistent with eccentric hypertrophy, which is initially an adaptive mechanism that allows the LV
to maintain CO in the setting of increasing volume overload. Multiple disease processes can lead to eccentric
hypertrophy, including ischemic heart disease, certain types of valvular disease (ie, aortic regurgitation, mitral
regurgitation), and primary myocardial dysfunction (eg, due to viral infection, chronic alcohol abuse, inherited disease)

Eventually progressive eccentric enlargement of the LV becomes maladaptive with overwhelming wall stress leading to
decreased ventricular contractility. The reduced CO leads to decompensated heart failure manifesting with fatigue,
dyspnea, orthopnea and peripheral edema. The structural changes to the LV also increase the risk of ventricular
arrhythmia (ie, ventricular tachycardia, ventricular fibrillation), a potential cause of sudden cardiac death in these px

(13600)

Truncating mutations (usually nonsense mutations) affecting the TTN gene, which encodes for the sarcomere protein
titin, are the most common cause of familial DCM. Titin is an elastic protein that anchors the beta-myosin heavy chain to
the Z-discs and likely contributes to passive myocardial tension; absence of complete titin proteins leads to myocardial
dysfunction

TTN gene mutations follow AD inheritance; however, they have incomplete penetrance, leading to delayed or absent
clinical manifestations in some family members.

(14993)

Risk of sudden cardiac death from entricular arrhythmia (ie, ventricular tachycardia, ventricular fibrillation). In addition,
the global hypokinesis of the LV leads to stagnation of blood flow and the possible development of LV mural thrombus
and subsequent systemic embolization.

(14922)

Peripartum cardiomyopathy is relatively uncommon and manifests as a dilated cardiomyopathy that occurs during the
last month of pregnancy or within 5 months after delivery. The pathogenesis of the condition is poorly understood, but it
may be related to impaired function of angiogenic growth factors (eg, vascular endothelial growth factor) during the
peripartum period.

Implantable cardioverter defibrillator (7646)

This px has a biventricular pacemaker, a device that requires 2 or 3 leads. If 3 leads are used, the first 2 are placed in the
RA and RV. The third lead is used to pace the LV. RA and ventricular leads are easy to place as they only need to traverse
the left subclavian vein and superior vena cava to reach these cardiac chambers. In contrast, the lead that paces the LV is
more difficult to position. The preferred transvenous approach involves passing the LV pacing lead from the RA into the
coronary sinus, which resides in the AV groove on the posterior aspect of the heart. It is then advanced into one of the
lateral venous tributaries in order to optimize LV pacing.

(15729) The RV lead of an implantable pacemaker or cardioverter-defibrillator passes through the superior vena cava
into the right atrium and then through the tricuspid valve orice to terminate on the endocardium of the right ventricle.
Dmg to the tricuspid valve leaflets or inadequate leaftlet coaptation can sometimes occur, leading to severe TR in some
px.

Severe TR typically presents with right-sided heart failure. Px can have distended jugular veins, pulsatile and tender
hepatomegaly, abd distension with ascites, and lower extremity edema. Cardiac examination typically reveals a
holosystolic murmur best heard at the left lower sternal border; the murmur intensifies with maneuvers that increase
right ventricular preload (eg, deep inspiration, leg raise).

Radiofrequency ablaton of AV node (11956)

Is occasionally performed in patients with certain arrhythmias who do not respond or are intolerant to pharmacologic
therapy. The AV node is located on the endocardial surface of the RA, near the insertion of the setpal leaflet of the
tricuspid valve and the orifice of the coronary sinus.

Another area frequently involved in atrial fibrillation pathogenesis is the opening of the pulmonary veins in the LA; this
area is often a target for radiofrequency ablation, but it is not where the AV node is located.

Vasospasm

Prinzmetal (38)
Spontaneous episodes of rest and nighttime angina + transient ST elevation -> Prinzmetal angina

Is caused yb transient, sudden, and significant reduction in the luminal diameter of an epicardial coronary artery due to
spasm, leading to brief myocardial ischemia

Dihydroergotamine is an ergot alkaloid commonly used to treat acute migraine headache. This drug may induce
vasospastic angina as it constricts vascular smooth muscle via stimulation of both alpha-adrenergic (partial agonist) and
serotonergic receptors. Other possible triggers include cigarette smoking, cocaine/amphetamines, and triptans.

(15001) vasospastic angina is usually dx by ambulatory ECG (Holter monitor) that shows ST elevation during an episode
of chest discomfort, followed by coronary angiography to rule out atherosclerotic CAD. Sublingual nitroglycerin is
effective in relieving an active episode of vasospastic angina, and calcium channel blockers (eg, diltiazem, amlodipine)
are effective in preventing episodes.

Wolff-Parkinson-White (WPW)

(90) WPW is caused by an accessory conduction pathway (bundle of Kent) that allows electrical conduction impulses to
bypass the AV node and cause preexcitation of the ventricles. This preexcitation leads to characteristic findings on
baseline ECG, including a shortened PR interval (often <0.12 s), early upslope of the QRS complex (delta wave), and a a
widened QRS complex

Many px with an accessory conduction pathway can be asymptomatic and are dx only when a WPW pattern is
incidentally recognized on ECG. However, some px will develop symptomatic arrhythmias. AV reentry tachycardia
(AVRT), a type of paroxysmal supraventricular tachycardia, is the most common arrhythmia that occurs with WPW. AVRT
results from a rapid reentrant circuit that typically travesl down the AV node to the ventricles and back up the accessory
pathway, with px often experiencing palpitations and a racing heart.

(11797)

Is characterized by a shortened PR interval, widening of the QRS complex, and slurred initial upstroke of the QRS
complex (delta wave). It is caused by an accessory pathywa that bypasses the AV node, causing preexcitation of the
ventricles. Px iwht WPW pattern can develop symptomatic arrhythmia (eg, AV reentrant tachycardia) due to reentry of
electrical impulses through the accessory conduction pathway.

Myocarditis (14789)

Most commonly caused by a viral infection (eg, coxsackievirus, adenovirus, influenza). It often resovles without
noticeable symptoms, but px can develop serious complications, including decompensated heart failure due to dilated
cardiomyopathy or sudden cardiac death due to ventricular arrhythmia. Histopathology typically demonstrates
myofibrillary necrosis with inflammatory mononuclear infiltrate.
Hypertensive emergency (449)

Is severely elevated BP (typically >180/120 mmHg) with evidence of end-organ dmg. In the kidneys, this can manifest as
malignant nephrosclerosis, characterized by fibrinoid necrosis and hyperplastic arteriolosclerosis (“onion-skin”
appearance). A microangiopathic hemolytic anemia can occur due to erythrocyte fragmentation and platelet
consumption at the narrowed arteriolar lumen.

ASD (6539)

The L to R shunt of ASD causes RV overload during diastole and an increase in pulmonary blood flow. Larger L to R
shunts tend to limit respiratory variation secondary to a delay in pulmonic valve closure. As a consequence, S2 (the
sound of the semilunar valves closing) is widely split and fixed. Because the blood flow across the ASD is low velocity and
minimally turbulent, it does not cuase an audible murmur. However, several other murmurs are associated with ASD,
including a midsystolic pulmonary flow or ejection murmur (secondary to increased flow across the pulmonic valve), a
diastolic rumble (secondary to increased flow across the tricuspid valve), and a low-pitched diastolic murmur (secondary
to pulmonic regurgitation).

(201) wide, fixed splitting of the second heart sound is a characteristic auscultatory finding in px with ASD. A
hemodynamically significant ASD can produce chronic pulmonary HTA as a result of L-R intracardiac shunting.
Eisenmenger syndrome is the late-onset reversal of a L-R shunt due to pulmonary vascular sclerosis resulting from
chronic pulmonary HTA. Closure of the ASD may be required to prevent irreversible pulmonary vascular sclerosis and a
permanent Eisenmenger syndrome

Atrial flutter (14745)

This px ECG strip shows rapid and regular atrial activity in a saw-toothed pattern (flutter or F waves), consistent with
atrial flutter. Narrow QRS complexes are typically present and the ventricular rhythm appears regular. Because the atrial
rate is approximately 300/min, typical ventricular rates in atrial flutter are 150/min, 100/min, or 75/min due to 2:1, 3:1
or 4:1 conduction through the AV node respectively.

Atrial flutter shares many of the same triggers as atrial fibrillation; underlying comorbidities that cause atrial dilation (eg,
HF) are often present and alcohol intake may contribute. Typical atrial flutter is caused by a large reentrant circuit that
traverses the cavotricuspid isthmus, the region of right atrial tissue between the inferior vena cava and the tricuspid
valve annulus. This region is ID during electrophysiologic study and is the target for radiofrequency ablation to interrupt
the reentrant circuit and abolish atrial flutter.

Subclavian steal syndrome (12046)

Typically occurs due to hemodynamically significant stenosis of the subclavian artery proximal to the origin of the
vertebral artery. Subclavian stenosis is typically caused by atherosclerosis, although less common etiologies include
Takayasu arteritis and complications from heart surgery (eg, aortic coarctation repair). The lowered distal subclavian
arterial pressure leads to reversal in blood flow (“steal”) from the contralateral vertebral artery to the ipsilateral
vertebral artery, away from the brainstem.

Most px with subclavian artery stenosis are asymptomatic. When symptoms occur, they are typically related to arm
ischemia in the affected extremity (eg, exercise-induced fatigue, pain, paresthesias) or vertebrobasilar insufficiency (eg,
dizziness, vertigo, drop attacks). PE can show significant difference (>15 mmHg) in brachial systolic bp between the
affected arm and normal arm. Doppler u/s of the cerebrovascular and upper extremity arterial circulation establishes
the dx in most px.

Carcinoid tumors (74)

- Endocardial thickening and fibrosis of tricuspid and pulmonary valves

- These tumors secret several products (including histamine, serotonin, and VIP) that are metabolizaed in the liver
- Px with liver metastasis, these hormones are released directly into the systemic circulation, leading to carcinoid
syndrome
- Excessive secretion of serotonin -> stimulates fibroblast growth and fibrogenesis
- Pathognomonic plaque-like deposits of fibrous tissue occur most commonly on th endocardium, leading to
tricuspid regurgitation, pulmonic valvulopathy and righ-sided heart failure (eg, ascites, peripheral edema)
- Endocardial fibrosis and thickening are generally limited to the right heart as vasoactive products are inactivated
distally by pulmonary vascular endothelial monoamine oxidase
- 5 hydroxyindoleaceitc acid (5-HIAA) is an end product of serotonin metabolism, and elevated 24 hr urinary 5-
HIAA levels are helpful in dx

Paroxysmal supraventricular tachycardia (1515)

Sudden onset of palpitations + rapid regular tachycardia; due to reentrant impulse traveling circularly between the
slowly and rapidly conducting segments of the AV node

Vagal maneuvers: carotid sinus massage, Vasalva, and cold water immersion can be used to acutely terminate PSVT
Carotid sinus massage leads to increased afferent firing from the carotid sinus, which in turn, increases vagal
parasympathetic tone. This slows conduction through the AV node and prolongs the AV node refractory period, helping
to terminate the reentant tachycardia.

Pharmacotherapy for supraventricular arrhythmias (898)

Medication Short-term adverse effects
Flecainide/propafenone (class IC) - Ventricular arrhythmias (especially with ischemic
or structural heart disease)
Metoprolol (Class II) - Bradycardia & advanced AV block
Amiodarone (Class III) - Bradycardia
- Hepatic toxicity, thyroid dysfunction
Ibutilide/dofetilide/sotalol (class III) - Torsades de pointes
Verapamil/diltiazem (class IV) - Bradycardia & advanced AV block
- Decreased ventricular contractility
- Constipation (verapamil)
Adenosine - Flushing & hypotension
- Bronchospasm
- High-grade AV block
Digoxin - Bradycardia & other arrhythmias
- Nausea & vomiting +/- visual disturbances

Adenosine is a coronary arteriole vasodilator, but it also affects cardiac conduction. As an anti-arrhythmic, it acts by
hyperpolarizing the nodal pacemaker and conducting cells to briefly block conduction through the AV node. Its effects
are rapid-onset and short-lived (half-life <10 sec); by temporarily blocking signal conduction from the atria to the
vetricles, admn of the drug will often terminate the reentrant circuit and lead to conversion of PSVT to normal sinus
rhythm

The most frequent adverse effects associated with adenosine are flushing, chest burning (due to bronchospasm),
hypotension, and high-grade atrioventricular block.

Vasalva maneuver (1730)

Increases vagal tone -> increase the refractory period in the AV node and can be used to abolish paroxysmal
supraventricular tachycardia. The rectus abdominis is the most important muscle in achieving the increased
intraabdominal and intrathoracic pressure of the Vasalva maneuver. If Vasalva measures fail, IV admn of adenosine is
recommended

Arginine in NO production (8563)

NO is synthesized from arginine by NO synthase. As a precursor of NO, arginine supplementation may play an adjunct
role in the tx of conditions that imprve with vasodilation, such as stable angina

CHF

(185) Alveolar hemosiderin-laden macrophages indicate alveolar hemorrhage. They most commonly result from chronic
elevation of pulmonary capillary hydrostatic pressure in the setting of left-sided heart failure.

(15534)
Left-sided HF leads to chronically elevated pulmonary venous and capillary pressures, with resulting pulmonary edema
and extravasation of RBC into the alveolar parenchyma. The iron from RBC is taken up by alveolar macrophages and
stored as hemosiderin, appearing as brown pigment on histopathology

(531) cardiogenic pulmonary edema is characterized by the accumulation of fluid in the alveoli due to elevations in the
hydrostatic pressure within the pulmonary capillaries. Examination often reveals bibasilar crackles and chest x-ray
typically shows perihilar alveolar edema with cephalization of the pulmonary vessels.

(1944) drugs that have been shown to improve long-term survival in px with HF due to LV systolic dysfunction include
beta blockers, ACE inh, angiotensin II receptor blockers, and aldosterone antagonists.

HCM

(76) Systolic anterior motion of the

toward the interventricular septum can cause eccentric mitral regurgitation and exacerbate LVOT obstruction.

(85)

Dynamic left ventricular outflow tract obstruction is seen in about 25% of px with HCM and causes a harsh crescendo-
decrescendo systolic ejection-type murmur that is best heard along the lower left sternal border and apex.
The degree of LVOT obstruction (and intensity of the murmur) varies based on LV end-diastolic volume.

Mechanism that decrease preload (ie, venous return) or afterload reduce LV chamber size, which decreases the
separation between the mitral valve and interventricular septum, increasing obstruction. Sudden standing (from a sitting
or supine position), Vasalva (straining phase), or nitroglycerin admn decreases preload and will result in increased
murmur intensity. In contrast, squatting (from a standing position), sustained hand grip, or passive leg raise will increase
preload and/or afterload, thereby decreasing murmur intensity.

(15516) HCM typically involves interventricular septal hypertrophy that obstructs LV outflow and creates a systolic
murmur that decreases in intensity with maneuvers that increase LV blood volume (eg, hand grip, passive leg elevation).
HCM is characterized by increased LV muscle mass with a small LV cavity, preserved ejection fraction and impaired LV
relaxation leading to diastolic dysfunction

(15310)

Echo findings:

- Overall increase in LV mass

- Reduced LV cavity size (leading to impaired diastolic fx)
- Asymmetric increase in LV wall thickness predominantly affecting the septum
- Normal or increased LV ejection fraction
- LA enlargement (secondary to increased LV end-diastolic pressure)

*another characteristic of HCM is a poorly developed coronary capillary network in hypertrophied regions with evidence
of chronic ischemia (ie, fibrosis, scarring)

(141)

Medications that should be avoided:

- Vasodilators (eg, dihydropyridine calcium channel blockers, nitroglycerin and ACE inh): decrease systemic
vascular resistance, leading to decreased afterload and lower LV volumes
- Diuretics: decrease LV venous filling (preload) and also result in greater outflow obstruction

TX: negative inotropic agents such as beta blockers (metoprolol, nondihydropyridine calcium channel blockers
(verapamil and disopyramide reduce LVOT obstruction and are helpful in symptopmatic px with HCM

Vs anabolic steroid abuse

Can cause pathologic concentric LV hypertrophy, characterized by reduced diastolic fx and poor coronary
vascularization. However, uniform ventricular wall thickening would b expected.

Vs athlete’s heart

Predominant eccentric hypertrophy with enlarged LV cavity size and a small degree of concentric hypertrophy with
uniformly increased LV wall thickness.

Vs severe coronary artery disease

Manifests as a dilated cardiomyopathy with an enlarged LV cavity and thin LV walls with impaired systolic fx
Clopidogrel irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface and prevents platelet
aggregation. Clopidogrel is as effective as aspirin in the prevention of CA events in px with coronary heart disease

Vs eptifibatide: is a platelet glycoprotein IIb/IIIa inh that inh the final common pathway of platelet aggregation.
Eptifibatide is occasionally used in some px with acute coronary syndrome, but it is not used for px w/ stable CHD

Vs LMWHs; are indirect thrombin inh that bind with antithrombin and convert it from a slow to rapid inactivator of
thrombin and factor Xa. They are used in px with acute coronary syndrome (unstable angina or myocardial infarction)

Vs. apixaban: direct factor Xa inh that prevents platelet activation and fibrin clot formation. Warfarin inh an enzyme
required for synthesis of active vit K, resultin gin decreased synthesis of vit K-dependent clotting factors (II, VII, IX, and
X). Both apixaban and warfarin are typically used for prevention and/or tx of thromboembolic events not coronary
artery disease.

TX: (11745)

- ACE Inh
- Beta blockers
- Angiotensin II receptor blockers
- Additional therapy: those involving natriuretic peptides
- ANP and BNP are released from the myocardium in response to high atrial and ventricular filling pressures
(myocardial stretch). These peptides induce vasodilation and diuresis by antagonizing the actions of RAAS and
also protect against the deleterious myocardial remodeling and fibrosis that occur in heart failure. Neprilysin is a
metalloprotease that cleaves and inactivates both ANP and BNP. Therefore, medications that inh neprilysin (eg,
sacubitril) lead to increased levels of ANP and BNP and promote beneficial effects of HF
However because neprilysin is also responsible for inactivating angiotensin II, inhibition of neprilysin further
stimulates deleterious vasoconstriction and fluid retention via increased angiotensin II levels. Therefore, in
treating heart failure, neprilysin inh are combined with an angiotensin II-receptor blocker (eg, sacubitril-
valsartan) to mitigate these negative effects.

acute pericarditis

(89)

Peri-infarction pericarditis (PIP) occurs between 2 and 4 days following a transmural myocardial infarction. PIP is an
inflammatory reaction to cardiac muscle necrosis that occurs in the adjacent pericardium.

Vs. dressler syndrome (postcardiac injury syndrome) is an autoimmune-mediated pericarditis that is likely provoked by
antigens exposed or created by infarction and necrosis of the cardiac muscle. It is less common and has later onset than
PIP, typically occurring a week to a few months after an MI.

(15000)

viral infection is thought to be the most common cause of acute pericarditis. It causes a fibrinous or serofibrinous
pericarditis that is often characterized by pleuritic chest pain, a friction rub on cardiac auscultation, diffuse ST elevation
on ECG, and mild to moderate-sized pericardial effusion

Constrictive pericarditis (98)

Etiology - Idiopathic or viral pericarditis
- Cardiac surgery or radiation therapy
- Tb (in endemic areas)
Pathogenesis - Rigid pericardium prevents ventricular expansion and restricts diastolic filling
- Predominantly right-sided manifestations
PE - Increased jugular venous pressure: with prominent x and y descents
- Pericardial knock: early diastolic sound that occurs before S3
- Pulsus paradoxus: >10 mmHg drop in systolic blood pressure during
inspiration
- Kussmaul sign
*under normal circumstances, the decrease in intrathoracic pressure during inspiration increases venous return to the
right side of the heart and lowers JVP. However, in constrictive pericarditis, the rigid pericardium prevents the right side
of the heart from accommodating increased venous return, which leads to paradoxical rise in JVP during inspiration,
referred to as Kussmaul sign.

(14999) fibrinous pericarditis is the most common type of pericarditis and consists of pericardial inflammation with
serous fluid and fibrin-containing exudate in the pericardial space.

Fibrin deposition causes roughening of the visceral and parietal pericardium, often heard as a triphasic friction rub
(occurring during atrial systole, ventricular systole, and early ventricular diastole) on cardiac auscultation; however, the
rub can be absent if significant pericardial effusion is present. ECG typically shows diffuse ST elevation due to
inflammation of the ventricular myocardium.

Jugular venous pulse

Retinal artery occlusion (11832)

Retinal artery occlusion is a cause of acute, painless, monocular vision loss. It is usually caused by thromboembolic
complications of atherosclerosis traveling from the internal carotid artery and through the ophthalmic artery.

Chronic venous insufficiency (474)

Amyloidosis (94)

- Progressive exertional dyspnea

- Edema
- Ascites
- Elevated JVP with rapid ‘y’ decent
- Prominent S4
- Echo findings: LA enlargement, LV hypertrophy, normal ejection fraction
 Diastolic heart failure due to restrictive cardiomyopathy

Restrictive cardiomyopathy due to amyloidosis results from abnormal extracellular deposition of insoluble proteins such
as monoclonal light chains (AL amyloidosis), mutated transthyretin (familial ATTR amyloidosis), or wild type transthyretin
(senile systemic amyloidosis) in myocardial tissue. Endomyocardial biopsy typically reveals cross-sections of normal
myocardial cells with other areas of myocardium infiltrated by an amorphous and acellular pink material. Congo red
stain classically shows apple-green birefringence under polarized light microscopy

Restrictive cardiomyopathy (93)

Diastolic HF is caused by decreased ventricular compliance and is characterized by normal LV ejection fraction, normal
LV end-diastolic volume and elevated LV filling pressures. HTA, obesity and infiltrative disorders (eg, transthyretin-
related amyloidosis, sarcoidosis) are important causes of DHF.

Vs viral myocarditis (15310)

May lead to dilated cardiomyopathy with eccentric hypertrophy and impaired LV systolic fx
Acute Heart Failure

(15528)

Asymptomatic LV systolic dysfunction is a common stage in the progression of HF. Neurohormonal mechanisms,
including the sympathetic nervous system and renin-angiotensin-aldosterone system, help maintain the asymptomatic
period by increasing volume retention and peripheral resistance to maintain organ perfusion. Although these
mehcanisms are beneficial in the short term, they are ultimately deleterious, increasing hemodynamic stress and cardiac
remodeling that eventually lead to decompensated heart failure.

(1585)

Left-sided heart failure is common following myocardial infarction affecting the left ventricle. The resulting accumulation
of edema in the pulmonary interstitium makes the lungs heavy and stiff, restricting inspiratory expansion and decreasing
lung compliance.

(15535)

Shortness of breath + abd distension (ascites) + hepatomegaly + JVD + lower extremity edema -> right-sided heart failure

(7676) engorged alveolar capillaries reflect increased pulmonary venous pressure, and pink, acellular material within the
alveoli results from transudation of fluid plasma across the alveolar-capillary membrane. These histopathologic findings
are most consistent with acute pulmonary edema caused by increased alveolar capillary hydrostatic pressure from left-
sided heart failure. This px likely had dilated cardiomyopathy due to chronic alcohol abuse and had an acute
exacerbation of heart failure, resulting in cardiogenic shock with pulmonary edema and acute respiratory failure

Vs. aspiration pneumonia may be chemical (eg, aspiration of gastric contents) or bacterial (eg, aspiration of oral flora).
Histopathology shows neutrophil-rich, inflammatory exudates within the bronchioles and alveolar spaces.
Congestive hepatopathy

In congestive heaptopathy, outflow of blood from the hepatic veins is impeded by elevated right atrial and vena caval
pressures, which leads to increased hydrostatic pressure in the central veins of the liver. There is consequent seepage of
fluid into the surrounding hepatocytes with resulting congestion and hepatic necrosis. The hepatocellular dmg favors the
centrilobular areas (zone 3) where congestion is most prominent. On microscopy, patchy hemorrhage is seen
surrounding the central veins consistent with centrilobular necrosis. These areas of necrosis contrast with the relatively
normal-appearing hepatocytes in the periportal regions (zone 1), creating an overall heterogenous appearance
sometimes referred to as “nutmeg liver”

(15650) anthracycline chemotherapeutic agents (eg, doxorubicin) are a common cause of dilated cardiomyopathy and
can precipitate symptomatic HF that presents years after exposure. Px with decompensated HF have elevated LV end-
diastolic pressure and decreased CO that is most often primarily due to LV dysfunction. Right atrial pressure (ie, central
venous pressure) is also elevated in advanced HF due to volume overload; right-sided heart failure (most often occurring
secondary to left-sided failure) can also contribute to elevated right atrial pressure.

Hypovolemic shock (1512)

The most important intervention other than ID and eliminating the source of bleeding is rapid infusion of blood products
and crystalloid solutionsn such as normal saline. By infusing IV fluids, intravascular volume and ventricular preload can
be increased rapidly. The increase in preload streatches the myocardium and increases the end-diastolic sarcomere
length, leading to an increase in stroke volume and CO by the Frank-Starling mechanism.

Atrial myxoma (14997)

Myxomas are the most common primary cardiac neoplasm and approximately 80% originate in the LA. Px may present
with symptomatic mitral valve obstruction that may worsen with certain body positions, constitutional findings (eg,
fever, weight loss), or systemic embolization (eg, stroke, mesenteric ischemia, acute limb ischemia)

Histopatho: amorphous extracellular matrix with scattered stellate myxoma cells in mucopolysaccharide ground
substance

(14998) Approximately 80% originate in the left atrium, and they can present with systemic embolization (Eg, stroke)
from tumor fragments passing into the systemic circulation. The tumors may also lead to constitutional symptoms (eg,
fatigue, weight loss, low-grade fever) resulting from cytokine release, and they may cause transient mitral valve
obstruction, leading to symptoms that can mimic mitral valve stenosis (eg, dyspnea, orthopnea, hemoptysis)

PE often reveals an intermittent or positional mid-diastolic murmur (“tumor plop”) that results from the motion of the
tumor mass obstructing the mitral valve orifice. Histopathologic examination of a myxoma reveals amorphous
extracellular matrix with scattered stellate or globular myxoma cells within abundant mucopolysaccharide (myxoid)
ground substance containing chondroitin sulfate and hyaluronic acid. Because of their high vascularity, these tumors
often demonstrate areas of hemorrhage accompoanied by brown, hemosiderin-laden macrophages.

(8296)

Histologically, these tumors demonstrate scattered cells within a mucopolysaccharide stroma and abnormal blood
vessels. Myxomas produce a large amount of vascular endothelial growth factor, which contributes to the angiogenesis
(white arrows), hemorrhaging (seen as a brown hemosiderin deposits), and friability characterizing these tumors.

BNP/ANP (15651)

Volume overload leads to stretching and increased wall stress of the ventriucular walls. In response, the ventricular
myocardium releases BNP; similarly, the atrial myocardium releases ANP in response to atrial stretching. These
natriuretic peptides stimulate both venous and arterial vasodilation to decrease cardiac preload and afterload and
reduce strain on the myocardium. In addition, ANP and BNP stimulate salt and water excretion by the kidneys to
facilitate diuresis.

Cor pulmonale

Peripheral edema (1578)

Peripheral edema results from the accumulation of fluid in the interstitial spaces. Factors that promote edema include
elevated capillary hydrostatic pressure, decreased plasma oncotic pressure, sodium and water retention, and impaired
lymphatic drainage. In chronic heart failure, increased lymphatic drainage initially offsets factors favoring edema,
whereas acute changes (eg, venous thrombosis, heart failure decompensation) are more likely to produce edema.

Cardiac catheterization (11764)

The optimal site for obtaining vascular access in the lower extremity during cardiac catheterization is the common
femoral artery below the inguinal ligament. Cannulation above the inguinal ligament can significantly increase the risk of
retroperitoneal hemorrhage.

Atherosclerosis

(446)
Formation of atheroma

- Initially factors including hyperlipidemia, HTA, hyperglycemia and smoking trigger endothelial injury and/or
dysfunction. This leads to increased vascular permeability, enhanced leukocyte adhesion, and a higher
propensity for thrombosis
- Lipoproteins (ie, LDL and oxidized LDL) enter the arterial wall intima and begin to accumulate. Monocytes
adhere to the endothelial wall and enter into the intima as well; these cells transform into macrophages and
engulf lipid particles to become foam cells. Platelets adhere to the abnormal endothelium and become activated
- Growth factors, namely platelet-derived growth factor (PDGF), are released from platelets, activated
macrophages, and endothelial cells. This triggers smooth muscle cell (SMC) recruitment from the media and
proliferation in the intima

(447) the likelihood of plaque rupture is related to plaque stability rather than plaque size or the degree of luminal
narrowing. Plaque stability largely depends on the mechanical strength of the fibrous cap. Inflammatory macrophages in
the intima may reduce plaque stability by secreting metalloproteinases, which degrade extracellular matrix proteins (eg,
collagen).

(39)

Gradually developing myocardial ischemia encourages the formation and maturation of collateral vessels and is most
likely to occur in the setting of a slow-growing, stable atherosclerotic plaque. An unstable atherosclerotic plaque (eg,
that with active inflammation, a lipid-rich core, and/or a thin fibrous cap) is more likely to rupture, resulting in the
abrupt onset of ischemia/infarction that precludes the development of viable collateral vessels.

(11636) the most susceptible vascular regions involve bends and branch points that encourage turbulent blood flow,
which disrupts vascular wall integrity and leads to endothelial cell dysfunction. Turbulent blood flow also leads to
decreased shear stress on the vascular walls and prolonged endothelial contact with cholesterol particles. The
hemodynamics of the lower abd aorta and the coronary arteires make these vascular beds the most susceptible to
atherosclerosis of all the major vascular beds in the body. In fact, atherosclerotic lesions (eg, intimal thickening, fatty
streaks) occur in these vessels as early as the second decade of life.

Endocarditis (12187)

Aortocavitary fistulas are uncommon complication of bacterial endocarditis (caused by extension of the infection from
the valve to the adjacent myocardium)

During the normal cardiac cycle, central aortic pressure (120/80 mmHg) is higher than RV pressure (25/5 mmHg) during
systole and diastole. Consequently, an intracardiac fistula between the aortic root and RV will most likely demonstrate a
left-to-right cardiac shunt as blood continuously flows from the aortic root (high pressure) to the RV (low pressure).

(231) sterile platelet-rich thrombi attached to the mitral valve leaflets is characteristic of nonbacterial thrombotic
endocarditis (NBTE) (marantic endocarditis). The pathogenesis of NBTE is thought to begin with valvular endothelial
injury caused by circulating inflammatory cytokines, which triggers platelet deposition in the presence of an underlying
hypercoagulable state. NBTE is most commonly associated with advanced malignancy (especially mucinous
adenocarcinoma) and systemic lupus erythematosus (Libman-Sacks endocarditis); less commonly, it can occur with
antiphospholipid syndrome, disseminated IV coagulation and extensive burns

Histologically, NBTE vegetations consist of bland thrombus with strands of fibrin, immune complexes, and mononuclear
cells (white thrombus). The vegetations typically affect the left-sided heart valves (mitral or aortic) and are often
asymptomatic; however, systemic embolization (eg, stroke, acute limb ischemia) can occur and is the most common
presentation of NBTE.

Aortic aneurysm

(462)

Myxomatous changes with pooling of proteoglycans in the media layer of large arteries are found in cystic medial
degeneration, which predisposes to the development of aortic dissections and aortic aneurysms. Medial degeneration is
frequently seen in younger individuals with Marfan syndrome.

Medial degeneration is characterized by the fragmentation of elastic tissue (“basket weave” pattern) and separation of
the elastic and fibromuscular components of the tunica media by small, cleft0like spaces that become filled with
amorphous extracellular matrix.

Beta aminopropionitrile (a chemical found in certain kinds of sweet peas) causes inh of lysyl oxidase, an enzyme
responsible for cross-linking elastin fibers and collagen fibers. Ingestion of this compound can cause a change in the
elasticity of the aorta that mimics the myxomatous degeneration seen in px with marfan syndrome.

(463)

Inflammatory cells (particularly macrophages) release matrix metalloproteinases and elastases that degrade
extracellular matrix components (Eg, elastin, collagen), leading to weakening and progressive expansion of the aortic
wall. Furthermore, ischemia of the tunica media may play a role as the infrarenal abdominal aorta has a tenuous vasa
vasorum, and atherosclerotic thickening of the intimal layer increases the diffusion distance for oxygen.

(15839) Complications:

- Impinges upon the esophagus -> dysphagia

- Compression of the left recurrent laryngeal nerve or left vagus nerve -> hoarseness
- Compression of the phrenic nerve ->hemidiaphragmatic paralysis
- Respiratory manifestations: wheeze, cough, hemoptysis and dyspnea may occur due to tracheobronchial
obstruction
- Other complications: HF due to aortic valve regurgitation and superior vena cava syndrome from venous
compression and occlusion

Aortic dissection (473)

This CT reveals a widened, ascending thoracic aorta with a nonenhancing septum dividng the lumen of the ascending
and descending aorta. The “septum” is actually the tunica intima of the aorta, which has been torn from the remainder
of the aortic wall. A tear in the tunica intima is thought to be the primary event in the process leading to aortic
dissection. HTA is the single most important risk factor for the development of intimal tears leading to aortic dissection.

Myocardial infarction

(37)

ST-elevation myocardial infarction involves transmural (full-thickness) infarction of the myocardial wall, and usually
results from acute atherosclerotic plaque rupture with the development of overlying thrombus that fully occludes the
coronary artery lumen. It classically presents with sudden-onset substernal chest pain that is not relieved by rest or
short-acting nitrates. ECG demonstrates ST elevation in the affected leads with subsequent development of Q waves.

VS. non-STEMI is associated with impaired blood flow to only the subendocardial region; the symptomatic presentation
is similar to STEMI, but ECG reveals ST segment and T wave abnormalities with no ST elevation

VS. Atherosclerotic plaque obstructing 80% of the coronary artery lumen is likely to cause stable angina, characterized
by substernal or left-sided chest pressure, tightness or pain that is precipitated by exertion and relieved by rest of short-
acting nitrates.

(42) loss of cardiomyocyte contractility occurs within 60 s after the onset of total ischemia. When ischemia lasts less
than 30 min, restoration of blood flow leads to reversible contractile dysfunction (myocardial stunning), with
contractility gradually returning to normal over the next several hrs to days. However, after about 30 min of total
ischemia, ischemic injury becomes irreversible.

(192) SCD typically occurs due to malignant ventricular arrhythmias (sustained ventricular tachycardia/fibrillation), and it
is related to coronary heart disease in approximately 70% of the p. ventricular fibrillation is the most frequent
mechanism of SCD in the first 48 hrs after acute MI and is related to electrical instability due to ac of perfusion in the
ischemic myocardium

(1882) when blood flow cannot meet myocardial demands, cardiac myocytes transition from aerobic to anaerobic
metabolism. However, anaerobic metabolism cannot maintain proper intracellular ATP levels, and ADP, AMP and
adenosine accumulate. Without ATP, the membrane Na+/K+-ATPases and the sarcoplasmic reticulum Ca2+-ATPases fail,
leading to increased intracellular Na+ and Ca2+ and increased intramitochondrial Ca2+ concentrations. These increased
concentrations attract free water, causing cellular and mitochondrial swelling. Failure of the sarcoplasmic reticulum to
resequester Ca2+ leads to cessation of contraction within ischemic zones of myocardium.

(11833)

The inferior wall of the LV is suppled by the posterior descending artery, which arises off the dominant right coronary
artery. Because the right coronary artery also gives off marginal branches that supply most of the RV, inferior wall MI is
often associated with right ventricular infarction. Right-sided HF typically presents with hypotension and distended
jugular veins, but the lungs are clear unless significant left-sided heart failure is also present. This px’s lack of crackles on
lung auscultation and absence of pulmonary edema on chest x-ray is indicative of isolated RV dysfunction

RV infarction decrease RV stroke volume, which in turn leads to diminished LV filling and CO despite preserved LV
systolic fx, resulting in hypotension and shock. Because left-sided filling pressures are reduced, pulmonary capillary
wedge pressure (PCWP) also decreases as it reflects left atrial pressure. In addition, px have elevated central venous
pressure due to impaired forward flow and backup of blood into the systemic venous system.

(8711)

Time after MI Predominant light microscopic changes

0-4 hrs - No visible change
4-12 hrs - Wavy fibers with narrow, elongated myocytes
12-24 hrs - Myocyte hypereosinophilia with piknotic (shrunken) nuclei
1-3 days - Coagulation necrosis (loss of nuclei & striations)
- Prominent neutrophilic infiltrate
3-7 days - Disintegration of dead neutrophils & myofibers
- Macrophage infiltration at border areas
7-10 days - Robust phagocytosis of dead cells by macrophages
- Beginning formation of granulation tissue at margins
10-14 days - Well developed granulation tissue with neovascularization
2 weeks-2 months - Progressive collagen deposition & scar formation
- Fibrosis continues until about 2 months after infarction, resulting in dense collagenous
scar composed primarily of type I collagen

(193) LV free wall rupture usually occurs within 5-14 days after an initial myocardial infarction and presents with sudden
onset of chest pain, profound shock, and rapid progression to death. Morphologically, ruptures appear as a slit-like tear
in the infarcted myocardium, with a preference for the left ventricle due to higher systolic pressures.

(12144) papillary muscle rupture is a life-threatening complication that typically occurs 3-5 days after myocardial
infarction and presents with acute mitral regurgitation and pulmonary edea. The posteromedial papillary muscle is
supplied solely by the posterior descending artery, making it susceptible to ischemic rupture.

(10467)
ECG infarct localization

Heart sounds

(2108)

S3 can be normal in young individuals and pregnant px, its presence in those age >40 is typically a sign of left ventricular
volume overload/failure. In early diastole, the ventricles relax and the AV valves open, allowing blood to rush in and fill
the ventricles. An S3 develops with forceful rapid passive filling that exceeds the expansion capacity of the ventricle,
leading to sudden deceleration of the entering blood column and reverberation of the ventricular walls. As a result, S3 is
often heard in pathologic settings causing high ventricular filling pressures and/or volume overload, particularly aortic or
mitral regurgitation and dilated cardiomyopathy

(15198)

Cardiac murmurs

Cardiac auscultotary locations

Splitting S2

Pulmonary stenosis

- Most commonly occurs as an isolated congenital defect and rarely occurs as an acquired defect (eg, rheumatic
fever, carcinoid syndrome)
- Typically dx early in life due to px w/ right-sided heart failure, but px with relatively mild PS often remain
asymptomatic throughout childhood and develop symptoms (eg, dyspnea, fatigue) in adulthood
 - The physiologic changes of pregnancy (eg, increased plasma volume) can unmask underlying PS
- Cardiac auscultation in PS reveals a pulmonic ejection click followed by a harsh crescendo-decrescendo systolic
murmur best heard at the left upper sternal border. The stenosis causes the pulmonic valve to close later than
usual as it takes longer for the right ventricle to push blood through the narrowed valve. This results in widened
splitting of the aortic and pulmonic components of S2. Inspiration draws additional blood into the right side of
heart, which increases the intensity of the murmur and further widens the splitting of S2

VS. benign flow murmur can occur in px with high CO states (eg, pregnancy) due to increased flow across the aortic and
pulmonic valves; however, the murmur is typically low grade (2/6 or less) and abnormal spltting of S2 is not present

VS. bicuspid aortic valve is the most common congenital heart defect seen in adults and can lead to aortic stenosis in
relatively young px (eg, those in their 50s). However, aortic stenosis causes delayed closure of the aortic valve, leading to
narrowed or even paradoxical splitting of S2.

VS. HCM can cause a systolic murmur that mimics that of aortic stenosis and is best heard at the mid-left sternal border.
Splitting of S2 may be narrowed due to prolonged ejection of blood through the aortic valve

VS. VSD, there is typically widened spltting of S2 due to early closure of the aortic valve (less blood is ejected into the
aorta because some blood is ejected into the right ventricle). However, a holosystolic murmur best heard at the left
lower sternal border is expected

PDA (2109) is characterized by a continuous murmur heard best in the left infraclavicular region with maximal intensity
at S2. A small PDA is often asymptomatic and is usually detected incidentally during routine cardiac auscultation. It
occurs most commonly in px born prematurely and those with cyanotic congenital heart disease.

Mitral regurgitation

(14987)
(944)

A holosystolic murmur at the apex with radiation to the axilla is consistent with mitral regurgitation (MR). The murmur is
generated by regurgitant blood flow from the left ventricle back to the left atrium during systole. Results in in:

- elevated pressure and blood volume in the left atrium -> increases the amount of blood reentering the left
ventricle during diastole
- audible S3 gallop occurs when the left ventricle is unable to accommodate the excess blood flow (best indicator
of severe MR with left sided volume overload, absence of this can be used to exclude severe chronic MR)

*S3 is generated by the sudden cessation of blood flow into the LV during the passive filling phase of diastole. A higher
volue of blood flow or a more dilated left ventricle is more likely to produce an S3

S4

A low-frequency diastolic sound that occurs during the atrial kick of ventricular diastole, and it reflects blood colliding
with a stiff ventricular wall. It can be normal in healthy older adults, but it can also indicate pathology such as
hypertrophic cardiomyopathy or concentric left ventricular hypertrophy (eg, due to hypertension or aortic stenosis)

(943) in px with MR, some of the blood in the LV is pumped forward through the aortic valve (forward stroke volume),
and some is forced backward through the incompetent mitral valve (regurgitant stroke volume). The amount of blood
flowing down each pathway is determined by the relative contribution of the resistnace of each pathway to the total left
ventricular afterload:

- Resistance to forward flow is primarily determined by the pressure in the aorta (systolic blood pressure)
 - Resistnace to regurgitant flow is determined by the mitral valve orifice size during systole and the degree of left
atrial compliance. In chronic MR, the left atrium becomes more compliant and the lower left atrial pressures
facilitate greater regurgitant flow.

LA pressure remains relatively constant over the short term, but aortic pressure can vary significantly with changes in
systemic vascular resistance. A reduction in systemic vascular resistance leads to reduced systemic blood pressure and
an increase in the ratio of forward to regurgitant blood flow. Pharmacologic vasodilators (eg, nitroprusside) therefore
help to increase forward CO and reduce pulmonary congestion in px with MR.

(11851)

(14987)

MI that develops a new systolic murmur that resolved following revascularization, which is consistent with MR due to
papillary muscle dysfunction. MI can cause ischemia of the papillary muscle and the adjacent LV wall on which it is
mounted. This results in hypokinesis and outward displacement of the papillary muscle, creating increased tension on
the attached chordae tendineae and preventing complete colosure of the corresponding mitral valve cusp. Timely
restoration of adequate blood supply with coronary revascularization restores papillary muscle and LV wall motion,
often leading to resolution of MR.

Aortic stenosis

(242) Calcific degeneration of the trileaflet aortic valve is the most common cause of aortic stenosis (AS) in developed
nations. AS is characterized by progressive aortic valve leaflet thickening and calcification, leading to restricted leaflet
excursion and mobility. AS murmur is usually a harsh ejection-type systolic murmur heard best at the base of the heart
in the “aortic area” (second right intercostal space) with radiation to the carotid arteries.

(244) Px with chronic aortic stenosis and concentric LV hypertrophy, atrial contraction contributes significantly to LV
filling. Loss of atrial contraction due to atrial fibrillation can reduce LV preload and CO sufficiently to cause systemic
hypotension. Decreased forward filling of the LV can also result in backup of blood in the LA and pulmonary veins,
leading to acute pulmonary edema.
(2106) a bicuspid aortic valve is a common cause of aortic stenosis in the US. The classic auscultatory finding in px with
aortic stenosis is a harsh, crescendo-decrescendo systolic ejection murmur heard best in the right second intercostal
space with radiation to the carotids.

(14964)

Soft S2 and late-peaking systolic ejection murmur that decreases in intensity with maneuvers that decreast LV blood
volume (eg, abrupt standing, Valsalva straining phase) are consistent with aortic stenosis, which most commonly occurs
due to age-related calcific aortic vavlve disease (CAVD)

The early pathogenesis of CAVD is analogous to that of arterial atherosclerosis. The endothelium lining the aortic side of
the aortic valve cusps is exposed to the same high pressure and turbulatne blood flow as the aortic vascular
endothelium. As occurs with atheroma development in the vascular endothelium, these mechanical forces (along with
smoking, hyperglycemia and hyperlipidemia) over time cause dmg to the aortic valve cusp endothelium, triggering
endothelial dysfunction and the onset of a simiar atherosclerotic process. There is subendothelial lipid deposition and
infiltration of inflammatory cells (ie, macrophages, T cells) followed by the release of inflammatory mediators (Eg, il-1-
beta, transforming growth factor beta-1)

Subsequently there is increased production of proteins involved in tissue calcification (eg, osteopontin). Fibroblasts
differentiate into osteoblast-like cells, leading to aberrant bone matrix deposition with progressive valvular calcification
and stenosis.

Chronic aortic regurgitation (238)

(2105)

When AR is due to aortic root dilation (Eg, in Marfan syndrome) the murmur is best heard at the right upper sternal
border (classic aortic valve auscultatory location). However, for AR due to valvular pathology (eg, bicuspid aortic valve,
rheumatic heart disease) the murmur is best heard at the left third intercostal space. In either scenario, the murmur is
best appreciated at the end of expiration with the px leaning forward (minimized lung volume with the heart closer to
the chest wall enhances left-sided murmurs)

Mitral regurgitation (200)

Decompensated heart failure is a common cause of secondary (functional) mitral valve regurgitation. Increased left
ventricular end-diastolic volume causes dilation of the mitral valve and restricted movement of the chordae tendineae
with subsequent regurgitation. Tx with diuretics and vasodilators can improve heart failure-induced MR.

Causes of primary MR: bacterial endocarditis, connective tissue disease (Marfan), or acute myocardial infarction,
rheumatic heart disease

Mitral valve prolapse (944)

- A mid-systolic click
- Casued by sudden tensing of the chordae tendineae as they are pulled taut by the valve leaflets ballooning into
the left atrium
- The timing of the click varies with left ventricular volume; it occurs earlier in systole with physical maneuvers
that decrease left ventricular volume
- + regurgitation is the most common predisposing condition for native valve infective endocarditis in developed
nations.

Mitral or tricuspid stenosis

- Opening spanp in early diastolic sound heard after S2

- S2-to-opening snap interval is the time between the closure of the aortic valve and the abrupt halting of leaflet
motion during opening of a stenotic mitral valve
- A shorter S2-to-opening snap interval is indicative of more severe mitral stenosis

(947) presence of a midsystolic click followed by a mid- to late systolic murmur at cardiac apex that disappears with
squatting is most consistent with mitral valve prolapse with mitral regurgitation. The click results from sudden tensing of
the chordae tendineae as they are pulled taut by the ballooning valve leaflets. The murmur is due to malalignment of
the valve margins during systole. Maneuvers that change left ventricular volume and cavity size can change the timing
and intensity of the murmur. Squatting from a standing position increases venous return and LV volume, helping to bring
the valve leaflets into a more normal anatomic arrangement. This, in turn decreases the degree of MVP, causing a delay
in the onset of click during systole, and the systolic murmur typically becomes shorter or disappears.

Primary MVP is most commonly a sporadic disorder and is characterized by myxomatous degeneration (ie, pathologic
deterioration of the connective tissue) affecting the mitral valve leaflets and chordae tendineae. Secondary MVP is
associated with inherited connective tissue disorders, including Marfan or Eherlers-Danlos syndrome and osteogenesis
imperfect. The myxomatous lesions are characterized by proliferation of spongiosa of the valve leaflets, fragmentation
of elastin fibers with increase in mucopolysaccharide and type III collagen deposits.

Pulmonary valve stenosis

- It delays pulmonic valve closure even further and accentuates the normal splitting of S2
 In normal physiology, venous return to the right side of the heart increases during inspiration, resulting in
delayed closure of the pulmonic valve in relation to aortic valve closure. Inspiratory splitting of the aortic
and pulmonic components of S2 can be appreciated on auscultation
Mitral stenosis

(236) in rare instances, the left recurrent laryngeal nerve may be compressed to the point of neurapraxia (failure of
nerve conduction due to blunt injury) by enlargement of the LA and/or other structures in the vicinity of its course as it
loops behind the ligamentum arteriosum, underneath and around the aortic arch, and back up alongside the trachea to
the larynx. Mitral stenosis can cause LA dilation sufficient to impinge on the left recurrent larynageal nerve (Ortner
syndrome).

The recurrent laryngeal nerves innervate all of the intrinsic muscles of the larynx except the cricothyroid muscle. Paresis
of vocal cord muscles innervated by left recurrent laryngeal nerve can cause hoarseness.

(1517)

1. Isovolumetric contraction:
Begins: closure of MV point A (S1 sound)
Point B systemic diastolic blood pressure is reached and the AV opens
2. Ventricular ejection:
Begins: opening of AV at point B
3. Isovolumetric relaxation:
Begins: closure of AV at point C (S2 sound)
4. Ventricular filling:
Begins: opening of MV at point D

Mitral stenosis: extra heart sound (termed an opening snap) being heart shortly after the S2 heart sound (just after the
point D) A diastolic rumbling murmur is heard after the opening snap as a result of turbulent blood flow through the
stenotic MV during left ventricular filling. Prior rheumatic carditis is the most common cause of mitral stenosis

(233) on auscultation, the best indicator of mitral stenosis (MS) severity is the length of time between S2 (specifically the
A2 component, caused by aortic valve closure) and the opening snap (OS). The OS occurs due to abrupt tensing of the
valve leaflets as the mitral valve reaches its maximum diameter during forceful opening. As MS worsens, left atrial
pressures increase due to impaired movement of blood into the left ventricle. Higher pressure causes the valve to open
more forcefully; as a result, the A2-OS interval becomes shorter as left atrial pressure increases. The current standard for
dx and determination of MS severity is measurement of mean transvalvular pressure gradients via 2-D Doppler
echocardiography.

Hemodynamic of mitral stenosis (234)

Tricuspid regurgitation (1983)

A holosystolic murmur that increases in intensity on inspiration most likely represents tricuspid regurgitation. The other
holosystolic murmurs (which are secondary to mitral regurgitation or a ventricular septal defect) do not typically
increase in intensity during inspiration

Aortic regurgitation
(227)

The peak intensity of the murmur occurs just after aortic valve closure when the pressure gradient between the aorta
and the LV is maximal

(237)

In chronic AR, persistent LV volume overload triggers eccentric hypertrophy due to regurgitant flow volume -> increase
in left ventricular end-diastolic volume (LVEDV) (volume overload). This causes a compensatory increase in stroke
volume to maintain CO. This compensatory mechanism allows for a relatively long asymptomatic period in most px;
however, LV dysfunction eventually occurs, leading to HF.

(1661)

PE:

- Early “blowing”diastolic descrescendo murmur best heard at the left sternal border in the third or fourth
intercostal space
- Bounding femoral and carotid pulses (“water-hammer” pulses, result of the wide pulse pressure
- Head bobbing with carotid pulsations (de Musset sign) due to transfer of momentum from the large LV stroke
volume to the head and neck

Mechanical complication (14987)

Mechanical complications of acute myocardial infarction

Complication Time course Involved Clinical findings Echocardiogram
coronary artery findings
RV failure Acute RCA - Hypotension - Hypokinetic RV
- Clear lungs
 - Kussmaul sign
Papillary muscle Acute or within RCA - Severe pulmonary - Severe mitral
rupture 3-5 days edema regurgitation
- New holosystolic with flail leaflet
murmur
Interventricular Acute or within LAD (apical - Chest pain - Left-to-right
septum rupture 3-5 days septal) or RCA - New holosystolic ventricular
(basal septal) murmur shunt
- Biventricular failure - Increase O2
- Shock level from RA
to RV
Free wall rupture Within 5 days to LAD - Chest pain - Pericardial
2 weeks - Shock effusion with
- Distant heart sounds tamponade
Left ventricular Up to several LAD - Subacute heart failure - Thin &
aneurysm months - Stable angina dyskinetic
myocardial wall

Atrial fibrillation (1977)

AF is the most common cardiac arrhythmia and is characterized by absent P waves, irregularly irregular R-R intervals and
narrow QRS complexes. Rapid, irregular, low amplitude fibrillatory waves are also frequently seen and represent chaotic,
continuous atria depolarizations.

AF is initiated by aberrant electrical impulses that arise within regions of heightened atrial excitability (most commonly
the pulmonary veins).

Ventricular response in AF is dependent on the transmission of abnormal atrial impulses through the AV node. Each time
the AV node is excited, it enters a refractory period during which additional atrial impulses cannot be transmitted to the
ventricles, consequently the majority of atrial impulses never reach the ventricles.

Tx: diltiazem and verapamil: nondihydropyridine CCBs that are frequently used for HTA, angina pectoris and
supraventricular arrhythmias (atrial flutter, AF, paroxysmal supraventricular tachycardia)

These drugs exert their primary action by blocking the L-type calcium channels, thereby decreasing phase 0
depolarization and conduction velocity in the sinoatrial and AV nodes. This leads to slowing of the sinus rate and
conduction through the AV node, which can cause bradycardia and varying degrees of AV block. The drugs also have a
negative inotropic effect and are relatively contraindicated in px with CHF due to LV systolic dysfunction. Constipation is
a major side effect of nondihydropyridine CCBs (verapamil > diltiazem)

(2055) palpitations + tachy + irregular irregular rhythm => AF

Typically shows an absence fo P waves and irregularly irregular rhythm with varying R-R intervals. Some px have
irregular, low amplitude, fine fibrillatory waves (f waves) between the QRS complexes that represent the chaotic atrial
activation. AF is the most common tachyarrhythmia and is often precipitated by acute systemic illness or increased
sympathetic tone. It is occasionally seen in px after excessive alcohol consumption (“holiday heart syndrome”). Systiemic
illnesses that can precipitate AF include long-standing HTA, HF, and hyperthyroidism.

(14743)
Atrial fibrillation is recognized by an irregularly irregular rhythm with variable R-R intervals and absence of P waves on
ECG. The development of AF most commonly involves ectopic electrical foci in the pulmonary veins that trigger
fibrillatory conduction in abnormal (remodeled) atrial tissue.

Pulsus paradoxus (2099)

Drop of systemic arterial pressure <10 mmHg during inspiration is normal. Pulsus paradoxus refers to an exaggerated
drop (>10mmHg). It is most commonly seen in patients with cardiac tamponade but can also occur in severe asthma,
chronic obstructive pulmonary disease, and constrictive pericarditis.

Coronary blood flow

(179) ECG shows sinus brady + ST segment elevantion in leads II, III, and aVF consistent with transmural ischemic injury
to the inferior wall of the heart. In 90% of individuals, the posteroinferior wall of the LV is supplied by the posterior
descending branch of the right coronary artery (RCA). The px’s brady and resultant hypotension suggests that there may
have been ischemic injury to the sinus node as well. (The sinus node normally receives its arterial blood supply from the
RCA)

VS. the left main coronary artery gives rise to the left anterior descending (LAD) and the left circumflex (LCX) coronary
arteries. The LAD supplies the interventricular septum and the anterior wall of the left ventricle. Thransmural ischemia
of the septum would produce ST elevation mianly in leads V1 and V2. Infranodal (Mobitz type II) second-degree or third
degree heart block is a possible result as well; but sinus bradycardia would not occur with this type of injury. Transmural
ischemia of the anterior left ventricular wall would produce ST elevations mainly in leads V3 and V4. An occlusion of the
proximal LAD would cause anteroseptal transmural ischemia, with ST elevations in leads V1-V4.

The LCX supplies the lateral wall of the LV. Transumural ischemia secondary to LCX occlusion would produce ST
elevations mainly in leads V5 and V6, and possibley also in leas I and aVL. An occlusion of the left main coronary artery
would therefore be expected to produce widespread transmural ischemia of the IV septum and LV, with ST elevations in
all the chest (V) leads, and possibly also in leads I and aVL.

(11837)

Coronary dominance is determined by the coronary artery that supplies blood to the posterior descending artery (PDA,
or posterior interventricular artery). The PDA originates from one of the following:

- Right coronary artery in approximately 70% of the population (right dominant)

- Left circumflex artery in approximately 10% of the population (left dominant)
- Both right coronary and left circumflex artery in 20% of the population (codominant)

The AV nodal artery most often arises from the dominant coronary artery.

(1871) the inferior wall of the left ventricle forms most of the inferior (diaphragmatic) surface of the heart and is
supplied by the posterior descending artery. In 85%-90% of individuals, the posterior descending artery derives from the
right coronary artery (right dominant coronary circulation).

(2009) myocardial oxygen extraction exceeds that of any other tissue or organ; therefore, the cardiac venous blood in
the coronary sinus is the most deoxygenated blood in the body. Due to the high degree of oxygen extraction, increases
in myocardial oxygen demand can only be met by an increase in coronary blood flow.
(183) during ventricular systole, the coronary vessels supplying the LV are compressed by the surrounding muscle. As a
result, the majority of LV blood flow occurs during diastole. The systolic reduction in coronary blood flow is the greatest
in the subendocardial region, making this portion of the LV most prone to ischemia and infarction.

Pulmonary Arterial HTA (196)

Pulmonary HTA should be suspected in young and otherwise healthy px with fatigue, progressive dyspnea, atypical chest
pain, or unexplained syncope. Long-standing pulmonary HTA leads to hypertrophy and/or dilation of the RV (cor
pulmonale).

(2124) the most common cause of coronary sinus dilation evident on echocardiography is elevated right-sided heart
pressure secondary to pulmonary HTA

Tx: (14959)

Medical therapy for PAH targets the mediator imbalance created by endothelial dysfunction. Endothelin receptor
antagonists (eg, bosentan) are used to reduce vasoconstriction, while prostacyclin analogues (Eg, esoprostenol and NO –
enhancing agents (eg, sildenafil) are used to promove vasodilation. All of these agents help reduce tissue proliferation

(903) bosentan is an endothelin-receptor antagonist that blocks the effects of endothelin (a potent vasoconstrictor that
also stimulates endothelial proliferation). Bosentan therapy decreases pulmonary arterial pressure and lessens the
progression of vascular remodeling and right ventricular hypertrophy

Brachipcephalic Vein obstruction (1943)

The brachiocephalic vein drains the ipsilateral jugular and subclavian veins. The bilateral brachiocephalic veins combine
to form the superior vena cava (SVC). Brachiocephalic vein obstruction causes symptoms similar to those seen in SVC
syndrome, but only on one side of the body

Vasculitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (667)

The small to medium vessel vasculitis is characterized by late-onset asthma, rhinosinuisitis, and eosinophilia, though it
can involve many other organ systems including the kidneys, GI tract and CV system. Asymmetric multifocal neuropathy
(mononeuritis multiplex) is particularly common due to th evasculitis affecting the epineural vessels (eg, wrist drop due
to radial nerve involvement). Other common manifestations include skin nodules, migratory/transient pulmonary
infiltrates, and paranasal sinus abnormalities in addition to peripheral eosinophilia, a frequent lab finding is antibodies
against neutrophile myeloperoxidase, which most commonly have a pattern of perinuclear staining (p-ANCA).

Giant cell arteritis (461)

Giant cell arteritis

Symptoms - Systemic: fever, fatigue, malaise, weight loss
- Headache
- Jaw claudication
- Visual disturbances (eg, ischemic optic neuropathy)
- Polymyalgia rheumatic
Diagnosis - Elevated erythrocyte sedimentation rate & c-reactive protein
- Temporal artery biopsy: intimal thickening, elastic lamina fragmentation, multinucleated giant
cells
Treatment - Glucocorticoids

(914) is most common form of vasculitis in persons of northern European descent and occurs almost exclusively in px
age >50. About half of px with GCA will also have polymyalgia rheumatica, which causes achy pain in the shoulder and
hip girdles.

ESR and C-reactive protein have very high sensitivity for giant cell (temporal) arteritis.

(913) on light microscopic exam, granulomas are seen in the media of the arteries, consisting of mononuclear infiltrates
and multinucleated giant cells. The changes in the arteries are segmental: abnormal areas are interspersed by segments
of normal-appearing arterial wall.

(11770) although both humoral and cellular immune mechanisms have been implicated in the pathogenesis of GCA, cell-
mediated processes are of primary importance. The inflammatory infiltrate in affected vessels is composed of
lymphocytes (predominantly CD4-positive T cells) and macrophages and frequently contains multinucleated giant cells.
the production of cytokines, in particular IL-6, appears to closely correlate with the severity of the disease; a monoclonal
antibody against IL-6 (tocilizumab) is effective in treating GCA.

(450) about half of px with GCA will also have polymyalgia rheumatic, which causes achy pain in the shoulder and hip
girdles. GCA also confers a higher risk of thoracic aortic aneurysms, but not berry aneurysms

GCA is characterized by a T-cell- mediated inflammatory process of medium to large arteries. It may occur diffusely but
predominatly affects the arteries of the head and neck, especially the temporal artery (ie, temporal arteritis). Biopsy
specimens of the temporal artery will show scattered, focal granulomatous inflammation centered on the media with
intimal thickening, elastic lamina fragmentation and giant cell formation (without distinct granulomas). GCA is
histologically identical to Takayasu arteritis, which typically involves the aortic arch and affects primarily younger px.

Granulomatosis with polyangiitis (459)

Nasal mucosal ulcerations and glomerulonephritis are most characteristic of granulomatosis w/ polyangiitis (Wegener’s).
C-ANCAs are virtually pathognomonic for granulomatosis with polyantiitis, with a better than 90% specificity and
sensitivity. C-ANCA may also be useful as a quantitative measure of disease activity.

Smooth muscle cell antibodies are commonly seen in px with autoimmune hepatitis

Antierythrocyte antibodies hemolysis of an intravascular and/or extravascular type.

(13)

Crescent formation on light microscopy is dx of rapidly progressive (crescentic) glomeruolonephritis (RPGN). Can be
caused by several different disease and is classified based on immunologic findings:

- Antiglomerular basement membrane (anti-GBM) RPGN: Linear GBM deposits of IgG and C3 are found on
immunofluorescence. In some px, anti-GBM antibodies cross-react with pulmonary alveolar basement
membranes, producing pulmonary hemorrhages (Goddpasture syndrome)
- Immune-complex RPGN: there is a “lumpy-bumpy” granular pattern of staining for both antibodies (eg, IgG, IgA)
and complement on immunofluorescence microscopy. This can be a complication of poststrep
glomerulonephritis, SLE, IgA nephropathy or Henoch-Schonlein purpura
- Pauci-immune RPGN: there are no ig or complement deposits on the basement membrane, as with this px. Most
px have elevated serum titers of ANCA. This condition is oftn associated with vasculitides (eg, granulomatosis
with polyangiitis, microscopic polyangiitis) but can also be idiopathic.

Buerger disease (451)

Takayasu arteritis (452)

Risk factors - Female
- Asian
- Age <40
Clinical/laboratory findings - Constitutional: fever, weight loss, fatigue
- Arterio-occlusive: claudication, BP discrepancies, bruits, pulse deficits
- Visual & neurologic deficits
- Arthralgias & myalgias
- Elevated inflammatory markers (eg, CRP, ESR)
Histopathology - Granulomatous inflammation of arterial media
 - Transmural fibrous thickening, narrowing of lumen
- Predominantly affects aorta & its branches

Henoch Schonlein purpura (758)

(1850)

The effects of Henoch Schonlein purpura are seen most prominently in the following organ systems:

1. GI tract: intermittent severe abd pain is common in HSP. Vasculitis within the GI tract may result in upper and
lower GI bleeding (hematemesis and bloody diarrhea, respectively) as well as bowel wall edema. Px with HSP
also have an increased risk of intussusception.
2. Kidneys: renal involvement in HSP is identical to that seen in IgA nephropathy (Berger disease), a condition
characterized by IgA leukocytoclastic vasculitis limited to the kidney. Both diseases cause mesangial proliferation
and crescent formation
3. Skin: HSP classically causes “palpable purpura” on the buttocks and lower extremities. These lesions may begin
as urticarial papuls in HSP results from leukocytoclasis of cutaneous vessels.
4. Joints: self-limited migratory arthralgias and arthritis are most commonly seen in the large joints of the lower
extremities (ankle and knee joints), possibly because of their dependent nature.

(458) small vessel leukocytoclastic angiitis associated with IgA and C3 deposition is typical of HSP. HSP is most common
in children 3 to 11 yo and is most often related to recent infection. Most children present with palpable skin lesions, with
or without abd pain and arthralgias. Although usually self-limiting, px afflicted with HSP should be observed carefully
because glomerulonephritis and even end-stage renal disease are possible complications.

Pharmacology

Pharmacodynamics (551)

Although cortisol has no direct vasoactive properties, it augments the vasoconstrictive effects of catecholamines and
angiotensin II. The above graph shows that admn of norepinephrine produced a limited degree of vasoconstriction that
was markedly increased following pretx with cortisol. This effect is termed permissiveness and occurs when one
hormone allows another to exert its maximal effect. Cortisol exerts its potentiating effect in part through upregulation of
alpha-1 adrenergic receptors on vascular smooth muscle cells. In adrenal insufficiency, low glucocorticoid levels can
contribute to hypotensive crisis by decreasing vascular responsiveness to angiotensin II and norepinephrine.

Direct arteriolar vasodilators (1252)

Direct arteriolar vasodilators lower bp but trigger reflex sympathetic activation and stimulate the renin-angiotensin-
aldosterone axis. This results in tachycardia and edema. To counteract such compensatory effects, these agnets are
often given in combination with sympatholytics and diurectics.

This does not raise bp above baseline by reflex sympathetic activation unless they are discontinued abruptly

Vasodilators

Sodium nitroprusside (1652)

Is a short acting agent that causes balanced vasodilation of the veins and arteries; as such, it decreases LV preload and
afterload, allowing for maintenance of CO (unchanged stroke volume) at a lower LV pressure (decreased LV work). LV
contractility is essentially unchanged.

Nitrates (136)

Are metabolized within vascular smooth muscle cells to NO, which activates guanylate cyclase and promotes the
conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Increased levels of cGMP lead
to decreased intracellular calcium (reduces the activity of myosin light-chain kinase) and activation of myosion light
chain phosphatase. This promotes myosin light-chain dephosphrylation and vascular smooth muscle relaxation.

(138)

Nitrates exert their effect by direct vascular smooth muscle relaxation that results in:

- Vasodilation of the peripheral veins and arteries, predominantly venodilation

- Decreased left ventricular wall stress due to reduced preload (decreased left ventricular end-diastolic volume
and pressure)
- Modest reduction in afterload due to systemic arterial vasodilation
- Mild coronary artery dilation and reduction of coronary vasospasm

This results in decreased myocardial oxygen demand, leading to improved exercise tolerance and relief of angina
symptoms.

(137) pharmacologic nitrates (eg, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate) are metabolized to NO and
S-nitrothiols in vascular smooth muscle cells, leading to an increase in cyclic guanosine monophosphate (cGMP) that
stimulates vasodilation. Large veins are predominantly affected, leading to increased venous capacitance and reduced
venous return (preload), which decreases left ventricular wall stress and myocardial oxygen demand to relieve angina
syptoms.

(143) the interaction between nitrates and phosphodiesterase inh used in erectile dysfunction (tadalafil, sildenafil,
vardenafil) is well known and very important to understand. Nitrates are converted to nitric oxide by vascular smooth
muscle cells, and nitric oxide causes increased intracellular cGMP as a second-messenger. Increased cGMP concentration
leads to vascular smooth muscle relaxation. Additionally, cGMP is metabolized within the cells by phosphodiesterase,
and phosphodiesterase inh will lead to increased intracellular cGMP. cGMP accumulation in vascular smooth muscle
cells due to both enhanced synthesis (nitrates) and inh degradation (PDE inh) is responsible for profound hypotension
due to extreme vasodilation when these drugs are used together.

Antiarrhythmic drugs

Class I (sodium channel-blocking) antiarrhythmics (1509): inh initial phase 0 depolarization of action potential,
thereby slowing conduction
Specific Inh of phase 0 Effect on length of Comments
agents depolarization action potential
Clas Quinidine, Intermediate Prolonged Also have moderate potassium channel-blocking
s IA procainamide, activity, leading to slow rate of repolarization and
disopyramide prolongation of action potential
Clas Lidocaine, Weak Shortened Weak sodium channel blocking activity at rest;
s IB mexiletine however, it is quite effective in blocking sodium
channels in depolarized cardiac myocytes. Also
shorten phase 3 repolarization (blockade of “plateau”
Na+ current), thereby decreasing action potential
duration.
(900) tends to bind to inactivated Na channels and
rapidly dissociates. As a result, it is effective in
suppressing ventricular tachyarrhythmias induced by
rapidly depolarizing and ischemic myocardium
Clas Fleicainide, Strong No change Flecainide: Strongly blocks NA channels. Exhibits a
s IC propafenone slow rate of receptor dissociation that makes it more
effective at higher rates of depolarization
Class IC drugs: slow phase 0 depolarization but do not
affect action potential duration

Adenosine:

Activates potassium channels and increases potassium conductance by interacting with A1 receptors on the surface of
cardiac cels. This causes membrane hyperpolarization, resulting in transient slowing of the sinus rate and an increase in
atrioventricular (AV) nodal conduction delay. Adenosine does not modulate the ventricular myocyte action potential

Digoxin:

Exerts its antiarrhythmic effects by increasing vagal output to the AV node and conduction system, thereby slowing
conduction in these tissues, it does not alter the ventricular myocyte action potential, but it does increase intracellular
calcium in ventricular myocytes, leading to increased cardiac contractility

Calcium channel blockers (classIV antiarrhythmic drugs [eg, verapamil, diltiazem])

Inhibits L-type calcium channels, slowing depolarization in the sinoatrial and AV nodes and decreasing calcium entry into
cardiomyocytes, calcium channel blockers slow the sinus rate, prolong AV node conduction and depress myocardial
contractility

(4506)

Mexiletine: is a class IB antiarrhythmic drug that blocks sodium channels, inhibiting the initial depolarization phase
(phase 0) of the cardiomyocyte action potential. It is occasionally used to maintain sinus rhythm in px with paroxysmal
symptomatic atrial fibrillation, but it does not prolong the QT interval.

Metoprolol is a class II antiarrhythmic drug that is a selective beta-1 receptor antagonist. It acts as a negative inotropic
and chronotropic agent by decreasing myocardial contractility and HR. Unlike sotalol, beta blockers do not have any K+
channel-blocking properties and do not prolong the QT interval.

Sotalol (4506) has both beta adrenergic-blocking and class III antiarrhythmic (K+ channel-blocking) properties and is
occasionally used in tx of atrial fibrillation. Major side effects of sotalol include bradycardia, proarrhythmia, and most
commonly torsades the pointes due to QT interval prolongation.

Diltiazem is a class IV antiarrhythmic drug (calcium channel blocker) that inh L-type calcium channels during phase 2
(cardiomyocyte action potential) and phase 0 (nodal action potential) depolarization. It slows the sinus rate, prolongs
conduction through the AV node, and depresses myocardial contractility (negative inotropic effect) but does not prolong
the QT interval.

Effects of calcium channel blockers (145)

Drug Location of action Physiologif effects
Dihydropyridines (Amlodipine, Vascular smooth muscle Peripheral vasodilation
felodipine, nifedipine)
VerapamilC Cardiac muscle Reduced HR & myocardial contractility
Diltiazem Vascular smooth muscle & cardiac Combined effects
 muscle

1. Dihydropyridines (nifedipine, amlodipine, felodipine) primarily affect arterial smooth muscle, causing
vasodilation with little or no effect on cardiac conduction or contractility.
2. Nondihydropyridines (verapamil, diltiazem) affect the myocardium, slowing HR (negative chronotropic effect)
and reducing contractility (negative inotropic effect)

Amiodarone (899)

Class III antiarrhythmic drug used for supraventricular and ventricular arrhythmias. Class III drugs predominantly block
potassium channels and inh the outward potassium currengs during phase 3 of the cardiac action potential, prolonging
repolarization and total action potential duration. Very little risk of inducing torsades de pointes.

Sympathomimetic agents

(1365)

Norepinephrine (1367)

Receptor stimulated Change in second messenger Primary effects

Alpha 1 Increase IP3 - Peripheral vasoconstriction
- Urethral constriction
- Pupillary dilation (via radial
muscle contraction)
Alpha-2 Decrease cAMP - CNS sympatholytic
- Decrease insulin release by
pancreatic beta cells
- Decrease intestinal motility
Beta 1 Increase cAMP - Increase cardiac contractility
& heart rate
- Increase renin release by JG
cells of kidney
Beta 2 Increase cAMP - Peripheral vasodilation
- Bronchodilation
- Increase glucagon release by
pancreatic cells
Epinephrine (1364)

Dobutamine (11925)

Is a beta agonist with beta1>beta 2 + alpha 1 -> Gs protein GTP binding, leading to activation of adenylyl cyclase and
increased production of cAMP in the target cells. In cardiac myocytes, increased cAMP causes Ca2+ channel activation
and increased cytosolic Ca2+ concentration -> conformational change in the troponin complex, facilitating actin-myosin
binding and increasing myocardial contractility (positive inotropy). Increased cAMP also causes a rise in HR by increasing
Na and Ca channel activation in pacemaker cells (positive chronotropy).

In the vasculature, alpha 1 agonist (vasoconstriction) balances beta 2 agonist effect (vasodilation

Net hemodynamic effects: increase in cardiac contractility and a decrease in systemic vascular resistance without
significant change in arterial blood pressure.

(1344)

The strong inotropic effect of dobutamine significantly increases myocardial oxygen consumption, which can trigger or
exacerbate myocardial ischemia. As such, dobutamine should not be used routinely in px with decompensated HF.
However, in px with cardiogenic shock, this drawback is often outweighed by improvement in CO and end-organ
perfusion

Beta-blockers (1509)

Propranolol slows conduction through the AV node and prolongs phase 4 depolarization in cardiac pacemaker cells. Beta
blockers do not affect ventricular myocyte action potential; their primary site of action is on the AV node and cells with
automaticity
(2006) beta blockers decrease AV nodal conduction, leading to an increased AV nodal refractory period. This correlates
to PR interval prolongation on an ECG. Beta blockers (except sotalol, which also has class III properties) do not have any
specific effects on QRS or QT interval durations.

(1082) Fibrinolytic agents (eg, alteplase) are indicated in px with acute STEMI who cannot receive percutaneous
coronary intervention in a timely manner. Admn of these agents leads to breakdown of fibrin clot and often restoration
of myocardial perfusion; some px develop a self-limiting reperfusion-related arrhythmia (most commonly an accelerated
idioventricular rhythm)

(8289)

At low doses, atenolol is a selective beta 1 adrenergic antagonist. Beta 1 receptors are found in cardiac tissue and on
renal juxtaglomerular cells, but not in vascular smooth muscle. The beta 1 receptor is a G protein-coupled receptor
(GPCR) associated with Gs, which increases intracellular cAMP levels. Blockade of the Beta 1 receptor leads to decreased
cAMP levels in cardiac and renal tissue without significantly affecting cAMP levels in vascular smooth muscle.

ARBs

(691) work by blocking angiotensin II type 1 receptors, inh the effects of angiotensin II. This results in arterial
vasodilation and decreased aldosterone secretion. The resulting fall in BP increases renin, angiotensin I, and angiotensin
II levels. ARBs do not affect the activity of angiotensin-converting enzyme, and therefore they do not affect bradykinin
degradation and do not cause cough.

Nitrates (6489)

Exert their effect primarily by direct vascular smooth muscle relaxation, which causes systemic venodilation and
decreased peripheral venous return. This lowers end-diastolic left ventricular volume and pressure (decreased preload),
which reduces myocardial oxygen demand by decreasing systolic wall stress. Nitrates can also cause a modest reduction
in afterload due to systemic arterial vasodilation, which further reduces LV wall stress and myocardial oxygen demand.
Nitrates do not directly affect cardiac chronotropy and/or inotropy; however, the drop in systemic blood pressure
typically leads to reflex tachycardia.

Digoxin toxicity (147)

Symptoms of digoxin toxicity

Cardiac - Life- threateningarrhythmias (bradycardia and junctional
escape beats due to increased AV nodal block
GI - Anorexia
- Nausea & vomiting
- Abdominal pain
Neurologic - Fatigue
- Confusion
- Weakness
- Colorvision alterations
A-fib

First line: Ca2+ channel blockers and beta blockers

Second line: digoxin (px with underlying systolic cardiac dysfunction)

- Major effects:
. Increased vagal tone, slowing conduction through the AV node (rate-control effect)
 . Na-K ATPase inh, increased intracellular Na and Ca (increases cardiac contractility) [causes hyperkalemia]

Amiodarone:

- Pulmonary toxicity
- Thyroid dysfunction
- Cardiac arrhythmias
- Elevated liver enzymes
- Visual disturbances
- Bluish-gray skin discoloration

Aspirin:

Acute OD:

- Vertigo
- Tinnitus
- Vomiting
- Diarrhea

Severe OD:

- Coma
- Hyperpyrexia
- Pulmonary edema
- Death

Beta blocker and/or calcium channel blocker OD:

- Profound bradycardia
- Hypotension
- Bronchospasm
- Hypoglycemia

(1444) glugon is the drug of choice for beta blocker OD. Glucagon acts on G protein-coupled receptors, increasing
intracellular cAMP and thus increasing the release of intracellular calcium during muscle contraction. This increases HR
and cardiac contractility. Improvements in HR and BP may be observed within minutes.

Furosemide:

- Volume depletion
- Hypokalemia
- Hypomagnesemia

Spironolactone:

- Hyperkalemia
- Gynecomastia
- Impotence
- Decreased libido

Valsartan:
 - Hypotension
- Renal failure
- Hyperkalemia

Antihypertensive side effects (154)

Diuretics (2005)
Thiazide diuretics

Metabolic effects of thiazide diuretics (2002)

*thiazide diuretics raise serum calcium, uric acid, glucose, cholesterol and triglyceride levels. They lower serum sodium,
potassium and magnesium levels.

(2003)

Thiazide diuretics effectively increase renal calcium reabsorption. In px with recurrent Ca nephrolithiasis, thiazide
diuretics can help prevent stone formation by decreasing urine Ca2+ excretion.
Mechanism:

- Inh of the Na/Cl cotransporter on the apical side of distal convoluted tubule cells decreases intracellular Na
concentrations. This activates the basolateral Na/Ca antiporter, which pumps Na into the cell in exchange for Ca.
The resulting decrease in intracellular Ca concentration enhances luminal Ca reabsorption across the apical
membrane
- Hypovolemia induced by thiazides increases Na and H2O reabsorption in the proximal tubule, leading to a
passive increase in paracellular Ca reabsorption

Thiazides (683)
Loop diuretics furosemide, bumetanide, torsemide Hypokalemia, hypomagnesemia, hypocalcemia, and
ototoxicity
Thiazide diuretics chlorthalidone, hydrochlorothiazide Hypokalemia, hyponatremia, hyperuricemia and
hypercalcemia
Potassium sparing diuretics triamterene, spironolactone All: hyperkalemia
Spironolactone: gynecomastia, antiandrogen effects
Carbonic anhydrase inh: acetazolamide Metabolic acidosis
Osmotic diuretics mannitol Hypernatremia, pulmonary edema

(993) thiazide diuretics increase calcium absorption in the distal convoluted tubules within the nephron. Thiazides are
associated with increased bone mineral density and are recommended for tx of HTA in px at risk for osteoporosis. Loop
diuretics increase urinary calcium loss.

(681) loop diuretics

Loop diuretics act by inh the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle, increasing Na, Cl-,
and H2O excretion. They are the most potent diuretics and are used as first-line therapy for rapid relief of symptoms in
px with acute decompensated heart failure.

Mineralocorticoid receptor antagonists (eg, spironolactone, eplerenone) (686)

Improve survival in px with CHF and reduced ventricular ejection fraction. They should not be used in px with
hyperkalemia or renal failure

Phenoxybenzamine (1947)

Phenoxybenzamine is an irreversible alpha 1 and alpha 2 adrenergic antagonist that effectively reduces the arterial
vasoconstriction induced by NE. Because phenoxybenzamine is an irreversible antagonist, even very high concentrations
of NE, such as those seen in pheochromocytoma, cannot overcome its effects.

Neprilysin inh (1978)

ANP and BNP are secreted by atrial and ventricular cardiomyocytes in response to myocardial stretching induced by
hypervolemia. These natriuretic peptides inh the renin-angiotensin-aldoesterone system and stimulate peripheral
vasodilation and increased urinary excretion of sodium and water. Neprilysin inhibitors (eg, sacubitril) prevent the
degradation of ANP and BNP, enhancing their beneficial effects in heart failure.
Medications that causes hyperkalemia (697)

Alpha-1-blockers (150)

Such as Doxazosin, prazosin and terazosin are useful for tx of both BPH and HTA. They act by blocking the alpha-1
adrenergic receptor leading to relaxation of smooth muscle in arterial and venous walls leading to a decrease in
peripheral vascular resistance. Additionally, via their blockade of the alpha-1 adrenergic receptor, these drugs induce
relaxation of smooth muscle in the bladder neck and prostate leading to a decrease in urinary obstruction caused by
BPH. Decreased peripheral vascular resistance can lead to orthostatic hypotension and vertigo which are common side
effects of this class of drugs.

Milrinone (149)

Is a selective PDE-3 enzyme inh that can be used in px with refractory HF due to LV systolic dysfunction. The PDE-3
enzyme is normally responsbiel for degrading cyclic adenosine monophosphate (cAMP) to AMP; the inh of cAMP
degradation via milrinone has 2 positive effects on heart failure:

- Cardiomyocytes, intracellular calcium influx is increased, which increases cardiac contractility (positive inotropy)
to improve stroke volume and cardiac output
- Vascular smooth muscle, uptake of calcium by the sarcoplasmic reticulum is increased, which reduces calcium-
myosin light chain kinase interaction to stimulate relaxation and vasodilation. Venous vasodilation reduces
preload and arterial vasodilation reduces afterload to provide a cumulative reduction in cardiac work
Although the vasodilatory action of milrinone can lead to hypotension, this effect is often compensated for by an
increase in stroke volume that maintains BP

Endocrine

Protein structures (1383)

G protein-coupled receptors that bind glycoprotein hormones (eg, TSH, LH, FSH) contain 3 major domains: an
extracellular domain responsible for ligand binding, a transmembrane domain, and an intracellular domain coupled with
heterotrimeric G proteins.

The transmembrane domain is made up of nonpolar, hydrophobic AAs (eg, alanine, valine, leucine, isoleucine,
phenylalanine, tryptophan, methionine, proline, glycine). These AAs are arranged in an alpha-helical fashion and project
their hydrophobic R groups outwardly, anchoring the transmembrane region of the protein to the hydrophobic core of
the phospholipid bilayer. The transmembrane domain may also play an important role in cellular signaling and transport.

Obesity

Leptin (8425)

Is a protein hormone produced primarily in adipocytes, and large fat cells produce more leptin than small ones. Serum
leptin concentrations are highly correlated with body fat content.

1. Leptin decreases the production of neuropeptide Y, a potent appetite stimulant, in the arcuate nucleus of the
hypothalamus
2. Leptin stimulates the production of proopiomelanocortin (POMC) in the arcuate nucleus. Alpha-MHC is
produced by cleavage of PMC and inh food intake.

Major homrones regulating glucose metabolism (6561)

Hormone Metabolic effects Receptor Signaling pathway
Glucagon - Increase glycogenolysis (liver) GPCR (Gs) Adenylate cyclase/cAMP
- Increase gluconeogenesis
Epinephrine - Increase glycogenolysis (liver, GPCR (Gs) (Beta2-
muscle) adrenergic)
- Increase gluconeogenesis
Insulin - Increase glucose uptake (liver, Receptor tyrosine kinase Phosphoinositide 3-kinase
muscle, fat pathway
- Increase glycogen synthesis (liver,
muscle
- Decrease gluconeogenesis

Diabetes Mellitus

(847)
Of the 5 major GLUTS, only GLUT 4 is responsive to insulin. GLUT-4 is expressed predominantly in skeletal muscle cells
and adipocytes.

- GLUT-1 contributes to basal glucose transport in erythrocytes and at the blood-brain barrier
- GLUT-2 is present in hepatocytes, pancreatic beta cells, and at the basolateral membrane of renal tubules and
small intestinal mucosa. It plays a role in absorption of dietary glucose, reabsorption of glucose from renal
tubules, hepatic glucose regulation and sensitivity of beta cells to circulating glucose.
- GLUT-3 is involved in placental and neuronal glucose transport
- GLUT-5 is a fructose transporter found in spermatocytes and the GI tract.

(934) in the polyol pathway, aldose reductase converts glucose into sorbitol, which is slowly metabolized into fructose
by sorbitol dehydrogenase. Chronic hyperglycemia overwhelms this pathway, causing intracellular sorbitol accumulation
and increased osmotic/oxidative stress. This accelerates cataract development in px with diabetes, and contributes to
the pathogenesis of diabetic retinopathy, neuropathy and nephropathy

(1010) Glucokinase has a lower glucose affinity than other hexokinases. This allows it to fx as a glucose sensor in beta
cells by varying the rate of glucose entry into the glycolytic pathway based on blood glucose levels. Heterozygous
mutations of the glucokinase gene cause a decrease in beta cell metabolism of glucose, less ATP formation and
diminished insulin secretion. This produces a type of maturity-onset diabetes of the young, which is characterized by
mild, nonprogressive hyperglycemia that often worsens pregnancy-induced insulin resistance. Homozygous mutations
lead to fetal growth retardation and severe hyperglycemia at birth

(1326)

TNF alpha is a proinflammatory cytokine that induces insulin resistance through the activation of serine kinases, which
then phosphorylate serine residues on the beta subunits of IR and IRS-1. This inh tyrosine phosphorylation of IRS-1 by IR
and subsequently hinders downstream signaling, resulting in resistance to the normal actions of insulin.Phosphorylation
of threonine residues has similar effects. Catecholamines, glucocorticoids, and glucagon can also induce insulin
resistance by this same mechanism.
(15308)

Insulin is a peptide hormone that has both renal and hepatic clearance. Degradation of circulating insulin in the kidneys
is dependent on an adequate GFR, which allows for delivery of insulin to the proximal tubule cells where it is broken
down. Chronic kidney disease causes decreased GFR, which impairs insulin clearance.

Diabetic neuropathy (15667)

Risk factors - Long duration of disease
- Chronic hyperglycemia/poor glycemic control
Pathogenesis - Accumulation of glycosylation end products and sorbitol -> altered metabolism and increased
oxidative stress
- Occlusion of vasa nervorum with nerve ischemia
- Length-dependent axonopathy
Clinical - Peripheral polyneuropathy: numbness, stocking-glove paresthesias, decreased proprioception
manifestations - Autonomic neuropathy: gastroparesis, orthostasis, neurogenic bladder, erectile dysfunction
- Motor neuropathy: distal limb weakness, hammer/claw toe deformities

Common peripheral neuropathy (1059)

Type of neuropathy Symptoms

Distal symmetric polyneuropathy - Sensory (most common):
Paresthesias (tingling, numbness)
Intense burning pain
Loss of pain/temperature/vibration/position
sensation
- Motor (commonly in combination with sensory
symptoms)
Weakness
Atrophy
Decreased DTR
Both motor and sensory deficits are symmetric and
bilateral, involving feet and hands in a “a stocking and
glove”distribution
Autonomic polyneuropathy GI: gastroparesis, constipation
CV: orthostatic hypotension
Urinary: overflow incontinence, neurogenic bladder
Sexual: erectile and ejaculatory abnormalities
Mononeuropathy Cranial mononeuropathy: Oculomotor (III), facial (VII), and
optic (ischemic optic neuropthy)
Somatic mononeuroapthies: a commonly bilateral
involvement of the median nerve, ulnar and common
peroneal nerves

Diabetic retinopathy (15668)

Categorized as follows:

- Nonproliferative (early disease): the earliest morphologic changes include thickening of the basement
membrane and failure of the blood-retinal barrier. Increased permeability allows leakage of fluid into the retina
 (macular edema), which can distor vision and leave behind lipid-rich deposits (hard exudates). Arteriolar
obstruction causes ischemic injury to the retina, which manifests as cotton-wool spots. Other findings include
microaneurysms and dot-blot hemorrhages (duet o microaneurysm rupture)
- Proliferative (advanced disease): progressive retinal ischemia stimulates production of angiogenic factors (eg,
vascular endothelial growth factor), leading to formation of new retinal vessels (neovascularization). The new
vessels are fragile and often extend into the adjacent vitreous. Traction from the vitreous can cause detachment
of the retina or laceration of the vessels, leading to acute hemorrhage and vision loss.

Triglyceride metabolism (1889)

Increased triglyceride breakdown in adipose tissue due insulin deficiency. Triglycerides stored in adipose tissue are
metabolized to free fatty acids and glycerol by hormone-sensitive lipase in response to low insulin and high
catecholamine levels. Adipocytes are unable to metabolize glycerol, so it is secreted into the circulation and transported
to the liver, where it is phosphorylated to glycerol-3-phosphate by glycerol kinase. Glycerol-3-phosphate is subsequently
conerted to glycerol-3-phosphate dehydrogenase to dihydroxyacetone phosphate, which can be used to produce
glucose through gluconeogenesis

Diabetic ketoacidosis (2073)

The tx of choice for diabetic ketoacidosis is IV normal saline and insulin. These therapies increase serum bicarbonate and
sodium and decrease serum glucose, osmolality and potassium.
Gestational diabetes (922)

(8330)

Human placental lactogen increases maternal insulin resistance during the second and third trimesters, leading to a rise
in serum glucose that helps provide adequate nutrition to the growing fetus. Gestational diabetes occurs when the
compensatory rise in maternal insulin secretion is inadequate to prevent serum glucose levels from reaching excessively
high levels.

Insulin synthesis and secretion (1768)

(1324)

HbA1c (1996)

Glucose freely diffuses across the RBC membrane and attaches irreversibly to HbA inside erythrocytes, forming HbA1c.
the degree of HbA1c elevation is directly correlatd to average blood glucose levels over the erythrocyte life-span. Both
higher glucose levels can longer exposure of red cells to glucose will increase HbA1c values. As such, conditions that alter
RBC survival time affect HbA1c levels.

Hypoglycemia
(1009) Glucose enters beta cells by GLUT-2 -> oxidative metabolism through glycolysis and citric acid cycle -> ATP

ATP -> ATP-sensitive K+ channel -> KATP channels are normally open at rest and maintain membrane polarization by
allowing outward movement of K+ from the beta cells -> binding of ATP -> KATP closes -> a high ATP/ADP ratio therefore
leads to decreased K+ efflux and membrane depolarization -> opens voltage dependent Ca2+ channels -> increase
intracellular calcium levels -> insulin release

Mutations:

- Neonatal diabetes: mutations of the KATP channels

Tx: sulfonylureas (bind to KATP channels and cause closure independent of ATP)
- Increased affinity for ATP and inappropriate closure of the KATP channels -> excessive insulin release and
frequent hypoglycemia

(1492)

Prolonged CNS hypoglycemia leads to irreversible neurologic deficits and death. To prevent injury, multiple counter-
regulatory systems are activated in response to hypoglycemia; these include glucagon, the sympathetic nervous system,
and to a lesser extent, growth hormone and cortisol. Glucaogon increases blood glucose primarily by increasing
glycogenolysis and gluconeogenesis. Epinephrine limits glucose use by insulin-sensitive tissues and also stimulates
hepatic glycogenolysis and gluconeogenesis. If hypoglycemia persist, the activity of higher brain centers diminishes to
reduce glucose requirements.

Symptoms fall into 2 broad categories:

- Neurogenic (autonomic): symptoms are caused by sympathoadrenal activation and are mediated via NE/EPI and
ACh released by sympathetic postganglionic nerve fibers. Symptoms of NE/EPI release include tremulousness,
palpitations, and anxiety/arousal, whereas cholinergic symptoms include sweating, hunger and paresthesias
- Neurolgycopenic: symptoms include behavioral changes, confusion, visual disturbances, stupor and seizures.

Non-selective Beta blockers (eg, propranolol, timolol, nadolol) inh NE/EPI mediated compensatory reactions to
hypoglycemia (cholinergic symptoms are unaffected). In addition, blockade of beta2-adrenergic receptors inh hepatic
gluconeogenesis and peripheral glycogenolysis and lipolysis. Non-selective beta-blockers should be used with caution in
diabetic px as these can increase the risk of hypoglycemia and reduce px awareness of hypoglycemia. Selective beta
blockers and beta blockers with intrinsic sympathomimetic activity (eg, pindolol, acebutolol) are preferred for diabetics
as these have minimal effect on glucose metabolism and adrenergic symptoms.

Prolonged fasting (989)

Unlike the other counterregulatory (ie, insulin-opposing) hormone receptors, cortisol receptors are located within the
cytoplasm and translocate to the nucleus after binding to their substrate. In the nucleus, the cortisol-receptor complex
binds to hormone-responsive DNA elements, altering gene transcription to enhance hepatic glucose production and
limit peripheral glucose utilization.

Dyslipidemia

(782)
Familial chylomicronemia syndrome (type 1 hyperlipoproteinemia)

- AR
- Caused by lipoprotein lipase deficiency
- LPL is normally bound to heparin sulfate moieities on the vascular endothelium, allowing it to interact with
chylomicrons and VLDL in the circulation and release free fatty acids into the adjacent tissues. Heparin admn
releases these endothelium-bound lipases, allowing LPL activity to be measured in the laboratory. Without
sufficient LPL activity, the body is unable to clear dietary lipid loads due to defective hydrolysis of serum
triglycerides (especially chylomicrons)

Familial dysbetalipoproteinemia (2064)

The primary defects in familial dysbetalipoproteinemia are in ApoE3 and ApoE4, apolipoproteins found on the
triglyceride-rich lipoproteins (chylomicrons and VLDLs) that are responsible for binding hepatic apolipoprotein receptors.
Without ApoE3 and ApoE4, the liver cannot efficiently remove chylomicrons and VLDL remnants from the circulation,
causing their accumulation in the blood and resultant elevations in cholesterol and triglyceride levels.

Antihyperlipidemic agents (163)

Bile acid-binding resins inh the enterohepatic circulation of bile acids. This leads to diversion of hepatic cholesterol to
synthesis of new bile acids, increased uptake of cholesterol from the circulation, and reduced blood LDL levels. However,
bile acid-binding resins increase hepatic production of triglycerides and can cause hypertriglyceridemia.

Ectopic thyroid (763)

The thyroid gland is formed from evagination of the pharyngeal epithelium and descends to the lower neck. Due to
failure of migration, the thyroid can reside anywhere along the thyroglossla duct’s usual path, including the tongue
(lingual thyroid)

Congenital hypothyroidism (1407)

Hypothyroidism (772)

An increase in estrogen activity, as seen in pregnancy or postmenopausal estrogen replacement therapy, increases the
level of thyroxine-binding globulin. This leads to an increase in total thyroid hormone levels, but feedback control
maintains normal levels of free (biologically active) thyroid hormone.

(14985) Excess thyroid hormone, whether due to endogenous hyperthyroidism or iatrogenic over-replacesment with
levothyroxine, causes increased beta-adrenergic receptor expression. The resulting hyperadrenergic state can lead to
significant CV complications

Cardiovascular effects of hyperthyroidism

Increased rate - Tachycardia/palpitations
- Atrial fibrillation
Increased contractility - Increased EF and CO
- Increased myocardial oxygen demand & angina
- Increased pulmonary artery pressure
Decreased afterload - Decreased systemic vascular resistance
Additional effects - Decreased diastolic pressure
- Increased systolic pressure
- Increased pulse pressure
- High output heart failure
Atrial fibrillation is the most common supraventricular arrhythmia and is a frequent complication of thyrotoxicosis.
Thyroxicosis also increases contractility, which increases myocardial oxygen demand and can precipitate angina in px
with underlying coronary disease.

(12512) prolactin is regulated primarily by the inh effects of dopaminergic neurons from the hypothalamus. Hwoever,
lactotroph cells express TRH receptors, and TRH stimulates synthesis and release of prolactin. The elevated TRH levels in
the pituitary in px with primary hypothyroidism can therefore increase prolactin secretion and lead to
hyperprolactinemia.

Hyperthyroidism

Hashimoto (6532)

Histopathology: characterized by intense, diffuse lymphocytic infiltration of the thyroid gland by B and T cells specific for
thyroid antigens. This is accompanied by formation of lymphoid germinal centers and destruction of thyroid follicles.
Hurthle cells (also known as Askanazy or oxyphil cells) are metaplastic, enlarged epithelial cells with prominent nucleoli
and abundant eosinophilic cytoplasm; they are commonly seensurrounding atrophic thyroid follicles.

(769)

Biopsy: intense mononuclear infiltrate consisting of lymphocytes and plasma cells, often with germina centers. Residual
follicles are often surrounded by Hurthle cells (large oxyphilic cells filled with granular cytoplasm) that represent
follicular epithelial cells that have undergone metaplastic change in response to inflammation

Grave’s disease (623)

Pretibial myxedema and Graves ophthalmopathy are specific features of Graves disease. They are caused by an
autoimmune response directed against the TSH receptor that results in the accumulation of glycosaminoglycans within
the affected tissues.
Hyperthyroidism also causes a hypermetabolic/hyperadrenergic state that can present with heat intolerance, tremor, lid
lag, tachycardia, or atrial fibrillation. In addition, increased bone turnover can lead in hyperthyroidism of any cause (eg,
thyroiditis, toxic multinodular goiter).

Tx for hyperthyroidism (626)

Methimazole and propylthiouracil are thioamide drugs used for treating hyperthyroidism. They inh thyroid peroxidase,
the enzyme responsible for both iodine organification and coupling of iodotyrosines. Propylthiouracil also decreases the
peripheral conversion of T4 to the active hormone T3, although methimazole does not have this effect.

(15016)

Exogenous hyperthyroidism is characterized by elevated free T4, suppressed TSH, and low/undetectable thyroglobulin. It
can occur with surreptitious levo abuse, use of animal-sourced thyroid supplements, and errouneous dosing of thyroid
replacement therapy. Over time, the lack of TSH stimulation causes the thyroid follicles to become atrophic

(1213) hyperthyroidism causes upregulation of beta-adrenergic receptor expression, leading to increased catecholamine
effect. Beta blockers are used to blunt the adrenergic manifestations of hyperthyroidism. In addition, lipid-soluble beta
blockers reduce conversion of T4 to T3 by inh 5’-monodeiodinase in peripheral tissues.

Radiation injury (767)

Potassium iodide is given prophylactically to protect the thyroid from excessive accumulation of radioactive I131

Energy-dependent transport of inorganic iodide into the thyroid follicular cell (iodide trapping) is accomplished by the
sodium-iodide symporter located on the basolateral membrane. Because this transporter takes up all isotopes of iodide
(as well as other ions such as perchlorate and pertechnetate), high serum levels of nonradioactive iodide can
competitively inh radioactive I131 from entering thyroid follicular cells. Large increases in serum iodide levels also inh
iodine organification (Wolff-Chaikoff effect) and reduce thyroid hormone release.

Hyperparathyroidism (631)

Recurrent nephrolithiasis + hypercalcemia -> primary hyperparathyroidism

Classic manifestations: bone paine, GI disturbances (eg, peptic ulcer disease), psychiatric symptoms (ie, “bones, stones
abdominal groans, and psychologic moans”). However asymptomatic hypercalcemia is the most common presentation.

85% of cases are caused by parathyroid adenoma, but PHPT can also be due to parathyroid hyperplasia or, rarely,
parathyroid cancer.

Hypercalcemia mechanisms:

- Increased renal tubular Ca2+ reabsorption (although most px have net hypercalciuria due to the increased
filtered calcium load)
- Increased renal production of 1, 25-dihydroxyvitamin D (which in turn increases GI Ca2+ absorption)
- Increased bone resorption (via osteoclast activation)

Px usually have hypophosphatemia due to decreased phosphate reabsorption in the proximal renal tubules.

Increased bone resorption, PHPT-> osteoporosis. However, unlike the typical osteoporosis of aging, which
predominantly affects trabecular bone, osteoporosis in PHPT is most pronounced in the cortical (compact) bone of the
appendicular skeleton (eg, pectoral girdle, pelvic girdle, limbs). Cortical thinning is characteristic and appears
radiologically as subperiosteal erosions. More advanced disease can present as osteitis fibrosa cystica, characterized by
granular decalcification of the skull (“salt-and-pepper skull”), osteolytic cysts and brown tumors.

Pseudohypoparathyroidism (6494)

Is a group of disorders characterized by end-organ resistance to PTH due to defects in the PTH receptor and downstream
signaling pathways. Px have hypocalcemia and hyperphosphatemia despite elevated PTH levels.

Albright hereditary osteodystrophy is an AD form of pseudohypoparathyroidism associated with skeletal defects (eg,
short stature, short metacarpal and metatarsal bones). It is caused by defects in GNAS1, which codes for the alpha
subunit of the G protein (Gsalpha) that mediates the effects of PTH.

Manifestation depends whether is maternally or paternally inherited (imprinting)

- The kidneys express only the maternal allel for GNAS1

- Paternal transmission causes the typical skeletal defects but with normal calcium, phosphorus, and PTH levels

Hypoparathyroidism (11664)

Postop thyroidectomy may injure parathyroid. Post op supplementation with oral calcium and vit D can be used to tx or
prevent postop hypocalcemia. Calcitril, the active form of vit D, should be chosen over calcidiol as the conversion of
calcidiol to calcitril is dependent on parathyroid hormone, and patients with hypoparathyroidism can have inadequate
production of calcitriol.

Biphosphonate: Alendronate inh osteoclast fx. Can worsen hypocalcemia by decreasing the release of Ca from bone.

Cinacalcet: is a calcimimetic that allosterically activates the calcium-sensing receptor in the parathyroid gland,
decreasing parathyroid hormone release. Cinacalcet is normally used for secondary hyperparathyroidism in patients on
dialysis

Glucocorticoids (eg, prednisone) can worsen hypocalcemia by decreasing expression of the vit D receptor

Sevelamer is a nonabsorbable phosphate-binding polymer that decreases absorption of phosphate in the GI tract, and is
used to treat hyperphosphatemia in px on dialysis. Calcium-based phosphate binders (eg, calcium carbonate, calcium
acetate) frequently raise calcium levels, but sevelamer has a lesser effect on calcium and would not be adequate
treatment for hypocalcemia.

Familial hypocalciuric hypercalcimia

AD disorder caused by abnormalities of the calcium sensing receptor that decrease sensitivity of the receptor and
require higher calcium concentrations to suppress PTH secretion. Px have mild hypercalcemia and high-normal or mildly
elevated PTH.

Growth hormone (224)

Gigantism is caused by excess GH during childhood and is characterized by accelerated linear growth, prognathism, and
bony enlargement of the hands and feet. GH excess after closure of the epiphyseal growth plates causes acromegaly. GH
has direct effects on target tissues and indirect effects mediated by insulin like growth factor-1 secretion from the liver.

Acromegaly (7651)
Excess GH both directly and indirectly (via release of insulin-like growth factor 1 from the liver) leads to overgrowth of
many tissues, including bone, cartilage, and visceral organs. In the heart, chronic GH elevation stimulates cardiac growth,
causing LV hypertrophy, diastolic dysfunction and possible HF.

Hyperaldosteronism

Primary mineralocorticoid excess (hyperaldosteronism) causes increased renal sodium reabsorption, leading to HTA,
hypokalemia, and metabolic alkalosis.

(2013)
 - Primary hyperaldosteronism (ie, Conn’s syndrome): adrenal adenoma or bilateral adrenal hyperplasia causes
excessive and unchecked aldosterone production that leads to feedback inh of renin secretion.
- Secondary hyperaldosteronism: overproduction of aldosterone occurs secondary to increased renin synthesis,
resulting in elevated serum levels of both renin and aldosterone. Causes of secondary hyperaldosteronism
include renal artery stenosis (typically associated with fibromuscular dysplasia and atherosclerosis), diuretic use,
malignant hypertension (which leads to microvascular damage and renal ischemia), and renin-secreting tumors.
Renin-secreting tumors (reninomas) are rare, small, solitary, benign juxtaglomerular cell neoplasms. Reninomas
should be strongly considered in px with marked hyperreninemia and HTA

Adrenal insufficiency (932)

Hx of hypothyroidism puts her at increased risk for other autoimmune endocrinopathies (eg, autoimmune adrenalitis),
and her weight loss and hyperpigmentation are suggestive of chronic primary adrenal insufficiency (Addison disease).

(609)

Suppression of the hypothalamus-pituitary-adrenal axis by glucocorticoid therapy is the most common cause of adrenal
insufficiency. In these px, adrenal crisis can be precipitated by stressful situations (eg, infections, surgery) if the
glucocorticoid dose is not increased appropriately.

Adrenal insufficiency (924)

Px with type 1 DM are prone to developing other autoimmune endocrinopathies including Hashimoto thyroiditis,
Grave’s disease, and primary adrenal insufficiency (Addison’s disease). Electrolyte abnormalities in px with primary
adrenal insufficiency include hyponatremia, hyperkalemia, hyperchloremia, and non-anion gap metabolic acidosis.

Thyroid cancer

(1747) the external branch of the superior laryngeal nerve is at risk of injury during thyroidectomy due to its proximity to
the superior thyroid artery and vein. This nerve innervates the cricothyroid muscle.

Pheochromocytoma (926)

Is a tumor arising from the chromaffin cells of the adrenal medulla characterized by excess production of
catecholamines. Clinical features include episodic HTA, diaphoresis and palpitations. Microscopic examination of the
tumor cells shows electron-dense, membrane-bound secretory granules, and immunohistochemistry is postivie for
synaptophysin, chromogranin and neuron-specific enolase.

MEN2

(15105)
Multiple endocrine neoplasia type 2
Inheritance - Autosomal dominant
- Germ-line activating mutations of RET proto-oncogene
Type 2A - Medullary thyroid cancer (>95%)
- Pheochromocytoma
- Parathyroid hyperplasia
Type 2B - Medullary thyroid CA (>95%)
- Pheochromocytoma
- Mucosal neuromas, marfanoid habitus

MEN2B (1844) is due to an AD germ-line mutation in the RET proto-oncogene. Other possible manifestations of MEN 2B
include pheochromocytoma and intestinal ganglioneuromas (which may cause constipation). The earliest manifestations
of the disease often appear in childhood or adolescence.

(988)

- enlarging thyroid nodule associated with an elevated calcitonin level -> medullary thyroid cancer (malignancy
arising from the thyroid C (parafollicular) cells
- mucosal neuromas
- marfaonoid habitus (eg, arm span > height, long fingers, joint laxity
- MEN2 caused by germline mutations of the RET protooncogene

(1659)

Px history pheochromocytoma + fam hx of thyroid CA

- Medullary thyroid CA
- Pheochromocytoma
- Either parathyroid hyperplasia (type 2A) or marfanoid habitus and mucosal neuromas (type 2B)

Approximately 20% of medullary thyroid cancers are familial, occurring as part of MEN2 or familiar medullary thyroid
cancer syndrome due to germ-line mutations of the RET proto-oncogene. Medullary thyroid cancer is a neuroendocrine
tumor that arises from parafollicular calcitonin-secreting C cells. Nests or sheets of polygonal or spindle-shaped cells
with extracellular amyloid deposits are seen microscopically. These amyloid deposits are derived from calcitonin
secreted by the neoplastic C cells and stain with Congo red. Despite overproduction of calcitonin, hypocalcemia is not
prominent ft.
Vs. papillary thyroid CA: may reveal formation of visible papillae. Microscopic inspection of papillae shows a
fibrovascular core, often with laminar calcifications (psammoma bodies).

The cells contain pale nuclei with finely dispersed chromatin, giving them an empty or ground-glass appearance (Orphan
Annie eye nuclei). Intranuclear inclusions and grooves can be seen due to invagination of the nuclear membrane.

(1658) papillary thyroid CA is the most common type of thyroid CA. characteristic findings on histopathology include
large cells with nuclei containing finely dispersed chromatin, giving an empty or ground-glass appearance (Orphan Annie
eye), and intranuclear inclusions or grooves

Vs. papillary thyroid CA is characterized by follicular hyperplasia lined by tall epithelial cells; this variant is seen in older
individuals and carries a relatively worse prognosis. Tall, crowded cells can also be seen in Graves disease, often with
hyperactive resorption of colloid leading to scalloping of the colloid edges.

Vs. anaplastic thyroid CA is an aggressive tumor with a very poor prognosis. It is most common in older px (age >60)
Cytologic features include markedly pleomorphic cells, including irregular giant cells and biphasic spindle cells.

Vs. benign follicular adenoma, presence of colloid containing microfollicles. Well-deffirentiated follicular
adenocarcinoma can also contain small follicles but will often show vascular invasion.
Common cause of cushing syndrome (1163)
Etiology Pathologic findings
ACTH-dependent Cushing disease (ie, pituitary Bilateral hyperplasia involving the zona fasciculate & reticularis
ACTH hypersecretion)
Ectopic ACTH syndrome (eg,
paraneoplastic ACTH
secretion
ACTH-independent Adrenal adenoma or Benign tumors are typically round, well circumscribed lesions
carcinoma with cells similar to normal zona fasciculate
Malignant tumors are often irregular and poorly demarcated
with considerable cellular pleomorphism
Atrophy of the zona fasciculate & reticularis in the uninvolved
cortex regions

Features of Cushing syndrome (1163)

Clinical manifestations - Central obesity (eg, fat accumulation in the cheeks
& dorsocervical & supraclavicular fat pads)
- Skin atrophy & wide, purplish striae
- Proximal muscle weakness
- HTA
- Glucose intolerance
- Skin hyperpigmentation (if ACTH excess)
Dx - 24 hrs urinary cortisol excretion
- Late-night salivary cortisol assay
- Low-dose dexamethasone suppression test

Biochemical findings in cushing syndrome (927)

Iatrogenic cushing syndrome (928)

Exogenous glucocorticoid use inh the entire hypothalamic-pituitary-adrenal axis, leading to low levels of corticotropin-
releasing hormone (CRH), ACTH, and endogenous cortisol. ACTH exerts a potent trophic (ie, growth promoting) effect on
the adrenal zona fasciculate and reticularis; long-term suppression leads to adrenocortical atrophy (the zona
glomerulosa is spared as angiotensin II is its primary trophic hormone). Sudden cessation of glucocorticoids after
prolonged use can precipitate adrenocortical insufficiency and adrenal crisis.

Conn’s syndrome (152)

Hyperaldosteronism:

- HTA
- Hypokalemia
- Metabolic alkalosis
- Decreased plasma renin activity

TX: surgical resection or medical therapy with aldosterone antagonists.

Spironolactone is the most frequently used first-line drug, and eplerenone is a new aldosterone antagonist that has
fewer side effects than spironolactone and is often used in those that can not tolerate spironolactone.

Most frequent side effect: gynecomastia (approximately 1% with eplerenone, 9% with spironolactone)

Steroids hormones (2016)

The initial step in the synthesis of steroid hormones is the conversion of cholesterol to pregnenolone in the
mitochondria. The remainder of steroidogenesis occurs in the smooth endoplasmic reticulum. Steroid-producing cells
contain a well-developed smooth endoplasmic reticulum.

By contrast, RER is characterized by numerous ribosomes on the outer membrane. The RER plays an important role in
the synthesis and modification of targeted proteins, including secretable polypeptide hormones. Some of the clinically
significant syndromes due to overproduction of peptide hormones by the RER include:

- SIADH
- Insulinomas
- Zollinger-ellison syndrome
- galactorrhea
Aromatase deficiency (955)

Aromatase is a key enzyme involved in steroidogenesis; it ocnverts androstenedione to estrone and testosterone to
estradiol. These metabolic steps are essential for estrogen synthesis and occur in numerous tissues throughout the
body. During later pregnancy, the placenta is responsible for the vast majority of estrogen synthesis.

Aromatase deficiency is an AR disorder that manifests early in embryonal life with high androgen and low estrogen
levels in the female fetus. Maternal virilization (eg, hirsutism) commonly occurs during pregnancy due to the transfer of
excess androgens into the maternal circulation. Affected newborn girls will have normal internal genitalia and
ambiguous or male-type external genitalia (eg, clitoromegaly, female pseudohermaphrodism). At puberty, impaired
ovarian estrogen synthesis causes primary amenorrhea, osteoporosis, and tall stature (low estrogen delays fusion of the
epiphyses). Men with aromatase deficiency have tall stature and osteoporosis but no genital abnormalities.

Congenital adrenal hyperplasia

(15105) in px with undiagnosed pheochromocytoma, induction of anesthesia can precipitate a catecholamine

(epinephrine and norephrine) surge, leading to hypertensive crisis, flash pulmonary edema, and atrial fibrillation.
Therefore, px who have MTC associated with germline RET mutations should be screened for pheochromocytoma (eg,
24-hr assay for urinary metanephrines and catecholamines) prior to surgery.

21-hydroxylase deficiency (793)

Clinical phenotypes of 21 hydroxylase deficiency

Classic, salt-wasting Classic, non-salt-wasting Non-classic, delayed
Degree of 21-hydroxylase Severe Moderate Mild
deficiency
Clinical presentation Girls present at birth with Girls present at birth with Premature pubarche or
ambiguous genitalia ambiguous genitalia sexual precocity in school-
age children
 Boys present at 1-2 weeks Boys present at 2-4 years
with failure to thrive with signs of early Young women can present
dehydration, hyperkalemia virilization with acne, hisurtims &
and hyponatremia menstrual irregularity

- The most common form of congenital hyperplasia

- Genetically female infants typically have ambiguous genitalia (virilization) at birth, whereas males have
phenotypically normal genitalia, with salt wasting or precocious puberty appearing later. Elevated 17-
hydroxyprogesterone is diagnostic

(2080)

Males with classic, non-salt-wasting form typically present during the first few years of life with early virilization and
accelerated linear growth due to shunting of corticosteroid precursors toward androgen production in the adrenal
cortex. Females with this variety present with ambiguous genitalia at birth. As in all forms of 21-hydroxylase deficiency,
px will have increased serum concentrations of 17-hydroxyprogesterone and androgens.

(2081) px with congenital adrenal hyperplasia due to 21-hydroxylase deficiency have defective conversion of 17-
hydroxyprogesterone to 11-deoxycortisol, which imapris cortisol synthesis. Decreased cortisol levels are sensed by the
hypothalamus and cause a consequential increase in adrenocorticotropic hormone (ACTH) secretion by the anterior
pituitary. This results in stimulation of the adrenal cortex and androgen overproduction.

Tx of congenital adrenal hyperplasia involves admn low (ie, physiologic) dosese of exogenous corticosteroids to suppress
ACTH secretion. By removing excessive ACTH stimulation, exogenous corticosteroids can decrease androgen production
by the adrenal cortex.

(930) px with classic, salt-wasting 21-hydroxylase deficiency have deficient cortisol and aldosterone synthesis combined
with adrenal androgen overproduction. Male infants have normal genitalia and present 1-2 weeks after birth with
vomiting, hypotension, hyponatremia, and hyperkalemia. Females present at birth with ambiguous genitalia.

5 alpha-reductase deficiency (954)

5alpha-reductase converts testosterone to dihydrotestosterone, which mediates development of the external genitalia
in the male fetus. Male neonates with 5alpha-reductase deficiency are born with feminized external genitalia that
typically masculinize at puberty. A small phallus and hypospadias are common.

11 beta hydroxylase deficiency (611)

Second most common cause of CAH

11 beta-hydroxylase is responsible for converting 11-deoxycorticosterone to corticosterone and 11-deoxycortisol to

cortisol. Enzyme deficiency results in the buildup of aldosterone and cortisol precursors, which are then shunted toward
adrenal androgen synthesis. In genetically female infants, androgen excess leads to ambiguous genitalia (virilization).
Although 11 beta hydroxylase deficiency inh aldosterone synthesis, 11-deoxycorticosterone accumulates and acts as a
weak mineralocorticoid, causing affected individuals to have HTA and hypokalemia

Kallmann syndrome (579)

Delayed puberty + anosmia = Kallmann syndrome

Results from a failure of GnRH-secreting neurons to migrate from their origin in the olfactory placode (situated outside
the CNS) to their normal anatomic location in the hypothalamus. Most often, the cause is a mutation in the KAL-1 gene
or the fibroblast growth factor receptor-1 gene, which code for proteins required in this migration.

Px with Kallmann syndrome classically have central hypogonadism and anosmia, although there may be other midline
defects as well (eg, cleft lip or cleft palate). Most often, these px present with delayed puberty. On PE, the testes are
often just 1-2 mL in volume. There is usually some pubic hair because adrenarche occurs normally.

Pituitary apoplexy (225)

Pathogenesis - Acute pituitary hemorrhage
- Usually occurs in preexisting adenoma
Clinical presentation - Severe headache
- Bitemporal hemanopsia (optic chiasm) &
ophthalmoplegia (CN III)
- Hemodynamic instability & altered sensorium
Complications - Panhypopituitarism (acute & chronic)
- Severe hypotension (central adrenal failure)
- Coma & death

Gynecomastia (14818)
Clinical findings Development of glandular breast tissue in males
Pathophysiology Increased estrogen/androgen ratio
Ductal epithelial hyperplasia & stromal fibrosis
Common etiologies Increased estrogen levels (eg, cirrhosis, obesity)
Decreased testosterone levels (eg, chronic kidney disease, hypogonadism)
Medication effect:
- Decreased androgen production (eg, GnRH agonists, ketoconazole)
- Decreased conversion to dihydrotestosterone (eg, 5-alpha reductase inh)
- Inhibition of androgen receptors (eg, spironolactone, bicalutamide)

Catecholamine synthesis (602)

Expression of PNMT in the adrenal medulla is upregulated by cortisol. Because the venous drainage of the adrenal cortex
passes through the adrenal medulla, cortisol concentrations in the medulla can be very high, and PNMT is expressed at
high level. However, following pituitary resection, the loss of ACTH leads to decreased synthesis of cortisol in the adrenal
cortex. The result is decreased PNMT activity and reduced conversion of norepinephrine to epinephrine

Lipid storage disease

Sphingolipidoses (1990)
Diagnosis Inheritance Deficiency Accumulated Key features
substrate
Fabry XLR Alpha-galactosidase Globotriaosylceramide - Angiokeratomas
- Peripheral neuropathy
 - Glomerulopathy
Tay-Sachs AR Beta-hexosaminidase GM2 (ganglioside - Macular cherry-red spot
A - Progressive
neurodegeneration
Gaucher Beta- Glucocerebrosidase - Hepatosplenomegaly
glucocerebrosidase - Pancytopenia
- Bone pain/osteopenia
Niemann-pick Sphingomyelinase Sphingomyelin - Macular cherry-red spot
- Progressive
neurodegeneration
- Hepatosplenomegaly
Krabbe Galactocerebrosidase Galactocerebrosidase - Progressive
& psychosine neurodegeneration
- Peripheral neuropathy
- Optic atrophy
Metachromatic Arylsulfatase A Cerebroside sulfate - Progressive
leukodystrophy neurodegeneration
- Peripheral neuropathy

Fabry disease
Pathophysiology - X-linked recessive
- Alpha-galactosidase A deficiency results in accumulation of globotriaosylceramide (alpha-
galactosidase A is a lysosomal enzyme responsible for the breakdown of
globotriaosylceramide (Gb3), a sphingolipid also known as ceramide trihexoside)
Clinical features - Neuropathic pain
- Angiokeratomas
- Telangiectasias
- Glomerular disease (eg, proteinuria)
- Cerebrovascular disease (eg, TIA, stroke)
- Cardiac disease (eg, left ventricular hypertrophy)
Clinical Adolescense:
presentations - Neuropathic pain
- Hypohidrosis
- Small fiber nerve involvement results in severe distal extremity pain and burning as well as
distal loss of hot/cold temperature sensation. Exacerbating factors include exercise, stress
and fatigue
Late adolescence
- Angiokeratomas: dark red, non-blanching macules and papules that classically occur in
clusters over the buttocks, groin and umbilicus
- Telangiectasias
Early and mid-adulthood:
- Cerebrovascular (eg, TIA, stroke)
- Cardiac (eg, left ventricular hypertrophy)
- Gb3 buildup in the glomerulus and distal tubule results in proteinuria and polyuria -> renal
failure

Vs. arylsulfatase A deficiency: accumulation of cerebroside sulfate in metachromic leukodystrophy -> progressive
demyelination leading to ataxia, peripheral neuropathy, seizures and hypotonia

Vs. Niemann-Pick disease: accumulation of sphingomyelin -> progressive neurodegeneration and cherry-red macular
spots
Vs. Hunter and Hurler syndromes: accumulation of heparin and dermatan sulfate -> developmental delay, skeletal
abnormalities and cardia disease (liver is not typically affected)

Vs. Krabbe disease: galactocerebrosidase deficiency -> optic atrophy, developmental regression and seizures

Tay sachs (8524)

Deficiency: beta-hexosaminidase A

Accumulation: glycolipid GM2 ganglioside within lysosomes

Clinical consequences:

- Weakness
- Hypotonia
- Developmental regression
- Seizures
- Blindness
- Spasticity

PE:

- Macrocephaly
- Abnormal startle reflex with acoustic stimuli
- Cherry-red macula spot surrounded by white macula (halo results from a loss of retinal transparency due to
ganglioside buildup in ganglion cells. The center of the fovea lacks ganglion cells, so the underlying choroid
transmits its red color)

Hereditary orotic aciduria (2066)

AR

Defect in uridine 5’-monophosphate (UMP) synthase (catalyzes the final conversion of orotic acid to UMP)

Presents:

- Physical and mental retardation

- Megaloblastic anemia
- Elevated urinary orotic acid (may also be seen in ornithine transcarbamylase deficiency, usually presents failure
to thrive and hyperammonemic encephalopathy within the first few weeks of life (due to impaired urea
synthesis)

Tx: Uridine supplementation, uridine is converted to UMP via nucleoside kinases

Pharmacology

(781)
Antihyperlipidemic medications (166)

Antihyperlipidemic medications
Drug Mechanism Major lipid effects Side effects
Statins - Inh HMG-CoA - ↓↓LDL - Hypatotoxicity
reductase - ↓Triglycerides - Muscle toxicity
Ezetimibe - ↓intestinal - ↓LDL - ↑Hepatotoxicity if
cholesterol given with statins
absorption
Bile acid sequestrants - Prevent - ↓LDL - Nausea, bloating,
reabsorption of bile cramping
acids in the intestine - Impaired absorption of
drug & fat-soluble
vitamin
Niacin - ↓ Fatty acid release - ↓LDL - Flushing & pruritus
- ↓VLDL synthesis - ↑↑HDL - Hepatotoxicity
- ↓HDL clearance - Hyperuricemia/gout
Fibrates - Activate PPAR-alpha - ↓↓Triglycerides - Muscle toxicity
- ↓VLDL synthesis - ↑HDL - Gallstones
-
Fish oil/omega-3 fatty - ↓VLDL synthesis - ↓Triglycerides - Fishy taste
acids - ↓apolipoprotein B - ↑HDL
synthesis

Fibrates (67)
Fibrate medications (Eg, fenofibrate, gemfibrozil) upregulation lipoprotein lipase, resulting in increased oxidation of fatty
acids. In addition, fibrates inh cholesterol 7 alpha-hydroxylase, which catalyzes the rate-limiting step in the synthesis of
bile acids. The reduced bile acid production results in decreased cholesterol solubility in bile and favors the formation of
cholesterol stones.

Niacin (160)

Main side effects are cutaneous flushing, warmth, and itching; these are primarily mediated by release of prostaglandins
(particularly PGD2 and PGE2). Aspirin, which inh prostaglandin synthesis, can significantly reduce these side effects if
given 30-60 min before niacin admn. The side effects are also reduced with slow release preparations or if niacin is taken
with meals. They are worst when niacin is first initiated and tend to fade over time due to tachyphylaxis

VS. vancomycin-induced “red man syndrome” is mediated by histamine release due to non-IgE mediated mast cell
degranulation

Ezetimibe (11634)

Decreases intestinal absorption of cholesterol by inh the Niemann-Pick C1-like 1 (NPC1L1) transporter protein, which
transports dietary cholesterol from the GI lumen into intestinal enterocytes.

Bile acid – binding resins (165)

Work by binding bile acids in the GI tract, thereby interfering with the enterohepatic circulation of bile acids and causing
increased bile acid extretion. This results in hepatic synthesis of new bile acids, a process that consumes liver cholesterol
stores.

Drug induced myopathy (778)

Statin-associated myopathy is usually characterized by mild muscular pain and resovles with discontinuation of the
medication. However, some px will develop severe myopathy with striking elevations in creatine kinase levels and
occasional rhabdomyolysis. The risk of severe myopathy is increased when statins are given concurrently with fibrates
(particularly gemfibrozil), which impair the hepatic clearance of statins and lead to excessive blood levels. An increasd
risk of statin myopathy is also likely with concurrent use of niacin or ezetimibe, but to a lesser extent.

(712)

Statins act through competitive inh of HMG-CoA reductase, preventing conversion of HMG-CoA to mevalonic acid (the
rate-limitng step in cholesterol biosynthesis). Decreased liver cholesterol synthesis leads to increased hepatic clearance
of LDL from the circulation by LDL receptors. After mediating endocytosis of LDL particles, the LDL receptors are
returned to the cell surface for reuse (receptor recycling); LDL is digested and used for metabolic purposes. This increase
in LDL receptor recycling allows intrahepatic cholesterol levesl to reamin at normal levels while blood levels are kept
low.

Corticosteroids (549)
Thiazolidinediones (605)

Bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma), an intracellular nuclear receptor that acts as
a transcriptional regulator of many genes involved in glucose and lipid metabolism

(599) exert their glucose-lowering effect by reducing insulin ressitance an effect achieved by binding to peroxisome
proliferator-activated receptor-gamma.

Main side effect: fluid retention due to increased sodium reabsorption in the renal collecting tubules. This can lead to
water weight gain, peripheral edema and decompensation of underlying congestive heart failure. Also cause adipose
weight gain, likely due to a combination of increased fat storage in adipocytes and an increased number of adipocytes in
subcutaneous tissue.

Insulin

(850)
Diabetic px often needs 2 types of insulin, a basal long-acting insulin anda postprandial short-acting insulin. The best
basal long-acting insulins are glargine and detemir insulin (admn as once-a-day shots). NPH is good for about 18 hrs
(shots given twice a day). The best short-acting insulins are lispro, aspart, and glulisine (shots given 3 times a day with
meals. They have a very rapid onset of action with peak effects coinciding with peak postprandial hyperglycemia.

(1121) decreases blood glucose levels by increasing glucose uptake into skeletal muscle and adipocytes. In addition to
having glucose lowering effects, insulin is an anabolic hormone that promotes synthesis of glycogen, triglycerides,
nucleic acids, and proteins. Furthermore, insulin inhibits glycogenolysis and gluconeogenesis.

The surface receptor for insulin is a transmembrane protein with intrinsic tyrosine kinase activity in its cytoplasmic
domain. Insulin binding activates tyrosine kinase, leading to phosphorylation of insulin receptor substrate 1 (IRS-1). IRS-1
then activates several intracellular pathways that induce the physiologic effects of insulin. Activation of the MAP kinase
pathway promotes mitogenic functions such as DNA synthesis and cell growth. In contrast, activation of
phosphatidylinositol-3-kinase (PI3K) stimulates metabolic functions such as translocation of GLUT-4 to the cell
membrane, glycogen synthesis, and fat synthesis. PI3K promotes glycogen synthesis by activating protein phosphatase,
an enzyme that dephosphorylates glycogen synthase, leading to its activation.

Non-insulin agents for type 2 DM (606)

SGLT2 inh (604)

(eg, canagliflozin, dapagliflozin) decrease renal reabsorption of glucose, leading to urinary glucose loss and decreased
blood glucose levels. In px with chronic kidney disease, these medications are less effective. Therefore, serum creatinine
should be measured prior to therapy

Side effects: include genitourinary tract infections due to glucosuria and moderate osmotic diurses that can cause
symptomatic hypotension (particularly in elderly individuals and px taking diuretics)

Sulfonylureas (11565)
Sulfonylureas increase insulin secretion by pancreatic beta cells independent of blood glucose concentration. Long-
acting sulfonylureas (eg, glyburide, glimepiride) have a high incidence of hypoglycemia, especially in the elderly.

(1655) proinsulin is cleaved into mature insulin and C-peptide, which are co-secreted from pancreatic beta cells in
equimolar amounts. Circulating levels of C-peptide can be used as a marker of endogenous insulin secretion.
Sulfonylureas and meglitinides lower blood glucose by stimulating pancreatic insulin secretion; hypoglycemia due to
these agents is associated with elevated C-peptide levels.

Metformin (607)

Metformin inh hepatic gluconeogenesis and increases peripheral glucose utilization. Lactic acidosis is a rare complication
of metformin therapy, but its risk is increased in px with underlying renal insufficiency.

Adverse effects of graves disease tx (637)

Antithyroid drugs are associated with an increased risk of agranulocytosis, typically in the first few months of therapy.
This is an idiosyncratic and potentially life-threatening side effect of therapy and is likely due to both immune-mediated
effects (via generation of antineutrophil cytoplasmic antibodies) and direct bone marrow toxicity (via generation of ROS)

Aromatase inh (584)

Estrogen is the main hormone responsbiel for the growth and development of estrogen receptor (ER)-postivei breast
tumors. Aromatase inh (eg, anstrozole, letrozole, exemestane) decrease the synthesis of estrogen from androgens,
suppressing estrogen levels and slowing progression of ER-postiive tumors.

Gastrointestinal

Liver enzymes (99)

To assess liver functionality:

- PT
- Bilirubin
- Albumin
- Cholesterol

Assess structural integrity and cellular intactness:

- Transminases

Biliary tract

- Alkaline phosphatase (bone and liver are the primary sources of alkaline phosphatase)
- Gamma glutamyl transferase

Gamma-glutamyl transpeptidase is an enzyme predominantly present in hepatocytes and biliary epithelia. While it too
can be found in various extrahepatic tissues (organs such as kidney, spleen, pancreas, heart, lung and brain), GGTP is not
present to a significant extent in bone. It is therefore particularly useful in determining whether an elevated alkaline
phosphatse is of hepatic or bony origin

Hiatal hernia (14880)

- Sliding hiatal hernias are the most common form and occur due to laxity of the phrenoesophageal membrane,
which typically results from repetitive stress on the membrane (eg, coughing, vomiting). This allows the GE
junction and proximal stomach to slide upward into the thoracic cavity and predisposes px to reflux symptoms
(eg, heartburn, regurgitation, epigastric/chest pain) due to incompetence of the lower esophageal sphincter.
- Paraesophageal hernias are rarer and occur due to a defect (hole) in the phrenoesophageal membrane. Laxity of
the gastrocolic and gastrosplenic ligamnets (which anchor the stomach in the abdomen) allows the gastric
fundus to migrate into the thoracic cavity. Larger defects can also result in the subsequent herniation of the GE
junction and surrounding structures (eg, bowel, spleen) into the chest. This predisposes px to gastric volvulus,
ulcerations and respiratory complications (due to lung compression)

Tracheoesophageal fistula (11962)

Tracheoesophageal fistula with esophageal atresia results from failure of the primitive foregut to appropriately devide
into separate trachea and esophageal structures. Infants present shortly after birth with excessive secretions and
choking/cyanosis during feeds. Dx can be confirmed by x-ray after the inability to pass a nasogastric tube into the
stomach.

VS. choanal atresia is characterized by congentital obstruction of the posterior nasal passages. Infants with bilateral
choanal atresia can present with upper airway obstruction and cyanosis with feeding, but not excessive drooling.
Inability to pass a nasogastric tube through the nares is suggestive of the dx.

Anterior abd wall (11850)

Horizontal transection of the rectus abdominis muscle must be performed with great caution as the inferior epigastric
arteries enter this muscle at the level of the arcuate line. The inferior epigastric arteries below the arcuate line are
susceptible to injury (eg, hematoma) due to lack of a supporting posterior rectus sheath

Intestinal atresia (319)

Duodenal Jejunum/ileum Colonic
Pathophysiology Failure of recanalization at Vascular injury Unkown
8-10 weeks gestation
Clinical findings Bilious or nonbilious emesis Bilious emesis Constipation
Double-bubble sign on xray Abd distension Abd distension
Associations Down syndrome Gastroschisis Hirchsprung disease

Intestinal atresias of the midgut (eg, jejunum, ileum, proximal colon) are the result of vascular occlusion in utero.
Diminished intestinal perfusion leads to ischemia of a segment of bowel, with subsequent narrowing (stenosis) or
obliteration (atresia) of the lumen. If a major vessel (eg, the superior mesenteric artery) is occluded, the area of
intestinal necrosis is large. The result is a proximal segment that ends in a blind pouch; followed by an area of absent
small bowel and associated dorsal mesentery; and, finally, a distal segment of ileum that assums a spiral configuration
around an ileocolic vessel. This specific pattern is known as an “apple-peel” or “Christmas tree” deformity.

RECANALIZATION FAILURE IS NOT THE CAUSE OF ATRESIA OR STENOSIS IN THE DISTAL GUT; DISTAL ATRESIAS ARE DUE
TO VASCULAR INJURY
Necrotizing enterocolitis (9920)

Necrotizing enterocolitis is one of the most common GI emergencies affecting newborns. It is characterized by bacterial
invasion and ischemic necrosis of the bowel wall, and is associated with prematurity and initiation of enteral feeding.
Abd x-ray showing pneumatosis intestinalis (ie, air in the bowel wall) confirms the dx

Malrotation (318)

Intestinal malrotation results when the midgut undergoes incomplete embryological counterclockwise rotation. It can
present as intestinal obstruction (due to compression by the adhesive bands) and midgut volvulus (intestinal ischemia
due to twisting around the blood vessels). Obstruction manifests as bilious emesis during the first days of life. In
addition, because the mesenteric base is abnormally narrowed, the mesentery is vulnerable to twisting around the
superior mesenteric artery.

Pancreatic secretion (6574)

The acinar cells primarily contribute to the enzymatic portion and the ductal cells are responsbiel for producing the
aqueous portion. The flow rate of pancreatic exocrine secretions increases in response to the hormone secretin. During
high flow, bicarbonate concentration increases while chloride concentration drops, whereas at low flow the opposite is
true. A chloride-bicoarbonate exchanger on the apical surface of ductal cells helps maintain this inverse relationship.

Neural crest migration (330)

They move caudally along the vagal nerve fibers. They are present in the wall of proximal colon at 8 th week of gestation
and in the rectum by 12th week.

The rectum is always involved in Hirschsprung disease. The absence of ganglion cells in the colonic wall causes the
affected segment to be narrowed because it cannot relax. The passage of intestinal contents through this area is
difficult, and compensatory dilation of proximal areas of the colon occurs.

Presents:

- Cant pass meconium within 48 hrs of birth

- Symptoms of intestinal obstruction: bilious vomiting and abd distention

Diverticular disease (415)

Colonic diverticula often involve the sigmoid colon and develop due to exaggerated contractions of colonic smooth
muscle segments. This results in increased intraluminal pressure, causing outpouching of the mucosa and submucosa
through the muscularis (false diverticula). Individuals (typically age >60) may be asymptomatic or have hematochezia or
diverticulitis.

Meckel diverticulum (329)

Meckel diverticulum results from failed obliteration of the vitelline (ompalomesenteric) duct and usually presents with
spontaneous but painless lower GI bleeding. May also be potential lead point for intussusception, which can present
with colicky abd pain and “cuarrant jelly” stools. Tc-pertechnetate localizes ectopic gastric mucosa, and its increased
uptake is diagnostic for Meckel diverticulum.

(322)
The omphalomesenteric (vitelline) duct normally obliterates during the 7 th week of embryonic development. Both
enterocysts and Meckel diverticula result from a failure of obliteration involving the omphalomesenteric duct.

1. Persistent vitelline duct: occurs due to complete failure of the vitelline duct to close. A small connection
between the intestinal lumen and the outside of the body exists at the umbilicus. Meconium discharge from the
umbilicus is seen soon after birth if such a fistula is present
2. Meckel diverticulum is the most common vitelline duct anomaly. It results from a partial closure of the vitelline
duct, with the patent portion attached to the ileum. A fibrous band may connect the tip of the meckel
diverticulum with the umbilicus
3. Vitelline sinus: results from a partial closure of the vitelline duct, with the patent portion open at the umbilicus
4. Vitelline duct cyst (enterocyst) forms if peripheral portions of the vitelline duct (connected to the ileum and
umbilicus) obliterate, but the central part remains. This cyst is connected with the ileum and abd wall by fibrous
bands

Lymphatic drainage (11817)

Lymphatic drainage of the rectum proximal to the anal dentate line occurs via the inferior mesenteric and internal iliac
lymph nodes. Areas distal to the dentate line drain primarily into the inguinal nodes.

(1631) Most of the cutaneous lymph from the umbilicus down, including the anus below the dentate line, drains to the
superficial inguinal lymph nodes. Exceptions are the glans penis and posterior calf, which drain to the deep inguinal
nodes.

(11830) in the lower extremities, the superficial lymphatic system is divided into medial and lateral tracks. The medial
track runs up to the superficial inguinal lymph nodes, bypassing the popliteal nodes. Consequently, lesions on the medial
foot cause inguinal lymphadenopathy, whereas lateral lesions are more likely to cause lymphadenopathy in both the
popliteal and inguinal areas.

Retroperitoneal organs (838)

Retroperitoneal hematoma is a common complication of abdominal and pelvic trauma. The pancreas is a retroperitoneal
organ, and pancreatic injury is frequently a source of retroperitoneal bleeding.

Penetrating abd trauma (10583)

The portal triad runs through the hepatoduodenal ligament and is composed of the hepatic artery, portal vein and
common bile duct. In the setting of traumatic liver injury with persistent bleeding, occlusion of the hepatoduodenal
ligament can be performed to identify the vascular source (ie, the Pringle maneuver). If liver bleeding does not cease
when the portal triad is occluded, it is likely that there has been injury to the inferior vena cava or hepatic veins.

Anastomosis (11839)

The sup mesenteric artery and inferior mesenteric artery are the 2 main vessels supplying the small and large intestines.
They are connected by a pair of anastomoses: the marginal artery of Drummond, which is the principal anastomosis, and
the inconsistently present arc of Riolan (mesenteric meandering artery)

Perforated viscus (14837)

Free air under the diaphragm (pneumoperitoneum), likely due to perforation of a hollow abd viscus. The most common
cause of pneumoperitoneum is a perforated duodenal ulcer, but perforation can occur anywhere along the GI (or female
reproductive) tract due to ulcers, tumors, trauma, or iatrogenic causes (eg, endocscopy, surgery)

Contamination of the sterile peritoneal cavity with bowel contents leads to chemical (acid or chime-related) or bacterial
peritonitis, which if left untreated, can progresss to sepsis and death. Diffuse irritation of the parietal peritoneum results
in severe abd pain with rigidity and rebound tenderness. Shoulder pain is another frequent finding and reflects referred
pain from diaphragmatic irritation.

Bilirubin (363)

Processing of bilirubin:

1. Carrier-mediated uptake of bilirubin at the sinusoidal membrane

2. Conjugation of bilirubin with glucuronic acid by UGT in the ER
3. Biliary excretion of the water-soluble, nontoxic bilirubin glucuronides

Criger-Najjar syndrome

- AR
- Lack of UGT enzyme needed to catalyze bile glucuronidation
- When bilirubin is not correctly enzymatically processed by the liver, unconjugated hyperbilirubinemia develops
- Indirect bilirubin levels typically approximate 20-25 mg/dL in these infants, but can rise to as high as 50 mg/dL
- Conjugated bilirubin is water soluble, loosely bound to albumin, and excreted in urine when present in excess. In
contrast, unconjugated bilirubin cannot be filtered by the glomerulus and is therefore not excreted in the urine.
Instead, the unconjugated bilirubin is gradually deposited into various tissues, including the brain. These
deposits can cause kernicterus (bilirubin encephalopathy), which is a potentially fatal condition characterized by
severe jaundice and neurologic impairment

Gastroesophageal reflux (14877)

Tx: magnesium salts (eg, magnesium trisilicate, magnesium hydroxide) and aluminum hydroxide are weak alkali mineral
salts. They temporarily increase the gastric pH by neutralizing hydrochloric acid, helping to relieve gastroesophageal
reflux symtpoms.

Aluminum hydroxide has a tendency to cause constipation due to interactions with intestinal secretions that form
insoluble salts. In contrast, magnesium salts cause osmotic diarrhea. Therefore, the two medications are combined to
offset the adverse effects of the individual medicaitons. Px with reflux symptoms and chronic constipation may benefit
from magnesium salt monotherapy, whereas aluminum hydroxide monotherapy may be of value in px with chornic
diarrhea.

Groin hernias

(417)
(8669)

(418)
Inguinal hernias are located above the inguinal ligmanet and are much more common in men. The inferior epigastric
vessels are clearly visible on the anterior abdominal wall during laparoscopic hernia repair and can be used as a
landmark to distinguish between direct and indirect inguinal hernias

Indirect inguinal hernias occur due to failure of the processus vaginalis to obliterate, allowing abd contents to protrude
lateral to the inferior epigastric vessels through the deep (internal) inguinal ring. The abd contents follw the path fo the
inguinal canal and may exit through the superficial (external) inguinal ring into the scrotum.

Direct inguinal hernias occur due to weakness in the transversalis fascia that allows abd contents to protrude medial to
the inferior epigastric vessels into the Hesselbach triangle. Compared to indirect inguinal hernias, direct hernias are less
prone to incarceration due to their wide neck. It is also uncommon for them to descend into the scrotum as there is no
direct path through the abd fascia

Hemochromatosis (6512)

Clinical manifestations of hereditary hemochromatosis

Skin Hyperpigmentation (bronze diabetes)
Musculoskeletal Arthralgia, arthropathy & chondrocalcinosis
GI Elevated hepatic enzymes with hepatomegaly (early), cirrhosis (later) & increased risk of
hepatocellular carcinoma
Endocrine DM, secondary hypognadism & hypothyroidism
Cardiac Restrictive or dilated cardiomyopathy & conduction abnormalities
Infections Increased susceptibility to Listeria, Vibrio vulnificus & Yersinia enterocolitica

Primary hemochromatosis (ie, hereditary hemochromatosis) (395)

Most commonly caused by mutations affecting the HFE protein. This protein normally interacts iwht the transferrin
receptor to form a complex that fx as a sensor of iron stores. Mutations that inactivate the HFE protein cause
enterocytes and hepatocytes to detect falsely low iron levels. This increases iron accumulation in the body through the
following 2 mechanisms:

1. Enterocytes respond by increasing apical expression of divalent metal transporter 1 (DMT1), increasing iron
absorption from the intestinal lumen
2. Hepatocytes respond by decreasing hepciding synthesis; low hepcidin levels result in increased ferroportin
expression on the basolateral surface of enterocytes. This allows increased iron secretion into the circulation,
leading to iron overload.

When body iron levels exceed 20g, px typically develop the classic triad of

- Micronodular cirrhosis
- DM
- Skin pigmentation (ie, “bronze diabetes”)

Px are at an increased risk for hepatocellular carcinoma, CHF and testicular atrophy/hypogonadism

(15663)

Chornic fatigue + sexual dysfunction + arthritis (involving middle MCP joints) think of HH

Disease manifestations: liver disease, skin hyperpigmentation, DM, pituitary hormone deficiencies (eg, central
hypogonadism) and cardiomyopathy
As opposed to primary osteoarthritis of the hands, which most commonly involves the proximal and distal
interphalangeal joints and the first MCP joint, arthritis in HH typically involves the second and third MCP joints. X-ray
often shows characteristic deformities (eg, hook-like osteophytes, squared-off bone ends affecting MCP joints) and
deposition of calcium pyrophoshphate dehydrate in the articular cartilage (chondrocalcinosis)

Enteropeptidase deficiency (1251)

Enteropeptidase, a duodenal brush border enzye, is responsible for activation of trypsin from its inactive precursor,
trypsinogen. Once active, trypsin functions to cleave peptide bonds in dietary proteins and activate the other pancreatic
enzymes. Enteropeptidase deficiency leads to both protein and fat amlabsorption as trypsin is required to activate
enzymes required for both lipid and protein digestion. The disease causes diarrhea, failure to thrive, and edema (due to
hypoproteinemia)

Malabsorption

(323) is a syndrome of impaired intestinal digestion and absorption. Fats are typically the most severely affected
macronutrient in generalized malabsorption, and testing the stool for fat (Eg, with Sudan III stain) is the most sensitive
strategy for screening for malabsorptive disorders.

Celiac disease (981)

Malabsorption caused by celiac disease can lead to VIt D def. Px have decreased serum phosphorus, increased serum
PTH (secondary hyperparathyroidism) and low (or normal) serum calcium.

Dx (326)

- Increased tissue transglutaminase IgA

- Increased antiendomysial antibodies
- Duodenal biopsy showing increased intraepithelial lymphocytes & flattened villi

Whipple disease (131)

Caused by grampositive actinomycete Tropheryma whipppelii, Whipple disease is a rare systemic illness that involves
the small intestine, joints and CNS. The actinomycte proliferates only within the macrophages of these tissues, provoking
no inflammatory response as a consequence. Classic histologic findings include small intestine mucosa containing
enlarged, foamy macrophages packed with both rod-shaped bacilli and PAS-positive, diastase-resistant granules (which
consist of lysosomes and partially digested bacteria)

(132) the glycoprotein in the cell walls of the actinomycete Tropheryma whippeli colors magenta with PAS and is
diastase-resistant, making this stain an excellent choice in evaluating tissue for Whipple disease.

Primary biliary cholangitis (403)

PBC is a chronic autoimmune liver disease characterized by a dense portal tract infiltrate of macrophages, lymphocytes,
plasma cells, and eosinophils that results in granulomatous destruction of intrahepatic, interlobular bile ducts (“florid
duct lesion”)

PBC most commonly presents insidiously in middle-aged women. Fatigue and pruritus (usually worse at night) are
normally the first symptoms. as the disease progresses, hepatosplenomegaly and cholestasis (eg, jaundice, pale stool,
dark urine) can develop. Reduced bile flow to the small intestine may cause malabsorption of fat-soluble vitamins (eg, A,
D, E, K). Reduced biliary cholesterol excretion may also promote hypercholesterolemia with xanthelasma formation. Late
manifestiations include cirrhosis and portal HTA.

(1867) Xanthelasma and other forms of xanthoma are classically associated with primary or secondary hyperlipidemia.
Chronic cholestatic processes including obstructive biliary lesions and primary biliary cirrhosis result in subsequent
hypercholesterolemia, leading to the formation of xanthelasmas. Correction of underlying lipid defects can lead to slow
resolution of these lesions.

Appendicitis (11782)

The teniae coli are 3 separate smooth muscle ribbons that travel longitudinally on the outside of the colon and converge
at the root of the vermiform appendix. If the appendix cannot be id by palpation during an appendectomy, it can be
located by following the teaniae coli to their origin at the cecal base.

(11775) appendicitis causes dull visceral pain at the umbilicus due to afferent pain fibers entering at the T10 level in the
spinal cord. Progressive inflammation in the appendix irritates the parietal peritoneum and abd wall to cause more
severe somatic pain shifting from the umbiliticus to McBurney point (2/3 of the distance from the umbilicus to the
anterior superior iliac spine)

Hemochromatosis (393)

Excessive intestinal iron absorption and organ dmg (eg, cirrhosis, DM, cardiomyopathy, arthropathy) due to iron
accumulation within parenchymal tissues

The HFE protein interacts with the transferrin receptor on the cell surface to facilitate endocytosis of the iron-transferrin
complex. Once inside the cell, transferrin is degraded and the released iron is added to the labile iron pool. Mutation of
the HFE protein leads to reduced iron uptake and causes enterocytes and hepatocytes to sense falsely low iron levels.
This enhances iron accumulation in the body via 2 mechanisms:

1. Enterocytes increase apical expression of divalent metal transporter 1 (DMT1), increasing intestinal iron
absorption from the lumen
2. Hepatocytes decrease hepcidin synthesis, which increases ferroportin expression on the basolateral surface of
enterocytes and promotes iron secretion into the circulation.

Excessive iron accumulation results in elevated levels of serum ferritin (cellular ioren storage protein) and increased
saturation of transferrin (major iron transporter in the plasma).

Superior Mesenteric Artery Syndrome (303)

Occurs when the transverse portion of the duodenum is entrapped between the SMA and aorta, causing symptoms of
partial intestinal obstruction. This syndrome occurs when the aortomesenteric angle cirtically dcreases, secondary to
diminished mesenteric fat, pronounced lordosis, or surgical correction of scoliosis.

Hemorrhoids (11840)

Hemorrhoids result from abnormal distension of a portion of the anal arteriovenous plexus. The vascular components of
internal hemorrhoids drain into the superior rectal vein, which subsequently drains into the inferior mesenteric vein.
Band ligation of hemorrhoids cuts off their blood supply, causing them to degenerate.

Hemangioma (54)
Cavernous hemangioma is the most common benign liver tumor. Microscopically, these tumors consist of cavernous,
blood-filled vascular spaces of variable size lined by a single epithelial layer. The biopsy of a suspected hemangioma is
not advisable, as the procedure has been known to cause fatal hemorrhage and is a low diagnostic yield.

Alcoholic liver disease (370)

The pathogenesis of alcohol-induced hepatic steatosis appears related primarily to a decrease in free fatty acid oxidation
secondary to excess NADH production by the 2 major alcohol metabolism enzymes, alcohol dehydrogenase and
aldehyde dehydrogenase.

Irritable bowel syndrome (1290)

Diphenoxylate is an opioid antidiarrheal drug that binds mu opiate receptors in the gut to slow motility. Overuse can
lead to euphoria and physical dependence. To discourage abuse, diphenoxylate is combined with atropine, which
induces adverse effects if taken in high doses.

Mesenteric ischemia (414)

Chronic mesenteric ischemia is characterized by atherosclerosis of the mesenteric arteries, resulting in diminished blood
flow to the intestine after meals. This causes postprandial epigastric pain (intestinal angina) with associated food
aversion/weight loss. Its pathogenesis is similar to angina pectoris.

Hirschsprung’s disease ( 331)

Submucosal (Meissner) and myenteric (Auerbach) autonomic plexi are absent in the affected segment of the bowel in
Hirschsprung disease. The submucosa of the narrowed area is the most superficial layer where the absence of ganglion
can be seen.

Mastocytosis (306)

In systemic mastocytosis, clonal mast cell proliferation occurs in the bone marrow, skin and other organs. Mast cell
proliferation often is associated with mutations in the KIT receptor tyrosine kinase. These cells are characterized by
prominent expression of mast cell tryptase. Excessive histamine release from degranulation of mast cells mediates many
of the symptoms of the disease, such as syncope, flushing, hypotension, pruritus, and urticarial. In addition, histamine
induces gastric acid secretion, which can lead to gastric ulceration. The excess acid also inactivates pancreatic and
intestinal enzymes, causing diarrhea. Other GI symptoms include nausea, voming, and abd cramps.

Gastric acid secretion by parietal cells in the fundus and body of the stomach is stimulated by:

1. Histamine binds H2 receptors and increases intracellular cAMP concentration

2. ACh binds M3 receptors and leads to an increase in intracellular Ca
3. Gastrin binds to the cholesystokinin B receptor and increases the intracellular Ca concentration. It also
stimulates histamine synthesis synthesis and release by enterochromaffin-like cells in the stomach

Diffuse esophageal spasm (280)

Diffuse esophageal spasm is characterized by periodic, simultaneous, and non-peristaltic contractions of the esophagus
due to impaired inh innervation within the esophageal myenteric plexus. Px typically present with liquid/solid dysphagia
and chest pain due to inefficient propulsion of food into the stomach.

Achalasia (828)
Pernicious anemia (124)

Pernicious anemia (12068)

GERD (14873)

Reflux occurs in most pregnant women and is common in all trimesters. The major underlying cause is elevated estrogen
and progesterone levels, which relax the smooth muscle of the LES leading to decreased LES tone and reduced
sensitivity to contractile stimuli (eg, high-protein meal). Later in pregnancy, reflux can also occur when the gravid uterus
compresses the stomach and results in an altered LES angle or increased gastric pressure.

Peptic Ulcer disease (291)

Duodenal ulcers are more common than gastric ulcers and tend to occur anteriorly. Ulcers located on the anterior wall
of the duodenal bulb are more prone to perforation; those on the posterior wall are more likely to cause hemorrhage.
The gastroduodenal artery lies along the posterior wall fo the duodenal bulb and is likely to be eroded by posterior
duodenal ulcers.

(130) duodenal ulcers are not associated with an increased risk of carcinoma in the same location. In contrast, ulcers
located in the esophagus, stomach (gastric), and colon may be malignant and biopsy is required.

(7710) H. pylori is a common cause of peptic ulcers. Duodenal ulcers are associated with heavy colonization in the gastric
antrum, whereas colonization in the gastric corpus is associated with gastric ulcers. Colonization of H pylori in the gastric
antrum is associated with decreased somatostatin formation and increased gastrin secretion.

(1918) if left untreated, chronic H pylori infection typically spreads to involve the corpus (body) and fundus of the
stomach and is characterized by patchy, multifocal gastric atrophy with intestinal metaplasia. Patchy destruction of
parietal and G cells results in diminished acid secretion and hypochlorhydria. Px with chronic gastritis are less likely to
develop duodenal ulcers but due to the associated chronic inflammation, they are at increased risk of gastric ulcers and
malignancy, particularly gastric lymphoma (ie, mucosa-associated lymphoid tissue [MALT] lymphoma and gastric
adenocarcinoma

(1603)

Chronic inflammation due to H pylori colonization in the gastric antrum leads to depletion of somatostatin-producing
cells (delta cells), which are located mostly in the antrum. Somatostatin inh gastrin release from G cells. in its absence,
elevated gastrin levels act directly (via cholecystokinin B receptors) and indirectly (via histamine release by
enterochromaffin-like cells) to increase acid secretion by parietal cells. in addition, H pylori release cytotoxins that inh
duodenal production of bicarbonate. The resultant increased acid load is emptied into the underprotected duodenum,
leading to duodenal ulcer formation.

In contrast, gastric ulcers occur when H pylori colonizes the gastric body (corpus). Chronic inflammation leads to
multifocal atrophic gastritis and a reduction in the number of acid-producing parietal cells, which are located mostly in
the gastric body. Gastric ulcer formation results from direct mucosal damage caused by bacterial products (eg,
ammonia, cytotoxins) and the resultant inflammatory response. Unlike antral-predominant disease, corpus-predominant
disease is associated with metaplasia and malignancies (eg, gastric lymphoma, adenocarcinoma)

Proton pump inh (1766)

Proton pump inh (eg, omeprazole, lansoprazole) block the final common pathway of gastric acid secretion from parietal
cells, which is stimulated by acetylcholine, histamine and gastrin

Drug induced liver injury (369)

Inhaled anesthetics, such as halothane, can be associated with highly lethal fulminant hepatitis that cannot be
distinguished histologically from acute viral hepatitis (widespread centrilobular necrosis and inflammation of the portal
tracts and parenchyma are observed, making the condition indistinguishable from fulminant viral hepatitis). Px have
significantly elevated aminotransferase levels due to massive hepatocellular injury and a prolonged prothrombin time
due to failure of hepatic synthetic function.

Stress-related mucosal disease (125)

Usually caused by local ischemia in the setting of severe physiologic stress (eg, shock, extensive burns, sepsis, severe
trauma). Ulcers arising in the setting of severe trauma/burns are called Curling ulcers. Ulcers arising from intracranial
injury are caused by direct vagal stimulation and are called Cushing ulcers.

Small intestinal bacterial overgrowth (SIBO) (11860)

Gastric bypass surgery can cause small intestinal bacterial overgrowth due to excessive bacterial proliferation in the
blind-ended gastroduodenal segment. SIBO results in deficiency of most vitamins (B12, A, D, and E) and iron, but
increased production of folic acid and vitamin K

Colonic manifestations of various diseases (8290)

Disease Colonoscopy findings Biopsy findings
Adenocarcinoma Usually a protuberant mass Dysplastic mucosal cells with variable
degree of gland formation
CMV Multiple ulcers and mucosal erosions Cytomegalic cells with inclusion
bodies
Cryptosporidium Nonulcerative inflammation Basophilic clusters seen on the surface
of intestinal mucosal cells
E. hystolytica Numerous discrete, flask-shaped Trophozoites containing red blood
ulcerative lesions cells
Kaposis sarcoma Reddish/violet, flat maculopapular Spindle-shaped tumor cells with small-
lesions or hemorrhagic nodules vessel proliferation
Ulcerative colitis Contiguous area of erythematous Inflammatory infiltrate involving the
friable, granular mucosa with possible mucosa and submucosa with crypt
pseudopolyps abscesses

Crohn’s disease (409)

Crohn’s disease (12047)

Extraintestinal manifestations: ankylosing spondylitis and peripheral arthritis (low back pain and joint stiffness that is
worse at night)

Crohn disease with ileal resection or extensive ileal involvement can cause bile acid malabsorption, which may lead to
impaired absorption of fat-soluble vitamins (A, D, E, K). Vitamin K deficiency can result in impaired coagulation with easy
bruising, large hematoma formation in deep tissues and joints (Eg, hemarthrosis) after minor trauma, and prolonged
bleeding after surgery.

Vs. immune thrombocytopenic purpura is characterized by autoimmune destruction of platelets and is often associated
with viral infections. Platelet abnormalities typically cause superficial microhemorrhages such as petechiae and mucosal
bleeding (eg, epistaxis, gingival bleeding)
(1783) Px are prone to developing fistulas and abscesses due to the transmural inflammation that occurs in CD. Fistulas
are abnormal connections between 2 epithelial-lined organs. They are usually formed between the bowel and nearby
structures. Perinal disease other than fistulas is also common and may include skin tags and fissures.

(406)

Noncaseating granuloma on biopsy are only seen in minority of px with CD but, when present, are highly suggestive of
the dx. Microscopically, granulomas contain a large number of epithelioid macrophages that may fuse together to form
multinucleated cells (Langhans giant cells), surrounded by a band of lymphocytes.

Granuloma formation is a product of chronic T-lymphocyte and macrophage activation in response to a difficult-to-
eradicate antigen (eg, mycobacterium, self-antigens). Macrophages release TNF-alpha and other proinflammatory
cytokines (eg, IL-6, IL-1, IL-12) that promote macrophage migration and Th1 cell differentiation. Th1 cells are thought to
be important in granuloma organization; they produce IL-2 and interferon-gamma, which promote further T-
cellresponse, activation of macrophages, and differentiation of macrophages into giant cells. Th17 cells are a
proinflammatory subset of Th1 cells and contribute to the cell injury seen in CD.

(405) histopathology in Crohn disease also demonstrates transmural inflammation, distortion of the normal architecture
and Paneth cell metaplasia

(408) crohn disease is associated with oxalate kdney stones. Impareid bile acid absorption in the terminal ileum leads to
loss of bile acids in feces with subsequent fat malabsorption. Intestinal lipids then bind calcium ions, and the resulting
soap complex is excreted. Free oxalate (normally bound by calcium to form an unabsorbable complex) is absorbed and
forms urinary calculi (enteric oxaluria)

Zollinger-ellison syndrome (305)

Is caused by gastrinomas located in the small intestine/pancreas and presents with peptic ulcers (especially distal
duodenal ulcers), heartburn and diarrhea. Px typically have elevated gastrin levels that rise in response to exogenous
secretin admn. In contrast, secretin inh release of gastrin from normal gastric G cells.

(304) Gastrin not only stimulates HCl secretion, but it also has a trophic effect on parietal cells. In px with Zollinger-
Ellison syndrome (such as this px), gastrin hypersecretion induces parietal cell hyperplasia, causing visible enlargement
of gastric folds on endoscopy.

Characteristics of gastroesophageal mural injury (1662)

Etiology Mallory-weiss tear Boerhaave syndrome
- Upper GI mucosal tear - Esophageal transmural tear
- Caused by forceful vomiting - Caused by forceful vomiting
(increased intragastric pressure) (increased intragastric
- Submucosal arterial or venous pressure)
plexus bleeding - Esophageal air/fluid leakage
into the mediastinum & pleura
Clinical presentation - Vomiting & retching - Vomiting & retching
- Mehatemesis - Chest & upper abd pain
- Epigastric pain - Fever, dyspnea & septic shock
rapidly ensue
 Reptitive vomiting leads to metabolic alkalosis due to net loss of acidic gastric secretions
Mallory Weiss (281)

Longitudinal mucosal tears at the esophagogastric-squamocolumnar junction describe Mallory Weiss syndrome. Most
commonly, these tears occur secondary to rapid increase of intraabdominal and intraluminal gastric pressure, as when
happens during retching and vomiting. Other precipitating factors include coughing, hiccupping, other repeated abd
straining and abd trauma. Additionally, hiatal hernias are found in about half of px with Mallory-Weiss syndrome and are
considered a strong predisposing factor. Mallory-weiss syndrome is very commonly associated with alcoholism

Mallory-weiss tears can be asymptomatic or can lead to GI hemorrhage that manifests as hematemesis. About 10% of all
upper GI bleeds are from Mallory-Weiss. The intensity of hemorrhage and amount of blood loss varies widely according
to the length of death of the tears but is almost never life-threatening

Vipoma (1938)

VIPoma can result in watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome (pancreatic cholera). VIP
stimulates pancreatic bicarbonate and chloride secretion, and its binding to intestinal epithelial cells leads to adenylate
cyclase activation and increased cyclic AMP production, causing sodium, chloride and water secretion into the bowel
(secretory watery diarrhea, often >3 L/day).

Diabetic gastroparesis (6705)

- Autonomic neuropathy
- Metoclopramide, a dopamine 2 receptor antagonist, can improve symptoms but is occasionally associated with
extrapyramidal side effects (eg, dystonia) and tardive dyskinesia (eg, involuntary movements)
- Erythromycin (a macrolide antibiotic) can be used as an alternate prokinetic agent. The prokinetic effects of
erythromycin stem from the activation of the motilin receptor in the smooth muscle of the upper digestive tract,
which results in coordinated peristaltic contractions that begin in the stomach and move through the entire
upper digestive system (thereby propelling food into the colon). When used as an antibiotic, erythromycin can
cause significant abdominal cramping. The agonist effects of erythromycin diminish over time (tachyphylaxis) so
it is generally used for short periods (<4 weeks)

Annular pancreas (438)

Pancreatic tissue encircling the descending duodenum, is caused by failure of the ventral pancreatic bud to properly
migrate and fuse with the dorsal bud during the seventh and eighth week of fetal development. Annular pancreas is
usually asymptomatic but may present with duodenal obstruction or pancreatitis.

Pancreas divisum (437)

The dorsal pancreatic bud forms the majority of pancreatic tissue (body, tail, and most of the head). The ventral
pancreatic bud is a precursor of the uncinate process, inferior/posterior portion of the head, and major pancreatic duct
(of Wirsung). Failure of the dorsal and ventral pancreatic buds to fuse leads to pancreas divisum. In this condition, the
pancreatic ductal systems remain separate, with the accessory duct draining the majority of the pancreas.

Acute pancreatitis (433)

Because of trypsin’s central role in the activation of pancreatic digestive proenzymes, multiple protective mechanisms
exist to limit the amount of trypsinogen that becomes prematurely activated:

- Serine peptidase inh Kazal-type 1 (SPINK1) is secreted by pancreatic acinar cells and fx as a trypsin inh. It
impedes the activity of trypsinogen molecues that become prematurely within the pancreas
 - In addition to functioning as its own activator, trypsin can serve as its own inh by cleaving active trypsin
molecules at a second site, rendering them inactive.

Hereditary pancreatitis is a rare disorder that results from mutations involving the trypsinogen or SPINK1 gene. The most
common mutation leads to the production of abnormal trypsin that is not susceptible to inactivating cleavage by trypsin.
Because a small amount of trypsinogen normally activates prematurely within the pancreatic acini and ducts, these
protective mechanisms are critical for preventing recurrent attacks of acute pancreatitis.

(441) pancreatic zymogens are normally converted into their active form by trypsin in the duodenal lumen. Premature
cleavage of trypsinogen to trypsin within the pancreas leads to uncontrolled activation of these zymogens, causing
pancreatic autodigestion and acute pancreatitis.

The pathogenesis of acute pancreatitis begins with either a toxic or an ischemic injury to the acinar cells that leads to
premature activation of trypsin inside the pancreatic acini. Trypsin then activates the other proteolytic enzymes and
starts a self-sustaining cycle of pancreatic inflammation and autodigestion with further release of digestive enzymes. In
severe cases, this process can result in necrotizing pancreatitis, which is characterized by gross areas of parenchymal
necrosis with a high propensity for secondary bacterial infection.

(1907) polysaccharides must be degraded to monosacchraides by pancreatic and brush border amylases before they can
be absorbed. Monosaccharides can be absorbed directly. D-xylose is a monosaccharide whose absorption is not affected
by exocrine pancreatic insufficiency, and can be used to differentiate between pancreatic versus mucosal causes of
malabsorption

(435) in contrast to a true cyst with walls lined by epithelial cells, the walls of a pseudocyst consist of granulation tissue
and no epithelial lining. Fibrosis, thickening and organization of the walls occur with time. The formation of firm fibrotic
pseudocyst walls (“maturation” of the pseudocyst) takes about 4 to 6 weeks following the episode of acute pancreatitis.
The most common location for a pseudocyst is in the lesser peritoneal sac, bordered by the stomach, duodenum and
transverse colon. The pseudocyst walls are closely adherent to the surrounding hollow organs.

(434) after gallstones, alcohol abuse is the second most common cause of acute pancreatitis. Macrocytosis and an
AST:ALT ratio >2 are indirect indicators of chronic alcohol consumption. Alcohol-related macrocytosis can occur
independently of folate deficiency.

Pancreatic adenocarcinoma (436)

Should be considered in any px with painless obstructive jaundice (elevated bilirubin, dark urine, pale stools) and weight
loss. Courvoisier sign (painless palpable gallbladder in a jaundiced px) can also raise suspicion, although this can be seen
in a number of conditions (eg, cholangiocarcinoma, hepatic duct obstruction). Symptoms of pancreatic malignancy vary
with location; tumors at the pancreatic head typically produce obstructive symptoms due to compression of the bile
duct (CBD), whereas those in the body and tail do not obstruct the CBD and often produce midepigastric pain due to
invasion of the splanchnic plexus.

Chronic pancreatitis (1547)

Alcohol-related chronic pancreatitis develops in part due to alcohol-induced secretion of protein-rich fluid. These
proteinaceous secretions can precipitate within the pancreatic ducts, forming ductal plugs that may calcify and be
detectable on abd imaging.

Ductal obstruction by such concretions may cause exocrine insufficiency due to atrophy of the pancreatic acinar cells
and pancreatic fibrosis. Pancreatic exocrine insufficiency (eg, failure to secrete adequate amylases, proteases and
lipases) leads to malabsorption with consequent diarrhea/steatorrhea. Weight loss and bulky, frothy stools are typical
clinical findings.

(11795) gastric varices are dilated submucosal veins that can cause life-threatening bleeding in the upper GI tract. The
varices are commonly due to portal HTA, which can be a complication of cirrhosis. Gastric varices can also be seen with
splenic vein thrombosis due to chronic pancreatitis, pancreatic cancer, and abd tumor. The splenic vein runs along the
posterior surface of the pancreas and can develop a blood clot from pancreatic inflammation. The short gastric veins
drain the fundus of the stomach into the splenic vein. Splenic vein thrombosis can increase pressure in the short gastric
veins and cause gastric varices only in the fundus. The rest of the stomach and esophagus are usually not affecte.

Biliary atresia (317)

Biliary atresia is a progressive, complete or partial obstruction of extrahepatic bile ducts. The biliary tree is normal at
birth and subsequently undergoes destruction that is thought to be immune-related or viral induced. Infants may appear
healthy at birth, but then present with jaundice within the first 2 months of life, along with dark urine and acholic (pale
or clay-colored) stools due to excessive renal excretion of bilirubin and lack of intestinal bile, respectively. Physical
examination may also reveal firm hepatomegaly due to inflammation. Lab findings: elevated direct bilirubin and gamma-
glutamyl transferase, are consistent with cholestasis.

Liver biopsy is usually diagnostic and reveals intrahepatic bile duct proliferation, portal tract edema, and fibrosis. Urgent
surgical intervention is required, as lack of intervention can lead to death (due to cirrhosis) usually within 2 years.

Cholestasis (364)

Cholestasis can arise secondary to hepatocellular dysfunction or intrahepatic or extrahepatic biliary obstruction. Both
obstructive and nonobstructive cholestasis are characterized by the deposition of bile pigment within the hepatic
parenchyma, often with green-brown plugs in the dilated bile canaliculi. When it is prolonged, the reduction in bile flow
causes intestinal malabsorption of fats and fat-soluble vitamins (A, D, E and K), which require bile salts for digestion

Hereditary hyperbilirubinemia
Dubin Johnson (101)

Defective hepatic excretion of bilirubin glucuronides due to mutation in the canalicular membrane transport protein.

Presents:

- jaundice (in context of trigger)

- Direct (conjugated) hyperbilirubinemia (eg, usually 2-5 mg/dL)
- Liver appears black due to impaired excretion of epinephrine metabolites that accumulate within lysosomes

Gilbert

Benign condition of reduced production of glucuronyl transferase, a hepatic enzyme for glucuronidation (ie, conversion
of bilirubin to its excretable form), px are usually asymptomatic except at times of stress (eg, fasting, illness) during
which mild, indirect hyperbilirubinemia and jaundice are present

Galactosemia (galactose-1-phosphate uridyl transferase [GALT] deficiency) is characterized by defective metabolism of

galactose, a breakdown product of lactose that is then normally metabolized to glucose. Both direct and indirect
bilirubin levels may be elevated. However, infants would present with vomiting, diarrhea and lethargy during the first
few days of life due to inability to digest breast milk or formula.

Breast milk jaundice causes an indirect hyperbilirubinemia that peaks at age 2 weeks. The pathogenesis likely involves an
enzyme, beta-glucuronidase, in breast milk that deconjugates bilirubin. Thise causes increased absorption and,
therefore, increased enterohepatic circulation of bilirubin. Urine and stool appearance are unaffected.

Acalculous cholecystitis (81)

Acute inflammation of the gallbladder in the absence of gallstones. Acalculous cholecystitis most commonly occurs in
critically ill px (eg, those with sepsis, severe burns, trauma, immunosuppression) and is associated with high mortality.
The condition is thought to arise secondary to gallbladder stasis and ischemia, which cause inflammation of and injury to
the gallbladder wall

Cholecystitis (79)

Acute calculous cholecystitis is an acute inflammation of the gallbladder initiated by gallstone obstruction of the cystic
duct. Subsequent steps in pathogenesis include mucosal disruption by llysolecithins, bile salt irritation of the luminal
epithelium, prostaglandin release with transmural inflammation, gallbladder hypomotility, increased intraluminal
pressure causing ischemia and bacterial invasion

Gallstone disease (70)

Gallstones can be categorized as cholesterol, pigment, or mixed stones

Cholesterol: yellow to pale gray and hard

Pigment: composed of calcium salts of unconjugated bilirubin, are comparatively soft, and are dark brown to black

Brown pigment stones: typically arise secondary to bacterial (eg, E. Coli) or helminthic (eg, Ascaris lumbricoides,
Clonorchis sinensis) infection of the biliary tract, which results in the release of beta-glucuronidase by injured
hepatocytates and bacteria. This enzymes hydrolyzes bilirubin glucuronides and increases the amount of unconjugated
bilirubin. The liver fluke C sinensis is a common cause of pigmented stones in East Asian countries and can have a
prolonged quiescent phase before inducing symptoms.

Pigment stones may also occur in the absence of infection when excess bilirubin is excreted, such as with chronic
hemolytic anemia. A small amount of conjugated bilirubin normally becomes deconjugated by endogenous beta-
glucuronidase in the biliary tract. When large amounts of conjugated bilirubin are excreted into the bile, enough
becomes deconjugaed to promote black pigment stone formation.

(77) A prolonged course of total parenteral nutrition (TPN) is often complicated by gallstones. In normal individuals,
enteral passage of fat and AAs into the duodenum triggers release of CCK, leading to contraction of the gallbladder. The
absence of normal enteral stimulation in patients receiving TPN leads to decreased CCK release and subsequent biliary
stasis. In addition, px with extensive resection of the ileum can have disruption to the normal enterohepatic circulation
of bile acids, leading to inadequate solubilization of biliary cholesterol and formation of cholesterol crystals

(78) in the liver, free cholesterol is converted into cholic and chenodeoxycholic acids through a seires of chemical
reactions beginning with cholesterol 7 alpha-hydroxylase (rate-limiting step in bile acid synthesis). These bile acids are
then conjugated to either glycine or taurine (improving solubility and emulsifying ability) to create the bile salts that are
actively secreted into the bile canaliculi. As water-insoluble cholesterol is secreted in bile, it is rendered soluble in small
amounts by the detergent action of these amphipathic (eg, hydrophobic and hydrophilic) bile salts and
phosphatidylcholine (a phospholipid). When there is more cholesterol than can be made soluble, it precipitates into
cyrstals that eventually grow and merge to form gallstones. Gallbladder hypomotility further promotes cholesterol
nucleation and gallstone formation.

(71) The gallbladder fx to actively absorb water from bile. Gallbladder hypomotility causes the bile to become
concentrated, promoting precipitation and accumulation of particulate material. This forms a viscous biliary sludge that
can cause transient bile duct obstruction (biliary colic) and promote cholesterol gallstone formation.
(88) Gallstone ileus is a mechanical bowel obstruction caused when a large gallstone erodes into the intestinal lumen.
Pneumobilia (air in the biliary tract) is a common finding.

(1525) gallstone ileus, an uncommon complication of longstanding cholelithiasis that usually occurs in eldery women. A
large (typicall >2.5 cm) gallstone causes formation of a cholecystoenteric fistula between the gallbladder and adjoining
gut (most often the duodenum) due to pressure necrosis and erosion of these tissues.

(69) black pigment stones arise from conditions that increase the amount of unconjugated bilirubin in bile, which
promotes calcium bilirubinate precipitation. This may occur in the setting of chronic hemolysis (eg, sickle cell anemia,
beta thalassemia, hereditary spherocytosis) and increased enterohepatic cycling of bilirubin (eg, ileal disease).

(11739) admn of hydrophilic bile acids (eg, ursodeoxycholic acid) reduces cholesterol secretion and increases biliary bile
acid concentration. This improves cholesterol solubility and promotes gallstone dissolution

Porcelain gallbladder (87)

Porcelain gallbladder is a potential manifestation of chronic cholecystitis and is often found in association with multiple
gallstones. It is due to dystrophic intramural deposition of calcium salts in the setting of chronic inflammation. Porcelain
gallbladder is associated with an increasd risk of adenocarcinoma of the gallbladder.

Hepatic encephalopathy (102)

Liver abscess (62)

s. aureus can cause hepatic abscesses via hematogenous seeding of the liver. Enteric bacteria (eg, E. coli, Klebsiella and
enterococci) can cause hepatic abscesses by ascending the biliary tract (ie, ascending cholangitis), portal vein pyemia, or
direct invasion from an adjacent area (eg, cholecystitis)

in underdeveloped countries, hepatic abscesses have a relatively high incidence and are usually caused by parasitic
infections (eg, e. hystolytica, echinococcal). In contrast, hepatic abscesses are uncommon in developed countries and
are caused by bacterial infection in about 80% of cases.

Drug induced liver injury (853)

Halothane hepatitis typically presents 2 days to 3 weeks after medication exposure with fever, nausea, jaundice (scleral
icterus), tender hepatomegaly, and elevated serum aminotransferases (eg, AST, ALT) and bilirubin levels. Although liver
biopsy is typically not necessary for dx, it can show centrilobular hepatic necrosis that is indistinguishable from viral
hepatitis. Tx is largely supportive as there are no specific beneficial therapies.

Hepatic encephalopathy (8578)

Recent GI bleeding -> increase in nitrogen absorption by the gut. The pathogenesis of hepatic encephalopathy is related
to increased circulatory levels of ammonia and other neurotoxins due to failure of the liver to metabolize waste
products.

Under normal conditions, astrocytes regulate neurotransmission by taking up glutamate present in the synapse,
preventing excessive neuronal excitation. Through the action of glutamine synthetase, glutamate undergoes a
condensation reaction with ammonia to form glutamine (a non-neuroactive compound). Glutamine is then released by
the astrocytes and taken up by neurons, where it is converted back to glutamate for use as a neurotransmitter
(glutamate-glutamine cycle)

When excess ammonia is present in the blood, it crosses the BBB and is taken up by astrocytes, increasing glutamine
production. The presence of excess glutamine within astrocytes leads to increased intracellular osmolarity, causing
astrocyte swelling and impaired glutamine release. Hyperammonemia consequently decreases the amount of glutamine
available for conversion to glutamate in neurons, resulting in disruption of excitatory neurotransmission

Cirrhosis (368)

Cirrhosis is characterized by diffuse hepatic fibrosis with replacement of the normal lobular architecture by fibrous-lined
parenchymal nodules. Chronic viral hepatitis (eg, hep B and C), alcohol, hemochromatosis and nonalcoholic fatty liver
disease are the most common causes of cirrhosis in the US

Vs. dilation of sinusoids and perivenular hemorrhage are associated with acute venous outflow obstruction within the
liver (eg, Budd-Chiari syndrome)

Vs. granulomatous destruction of bile ducts is seen in px with primary biliary cirrhosis (PBC)

Vs. intrahepatic hydatid cysts with surrounding fibrous reaction can be seen in px with Echinococcus infection

Vs. pigment accumulation within hepatocytes occurs in conditions such as Dubin-Johnson syndrome, an AR disorder
causing conjugated hyperbilirubinemia. In this condition, hepatocellular accumulation of coarse pigmented granules
causes the liver to appear grossly black.

Laboratory abnormal.ities in cirrhosis (1423)

Indicators of liver fx Impaired biosynthetic capacity
- Elevated PTT
- Hypoalbuminemia
Impaired transport and metabolic capacity
- Elevated bilirubin
Indicators of liver injury Markers of hepatocyte injury
- Elevated AST and ALT (AST usually >ALT)
Markers of cholestasis
- Elevated alkaline phosphatase
- Elevated gamma-glutamyl transpeptidase
Other - Thrombocytopenia (due to splenic sequestration of platelets)
(100) hyperestrinism in liver cirrhosis likely arises due to increases in androstenedione production, androgen
aromatization and sex hormone-binding globulin concentration (preferentially binds testosterone). Impaired estrogen
metabolism by the liver may also be contributing factor. A decreased free testosterone/estrogen ration leads to
gynecomastia, testicular atrophy, decreased body hair and spider angiomata

(6517)

Disruption of the hepatic vasculature causes portal HTA, leading to portosystemic anastomoses (eg, esophageal varices)
and ascites. The portal venous system is valveless; therefore, portal HTA can cause retrograde flow of portal blood away
from the liver and increased pressure within the splenic vein. This leads to congestion of the splenic red pulp and
resulting splenomegaly.

(7214)

Fibrosis and distortion of intrahepatic vasculature in ALD obstructs blood flow through the liver, leading to portal HTA.
Because the splenic vein is part of the portal circulation, any condition that causes portal hypertension can lead to
splenomegaly with congestive hypersplenism. Venous congestion causes apparent expansion of the red pulp of the
spleen, which is composed of blood-filled sinuses and cords lined by reticuloendothelial-type cells.

(1291)

The liver synthesizes many proteins, including clotting factors. Cirrhosis leads to acquired coagulopathy.

Clotting factors II, VII, IX and X are produced initially by the liver in an inactive form and then activated by vitamin K-
dependent carboxylation. Factor VII, part of the extrinsic pathway, has the shortest half-life of all coagulation factors.
Prothrombin time (PT assesses the extrinsic and common pathways of coagulation and is the first to become abnormal
in liver disease. Because clotting actor synthesis is impaired, PT may not improve with vit K supplementation as there are
insufficient quantities of clotting factors to undergo vitamin K-dependent carboxylation/activation.

Esophageal varices

(1701) portal vein thrombosis causses portal hypertension, splenomegaly, and varicosities at portocaval anastomoses. It
does not cause histologic changes to the hepatic parenchyma. Ascites is uncommon as the obstruction is presinusoidal

(7215)

Acute management of variceal hemorrhage requires rapid lowering of portal pressure. Somatostatin and octreotide (a
long-acting somatostatin analog) inh the release of endogenous hormones (eg, glucagon, VIP) that induce spnachnic
vasodilationg, thereby indirectly reducing portal blood flow. Vasopressin directly causes splanchnic vasoconstriction and
also can lower portal flow in acute variceal hemorrhage, but its use is limited by systemic vasoconstriction.

Hepatocellular cancer (471)

Carcinogen-related neoplasm composed of cells that express CD31, which is PECAM 1 (platelet endothelial cell adhesion
molecule). PECAM1, a member of IG family of proteins, is expressed on the surface of endothelial cells and fx in
leukocyte migration through the endothelium. The px’s tumor thus appears to have arisen from vascular endothelila
cells. The most likely dx is liver angiosarcoma, a rare malignant vascular endothelial cell neoplasm that is associated with
carcinogen xposure. Implicated chemicals include arsenic (exposure to pesticides), thorotrast (a former radioactive
contrast medium), and polyvinyl chloride (a plastic widely used in industry).

Esophageal cancer (14879)

Major risk factors:

- Chronic GERD
- Obesity – increases intragastric pressure, frequency of lower esophageal sphincter relaxation, and rates of hiatal
hiatal hernia, which promote GERD
- Smoking
- Use of meidcations that lower esophageal sphincter pressure (eg, nitroglycerin)
- Consumption of foods containing nitroso compounds (eg, processed meats)

Gastric adenocarcinoma (307)

- Intestinal type: forms a solid mass that projects into the stomach lumen and is composed of glandular-forming
cuboidal or columnar cells
- Diffuse carcinoma (linitis plastic): infiltrates the stomach wall and displays signet-ring cells on light microscopy.
Signet ring cells: cells that do not form glands. Often contain abundant mucin droplets (pushes nucleus to one
side). On gross examination, signet-ring carcinomas are characterized by diffuse involvement of the stomach
wall (due to loss of the cell adhesion protein E-cadherin). They have a plaquelike appearance, are ill-defined and
often infiltrate large areas of the stomach wall, causing a “leather-bottle stomach”

Lynch syndrome (2028)

Is AD caused by abnormal nucleotide mismatch repair. The mismatch repair system involves several genes, including
MSH2 and MLH1, which code for components of the human MutS and MutL homologs. Mutations in these 2 genes
account for around 90% of cases of Lynch syndrome.

Colonic ischemia (6435)

Early ischemic colitis is characterized by mucosal hemorrhage and patchy areas of necrosis. Eventually the bowel wall
thickens and becomes edematous, and transmural infarction develops.

Colonic ischemia (413)

The splenic flexure and rectosigmoid junction lie between regions of perfusion of major arteries. These “watershed”
areas are susceptible to ischemic dmg during hypotensive states, especially in px with underlying arterial insufficiency

Colonic polyps (430)

Adenomatous polyps are either tubular, villous, or tubulovillous, depending on their histologic appearance. Villous
adenomas tend to be larger, sessile and more severely dysplastic than tubular adenomas. Villous adenomas can cause a
secretory diarrhea from increased mucin production; px may develop hypoproteinemia and hypokalemia.

Colorectal cancer

Colorectal cancer staging (15011)

(411)
(253) Carcinoembryonic antigen (CEA) levels are increased in colon cancer and in other malignancies and certain benign
diseases. CEA cannot be used to dx colon cancer, but it is helpful for detecting residual disease and recurrence.

(421)

Transformation of normal mucosal cells into malignant ones is caused by a series of gene mutations called the adenoma
to carcinoma sequence:

1. Progression from normal mucosa to a small adenomatous polyp (adenoma). The initial appearance of small
adenomatous polyps is attributed to mutation of the APC tumor suppressor gene.
2. Increase in the size of the adenoma. Mutation of the KRAS protooncogene is thought to facilitate this step (going
from a small early to a large adenoma, as with this patient) by leading to uncontrolled cell proliferation.
Normally, KRAS encodes for a G protein-like protein that regulates the cell cycle by stimulating and inhibiting it
as necessary. Mutation of KRAS into its oncogene form leads to a constitutively activated GTP-bound protein.
3. Malignant transformation of adenoma into carcinoma. This step requires mutation of TP53, a tumor suppressor
gene that regulates the cell cycle and promotes repair of damaged DNA; mutations are found in most colon
carcinomas but rarely in adenomas.

(420) TP53 is sometimes called a “molecular policeman”. Is an antioncogene (tumor suppressor gene) that codes for
protein p53, which triggers apoptosis of cells with damaged DNA. A TP53 mutation allows cells with genomic errors to
enter the cell cycle. Such a mutation is considered the last “hit” in the adenoma to carcinoma sequence (mutations are
found in most colon carcinomas but rarely in adenomas)

(15020)
Familial adenomatous polyposis (FAP) is an AD disorder caused by germline mutation to the tumor suppressor gene
adenomatous polyposis coli. Px with FAP develop hundred or thousands of colonic polyps; lifetime risk of colon cancer is
close to 100%

Gastric adenocarcinoma (GA) (7649)

Weight loss + early satiety + positive smoking hx + left supraclavicular adenopaty + epigastric pain + hematemesis +
occult blood loss

PE findings in advanced (metastatic) disease: left supraclavicular (Virchow node) or left axillary lymphadenopathy or a
periumbilical mass (Sister Mary Joseph nodule

Rapid onset of numerous seborrheic keratosis (pigmented macules or palques with a greasy surface and well
demarcated borders) is a classic indicator of internal malignancy (Leser-Trelat sign), particularlyk GA, and is thought to
occur in response to increased tumor production of cytokines and growth factors (eg, IGF-1, fibroblast growth factor)

Liver cancer (15012)

Most hepatic neoplasms are due to metastatic disease from a distant site. Colorectal cancer is the most common cause
of hepatic metastases due to direct blood flow from the colon (and superior rectum) to the liver via the portal venous
circulation. Metastatic disease to the liver is particularly likely when multiple tumors are present (as seen in this case)

Carcinoid tumor (424)

Carcinoid tumors are composed of islands or sheets of uniform cells with eosinophilic cytoplasm and oval-to-round
stippled nuclie. These tumors are often derived from neuroendocrine cells in the GI tract. Appendiceal carcinoids
typically have a benign course but may cause appendicitis or, rarely, carcinoid syndrome (eg, with liver metastasis)

Nutrition

(755) metabolism of 1 g of protein or carbohydrate produces 4 calories of energy; metabolism of 1 g of fat produces 9
calories.

(790)

RAS genes code for a family of small G-proteins involved in signal transduction in the Ras-MAPK pathway. Ras pathway
exist in 2 different states: an inactive GDP-bound state and an active GTP bound state. Ras becomes activated when a
growth factor ligand binds to a receptor tyrosine kinase located on the cell membrane, causing autophosphrylation of
the receptor. This triggers binding of adaptor proteins that interact with Ras, promoting GDP removal and GTP binding.
Activated Ras then begins a phosphorylation cascade that results in the activation of mitogen activated protein kinase
(MAPK), which enters the nucleus to influence gene transcription.

Ras proteins have intrinsic GTPase activity that allows them to hydrolyze GTP; this mechanism prevents accumulation of
active Ras (GTP-bound) in the absence of hormonal signaling. RAS gene mutations can lead to decreased intrinsic GTPase
activity; this results in a constitutively activated Ras protein that causes constant and upregulated cell proliferation. RAS
mutations are commonly ided in cancerous tumors, specifically colorectal and pancreatic malignancies.

Anal fissure (255)

Anal fissures are longitudinal tears in the mucosa. They are usually due to passage of hard stool in px with chronic
constipation. Most fissures occur at the posterior midline, likely due to decreased blood flow in this area. Fissures in
other areas may be due to less common causes

Pharmacology

Antiemetics (10999)
The choice of antiemetic therapy depends on the source of the emetogenic stimulus. Conditions that causes GI irritation
(eg, infections, chemotherapy, distention) result in increased mucosal serotonin release and activation of 5-HT3
receptors on vagal and spinal afferent nerves.

Eg: ondasetron

u-opioid receptor agonist (loperamide) it is commonly used in traveler’s diarrhea to reduce diarrhea but can worsen
nausea and vomiting due to colonic retention

dopamine receptor antagonists (eg, metoclopramide, prochlorperazine) are effective in tx central nausea (seen in acute
migraines). Have significant adverse effects including sedation and extrapyramidal symptoms

first generation H1 receptor antagonists (eg, diphenhydramine, meclizine) and muscarinic acetylcholine receptor
antagonists (eg, scopolamine) are frequently used to treat vestibular nausea (eg, motion sickness). Promethazine is a
dopamine and H1 receptor antagonist that can also treat vestibular nausea (all of these causes significant sedation)

somatostatin receptor agonists (eg, octreotide) inh bioactive amine release and are used to tx diarrhea in px with
carcinoid syndrome and VIPoma. Also used for tx of acute esophageal variceal hemorrhage.

Characteristics of antiemetic drugs

Drug class Examples Clinical uses
Antimuscarinics (anticholinergics) Scopolamine Motion sickness
Antihistamines Diphenhydramine Hyperemesis gravidarum (promethazine)
Meclizine
Prometahzine
Dopamine receptor antagonists Prochlorperazine Chemotherapy-induced emesis
Metoclopramide
Serotonin (5-HT3) receptor antagonists Ondasetron
Granisetron
Neurokinin-1 (NK1) receptor antagonists Aprepitant
Fosaprepitant

Hematology and Oncology

2, 3-bisphosphoglycerate metabolism

2, 3-BPG decreases hb’s affinity for O2. Therefore, in the presence of lower blood O2 concentrations, higher 2, 3-BPG lvls
within erythroyctes enable increased O2 delivery in the peripheral tissues. 2, 3-BPG is produced from 1, 3-BPG by the
enzyme bisphosphoglycerate mutase. This reaction bypasses an ATP-generating step of glycolysis, causing no net gain in
ATP.

Familial erythrocytosis (1387)

Due to a beta-globin mutation resulting in reduced binding of 2,3-BPG. 2, 3-BPG is synthesized from glycolytic
intermediates and binds strongly to deoxyhemoglobin in a pocket formed between the 2 beta chains. This binding
reduces the oxygen affinity of hemoglobin, allowing more oxygen to diffuse into the peripheral tissues. The Hb 2,3-BPG
binding pocket contains positively charged AA (eg, histidine and lysine) that attract the negatively charged phosphate
groups in 2, 3-BPG. Mutations that decrease the postivie charge of the binding site decrease 2, 3-BPG binding and
increase hb oxygen affinity.
Fetal hb is synthesized primarily during fetal development (~8 weeks until term) and consists of the usual 2 alpha chains
with 2 gamma chains in place of beta chains. The gamma chains do not bind effectively to 2,3-BPG due to replacement
of histidine residue with serine. As a result, fetal hemoglobin has significantly higher oxygen affinity than adult
hemoglobin A. This allows fetal hemoglobin to extract more oxygen from the mother’s adult hb in the placenta,
providing the developing fetus with an adequate supply of oxygen.

Metheglobinemia (1416)

Iron bound to heme is normally in the reduced ferrous (Fe2+) state. Nitrites cause poisoning by inducing the conversion
of this heme iron to the oxidized ferric (Fe3+) state, leading to the formation of methemoglobin. With iron in the
oxidized ferric state, methemoglobin is unable to bind oxygen. In addition, the affinity of any residual ferrous iron in the
hb tetramer is increased, causing a leftward shift of the oxygen-dissociation curve. However, the partial pressure of
oxygen in blood which represents the amount of oxygen dissolved in the plasma, is unchanged.

Methemoglobinemia causes dusky discoloration of the skin (similar to cyanosis), and because methemoglobin is unable
to carry oxygen, a state of functional anemia is induced.

Carcinogens (1797)

Many chemicals can induce cancer in humans, with most such substances existing in an inactive, procarcinogenic state.
Pro-carcinogens are metabolized by cytochrome P450 monooxygenase, an enzyme system present in hepatic
microsomes and the endoplasmic reticula of varied other tissues. Cytochrome P450 monooxygenase metabolizes
steroids, alcohol, toxins, and other foreign substances by rendering them soluble and easier to excrete. Unfortunately,
this metabolic processing also converts pro-carcinogens into carcinogens capable of causing mutations in human DNA.

Vs. glutathione-S-transferase is involved in the detoxification of some chemical carcinogens. This enzyme converts toxic
substances into inactive metabolites.

Vs. glucuronide transferase converts bilirubin into soluble bilirubin diglucuronide in the hepatocytes. This enzyme is not
involved in the metabolism of chemical carcinogens.

Vs. mitochondrial cytochrome oxidase (cytochrome a+a3) is a component of electron transport chain that reacts with
molecular oxygen to produce water. This enzyme is not involved in the metabolism of chemical carcinogens
Vs. superoxide dismutase converts superoxide into oxygen and hydrogen peroxide during phagocytosis. This enzyme is
not involved in the metabolism of chemical carcinogens.

Apoptosis (6464)

DNA laddering is a sensitive indicator of apoptosis (programmed cell death) and refers to the appearance of DNA
fragments in multiples of 180 base pairs on gel electrophoresis. Lymphoid malignancies (eg, follicular B cell lymphoma)
often evade programmed cell death by overexpressing CL2, an antiapoptotic protein.

Cellular proliferation (8632)

Signal transduction systems:

1. MAP-kinase pathway
2. Pi3k/Akt/Mtor pathway
3. Inositol phospholipid pathway
4. cAMP pathway
5. JAK/STAT pathway

The PI3K/Akt/mTOR pathway is an intracellular signaling pathway that is important for cellular proliferation. This
pathway is typically activated when a GF binds to its receptor tyrosine kinase, causing autophosphorylation of specific
tyrosine residues within the receptor. These phosphotyrosine residues activate PI3K, which htne phosphorylates PIP2
found in the plasma membrane to PIP3. This leads to activation of a protein called Akt (or protein kinase B), a serine/
threonine-specific protein kinase. Subsequently, Akt activates mTOR (mammalian target rapamycin), which translocates
to the nucleus to induce genes involved in cell survival, anti-apoptosis, and angiogenesis. mTOR activation is inh by PTEN
(phosphatase and tensin homolog), a tumor suppressor protein that removes the phosphate group from PIP3.

Hb (1243)

The initial hb formed by a fetus in utero is called embryonic hb (Gower). This hb is composed of two zeta and two
epsilon chains and is produced in the embryonic yolk sac. Within a few weeks the fetal liver starts synthesizing hb F
(composed of two alpha and two gamma chains. HbF is the major hb in the fetus during last few months of gestation
and in infants during first few weeks of postnatal life. HbA synthesis starts during the final month of gestation and
gradually replaces HbF during postnatal life.

(868)
Oxygen-hb dissociation curve (1385)

Heme metabolism (1455)

Maturing erythrocytes lose their ability to synthesize heme when they lose their mitochondria, which are necessary for
the first and final 3 steps of heme synthesis.

Folic acid def (1847) folate def inh the synthesis of nucleic acids, particularly the formation of deoxythymidine
monophosphate (dTMP). This leads to defective DNA synthesis that characteristically causes increased apoptosis of
hemopoietic cells and megaloblastic anemia. Thymidine supplementation bypasses this enzyme and can reduce
erythroid cell apoptosis

(1456) heme oxygenase converts heme to biliverdin, a pigment that causes the greenish color to develop in bruises
several day after an injury. Heme oxygenase (contained in macrophages, among other cells) degrades heme into
biliverdin, CO, and ferrous iron while consuming oxygen and electrons provided by NADH and NADH-cytochrome P450
reductase. Biliverdin is green in color and is further reduced (by the enzyme biliverdin reductase) to the yellow pigment
bilirubin, which is the transported to the liver bound to albumin.

Heparin induced thrombocytopenia (15120)

Significant drop in platelet cout + acute venous thromboembolism -> heparin-induced thrombocytopenia and
thrombosis (HITT)/heparin-induced thrombocytopenia type 2

- Typically occurs 5-10 days following exposure to heparin products

- More common following exposure to unfractionated heparin but can occur following exposure to low-molecular
weight heparin as well
- Platelet factor 4 (PF4) is a protein released from the alpha granules of platelets that plays a role in platelet
aggregation
 - It also binds heparin and helps inactivate the molecule
- The mechanism of HITT involves the generation of IgG antibodies to these complexes of heparin and PF4
- The Fc component of the inactivated IgG antibodies then binds to additional platelets, resulting in further PF4
release and widespread platelet activation -> prothrombotic state that places px at high risk for both arterial and
venous thrombosis.

VS. Acquired protein C deficiency occurs early in the course of warfarin therapy, as the inh of protein C by warfarin
occurs more rapidly than the inh of other factors (ie, factors II, VII, IX, X). if not bridged with heparin when starting
therapy, px may develop warfarin-induced skin necrosis due to localized cutaneous thrombus formation.

VS. idiopathic thrombocytopenic purpura (ITP) results from splenic destruction of platelets labeled by IgG antibodies to
glycoprotein IIb/IIIa receptors. ITP often causes very low platelet levels and is associated with bleeding complications
rather than thrombosis

VS. cryoglobulinemia can occur in the setting of autoimmune disease (eg, SLE) or viral infection (eg, hep C) and causes
systemic vasculities characterized by fatigue, arthralgia, and purpuric rash. Marked thrombocytopenia is not typical

VS. thrombotic thrombocytopenic purpura (TTP) results from decreased levels of the von Willebrand factor-cleaving
protease ADAMTS13. The classic px of TTP is the pentad of fever, thrombocytopenia, microangiopathic hemolytic
anemia, renal insufficiency and neurologic dysfunction

Tx (1078)

Direct thrombin inh (hirudin, lepirudin and argatroban) do not require antithrombin-III for their action and are drugs of
choice in the tx of HIT. Px with HIT need ongoing anticoagulation due to the presence of, or possibility of thrombosis.
Upon clinical suspicion of HIT, the most important initial step in tx is to stop all forms of heparin. Copyright (c) UWorld,
Please do not save, print, cut, copy or paste anything while a test is active.

Inherited thrombophilia (465)

Mutation in the factor V gene, which renders factor Va resistant to inactivation by activated protein C. approximately 2-
15% of Caucasians carry a specific factor V mutation, the leiden mutation. The factor V Leiden mutation and mutations in
the prothrombin gnee are the most common inherited causes of hypercoagulability. Activated protein C resistance
(factor V leiden mutation) is detected in approximately 20% (range 12-40%) of px with abnormal venous thromboses.

Polycythemia (1586)

The following tests can help determine the cause of erythrocytosis:

1. Absolute vs relative erythrocytosis: Direct measurement of the RBC mass is necessary. An increased total RBC
mass indicates an absolute erytrhocytosis; a normal RBC mass indicates a relative erytrhocytosis.
2. Primary vs secondary erytrhocytosis: serum erythropoietin levels can be used to differentiate primary from
secondary erythrocytosis. Primary erytrhocytosis is associated with low erythropoietin lvs and is caused by
myeloproliferative disorders such as polycythemia vera. Secondary erytrhocytosis is characterized by increased
erythropoietin levels due to chronic hypoxia from high altitudes, smoking, or chronic obstructive pulmonary
disease; or abnormal secretion by neoplastic or otherwise disease tissues
3. Hypoxic vs other causes of secondary erythrocytosis: measurement of the arterial oxygen saturation (SaO2) is
important to exclude hypoxemia as a cuase of the erytrhocytosis. SaO2 <92% (PaO2 <65 mmHg( can cause
secondary polycythemia. SaO2 (measured as a percentage) should not be confused with PaO2 (measured as a
partial pressure in mmHg)
(8559)

PV is a clonal myeloproliferative disease of pluripotent hematopoietic stem cells. characteristic features include an
increased RBC mass, increased plasma volume, and low erythropoietin levels. The majority of px with PV have the JAK2
V617F mutation, rendering hematopoietic stem cells more sensitive to growth factors. Secondary polycythemia is a
misnomer since not all (poly) cell line are increased but only red cells. a better term is secondary erythrocytosis.

Traumatic hemolytic anemia (829)

Haptoglobin is a serum protein that binds to free hb and promotes its uptake by the reticuloendothelial system.
Haptoglobin levels decrease when significant quantities of hb are released into the circulation, as occurs with IV
hemolysis.

Myoglobin (1413)

Is a monomeric protein and the primary oxygen-storing protein in skeletal and cardiac muscle tissue; it is only found in
the bloodstream after muscle injury. The partial pressure of oxygen at which 50% of myoglobin molecules are oxygen
saturated (P50) is only 1 mmHg, which is much lower than the P50 of hb (26 mmHg). Myoglobin also has only a single
heme group and so does not experience heme-heme interactions; therefore, its oxygen-dissociation curve is hyperbolic.

Lead poisoning (1156)

Lead poisoning in adults typically occurs through occupational exposure. Symptoms include colicky abd pain,
constipation, lead lines on the gum, peripheral neuropathy and anemia. Lab testing shows microcytic anemia with
normal iron studies, and peripheral blood smear may reveal basophilic stippling

Lead inh the heme synthesis pathway (gamma-aminolevulinate dehydratase and ferrochelatase) -> microcytic,
hypochromic anemia

(1454) lead directly inh ferrochelatase and ALA dehydratase, resulting in anemia, ALA accumulation, and elevated zinc
protoporphyrin levels. Neurotoxicity is also a significant long-term complication.

Sideroblastic anemia (11816)

Is dx by bone-marrow examination with Prussian blue stain. Causes include x-linked sideroblastic anemia (due to an
gamma aminolevulinate synthase mutation), myelodysplastic syndrome, alcohol abuse, copper deficiency and certain
medications (Eg, isoniazid, chloramphenicol, linezolid)

Target cells (14983)

Occurs:

- Reduced erythrocyte cell volume from deficient hemoglobin synthesis (eg, thalassemia, iron def) or structural
mutations to hb (eg, sickle cell)
- Excessive erythrocyte cellular membrane due to greater cholesterol-to-phospholipid rations (Eg, obstructive
liver disease) or splenectomy

Px who undergo splenectomy usually develop target cells because the spleen is the primary organ that prunes
excessive red cell membrane.

Hereditary spherocytosis (889)

Hereditary spherocytosis
Epidemiology - AD (~75%)
- Northern European descent
Clinical presentation - Hemolytic anemia
- Jaundice
- Splenomegaly
Lab findings - Increase MCH concentration
- Spherocytes on peripheral smear
- Negative Coombs test
- Increased osmotic fragility on acidified glycerol lysis test
- Mutations affects the plasma membrane scaffolding proteins spectrin and ankyrin
-> less deformable -> sequestration and subsequent accelerated destruction in the
spleen
Tx - Splenectomy
Compliacations - Pigmented gallstones
- Aplastic crises from parvovirus B19 infection

(890)

- MCHC is increased due to mild dehydration of RBC

 - Markers of hemolysis are often evident and include elevated lactate dehydrogenase, reticulocytosis, and
decreased haptoglobin

Iron deficiency anemia

(1796)

Iron deficient individuals on replacement therapy should experience hb lvl increases of approximately 2 g/dL per week
for the first three weeks. This increase in hb results from enhanced erythropoiesis and the accelerated release of both
mature red blood cells (RBCs) and reticulocytes into the bloodstream.

The reticulocyte is an immature RBC that is slightly larger and bluer than a mature RBC. It lacks a cell nucleus but retains
a basophilic, reticular (mesh-like) network of residual ribosomal RNA. The ribosomal RNA appears blue microscopically
after the application of the Wright-Giemsa stain.

After spending a day or so in the bloodstream, the reticulocytes are transformed into mature red blood cells that have a
lifespan of approximately 120 days.

(787) hepcidin is an acute phase reactant synthesized by the liver that acts as the central regulator of iron homeostasis.
High iron levels and inflammatory conditions increase the synthesis of hepcidin, while hypoxia and increased
erythropoiesis act to lower hepcidin levels. Hepcidin influences body iron storage thorugh its interaction with
ferroportin, a transmembrane protein responsible for transferring intracellular iron to the circulation. Upon binding
hepciding, ferroportin is internalized and degreaded, decreasing intestinal iron absorption and inh the release of iron by
macrophages.

Regulation of intestinal iron absorption is crucial for maintaining iron homeostasis, since blood loss is the only way of
removing large amounts of iron from the body. Iron absorption from the proximal small intestine is facilitated by the
divalent metal transporter-1 (DMT-1). Once inside the intestinal cells, iron may take 1 of 2 paths:

1. Iron may bind to ferritin (a primarily intracellular iron-binding protein) and remain stored within the enterocyte.
The stored iron is excreted in the stool as enterocytes sloughoff and are replaced
2. Iron may enter the circulation through ferroportin, the basolateral iron transporter of the enterocyte. Free iron
released into the circulation is transported throughout the body by transferrin (an iron-binding transport
protein), which becomes internalized after interacting with transferrin receptors present on all cells.

Plummer-Vinson syndrome (1075) is a rare disease characterized by dysphagia and iron deficiency anemia. Px develop
weakness, fatigue and dyspnea secondary to the anemia; dysphagia develops due to esophageal web formation. Othe
rPE findings associated with iron deficiency include koilonychias (spoon-shaped nails) and a shiny red tongue secondary
to atrophy of lingual papillae. PVS is tx with iron supplementation

(1794) anemia in a woman of childbearing age is most commonly caused by iron deficiency secondary to menstrual
blood loss. Iron deficiency is associated with decreased serum ferritin, increased total iron-binding capacity (transferrin)
and microcytic, hypochromic RBC.

(7584) iron absorption occurs predominantly in the duodenum and proximal jejunum. Bypass of this segment of small
bowel by gastrojejunostomy results in iron deficiency anemia. Malabsorption of Vit B12, folate, fat-soluble vitamins
(especially vitamin D), and calcium may also be observed following gastric bypass procedures.

Thrombotic thrombocytopenic purpura

(11624)
(11625)

Thrombotic thrombocytopenic purpura results from impaired function of the vWF-cleaving protease ADAMTS13,
resulting in uncleaved vWF multimers that are significantly more prothrombotic and cause diffuse microvascular
thrombosis, microangiopathic hemolytic anemia, and thrombocytopenia. In PT and PTT are usually normal

Coagulation pathway (1903)

Lab characteristics of coagulopathies (2097)

Uremic platelet dysfunction (1293)

Excessive bleeding is common in px with significant renal dysfunction due in part to the accumulation of uremic toxins in
the circulation. These toxins impair platelet aggregation and adhesion, resulting in a qualitative platelet disorder
characterized by prolonged bleeding time with normal platelet count, prothrombin time (PT), and activated partial
thromboplastin time (aPTT). Uremic bleeding can be improved with dialysis as it removes the toxins and partially
reverses the bleeding abnormality.

Von willebrand disease (346)

- vWF binds GP IB receptors on the platelet memebrane and mediates platelet adhesion to subendothelial
collagen
- Deficiency of vWF impairs platelet adhesion and can lead to easy bruising and prolonged mucutaneous bleeding
- Lab workup:
normal platelet
Abnormal ristocetin cofactor assay: ristocetin activates GP Ib receptors on platelets and makes them
available for vWF binding; when the vWF level is decreased, there is poor platelet agglutination in the
presence of ristocetin. When normal plasma that contains vWF is added, appropriate platelet
agglutination occurs
- vWF also serves as a carrier for factor VIII to prolong its half-life, and vWF deficiency can lead to functional
deficiency of factor VIII that further contributes to bleeding complications. PTT may be normal or prolonged
depending on the degree of factor VIII impairment.
- Tx: combined oral contraceptives are often used for tx of menorrhagia due to vWF deficiency. Px can also be
treated with desmopressin, which stimulates vWF release from endothelium

Effects of DDAVP therapy (219)

Bernard-soulier syndrome (hereditary deficiency of GP Ib receptors) is characterized by thrombocytopenia, enlarged
platelets, and mucocutaneous bleeding. Platelet agglutination to ristocetin will be abnormal and, because the deficiency
is with GPIB receptors and not vWF, the addition of normal plasma will not correct the agglutination

Hereditary deficiency of GP IIb/IIIa receptors occurs in Glanzmann thrombasthenia, which manifests with
mucocutaneous bleeding. Platelet agglutination in response to ristocetin is normal because the levels of vWF and GP Ib
receptors are normal

Congenital deficiency of factor XII (Hageman) causes makred PTT prolongation; however, it does not cause clinical
bleeding complications. Instead, px may have a tendency for thromboembolic complications for unclear reasons

Thromboxane A2 def is associated with aspirin tx due to irreversible inactivation of cyclooxygenase in platelets. The
major effect is on GP IIb/IIIa- mediated platelet aggregation rather than GP Ib-mediated platelet adhesion; therefore,
platelet agglutination to ristocetin is normal

ITP (1954)

Autoimmune platelet destruction is a common cause of thrombocytopenia and should be suspected in px with
ecchymoses, petechiae, mucosal bleeding and no other obvious causes of thrombocytopenia. Most likely IgG
autoantibodies against the platelet membrane glycoproteins GPIIb/IIIa. A peripheral blood smear with isolated
thrombocytopenia and no other platelet abnormalities would helpc confirm the dx (megakaryocytes can sometimes be
seen). Tx involves systemic immunosuppression (corticosteroids). Secondary ITP is sometimes associated with HIV or
Hep C

Inherited thrombophilia

Factor V Leiden (1879)

Clinical manifestations;

- DVT -> pulmonary thromboembolism

- Cerebral vein thrombosis
- Recurrent pregnancy loss

Pathophysio:
 - In normal hemostasis, activated protein C (APC) restricts clot formation by protelytically inactivating factors Va
and VIIIa. Factor Va Leiden has reduced susceptibility to cleavage by APC, however. Because factor Va is a
cofactor in the conversion of prothrombin to thrombin, persistently circulating factor Va Leiden results in
increased thrombin production. Additionally, factor V Leiden is unable to support APC anticoagulant activity.

Hereditary spherocytosis (891)

Epidemiology -
AD inheritance (~75%)
-
Northern European descent
Clinical presentation -
Hemolytic anemia
-
Jaundice
-
Splenomegaly
Lab findings -
Increased MCHC
-
Spherocytes on peripheral smear
-
Negative Coombs test
-
Increased osmotic fragility on acidified glycerol
lysis test
Treatment - splenectomy
Complications - pigmented gallstones
- aplastic crises from parvovirus B19 infection
HS most often affects spectrin and ankyrin, the plasma-membrane scaffolding proteins.

Paroxysmal nocturnal hemoglobinuria (897)

- Hemolytic anemia
- Hypercoagulability (eg, hepatic vein thrombosis) (eg, Budd-Chiari syndrome)
- Pancytopenia

Caused by an acquired mutation of the PIGA gene which is involved in the synthesis of the glycosylphosphatidylinositol
(GPI) anchor, a glycolipid necessary for the attachment of several cell-surface proteins, including CD55 (decay-
accelerating factor) and CD59 (MAC inh protein). These proteins help inactivate complement and prevent the membrane
attack complex from forming on normal cells.

Absence of GPI anchor results in CD55 and CD59 deficiency and complement-mediated hemolysis. The hemolysis occurs
more often at night because complement activity is increased during sleep due to lower blood pH. Px also develop:

(11869)

- Fatigue and jaundice due to hemolytic anemia (elevated bilirubin and LDH, low haptoglobin, hemoglobinuria
[which may be nocturnal])
- Thrombosis at atypical sites (eg, hepatic, portal, or cerebral veins) possibly due to the release of prothrombotic
factors from lysed RBC and platelets (mesenteric vein thrombosis may explain this px’s abd pain)
- Pancytopenia due to stem cell injury

Chornic hemolysis with breakdown of iron-containing erythroyctes can also lead o iron deposition in the kidney
(hemosiderosis), which can interfere with proximal tubule function and cause interstitial scarring and cortical infarcts.
The hemosiderosis combined with microvascular thrombosis can increase the risk of chronic kidney disease.

Gold standard for dx: Flow cytometry (shows absence of the GPI anchor and CD55 and CD59 deficiency

vWD
Mutation results in impaired synthesis of vWF leading to qualitative defect in platelet binding and aggregation. As a
result, patients with vWD experience easy bleeding from skin and mucosal sites, including gingivae, nasal mucosa, GI
tract and endometrium

vWF serves 2 important roles in hemostasis:

1. vWF promotes platelet adhesion at sites of vascular injury by binding to and crosslinking platelet glycoproteins
(primarily GpIb) with exposed collagen underneath dmged endothelium. vWF also enhances platelet
aggregation, particularly under conditios of high shear stress (such as small vessels)
2. vWF fx as a protective carrier protein for factor VIII that increases its plasma half-life. In the absence of vWF,
factor VIII is rapidly degraded in the circulation via proteolytic inactivation.

Antiphospholipid syndrome causes a hypercoagulable state that increases the risk of thromboses and spontaneous
abortion

Factor VIII deficiency causes hemophilia A. severe forms of vWD can also result in factor VIII deficiency as factor VIII is
protected from degradation by vWF. However, this patient does not have the characteristic deep-tissue bleeding (eg,
bleeding into joints/muscles, GI bleeding, hematuria) typically seen with clotting factor deficiencies.

Factor XIII deficiency is an extremely rare autosomal recessive disorder that causes clot instability. Affected patients
often have delayed, recurrent bleeding after trauma or surgery. Hemophilia-like bleeding (Eg, deep tissue bleeding) is
seen in factor XIII deficiency.

Immune thrombocytopenia (formerly immune thrombocytopenic purpura) produces isolated thrombocytopenia with
episodic bleeding that is typically mucocutaneous (eg, petechiae, purpura, epistaxis). However, the associated bleeding
is unlikely to be chronic and unrelenting since childhood

Protein C is a natural anticoagulant protein, and deficiency results in a procoagulant state that most commonly
manifests with recurrent DVT

Hemophilia A (15489)

Hemophilia A is an X-linked, recessive bleeding disorder caused by mutations to the gene that encodes clotting factor
VIII. Factor VIII is part of the intrisinc coagulation cascade; it acts as a bridging protein that brings together the catalytic
component of factor IXa (the protease) with factor X (the substrate), thereby amplifying formation of factor Xa, which
promotes fibrin clots.

Px with hemophilia A have severe reductions in factor VIII and are unable to form fibrin clots at sites of minor trauma,
leading to potentially life-threatening hemarthroses and mucosal bleeding. Tx with factor VIII replacement products (eg,
factor VIII concentrate from plasma) can prevent or treat bleeding in these px. However, long-term efficacy is often
limited by the formation of neutralizing antibodies (factor VIII inh)

Emicizumab, a bispecific monoclonal antibody, mimics the normal physiologic fx of factor VIII and can be used to prevent
or tx bleeding in px who have factor VIII inh. This antibody has 2 binding sites; on ebinds to factor IX a and the other
binds to factor X, which brings them into close proximity and allows factor IXa to cleave factor X into its active form (Xa).

Hemophilia A & B (1953)

Both conditions are characterized by isolated prolongation of PTT due to defects in the intrinsic coagulation pathway. PT
and TT are normal in px with hemophilia.

Px with hemophilia have normal platelet fx and can form a platelet plug, so bleeding after procedures can be delayed
rather than immediate, in contrast to px with platelet disorders. Manifestations include IM hemorrhage, hemarthrosis,
and prolonged or delayed bleeding after surgical procedures.

(941) bleeding after a tooth extraction and hx of hemarthrosis are suggestive of hemophilia. Decreased levels of factor
VIII or IX lead to failure to convert prothrombin into thrombin and deficient thrombus formation. The addition of
thrombin to the blood of a px with hemophilia results in clotting.

Glanzmann thrombasthenia (1079)

- AR
- Deficient/defective glycoprotein (GP) IIb/IIIa on platelet surfaces and thattypically presents in childhood with
mucocutaeous bleeding
- Peripheral smear shows no platelet cumpling (an important clue for dx)

*platelet attachment to exposed collagen is strengthened by GP Ib binding to von Willebrand factor on the vessel wall.
The resulting platelet activation leads to the following:

- Release of mediators (eg, ADP, thromboxane A2 [TXA2]) into circulation, which in turn activates other platelets
- Conformational structural change for GP IIb/IIIa on platelet surfaces; this allows thousands of copies of GP
IIb/IIIa to bind fibrinogen, thereby forming a platelet plug
Abciximab, a GP IIb/IIIa receptor antagonist, inh binding of this receptor to fibrinogen. Abciximab and other GP IIb/IIIa
inh are useful for tx of unstable angina and acute coronary syndrome, particularly in px undergoing percutaneous
coronary intervention

Aplastic anemia (1785)

Aplastic anemia
Pathogenesis Bone marrow failure due to hematopoietic stem cell deficiency (CD34+)
Causes Autoimmune
Infections (eg, parvovirus B19, Epstein-Barr virus)
Drugs (eg, carbamazepine, chloramphenicol, sulfonamides)
Exposure to radiation or toxins (eg, benzene, solvents)
Clinical & laboratory findings Laboratory studies: pancytopenia
Anemia (fatigue, weakness, pallor)
Thrombocytopenia (mucosal bleeding, easy bruising, petechiae)
Leukopenia (recurrent infections)
Biopsy: hypocellular bone marrow with fat and stromal cells

Bone marrow examination reveals marked hypocellualrity with the hematopoietic elements replaced by fat cells and
marrow stroma; aspiration typically produces a “dry tap”

Pancytopenia without splenomegaly

Other causes of pancytopenia without splenomegaly include severe vit B12 and folic acid deficiency anemia, acute
leukemias, and certain forms of myelodysplastic syndrome (MDS). Bone marrow examination can be extremely helpful
in distinguishing among these conditions.

VS. Hypercellular marrow with increased blasts can be found in myeloproliferative disorders such as primary
myelofibrosis (would present with splenomegaly and fatigue) or chronic myelogenous leukemia (would present with
leukocytosis), MDS (would present in older patients), and certain leukemias (eg, acute myeloid leukemia [AML] – blasts
would be seen on peripheral smear).

VS. hypercellular marrow with megaloblastic hematopoiesis can be seen in MDS or megaloblastic anemia. However,
MDS typically occurs in elderly px (median age ~65) and has a male predominance. Px with severe megaloblastic anemia
usually have macrocytosis rather than normo
VS. acute promyelocytic (FABM3) leukemia is characterized by the presence of promyelocytes iwht Auer rods (rod-
shaped cytoplasmic inclusions). The cell cytoplasm also has numerous coarse azurophilic granules. This type of AML is
characterized clinically by DIC (acquired hypercoagulability and bleeding); immature WBC would also be present on
peripheral smear.

(1861) the triad of low hb, thrombocytopenia and absent hematopoietic cells in the bone marrow is consistent with
aplastic anemia. A compensatory increase in circulating erythropoietin levels would be expected in iindividuals with
aplastic anemia and normal renal fx

Sickle cell

(1241) HbS aggregates in the deoxygenated state. HbS polymers form fibrous strands that reduce red blood cell
membrane flexibility and promote sickling. Sickling occurs under conditions associated with anoxia including low pH and
high levels of 2, 3-bisphosphoglycerate. These inflexible erythrocytes predispose to microvascular occlusion and
microinfarcts.

(1242) globin chains in the hb tetramer are compactly folded due to nonpolar hydrophic residues in the interior and
charged polar residues on the surface. In sickle cell disease, the usual acidic (negatively charged) glutamic acid (glu)
residue at the sixth position on the beta globin chain is replaced by a non polar (neutral charge) valine (val) residue,
forming HbS. This single glu->val substitution leads to the formation of a hydrophobic pocket on the beta globin surface
that interacts with a complementary nonpolar residue on another hb molecule. The hydrophobic interaction causes
polymerization of HbS molecules and subsequent erythrocyte sickling, leading to membrane dmg and permanent
distortion of RBC. Red cell sickling is promoted by low oxygen levels, increased acidity, and dehydration.

In px with HbC, glu is replaced by basic polar (positively charged) lysine (lys) residue. Because lys is charged (although it
has opposite polarity to glu), there is no hydrophic interaction between hb molcules and no polymerization/sickling.
However, the positive charge of lys causes HbC to have decreased mobility on electrophoresis.

(1855) sickling episodes result in hemolysis -> increased indirect bilirubin and lactate dehydrogenase and decreased
levels of haptoglobin

(1496)

In px with sickle cell anemia and other chronic hemolytic disorders, the most common viral cause of an aplastic crisis is
infection of erythroid progenitor cells with parvovirus B19, a nonenveloped single-stranded DNA virus.

Vs.

- Epstein barr virus (enveloped double-stranded DNA virus)

- Hepatitis C virus (enveloped single-stranded positive-sense RNA virus)
- Hepatitis E virus (nonenveloped single-stranded positive-sense RNA virus)
Can cause hematopoietic depression and some measure of aplastic anemia (also HIV)
- Orthomyxoviruses, paramyxoviruses and rhabdoviruses (enveloped negative-sense RNA viruses)
- Adenoviruses, papillomaviruses and polyomaviruses (nonenveloped double-stranded DNA viruses)

(11960) Offspring of carrier parents have a 25% chance of being affected and a 50% chance of being heterozygous
carriers, resulting in a 75% chance of inheriting at least one mutant allele.

Iron overload (294)

Irono overload (hemosiderosis) is a common and serious complication of chronic hemolytic anemia and frequent blood
transfusions. Hemosiderin accumulation is the cardinal histologic finding. Chelation therapy is indicated to reduce
parenchymal iron deposition.

Circulating iron is carried by transferrin. Once deposited in cells, iron binds to apoferritin to form ferritin micelles.
Because iron is utilized poorly in px with thalassemia and cannot be excreted activtely, the ferritin micelles accumulate
in macrophages of the reticuloendothelial system. The resulting iron-storage complex is known as hemosiderin and
microscopically appears as brown or yellowish-brown pigments in either granular or crystalline form. Hemosiderin can
be identified histologically with a Prussian-blue stain. In the liver, hemosiderin is typically seen in Kupffer cells (hepatic
macrophages that line the walls of the sinusoids and participate in RBC breakdown)

DIC (1295)

(associated with sepsis, acute pancreatitis and burn injury among others)

Due to gram-negative sepsis, the coagulation cascade is activated by bacterial endotoxins, leading to widespread fibrin
deposition and consumption of coagulation factors and platelets, with eventual bleeding. The excess fibrin strands exert
shearing forces on circulating erythrocytes, resulting in schistocytes. Lab shows decreased platelet count, fibrinogen, and
factor V and VIII levels, with prolonged prothrombin and partial thromboplastin times.

Vs acanthocytes: abetalipoproteinemia

Vs bite cells: G6PD

Vs spherocytes: hereditary spherocytosis also autoimmune hemolytic anemia, burns and blood samples that are not
fresh

Vs target cells: obstructive liver disease, thalassemia, iron deficiency anemia, and asplenia

Hemophilia B (Christmas disease) (1728)

Is an x-linked recessive disorder, affecting males that causes factor IX deficiency with easy bruising and bleeding (eg,
hemarthrosis, oral bleeding, intracranial hemorrhage). Affected males will have asymptomatic carrier mothers.

Alpha thalassemia (6551)

Alpha-thalassemia minor have a mild anemia with hypochromic and microcytic cells. However, offspring of 2 parents
with alpha thalassemia minor are at risk for absent alpha globin production – the most severe form of alpha thalassemia
– which leads to hemoglobin Barts formation and death in utero from hydrops fetalis (anasarca, ascites and effusions)

Beta thalassemia (2087) results in hypochromic, microcytic anemia due to decreased beta globin chain synthesis.
Unpaired alpha chains precipitate within red cells and cause membrane dmg, leading to ineffective erythropoiesis and
extravascular hemolysis.

(1940) affects beta-chain production and can be caused by a variety of DNA mutations affecting the transcription,
processing and translation of beta-globin mRNA. Most commonly, these mutations causes aberrant precursor mRNA
splicing or premature chain termination during mRNA translation. In some cases, point mutations prevent RNA
polymerase from binding to the promoter region. The resulting beta-globin deficiency occurs in the setting of normal
heme and alpha-chain synthesis, leading to increased formation of hb A2 and (in some patients) hb F.

Common hereditary cancer syndromes (904)

Syndrome Gene Associated neoplasms Pathogenesis
Lynch syndrome - MSH2 - Colorectar CA - AD
- MLH1 - Endometrial CA - Caused by inactivating
- MSH6 - Ovarian CA mutations in corresponding
- PMS2 tumor suppressor gene
Familial - APC - Colorectar CA - Deletion of remaining
adenomatous - Desmoids & osteomas normal allele (second hit)
polyposis - Brain tumors leads to loss of
Von Hippel-Lindau - VHL - Hemangioblastomas heterozygosity & malignant
syndrome - Clear cell renal carcinoma transformation
- Pheochromocytoma
Li-Fraumeni - TP53 - Sarcomas
syndrome - Breast CA
- Brain tumors
- Adrenocortical carcinoma
- Leukemia
MEN type 1 - MEN1 - Parathyroid adenomas
- Pituitary adenomas
- Pancreatic adenomas
MEN type 2 - RET - Medullary thyroid CA
- Pheochromocytoma
- Parathyroide hyperplasia
(MEN2A)

Sporadic and hereditary (associated with von Hippel-Lindau disease) renal cell carcinomas are associated with mutations
involving the VHL gene on chromosome 3p. The VHL gene is a tumor suppressor that inh hypoxia-inducible factors;
mutations lead to constitutive activation of these proteins, resulting in the activation of multiple angiogenic and
tumorigenic growth factors (eg, VEG-F, PDG-F)

Thrombophlebitis (475)

Migratory thrombophlebitis should raise suspicion for CA. hypercoagulability is very common paraneoplastic syndrome
seen most frequently in visceral adenocarcinomas of the pancreas, colon and lung. Hypercoagulability develops because
adenocarcinomas produce a thromboplastin-like substance capable of causing chronic IV coagulations that can
disseminate and tend to migrate

Migratory superficial thrombophlebitis, known as Trousseau syndrome, is named after Armand Trousseau, a well-
respected French physician who first described the association with CA. trousseau later dx his own visceral cancer after
developing the syndrome

Trousseau also described the Trousseau sign (hand/forearm muscle spasms on sphygmomanometric measurement)
associated with hypocalcemia.

Retinoblastoma (863)

Rb gene is a tumor suppressor; the corresponding protein exists in an active and inactive state. The active
(dephosphorylated) Rb protein does not allow the cell to proceed from G1 to the S stage of the cell cycle. When the cell
is stimulated by a growth factor, the Rb protein is phosphyrlated and converted into the inactive state. Inactivation of
the Rb protein permits cell division. Cells with two inactive Rb genes divide uncontrollably and give rise to alignancy.
Familial retinoblastoma occurs as a result of mutations of each of the two Rb genes (“two hits” chromosome 13). These
paients have increased risk of secondary tumors, especially osteosarcomas, later in life.
Primary myelofibrosis (15248)
Pathogenesis Chronic myeloproliferative disorder with clonal megakaryocytes -> secrete transforming growth
factor-beta -> stimulates fibroblasts in BM to produce collagen -> BM fibrosis -> hematopoietic stem
cells migrate to liver & spleen -> extramedullary hematopoiesis
Manifestations - Severe fatigue
- Hepatomegaly + massive splenomegaly (can compress stomach)
- >cytopenias
- Dacryocytes (teardrop cells) on peripheral blood smear
- BM aspiration – often dry tap due to fibrosis

(14816)

Pancytopenia + hepatosplenomegaly + teardrop cells -> primary myelofibrosis, hematopoietic stem cell malignancy
associated with the clonal expansion of megakaryotes. Neoplastic megakaryocytes secrete the cytokine transforming
growth factor-beta, which stimulates bone marrow fibroblasts to fill the medullary space with collagen. Subsequent
bone marrow fibrosis usually leads to the following

- Extramedullary hematopoiesis – because the bone marrow is destroyed by fibrotic tissue, hematopoiesis occurs
in secondary hematopoietic tissue such as the spleen and liver. This typically results in marked splenomegaly
and a palpable liver edge liver edge on examination
- Cytopenias – extramedullary hematopoiesis is much less efficient than medullary hematopoiesis. Therefore, px
often have deficits in 1 (eg, anemia) or more (eg, pancytopenia) cell lines
- Dacrocytes on peripheral blood smar – the red cell membrane is dmaamged when squeezing out of the fibrotic
bone marrow or passing through the enlarged spleen, which leads to the formation of teardrop-shaped red cells

The dx of primary myelofibrosis requires bone marrow examination. Bone marrow aspiration frequently results in a “dry
tap” (no marrow) deu t significant bone marrow fibrosis. Therefore, bone marrow biopsy is usually required; the
presence of a diffusely fibrotic marrow with occasional clusters of atypical megakaryocytes confirms the dix

Multiple myeloma

(1054)

Multiple myeloma
Pathophysiology - Plasma cell neoplasm produces monoclonal paraprotein (immunoglobulin)
Manifestations - Bone pain, fractures
- Constitutional symptoms (weight loss, fatigue)
- Recurrent infections
Laboratory - Normocytic anemia
- Renal insufficiency (light chain cast nephropathy: free light chains (Bence Jones proteins
that can’t be precipitated with Tamm-Horsfall protein -> casts. On light microscopy,
numerous large, glassy eosinophilic casts are seen, deposition of light chain fragments in
the glomerular mesangium and capillary loops can also cause renal failure in MM
[amyloid light-chain amyloidosis])
- Hypercalcemia (constipation, muscle weakness)
- Monoclonal paraproteinemia (M-spike)
- Gamma gap (serum total protein – serum albumin ≥4 g/dL)
Radiology - Osteolytic lesions/osteopenia (osteoclast activation)
(15466) plasma cells, are distinguished by the presence of abundant basophilic cytoplasm, perinuclear paleness (large
Golgi apparatus), and nuclei with “clock-face” (peripheral) chromatin. The presence of >10% plasma cells in the bone
marrow raises strong suspicion for MM

(872)

- Numerous plasma cells (ID by abundant basophilic cytoplasm, well-developed Golgi apparatus (perinuclear
paleness) and “clock-face” (peripheral) chromatin
- A bone marrow sample with >10% plasma cells is strongly suggestive of MM
- Plasma cells replicate in the bone marrow and choke out normal hematopoiesis, leading to normo, normo
(impaired erythropoiesis) and increased risk of infection (impaired B-cell lymphopoiesis)
- Secret osteolytic cytokines, leading to bone pain, osteolytic (radiolucent) bone lesions, and hypercalcemia
- Produce large quantities of monoclonal IG (paraprotein) composed of heavy and light chains (eg, IgG, IgA) or
light chains alone. Light chains can deposit in the renal tubules, leading to light-chain cast nephropathy, which is
usually characterized by midl renal insufficiency and waxy, laminated urinary casts (Bence Jones)
- Light chains can also form insoluble fibrils and deposit in major organs, leading to amyloid light-chain
amyloidosis. This can contribute to the already elevated risk of renal failure as well as heart failure and
neurologic dysfunction. Amyloidosis can often be identified on biopsy using hematoxylin and eosin stain
(eosinophilic extracellular deposits) or Congo red stain viewed under polarized light (apple-green birefringence)

(11584) as a result of this increased protein production, plasma cells are particularly susceptible to the effects of
proteasome inh such as bortezomib, a boronic acid-containing dipeptide

Proteasomes act as recycling centers for proteins, breaking down misfolded, dmged and cytotoxic proteins into their
component building blocks for reunse in new proteins. Proteasome inh results in the accumulation of toxic intracellular
proteins. In addition, proteasomes regulate the balance of pro- and antiapoptotic proteins, and their inh leads to an
excess of proapoptotic proteins. Both of these effects induce apoptosis of the malignant plasma cells.

(6530) Rouleaux formation is due to elevated levels of circulating proteins, which disrupts the repulsive electrostatic
charge on the erythrocyte surface and causes stacked aggregation. Although rouleaux formation can be seen with
inflammatory conditions (eg, infection, rheumatic disease) that increase acute-phase reactants (eg, fibrinogen), it is
classically linked to lymphoproliferative/plasma cell disorders such as multiple myeloma and Waldenstrom
macroglobulinemia, which generate high levels of monoclonal paraprotein (immunoglobulins)

VS. Cold agglutinins are cross-reactive IgM antibodies that form with some infections (particularly M. pneumonia) and
hematologic malignancies. Cold agglutinins typically cause clumping agglutination (not stacked-coin agglutination) and IV
hemolysis.

Hemangioma (1873)

Angiogenesis

- Vascular endothelial growth factor (VEGF): stimulates angiogenesis in a variety of tissues (normal, chronically
inflamed, healing or neoplastic). As VEGF increases endothelial cell motility and proliferation, new capillaries
begin to sproud.
- Fibroblast growth factor (FGF): FGF-2 is produced by a wide range of cells and is involved in endothelial cell
proliferation, migration and differentiation. FGF-2 also appears to play an important role in embryogenesis by
stimulating angioblast production. As a group, FGFs not only contribute to angiogenesis, but also to embryonic
 development, dematopoiesis, and wound repair (by recruiting macrophages, fibroblasts and endothelial cells to
damaged tissues).

Insulin-like growth factor 1 (IGF-1), or somatomedin C, is synthesized predominantly by growth hormone-influenced

hepatocytes and serves to stiulate cell growth and multiplication. IGF-1 does not appear to directly stimulate angionesis,
but it can indirectly promote it by encouraging cell growth.

Although the proinflammatory nature of IL-1 can induce the release of other proinflammatory cytokines that trigger
cellular VEGF expression, IL-1 does not appear to directly stimulate angiogenesis. Similarly, although interferon-gamma
can indirectly promote neovascularization through activation of macrophages (can release VEGF), it does not appear to
directly stimulate angiogenesis.

(466) cutaneous, strawberry-type capillary hemangiomas are common, benign, congenital tumors, which are composed
of unencapsulated aggregates of closely packed, thin-walled capillaries. Initially, strawberry hemangiomas grow in
proportion to the growth of the child, before eventually regressing. In 75-95% of cases, the vascular tumor will regress
completely by age 7

Breast cancer

(1056) invasive breast carcinoma typically presents as an irregularly shaped adherent breast mass. The upper outer
quadrants of the breast are the most common site of breast cancer. Overlying skin retractions (eg, dimpling) signal
involvement of suspensory ligaments of the breast (eg, cooper ligament). Malignant infiltration of these ligaments
causes fibrosis and shortening, leading to traction on the skin with distortion in breast contour.

Direct invasion of the dermis by a rare type of cancer called inflammatory breast carcinoma can cause skin changes with
erythema, and ivasion of the lymphatic spaces by malignant cells leads to lymphedema with a finely pitted appearance
known as peau d’orange. These findings have a differnet pathogenesis from invasion of the suspensory ligament by a
malignant mass.

Invasive vs. non invasive (1877)

peau d’orange is an erythematous, itchy breast rash with skin texture changes analogous to an orange peel. This is the
key dermatologic presentation of inflammatory breast cancer and is caused by cancerous cells obstructing lymphatic
drainage due to spread to the dermal lymphatic spaces.

(2092)

Cytokeratins are proteins that help form the keratin-containing intermediate filaments that make up the cytoskeleton of
almost all epithelial cells. Keratin proteins are highly abundant in exposed stratified squamous epithelium such as the
epidermis and oral mucosa and are less abundant but still present in simple epithelium such as that found in the liver,
gut, and pancreas. As a result, cytokeratin is a commonly used immunohistochemical marker for epithelial-derived
tumors, such as breast cancer. Keratin is also the major protein component of hair and nails.

(2093)

The HER2 oncogene encodes for a transmembrane glycoprotein with intrinsic tyrosine kinase activity and is a member of
the family of epidermal growth factor receptors. Overexpression of this protein is associated with a worse prognosis and
increased risk of disease recurrence.

Ductal carcinoma in situ (1057)

Arises from the breast ducts. It is a precursor to the most common type of breast cancer, invasive ductal carcinoma. Age
and nulliparity are risk factors for breast cancer, and breastfeeding has a protective effect. DCIS is typically ID by biopsy
after mammography screening shows microcalcifications in asymptomatic px with normal breast examinations.
Histopathology demonstrates ducts distended by pleomorphic cells with prominent central necrosis without extension
beyond the ductal basement membrane. Spread of these malignant cells to the nipple thorugh the duct system results in
eczematous nipple changes and indicates Paget disease
Pure red cell aplasia (1789)

A rare form of marrow failure characterized by severe hypoplasia of marrow erythroid elements in the setting of normal
granulopoiesis and thrombopoisies.

The pathogenesis of PRCA often involves the inh of erythropoietic precursors and progenitors by IgG autoantibodies or
cytotoxic T lymphocytes. It has been associated with immune system diseases such as thymomas and lymphocytic
leukemias. When a thymoma is present, removal can occasionally cure PRCA. Thus, all px with PRCA should undergo a
chest CT scan. PRCA can also result from parvovirus B19 infection. This virus preferentially attacks and destroys
proerythroblasts. Recent parvovirus infection can be confirmed via the detection of anti-B19 IgM antibodies in the
serum.

Lymphoma

(1754)

Benign lymph node enlargement in response to antigenic stimulation is associated with a polyclonal proliferation of
lymphocytes. Can be classified:

- Follicular hyperplasia: occurs when the follicles increase in size and number
- Sinus hyperplasia: the sinuses enlarge and fill with histiocytes
- Diffuse hyperplasia: nodal architecture is diffusely effaced by sheets of lymphocytes, immunoblasts and
macrophages

Malignancy: monoclonal lymphocytic proliferation that results from the unckeced proliferation of a single genetically
unique cell from only one cell line.

ALL (1571)

(1798)

T-cell ALL is more likely to present with a large anterior mediastinal mass that can compress the great vessels, causing
superior vena cava syndrome. The mediastinal mass can also compress the esophagus causing dysphagia, while
compression of the trachea may lead to dyspnea and stridor.
APL (6497)

Auer rods are azurophilic, needle-shaped cytoplasmic inclusions formed by the fusion of primary granules found in
myeloblasts and promyelocytes. The rods can be seen on peripheral blood smears and bone marrow aspirates of px with
AML, particularly AP. APL is caused by a t(15;17) involving the retinoic acid receptor-alpha gene on chromosome 17 and
the promyelocytic leukemia gene con chromosome 15. This translocation is highly specific for APL and is not seen in
association with other leukemias or solid tumors

Clinical features:

- Pancytopenia (eg, weakness, fatigue, infections, gingival bleeding, ecchymoses)

- DIC

(1405)

This cytogenetic change represents a translocation between the retinoic acid receptor alpha (RARalpha) gene on
chromosome 17 and the promyelocytic leukemia (PML) gene on chromosome 15. Fusion of these 2 genes produces a
chimeric gene product, PML/RARalpha, which codes for an abnormal retinoic acid receptor. This abnormal fusion gene
inh promyelocyte differentiation and triggers the development of APML

Tx: all trans retinoic acid

Vs Burkitt lymphoma t(8;14): classically have round nuclei with basophilic cytoplasm containing prominent lipid vacuoles
(1755) translocation between the c-Myc oncogene (14;18). The product of c-Myc is a nuclear phosphoprotein that
functions as a transcription activator controlling cell proliferation, differentiation and apoptosis.

Vs. CML t(9;22): peripheral blood smear shows leukocytosis with many immature myeloid cells (myelocytes)

Vs: ALL t (12;21) most common translocation in childhood B-cell. Typically demonstrates anemia, thrombocytopenia and
lymphoblasts.
Vs: follicular lymphoma t(14;18): peripheral blood smear will often show malignant cells with notches or clefts
(centrocytes)

CLL (15545)

Symptomatic anemia + thrombocytopenia + leukocytosis are associated with clonal proliferation of CD20-positive cells (a
B-cell surface marker), raising strong suspicion for CLL. In CLL, mature B cells progressively accumulate in the bone
marrow and peripheral blood due to oncogenic mutations that inh apoptosis. Although most px are asymptomatic for
years, accumulation of B-cells in the bone marrow eventually chokes out normal hematopoiesis, leading to symptomatic
anemia, thrombocytopenia, and infections (due to neutropenia).
Px with CLL usually have dramatic elevations in peripheral leukocyte count (often >100,000/mm3) and characteristic
findings on peripheral blood smear (eg, smudge cells. The dx is confirmed when flow cytrometry of peripheral blood
reveals a clonal population of leukocytes with B-cell surface markers such as CD19, CD20 and CD23

(15821) in most cases of CLL, B-cell survival is promoted by the overexpression of BCL-2 on the mitochondrial
membrane. BCL-2 is an antiapoptotic protein that prevents stress signals from triggering the intrinsic apoptotic cascade,
which is mediated by the release of cytochrome c from the mitochondria and the subsequent activation of caspases. Tx
of CLL with BCL-2 inh (eg, venetoclax) makes tumor cells more sensitive to stress signals (eg, chemotherapy) by
increasing the activation of caspases, which leads to cell death.

CML is a myeloproliferative neoplasm characterized by peripheral leukocytosis due to circulating granulocytes

(neutrophils in different stages of maturation). Dx is generally made when cytogenetic studies reveal the BCR-ABL fusion
gene (Philadelphia chromosome). A clonal population of CD20-positive cells (B cells would not be seen)

(8281) approximately 4% of px with non-small cell lung carcinoma have an inversion of the short arm of chromosome 2
that creates a fusion gene between EML 4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic
lymphoma kinase). This results in a constitutively active tyrosine kinase that causes malignancy. Interestingly, px who
harbor this gene fusion are usually young non-smokers, often with adenocarcinoma, who lack mutations in either the
epidermal growth factor receptor gene or the K-ras gene. The kinase activity of this fusion protein is a target of the
protein kinase inh, crizotinib.

The pathophysiology of EML4=ALK NSCLC is most similar to the pathophysiology of CML. In CML, the classic and most
common cause is a translocation between chromosomes 9 and 22. The ABL proto-oncogene is transported from
chromosome 9 to chromosome 22 where it is placed adjacent to the BCR gene. The resulting oncogene, BCR-ABL, codes
for a fusion protein with constitutive tyrosine kinase activity. This protein stimulates the proliferation of granulocytic
precursors and leads to the development of CML. The kinase activity of this fusion protein is a target of the protein
kinase inhibitior, imatinib

Hairy cell leukemia (11750)

- Lymphocytes with cytoplasmic projections are seen in hairy cell leukemia

- Predonminantly dx in middle-aged men
- Indolent B-cell neoplasm that infiltrates the bone marrow and reticuloendothelial system
- Bone marrow infiltration and cytokine production produces fibrosis and bone marrow failure -> pancytopenia
- Usually “dry tap”
- Splenic red pulp infiltration can result in massive splenomegaly (ie, crossing midline or extending into left lower
quadrant)
- Common manifestation: LUQ pain, fatigue, weakness, fever and recurrent infections
- Dx: bone marrow biopsy and flow cytometry, which has replaced tartrate resistant acid phosphatase (TRAP)
activity testing

Bone tumors (15645)

Most cases of osteosarcoma are associated with sporadic or inherited mutations in RB1 (hereditary retinoblastoma) and
TP53 (Li-Fraumeni syndrome)

Specific CA risk factors (7623)

ALL (15278)

The presence of terminal deoxynucleotidyl transferase (TDT) is expressed only by lymphoid progenitor cells.
Lymphoblasts are hten further differentiated by the presence or absence of specific surface markers unique to B cells
(eg, CD19, CD20) or T-cells (eg, CD3)
TDT + CD3 -> T-cell acute lymphoblastic leukemia.

Unlike B-cell ALL, which usually occurs in early childhood, T-cell ALL is most common in the teenage years or early
adulthood. Tumors classically develop in the thymus, the organ charged with T-cell development, and often result in the
formation of a mediastinal mass that compresses the airway or nearby blood vessels.

Acute myeloid leukemia (1570)

Auer rods (linear purple-red inclusions within immature myeloid precursors) is helpful in making the dx of acute myeloid
leukemia. Auerrods are not found int ALL. In chronic myelogenous leukemia, there are more mature cells and fewer
blasts. Most commonly in M1, M2, and M3, subtype. The vast majority of AML cases occur in adults, with a median age
of 65. Most px present with complications of pancytopenia (eg, fatigue from anemia, bruising/bleeding from
thrombocytopenia, infection from possible functional neutropenia despite leukocytosis). The median white blood cell
count is around 15,000/m3 at dx. WHO dx criteria require the presence of >20% myeloblasts in the bone marrow

Nasopharyngeal carcinoma (1757)

Sore throat, moderate to high fever, palatal petechiae, lymphadenopathy (commonly posterior cervical or auricular),
splenomegaly and atypical (reactive) lymphocytosis are classic sigsn and symptoms of infectious mononucleosis.

EBV infection induces heterophile antibodies, which react to antigens from animal erythrocytes (sheep in the Paul-
Bunnell test and horse in the Monospot test). The heterophile antibody tests are sensitive and specific for EBV-
associated infectious mononucleosis.

Hodgkins lymphoma (1864)

Reed-Sternberg cells are large binucleated cells with an “owl’s eyes” appearance that appear on a background of
lymphocytic infiltrates. Reed-Sternberg cells must be present histopathologically in order to make the dx of Hodgkin
lymphoma.

Nonhodgkin lymphoma (1627)

Follicular lymphoma is a Bcell tumor composed predominantly of centrocytes (small cleaved cells) and a fewer numbers
of centroblasts (large noncleaved cells). The t(14,18) translocation is found in 80%-90% of follicular lymphomas. The
result is overexpression of the antiapoptotic gene product, BCL-2, and tumor formation.

(1911) follicular lymphoma is a non-Hodgkin lymphoma of follicular B-lymph. Px with follicular lymphoma
characteristically have a translocation between chromosomes 14 and 18 which causes Bcl-2 overexpression. Bcl-2 is
considered a protooncogene because it has anti-apoptotic effects.

(1628)

Rituximab is a monoclonal antibody used in lymphoma immunotherapy that specifically targest the CD20 surface ig

Another monoclonal antibody used in CA tx is trastuzumab (Herceptin), which is used in the tx of breast cancer

Infliximab is a chimeric (human/murine) IgG1 monoclonal antibody to TNF-alpha. This medication has had a significant
impact on the management of rheumatoid arthritis. Is also used to tx ankylosing spondylitis and fistulizing Crohn’s
disease

IL-2 is a cytokine that regulates the activation and differentiation of T-cells to aid in tumor cell destruction. It is FDA-
approved for the tx of renal cell carcinoma and melanoma
Imatinib is a potent inh of the BCR/ABL protein tyrosine kinase. It inh the cellular proliferation of BCR/ABL-expressing
cells without inducing apoptosis.

Abciximab is a chimeric mouse-human monoclonal antibody against the platelet GP IIb/IIIa receptor. It works by
blocking the final step in platelet aggregation. Abciximab is often admn during angioplasty in px with acute coronary
syndrome.

Proto-oncogenes/anti-oncogenes (1760)

Proto/oncogenes (1083)
CML (1569)

Chronic myelogenous leukemia (CML) and leukemoid reaction can have presentations similar to leukocytosis; however,
leukocyte (neutrophil) alkaline phosphatase level is normal or elevated in leukemoid reaction but decreased in CML. The
definitive diagnosis of CML requires demonstration of the Philadelphia chromosome t(9;22) or BCR-ABL fusion gene or
mRNA

Cyclin-dependent kinases (CDKs) 4/6 (15299)

Regulate the movement of cells from G1->S phase. Cancers often have mutations that enhance the activity or
downstream effects of CDK 4/6, which contribute to unregulated cellular growth. Inhibitors to CDK4/6 can be used to tx
certain forms of cancer. However, they can inh cellular replication in other rapidly dividing cells such as the hematologic
cells in the bone marrow (eg, neutropenia, anemia or thrombocytopenia).

Chemo specific toxicities (14848)

Radiation therapy (1474)

Exposure to ionizing radiation, including therapeutic and palliative radiation therapy, induces DNA dmg through DNA
double-strand fractures and the formation of oxygen free radicals.

Matrix metalloprotease (1084)

Metalloproteinases are zinc-containing enzymes that degrade the extracellular matrix. They participate in normal tissue
remodeling and in tumor invasion through the basement membrane and connective tissue.

Tumor lysis syndrome (8542)

The risk of TLS can be reduced by aggressive fluid hydration. Allopurinol (a xanthine oxidase inh) or rasburicase can also
be used to reduce uric acid levels during breakdown of tumor cells. Rasburicase is a recombinant version of urate
oxidase, it catalyzes the conversion of uric acid to allantoin, which is 5-10 times more soluble than uric acid. Unlike
rasburicase, which degrades uric acid, allopurinol inh uric acid formation during cell lysis.

(1050) Uric acid is soluble at physiologic pH, but it can precipitate in the normally acidic environment of distal tubules
and collecting ducts. The prevention of tumor lysis syndrome includes urine alkalinization and hydration, as high urine
flow and high pH along the nephron prevents crystallization and precipitation of uric acid.

Cancer anorexia cachexia syndrome (14772)

Cachexia is a hypermetabolic state driven by elevated pro-inflammatory cytokines (eg, TNF-alpha, IL-6), which stimulate
the ubiquitin-proteasome pathway to degrade skeletal muscle proteins (eg, actin, myosin)

The ubiquitin-proteasome pathway is the major eukaryotic mechanism for selective proteolysis (the destruction of
targeted proteins).
(1039) TNF alpha is also called cachectin and is considered a main mediator of paraneoplastic cachexia (along with
interleukin [IL]-1beta, and IL-6)

TNF alpha is produced by macrophages in response to infection as well as by some neoplastic cells. it influences on the
hypothalamus -> appetite suppression. It also increases basal metabolic rate.

In bacterial infections, TNF-alpha produces fever (along with IL-1), mediates many symptoms of septic shock, and causes
hepatic release of acute-phase reactants (eg, C-reactive protein and fibrinogen)

Fibronectin (1872)

The integrins are a family of transmembrane protein receptors that interact with the extracellular matrix by binding to
specific proteins, including collagen, fibronectin and laminin. Other adhesion molecule classes include adherins, selectins
and Ig superfamily memebers.

Fibronectins are large glycoproteins produced by fibroblasts and some epithelial cells. Fibronectin binds to integrins,
matrix collagen, and glycosaminoglycans, serving as a mediator of cell adhesion and migration. Differential expression of
integrin subtypes affects adhesion properoties of individual cells and correlates with malignant behavior in a number of
tumors, including melanoma.

Pharmacology

Anticoagulants (2133)
Direct factor Xa inhibitors (eg, apixaban, rivaroxaban) increase the prothrombin and activated partial thromboplastin
times but do not affect the thrombin time. Unfractioned heparin and direct thrombin inhibitors (eg, dabigatran) prolong
the thrombin time.

Warfarin

(1292) People w/ protein C or S deficiency may present with warfarin-induced skin necrosis shortly after starting
warfarin. Protein C and S are innate anticoagulants that are vit K dependent, as are coagulation factors, II, VII, IX and X.
Warfarin inhibits epoxide reductase (responsible for regenerating vit K), which leads to decreased levels of these
proteins. Factor VII and protein C are depleted first due to their shorter half-life. The early loss of protein C leads to a
transient hypercoagulable state that persists until the other coagulant factors are sufficiently inhibited. In px w/ protein
C or S deficiency, this prothrombotic state is exaggerated, promoting microvasculature occlusion and hemorrhagic skin
necrosis.

Tx: discontinue warfarin and admn fresh frozen plasma or protein C concentrate

(1087)

(1090) Rifampin, phenobarbital, and phenytoin are universal enhancers of the cytochrome P-450 pathway; concurrent
use of warfarin with these medications results in decreased efficacy of warfarin. In contrast, cimetidine, amiodarone,
and tmx-sulfa inh warfarin metabolism, increasing the rsik of bleeding.

Warfarin reversal (709)

Fresh plasma protein acts faster than vitamin K

Vs. protamine: used for heparin reversal. It acts by binding and chemically inactivating heparin.

Vs. aminocaproic acid is an antifibrinolytic agent that inh plasminogen activators and, to a lesser degree, antiplasmin
activity. Aminocaproic acid helps achieve hemostasis when fibrinolysis is the cause of bleeding

Vs. wheares fresh frozen plasma contains all of the coagulation factors, cryoprecipitate contains only cold-soluble
proteins (Factor VIII, fibrinogen, von Willebrand factor and vitronectin)

Vs. desmopressin: synthetic analogue of ADH used in tx of diabetes insipidus. At high doses, desmopressin increases
factor VIII activity in px with hemophilia A and von Willebrand disease. High-dose desmopressin can help control
bleeding associated with these disorders.

ALL (1890)
Tx

6-mercaptopurine (6-MP) (1890) is mainly degraded in the liver by xanthine oxidase (XO). Allopurinol, an XO inhibitor,
can increase the concentration of 6-MP significantly. Both 6-MP and 6-thioguanine are prodrugs that require activation
by hypoxanthine-guanine phosphoribosyl transferase (HGPRT).

Trastuzumab (11585)

Is a monoclonal antibody used in the management of patients with HER2-positive breast cancer. It binds to a portion of
the extracellular domain of HER2 and prevents activation of transmembrane tyrosine kinase. This downregulates cellular
proliferation and promotes apoptosis.

(14844) the major adverse effect of trastuzumab is a risk of cardiotoxicity, likely because HER2 signaling plays a role in
minimizing oxidative stress on cardiomyocytes and preserving cardiomyocyte function. Cardiotoxicity typically manifests
as a decrease in myocardial contractility (myocardial stunning) without cardiomyocte destruction or myocardial fibrosis.
Px usually experience an asymptomatic decline in left ventricular ejection fraction; however, overt heart failure can also
occur. Unlike the cardiotoxicity that occurs with anthracyclines (eg, doxorubicin), trastuzumab-induced cardiotoxicty is
not related to the cumulative chemotherapy dose and is often reversible with discontinuation of therapy.

Methotrexate (1857)

Is a folic acid antagonist used to tx ectopic pregnancy. It competitively inh the enzyme dihydrofolate (DHF) reductase,
which catalyzes the synthesis of tetrahydrofolate. DHF reductase inhibition causes the intermediate DHF to accumulate
intracellularly.

(718) preferentially inh growth of rapidly dividing cells, such as inflammatory and neoplastic cells. However, this
inhibitory effect also causes toxicity to tissues with rapid cellular turnover, such as oral and GI mucosa (ulcerations, hair
follicles (alopecia), and bone marrow (pancytopenia). Methotrexate can also cause hepatotoxicity (hepatitis, fibrosis,
cirrhosis) and pulmonary fibrosis.

(1892) methotrexate and 5-FU both effectively inh thymidylate formation, but the chemotherapeutic effect of
methotrexate is overcome by N-formyl-tetrahydrofolate (folinic acid, leucovorin) supplementation.

Etanercept (8523)

Is a TNF alpha inh added to methotrexate to tx moderate to severe RA. It is a fusion protein linking a soluble TNF alpha
receptor to the Fc component of human IG G1. Etanercept reduces the biological activity of TNF alpha by acting as a
decoy receptor

Etoposide (2018)

Etoposide is derivative of the plant alkaloid podophyllotoxin, which targest topoisomerase II. The topoisomerases are
enzymes that relieve the DNA supercoiling that occurs during DNA replication as a result of separation and unwinding of
the double helix. Topoisomerase I makes single-stranded nickes to relieve negative supercoiling, while topoisomerase II
induces transient breaks in both DNA strands simultaneously to relieve both positive and negative supercoiling.
Etoposide and podophyllin specifically inh topoisomerase II’s abitlity to seal the strand breaks it induces, causing
chromosomal breask to accumulate and eventual cell death. Two major uses of etoposide are in testicular cancer and
small cell lung cancer. Podophyllin is used topically to tx genital warts.
Vs. antimetabolites are medications that interfere with nucleotide metabolism, thus inh incorporation of new
nucleotides into elongating DNA strands. Fluorouracil and 5-deoxyuridine are antimetabolites that inh thymidylate
synthase, and methotrexate is an antimetabolite that inh dihydrofolate reducatse.

Vs. Irinotecan and topotecan inh topoisomerase I, an enzyme that induces single-strand breaks in DNA to relieve
negative supercoiling during replication

Vs. vinka alkaloids like vincristine and vinblastine bind tubulin monomers, disrupting the microtubules necessary for
separating chromosome strands during mitosis. Taxanes like placlitaxel also cause microtubular dysfunction.

Specific toxicities of common chemotherapeutic agents

Chemotherapy agent Mechanism of action Toxicity
Anthracyclines (eg, doxorubicin) - Binds with topoisomerase II to - Dilated cardiomyopathy
cleave DNA
- Binds with iron to generate
free radicals
Bleomycin - Induces free radical formation - Pulmonary fibrosis
Cisplatin - Cross-links DNA to inh DNA - Nephrotoxicity
synthesis - Ototoxicity
- Peripheral neuropathy
Cyclophosphamide - Cross-links DNA to inh DNA - Hemorrhagic cystitits
synthesis - Bladder cancer
Paclitaxel - Inh microtubule disassembly - Neuropathy
Vincristine/vinblastine - Binds beta-tubulin to inh - Neuropathy
microtubule formation

Cancer cell cycle (1893)

- G1: cells in this phase prepare the building blocks for DNA synthesis
- G0: this is a resting stage
 - S: DNA replication occurs during this phace. Topoisomerase I and II inhibitors (eg, etoposide, irinotecan), as well
as some antimetabolites (eg, methotrexate, 5-fluorouracil), function during this phase
- G2: in this phase, DNA is checked for errors and corrections are made if possible. If corrections cannot be made,
then apoptosis will result unless loss-of-function mutations to the genes controlling this process are present, a
condition frequently encountered in tumor cells. Chemotherapeutic agents active at this stage include drugs
that intercalte with DNA and induce free radical formation. Examples are bleomycin (can cause lung fibrosis) and
doxorubicin (can cause cardiomyopathy)
- M: division occurs during this stage. Vinca alkaloids and taxanes are specific to this phase

Some chemotherapeutic agents are cell-cycle nonspecific; these include cyclophosphamide, an alkylating agent with side
effects that include bone marrow suppression, alopecia and hemorrhagic cystitis

Immunotherapy (12048)

CA immunotherapy: anti-PD-1 & anti-CTLA-4 antibodies

Neoplastic cells can blunt the cytotoxic T-cell response through a variety of mechanisms including the overexpression of
programmed death-ligand 1 (PD-L1), which binds to the PD-1 receptor on cytotoxic T cells and inh their ability to induce
apoptosis (T-cell exhaustion)

Tx with monoclonal antibodies against PD-1 (eg, pembrolizumab, nivolumab) or PD-L1 (eg, atezolizumab) results in T-
cell disinhibition and a restoration of the cytotoxic response (thereby increasing CA cell apoptosis). Anti-PD-1 therapy is
currently used in advanced melanoma, certain types of lung CA, and renal cell CA

Musculoskeletal, Skin and Connective Tissue

Radial head subluxation (8579)

Radial head subluxation (nursemaid’s elbow) results from sudden traction of the outstretched and pronated arm of a
child. Affected children are usually in little distress unless attempts are made to move the elbow. The annular ligament is
torn and displaced in this injury
VS. the long head tendon of the biceps brachii courses intra-articularly to insert into the supraglenoid tubercle, while the
short head tendon attaches to the tip of the coracoid process. The common distal tendon inserts into the radial
tuberosity and the fascia of the forearm. Biceps tendon ruptures can occur both proximally and distally, and present
with a visible or palpable mass in the mid-upper arm (“Popeye” deformity)

VS. ulnar collateral ligament lies on the medial side of the elbow joint and strengthens the ulnohumeral joint. Ulnar
collateral ligament injuries occur most commonly in throwers (eg, baseball pitchers) due to intense valgus stress at the
elbow. Treatment often involves ulnar collateral ligament reconstruction (“Tommy John” surgery)

Shoulder dislocation (1924)

Flattening of the deltoid muscle with acromial prominence after a shoulder injury suggests an anterior humerus
dislocation. This injury most commonly resuts from a blow to an externally rotated and abducted arm. There is often
associated axillary nerve injury, resulting in deltoid dparalysis and loss of sensation over the lateral shoulder.

Vs. acromioclavicular joint subluxation typically results from a downward blow on the tip of the shoulder and produces
swelling and upward displacement of the clavicle. It is not usually associated with specific nerve injuries/deficits

Axillary nerve injury (11681)

Injury to the axillary nerve most commonly occurs in the setting of shoulder trauma (eg, anterior dislocation, humeral
fracture) and presents with sensory loss over the lateral shoulder and weakness on shoulder abduction (due to
denervation of the deltoid muscle).

Vs. the dorsal scapular nerve provides motor innervation to the rhomboids (retract the scapula) and levator scapulae
muscles (elevate the scapula)

Vs. long thoracic nerve injury classically occurs during axillary lymph node dissection and results in paralysis of the
serratus anterior muscle, leading to winging of the scapula

Vs. proximal injury to the median nerve (eg, due to supracondylar humerus fracture) may result in palmar sensory loss
over the first 3 digits and impairment of thumb flexion/opposition, flexion of the second/third digits and wrist
flexion/abduction.

Vs injury to the musculocutaneous nerve can cause sensory loss over the lateral forearm and weakened elbow flexion
due to denervation of the biceps brachii and brachialis muscles

Vs. injur to the radial nerve at the axilla (eg, “crutch palsy”) typically causes weakness of the forearm, hand and finger
extensor muscles (eg, wrist drop, absent triceps reflex) with sensory loss over the posterior arm, forearm and
dorsolateral hand

Vs. the thoracodorsal nerve provides motor innervation to the latissimus dorsi muscle, which is responsible for shoulder
extension, adduction and internal rotation

Vs. ulnar nerve injury most commonly occurs at the elbow, resulting in sensory loss over the medial 1 ½ digits of the
hand and weakness on wrist flexion/adduction, finger abduction/adduction and flexion of the fourth/fifth digits

Clavicle fracture (1702)

The clavicle is the most commonly fractured bone, and most clavicle fractures occur in young children. The
sternocleidomastoid muscle causes superior displacement of the medial fragment; the weight of the arm and the
pectoralis major muscle cause inferior displacement of the lateral fragment.
The clavicle is the point of origin or insertion for numerous muscles, including:

- Deltoid – inferolateral aspect

- Pectoralis major – inferomedial aspect
- Subclavius – inferolateral aspect
- Sternohyoid – inferomedial aspect
- Trapezius – superolateral aspect
- Sternocleidomastoid – superomedial aspect

Knee dislocation

(6516) injury to the popliteal artery is the primary concern with both anterior and posterior dislocations of the knee
joint. This vessel is rigidly fixed proximal and distal to the knee joint by the adductor magnus and soleus muscles,
respectively

Paralysis serratus anterior (6569)

Serratus anterior muscle, originates on the first 8 ribs and inserts on the medial border of the scapula. It stabilizes and
rotates the scapula upward, allowing complete abduction of the arm over the head. Paralysis results in inability to raise
the arm over the head and protrusion (“winging”) of the medial border of the scapula when the outstretched arm is
pushed forward against resistance.

Innervation of the serratus anterior is from the long thoracic nerve, which follows a lengthy course along the lateral
chest wall. Injury to the nerve can occur during penetrating trauma or iatriogenically during axillary lymph node
dissection or chest tube insertion.

Knee trauma

Femoral neuropathy (8671)

Lesions of the femoral nerve can occur due to trauma, nerve compression (eg, retroperitoneal hematoma due to
warfarin use. The risk of bleeding while on warfarin therapy is greatest in px with risk factors such as increased age, DM,
HTA and alcoholism), stretch injury or ischemia. Px develop weakness of the quadriceps muscle, loss of the patellar
reflex, and loss of sensation over the anterior and medial thigh and medial leg.

Lateral epicondylitis (11684)

Tennis elbow, is caused by overuse of the extensor carpi radialis brevis and is characterized by angiofibroblastic
tendinosis at its origin on the lateral epicondyle.

Supraspinatus (1732)

Assists in abduction of the arm and stabilization of the glenohumeral joint. The supraspinatus tendon is vulnerable to
injury to impingement between the acromion and the head of the humerus. Supraspinatus tendinopathy is the most
common cause of rotator cuff syndrome. On examination, the action of the supraspinatus can be isolated with “empty-
can” supraspinatus test: abduction of the humerus in parallel to the axis of the scapula (30 degrees forward flexion)
while in full internal rotation (thumbs pointed to the floor)
Knee trauma (1968)

The posterior cruciate ligament prevents posterior displacement of the tibia relative to the femur. It originates from the
anterolateral surface of the medial femoral condyle and inserts into the posterior intercondylar area of the tibia. Its
integrity can be tested in the clinical setting by using the posterior drawer test.

(1969) The ACL is injured more commonly than the PCL. It spans from the anterior portion of the intercondylar tibia to
the posterior medial side of the lateral femoral condyle. It prevents anterior displacement of the tibia relative to the
femur when the knee is flexed (anterior drawer test)

(11659)

Signs include an acutely swollen knee, focal patella tenderness, inability to extend the knee against gravity, and a
palpable gap in the extensor mechanism.
Peroneal neuropathy (1149)

The common peroneal nerve is susceptible to injury at the lateral neck of the fibula caused by compression or fracture.
Px often have weakness on foot dorsiflexion (“foot drop”) and eversion, as well as toe extension. Sensory loss typically
occurs over the lateral leg and dorsolateral foot.

(1742)

Px typically presents equinovarus (plantarflexed and inverted) posture due to paralysis of the peroneus longus and
peroneus brevis muscles (mediate foot eversion), paralysis of the tibialis anterior muscle (mediates dorsiflexion), and
paralysis of the extrinsic extensors of the toes. Injury also causes loss of sensation to the anterolateral leg and dorsum of
the foot. The classic finding on gait examination is “foot drop,” where the affected toe points the ground as the foot is
raised due to inability to dorsiflex against gravity. Px compensate for this by walking with a “steppage gait,” where the
leg is lifted high off the ground. In addition, the affected foot will often slap to the ground with each step (“foot slap”)
due to inability to gently lower the forefoot upon heel strike.

(1803) the common peroneal nerve divides into superficial and deep branches. The superficial branch innervates the
muscles of the lateral compartment of the leg, which function primarily to evert the foot. The deep peroneal nerve
innervates the anterior compartment of the leg, whose muscles act mainly as dorsiflexors of the foot and toes. The
superficial peroneal nerve provides sensory innervation to the dorsum of the foot. The deep peroneal nerve provides
sensory innervation to the region between the first and second digits of the foot. Injury to the common peroneal nerve
from a proximal fibula fracture would cause loss of dorsal foot sensation as well as impaired dorsiflexion and eversion
resulting in foot drop.

Psoas abscess (8710)

Can occur as the result of hematogenous or lymphatic seeding from a distant site or by spread from an adjacent site. Px
can present with fever, back or flank pain, inguinal mass, and difficulty walking. Inflammation of the psoas muscle causes
pain when the hip is extended (psoas sign)

Compartment syndrome (11635)

Most common site for ACS is the anterior compartment of the leg, which includes the foot extensor muscles, anterior
tibial artery and the deep peroneal (fibular) nerve. Injury to the deep peroneal nerve causes decreased sensation
between the first and second toes, decreased dorsiflexion of the foot, foot drop and claw foot

Vs the deep posterior compartment contains the posterior tibial artery, peroneal artery and tibial nerve. ACS involving
this compartment may cause decreased sensation in the plantar surface, decreased toe flexion and pain with passive toe
extension

Vs. the lateral compartment of the leg contains the superficial peroneal nerve and the proximal part of the deep
peroneal nerve. ACS in this compartment can produce loss of sensation in the lower leg and dorsum of the foot as well
as foot drop.

Brachial plexus (1636)

Musculocutaneous nerve injury, which most commonly occurs in the setting of trauma (eg, shoulder dislocation) and
strenuous upper extremity activity (eg, baseball pitching). The musculocutaneous nerve is derived from the C5-C7 spinal
nerve roots and arises from the lateral cord of the brachial plexus. It innervates the major forearm flexors (eg, biceps
brachii, brachialis) and coracobrachialis (flexes and adducts the arm). After innervating these muscles, the remaining
fibers become the lateral cutaneous nerve of the forearm and provide sensory innervation to the skin of the lateral
forarm.
(11744) Interscalene nerve block anesthetizes the brachial plexus as it passes through the scalene triangle. It is used to
provide anesthesia for the shoulder and upper arm. Nearly all px develop transient ipsilateral diaphragmatic paralysis
due to involvement of the phrenic nerve roots as they pass through the interscalene sheath

Femoral fracture (1956)

The blood supply to the femoral head derives mainly from the ascending cervical and retinacular branches of the medial
circumflex artery. These vessels are especially vulnerable to dmg from fractures of the femoral neck due to their close
association with it. Branches of the lateral circumflex and superior and inferior gluteal arteires join with the medial
circumflex artery to form the trochanteric anastomosis. However, these arteries provide only minor contributions to the
blood supply of the femoral head and neck.

Radial neuropathy (11855)

The brachial artery, median nerve, and radial nerve all run anterior to the elbow and may be injured in supracondylar
humeral fractures. The radial nerve is the structure most likely to be injured with lateral displacement of the proximal
fracture fragment.

(1685) radial nerve injury can occur with repetitive pressure/trauma at the axilla (eg, improperly fitted crutches).
Findings include weakness of the forearm, hand and fingers extensors (eg, wrist drop, absent triceps reflex) and sensory
loss over the posterior arm and ofrearm, dorsolateral hand, and dorsal thumb. More distal lesions spare the triceps
brachii.

Spinal accessory nerve injury (11772)

The spinal accessory nerve is vulnerable to injury in the posterior triangle of the neck. Injury results in weakness of the
trapezius muscle, which presents with drooping of the shoulder, impaired abduction of the arm above horizontal (due to
weakness in rotating the glenoid upward), and winging of the scapula.

Scaphoid fracture (8670)

A fall onto an outstretched hand may cause fracture of the scaphoid bone. Examination shows tenderness in the
anatomical snuff box. The scaphoid bone is vulnerable to avascular necrosis due to its tenuous blood supply. Supplied by
dorsal scaphoid branch of the radial artery

Presents: tendernesss at the anatomic snuffbox and a scaphoid fracture on x-ray -> avascular necrosis

Vs. acute compartment syndrome:

Occurs when increased pressure within a fascial compartment compromises blood circulation within that space, it
develops after significant trauma, particularly long-bone fractures of the leg or forearm

Vs. carpal tunnel

Median nerve compression within the carpal tunnel, it can develop following a fall on an outstretched hand due to
dislocation of the lunate

Vs. trapezius muscle – CN XI

Vs. omohyoid muscle – cervical plexus branches (ansa cervicalis)

Vs. platysma – cervcal branch of the facial nerve

Sternocleidomastoid – CN XI

Rheumato

Muscle structure & physiology (824)

Transverse tubules (T-tubules) are invaginations of the sarcolemma that transmit depolarization signals to the
sarcoplasmic reticulum to trigger the release of calcium and induce muscle contraction. The uniform distribution of T-
tubules in striated muscle fibers ensures that each myofibril contracts at the same time, which is necessary for efficient
contraction.

- A form of limb girdle muscular dystrophy due to a mutated sarcolemma protein (eg, caveolin) affecting
excitation-contraction coupling. Decreased numbers of functional T-tubules in affected muscle fibers lead to
uncoordinated contraction of myofibrils, which manifests as muscle weakness
- McArdle disease is one cause of impaired ATP production and occurs due to a failure of muscle glycogen
breakdown
- Impaired relaxation after sustained contraction occurs in myotonic dystrophy due to a trinucleotide repeat
expansion altering myotonin-protein kinase. This protein facilitates myosin head detachment from the actin
filament to enable muscle relaxation; T-tubules do not play a role
- A mutation in troponin C may block its response to intracellular calcium and prevent muscle contraction.
However, muscle fibers with decreased numbers of T-tubules will maintain limited contractility

Golgi tendon organs (8266)

The GTOS are sensory receptors located at the junction of the muscle and tendon that are innervated by group Ib
sensory axons. GTOs are connected in series with the contracting extrafusal skeletal muscle fibers. When a muscle
actively contracts against resistance, the increase in tension is transmitted through the tendon activating the GTOs in the
process. In contrast, GTOs are relatively insensitive to changes in muscle length because the lengthening that occurs
when a muscle is passively stretched takes place primarily in the muscle fibers and not in the tendon

The Ib sensory axons from the GTOs contact inhibitory interneurons in the spinal cord, which in turn synapse with the
alpha motor neurons that innervate the same muscle. Thus, the golgi tendon circuit is a negative feedback system that
regulates and maintains muscle tension. When a muscle exerts too much force, the GTOs inh contraction of the muscle,
causing sudden muscle relaxation. This prevents dmg to the musculoskeletal system

Causes of osteomyelitis (646)

Associated condition Mode of infection Most frequent pathogen Typical location
Childhood age Hematogenous seeding s. aureus Long bones
during an episode of
bacteremia
Sickle cell disease Hematogenous seeding to Salmonella Long bones
infarcted bone s. aureus
Pott disease Hematogenous seeding TB Vertebrae
from lungs
DM Contiguous spread from Polymicrobial Bones of the feet
 infected foot ulcer
Recumbent px with Contiguous spread from Polymicrobial Sacrum & heels
impaired mobility pressure sore
Recent trauma or Direct inoculation Polymicrobial Variable
orthopedic surgery

(721) Hematogenous osteomyelitis, a disease that predominantly affects children, particularly boys. It usually affects the
metaphysis of long bones, as this region contains slow-flowing, sinusoidal vasculature that is conducive to microbial
passage.

Without treatment, the infection can progress to chronic suppurative osteomyelitis, a condition in which necrotic bone
(ie, sequestrum) serves as a reservoir for infection and becomes covered by a poorly constructed shell of a new bone
called an involucrum. One or more sinus tracts develop to drain the purulent material into the soft tissue or out to the
skin surface. Proper tx includes antibiotic therapy and debridement of necrotic bone.

Osteogenesis imperfect (702)

AD

Type 1 collagen is the predominant collagen in osteoid (organic portion of bone matrix) and allows bone to be
somewhat flexible while still maintaining strength. Type 1 collagen is also present in teeth, ligaments, skin and sclerae. In
OI, deficiency of type 1 collagen causes brittle bones that are prone to fracture. Other manifestations include blue
sclerae due to the deficient connective tissue allowing transparency of underlying vessels and small, malformed teeth
(dentinogenesis imperfecta). Joints can have excessive laxity, and some px are also susceptible to bruising and hearing
loss.

Radiculopathy (15553)

Motor and sensory deficits across multiple peripheral upper extremity nerves (eg, radial: triceps reflex and digital
extensors and median: sensation to the distal half of the third finger). Indicate a lesion in the brachial plexus proximal to
the formation of the terminal branches. In the absence of acute trauma, the most likely cause is nerve root compression
due to cervical spondylosis or disc herniation (cervical radiculopathy)

Bursitis (1491)

Active range of motion is often decreased or painful, but passive motion is usually normal as it results in less pressure on
the inflamed bursa.

Prepatellar bursitis: associated with repetitive anterior knee trauma from kneeling, sometimes called “housemaid’s
knee.” The prepatellar bursa is located between the patella and the overlying skin. Other occupations associated with
prepatellar and infrapatellar bursitis include carpet layers, mechanics and plumbers.

Anaserine bursitis: presents with pain along the medial knee and well defined tenderness approximately 4 cm distal to
the anteromedial joint margin of the knee. It frequently results from obesity or overuse in athletes

Popliteal (Backer) cysts are caused by swelling of the gastrocnemius or semimembranosus bursa. They often form due to
extrusion of synovial fluid from the knee joint into the bursa in px with osteoarthritis or inflammatory joint disease.

Suprapatellar bursa: is located anteriorly between the distal femur and quadriceps. Bursitis here is often caused by a
direct blow to the distal thigh or prolonged/repetitive quadriceps activity (eg, running).
Septic arthritis (6439)

Knee pain + effusion + synovial fluid with numerous polymorphonuclear leukocytes + microorganisms

Septic arthritis can sometimes develop following trauma

Common causative:

- S. aureus
- N. gonorrhoeae
- Strepto
- H. influenzae
- Gram negative bacilli (eg, E. Coli, Salmonella, pseudomonas)
- Children <2 years especially vulnerable to H. influenzae
- Children >2 years tend to develop S. aureus
- Late adolescence and early adulthood => N gonorrhoeae (especially in women)
- Sickle cell px prone to Salmonella, regardless of age

H. Influenzae (964)

Gram negative coccobacillus that requires both X factor (hematin) and V factor (NAD+) to grow. H. influenzae type B has
an antiphygocytic polysaccharide capsule, which allows it to spread hematogenously and cause invasive disease such as
septic arthritis and meningitis.

McCune-Albright syndrome (11653)

Pathogenesis - Mutation GNAS gene
- Constant G protein activation
- Hormone overproduction
Clinical features - Peripheral precocious puberty
- Irregular café-au-lait macules
- Polyostotic fibrous dysplasia
Complications - Thyrotoxicosis
- Acromegaly
- Cushing syndrome
MAS results from a mosaic somatic mutation during embryogenesis in the GNAS gene encoding the stimulatory alpha
subunit of G protein. This mutation causes constitutive activation of the G protein/cAMP/adenylate cyclase signaling
cascade, which leads to a gain of fx of the affected cells. Persistent G-protein stimulatory activity in melanocytes results
in prominent café-au-lait macules. CALMs, usually the first manifestation of MAS, are often large and unilateral with an
irregular, “coast of Maine” border.

In addition, autonomous endocrine fx most commonly results in precocious puberty (onset of secondary sexual
development before age 8 in girls). The mutation also results in increased proliferation of fibroblast-like cells, increased
secretion f IL-6, and activation of osteoclasts (fibrous dysplasia). The term polyostotic refers to the presence of lesions in
many bones, although they are typically unilateral.

Carpal tunnel syndrome (11683)

Carpal tunnel: defined by the carpal bones on the dorsal aspect and the transverse carpal ligament (flexor retinaculum)
on the volar aspect. The ligament attaches to the hamate and pisiform on the ulnar side and to the trapezium and
scaphoid tuberosity on the radial side. IT contains flexor digitorum profundus tendons, the flexor digitorum superficialis
tendons, the flexor pollicis longus tendon, and the median nerve.
Compression of the median nerve is characterized by pain and paresthesias in the median nerve territory (first 3 digits
and the radial half of the fourth). Motor involvement causes weakness of thumb abduction and opposition, and atrophy
of the thenar eminence. A longitudinal incision through the ligament relieves the pressure on the nerve.

Osgood schlatter disease (11819)

The quadriceps muscle group is connected to the patella, which in turn is attached to the tibial tubercle by the patellar
ligament. Repetititve quadriceps contraction can lead to Osgood-Schallter disease, which is characterized by focal pain
and swelling at the tibial tuberosity

Achondroplasia (6531)

Achondroplasia is caused by a gain-of-function point mutation of the fibroblast growth factor receptor 3 (FGFR3) gene
and presents with proximal limb shortening with resultant short stature, midface hypoplasia, and frontal bossing.

Marfan syndrome (1250)

Marfan syndrome is due to defect in fibrillin-1, an extracellular glycoprotein that acts as a scaffold for elastin. It is
abundant in the zonular fibers of the lens, periosteum, and aortic media. Aortic root dilation with dissection and rupture
is a common cause of death.

Spinal stenosis (12073)

Spinal stenosis occurs most commonly in the lumbar region and presents with posture dependent lower extremity pain,
numbness/paresthesia and weakness. The most common cause is degenerative arthritis of the spine, which results in
narrowing of the spinal canal due to intervertebral disc herniation, ligamentum flavum hypertrophy and osteophyte
formation affecting the facet joints.

Paget bone disease (6428)

Pathogenesis - Osteoclast dysfunction
- Excessive & disordered bone formation
Clinical manifestations - Often asymptomatic
- Bone pain & deformity
Skull: headache, dizziness, hearing loss
Spine: spinal stenosis, radiculopathy
Long bones: bowing, focal enlargement, arthritis of adjacent joints
- Elevation in alkaline phosphatase
- X ray: lytic or mixed lytic/sclerotic lesions; cortical & trabecular thickening
Complications - Fracture
- Excessive blood flow: high-output heart failure, vascular steal
- Malignant transformation (eg, osteosarcoma)

(987) the disease is thought to be caused by environmental factors and gene mutations (eg, affecting RANK,
osteoprotegerin) that result in excessive RANK and NF-kB activation.

The disease typically progresses through 3 phases:

1. Osteolytic (osteoclast-dominant) phase – characterized by increased numbers of osteoclasts that appear

abnormally large with an excessive number of nuclei. Increased resorption activity is prominent
 2. Mixed (osteoclastic-osteoblastic phase – defined by a rapid increase in osteoblastic bone formation with
persistent osteoclastic activity. The newly made bone is abnormal, with interspersed areas of disorganized
lamellar and woven bone.
3. Osteosclerotic (osteoblast-dominant) phase – characterized by continued osteoblastic bone formation and
remodeling that result in a dense, hypovascular, mosaic pattern of lamellar bone with irregular, haphazardly
oriented sections separated by prominent cement lines

(15677) characterized by disordered bone formation. Involvement of long bones can lead to bone pain, bowing, fracture
or arthritis of adjacent joints. Serum alkaline phosphatase is elevated due to increased production of new bone, but
calcium and phosphorus levels remain normal.

(15696) radiographs typically reveal lytic or mixed lytic-sclerotic lesions, thickening of cortical and trabecular bone, and
bony deformities. In the vertebrae, bony enlargement and cortical thickening may create an appearance resembling a
picture frame.

(639) osteoclasts originate from hematopoietic progenitor cells. macrophage colony-stimulating factor and receptor for
activated nuclear factor kappa-B ligand (RANK-L) play an important role in osteoclast differentiation. Paget’s disease of
bone is characterized by increased numbers of abnormal osteoclasts, excessive bone turnover and disorganized bone
remodeling.

Rheumatoid arthritis (754)

Rheumatoid arthritis results from an immune response directed against autoantigens in the joints. Infiltrating CD4+ T ells
secrete cytokines that promote inflammatory synovitis. They also stimulate B cells to produce RF (IgM antibody specific
for Fc component of IgG) and anti-CCP antibodies that contribute to chronic inflammation and joint destruction.

(14677)

Pathogenesis of RA involves early activation of CD4 T cells (especially Th1 and Th17 subsets) with release of cytokines
such as tumor necrosis factor-alpha and IL-1 that cuase destruction of cartilage and bone. Monoclonal antibodies that
inh TNF-alpha or IL-1 receptors can slow progression of the disease.

The proteases (eg, collagenase, metalloproteinase) contribute to cartilage destruction. In addition, both cytokines
indirectly activate osteoclasts, resulting in bony erosions. Monoclonal antibodies that inh TNF-alpha (eg, adalimumab,
etanercept) or IL-1 receptors (eg, anakinra) are widely used in the tx of RA and can slow progression of the disease.

VS GF-beta and IL10 are anti-inflammatory cytokines that downregulate lymphocyte activation and proliferation and
reduce the production of proinflammatory cytokines (eg, TNF-alpha).

VS. activated Th1 cells produce significant quantities of IL-2 and interferon gamma, among other cytokines. Although
Th1 cells and interferon gamma play a role in the pathogenesis of RA, IL-2 is less prominent. These cytokines are present
in higher quantities in granulomatous diseases (eg, tb, sarcoidosis)

(719) the foundation of management for RA is disease-modifying antirheumatic drugs, which alleviate pain and
inflammation and reduce long-term joint destruction. However, the response to tx may take several weeks. NSAID and
gluco can provide rapid symptom relief in the interim.

(11793)

Rheumoatoid arthritis + endotracheal intubation -> sudden-onset quadriparesis. Think of subluxation.

Long-standing RA frequently involves the cervical spine and cuases joint destruction with vertebral malaligment. The
atlantoaxial joint is most often involved as the atlas (C1) has a high degree of mobility relative to the axis (C2 odontoid
and body)

Chronic symptoms of cervical subluxation include neck pain, stiffness, and neurologic findings (eg, sensory loss, muscle
weakness). Endotracheal intubation can actuely worsen the subluxation and cause compression of the spinal cord
and/or vertebral arteries. Acute spinal cord injury results in flaccid paralysis with decreased or absent reflexes below the
level of the compression due to the spinal shock; the paralysis eventually becomes spastic as spinal shock resovles over
the ensuing days to weeks.

(15629)

The pathogenesis of RA begins with activation of T lymphocytes in response to rheumatoid antigens (eg, citrullinated
peptides, type II collagen). Activated T cells release cytokines that cause synovial hyperplasia with recruitment of
additional mononuclear cells. the accelerated metabolic rate of the inflamed synovial tissue leads to local hypoxia and
increased production of hypoxia-inducible factor 1and vascular endothelial growth factor by local macrophages and
fibroblasts, resulting in synovial angiogenesis (neovascularization)

(11821) Cervical spine involvement is also common in longstanding disease, and may lead to severe pain and siability
due to spinal instability with potential radiculopathy/cord compression. The hips and lumbosacral joints are usually
spared in RA.

Osteoarthritis (1771)

Rheumatic fever (239)

Alkaptonuria (1503)

- Disorder of tyrosine metabolism (1502)

- AR
- Deficiency of homogentisic acid dioxygenase (normally metabolizes homogentisic acid into maleylacetoacetate)
- Accumulated homogentisic acid causes pigment deposits in connective tissue throughout the body
- Adulthood -> blue-black deposits become apparent in the sclerae and ear cartilage
- Deposits also occur in the large joints and spine -> ankylosis, motion restriction, and significant pain.
- Urine turnst black when exposed to air due to oxidization of homogentisic acid

Gout

(1450)

Predispositions:

- Idiopathic (primary gout)

- Increased urate production (eg, myeloproliferative disorders)
- Decreased urate clearance by the kidneys

(2090)

Gout is a disease caused by tissue deposition of monosodium urate crystals. Elevated uric acid levels are known risk
factor for gout and increased purine metabolism is one possible cause of hyperuricemia. Phosphoribosyl pyrophosphate
(PRPP) synthetase is the enzyme responsible for the production of the activated ribose necessary for de novo synthesis
of purine and pyrimidine ncleotides. The mutation described in the question stem will cause increased production of
purines due to feed-forward activation of the purine synthesis pathway. As a result, more purine molecules will undergo
degradation, resulting in hyperuricemia and an increased risk of gout.

(2091)

Neutrophils are the primary cells responsible for the intense inflammatory response seen in px with gout. Phagocytosis
of urate crystals by neutrophils causes the release of various cytokines and inflammatory mediators that lead to further
neutrophil activation and chemotaxis, resulting in a positive feedback loop that amplifies the inflammatory response.
(6438)

Is caused by precipitation of urate crystals in joints and is most common when uric acid levels are elevated or fluctuating
(eg, initiation of diuretic therapy). Normally, the urate crystals have a protective coating of apolipoprotein E or B. when
uric acid levels fluctuate or microtrauma occurs, bare urate crystals are shed and exposed to IgG antibodies. The
subsequent antibody binding leads to neutrophil phagocytosis and release of inflammatory cytokines (primarily IL-1).
This leads to infiltration by neutrophils and macrophages and subsequent inflammatory changes.

(167) most diuretics (eg, hydrochlorothiazide, furosemide) can cause hyperuricemia and trigger gout flares by causing
relative volume depletion, which decreases the fractional excretion of uric acid. Other medications that can cause
hyperuricemia include certain immunosuppressants (Eg, cyclosporine, tacrolimus) and cytotoxic chemotherapeutic
agents. In addition, medications that rapidly lower uric acid levels (eg, allopurinol) can paradoxically trigger an acute
attack of gout due to mobilization of tissue urate stores (ie, dissolving crystals become fragile and more easily shed into
the joint space.

(14967)

Cyclosporine is a common cause of gout exacerbations in px who have undergone solid organ transplantation,
particularly renal transplantation. This medication impairs renal excretion of uric acid, resulting in hyperuricemia.
Although high doses of systemic glucocorticoids (eg, prednisone) can be used to tx acute gout, the low dosese used for
immunosuppression in px who have undergone transplantation are usually not sufficient to prevent gout flares.

Furosdemide (684)

Is a loop diuretic that works by inh Na-K-2Cl symporters in the loop of Henle effectively causing increased Na, Cl, and
fluid excretion. Additionally, loop diuretics also stimulate prostaglandin release. By stimulating renal prostaglandin
release, loop diuretics also increase renal blood flow leading to increased GFR and enhanced drug delivery. Thus
concurrent use of NSAIDs with loop diuretics can result in a decreased diuretic response.

(1168)

Tx: colchicine is an effecti anti-inflammtory agent in acute gouty arthritis and acts by binding to the intracellular protein
tubulin, preventing tubulin polymerization into microtubules. This leads to impaired leukocyte migration and
phagocytosis, reducing the inflammation seen in gouty arthritis. Also disrupts microtubule formation in GI mucosal cells,
many px develop diarrhea and, less commonly, nausea, vomiting and abd pain.

Tx: (859)

Colchicine binds to intracellular protein tubulin and inh its polymerization into microtubules. This, in turn, disrupts
cytoskeletal-dependent fx such as chemotaxis and phagocytosis. Colchicine is admn initially at the first signs of a gout
flare and can be repeated an hr later. It may also be used for prophylaxis while initiating urate-lowering therapy (eg,
allopurinol). Important adverse effects of colchicine include nausea, abd pain and diarrhea, which are most common at
higher doses. Colchicine should be avoided in patients who are elderly or have sever renal dysfunction.

(860) NSAIDS are the first-line tx for most px with acute gouty arthritis. They inh cyclooxygenase enzymes and therefore
decrease prostaglandin synthesis and exert a broad anti-inflammatory effect that includes inhibition of neutrophils.
NSAIDS should be avoided in px with renal and hepatic dysfunction or those at high risk for peptic ulcer.

Pseudogout (1451)
Synovial fluid analysis showing rhomboid-shaped calcium pyrophosphate cyrstals is dx of pseudogout. These crystals are
positively birefringent under polarized light. The knee joint is involved in >50% of cases.

Septic arthritis (11818)

Synovitis is characterized by pain, erythema, swelling, and reduced range of motion in a joint. Acute synovitis may
represent serious pathology (eg, segptic arthritis), especially if accompanied by fever or leukocytosis; it should be
evaluated urgently with synovial fluid analysis. Delayed dx of septic arthritis may lead to loss of the joing and long-term
disability and may be fatal

Polymiositis and dermatomyositis

Dermatomyositis (15603)

- Proximal muscle weakness

- Helitrope rash
- Gottron papules, which are raised erythematous plaques over the joints and bony prominences of the hands
- An inflammatory myopathy that primarily affects striated muscle and skin
- Dx: elevated muscle enzymes (eg, creatinine kinase) + positive autoantibodies (ie, antinuclear antibody [high
sensitivity, low specificity], anti-Jo-1 [low sensitivity, high specificity]).
- Muscle biopsy in dermatomyositis shows perimysial inflammatory infiltrates and atrophy involving the fibers
around the periphery of muscle fascicles (perifascicular atrophy)
- The oropharynx and upper esophagus also contain skeletal muscle that can be affected in dermatomyositis and
polymyisitis, leading to dysphagia and pulmonary aspiration
- Other important complications of inflammatory myopathies include interstitial lung disease and myocarditis
(due to involvement of striated cardiac muscle)

(11805) may occur alone or as paraneoplastic syndrome of an underlying malignancy, most commonly due to underlying
adenocarcinoma (eg, ovary, lung, pancreas). Symptoms may preced the diagnosis of malignancy but often parallel the
course of the cancer.

Polymyositis (11646)
Clinical presentation - Symmetrical proximal muscle weakness
- Increasing difficulty climbing stairs, getting up from a chair, carrying heavy objects
Pathologic features - Elevated muscle enzymes (CK, aldolase)
- Autoantibodies (ANA, anti-Jo-1)
- Biopsy: endomysial mononuclear infiltrate, patchy necrosis
Associated complications - Interstitial lung disease
- myocarditis
Autoantibodies, especially antinuclear antibodies, are also present in most cases; anti-histidyl-tRNA synthetase (anti-Jo-
1) antibodies are less sensitive but more specific for dermatomyositis and polymyositis. A biopsy can differentiate
polymyositis from dermatomyositis, which typically shows an endomysial inflammation without prominent vascular
involvement in a scattered or patchy distribution (in contraste, dermatomyositis causes perifascicular inflammation in a
segmental pattern without vasculopathy)

(940)

Dermatomyositis is an autoimmune disorder characterized by inflammatory myopathy (similar to polymyositis) and

cutaneous involvement
 - cutaneous manifestation: Gottron papules (red or violaceous, flat-topped papules over joints and bony
prominences, especially on the hands) and heliotrope rash (erythematous or violaceous edematous eruption on
the upper eyelids and periorbital skin)
- myopathy: proximal muscle weakness (eg, difficulty climbing stairs, combing hair), elevated muscle enzymes (eg,
creatine kinase, aldolase)

antinuclear antibody titers are freuqnetly elevated in dermatomyositis, although anti-Jo-1 is more specific. Muscle
biopsy confirms the diagnosis and shows a perimysial inflammatory infiltrate, patchy ischemia and necrosis, and
perifascicular atrophy and fibrosis. Dermatomyositis may occur alone or as a paraneoplastic syndrome associated with
malignancy (especially adenocarcinoma). Patients who develop dermatomyositis after age 50 have an increased risk of
an underlying occult malignancy

Reactive arthritis (743)

Reactive arthritis
Preceding infection - genitourinary infection: chlamydia trachomatis
- enteritis: salmonella, shigella, yersinia, campylobacter, c. difficile
Musculoskeletal - asymmetric oligoarthritis
- enthesitis
- dactylitis
Extraarticular symptoms - ocular: conjunctivitis, anterior uveitis
- genital: urethritis, cervicitis, prostatitis
- dermal: keratoderma blennorhagicum, circinate balanitis
- oral ulcers

Urethritis + conjunctivitis + mono- or oligoarticular arthritis -> reactive arthritis

Seronegative (Rheumatoid factor-negative) spondyloarthropathy most commonly affects patients age 20-40 and is
associated with HLA-B27. Symptoms generally manifest 1-4 weeks following a primary infection causing urethritis or
enteritis and are caused by an autoimmune reaction initiated by the infecting pathogen. Skin findings include
keratoderma blennorrhagicum (hyperkeratotic vesicles on the palms and soles) and circinate balanitis (serpiginous
annular dermatitis of the glans penis). Axial involvement, including sacroillitis, may occur in about 20% of cases.

(1600) reactive arthritis is a spondyloarthropathy associated with HLA-B27 that can occur following infection with
chlamydia, campylobacter, salmonella, shigella or Yersinia. It px with sterile arthritis due to deposition of immune
complexes.

Polymyiositis
Increased expression of MHC I antigens on the sarcolemma has been demonstrated and likely leads to presentation of
autoantigens to CD8+ cytotoxic cells that subsequently initiate myocyte destruction. Infiltration of the endomysium by
macrophages and CD8+ lymphocytes is typically seen

Ankylosing spondylitis (753)

- Low back pain (onset age <40, insidious onset, improves with exercise but not with rest, pain at night)
- Hip & buttock pain
- Limited chest expansion & spinal mobility
- Enthesitis (inflammation at the site of insertion of a tendon to the bone)
- Systemic symptoms (eg, fever, chills, fatigue, weight loss)

Additional extraskeletal systems:

- Respiratory: involvement of the thoracic spine and enthesopathies of the costovertebral and costosternal
junctions can limit chest wall expansion, leading to hypoventilation. Chest expansion should be monitored
regularly in px with AS.
- CV: the most common cardiovascular complication of AS is ascending aortitis, which can lead to dilation of the
aortic ring and aortic insufficiency.
- Eye: anterior uveitis develops in some px with AS and presents with pain, blurred vision, photophobia and
conjunctival erythema

SLE (1253)
Constitutional symptoms + arthralgias + pleuritic chest pain + anti-histone antibodes + recent isoniazid -> drug-induced
lupus erythematosus (DILE). Procainamide, hydralazine, and isoniazid are metabolized via phase II acetylation in the
liver. Hepatic expression of N-acetyltransferase is genetically determined, and patients with a slow acetylator phenotype
are at greater risk of developing DILE.

(875) hematologic abnormalities are common in SLE. The most common cause of anemia is chronic inflammation
(anemia of chronic disease; however, pancytopenia can also occur due to autoantibodies against blood cell antigens (ie,
type II hypersensitivity). Autoimmune hemolytic anemia in SLE is caused by IgG antibodies against erythrocytes;
manifestations include spherocytoiss, a positive direct Coombs test, and extravascular hemolysis. Antiplatelet antibodies
in SLE can cause thrombocytopenia resembling immune thrombocytopenic purpura. Leukopenia can also occur,
primarily due to antibody-mediated destruction fo neutrophils.

Lupus nephritis is caused by immune complex deposition (ie, type III hypersensitivity) in the mesangium, subendothelial
and/or subepithelial spaces. Histopathology is variable but diffuse proliferative glomerulonephritis (class IV) is the most
common pattern.

(11798) autoantibodies directed against nuclear components (anti-nuclear antibodies) are the most characteristic
feature of SLE. Autoantibody binding to self-antigens leads to the formation of circulating immune complexes that
deposit in various organs and cause complement activation. Active SLE is therefore characterized by consumption of
complement with reduced serum complement levels.

Antiphospholipid antibody syndrome (742)

Up to 30% of px with SLE have antiphospholipids antibodies, which can cause paradoxical aPTT prolongation and a false-
positive RPR/VDRL. Px with antiphospholipid antibodies are at risk for venous and arterial thromboembolism and
unexplained recurrent pregnancy loss.

Osteoporosis

(640) bone turnover is regulated by the ratio of OPG to RANK-L; bone turnoever increases when OPG is low and RANK-L
is high.

Estrogen maintains bone mass in premenopausal women by inducing the production of OPG by osteoblasts and stromal
cells. it also decreases the expression of RANK on osteoblast precursors. By contrast, the loss of estrogen effect (eg,
menopause, oophorectomy) increases the expression of RANK-L and decreases production of OPG. The decreased OPG
to RANK-L ratio leads to increased osteoclast activity and bone resorption. Denosumab is a monoclonal antibody used in
the t of postmenopausal osteoporiss. It works in a manner similar to OPG by binding RANK-L and blocking its interation
with RANK.

Medications associated with osteoporotic fractures (10930)

tx (11564)

Selective estrogen receptor modulators (1795)

(1773)

Medications associated with osteoporotic fractures (1773)

Medication Possible mechanism
Anticonvulsants that induce cytochrome P450 Increase vit D catabolism
(phenobarbital, phenytoin, carbamazepine)
Aromatase inh Decrease estrogen
Medoxyprogesterone
GnRH agonists Decrease testosterone & estrogen
Proton pump inh Decrease calcium absorption
Glucocorticoids Decrease bone formation

Bone tumor

Osteosarcoma (15636)

Osteosarcomas arise from a malignant mesenchimal stem cell that generates cartilage, bone, or fibrous tissue.
Therefore, the dx is confirmed when histopathology reveals neoplastic spindle-shaped stromal cells admixed with tumor
osteoid and thin trabeculae of bone.

VS. chondrosarcomas, characterized by neoplastic chondrocytes in a hyaline cartilage matrix, usually with small
calcifications.

VS. Ewing sarcoma, the second most common primary bone malignancy in young px, often arises in long bones and
causes progressive pain, swelling, and lytic bone lesions. However, histopathology reveals sheets of small, round, cells
separated by fibrous septae and patches of necrosis/hemorrhage; no osteoid or bone is produced.

VS. adenocarcinoma of the lung often metastasizes to bone. However, histology would show neoplastic glands lined with
mucin-producing cells

VS. osteoid osteoma is a small, benign, bone-forming tumor that typically occurs in adolescent boys. Histopathology
shows irregular patterns of woven bone lined by a single layer of benign-appearing osteoblasts. The presence of a large
lytic bone lesion and highly pleomorphic spindle-shaped tumor cells makes this dx unlikely.

Neurology and NET

Nerve conduction study (15612)

Measures the amplitude, velocity and latency of an electrical stimulus applied to an isolated nerve and can help
differentiate between demyelinating and axonal neuropathies:

- Demyelinating neuropathis are caused by dmg to the myelin sheath. Loss of insulation results in delayed
(blocked) nerve conduction velocity
- Axonal neuropathies are caused by dmg to the nerve axon. Loss of axon fibers results in reduced signal
amplitude

Example of demyelinating neuropathy:

- Demyelinating ulnar mononeuropathy: most common cause focal nerve compression (eg, compression of the
nulnar nerve at the elbow) results in nerve ischemia, leading to apoptosis of Schwann cells and localized
demyelination. In addition to sensory symptoms, px with ulnar neuropathy may also have weakness of the
 fourght and fifth digits, elbow pain, and worsening of symptoms with elbow or wrist flexion. Severe disease can
lead to wasting of the hand muscles and an ulnar claw deformity

CSF fluid analysis (908)

Internuclear ophthalmoplegia (12083)

- A disorder of conjugate horizontal gaze resulting from dmg to the heavily-myelinated fibers of the MLF. The MLF
is paired neural tract that mediates communication between CN III and CN VI nuclei, allowing for coordinated
horizontal eye movements
1. Initiated with activation of the frontal eye field in the cerebral cortex
2. Frontal eye field projects the contralateral paramedian pontine reticular formation
3. Sends efferents to the ipsilateral CN VI nucleus at the level of facial colliculus in the dorsal pons
4. CN VI nucleus projects to the ipsilateral lateral rectus muscle (abducts the eye) and contralateral medial rectus
subnucleus of CN III (adducts the eye) via de MLF

Unilateral MLF lesions can occur with lacunar stroke in the pontine artery distribution, although bilateral lesions are
classically seen in multiple sclerosis. Lesions to the left dorsal pons can disrupt the left MLF, resulting in impaoired
adduction of the ipsilateral (left) eye during right conjugate horizontal gaze. Px also develop diplopia and horizontal
nystagmus of the abducting (right) eye. Convergence and the pupillary light reflex are generally preserved.

VS. unilateral infarction of the primary visual cortex in the occipital lobe (Due to posterior cerebral artery occlusion)
typically results in contralateral homonymous hemianopsia with macular sparing as the macula receives collateral
circulation from the middle cerebral artery

VS. oculomotor nerve palsy (ipsilateral mydriasis, ptosis, “down and out” deviation of the eye) may occur with nerve
compression (eg, posterior communicating artery aneurysm) or microvascular nerve ischemia (eg, diabetes mellitus).
Nerve compression is more likely to cause mydriasis as parasympathetic fibers are situated on the periphery of the
oculomotor nerve.
VS. a lesion involving the right abducens nerve would result in impaired abduction of the right eye during rightward gaze
due to lateral rectus muscle palsy

VS. the right lateral geniculate nucleus is located in the thalamus and relays visual information to the ipsilateral primary
visual cortex. Dmg to this structure would result in a contralateral homonymous hemianopsia

VS. the superior colliculus controls vertical gaze. Dmg to the dorsal midbrain in the superior colliculus region causes
Parinaud syndrome (upward gaze palsy, absent pupillary light reflex, impaired convergence)

Trigeminal neuralgia

(1199)

Tic douloureux, a neuropathic disorder that typically px with episodic, severe, unilateral, electric shock-like pain in the
distribution of CN V (particularly V2 and V3). symptoms are often triggered by innocuous stimuli such as shaving or
washing the face. The first-line tx of trigeminal neuralgia is carbamazepine, a neuroleptic medication that inh neuronal
high frequency firing by reducing the ability of sodium channels to recover from inactivation.

Carbamazepine may cause the following important AE:

1. Bone marrow suppression, which may lead to anemia, agranulocytosis, and thrombocytopenia (complete blood
cell counts should be monitored periodically)
2. Syndrome of inappropriate ADH secretion leading to hyponatremia

(354) carbamazepine is the drug of choice

Inh neuronal high-frequency firing by reducing the ability of Na channels to recover from inactivation

Carbamazepine is a P450 inducer that increases the metabolism of many other medications

Amyotrophic lateral sclerosis (674)

Voluntary muscle activity is mediated by the corticospinal (pyramidal) tracts. First-order neurosn of these tracts are
located in the premotor and motor cortex of the frontal lobe (Brodmann areas 6 and 4, respectively). Their efferent
fibers descend through the internal capsule, midbrain, and pons and continue to form the pyramids on the anterior
aspect of the medulla. In the medulla, 90% of the fibers decussate (cross) to form the lateral corticospianl tract. Fibers
that do not decussate descend as the anterior corticospinal tract. The axons of both tracts synapse on the motor
neurons of the anterior horn (second-order neurons). Dmg ot the corticospinal tract is divided into the upper and lower
motor neuron lesions

UMN - Spastic paralysis

- Clasp-knife rigidity
- Hyperreflexia
- Babinski sign
- Anything above the anterior horn
LMN - Flaccid paralysis
- Hypotonia
- Hyporeflexia
- Muscle atrophy & fasciculations
- Dmg to the motor neurons of the anterior horn
Von Hippel Lindau syndrome (468)

- Is a rare, AD condition
- Characterized by the presence of capillary hemangioblastomas in the retina and/or cerebellu, as well as
congenital cysts and/or neoplasms in the kidney, liver and pancreas
- Px are also at increased risk for renal cell carcinoma, which can be bilateral

VS. von recklinghausen’s disease, NF1

- Inherited peripheral nervous system tumor syndrome

- Px develop neurofibromas, optic nerve gliomas, Lisch nodules (pigmented nodules of the iris) and café au lait
spots

VS. NF 2

- AD nervous system tumor syndrome

- Px commonly develop bilateral schwannomas and multiple meningiomas

VS. Sturge-Weber syndrome (encephalotrigeminal angiomatosis)

- Rare congenital neurocutaneous disorder characterized by the presence of cutaneous facial angiomas as well as
leptomeningeal angiomas
- Skin involvement typically overlies the ophthalmic V1 and maxillary V2 distributions of the trigeminal nerve
- Is associated with mental retardation, seizures, hemiplegia and skull radiopacities
- Skull xray may show “tram-track” calcifications

VS. Tuberous sclerosis

- Causes kidney, liver and pancreatic cysts, CNS involvement manifests not as angiomatous lesions, but as cortial
and subependymal hamartomas
- AD
- Also characterized by cutaneous angiofibromas (adenoma sebaceum), visceral cysts and a variety of other
hamarotmas, as well as renal angiomyolipomas and cardiac rhabdomyomas
- Clinically seizures are major complications

VS. Osler-Weber-Rendu syndrome

- Hereditary hemorrhagic telangiectasia

- AD
- Rupture of these may cause epistaxis, GI bleeding or hematuria

Brain abscess (14898)

Is a contained area of liquefactive necrosis with a surrounding inflammatory capsule and marked vasogenic edema. It
usually appears on imaging as a ring-enhancing lesion and often presents with headache, fever, and/or focal neurologic
findings (eg, seizure). Most cases are bacterial in origin (eg, viridian streptococcus, s. aureus) and stem from an
underlying adjacent or distant infection.

The number and location of lesions helps differentiate the likely underlying source, as follows:
 - Single abscess is usually due to the direct invasion of a contiguous infection. Px with otitis media that spread to
the mastoid air cells and then invaded the adjacent temporal lobe leading to temporal lobe abscess. In contrast,
frontal lobe abscess is generally due to direct spread of ethmoid or frontal sinusitis
- Multiple abscesses usually arise dueto hematogenous dissemination of a distant infection, most commonly the
heart (eg, endocarditis) or lungs (eg, abscess, empyema)

Migraine (15684)

Tx is divided into

- Abortive therapy: mild analgesics, triptans, antiemetics, ergotamines for acute symtpoms
- Preventive therapy: beta blockers, tricyclic antidepressants, anticonvulsants [topiramate, valproate]) to reduce
the frequency of headaches

Siryngomyelia

(503)

These cavities can enlarge over time and destroy adjacent portions of the spinal cord. The areas most commonly dmged
are the ventral white commissure and ventral horns.

The ventral white commissure is located just anterior to the grey commissure. It is the area of decussation for the fibers
of the lateral spinothalamic tract, which transmits pain and temperature sensation from peripheral receptors to the
somatosensory cortex. Its first-order neurons are located in the dorsal root ganglia, and its second-order neurons are
found in the dorsal horn. The axons of the second order neurons decussate in the ventral white commissure and ascend
in the contralateral lateral funiculus. Third-order neurons are located in the ventral posterolateral nucleus of the
thalamus. Fourth-order neurons are found in the primary somatosensory cortex in a parietal lobe.

Destruction of the ventral white commissure leads to loss of pain and temperature sensation bilaterally over the
affected dermatomes (starting 1 to 2 levels below the lesion, as first-order axons briefly ascend in the zone of Lissauer
before synapsying). Touch, vibration and position senses are preserved when the syrinx is small enough to affect only
the ventral white commissure.

(1904)

Chronic loss of upper extremity pain and temp sensations, upper extremity weakness and hyporeflexia, lower extremity
weakness and hyperreflexia and kyphoscoliosis.

In syringomyelia, a central cystic dilation in the cervical spinal cord (a syrinx) slowly enlarges, characteristically causing
dmg to the ventral white commissure and anterior horns. The ventral white commissure is the site of decussation of
second-order lateral spinothalamic tract neurons, and the ventral horns are the site of lower motor neuron cell bodies.
The syrinx is most commonly situatied at the C8-T1 cord levels and may extend rostrally, caudally, and centrifugally.
Further expansion within the cervical cord in later stages of the disease can produce lower extremity weakness and
hyperreflexia (an upper motor neuron defect) by affecting the lateral corticospinal tract and can also lead to loss of
position and vibration senses in the feet due to involvement of posterior columns. Scoliosis can occur due to paresis of
paravertebral muscles.

Hemiballismus (635)
The subthalamic nucleus is a lens-shaped structure located ventral (inferior) to the thalamus, dorsal (superior) to the
substantia nigra, and medial to the internal capsule. It is a component of the basal ganglia and plays an important role in
the modulation of basal ganglia output.

Dmg to the subthalamic nucleus can decrease excitation of the globus pallidus internus, thereby reducing inh of the
thalamus. This may result in contralateral hemiballism, a movement disorder characterized by wild, involuntary, large-
amplitude, flinging movements involving the proximal limbs (eg, arm and/or leg) on one side of the body. This most
commonly cocurs in the setting of lacunar stroke, which is often a consequence of long-standing HTA and DM

Brain tumors

Pilocytic astrocytomas (615)

Pilocytic astrocytomas are low-grade gliomas that occur most frequently in the cerebellum. Px typically have headaches
and cerebellar findings (eg, loss of balance, incoordination). Is a well demarcated lesion comprised of cystic and solid
components. Microscopic examination shows pilocytic astrocytes with bundles of glial fibrillary acidic protein (GFAP)-
positive hairlike processes and classic Rosenthal fibers (eosinophilic intracytoplasmic inclusions). Due to the slow-
growing (benign) nature, the majority of px can be tx with surgical resection and have a favorable prognosis.

Pilocytic astrocytomas are the most common brain tumors in children. They frequently arise in the cerebellum and can
be differentiated from medulloblastomas by the presence of both cystic and solid components on imaging.

Pineal gland mass (1261)

- Obstructive hydrocephalus from aqueductal stenosis (papilledema, headache, and vomiting)

- Dorsal midbrain (Parinaud) syndrome due to direct compression fo the pretetal region of the midbrain
- Parinaud syndrome -> upward gaze with a downward gaze preference, bilateral eyelid retraction (Eg, Collier
sign, sclera visible above the superior corneal limbus), and light-near dissociation (Eg, pupils that react to
accommodation but not to light)
- Most common pineal mass is germinoma, a midline malignant tumor thought to arise from embryonic germ cells
- Germinoma can arise in the gonads or mediastinum and is more common in young boys
- Most common locations for intracranial germinomas are the pineal gland and the suprasellar region (less
common)
- Due to their proximity to the pituitary gland and hypothalamus, suprasellar germinomas do not lead to Parinaud
syndrome, but they are more likely to present with endocrinopathies (eg, central precocious puberty, diabetes
insipidus

(880)

Synaptophysin is a transmemebrane glycoprotein found in the presynaptic vesicles of neurons, neuroectodermal

andneuroendocrine cells. Immunereactivity of a CNS tumor for synaptophysin indicates a neuronal origin. Such
neoplasms are rare and compose less than 1% of CNS tumors. The majority of primary CNS tumors in adults are of glial
origin, meningiomas and pituitary adenomas are the next most common. Primary tumors in adults tend to be
supratentorial while those in children tend to lie below the tentorium. Metastatic disease to the CNS occurs more
commonly than primary CNS tumors.

Unlike tumors of neuronal origin, gliomas stain positively for glial fibrillary acidic protein (GFAP). Immunoreactivity for
GFAP is characteristic for astrocytomas including glioblastom multiforme, oligodendrogliomas, ependymomas and
peripheral neural sheath tumors.
Craniopharyngiomas (1152)
craniopharyngiomas are suprasellar tumors found in children and composed of calcified cysts containing cholesterol
crystals. They arise from remnats of Rathke’s pouch, an embryionic precursor of the anterior pituitary

(221) craniopharyngiomas are tumors arising from remnants of Rathke’s pouch. The anterior pituitary is formed from an
out-pouching of the pharyngeal roof and is called Rathke’s pouch. The posterior pituitary gland arises from an extension
of the hypothalamic neruons. Together, the anterior and posterior pituitary glands lie in the sella turcica at the skull
base. During the time of pituitary development, remnants of Rathke’s pouch cells can remain in the diencephalon (the
posterior region of the forebrain). Neoplastic transformation of these “pouch cells” is called a craniopharyngioma.
Typically, craniopharyngiomas have three components: solid, comprised of the actual tumor cells; cystic, filled with
“machinery oil” liquid; and a calcified component. Any suprasellar mass with three compontents is highly suggestive of
craniopharyngioma. Craniopharyngioma symptoms include headahes, visual field defects, and hypopituitarism,
eveidenced by the growth retardation of this child. Ultimately, compression of the pituitary stalk by craniopharyngioma
leads to hyperprolactinemia by loss of dopaminergic inh. Craniopharyngiomas are usually tumors of childhood, being
most frequently discovered between the age of 5 and 10

Meningioma (1150)

Meningiomas are common adult intracranial tumors that typically arise in regions of dural reflection (eg, falx cerebri,
tentorium cerebelli). Lesions involving the primary somatosensory cortex typically result in contralateral sensory loss,
whereas dmg to the parietal association cortex (particularly in the nondominant hemisphere) may cause contralateral
hemineglect due to impaired visuospatial processing.

(1151) are slow-growing, well-circumscribed, benign intracranial tumors typically found at the cerebral convexities in
adults. Characteristic histopathologic features include a whorled pattern of growth that forms nests, which may calcify
into round, eosinophilic laminar structures called psammoma bodies

*other tumors that forms psammoma bodies include: papillary thyroid carcinoma, mesothelioma and papillary serous
carcinoma of the ovary and endometrium
VS. adamantinomatous craniopharyngiomas most often present as benign suprasellar tumors in children and appear as
cords/nests of palisading squamous epithelium with internal areas of lamellar “wet”keratin under light microscopy

VS. ependymomas typically present as paraventricular tumors (eg, floor of the fourth ventricle) and have characteristic
perivascular rosettes under light microscopy

VS. glioblastomas are the most common primary malignant brain tumor in adults. They are often located in the cerebral
hemispheres and may cross the corpus callosum (“butterfly glioma”). Light microscopy shows hypercellular areas of
atypical astrocytes bordering regions of necrosis (pseudo-palisading)
VS. Medulloblastomas are malignant cerebellar tumors that typically occur in children and are characterized by small
blue cellst that may surround neuropil, forming Homr-Wright rosettes under light microscopy

VS. oligodendrogliomas typically involve the white matter of the cerebral hemispheres and tumor cells have a “fried egg”
appearance (round nuclei surrounded by a halo of clear cytoplasm) under light microscopy
VS. pilocytic astrocytomas are usually benign tumors that involve the cerebellum in children and young adults. Tumor
cells typically have eosinophilic granular bodies and elongated hairlike processes (Rosenthal fibers) under light
microscopy

VS. schannomas are mostly benign tumors that commonly arise from the vestibular branch of CNVIII at the
cerebellopontine angle. Light microscopy typically shows spindle cells with palisading nuclei arranged around Verocay
bodies composed of eosinophilic cores.
Glioblastoma

Glioblastoma multiforme (614)

Criteria Description
Age of onset 40-70 yo
Cell of origin Astrocyte
Location - Frontal & temporal lobes, basal ganglia
- Commonly crosses the midline (butterfly distribution)
Macroscopic appearance - Areas of necrosis & hemorrhage (variegated appearance, thus termed multiforme)
- Poorly demarcated from the surrounding tissue
Microscopic appearance - Pseudopalisading necrosis (foci of necrosis surrounded by tumor cells)
- New vessel formation
- Small round cells, bizarre giant cells, large number of mitoses
Symptoms - Headache, seizure, mental status change, focal neurologic symptoms
Prognosis - Highly malignant
- Px usually die within 1 to 2 years of dx

(15659)

A number of characteristic oncogenic mutations are usually present in GBM, but >95% of cases are associated with the
overexpression of epidermal growth factor receptor (EGFR) on the surface of neoplastic cells.

EGFR is a tyrosine-kinase signal transduction system that conducts external growth signals into the nucleus, thereby
promoting cellular survival and proliferation. Mutations that enhance this pathway (eg, overexpression of EGFR or EGFR-
ligand) are associated with uncontrolled cellular proliferation and are seen in GBM and other cancer types (eg, non-cell
lung cancer, breast cancer, prostate cancer). Therefore, drugs that inh the EGFR/EGFR-ligand interaction (eg, erlotinib)
are often used as part of tx

Cerebellar tumor (11995)

The cerebellar hemispheres are primarily responsible for motor planning and coordination of the ipsilateral extremities
via their connections with the lateral descending motor systems (eg, lateral corticospinal tract, rubropsinal tract).
Consequently, lesions affecting the left cerebellar hemisphere typically result in left dysdiadochokinesia (impaired rapid
alternating movements), limb dysmetria (overshoot/undershoot during targeted movement), and intention tremor
(tremor during targeted movement)

Neuronal physiology

(1922)

Kinesin is a microtubule-associated motor protein that functions in the anterograde transport of materials and
organelles within cells. Reactivation of latent herpes simplex virus requires anterograde transport of viral particles from
neuronal cell bodies in the sensory ganglia to the skin and oral mucosa.

(1936)

Kinesin is a microtubule-associated, ATP-powered motor protein that facilitates the anterograde transport of
neurotransmitter-containing secretory vesicles down axons to synaptic terminals.

Neuronal injury (492)

(494)

Wallerian degeneration:

1- Swelling and irregularity are noted in the distal segment of the axon
2- Within a week the axon is destroyed and its fragments are digested by schwann cells and macrophages

Axonal reaction (changes seen in the neuronal body after the axon is severed):

- The cell body shows signs of cellular edema

- It becomes swollen and rounded, with the nucleus displaced to the periphery
- Nissl substance becomes fine, granular and dispersed throughout the cytoplasm (central chromatolysis)
- Becomes visible in 24-48 hrs
- Maximal changes in the neuronal body occur approximately 12 days after the injury
Vs. irreversible injury

Manifests with

- Shrinkage of the neuronal body

- Deep eosinophilia of the cytoplasm
- Pyknosis of the nucleus and loss of Nissl substance

(11576) Wallerian degeneration refers to the process of axonal degeneration and breakdown of the myelin sheath that
occurs distal to a site of injury. Axonal regeneration does not occur in the central nevous system due to the persistence
of myelin debris, secretion of neuronal inhibitory factors, and development of dense glial scarring.

Hypothalamic nuclei Major functions

Ventromedial Mediates satiety; destruction leads to hyperphagia
Lateral Mediates hunger; destruction leads to anorexia
Anterior Mediates heat dissipation; destruction leads to hyperthermia
Posterior Mediates heat conservation; destruction leads to hypothermia
Arcuate Secretion of dopamine (inh prolactin), GHRH & Gonadotropin-releasing hormone
Paraventricular Antidiuretic hormone, corticotropin-releasing hormone, oxytocin & thyrotropin-releasing
hormone secretion
Supraoptic Secretion of antidiuretic hormone & oxytocin
Suprachiasmatic Cicardian rhythm regulation & pineal gland function

Neuroblastoma (1263)
Pathogenesis - Neural crest origin
- Involves adrenal medulla, sympathetic chain
Clinical features - Median age <2
- Abd mass
- Periorbital ecchymoses (orbital metastases)
- Spinal cord compression from epidural invasion
(“dumbbell tumor”)
- Opsoclonus-myoclonus syndrome
Diagnostic findings - Elevated catecholamine metabolites
- Small, round blue cells on histology
- N-myc gene amplification

NMJ (1934)

Acetylcholine release from presynaptic terminal vesicles at the neuromuscular junction depends upon the influx of
extracellular calcium into the presynaptic terminal. Calcium influx into the nerve terminal occurs following neuronal
depolarization and opening of voltage-gated calcium channels.

Central pontine myelinolysis (915)

Ectopic ADH production -> chronic hyponatremia -> decreased serum tonicity causes water to cross the BBB -> enters
CNS -> in response to cellular swelling -> brain cells excrete osmolytes (organic solutes [glutamate, myoinositol],
electrolytes) -> intrallceular water loss and normalization of brain volume

Overly rapid correction -> osmotic demyelination syndrome

Rapid increase in extracellular tonicity -> quickly draws water out of CNS cells -> uncontrolled cell shrinkage ->
degeneration of astrocytes (crucial for myelin maintenance) and oligodendrocytes

Demyelination typically affects the pons, but can also occur at extrapontine sites (eg, basal ganglia and cerebral white
matter)

Clinical features: (apparent within 2-6 days)

- Spastic quadriplegia (corticospinal tract involvement)

- Pseudobulbar palsy (dysphagia, dysarthria, tongue paresis)
- Px with involvement of bilateral pons -> locked in syndrome (with near-total paralysis and aphasia but with
intact cognitive abilities, blinking and vertical eye movements)

Spinal muscular atrophy (2036)

- Caused by mutations in the survival motor neuron (SMN1) gene, which encodes a protein involved in assembly
of small nuclear ribonucleoproteins (snRNPs) in LMN
- Defective snRNP assembly results in impaired spliceosome fx and degeneration of anterior horn cells in the
spinal cord
- RNA molecules that carry out fx without first being translated into proteins are called non-coding RNAs
- These include small nuclear RNA (snRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA)
- snRNA is transcribed by RNA polymerase II and associates with specific proteins to form snRNPs
- a collection of snRNPs and other proteins on pre-mRNA is referred to as a spliceosome
- spliceosomes remove introns from pre-mRNA by cleaving the 5’ end of intron 1 (splice donor site) and joining
that end to the branch point. The freed 3’-OH of exon 1 then forms a phosphodiester bond with the 5’-
phosphate at the splice acceptor site, joining exons 1 and 2

Malignant hyperthermia (855)

Is a syndrome that occurs due to hypersensitivity of skeletal muscles to inhalation anesthetics (especially halothane) and
muscle relaxant succinylcholine. Susceptibility to malignant hyperthermia is inherited as an AD trait. In the majority of
cases it is realted to the defect on ryanodine receptors of sarcoplasmic reticulum. Ryanodine receptor is located on the
surface of the sarcoplasmic reticulum of skeletal muscles and is a calcium channel. It releases small amounts of calcium
in the cytoplasm of the muscle fiber during muscle contraction. Abnormal rynadoine receptors release large amounts of
Ca after exposure to anesthetic. Excess of free Ca in the cytoplasm of muscle fibers stimulates its ATP-dependent
reuptake by sarcoplasmic reticulum. Excessive consumption of ATP generates heat; loss of ATP along with high
temperature induces muscle dmg. Rhabdomyolysis leads to release of potassium, myoglobin and creatine kinase into
circulation.

Tx: dantrolene is a muscle relaxant, acts on ryanodine receptor and prevents further release of Ca into the cytoplasm of
muscle fibers.

Epistaxis (11783)

May be classified as anterior or posterior, depending on the bleeding source. Anterior nosebleeds are by far the most
common, and the vast majority occur within the vascular watershed area of the nasal septum (anteroinferior part of the
nasal septal mucosa) known as Kiesselbach plexus. Anastomosis of the following vessels occurs in this region:

- Septal branch of the anterior ethmoidal artery

- Lateral nasal branch of the sphenopalatine artery
 - Septal branch of the superior labial artery (branch of the facial artery)

Raphe nuclei (1834)

Serotonin-releasing neurons in the CNS are located in the raphe nuclei. These neurons disseminate widely to synapse on
numerous structures in the CNS. Antidepressants such as selective serotonin reuptake, serotonin-noropinephrine
reuptake inh, and tricyclic antidepressants inh serotonin reuptake at these synapses.

Headaches (1962)

Cavernous sinus thrombosis (12029)

Is most commonly due to contiguous spread of an infection from the medial third of the face, sinuses (ethmoidal or
sphenoidal), or teeth. The infection can communicate in a retrograde fashion into the cavernous sinus through the
valveless facial venous system (via the superior and inferior ophthalmic veins). Common pathogens include s. aureus
(most common) and streptococci, although fungal organism (Eg, Mucor, Rhizopus) are responsible in rare cases.

Px typically experience headache, fever and diplopia. Ocular muscle paralysis occurs due to injury of CN III, IV, and VI. CN
III palsy may also result inptosis and mydriasis. Involvement of the ophthalmic and maxillary branches of CN V can cause
loss of both upper facial sensation and the afferent limb of the corneal reflex. Proptosis (eye protrusion) and chemosis
(conjunctival swelling) may also be evident due to impaired venous drainage through the ophthalmic veins.

Hyperhidrosis (6565)

Systemic anticholinergic medications (eg, oxybutynin), local anticholinergic injectable medications (eg, botulinum toxin),
or surgical sympathetctomy may be used to tx hyperhidrosis. Surgical sympathectomy for primary focal hyperhidrosis of
the axilla uses electrocoagulation to target the thoracic sympathetic trunk at the T2 sympathetic segment.

Ataxia telangiectasia (673)

Is an AR disorder. Cerebellar atrophy leads to the ataxia that occurs in the first years of life. (Oculocutaneous
telangiectasia is another manifestation, but is usually delayed. Telangiectasias are abnormal dilations of capillary
vessels.) Px with ataxia-telangiectasia also have severe immunodeficiency with repeated sinopulmonary infections. The
risk of cancer in these px is increased significantly because of inefficient DNA repair.
(587) also predisposes to an increased risk of hematologic malignancies and causes an immune deficiency consisting of
both cell-mediated and humoral dysfunction. The immune deficiency primarily manifests as an IgA deficiency and
predisposes to infections of the upper and lower airways

It is an AR condition that occurs due to mutation of ATM gene. ATM gene is responsible for DNA break repair. DNA in px
with ataxia-telangiectasia is hypersensitive to X-ray radiation that causes multiple chromosomal breaks

Anticholinergic toxicity (1321)

Anticholinergic toxicity
Symptom Mechanism
“hot as a hare” ↓ sweating leads to ↓ heat dissipation
↑ body temperature
“Dry as a bone” ↓Glandular secretion & smooth muscle contraction
↓ secretions (eg, mucous membranes, sweat glands)
“Red as a beet” Superficial vasodilation from ↑ body heat
Flushed skin
“blind as a bat” Paralysis of ciliary muscle & iris sphincter
Cyclopegia, mydriasis
“mad as a hatter” Permeates blood-brain barrier & affects CNS pathways
Altered mental status
“full as a flask” ↓intestinal smooth muscle contraction
Urinary retention ↓detrusor contraction & ↓ internal urethral sphincter
Constipation relaxation
“fast as a fiddle” ↓vagal tone at the sinoatrial node
Tachycardia

(1868) anticholinergic toxicity is associated with numerous OTC (eg, antihistamines, sleep aids, cold preparations) and
prescription medications. TCAs are commonly implicated, particularly ones with strong anticholinergic properites such as
amitriptyline. When taken in excess, TCAs can also increase QRS duration, causes arrhythmias and precipitate seizures.

Organophosphate poisoning (1998)

Organophosphates are cholinesterase inh that are widely used as pesticides in agriculture. They inh the breakdown of
acetylcholine, leading to a state of cholinergic excess. Symptoms of organophosphate poisoning include salivation,
lacrimation, diaphoresis, bradycardia, and bronchospasm.

Myasthenia gravis

(749) MG is caused by circulating antibodies directed against ACh receptors of the NMJ. Autoantibody binding leads to
receptor degradation, producing fluctuating weakness that worsens over the course of the day and most commonly
affects the extraocular muscles (eg, ptosis, diplopia). Most px also have thymic abnormalities (eg, thymoma)

VS. Lambert-Eaton syndrome is due to autoantibodies directed against the presynaptic calcium channel, which cuases
reduced ACh release. Px usually have proximal extremity weakness that improves with muscle use, as opposed to the
fatigable weakness of the extraocular and bulbar muscles common in MG. Lambert-Eaton syndrome commonly occurs in
px with small cell lung cancer

(756)
Myasthenia gravis is associated with abnormalities of the thymus (eg, thymoma, thymic hyperplasia). The thymus and
inferior parathyroid glands arise from the 3 rd pharyngeal pouch.

(6554)

Autoimmune disorder caused by an autoantibody-mediated attack on the acetylcholine receptors of the postsynaptic
NMJ -> reduced number of ACh receptors.

VS. Lambert-Eaton -> due to autoantibodies directed against the voltage-gated calcium channels on presynaptic nerve
terminals, leading to reduced calcium entry and impaired ACh release. Associated with malignancy (small cell lung
cancer, typically young female). Causes proximal extremity weakness that is worse in the mornings and improves with
repetition. Autonomic findings (eg, dry mouth, erectile dysfunction in males)

VS. botulinum toxin: irreversibly blocks ACh release from presynaptic membranes of NMJ. Presents ptosis and facial
weakness, symmetric descending weakness and respiratory failure.

(2061) causes decrease in the number of functional ACh receptors within the NMJ. This reduces the number of
postsynaptic cation channels that can open in response to ACh, which reduces the amplitude of motor end plate
potential and prevents muscle fiber depolarization.

(2062) the tx of MG involves the use of cholinesterase inh, immunosuppressants and possible thymectomy.
Cholinesterase inh may cause adverse effects related to muscarinic overstimulation, which can be ameliorated by the
use of an antimuscarinic agent such as glycopyrrolate, hyoscyamine, or propantheline

(14850) MG is caused by autoantibodies against postsynaptic nicotinic ACh receptrs, leading to fewere functional AChRs
and fatigable muscle weakness. Nondepolarizing neuromuscular blocking agents (eg, vecuronium) are competitive
antagonists of AChRs; due to the depletion of receptors, px with MG are extremely sensitive to these agents and very
small doses can induce paralysis and impair airway protection.

Seizures (12175)

Seizure type Description Preferred anticonvulsants

Focal (involves 1 cerebral hemisphere at onset)
Simple - No loss of consciousness or postictal state Narrow spectrum:
- Motor, sensory, autonomic, or psychic symptoms - Carbamazepine
Complex - Loss of consciousness & postictal state - Gabapentin
- May have automatisms (eg, lip smacking) - Phenobarbital
- Phenytoin
Generalized (involves both hemispheres at onset)
Tonic-clonic - Loss of consciousness & postictal state Broad spectrum:
- Diffuse muscle contraction of limps (tonic) followed by - Lamotrigine
rhythmic jerking (clonic) - Levetiracetam
Myoclonic - No loss of consciousness of postictal state - Topiramate
- Brief jerking movements - Valproic acid
Absence - Brief loss of consciousness (eg, blank stare) Ethosuximide
- May have automatisms
- Usually no postictal state

Mechanism of antiseizures (509)

Phenytoin Blocks Na+ channels
Carbamazepine
Valproic acid Blocks Na+ channels & increase GABA levels
Benzodiazepine Increase GABAA action
Phenobarbital
Levetiracetam Modulates GAB & glutamate release
Ethosuximide Blocks thalamic T-type Ca2+ channels

Phenytoin (353)

IV lorazepam is a benzo that potentiates the effects of the inh neurotransmitter GABA in the CNS. Is the initial drug of
choice for tx for status epilepticus due to its efficacy and rapid onset of action. IV phenytoin (or fosphenytoin) is a long-
acting anticonvulsant that is admn concurrently to prevent the recurrence of seizure activity, regardless of px
responsiveness to lorazepam. Phenytoin inh neuronal high-frequency firing in the cortex by reducing the ability fo Na+
channels to recover from inactivation

Benzos (11665)

Are intial drug of choice for status epilepticus. They work by enhancing the effect of GABA at the GABA-A receptor,
leading to increased chloride influx and suppression of action potential firing.

Vs. gabapentin is an anticonvulsant that works by blocking voltage-gated calcium channels, thereby attenuating
excitatory neurotransmitter release.

Vs. phenytoin, blocks presynaptic voltage-gated sodium channels and can be used to prevent recurrence of status
epilepticus due to its long duration of action

(6479) slower benzo metabolism and elimination in the elderly increase the likelihood of adverse effects such as
confusion, anterograde amnesia, ataxia and falls.

Benzos are metabolized in the liver and then excreted in the urine. Most benzos are metabolized via CYP-mediated
hepatic oxidative reduction (phase I) followed by glucuronide conjugation (phase II). Elderly individuals have reduced
oxidative reduction, resulting in slower elimination of many drugs metabolized by the liver. However, certain benzos
(lorazepam, oxazepam, temazepam) undergo only glucuronide conjugation, which tends to be relatively preserved in the
elderly and those with liver disease. In addition, elderly individuals have an increased volume of distribution of lipid
soluble drugs (decreased total body water and mass; increased body fat) as well as decreased renal function, which also
contribute to prolonged with liver disease.

(13907) benzo withdrawal

Characterized by rebound anxiety, tremor, insomnia and sympathetic hyperactivity (eg, diaphoresis, palpitations). In
severe cases, psychotic symptoms (eg, hallucinations, delusions), seizures and even death may occur. Risk of withdrawal
is greatest with short-acting agents (Eg, alprazolam), prolonged use and use of higher doses.

Lamotrigine (356)

Tx partial and generalized sizures and works by blocking voltage-gated sodium channels. Stevens-Johnson syndrome and
toxic epidermal necrolysis are rare, life-threatening adverse effects characterized by flu-like symptoms followed by
widespread mucocutaneous epidermal necrosis.

Phenytoin (1197)

Adverse effects:
 1. Phenytoin toxicity is mainly characterized by CNS manifestations. Its effect on the cerebellum and vestibular
system can cause ataxia and nystagmus
2. Long-term therapy with phenytoin may cause gingival hyperplasia, coarsening of the facial features, and
hisurtism
3. Phenytoin interferes with the metabolism of folic acid and may cause megaloblastic anemia
4. Phenytoin induces the P450 cytochrome oxidase system. It increases the metabolism - and therefore decreases
the blood level - of many meidcations
5. If taken during pregnancy, phenytoin may cause fetal hydanoin syndrome

Dystonia (634)

Dystonia is a syndrome of prolonged, repetitive muscle contractions. This condition may be the result of impaired
function of the basal ganglia. Cervical dystonia (spasmodic torticollis), blepharospasm, and writer’s cramp are the most
common types of focal dystonia.

Intraventricular hemorrhage (8564)

Neonatal intraventricular hemorrhage usually occurs in the fragile germinal matrix and increases in frequency with
decreasing age and birth weight. It is a common complication of prematurity that can lead to long-term
neurodevelopmental impairment. It occurs most frequently in infants born before 32 weeks and/or with birth weight
<1500 g, and almost always occurs within the first 5 postnatal days. Can be clinically silent or present with an altered
level of consciousness, hypotonia and decreased spontaneous movements. Symptoms of catastrophic bleeding include a
bulging anterior fontanelle, hypotension, decerebrate posturing, tonic-clonic seizures, irregular respirations and coma.

Essential tremor (2000)

ET is a common movement disorder, and beta blockers are often used as first-line therapy for debilitating or distressful
symptoms. beta blockers prevent the interaction of epinephrine and norepinephrine with receptors at adrenergic
synapses; in ET, this is thought to help dampen the sensitivity of muscle spindles, which improves tremor symptoms by
smoothing out the force of contraction

Propranolol, the most commonly used medication for tx of ET, is a nonselective beta blocker (ie, inh both beta-1 and
beta-2 receptors). In px with reactive airway disesase (eg, asthma, chronic obstructive pulmonary disease), inhibition of
beta-2 receptors can cause bronchoconstriction with resultant asthma symptoms. Selective beta-1 blockers are often
better tolerated in px with asthma; however, selectivity is does-dependent and px can develop bronchoconstriction at
high doses.

(1946) px commonly report that their symptoms improve with alcohol consumption. Propranolol is the first-line tx for
essential tremor. This nonselective beta-adrenergic antagonist is thought to lessen the tremor via CNS effects.

Wernicke korsakoff (63)

Oculomotor dysfunction, ataxia, and confusion form the triad of Wernicke syndrome. Most of these symptoms usually
resolve after thiamine admn. Korsakoff syndrome is a complication of Wernicke encephalopathy, the hallmarks of which
are permanent memory loss and confabulation

(598) Thiamine (vit B1) participates in glucose metabolism and is a cofactor for the following enzymes:

1. Pyruvate DHA, which converts pyruvate (glycolysis end product) into acetyl-CoA (enters the citric acid cycle
2. Alphaketoglutarate DHA, enzyme of the citric acid cycle
 3. Branched chain alpha keto-acid DHA, which is essential for catabolism of branched chain aa (eg, leucine,
isoleucine, valine)
4. Transkelotase: enzyme of the pentose phosphate pathway that helps convert ribulose 5-P (derived from
glucose) to glycolysis intermediates (eg, glycerldehyde 3-p)

(1021) Thiamine is necessary cofactor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and
transkelotase. Admn of glucose to thamine-deficient px can cause rapid depletion of the small amount of thiamine
remaining in the circulation. This can result in neuronal injury within highly metabolic brain regions, leading to acute
Wernicke encephalopathy

ALS (675)

Criteria Description
Macroscopic - Thin anterior roots
- Mild atrophy of the precentral gyrus
Microscopic - Loss of neurons in the anterior horn (LMN lesion)
- Degeneration and atrophy of lateral corticospinal
tracts (UMN lesion)
- Loss of neurons in the motor nuclei of CN V, IX, X,
XII
- Muscle: denervation atrophy (small angular fibers)
Clinical - LMN symptoms: muscle weakness, atrophy and
fasciculation
- UMN symptoms: spasticity, hyperreflexia, and
pathologic reflexes
Genetic - Mutation of the gene that codes for copper-zinc
superoxide dismutase (SOD1) may be implicated
TX - Riluzole
- MOA: decreases glutamate release

Brain tumors

Schwannomas (1304)

Schwannomas present histologically with a biphasic pattern of cellularity (Antoni A and B areas) and S-100 positivity
(indicating neural crest origin). Schwannomas can arise from the peripheral nerve,s nerve roots and cranial nerves
(except CN II). Acoustic neuromas are the most common type of intracrinal schwannoma and are located at the
cerebellopontine angle at CN VIII.

Juvenile pilocytic astrocytomas (1153)

Usually arise in the cerebellum, brainstem, hypothalamic region, or optic pathways. Microscopically, pilocytic
astrocytomas are well-differentiated neoplasms comprised of spindle cells with hair-like glial processes that are
associated with microcysts. These cells are mixed with Rosenthal fibers and granular eosinophilic bodies.

Vs. glioblastomas

Occur most often in the subcortical white matter of the cerebral hemispheres. When a tumor in the frontal cortex
spreads across the corpus callosum into the contralateral hemisphere, it creates the appearance of a bilateral
symmetrical lesion, hence the term “butterfly glioma.” GBMs are composed of poorly-differentiated, often-pleomorphic
astrocytic cells with marked nuclear atypia and brisk mitotic activity. Necrosis is an essential dx ft and prominent
microvascular proliferation is common

Vs. medulloblastoma (primitive neuroectodermal tumor, or PNET) is the second most common posterior fossa tumor in
children. On microscopic examination, cells are small and poorly differentiated, with scant cytoplasm and little stroma. A
high mitotic index is common. Classic Homer-Wright rosettes can be seen in one fifth of cases

Vs. ependymomas account for 10% of posterior fossa tumors in children. Intracranial lesions usually occur
infratentorially, arising from the roof of the fourght ventricle in children while spinal ependymomas typically occur in
adults. Histologically, ependymal pseudorosettes with glial fibrillary acidic protein (GFAP) - positive processes tapering
toward blood vessels characterize ependymomas

Vs. neuroblastomas are the most common extracranial solid tumors occurring in children. Undifferentiated
neuroblastomas are small, round, blue-cell tumors. A neuritic process also called neuropil, is a pathognomonic feature of
neuroblastoma cells. NSE, chromogranin, synaptophysin and S-100 immunohistochemical stains are usually positive.
More than 90% of px have elevated urinary levels of homovanillic acid (HVA) and/or vanillylmandelic acid (VMA). The
most important biologic marker is MYCN (N-MYC) of chromosome 2

Appendicitis (11769)

The iliohypogastric nerve provides sensation to the suprapubic and gluteal regions and motor fx to the anterolateral abd
wal muscles. Abd surgery (eg, appendectomy) can dmg the nerve and cause decreased sensation and/or burning pain at
the suprapubic region.

Mushroom poisoning (1361)

Muscarine, a mushroom toxin, acts as muscarinic agonist in place of acetylcholine, resulting in an increase in
parasympathetic nervous system activity. The M2 and M3 subtype receptors are responsible for most of the toxicities.

Activation of M3 receptors -> promotes synthesis of NO -> NO diffuses into vascular smooth muscle cells -> activates
guanylate cyclase -> increases intracellular cyclic-GMP -> activates myosin light chain phosphatase -> prevents
interaction of myosin head with actin -> smooth muscle relaxation and vasodilation

Vs. activation M3 receptors in other sites leads to a G-protein-coupled increase in intracellular calcium -> smooth muscle
contraction

(8483) Amatoxins are found in a variety of poisonous smushrooms eg, amanita phalloides, known as death cap) and are
potent inhibitors of RNA polymerase II (halting mRNA synthesis) resulting in apoptosis within liver cells. Also other organ
systems with rapid cellular turnover can also be affected in amatoxin poisoning, including the GI tract and proximal
convoluted renal tubules.

Symptoms typically starts 6-24 hrs after:

- Abd pain
- Vomiting
- Severe
- Cholera-like diarrhea (may contain blood and mucus)
- Severe poisoning can lead to acute hepatic and renal failure
Urine testing for alpha-amanitin can confirm suspected amatoxin poisoning

Vs. ricin (from the castor oil plant Ricinus communis) is a potent toxin that inh protein synthesis by cleaving the rRNA
component of the eukaryotic 60S subunit

Brain herniation

(495) transtentorial (ie, uncal) herniation occurs when the medial temporal lobe (ie, uncus) herniates through the gap
between the crus cerebri and the tentorium. In subfalcine herniation, the cingulate gyrus herniates under the falx
cerebri, potentially compressing the anterior cerebral artery. In tonsillar herniation, the cerebellar tonsils displace
through the foramen magnum and compress the medulla.

The most common cause of transtentorial herniation is an ipsilateral mass lesion (eg, brain tumor, subdural or epidural
hematoma, and intracerebral hemorrhage). This mass causes an increase in supratentorial pressure on the side of the
lsion and forces the ipsilateral parahippocampal uncus through the tentorial incisures. As a result, the following
structures may become compressed:

1. Ipsilateral CNIII compression leads to a fixed and dilated pupil on the side of compression. Paralysis of the
oculomotor muscles occurs later and leads to ptosis and a “down-and-out” position of the ipsilateral eye
2. Ipsilateral posterior cerebral artery compression leads to contralateral homonymous hemianopsia with macular
sparing
3. Compression of the contralateral cerebral peduncle against the tentorium may occur. The dmg to the
contralateral corticospinal tract leads to ipsilateral hemiparesis. Compression of the ipsilateral cerebral peduncle
can also cause contralateral hemiparesis
4. Brainstem hemorrhages (ie, Duret hemorrhages) may occur in the pons and midbrain due to stretching and
rupture of the basilary artery. This is usually fatal.

(11804)

Expanding space occupying lesions within the temporal lobe can cause elevated intracranial pressure with transtentorial
herniation of the uncus. Uncal herniation often compresses the ipsilateral third cranial nerve as it exits the midbrain,
resulting in oculomotor nerve palsy with a fixed dialted pupil (eg, due to preganglionic parasympathetic fiber dmg)

Anoxic brain injury (12119)

The upper midbrain contains neural structures (eg, optic nerve, pretectal nuclei, Edinger-WEstphal nuclei, oculomotor
nerve) that mediate the direct and consensual pupillary light reflex.

Vs. occipital lobe contains the primary visual cortex. Unilateral occipital lobe dmg can cause contralateral homonymous
hemianopia, whereas bilateral occipital lesions may result in cortical blindness

Vs parietal lobes process and interpret visual, auditory and motor signals received from other brain areas. Parietal lobe
dmg results in difficulties with spatial and visual perception. Nondominant (eg, right-sided) lesions result in hemi-neglect
and constructional apraxia, whereas dominant (eg, left-sided) lesions result in Gerstmann syndrome (eg, right-left
confusion, agraphia, acalculia)

Vs the pons, contains the horizontal gaze center, which helps mediate the oculocephalic (doll’s eye) reflex. It also
contains the trigeminal (CNV) and facial (CN VII) nerves, which mediate the afferent and efferent limb of the corneal
reflex, respectively. Bilateral pontine injury is associated with pinpoint pupils due to dmg of the descending sympathetic
fibers.
Differential dx of dementia subtypes (594)
Alzheimer disease - Early, insidious short-term memory loss
- Language deficits & spatial disorientation
- Later personality changes
Vascular dementia - Stepwise decline
- Early executive dysfunction
- Cerebral infarction &/or deep white matter
changes on neuroimaging
Frontotemporal dementia - Early personality changes
- Apathy, disinhibition & compulsive behavior
frontotemporal atrophy on neuroimaging
Dementia with Lewy bodies - Visual hallucinations
- Spontaneous parkinsonism
- Fluctuating cognition
Normal-pressure hydrocephalus - Ataxia early in disease
- Urinary incontinence
- Dilated ventricles on neuroimaging
Prion disease - Behavioral changes
- Rapid progression
- Myoclonus &/or seizures

Frontotemporal dementia is associated with pronounced atrophy of the prefrontal cortex with later degeneration of the
anterior temporal cortex. It manifests initially with changes in personality, social behavior and language that progress
over time to a more global dementia with obvious neurocognitive deficits.

Normal pressure hydrocephalus (17)

Normal pressure hydrocephalus occurs in elderly px. It causes the triad of ataxic gait and urinary incontinence, then
dementia. These symptoms are explained by distortion of periventricular white matter. Bladder control is influenced by
descending cortical fibers that run in the distended paraventricular area. Later, loss of cortical inhibition on the sacral
micturition center causes the development of urge incontinence.

Micturition reflex (urination) is regulated by the following centers:

1. Sacral micturition center – located in S2-S4 level and responsible for bladder contraction. Parasympathetic fibers
travel from S2-S4 ventral white matter within pelvic nerves and stimulate cholinergic receptors in the bladder
wall
2. Pontine micturition center – located in the pontine reticular formation. It coordinates relaxation of external
urethral sphincter with bladder contraction during voiding
3. Cerebral cortex – inh sacral micturition center.

Transient ischemic attack (15766)

Px with TIA are at markedly increased risk of future stroke; therefore, intensive medical management is indicated.
Secondary prevention includes antiplatelet agents (eg, aspirin, clopidogrel) to prevent thrombus formation and statin
therapy (HMG-CoA reductase inh; eg, atorvastatin, rosuvastatin) to reduce atherosclerotic plaque formation. Lifestyle
modificiations (eg, exercise, tabacco cessation) are also recommended

Traumatic brain injury (11574)

Intraprenchymal brain hemorrhage can cause mass effect, leading to horizontal shifts in midline structures and impaired
consciousness -> increasing intracranial pressure may cause seizure and brainstem compression with Cushing triad (HTA,
bradycardia, respiratory depression) -> uncal herniation, disrupts the ipsilateral oculomotor nerve leading to a fixed
dilated pupil with”down and out” eye deviation -> injury to the midbrain and upper pons results in mid-positioned and
fixed pupils bilaterally with loss of vestibule-ocular reflexes

Dmg to the brainstem at or below the level of red nucleus (eg, midbrain tegmentum, pons):

- decerebrate (extensor) posturing due to loss of descending excitation to the upper limp flexors (via the
rubrospinal tract)
- extensor predominance (due to unopposed vestibulospinal tract output)

Dmg to above red nucleus (eg, cerebral hemispheres, internal capsule)

- decorticate (flexor) posturing due to loss of descending inhibition of the red nucleus -> hyperactivity of upper
limb flexors

(1493)

CO is a potent vasodilator of cerebral vasculature. Tachypnea causes hypocapnia and cerebral vasoconstriction, thereby
decreasing cerebral blood volume and intracranial pressure.

(7752) px with orbitofrontal cortex injury often experience personality changes, disinhibition and irritability secondary to
impairment of the behavioral and emotional modulatory systems.

(1813) the middle meningeal artery is a branch of the maxillary artery, which enters the skull at the foramen spinosum
and courses intracranially deep to the pterion (where the frontal, parietal, temporal and sphenoid bones meet). Skull
fractures at this site may cause laceration of this vessel, leading to an epidural hematoma.

Vs. facial artery, branch of the external carotid artery, which courses over the mandible anterior to the insertion of the
masseter muscle to supply the oral, nasal and buccal regions

Vs. the middle cerebral artery is a branch of the internal carotid artery and supplies much of the parietal and temporal
regions of the brain. Injury to this artery or its branches can cause subarachnoid or intracerebral hemorrhage.

Vs. the occipital artery arises opposite the facial artery from the external carotid, coursing posteriorly instead of
anteriorly. This vessel supplies the posterior scalp and the sternocleidomastoid muscles.

Vs. the ophthalmic artery is the first branch of the internal carotid artery, suppling the eye and orbital contents as well
as the eyelids, forehead, and nose. The internal carotid artery has no branches in the neck

Vs. the sphenopalatine artery is a branch of the third part of the maxillary artery and supplies much of the nasal mucosa.
It anastomoses with branches of the ophthalmic and facial arteries within the anterior part of the nasal septum in a
region known as Kiesselbach’s plexus (a frequent site of nosebleeds).

Epidural hematoma (505)

Accumulation of blood between the skull and bone and dura mater

Type of hemorrhage Epidural hematoma Subdural hematoma Subarachnoid hemorrhage

Blood vessel involved Middle meningeal artery Bridging cortical veins Aneurysm or AV
malformation of anterior
 and posterior
communicating arteries
Location Between the skull and the Between the dura and the Between the arachnoid and
dura arachnoid pia mater
Clinical manifestation Lucid interval, followed by Gradual onset of headache Severe headache “the
loss of consciousness and confusion worst”), fever, nuchal
rigidity
Px on CT scan Boconvex hematoma Crescent-shaped hematoma Blood in the basal cisterns

Bell’s palsy (8329)

CN VII fx:

- motor output to the facial muscles

- parasympathetic innervation to the lacrimal, submandibular, and sublingual salivary glands
- special afferent fibers for taste from the anterior 2/3 of the tongue
- somatic afferents from the pinna and external auditory canal

Bell’s palsy typically present with sudden onset of unilateral facial paralysis. Specific findings include imapried eye
closure, eyebrow sagging, inability to smile and frown on the affected side, disappearance of the nasolabial fold, and the
mouth being drawn to the non-affected side. Px afflicted w/ Bell’s palsy may also have decreased tearing, hyperacusis,
and/or loss of taste sensation over the anterior 2/3 of the tongue.

Visual pathway

(11685) dmg to the left temporal hemiretina will disrupt the transmission of visual information along the ipsilateral optic
nerve, lateral optic chiasm, optic tract, lateral geniculate body, optic radiations, and primary visual cortex.

(1735) the afferent limb of the light reflex pathway is the optic nerve; the efferent limb is the parasympathetic fibers of
the oculomotor nerve. When an optic nerve is damaged, light in that eye will cause neither pupil to constrict (the nerve
cant sense the light). However, light in the contralateral eye will cause both pupils to constrict (because the motor
pathways are intact).

Optic tract lesion (8595) can produce contralateral homonymous hemianopsia and a relative afferent pupillary defect
(Marcus Gunn pupil) in the pupil contralateral to the tract lesion.

(8636)
Phrenic nerve irritation (647)

Can cause dyspnea, hiccups (diaphragmatic irritation) and referred pain to the shoulder (area innervated by
supraclavicular nerve originating from C3 and C4)

Phrenic nerve palsy is associated with respiratory distress and diminished breath sounds on the affected side, with
elevation of the affected hmidiaphragm on chest x-ray

Ischemic stroke

Ischemic stroke (501)

Time after injury Microscopic changes Macroscopic changes
12-24 hrs Red neurons (eosinophilic cytoplasm,
pyknotic nuclei, loss of Nissl
substance)
24-72 hrs Neutrophilic infiltration
3-7 days Macrophage/microglia infiltration &
phagocytosis begins
1-2 weeks Reactive gliosis & vascular Liquefactive necrosis (1 week-1
proliferation around the necrotic area month)
>2 weeks Glial scar formation Cystic area surrounded by dense glial
fibers (>1 month)

>2 weeks: the periphery of the necrotic area becomes populated with new blood vessels and proliferating astrocytes
that form a network of cytoplasmic extensions (reactive gliosis). Several months to years after brain infarction, the
necrotic area appears as a cystic cavity surrounded by a wall composed of dense fibers formed by astrocytic processes
(glial scar).

(1687)

- “Clasp-knife” spasticity, characterized by initial resistance to passive extension followed by a sudden release of
resistance
- This form of spasticity is seen with upper motor neuron lesions and results from a lack of upper motor neuron
inhibition on the spinal stretch reflex arc
- UMN lesions can affect any part of pyramidal motor system, including corticospinal tracts of the spinal cord; the
medulla, pons, and midbrain, the internal capsule and the precentral gyrus (primary motor cortex)
- Px with internal capsule stroke commonly have pure motor weakness affecting the contralateral arm, leg and
lower face
- Contralateral spasticity or increased tone, hyperreflexia and a positive Babinski sign are also present

VS. caudate nucleus (basal ganglia) can lead to extrapyramidal symptoms such as chorea and athetosis

VS. insula, is involved with integrating body states with emotions (limbic system), ANS control, and conscious experience
of visceral sensations

VS. putamen is part of basal ganglia (extrapyramidal motor system) and plays a role in initiation of movement. Lesions in
the putamen can cause contralateral tremor, bradykinesia and rigidity

VS. globus pallidus, also part of basal ganglia/extrapyramidal motor system. It consists of an external internal segment.
Dmg to the external segment results in decreased motion/movement; dmg to the internal segment will result in
excessive motion/movement

Lacunar infarctions (2077)

Are the result of small vessel occlusion (eg, due to lipohyalinosis and microatheroma formation) in the penetrating
vessels supplying the deep brain structures. Uncontrolled HTA and DM are major risk factors for this condition.
Lipohyalinosis occurs secondary to leakage of plasma proteins through damaged endothelium and is characterized by
hyaline thickening of the vascular wall, collagenous sclerosis and accumulation of mural foamy macrophages.
Microatheromas result from atherosclerotic accumulation of lipid-laden macrophages within the intimal layer of a
penetrating artery near its origin off the parent vessel. These changes predispose to small vessel occlusion and infarction
of CNS tissue with liquefactive necrosis and the formation of a fluid-filled cavity

VS. embolism due to carotid atherosclerosis and mitral valve disease (eg, bacterial endocarditis) most commonly causes
cortical infarcts. Although microemboli released from atherosclerotic lesions or valvular disease may be the cause of
some lacunar infarcts, lipohyalinosis/microatheromas are a much more common etiology.

UMN injury (1920)

Can occur anywhere proximal to the anterior horn; common etiologies include stroke, MS, or spinal cord transection

UMN signs:

- hyperreflexia
- spastic paralysis
- increased muscle tone
- clasp-knife rigidity (increased muscle tension with sudden release on passive flexion
 - pyramidal weakness (weakness is more pronounced in lower extremity flexoers and upper extremity extensor
- pronator drift

LMN signs:

- flaccid paralysis
- weakness with hypotonia and muscle atrophy
- fasciculations
- suppressed or absent reflexes

Acute intracerebral hemorrhage (12226)

Hypertensive hemorrhage ein the pons at the level of the locus ceruleus, a paired pigmented brainstem nucleus located
in the posterior rostral pons near the lateral floor of the fourth ventricle. The locus ceruleus functions as the principal
site for norepinephrine synthesis in the brain and projects to virtually all parts of the CNS. It is involved in the control of
mood, arousal (reticular activating system), sleep-wake states, cognition and autonomic function (eg, blood pressure
control). Abnormal activation of the locus ceruleus has been implicated in the pathogenesis of anxiety disorders (eg,
panic attacks).

Patients with bilateral pontine hemorrhage typically present with coma due to disruption of the reticular activating
system. Other features usually include total paralysis with extensor posturing due to corticospinal and corticobulbar
tract injury and pinpoint pupils secondary to descending sympathetic tract dmg.

Thalamic stroke (2076)

The thalamic ventral posterior lateral nucleus (receives input from the spinothalamic tract and dorsal columns) and
ventral posterior medial nucleus (receives input from the trigeminal pathway) send somatosensory projections to the
cortex via thalamocortical fibers. Damage to these nuclei may result in complete contralateral sensory loss (eg, touch,
pain/temperature, vibration/proprioception). Severe proprioceptive defects may cause unstead gait.

VS. injury to the base of the pons is frequently associated with contralateral weakness and ataxia due to involvement of
the descending motor tracts (eg, corticospinal, coritcobulbar) and pontocerebellar fibers

VS. dmg to the caudate nucleus typically causes behavioral abnormalities (eg, agitation, psychosis, abulia),
speech/language disturbances, and movement disorders (eg, choreathetosis)

VS. frontal cortex lesions usually cause social disinhibition and defictis in attention and executive function (eg, planning,
organizing, decision making)

VS. the anterior 2/3 of the posterior limb of the internal capsule is mainly composed of motor fibers (eg, corticospinal
tract), and the posterior 1/3 contains sensory fibers (eg, thalamocortical tract). Although very small lesions to the
posterior limb may cause contralateral pure sensory deficits, most lesions result in pure motor or combined
sensorimotor deficits.

Gerstmann syndrome (12023)

Stroke affecting the angular gyrus of the dominant parietal lobe (supplied by MCA)

Broca aphasia (6566)

Caused by lesions to the inferior frontal gyrus of the dominant (usually left) hemisphere. It is a nonfluent aphasia usually
characterized by agrammatism, intact comprehension, and poor repetition.

Lesons in Wernicke area (caudal superior temporal gyrus, Brodmann area 22), however, typically result in receptive
(sensory) aphasia with impaired comprehension. Px classically lack insight into their problem. Wernicke aphasia is also
known as fluent aphasia because speech flows readily but is meaningless (“word salad”)

ACA stroke (1696)

Occlusion of the anterior cerebral artery would affect sensory and motor fx of the contralateral leg and foot while
predominantly sparing the contralateral arm/face (cortical homunculus). Px with bilateral anterior cerebral artery
occlusion can also develop significant behavioral symptoms (eg, abulia) and urinary incontinence if the frontal
micturition center (eg, medial frontal lobe/cingulate gyrus) is affected.

MCA stroke (21)

Px with MCA occlusion often present with contralateral hemiparesis and hemisensory loss involving the face and upper
limb due to infarction of the corresponding motor and sensory cortices. The lower limbs are typically spared or
minimally affected. Other features may include anosognosia (lack of insight) and spatial neglect of the contralateral side
(due to dmg of the nondominant [right] parietal lob), conjugate gaze deviation toward the side of the stroke, and
contralateral homonymous hemianopsia (due to a dmg of the optic radiations in the subcortical temporoparietal lobe).
Occlusion of the left MCA usually results in righ-side hemiparesis and hemi-sensory loss. Speech areas are located in the
dominant (usually left) hemisphere. Consequently, px with left MAC stroke also often have expressive and receptive
aphasia due to infarction of Broca and Wernicke areas.

PCA stroke (8592)

The PCA supplies the occipital lobe, which contains the striate or primary visual cortex. The striate cortex of each
hemisphere receives information about the contralateral visual field from the ipsilateral lateral geniculate nucleus via
the optic radiation. Specifically, the cuneus gyrus of the striate cortex receives information from the upper retina (lower
visual field), while the lingual gyrus of the striate cortex receives information from the lower retina (upper visual field).
Macula is spared because collateral blood is supplied by the MCA

(2127) the PCA branches off the basilar artery at the level of pontomesencephalic junction and supplies CNIII and IV
other structures in the midbrain. It also supplies the thalamus, medial temporal lobe, splenium of the corpus callosum,
parahippocampal gyrus, fusiform gyrus and occipital lobe.

Most common finding in PCA territory infarction is

- contralateral hemianopia often with macular sparing due to collateral circulation from the MCA
- Involvement of lateral thalamus frequently results in contralateral paresthesias and numbness affecting the
face, trunk and limbs
- Variety of cortical symptoms: dyslexia, visual agnosia (eg, impaired visual recognition of objects) and
propagnosia (eg, inability to recognize faces)

VS: ACA: artery distribution includes the inferior frontal, medial frontal and superior medial parietal lobes; anterior 4/5
of the corpus callosum; olfactory bulb and tract; anterior portions of the basal ganglia and internal capsule

VS: anterior choroidal artery is the last branch off the internal carotid artery before it trifurcates. It supplies the posterior
limb of the internal capsule, optic tract, lateral geniculate body, choroid plexus, uncus, hippocampus and amygdala

VS: artery of Percheron branches off either the right or left PCA and supplies the bilateral thalami and dorsal midbrain. It
is considered to be a rare normal variant and can be seen in px with bilateral thalamic or dorsal midbrain strokes.
VS: basilar artery: supplies a large portion of the brain, including most of the brainstem and bilateral cerebellar
hemispheres.

VS: MCA: includes the lateral convexity of the frontal, parietal and temporal lobes. It also supplies deep cubcortical
structures, such as the internal capsule and basal ganglia. Ischemic stroke occurs most frequently within this region,
causing contralateral motor and sensory deficits involving the upper and lower extremities and face.

Lacunar infarcts (22)

Pure motor hemiparesis and a small cavitary lesion in the internal capsule – most likely a lacunar infarct (a form of
ischemic stroke involving small penetrating arterioles that supple the deep brain structures (eg, basal ganglia, pons) and
subcortical white matter (eg, internal capsule, corona radiate))

Lacunar infarcts are primarily caused by chronic HTA, which promotes lipohyalinosis, microatheroma formation and
hardening/thickening of the vessel wall (hypertensive arteriolar sclerosis). This leads to progressive narrowing of the
arteriolar lumen and predisposes to thrombotic vessel occlusion. Diabetes and smoking are additional risk factors.
Depending on the portion of the brain affected, characteristic clinical syndromes develop, such as the following:

- Pure motor hemiparesis -> posterior limb of the internal capsule or basal pons
- Pure sensory stroke -> ventroposterolateral or ventroposteromedial thalamus
- Ataxia-hemiplegia syndrome -> posterior limb of the internal capsule or basal pons
- Dysarthria-clumsy hand syndrome -> genu of the internal capsule or basal pons

VS. Charcot-Bouchard aneurysms are caused by chronic hypertension and involve the same small penetrating arterioles
as lacunar stroke; however, aneurysm rupture typically leads to intraparenchymal hemorrhage within deep brain
structures, which would appear acutely as a relatively large intracerebral hyperdensity on CT scan.

Retinal artery occlusion (360)

Central retinal artery occlusion presents with sudden, painless, and permanent monocular blindness. Fundoscopic
examination reveals a pale retina and a “cherry-red” macula

Trigeminal nerve (2125)

Infarcts involving the anterior portion of the medial pons can produce dsarthria and contralateral hemiparesis/lower
facial palsy due to disruption of the ipsilateral corticospianl and corticobulbar tracts. The trigeminal nerve arises at the
level of the middle cerebellar peduncle at the lateral aspect of the mid-pons

Vs. facial nerve: facial nucleus is located in the dorsolateral aspect of the caudal pons, and the nerve exits at the
ventrolateral pontomedullary junction (below the middle cerebellar peduncles). Sparing of the forehead muscles, which
indicates that the facial weakness is a result of a central lesion affecting the corticobulbar tract and is not due to direct
damage to the facial nucleus/nerve

Vs. hypoglossal nucleus: located medially on the floor of th fourth ventricle at the level of the medulla, and the nerve
exits at the rostral end of the preolivary sulcus

Vs. oculomotor nucleus is located at the rostral midbrain at the level of the superior colliculus and red nucleus, and the
nerve exits at the interpeduncular fossa
Vs. the trochlear nucleus is located in the caudal midbrain, and the nerve exits the dorsal midbrain just below the
inferior colliculus (below the red nucleus). The trochlear nerve is the only cranial nerve to decussate before innerating its
target (superior oblique muscle).

Spinal cord injury

B12 deficiency (65) subacute combined degeneration

1. dorsal columns of the spinal cord. Dmg to these tracts leads to bilateral loss of position and vibration sensation.
Gait abnormalities are typical, especially when the px’s eyes are closed (sensory ataxia)
2. lateral corticospinal tracts: upper motor neuron signs: spastic paresis, hyperreflexia and pathologic reflexes
(Babinski sign)
3. axonal degeneration of peripheral nerves can cause numbness or paresthesias

Brown Sequard syndrome (12030)

Characterized:

1. Anterior horn (lower motor neuron) injury produces ipsilateral flaccid paralysis at the level of the lesion
2. Lateral corticospinal tract (upper motor neuron) injury results in ipsilateral spastic paralysis below the level of
the lesion
3. Dorsal column (gracile and cuneate fasciculi) involvement causes ipsilateral loss of touch, vibratory sensation
and proprioception below the level of the lesion
4. Damage to the lateral spinothalamic tract causes contralateral loss of pain and temperature sensation 1-2 levels
below the lesion
Spinal cord injury above T1 can also cause ipsilateral Horner syndrome (ptosis, miosis, anhidrosis) if there is concurrent
dmg to the oculosympathetic pathway.

Cauda equine syndrome (1693)

Cause:

- massive rupture of an intervertebral disk that is capable of causing compression of 2 or more of the 18 spinal
nerve roots of the cauda equina
- trauma
- space occupying lesion of the lower vertebral column

The cauda equine nerve roots provide the sensory and motor innervation of most of the lower extremities, the pelvic
floor and the sphincters

Classic symptoms:

- low back pain radiating to one or both legs

- saddle anesthesia
- loss of anocutaneous reflex
- bowel and bladder dysfunction (S3-S5 roots)
- loss of ankle-jerk reflex with plantar flexion weakness of the feet

Vs. conus medullaris syndrome

Refers to lesions at L2

Symptoms:

- flaccid paralysis of the bladder and rectum, impotence and saddle (S3-S5 roots) anesthesia
- Usually mild weakness of the leg muscle if the lesion spares both the lumbar cord and the adjacent spinal and
lumbar nerve roots

Common causes:

- Disk herniation
- Tumors
- Spinal fractures

Cranial nerve palsy

(8557) CN III

Symptoms:

- a somatic component innervates the inferior, superior, and medial rectus; inferior oblique; and levator
palpebrae muscles. Ptosis occurs due to paralysis of the levator palpebrae, and the unopposed action of the
lateral rectus (CN VI) and superior oblique (CN IV) muscles leads to a “down and out” gaze
- parasympathetic fibers of CN III innervate the iris sphincter and ciliary muscle. Paralysis of these fibers causes a
fixed, dilated pupil and loss of accommodation.
CN III palsy can result from lesions anywhere along the nerve’s path from the oculomotor nucleus in the midbrain to the
extraocular muscles within the orbit. The most dreaded cause of isolated acute third nerve palsy is an actively enlarging
intracranial aneurysm (at risk of imminent rupture)

(8701) Lesions involving CN III cause ptosis, a downward and laterally deviated eye, impaired pupillary constriction and
accommodation, and diagonal diplopia. The most dreaded cause of CN III palsy is an enlarging intracranial aneurysm
(posterior communicating)

CN IV (1933)

The trochlear nerve innervates the superior oblique muscle, which causes the eye to intort (internally rotate) and
depress while adducted. Trochlear nerve palsy is typically traumatic or idiopathic and presents with vertical diplopia that
worsens when the affected eye looks down and toward the nose (eg, walking downstairs, up-close reading). Px may
compensate by tucking the chin and tilting the head away from the affected eye.

Cavernous carotid aneurysm (15646)

The abducens nerve (CN VI), which passes through the cavernous sinus next to the internal carotid arery, is the most
likely structure to be damaged by an expanding aneurysm. Compression or stretching of the nerve results in ipsilateral
lateral rectus weakness, which can cause esotropia (inward eye deviation) and horizontal diplopia (double vision) that is
worse when looking toward the side of the lesion

Other nerves that can be dmged by a cavernous carotid aneurysm include the CN III, CNIV, and V1 and V2, all of which
run on the lateral wall of the cavernous sinus

(2024)

Skull foramen Traversing structures

Anterior cranial fossa Cribiform plate CN I olfactory bundles
Middle cranial fossa Optic canal CN II, ophthalmic artery, central retinal vein
Superior orbital fissure CN III, IV, V1, VI, ophthalmic vein, sympathetic fibers
Foramen rotundum CN V2 (maxillary)
Foramen ovale CN V3 (mandibular
Foramen spiosum Middle meningeal artery & vein
Posterior cranial fossa Internal acoustic meatus CN VII, VIII
Jugular foramen CN IX, X, XI, jugular vein
Hypoglossal canal CN XII
Foramen magnum Spinal roots of CN XI, brain stem, vertebral arteries

Cranial fissures (1703)

CN III, CNV1, CNIV, CNVI, and superior ophthalmic vein enter the orbit via de superior orbital fissure

The CNV2, infraorbital vessels and branches from the sphenopalatine ganglion passes through inferior orbital fissure but
do not enter the orbit

The optic canal is medial to the superior orbital fissure and transmits only the CNII and ophthalmic artery

The foramen rotundum transmits the maxillary division of the CNV2 from within the skull to pterygopalatine fossa. From
there it courses through the inferior orbital fissure to appear on the face at the infraorbital foramen as the infraorbital
nerve
The foramen lacerum is occluded by cartilage. The internal carotid artery courses just superior to the foramen lacerum
in the lacerum portion of the carotid canal

The CNV3 passes through the foramen ovale

Jugular foramen (Vernet) syndrome (8522)

Characterized by CN IX, X, and XI dysfunction. Symptoms:

- loss of taste from the posterior 1/3 of the tongue (CN IX)
- loss of gag reflex (CN IX, X)
- dysphagia (CN IX, X)
- dysphonia/hoarseness (CN X)
- soft palate drop with deviation of the uvula toward the normal side (CN X)
- sternocleidomastoid and trapezius muscle paresis (CN XI)

Huntington disease (840)

AD neurodegenerative disease caused by an increase in the number of CAG trinucleotide repeats in the gene that codes
for the huntingtin protein. Expansion of the protein’s polyglutamine region results in a gain-of-fx that leads to
pathological interaction with other proteins, including various transcription factors

Transcriptional repression (silencing) is one of the mechanisms by which mutated huntingtin is thought to cause disease.
Regulation of transcription occurs in part due to pthe presence of histones, small proteins that complex with DNA to
help compact the strands. Histones can undergo a variety of modifications (eg, methylation, acetylation,
phosphorylation) that affect the accessibility of the genome for transcription. Acetylation of histones weakens the DNA-
histone bond and makes DNA segments more accessible for transcription factors and RNA polymerases, enhancing gene
transcription. In Huntington disease, abnormal huntingtin causes increased histone deacetylation, silencing the genes
necessary for neuronal survival. As a result, one of the tx options under investigation includes histone deacetylase inh
that help upregulate survival genes.

Criteria Description
Clinical - Chorea: varies from fidgetiness to uncontrollable, swinging movements of the extremities
- Dementia: memory and cognitive decline
- Behavioral abnormalities: aggressiveness, apathy or depression
Macroscopi - Pronounced atrophy of caudate nucleus
c - Moderate atrophy of the putamen and frontal lobes
Microscopic - Loss of neurons in the caudate nucleus and putamen
Biochemical - Decrease in GAB, ACh and substance P in the striatum (caudate nucleus and putamen)
Genetic - AD
- Increased number of CAG trinucleotide repeats in HD gene (chromosome 4)

Moleuclar - NMDA receptors bind glutamate and cause neuronal death (NMDA-associated toxicity)
Huntington Disease (1690)
The head of the caudate lies in the inferolateral wall of the anterior horn of the lateral ventricle. It is separated from the
globus pallidus and putamen by the interal capsule. The caudate is atrophied in Huntington’s disease.

Aphasia (1955)

Wernicke aphasia (1846)

A lesion in Wernicke’s area can cause receptive aphasia, which is characterized by well-articulated, nonsensical speech
paired with a lack of language comprehension (Wernicke-Word salad). Wernicke’s area is located in the auditory
association cortex within the posterior portion of the superior temporal gyrus in the dominant temporal lobe. The
middle cerebral artery supplies Broca’s area (superior division) and wernickes area (inferior division)

Multiple sclerosis

(918) is an autoimmune demyelinating disease that results from oligodendrocyte depletion. Within the lesions,
inflammatory infiltrate of lymphocytes and macrophages are seen surrounding oligodendrocytes and myelin sheaths.
Oligoclonal bands are highly sensitive but nonspecific in px with MS.

(919) histologically, active MS plaques are characterized by perivenular inflammatory infiltrates made up primarily of
autoreactive T lymph and macrophages directed against myelin components. Extensive inflammation dmgs the BBB,
increasing inflammatory cell recruitment into the CNS (with the vessel wall remaining intact, unlike in CNS vasculitis).
Infiltrating macrophages containing myelin debris are seen throughout the lesion and recruitment of B lymphocytes to
the perivascular spaces leads to the formation of myelin-specific antibodies. Patchy demyelination occurs and while
axons are typically spared, significant or prolonge disease may result in neuron death. Residual chronic findings include
hypertrophy and hyperplasia of astrocytes (glial scarring)

(1318) the speed of conduction down an axon depends on 2 constants: the length constant and the time constant (ie,
velocity = length/time). Myelination increases the length constant and decreases the time constant, both of which
improve axonal conduction speed. Demyelination thus impairs stimulus transmission.

(11464)

Px with multiple sclerosis often develop a spastic bladder a few weeks after developing an acute lesion of the spinal
cord. These px present clinically with increased urinary frequency and urge incontinence. Urodynamic studies show the
presence of bladder hypertonia.

(11458) Spasticity manifests clinically as muscle stiffness, painful muscle spasm, scissoring gait, and lack of dexterity. The
loss of descending inhibitory control from the upper motor neurons results in lower motor neuron overactivity, leading
to increased tone and hyperreflexia

A number of medications are beneficial in the tx of spasticity by decreasing the excitability of spinal reflexes. Baclofen,
an agonist at the GABA-B receptor, is effective as monotherapy for the tx of spasticity secondary to both brain and spinal
cord disease, including MS. Tizanidine (alpha-2 adrenergic agonist) is also effective and commonly used.

(917) MS is an autoimmune disorder of the CNS characterized by recurrent episodes of demyelination, leading to
reduced salutatory conduction. Internuclear ophthalmoplegia and optic neuritis are common manifestations

Wilson disease (1167)

Wilson disease
Pathogenesis - AR mutation of ATP7B -> hepatic copper accumulation -> leak from damaged hepatocytes ->
deposits in tissues (eg, basal ganglia, cornea)
Clinical findings - Hepatic (acute liver failure, chronic hepatitis, cirrhosis)
- Neurologic (parkinsonism, gait disturbance, dysarthria)
- Psychiatric (depression, personality changes, psychosis)
Dx - ↓ceruloplasmin & ↑ urinary copper excretion
- Kayser-Fleischer rings
- ↑ Copper content on liver biopsy
Tx - Chelators (eg, D-penicillamine, trientine)
- Zinc (interferes with copper absorption)

(1689) wilson’s disease can cause cystic degeneration of the putamen as well as dmg to other basal ganglia structures.
The putamen is located medial to the insula and lateral to the globus pallidus on coronal sections.

(15602)

VS. prodromal schizophrenia often presents with personality changes and social withdrawal prior to the onset of overt
psychosis. However, psychosis in a child or adolescent is rare, and medical or substance-induced causes must be ruled
out.

(398) the Kayser-Fleischer ring is an ophthalmologic finding most strongly associated with Wilson’s disease. It is seen
most frequently in px with neuropsychiatric complications. Basal ganglia atrophy is typically present in these px.

Myasthenia gravis

6429
Pathophysiology - Autoantibodies against ACh receptors at motor
endplate
- Thymus involved in autoimmunity:
Thymic hyperplasia
Thymoma
Symptoms/signs - Fluctuating & fatigable proximal muscle weakness;
worse later in the day
Ocular (eg, diplopia, ptosis)
Bulbar (eg, dysphagia, dysarthria)
Respiratory muscles (eg, myasthenic crisis)
Tx - Acetylcholinesterase inh (eg, physostigmine)
- Thymectomy

(1320)

Exacerbations of myasthenia gravis

- Px undertrated -> not enough ACh is available in the NMJ (myasthenic crisis). Infusion of the short-acting AChE
inh edrophonium (Tensilon test) increases neuromuscular transmission and can provide temporary
improvement in symptoms. The pyridostigmine dose should be increased in the long-term management of these
px
- Second: cholinergic crisis. Px receives inappropriately high doses of AChE inh and has excessive ACh. This cuases
excessive stimulation of the skeletal muscle and results in muscle that is refractory to future impulses.
Cholinergic crisis also presents with muscle weakness; however, because the NMJ becomes insensitive to ACh,
edrophonium infusion produces no improvement in symptoms.

Hydrocephalus (15)

Symmetrical enlargement of the ventriculi is characteristic of communicating hydrocephalus. Communicating

hydrocephalus usually occurs secondary to dysfunction or obliteration of subarachnoid villi. This dysfunction is usually a
sequeale of meningeal infection (including TB meningitis) or subarachnoid/intraventricular hemorrhage.
(1854)

Prion disease (912)

Prion disease are rapidly progressive neurodegenerative disorders caused by the accumulation of an abnormally folded
protein within the brain. Prion proteins are normally found in an alpha helix form; a conformation change into a beta-
sheet form confers resistance to proteases and can trigger similar conformational changes in other normally folded
proteins. Characteristic microscopic findings include spongiform degeneration of the gray matter with vacuolization of
neurons, gliosis and cyst formation.

(911) rapidly progressive dementia and myoclonic jerks are typical for CJD. CJD is a rare disorder that can be sporadic or
infectious. Most of the transmitted cases are iatrogenic, seen in px that received contaminated corneal transplants,
implantable electrodes or preparation of growth hormone.

Romberg test (12035)

The Romberg test is a test of proprioception in which px are observed for unsteadiness as they stand with their feet
close together, arms to the sides and eyes closed. Failure to maintain this posture indicates sensory ataxia, which may
be caused by defects in the posterior column or peripheral nerves (eg, tabes dorsalis, vit b12 def)

Urinary retention (1362)

Cholinomimetics are indicated in non-obstructive urinary retention, paralytic ileus and glaucoma. Their side effects
include nausea, vomiting, abd cramps, diarrhea, dyspnea and increased secretions (sweting, lacrimation and salivation)

Glaucoma (1322)

Inferior MIs are often associated with bradycardia. Atropine blocks vagal influence on the SA and AV nodes and is
effective in increasing HR in such px. Atropine’s side effects are due to muscarinic receptor blockade in other organ.s in
the eye, atropine causes mydriasis, resulting in narrowing of the anterior chamber angle and diminished outflow of
aqueous humor. Which can precipitate angle-closure glaucoma in px with shallow anterior chambers or higher than
normal intraocular pressures.
Tx: (11841)

Is managed with agents that either decrease production or increase outflow of aqueous humor. Latanoprost is a topical
prostaglandin used in the tx of glaucoma. It is applied as a prodrug and converted to the active form by esterases in the
cornea. Prostaglandins are the preferred first-line agents for the tx of glaucoma, and although the exact mechanism of
action is uncertain, they have been found to decrease the collagen content in the uveoscleral outflow pathway and
increase outflow of aqueous humor. They are also known to cause increased pigmentation in the iris and eyelashes.

(11708)

The bladder is extraperitoneal. In placement of a suprapubic cystostomy, the trocar and cannula will pierce the layers of
the abd wall but will not enter the peritoneum.

Parkinson disease (265)

Levodopa is admn with DOPA decarboxylase inh (eg, carbidopa) and sometimes catechol-O-methyltransferase inh
(COMT) (eg, entacapone) to reduce the peripheral metabolism of levodopa, resulting in increased delodopa
bioavailability to the brain

(262) adding carbidopa can reduce most of the peripheral side effects of levodopa. However, behavioral changes from
levodopa can actually worsen with addition of carbidopa because more dopamine becomes available to the brain. Such
as anxiety, agitation, insomnia, confusion, delusions and hallucinations. If reduced dosage is not possible, atypical
antipsychotics, such as clozapine may be helpful.

(11462) long-term levodopa tx for Parkinson disease has likely developed motor fluctuations and dyskinesia, which often
occur >5 years after starting therapy. Motor fluctuations can initially correlate with serum drug levels and are
characterized by good mobility during “on” periods and increased bradykinesia/rigidity during “off” periods when the
drug wears off. Dyskinesia typically occurs when the px is “on” and is characterized by excessive involuntary movements
Nigrostriatal degeneration in Parkinson disease results in excessive excitation of the globus pallidus internus by the
subthalamic nucleus, which in turn causes excessive inhibition of the thalamus. Reduced activity of the thalamus and its
projections to the cortex consequently result in rigidity and bradykinesia. Px with medically intractable symptoms of
Parkinson disease my benefit from high-frequency deep brain stimulation of the globus pallidus internus or subthalamic
nucleus. High frequency stimulation inhibits firing of these nuclei. This causes increased activity in the downstream
nuclei, resulting in thalamo-cortical disinhibition with improved mobility.

Tx (259)

Selegiline:

- is an inh of MAO, type B and can prevent MPTP-induced dmg of dopaminergic neurons.
- Used clinically to delay the progression of Parkinson disease
- Many favor the use of combinations of selegiline, anticholinergics and amantadine until they no longer provide
control of symptoms. only then is levodopa/carbidopa introduced

Vs. amantadine:

- Also known as antiviral influenza agent

- Also known to have dopaminergic activity and possibly anticholinergic action

Vs. levodopa:

- Dopamine analog that remains the most effective tx of symptoms

- Absorbed in the small intestine via a large, neutral-amino-acid transporter system and is then converted to
DOPA by the enzyme dopa-decarboxylase.

Vs. Pergolide:

- Dopamine agonist which directly stimulates dopa D2 receptors

- Modest improvement when used as monotherapy; however, this modest improvement may be sufficient to
delay the introduction of levodopa by months or years, thus delaying levodopa-related side effects.

Dopamine agonists (703)

Have a chemical structure similar to the neurotransmitter dopamine and directly stimulate dopamine receptors. They do
not have to be metabolized to be active. There are 2 classes of dopamine agonists:

- Ergot compounds (derived from ergot fungi): bromocriptine

- Nonergot compounds: pramipexole and ropinirole

They have a long half-life and can dely the need to start levodopa, thereby postponing the development of motor
fluctuations until later in the disease course. Bromocriptine also tx hyperprolactinemia.

Restless leg syndrome (10362)

Clinical features Uncomfortable urge to move the legs with:
- Unpleasant sensations in the legs
- Onset with inactivity or at night
- Relief with movement (eg, walking, stretching)
Causes - Idiopathic
 - Iron deficiency
- Uremia
- Diabetes (especially with neuropathy)
Tx - Avoidance of aggravating factors (eg, alcohol, sleep deprivation)

The pathophysiology of RLS strongly centers on dopaminergic pathways, and dopamine agonists (eg, ropinirole,
pramipexole) are rapidly effective in most cases. In addition, functional iron deficiency in the CNS is linked to dysfunction
of dopaminergic pathways (iron-dopamine model). Iron deficiency is common in RLS, and low iron concentrations have
been found in the substantia nigra of px with RLS, even in the absence of systemic iron deficiency.

Alzheimer’s disease

(590)

Pathologic changes:

- neurofibrillary tangles are composed of tau protein, a primary component of intracellular microtubules. In AD,
tau protein is hyperphosphorylated, causing microtubule structures to collapse into “tangles” that contribute to
global neuronal dysfunction
- amyloid beta is an abnormal fragment of amyloid precursor protein, which is normally involved in synaptic
formation and repair. In AD, the protein is not properly cleared and forms amyloid fragments; these then harden
into insoluble plaques that accumulate in brain tissue and vessel walls.

The amyloid precursor protein (APP) gene is located on chromosome 21. The extra copy of APP present in trisomy 21 is
thought to accelerate amyloid accumulation and lead to early onset AD

(593)

- prevailing clinical symptom: slow, progressive memory loss

- macroscopic brain appearance: mild-to-moderate generalized brain atrophy
- microscopic brain changes: neurofibrillary tangles, senile plaques, and amyloid angiopathy
- biochem abnormalities: decreased ACh levels in the hippocampus and nucleus basalis of Meynert

(794) the hippocampus is the area of the brain demonstrating the greatest degree of atrophy in Alzheimer’s disease.
Hippocampal atrophy on MRI is highly suggestive of the dx
(591) early-onset familial Alzheimer disease is associated with three gene mutations: APP (chromosome 21), presenilin 1
and presenilin 2. Late-onset familial Alzheimer disease is associated with apolipoprotein E4 genotype.

(7490)

Histopathologic findings: include amyloid plauqes and neurofibrillary tangles. Neuritic (senile) plaques are extracellular
deposits often found in the medial temporal lobe (eg, hippocampus, amygdala, entorhinal cortex) and are composed of
a central amyloid beta (Abeta) core surrounded by dystrophic neuritis. Abnormal accumulation of Abeta is toxic to
neurons and is thought to occur secondary to impaired clearance or overproduction of amyloid precursor protein.
Neurofibrillary tangles are found in the neuronal cytoplasm and consist of aggregates of hyperphosphorylated tau
protein, which normally mediates microtubule stabilization.

AD treatment (1442)

Currently available AD-specific therapies offer:

1. Enhanced cholinergic neurotransmission (donepezil, a cholinesterase inh)

2. Neuroprotection via antioxidants (vitamin E [alpha-tocopherol])
3. NMDA receptor antagonism (Memantine)

Antihistamines (173)

First generation antihistamines can have prominent side effects due to blockade of other receptors, including alpha-
adrenergic, serotonergic and cholinergic receptors

The ciliary muscle attaches to the lens via the zonular fibers. Contraction of the muscle reduces tension on the fibers,
allowing the lens to become more spherical and increasing its refractive power. The ciliary muscle is under
parasympathetic control from the Edinger-Westphal nucleus/ciliary ganglion. Inh of this pathway by antimuscarinic
agents will limit accommodation and cause blurring of vision for close objects. The pupillary sphincter also receives
parasympathetic innervation from the Edinger-Westphal nucleus, and px on antimuscarinic agents may have mydriasis
(pupillary dilation) as well.

Opioids (776)

Morphine and other commonly used opiates have an especially high affinity for the mu receptor, which exerts the
strongest analgesic effects

In the spine, opiates bind to mu receptors on the primary afferent neuron, resulting in closure of voltage-gated calcium
channels, reduced calcium influx, and decreased excitotatory neurotransmitter release (eg, acetylcholine, NE, serotonin,
glutamate, substance P) from the presynaptic terminal. Opiates also bind to mu receptors on the postsynaptic
membrane, which opens potassium channels and leads to membrane hyperpolarization due to potassium efflux. Opiate-
induced inhibition of synaptic activity in the CNS attenuates pain transmission, producing analgesia

Drugs for neuropathic pain (11680)

Topical capsaicin causes defunctionalization of afferent pain fibers and depletion of substance P. initial application
results in a burning and stinging sensation, but chronic exposure leads to reduced pain transmission.

ENT

Tongue (1453)

1. Motor innervation: is provided by the hypoglossal nerve CNXII with the exception of the palatoglossus muscle,
which is innervated by the vagus nerve (CN X)
2. General sensory innervation:
- Anterior 2/3 of the tongue: mandibular branch of trigeminal nerve (CN V3)
- Posterior 1/3 of the tongue: glossopharyngeal nerve (CN IX)
- Posterior area of the tongue root: vagus nerve (CN X)
3. Gustatory innervation (taste buds)
- Anterior 2/3: chorda tympani branch of facial nerve (CN VII)
- Posterior 1/3: glossopharyngeal nerve (CN IX)
- Posterior area of the tongue root and taste buds of the larynx and upper esophagus: vagus nerve (CN X)

Orbital fracture (11742)

Fractures to the orbital floor commonly result from direct frontal trauma to the orbit. The infraorbital nerve runs along
the orbital floor in a groove in the maxilla before exiting the skull just inferior to the orbit. Dmg can result in paresthesia
of the upper cheek, upper lip and upper gingiva. In addition, the inferior rectus muscle can also become entrapped,
limiting vertical gaze

Hypertensive retinopathy (11675)

HTA retinal hemorrhage typically causes painless, unilateral visual disturbances, ranging from mild obscuration without
loss of visual acuity to permanent blindness. Severe HTA in retinal precapillary arterioles causes endothelial disruption,
leakage of plasma into the arteriolar wall and fibrinous necrosis. The necrotic vessels can then bleed into the nerve fiber
layers, causing dot-and flamed-shaped hemorrhages.

Other findings of HTA retinopathy include thickening of the arteriolar walls (“copper or silver wiring”), compression of
the associated veins (arteriovenous nicking), and small, white foci of retinal ischemia (cotton-wool spots)

Internal laryngeal nerve (8703)

Mediates the afferent limb of the cough reflex above the vocal cords. Foreign bodies (eg, chicken or fish bones) can
become lodged in the piriform recess and may cause dmg to the nerve, imapriign the cough reflex. Unlike the recurrent
and external laryngeal nerves that carry motor fibers to the muscles involved in vocal cord fx, the internal laryngeal
nerve contains only sensory and autonomic fibers.

Cleft lip and cleft palate (1740)

The lip and palate form during the 5 th-6th week of embryonic development

1. The first pharyngeal arch splits into the upper maxillary prominence and the lower mandibular prominence
2. Fusion of the 2 medial nasal prominences forms the midline intermaxillary segment. The intermaxillary segment
will become the philtrum of the upper lip, the 4 medial maxillary teeth and the primary palate
3. The left and right maxillary prominences then fuse with the midline intermaxillary segment to form the upper lip
and primary palate. If one of the maxillary prominences fails to fuse with the intermaxillary segment, a unilateral
 cleft lip results. If both maxillary prominences fail to fuse with the intermaxillary segment, bilateral cleft lip

results.

Age related macular degeneration (7721)

- Dray AMD: gradual vision loss in one or both eyes. This is due to chronic oxidative dmg to the retinal pigment
epithelium and choriocapillaris, leading to subretinal inflammation with abnormal extracellular matrix formation
(eg, confluent drusen, basement membrane thickening). These changes appear on funduscopy as subretinal
drusen deposits with pigment abnormalities.
- Wet AMD: progressive extracellular atrix accumulation can eventually result in retinal hypoxia, which stimulates
local vascular endothelial growth factor (VEGF) production and causes subretinal neovascularization with
formation of leaky vessels. Presents with acute vision loss (days to weeks) with metamorphopsia (distortion of
straight lines). Funduscopy shows a grayish-green subretinal discoloration with adjacent fluid/hemorrhage.
- Tx: may benefit from antioxidant vitamins and zinc, and smokers should receive smoking cessation counseling.
Wet AMD: VEGF inh (eg, ranibizumab, bevacizumab).

Hearing loss

(8589)
(1633)

High-frequency hearing loss due to chronic noise exposure. Transduction of mechanical sound waves into nerve
impulses occurs in the organ of Corti through the following steps:

1. Sound reaches the middle ear by vibrating the tympanic membrane

2. The vibration is transferred to the oval window by the ossicles
3. Vibration of the oval window causes vibration of the basilar membrane, which in turn causes bending of the hair
cell cilia against the tectorial membrane
4. Hair cell bending causes oscillating hyperpolarization and depolarization of the auditory nerve, thereby creating
nerve impulses from sound

Noise-induced hearing loss results from trauma to the stereociliated hair cells of the organ of Corti. The acoustic reflex
normally dampens the effects of loud noise by causing the stapedius and tensor tympani muscles to contract, which
lessens the responsiveness of the ossicles to sound. However, prolonged noise exposure can cause distortion or fracture
of the stereocilia due to shearing forces against the tectorial membrane. High-frequency hearing is lost first, regardless
of the frequency of the sound causing the dmg.

Nonallergic rhinitis (1345)

Topical preparations of alpha-adrenergic agonists cause vasoconstriction of the nasal mucosa vessels and are used as
decongestants. Overuse of these drugs causes negative feedback, resulting in decreased NE synthesis and release from
nerve endings, which diminishes their effect (ie, tachyphylaxis)

Cholesteatoma (11628)

Cholesteatomas are collections of squamous cell debris that form a mass behind the tympanic membrane.
Cholesteatomas can be congenital or may occur as an acquired primary lesion or following infection, trauma or surgery
of the middle ear. They can use hearing loss due to erosion into auditory ossicles.

Another example is the nitroglycerin.

Cricothyrotomy (8631)

Requires incision through the following structures:

1. Skin
2. Superficial cervical fascia (including subcutaneous fat and platysma muscle)
3. Investing and pretracheal layers of the deep cervical fascia
4. Cricothyroid membrane

Otitis externa (1814)

The vagus nerve provides cutaneous sensation to the posterior external auditory canal via its small auricular branch.
Sensation to the rest of the canal is from the mandibular division of the trigeminal nerve.

Traumatic brain injury (12227)

Smell occurs when odorants bind to nasal chemoreceptors that relay signals via the olfactory nerve through the
cribiform plate to the olfactory bulb, which then projects to the primary olfactory cortex in the medial temporal lobe.
Head trauma can tear olfactory nerve rootlets as they cross the cribiform plate, causing anosmia. Anosmia is often
associated with ageusia (loss of taste).

Idiopathic intracranial HTA (12257)

- Young obese women

- Daily headache
- Bilaterally symmetric papilledema
- Transient visual disturbances (related to impaired cerebral venous outflow and elevated intracranial pressure)
 - Symptoms characteristically worsen during Valsalva (eg, bending down, coughing -> intracranial pressure
increases
- Increased intracranial pressure is transmitted through the cerebrospinal fluid in the subarachnoid space, which
is continuous with the optic nerve sheath -> buildup pressure compresses the optic nerves externally -> impairs
axoplasmic flow within the optic nerves -> bilateral optic disc edema (papilledema)

Psychiatry

Management of somatic symptom disorder (10581)

Dissociative disorders (11824)

Depersonalization/derealization disorder 1 or both:
- Depersonalization (detachment, unreality of self)
- Derealization (detachment, unreality of
surroundings)
Dissociative amnesia Inability to recall personal information, usually of a
traumatic or stressful nature
Dissociative identity disorder Fragmentation into >2 distinct personalities
Discontinuity in identity & personal agency

Inhalants (15613)

Inhalants cause immediate effects as they are highly lipid soluble and act as CNS depressants. They can produce brief
transient euphoria, lethargy, disorientation, loss of consciousness, poor coordination and slurred speech. Effects
typically last 15-45 min. severe complications include cardiac dysrhythmias, dangerous behavior, seizures and death.
Nitrous oxide misuse in particular is associated with vit B12 deficiency and resultant symptoms of polyneuropathy (eg,
symmetric numbness, gait abnormalities)

Common withdrawal syndromes (1353)

Substance Symptoms Examination findings
Alcohol - Tremors - Seizures
- Agitation - Tachycardia
- Anxiety - Palpitations
- Delirium
- Psychosis
Benzo - Tremors
- Anxiety
 - Perceptual disturbances
- Psychosis
- insomnia
Heroin - Nausea - Dilated pupils
- Vomiting - Yawning
- Abd cramping - Piloerection
- Diarrhea - Lacrimation
- Muscle aches - Hyperactive bowel sounds
Stimulants (eg, cocaine, - Increased appetite No significant findings
amphetamines - Hypersomnia
- Intense psychomotor
retardation
- Severe depression (“crash”)
Nicotine - Dysphoria
- Irritability
- Anxiety
- Increased appetite
Cannabis - Irritability No significant findings
- Anxiety
- Depressed mood
- Insomnia
- Decreased appetite

Alcohol use disorder

(11577)

Naltrexone blocks the mu-opioid receptor and inh the rewarding and reinforcing effects of alcohol, helping to reduce
cravings and improving motivation to quit. The long acting depot form (given as monthly injections) is useful for px at
risk for nonadherence with daily admn. Acamprosate, another abstinence-promoting durg, works by modulating
glutamate neurotransmission at the N-methyl-D-aspartate receptor.

Fetal alcohol syndrome (15609)

Typical features of fetal alcohol syndrome include facial dysmorphism (short palpebral fissures, thin upper lip, smooth
philtrum), growth retardation, neurological abnormalities and behavioral difficulties

Acute stress disorder (6608)

Clinical features - Exposure to actual or threatened trauma
- Intrusive memories, nightmares, flashbacks with intense psychological/physiological
reactions
- Amnesia for event, detachment, avoidance of reminders
- Negative mood
- Arousal with sleep disturbance, irritability, hypervigilance, exaggerated startle, impaired
concentration
- Lasting >3 days & <1 month
Management - Trauma-focused, brief cognitive-behavioral therapy
- Consider pharmacotherapy for insomnia, intense anxiety
- Monitor for development of PTSD
Vs. PTSD distinguished mainly by duration, not all px with ASD develop PTSD, but they do have a greater risk of doing so
and should be monitored regularly. If the symptoms persist for >1 month and meet criteria for PTSD, the dx is changed
from ASD to PTSD

(15349) acute stress disorder is characterized by intrusive experiences (flashbacks, nightmares), arousal (poor
concentration, restless sleep), dissociative symptoms, and avoidance of traumatic reminders, as well as mood
disturbances in response to a life-threatening trauma. Symptoms last between 3 days and 1 month.

Rett syndrome (11796)

Rett syndrome is characterized by loss of speech and motor skills, deceleration of head growth, and stereotypic
purposeless hand movements after a period of normal development. It affects mainly girls and is associated with
mutations in the MECP2 gene

Parasominias (15762)

DSM-5 personality disorders (1431)

Differential dx of DSM-5 psychotic disorders (2063)
Brief psychotic disorder >1 day & <1 month, sudden onset, full return to function
Schizophreniform disorder >1month & <6 months, same symptoms as schizophrenia, functional decline not required
Schizophrenia >6 months (includes >1 month of active symptoms, can include prodromal & residual
periods), requires functional decline
Schizoaffective disorder Mood episode with concurrent active-phase symptoms of schizophrenia + >2 weeks of
delusions or hallucinations in the absence of prominent mood symptoms
Delusional disorder >1 delusions & >1 month, no other psychotic symptoms, normal functioning apart from
direct impact of delusions

Delusional disorder (2046)

Is characterized by >1 delusions for >1 months in the absence of other psychotic symptoms. behavior is not obviously
bizarre, and functioning is not significantly impaired apart from the direct impact of the delusions (eg, persistent false,
fixed beliefs). Paranoid personality disorder is characterized by overarching suspiciousness or distrust.

VS. Personality disorders involve persistent patterns of behavior usually arising in early adulthood. They are pervasive
acorss a broad range of situations (eg, interpersonal, vocational) but do not involve specific delu

Key features of somatic symptom & related disorders (1433)

Somatic symptom disorder Excessive anxiety & preoccupation with >1 unexplained
symptoms
Illness anxiety disorder Fear of having a serious illness despite few or no symptoms &
consistently negative evaluations
Conversion disorder (fx neurologic symptom disorder) Neurologic symptom incompatible with known disease
Factitious disorder Intentional falsification of illness in the absence of obvious
external rewards
Malingering Falsification or exaggeration of symptoms to obtain external
rewards

Clinical features of delirium, dementia & depression in the elderly (2122)

Delirium Dementia Depression
Onset Acute Gradual (months to years) Gradual (months)
Consciousness Impaired Intact Intact
Course Fluctuating Progressive Episodic
Prognosis Reversible Irreversible Reversible
Memory impairment Global impairment Remot memory spared Moderately impaired focus/concentration

Delirium (15410)

Delirium is frequently associated with psychotic symptoms. it is differentiated from primary psychotic disorders by
fluctuating levels of consciousness, impaired attention and disorientation. Delirium can occur post op and/or in
association with underlying medical illnesses or the introduction of certain medications.

VS. primary psychotic illnesses can be differentiated from delirium by the presence of a clear sensorium and are
excluded if the psyhchotic symptoms are better explained by medical condition. Brief psychotic disorder is characterized
by psychotic symptoms lasting > 1 day but <1 month. Delusional disorder is characterized by delusions lasting >1 month.

VS. Delirium tremens may occur in the context of severe alcohol withdrawal in px who are alcohol-dependent. It
typically occurs 48-96 hrs after the last drink.

(11899)

Delirium may manifest as acute changes in cognition and behavior. When nonpharmacological interventions are
ineffective, low-dose antipsychotics (eg, haloperidol) are the medications of choice to treat the behavioral (eg, severe
agitation) and psychotic manifestations of delirium.

(15702) Delirium is chacterized by the acute onset of fluctuating disturbance in attention and general cognition (eg,
altered level of consciousness, disorientation, hallucianations). Common mediations that may precipitate delirium in
high-risk populations (eg, elderly px) include sedative-hypnotics, benzodiazepines, opioids and anticholinergic
medications.

(11866) the differential diagnosis of anxiety includes medical conditions and substance-induced etiologies (eg,
intoxication, withdrawal). Primary anxiety disroders are not dx when anxiety is caused by the physiological effect of a
medical condition (Eg, hyperthyroidism) or drug

Generalized anxiety disorder (248)

Tx:

First lines:

- Cognitive behavioral psychotherapy

- SSRIs (Selective serotonine reuptake inhibitors such as citalopram)
- SNRIs (serotonin NE reuptake inh

Second line:

- benzos (eg, alprazolam, clonazepam and diazepam) but is second lie due to risks of dependence and tolerance,
and the potential for rebound and withdrawal syndromes with abrupt discontinuation
- buspirone: a nonbenzo anxiolytic

VS. propranolol, beta adrenergic blocker, can be used as needed for the performance subtype of social anxiety disorder

Panic disorder (15701)

Panic disorder consist of recurrent and unexpected panic attacks characterized by an abrupt surge of anxiety and
distressing cardiopulmonary/neurologic symptoms. agoraphobia, a common comorbid disorder, results in axiety about
and avoidance of situations where patients may feel trapped and helpless in the event of a panic attack (eg, crowds,
enclosed spaces, public transportation)

Language disorder (11810)

At age 2, children should have a vocabulary of 50-200 words and be using 2-word phrases. Parents’ concerns about
delayed milestones should be validated; they should be reassured that children often catch up but may need help.
Further evaluation and regular monitoring are required.

Narcolepsy (8878) DSM 5 criteria

Recurrent lapses into sleep or napping multiple times within the same day, occurring at least 3 times weekly for 3
months
At least 1 of the following:
- Cataplexy, defined either:
 Conscious, brief episodes of sudden bilateral muscle tone loss precipitated by emotions such as laughter or
joking
 Spontaneous, abnormal facial movements without emotional triggers
- Hypocretin-1 deficiency by cerebrospinal fluid analysis
- Rapid eye movement sleep latency <15 min
- Shortened REM sleep latency
Associated features:
- Hypnagogic or hypnopompic hallucinations
- Sleep paralysis
Narcolepsy with cataplexy is most often caused by the lack of 2 related neuropeptides, hypocretin-1 (orexin-A) and
hypocretin-2 (orexin-B), which are produced only in neurons located in the lateral hypothalamus. These neuropeptides
function to promote wakefulness and inh REM sleep-related phenoma.

(1458)

Vs. obstructive sleep apnea, the most common cause of excessive daytime sleepiness, is characterized by loud snoring,
gasping and apneas during sleep. It is caused by upper airway obstruction and is not associated with cataplexy, sleep-
related hallucinations, or sleep paralysis

Alcohol use disorder (11787)

Alcohol withdrawal (350)

Should be considered in hospitalized px who develop tremulousness, agitation, and elevated pulse and bp within 48 hrs
following admission. Benzo act as a substitute for the effects of alcohol on GABA receptors, preventing alcohol
withdrawal from occurring.

Bipolar disorder
Bipolar I disorder is dx in px with >1 episodes of mania, although most bipolar I px will experience both major depressive
and manic episodes, depressive episodes are not required for dx of bipolar I.

Manic episode (15730)

(11587)

Bipolar & related disorders

Manic episode Hypomanic episode
- Symptoms more severe - Symptoms less severe
- 1 week unless hospitalized - >4 consecutive days
- Marked impairment in social or occupational - Unequivocal, observable change in functioning
functioning or hospitalization necessary from px’s baseline
- May have psychotic features; makes episode - Symptoms not severe enough to cause makerd
manic by definition impairment or necessitate hospitalization
- No psychotic features
Bipolar I
- Manic episode (s)
- Depressive episodes common but not required for dx
Bipolar II
- Hypomanic episode (s)
- >1 major depressive episodes
Cyclothymic disorder
- >2y of fluctuating, mild hypomanic & depressive symptoms that do not meet criteria for hypomanic or major
depressive episodes

Mood stabilizers in bipolar disorder (1348)

Borderline personality disorder (11593)

NMS (512)
Serotonin syndrome (8327)

Increased serotonergic effect in the CNS, possibly through increased serotonin effect on 5-HT1A and 5-HT2A receptors

- Autonomic instability (eg, hyperthermia, HTA, tachy)

- Altered mental status (Eg, agitation, confusion)
- Neuromuscular hyperactivity (eg, tremor, hyperreflexia, myoclonus)
- GI symptoms and diaphoresis

Usually occurs combination of MAOI + serotonergic antidepressant (SSRI, SNRI or tricyclic antidepressant) may also
develpp if px uses 3, 4-methylenedioxy-methamphetamine

*Linezolid is used to tx infections caused by gram (+) bacteria, particularly vancomycin-resistant enterococcus and
methicillin-resistant s. aureus. Linezolid has MAOI activity

(2089) cyproheptadine is an antihistamine with antiserotonergic properties that can be used as an antidote in severe
cases of serotonin syndrome that do not respond to supportive measures.

ADHD (11784)

Reduced levels of NE and DOPA in the prefrontal cortex

Tx: stimulat drugs

Methylphenidate and amphetamines: work by blocking NE and DOPA reuptake

*amphetamines increase the release of NE and DOPA from presynaptic storage vesicles and inh MAO

(11809) decreased appetite and insomnia are the most common adverse effects of psychostimulant medications used to
tx ADHD. They are usually mild and can be managed without stopping the medication

Major depressive disorder

(573) MAOIs are particularly useful in px with tx-resistant major depressive disorder with atypical features. Increased
appetite and sleep, leaden paralysis, rejection sensitivity and mood reactivity are hallmarks of the atypical subtype.

(11622)
Vs. adjustment disorder:

Px with sufficient depressive symptoms are dx with MDD even if there is a clear psychosocial stressor that precipitated
the depression. In px who do not meet the criteria for MDD, adjustment disorder with depressed mood may be dx if
sadness, distress, and functional impairment develop <3 months following a psychosocial stressor.

MDD with psychotic features (11617)

Develops psychotic symptoms exclusively during a depressive episode

Eating disorders (11807)

DIAGNOSIS CLINICAL FEATURES TX
Anorexia nervosa - BMI <18.5 - Cognitive-behavioral therapy
- Intense fear of weight gain - Nutritional rehabilitation
- Distorted views of body weight & shape - Olanzapine if no response to
above
Bulimia nervosa - Recurrent episodes of binge eating - Cognitive-behavioral therapy
- Binge eating and compensatory behavior - Nutritional rehabilitation
(purge, exercise, fast, laxatives) - SSRI (fluoxetine), often in
- Excess worrying about body shape & weight combination with above
- Maintains normal to increased body weight
(MI 18.5-30)
Binge-eating disorder - Recurrent episodes of binge eating - Cognitive- behavioral therapy
- No compensatory behaviors - Behavioral weight loss therapy
- Lack of control during eating - SSRI
- Lisdexamfetamine

Bulimia nervosa (1843)

- Hypotension
- Tachycardia
- Dental erosion
- Electrolyte abnormalities (eg, hypokalemia, hypochloremia, elevated bicarbonate [likely due to metabolic
alkalosis])
- Chronic vomiting can also result in calluses on the dorsum of the hands (Russell sign)
 - Enlarged parotid glands with resultant increased salivary amylase

(15500)

Hypokalemia in an otherwise healthy young adult with a normal BMIA and preoccupation with body size is concerning
for self-indcued vomiting associated with bulimia nervosa. Common physical examination findings in bulimia nervosa
include tachy, hypotension, painless bilateral parotid gland swelling, calluses or scarring on the dorsum of the hand and
erosion of dental enamel

Cognitive impairment in elderly px (15447)

Normal aging - Slight decrease in fluid intelligence (ability to
process new information quickly)
- Normal functioning in all activities of daily living
Mild neurocognitive disorder (mild cognitive impairment) - Mild decline in >1 cognitive domains
- Normal functioning in all activities of daily living
with compensation
Major neurocognitive disorder (dementia) - Significant decline in >1 cognitive domains
- Irreversible global cognitive impairment
- Marked functional impairment
- Chronic & progressive, months to years
Major depression - Reversible mild-moderate cognitive impairment
- Features of depression (mood, interest, energy)
- Episodic, weeks to months

Schizoaffective disorder (2047)

Oppositional defiant disorder (11592)

Oppositional defiant disorder is a behavioral disorder of childhood characterized by argumentative and defiant behavior
toward authority figures. It does not involve the more severe violations of the basic rights of others seen in conduct
disorder.

For dx, the oppositional behaviors must be excessive in frequency and duration when compared to normative age-
appropriate behaviors. Although adolescents may test boundaries and assert their independence, this px’s 1-year hx of
persistent defiance, skipping classes, repeated refusal to follow rules, and irritable mood are beyond what would
expected for a 12-yo girl.

Defense mechanism
Countertransference (15242)

Countertransference consists of a provider’s response (eg, attitudes, thoughts, feelings, behaviors) toward a px based on
past personal relationships. Countertransference can be positive or negative, conscious or unconscious; if unrecognized,
it may have detrimental effect on px care.

Pharmacology

Common toxidromes & antidotes (15606)

Drug class Clinical features Antidote
Anticholinergic agents - Agitated delirium with Physostigmine
sympathetic hyperactivity
- Mydriasis, dry skin/mucous
membranes, urinary retention
Benzos - Sedation with normal vital Flumazenil
signs
- Slurred speech, ataxia
Opioids (eg, oxycodone) - Sedation with respiratory Naloxone
suppression
- Miosis, decreased bowel
sounds
Serotonergic agents - Serotonin syndrome: altered Cyproheptadine
mental status, mydriasis,
sympathetic hyperactivity,
hyperreflexia/clonus

Opioids (775)

Beta-endorphin is one endogenous opioid peptide that is derived from proopiomelanocortin (POMC). POMC is a
polypeptide precursor that goes through enzymatic cleavage and modification to produce not only beta-endorphins, but
also ACTH and MSH. The fact that beta-endorphin and ACTH are derived from the same precursor suggests that tere
may be close physiological rs between the stress axis and the opioid system

Antidepressants

(518) antidepressant monotherapy can induce mania in susceptible px, especially those with unrecognized bipolar
disorder

(11854) selective serotonin reuptake inh are considered first-line antidepressants that work by inh the serotonin
transporter (SERT) protein, which is normally responsible for transporting serotonin out of the synaptic cleft back into
the presynaptic neuron.

Potent antagonism of DOPA 2 receptors is the mechanism of action of first-generation antipsychotics such as
haloperidol. Second-generation antipsychotics have comparatively less affinity for D2 receptors and additional property
of serotonin 5-HT2 receptor antagonism, which underlies their lower risk of extra pyramidal side effects.

(8323) acute extrapyramidal symptoms (eg, dystonia, akathisia, parkinsonism) are due to the D2 blockade in the
nigrostriatal pathway. In the striatum, the inh effects of D2 are normally balanced by the excitotry actions of muscarinic
cholinergic neurons (M1). Strong dopa blockade causes an excess of cholinergic activity, resulting in extrapyramidal side
effects. Medications with M1 receptor antagonist properties, such as benztropine or antihistamine diphenhydramine,
helper re-establish the dopaminergic-cholinergic balance and effectively tx acute dystonia.

(706) bupropion is an antidepressant that does not cause sexual dysfunction. It is classified as a norepinephrine-
dopamine reuptake inh. Because of its stimulating effects, bupropion is useful in treating depression associated with
hypersomnia and low energy. Bupropion is also preferred because it causes less weight gain compared with other
antidepressants

Bupropion is contraindicated in px with bulimia nervosa, anorexia nervosa and seizure disorders because it lowers the
seizure threshold

(704) bupropion is a first-line antidepressant that is not associated with sexual side effects or weight gain. However, it is
associated with an increased seizure risk at high doses and is contraindicated in px with seizure disorders, anorexia
nervosa, and bulimia.

Trazodone (707)

Serotonin modulator (antagonizes postsynaptic serotonin receptors and inh serotonin reuptake) and has minimal effects
on NE and DOPA. Also alpha-adrenergic blockade (causes orthostatic hypotension and priapism) and H1 receptor
antagonism (sedating effect)

Treats: insomnia + depression

Tricyclic antidepressants (imipramine and clomipramine)

Used as second-line theray due to their higher side effect burden and risk for cardiotoxicity in OD

Tricyclic side effects (575)

Tricyclic action Corresponding side effects

Inh of presynaptic neurotransmitter reuptake (NE & - Tremor
serotonin) - Insomnia
Blockade of cardiac fast Na channels - Conduction defects
- Arrhythmias
- Hypotension
Antagonism of central & peripheral muscarinic - Confusion
acetylcholine receptors - Dry mouth
- Constipation, intestinal ileus
- Hyperthermia, flushing
- Urinary retention
Antagnosnism of peripheral alpha-1 adrenergic receptors - Orthostatic hypotention, falls
Antagonism of histamine (H1) receptors - Sedation

Clinical features of tricyclic antidepressant OD (708)

Symptoms of OD are caused by blockage of cardiac fast sodium channels and inh of muscarinic ACh, histamine, and
alpha-1 adrenergic receptors.

Blockage of fast sodium channels has deleterious effects on the cardiac conduction system, causing QRS and QT
prolongation and cardiac dysrhythmias. A widened QRS interval or ventricular arrhythmias are an indication for sodium
bicarbonate (NaHCO3) therapy. NaHCO3 increases serum pH, which favors the non-ionized (neutral) form of the drug,
making it less accessible to bind to sodium channels. NaHCO3 also increases extracellular sodium concentration, which
helps overcome the competitive, rapid sodium channel blockade induced by TCAs.

Clomipramine: tx OCD

Phenelzine: MAO inh tx resistant depression

Fluvoxamine and paroxetine:

Selective serotonin reuptake inh associated w/ high rates of sexual side effects (eg, decreased libido, anorgasmia,
delayed ejaculation)

Duloxetine is a serotonin and NE reuptake inh.

Zolpidem: non-benzo hypnotic, tx insomnia

(349) other medications in this class include zaleplon and eszopiclone. Like benzos, these medications bind to the GABAa
receptor at the benzo receptor site, where they act as GABAa agonists. However they are chmically distinct from benzo
and their binding is more specific for certain receptor subtypes. As a result, nonbenzos are primarily hypnotics and do
not produce the anxiolytic, muscle relaxant or anticonvulsant effects associated with benzos.

Antipsychotics

Primary mechanism of action Key side effects

First-generation - Potent dopamine D2 receptor - Extrapyramidal symptoms (acute dystonia,
antagonism akathisia, parkinsonism, tardive
dyskinesia)
Second generation - Dopamine D2 receptor - Metabolic syndrome, weight gain
antipsychotics antagonism - Extrapyramidal symptoms (less common
- Serotonin 2A receptor antagonism than FGAs)
Common antipsychotic side effects (15416)
First generation High-potency (eg, haloperidol)
- Extrapyramidal symptoms (acute dystonia, akathisia, parkinsonism), tardive
dyskinesia
Low-potency (eg, chlorpromazine)
- Sedation, cholinergic blockade, orthostatic hypotension, weight gain
Second generation antipsychotics - Metabolic syndrome, weight gain
- Extrapyramidal symptoms (less common than FGAs)

(15254) antipsychotic medications are first-line pharmacotherapy for schizophrenia. The primary mechanism of action of
antipsychotics is antagonism at postsynaptic dopamine D2 receptors. Second-generation antipsychotics (SGAs) have the
additional property of serotonin type 2 receptor antagonism, and some SGAs (eg, aripiprazole) also act as D2 receptor
partial agonists.

Clozapine tx guidelines
Indications - Tx-resistant schizophrenia
- Schizophrenia associated with suicidality
Adverse effects - Agranulocytosis
- Seizures
- Myocarditis
- Metabolic syndrome

Metabolic effects of second-generation antipsychotics (11848)

Metabolic syndrome - Weight gain
- Dyslipidemia
- Hyperglycemia (including new-onset diabetes)
Highest-risk drugs - Clozapine
- Olanzapine
Monitoring guidelines Baseline & regular follow-up
- BMI
- Fasting glucose & lipids
- BP
- Waist circumference

First generation antipsychotics side effects (515)

Type Side Effecs Examples
Low-potency (non-neurological) - Sedation (histaminergic - Chlorpromazine
blockade) - Thioridazine
- Anticholinergic side effects
(cholinergic blockade)
- Orthostatic hypotension
(alpha-1 adrenergic blockade
High-potency (neurological) Extrapyramidal symptoms: - Haloperidol
- Acute dystonia - fluphenazine
- Akathisia
- Parkinsonism
*due to potent D2 dopamine receptor
 antagonism in the nigrostriatal
pathway

Important antipsychotic side effects (510)

Extrapyramidal side effects - acute dystonic reaction: sudden-onset, sustained
muscle contractions
- akathisia: subjective restlessness with inability to
sit still
- drug-induced parkinsonism: tremor, rigidity,
bradykinesia, masked facies
Tardive dyskinesia - involuntary movements after chronic use (eg, lip
smacking, choreoathetoid movements)
Neuroleptic malignant syndrome - fever, rigidity, mental status changes, autonomic
instability

(513) there are 4 major dopaminergic pathways in the brain:

- Mesolimbic
- Mesocortical
- Tuberoinfundibular
- Nigrostiatal

DOPA hyperactivity in the mesolimbic pathway is associated with positive psychotic symptoms (eg, hallucinations,
delusions).

Antipsychotic medications work by blocking dopa-2 receptors in the mesolimbic dopamine pathway. Dopamine-2
receptor blockade in the tuberoinfundibular pathway can result in galactorrhea and amenorrhea.

(222)

The secretion of prolactin is controlled by the inhibitory effect of hypothalamic dopamine. Risperidone and other
antipsychotics cause hyperprolactinemia by blocking D2 receptors on lactotrophs. Elevated prolactin leads to
amenorrhea (inhibition of gonadotropin-releasing hormone release), galactorrhea, and breast soreness.

Neuroleptic malignant syndrome (11676)

Tx: dantrolene, which antagonizes ryanodine receptors and inh calcium release from the sarcoplasmic reticulum.
Bromocriptine, a dopamine agonist, has also shown clinical benefit in NMS

Drug induced parkinsonism (261)

Opioids (1287)

Methadone is a full mu-opioid receptor agonist used for the control of chronic pain and in opioid withdrawal and
maintenance tx of addiction. It has a long half-life with sustained effects after chronic dosing and suppresses cravings
and withdrawal symptoms for >24 hrs. Methadone has good bioavailability (36%-100%) allowing for oral admn. It is a
potent opioid agonist with high affinity for the opioid receptor, which blocks the euphoric effects of other opioids and
also accounts for its potent analgesic effects. Adverse effects of methadone include QT interval prolongation and
respiratory depression with lethality in OD

(1258) opioid analgesics can cause contraction of smooth muscles in the sphincter of Oddi, leading to increased
pressures in the common bile duct and the gallbladder.

Opioid intoxication (12540)

- Decreased RR
- Depressed mental status
- Miosis
- Decreased bowel signs
- Decreased tidal volume
- Hypotension, occurs due to opioid-induced histamine release from mast cells

Panic disorder tx (11838)

First line: selective serotonin reuptake inh (SSRIs) and serotonin-norepinephrine reuptake inh are preferred first-line
therapy due to their relatively benign side effect profile compared to tricyclic antidepressants and MAOIs

Vs Benzos: are also effective and have more rapid onset of action. Useful in severely symptomatic and functionally
impaired px who require rapid relief. However, benzos carry risks for abuse and result in physiological dependence and
withdrawal if stopped abruptly. Benzos should be avoided in px with a hx of substance abuse.

(937) Benzodiazepines act by binding to the benzodiazepine binding site, which allosterically modulates the binding of
GABA, resulting in an increased frequency of chloride ion channel opening. The influx of chloride ions into the neurons
causes neuronal hyperpolarization and inhibition of the action potential.

Renal, Urinary systems & electrolytes

Embryology (837)
The fetal genitourinary tract is derived from the metanephric blastema and the ureteric bud (a dorsal outgrowth from
the mesonephric duct). The metanephric blastema gives rise to functioning renal parenchyma by 10 weeks gestation
while the ureteric bud develops into the renal pelvis and ureters through dilation and canalization. The UPJ is the last
segment of the fetal ureter to canalize. The pathogenesis of UPJ obstruction may involve failure of this canalization
through abnormal development of circular musculature and/or collagen fibers. The UPJ is the most common cause of
unilateral fetal hydroneprhosis.

(1736) development of the metanephros, or true kidney, begins with formation of the metanephric diverticulum
(ureteric bud), which sprouts off the caudal portion of the mesonephric duct. The ureteric bud then penetrates into the
sacral intermediate mesoderm to induce the formation of the metanephric mesoderm (metanephric blastema). The
reciprocal exchange of inductive signals between the ureteric bud and metanephric blastema dirves their differentiation
into the structures that form the mature kidney. The ureteric bud ultimately gives rise to the collecting system of the
kidney, including the collecting tubules and ducts, major and minor calyces, renal pelvis and the ureters. The
metanephric blastema gives rise to the glomeruli, Bowman’s space, proximal tubules, the loop of Henle and distal
convoluted tubules.

Congenital anomalies (652)

Failure of the urachus to obliterate before birth leads to several abnormalities:

1. Complete failure of obliteration of the urachus results in a patent urachus that connects the umbilicus and
bladder. Px present with straw-colored urine discharge from the umbilicus, which is exacerbated by crying,
training, or prone position. Local skin irritation can cause erythema
2. Failure to close the distal part of the urachus (adjacent to the umbilicus) results in a urachal sinus. This presents
with periumbilical tenderness and purulent umbilical discharge due to persistent and recurrent infection.
3. Failure of the central portion of the urachus to obliterate leads to urachal cyst

Filtration fraction (1555)

The GFR can be estimated by inulin or creatinine clearance, while the RPF is calculated using the PAH clearance. The
FF=GFR/RPF is the fraction of the RPF that is filtered across the glomerular capillaries into Bowman’s space. It is usually
equal to 20% in healthy individuals.

Diffusion (1988)

Diffusion speed across a semipermeable membrane increases with higher molecular concentration gradients, larger
membrane surface areas, and increased solubility of the diffusing substance. Diffusion speed decreases with increased
membrane thickness, smaller pore size, higher molecular weights and lower temperatures.

H2O permeability (1043)

RBF (1556)

RBF = (urine [PAH] x urine flow rate) / plasma [PAH]

RBF= (PAH clearance)/ (1-hematocrit)

PAH (1588)

PAH is primarily secreted into the nephron by the proximal tubule, but some is also freely filtered by the glomerulus.
PAh is not reabsorbed by any portion of the nephron. Therefore, tubular fluid concentration of PAH is lowest in
Bowman’s space.

GFR (1618)

Increases in the capillary hydrostatic pressure or the Bowman’s space oncotic pressure will increase GFR, while increase
in capillary oncotic pressure or Bowman’s space hydrostatic pressure will decrease GFR. The filtration fraction (FF) can
be calculated by dividing the GFR by the renal plasma flow (RPF). Increases in GFR or decreases in RPF will increase the
FF.

(1651)

The GFR depends on the interplay fo hydrostatic and oncotic pressures in the glomerular capillaries and Bowman’s
space. The GFR increases with higher glomerular hydrostatic pressure and decreases with increasing Bowman’s capsule
hydrostatic pressure or higher glomerular capillary oncotic pressure. Acute ureteral obstruction increases hydrostatic
pressure proximal to the constriction. This pressure rise is transmitted back to the Bowman’s space, resulting in
decreased GFR.
The filtration fraction is the portion of the renal plasma flow that is filtered from the glomerular capillaries into
bowman’s space (ie, the GFR:RPF ratio). With acute ureteral obstruction (first 12 hrs), the RPF may transiently increase;
however, with time, efferent arteriolar constrction (in response to reduced GFR) will decrease RPF. Even at later stages,
though, the GFR remains depressed to a greater extent than the RPF, resulting in reduced FF.

GFR estimation (8881)

When the GFR is normal, relatively large decreases in GFR result in only small increases in serum creatinine. Conversely,
when the GFR is significantly decreased, small decrements in GFR produce relatively large changes in serum creatinine. A
good rule of thumb is that every time GFR halves, serum creatinine doubles.

Urinary tract obstruction

(1916) flank pain radiating to the groin with a ballotable flank mass that develops within a week of pelvic surgery
suggests ureteric obstruction. The ureter runs in close proximity to the pelvic vessels. It courses anterior to the iliac
vessels (area of resection of the pelvic nodes, which drain the uterus and cervix) and just posterior to the uterine artery
near the lateral fornix of the vagina. It is vulnerable to injury during pelvic surgery, such as that involved in hysterectomy
with pelvic lymphadenectomy. Unintentional ureteral ligation causes obstruction with hydronephrosis and flank pain
due to distension of the ureter and renal obstruction.

(15200)

Anuria + suprapubic fullness => acute urinary retention

Etiologies:

- Bladder outlet obstruction: precipitated by urethral compression, typically due to BPH (men > 50yo). Other
etiologies: transitional carcinoma and rectal or uterine malignancy
- Medications: anticholinergic medications (eg, oxybutynin, atropine and sympathomimetics (Eg,
pseudoephedrine)
- Neurologic dysfunction: diabetic neuropathy, spinal cord injury and stroke

(15193)

Urinary tract obstructon causes reflux of urine into the renal tubules and increased tubular hydrostatic pressure. The
intraglomerular capillary hydrostatic pressure is unchanged, resulting in a decreased hydrostatic pressure gradient
across the glomerular capillary wall and a reduction in glomerular filtration. Oncotic pressure is maintained by large
plasma proteins which are not filtered across the glomerular capillary basement membrane; it is unaffected by a urinary
tract obstruction.

Vesicoureteral reflux (833)

When ureter enters the bladder wall at a more perpendicular angle

Px with VUR are at much higher risk of chronic pyelonephiritis. Inflammation can occur from pyelonephiritis or from VUR
itself due to hydrostatic pressure on the papillae. Ongoing injury leads to renal scarring, most commonly at the upper
and lower poles of the kidney in which compound papillae are found. Compound papillae are always open, unlike simple
papillae in the mid kidney, and are therefore much more susceptible to dilation and subsequent injury. If uncorrected,
VUR can lead to loss of nephrons and secondary HTA

CKD
(15324) EPO is produced primarily by peritubular fibroblast cells in the renal cortex in response to decreased renal
oxygen delivery (eg, decreased blood hb content). EPO acts on erythrocyte precursor cells in the bone marrow to
stimulate red blood cell production. Px with CKD have inflammatory dmg to renal EPO-producing cells and often develop
normocytic anemia due to insufficient EPO.

(15323) erythropoietin signal transduction is primarily mediated by the Janus kinase 2/signal transducers and activators
of transcription (JAK2/STAT) pathway, which promotes erythrocyte precursor survival.

Polycystic kidney disease (3)

Mutations in the polycystin genes (PKD1, PKD2)

HTA is often the earliest clinical sign. Stretching of the renal capsule and dilation/rupture of the cysts can result in
abd/flank pain; cyst rupture can also cause gross hematuria. Renal dysfunction worsens with age, and approximately
50% of adults progress to end-stage renal disease by age 70. Extrarenal manifestations include liver cysts and
intracranial aneurysms that may rupture.

Erythropoiesis-stimulating agents (ESAs) (eg, erythropoietin, darbepoetin alpha) (11945)

Are associated with increased risk for thromboembolic events (eg, vascular graft thrombosis, stroke) due to increased
blood viscosity, as a result of the elevation in red cell mass, many px also develop HTA, possibly due to activation of
erythropoietin receptors on vascular endothelial and smooth muscle cells.

Hypertensive (malignant) nephrosclerosis (7571)

Histologic characteristics:

- Leakage of fibrinogen and coagulation factors through the damaged endothelium causes fibrin deposition in
vessel walls, which appear as circumferential, acellular eosinophilic deposits (fibrinoid necrosis)
- Over time, release of growth factors by dmged tissue stimulates the formation of concentric layers of collagen
and proliferating smooth muscle cells, resulting in an “onion skin” appearance (hyperplastic arteriosclerosis) of
the arteriole

Renal infarction (15288)

Are most commonly caused by cardioembolic disease; atrial fibrillation is the greatest risk factor. Clinical features
include flank pain, nausea, vomiting, low-grade fever, and HTA (due to renin release from hypoxic tissue). Gross
pathology demonstrates sharply demarcated, yellow-white, wedge-shaped areas with surrounding hyperemia.

Diabetic nephropathy (6425)

Is characterized by mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis

(1913) moderately increased albuminuria (urine albumin 30-300 mg/day) is the earliest manifestation of diabetic
nephropathy. Screening for diabetic nephropathy is best achieved using an albumin-specific urine assay (regular dipstick
urinalysis has low sensitivity)

(884) KW nodules

- Location in the peripheral mesangium

- Ovoid or spherical shape
- Lamellated appearance
 - Eosinophilic (heamtoxylin and eosin stain)
- Periodic acid-schiff-positve

(151)

Nephritic vs nephrotic syndrome (385)

(15353)
Nephritic syndromes are characterized by glomerular inflammation, resulting in hematuria and RBC casts on urinalysis.
Renal dysfunction (Eg, azotemia) and HTA are common but not always present in early disease. Px may also have mild to
moderate proteinuria and edema, although typically not as severe as in nephrotic syndrome

The most common cause of nephritic syndrome is immune complex deposition. Most immune complex-related nephritic
syndromes (eg, PSGN, membranoproliferative glomerulonephritis, lupus nephritis) are associated with IgG and/or IgM
complexes and have heavy glomerular complement deposition and subsequent serum hypocomplementemia
(consumption)

However, IgA nephropathy is typically associated with normal serum complement levels, likely due to the weak
complement-fixing activity of IgA as compared to IgG and IgM.

IgA nephropathy is characterized as recurrent gross hematuria that ypically occurs spontaneously (as in this px) or within
5-7 days of an upper respiratory or pharyngeal infection (synpharyngitic hematuria). When IgA nephropathy is
accompanied by extrarenal symptoms (eg, abd pain, arthralgias, skin purpura), the syndrome is called Henoch-Schonlein
purpura.

Pathological findings in nephritic syndromes (11)

Cause of glomerular injury Characteristic biopsy features
Post-strep glomerulonephritis Antibodies against streptococcal IF: C3 granular staining along GBM
antigens that deposit in GBM EM- subepithelial humps
*lumpy-bumpy
Anti-GBM disease Antibodies against type IV collagen in LM: glomerular crescents
GBM IF: linear staining (IgG) along GBM
IgA nephropathy Deposition of IgA-containing LM: mesangial hypercellularity
complexes IF: IgA in mesangium
Alport syndrome Defective type IV collagen in GBM EM: lamellated appearance of GBM

IgA nephropathy (10)

IgA nephropathy (Berger disease), the most common cause of glomerulonephritis. It typically affects older children and
young adults and presents with painless hematuria within 5-7 days of an upper respiratory tract infection. The
hematuria lasts for several days and then subsides temporarily, returning every few months or with another upper
respiratory infection (synpharngitic hematuria). Complement levels are usually normal. Renal biopsy will show mesangial
hypercellularity with mesangial IgA deposits seen on immunohistochemical staining.

When IgA nephropathy is accompanied by extrarenal symptoms (eg, abd pain, arthralgias, purpuric skin lesions), the
syndrome is called Henoch-Schonlein purpura

Poststreptococcal glomerulonephritis (1)

Acute poststreptococcal glomeruolonephritis

Clinical features - Can be asymptomatic
- If symptomatic:
Gross hematuria (tea- or cola-colored urine)
Edema (periorbital, generalized)
HTA
Lab findings - Urinalysis: + protein, + blood, +RBC casts
- Serum:
Decrease C3 & possible decrease C4
Increase Serum creatinine
Increase Anti-DNase B & increase AHase
Increase ASO & increase anti-NAD (from preceding pharyngitis

Glomerular disorder

Minimal change disease is caused by immune dysregulation and overproduction of a glomerular permeability factor,
which dmgs podocytes and decreases the anionic properties of the glomerular basement membrane. This results in
selective loss of albumin in the urine, in contrast to the non selective proteinuria sen in other forms of nephrotic
syndrome.

(384) is often idiopathic but can occur after an inciting event, including respiratory infections, immunizations or insect
sting/bite. Subsequent T-cell dysfunction leads to the production of a glomerular permeability factor, possibly IL-13,
which dmgs podocytes and decreases the anionic properties of the glomerular basement membrane. Loss of negative
charge results in the selective loss of albumin in the urine, which causes hypoalbuminemia and edema.

In light microscopy shows normal glomeruli and no immunoglobulin or complement deposits are seen with
immunofluorescent staining. However, electron microscopy (EM) shows diffuse podocyte foot process effacement and
fusion. These abnormal findings are generally reversible after corticosteroid therapy, and most children experience rapid
resolution with an excellent long-term prognosis.

(383) most common cause of nephrotic syndrome in children. Systemic T-cell dysfunction leads to the production of
glomerular permeability factor, which causes podocyte foot process fusion and decreases the anionic properties of the
glomerular basement membrane. The loss of negative charge leads to selective albuminuria.

Membranous glomerulopathy (382)

MG is caused by immune-complex deposition in the subepithelial portion of the glomerular capillary wall. Light
microscopy shows diffuse thickening of the glomerular basement membrane (GBM) without an increase in glomerular
cellularity. Immunofluorescence reveals granular deposits of IgG and C3 deposits located between the GBM and
epithelial cells. Protrusion of the GBM through the deposits resemble spikes and domes when stained with a silver stain.

MG is a common cause of nephrotic syndrome in adults. Most cases are idiopathic, with the remainder due to chronic
infection (Eg, viral hepatitis, syphilis), solid tumors (eg, lung, colon) or systemic lupus erythematous (SLE). This px with
inflammatory arthritis, oral ulcers, and antinuclear antibodies likely has MG secondary to SLE (which leads to renal
disease from anti-double stranded DNA immune complex formation)

Thrombotic thrombocytopenic purpura (11608)

Thrombocytopenic thrombotic purpura-hemolytic uremic syndrome, one of the thrombotic microangiopathy syndromes

Primary thrombotic microangiopathy (TMA) syndromes share common clinical and pathologic features and result in
platelet activation and diffuse microthrombocsis in arterioles and capillaries. TMA syndromes present with hemolytic
anemia w/ schistocytes, thrombocytopenia and organ injury (eg, brain, kidneys, heart)

Pentad:

- Fever
- Neurologic symptoms (progressive lethargy)
- Renal failure
- Anemia
- Thrombocytopenia

Unlike DIC in which coagulation cascade activation leads to prolongation of coagulation studies (PT and aPTT), TTP is
almost always characterized by normal PT and aPTT

Renal artery stenosis (15246)

Renal artery stenosis (eg, severe HTA, abd bruits) causes decreased renal artery perfusion, which activates the renin-
angiotensin-aldosterone system. Increased secretion of renin leads to increased production of angiotensin I and
angiotensin II, which causes increased peripheral resistance and elevated systemic bp. Increased aldosterone secretion
causes increased renal Na+ reabsorption and K+ and H+ excretion, resulting in relative hypokalemia and metabolic
alkalosis.

(7569) Renal artery stenosis causing significant renal hypoperfusion will result in a decreased glomerular filtration rate
and activation of the renin-angiotensin-aldosterone system. This leads to increased renin release by modified smooth
muscle (juxtaglomerular) cells in the walls of afferent glomerular arterioles. Chronic renal hypoperfusion can cause
hyperplasia of the juxtaglomerular apparatus.

(694) px with bilateral renal artery stenosis have reduced renal perfusion (due to atherosclerotic blockage) and are
dependent upong angiotensin II-induced efferent vasoconstriction to maintain glomerular filtration rate. ACE inh block
angiotensin II-mediated vasoconstriction, which may reduce systemic bp and lower renal perfusion. In addition, ACE inh
cause dilation of the efferent arteriole, leading to a reduction in GFR and renal filtration fraction

Fibromuscular dysplasia (15247)

FMD is a nonatherosclerotic disease characterized by abnormal tissue growth within arterial walls, leading to arterial
stenosis, tortuosity, aneurysms or dissections.

FMD can involve any artery but most commonly the renal, cerebral (eg, carotid, vertebral) and visceral arteires. Up to
80% of px develop renal artery stenosis.

Congenital anomalies of kidney and urinary tract (2)

In horseshoe kidney, the kidneys are fused at the poles. The isthmus of the horseshoe kidney usually lies anterior to the
aorta and posterior to the inferior mesenteric artery (IMA). During fetal development, the IMA limits the ascent of the
horseshoe kidney.

Renal vein thrombosis (26)

Nephrotic syndrome is a hypercoagulable state. Sudden-onset abdominal or flank pain, hematuria and left-sided
varicoceles suggest renal vein thrombosis, a well-known complication of nephrotic syndrome. Loss of anticoagulant
factors, especially antithrombin III, is responsible for the thrombotic and thromboembolic complications of nephrotic
syndrome.

.Sudden onset abd or flank pain and gross hematuria with elevated lactate dehydrogenase as a result of renal infarction

Renal calculi

(815)

Nephrolithiasis
Content Frequency Radiograph opacity pH Microscopic appearance
Calcium oxalate 70-80% ↑↑ -- Octahedron (square with an “x” in the center)
Calcium phosphate >7.0 - Elongated, wedge-shaped
- Forms rosettes
Magnesium 15% ↑ >7.0
ammonium
phosphate (struvite or
triple phosphate)

- Rectangular prism (“coffin lids”)

Uric acid 5% -- <7.0

- Yellow or red-brown, diamond or rhombus

Cystine 1% ↑ <7.0

- Flat, yellow, hexagonal

Cystinuria is an AR disorder caused by defective transportation of Cystine, Ornithine, Arginine, and Lysine (COLA) across
the intestinal and renal tubular epithelium.

- in the intestine, this causes absent (or diminished) intestinal absorption of these free AA. However, px do not
develop aa deficiencies, as these amino acids are absorbed in sufficient quantities as oligopeptides
- In the kidneys, impaired tubular reabsorption of these AAs leads to a high urinary cystine concentration,
resulting in the formation of cystine kidney stones. The other AA (eg, ornithine, lysine and arginine) are relatively
soluble in urine and do not result in the formation of kidney stones

Risk factors for cysteine precipitation include low urine pH (pH<7), the presence of a preexisting crystal nidus and urine
superstauration.
(817) normally, citrate excreted by the kidneys binds to ionized calcium in the urine, preventing the formation of
insoluble calcium-oxalate complexes. When urinary citrate is low (hypocitraturia), increased calcium availability leads to
increased formation of calcium-oxalate complexes that can precipitate and form calcium oxalate stones. Hypocitraturia
often occurs in the setting of chronic metabolic acidosis (eg, distal renal tubular acidosis, chronic diarrhea) due to
enhanced renal citrate reabsorption

(814) results from defective dibasic aa transport in intestinal and proximal renal tubular epithelial cells. it most often
presents with recurrent stone formation at a young age due to decreased reabsorption of cysteine from the urine.
Urianalysis shows pathognomonic hexagonal cystine crytals, and the sodium cyanide-nitroprusside test can be used to
detect excess cystine in the urine

Struvite (6739)

Struvite stones are typically seen in px with recurrent upper urinary infection caused by urease-producing organisms (eg,
Ureaplasma, Proteus, Staphylococcus, Klebsiella, Providencia, Pseudomonas species).

Uric acid kidney stones (12081)

Risk factors - Increased uric acid excretion: gout, myeloproliferative disroders
- Increased urine concentration: hot, arid climates; dehydration
- Low urine pH: Chronic diarrhea (GI bicarbonate loss), metabolic syndrome/DM
Pathophysiology - Acidic urine favors formation of uric acid (insoluble) over urate (soluble)
- Supersaturation of urine with uric acid precipitates crystal formation
Clinical characteristics - Radiolucent stones (not visible on x-ray)
- Uric acid crystals on urine microscopy
- Urine pH usually <5.5
Treatment - Alkalinization of urine (potassium citrate)

(15217)

Urinary cast Composition Associated conditions

Hyaline Tamm-horsfall protein Nonspecific, concentrated urine
Fatty Lipid droplets Nephrotic syndrome
Waxy Degenerated hyaline cast Chronic kidney disease
Granular (muddy brown) Sloughed tubular epithelial cells with Acute tubular necrosis
pigmented granules
WBC White blood cells Pyelonephritis, interstitial nephritis
RBC Red blood cells Glomerulonephritis

Rhabdomyolysis usually presents with myalgia, proximal muscle weakness, and dark urine (myoglobinuria) in the setting
of trauma, sepsis, or overexertion. Kidney injury occurs due pigment-mediated tubular injury, leading to acute tubular
necrosis. Urine microscopy typically reveals granular, muddy brown casts

Hypertensive nephrosclerosis (7570)

Chronic HTA -> HTA nephrosclerosis, which is characterized by compensatory medial hypertrophy and fibrointimal
proliferation; endothelial dmg from elevated systemic pressure also leads to hyaline arteriolosclerosis. The narrowed
arteriolar lumens cause a progressive decrease in renal blood flow, resulting in glomerular ischemia and fibrosis
(glomerulosclerosis)

Varicocele (1805)

Pressure in the left renal vein may become elevated due to compression where the vein crosses the aorta beneath the
superior mesenteric artery. This “nutcracker effect” can cause hematuria and flank pain. Pressure can also be elevated in
the left gonadal vein, leading to formation of a varicocele.

Chornic kidney disease (1663)

The abnormal bone pathology seen in CKD is referred to as renal osteodystrophy. In CKD, failure of glomerular and
tubular function results in hyperphosphatemia and hypocalcemia. -> hyperparathyroidism -> mobilizes calcium from
bones by activating osteoclastic and osteocytic activity. This high-turnover osteodystrophy increases bone resorption
more than bone formation, causing osteopenia and pathologic bone changes similar to those seen in primary
hyperparathyroidism (osteitis fibrosa cystica). Px can also develop PTH resistance, resulting in low-turnover adynamic
bone disease and osteomalacia

(979) CKD usually causes hyperphosphatemia (binds serum Ca2+) and low 1, 25-dihydroxyvitamin D (creases intestinal
Ca2+ absorption and Ca2+ release from bone). The resulting hypocalcemia stimulates release of parathyroid hormone,
causing secondary hyperparathyroidism.

Analgesic nephropathy/chronic interstitial nephritis (1049)

Presents:

- Modest elevation in serum creatinine

- Mild proteinuria
- Evidence of tubular dysfunction (polyuria, nocturia)
- Microscopic hematuria
- Sterile pyuria

NSAIDS concentrates in the renal medulla along the medullary osmotic gradient, with higher levels in the papillae. These
drugs uncouple oxidative phosphorylation and are thought to cause glutathione depletion with subsequent lipid
peroxidation, resulting in dmg to tubular and vascular endothelial cells. Prolonged use results in chronic interstitial
nephritis, seen as patchy interstitial inflammation with subsequent fibrosis, tubular atrophy, papillary necrosis and
scarring and caliceal architecture distortion. Also decrease prostaglandin synthesis, causing constriction of medullary
vasa recta and ischemic papillary necrosis.

Membranous nephropathy (2131)

Weight gain + edema with 4+ protein and oval fat bodies on urinalysis has nephrotic syndrome. The presence of
phospholipase A2 receptor (PLA2R) antibodies suggests a dx of membranous nephropathy. Antibodies against PLA2R,
primarily IgG4, can lead to immune deposition in the glomerulus and are thought to be a major factor in the
pathogenesis of primary (idiopathic) membranous nephropathy, a common cause of neprhotic syndrome in adults.

Anti-PLA2R antibodies are highly specific for membranous nephropathy; positive titers effectively rule out other causes
of nephrotic syndrome (Eg, focal segmental glomerulosclerosis) and may eliminate the need for invasive renal biopsy. In
addition, titers correlate with disease activity and serial measurements can be used to determine the efficacy of
immunosuppressive therapy.

Diabetes insipidus

(206) DI is due to inadequate secretion (central) or renal action (nephrogenic) of ADH. Admn of ADH distinguishes
central from nephrogenic DI. Dmg to the posterior pituitary gland may produce only transient central DI, whereas dmg
to the hypothalamic nuclei often causes permanent central DI.

(211)

Water deprivation test w/ desmopressin (DDAVP) interpretation

The urine osmolality is persistently low despite an increase in serum osmolality with water deprivation. When
desmopressin is administered, patients with central DI show a rapid increase in urine osmolality and reduction in urine
volume, whereas those with complete nephrogenic DI do not.

Polyuria & polydipsia (212)

Water deprivation test
Serum sodium Urine osmolality after water Urine osmolality with
deprivation vasopressin injection
Normal Normal Increased No additional increase
Central diabetes insipidus High No change or mild increase Large increase
Nephrogenic diabetes High No change or mild increase Mild increase
insipidus
Primary polydipsia Low Increased No additional increase

Renal cell carcinoma (905)

Renal cell carcinoma (905) + (818)

Presentation - Asymptomatic (most common)
- Hematuria
- flank pain
- palpable abd mass
Risk factors - Smoking, HTA, obesity
- Toxin exposure (eg, heavy metal, petroleum by-products)
Gross - Spherical mass, often with invasion of the renal vein
- Golden-yellow tissue (due to high lipid content)
Histology (Clear cell) - Cuboidal or polygonal cells with abundant, clear or yellow cytoplasm
- Branching, “chicken-wire” vasculature
Paraneoplastic syndromes - Polycythemia (erythropoietin production)
- Hypercalcemia (parathyroid hormone-related peptide production)
 - Hormone production (eg, ACTH, renin)
Common metastatic site - Lungs (“cannonball metastases”)
- Bone (osteolytic)

RCC is classified into subtypes based on cellular origin; clear cell carcinoma is the most common type and accounts for
up to 85% of RCCs. CCC originates from the epithelium of the proximal renal tubules. Gross pathology typically
demonstrates a sphere-like mass composed of golden-yellow tissue (due to high lipid content) with areas of focal
necrosis and hemorrhage. It often invades the renal vein and may extend into the inferior vena cava. On microscopy,
CCC appears as cuboidal or polygonal cells with abundant clear cytoplasm and eccentric nucli.

(1862) rounded/pologonal cells with abundant clear cytoplasm -> characteristic of clear cell carcinoma. It originates
from proximal tubular epithelial cells and contains copious amounts of intracellular glycogen and lipids.

(11806) paraneoplastic ysndormes are common in RCC due to the secretion of biologically active substances by the
tumor cell.s hypercalcemia is frequently seen due to increased production of parathyroide hormone – related peptide or
overproduction of prostaglandins that promote bony resorption. Erythrocytosis (due to ectopic erythropoietin
production) and hepatic dysfunction unrelated to liver metastases may also be seen.

(7226) tends to invade the renal vein; IVC obstruction can occur by intraluminal extension of the tumor. Obstruction of
the IVC produces symmetric bilateral lower extremity edema, often associated with prominent development of venous
collaterals in the abd wall.

Acute pyelonephritis (888)

Urine sediment microscopy reveals WBCs, WBC casts, and bacteira.

Pyuria and bacteriuria are also found in infections of the lower urinary tract, but WBC casts are pathognomonic for
pyelonephritis in the setting of UTI. They are formed only in tubules, where WBCs precipitate with Tamm-Horsfall
protein secreted by tubular epithelial cells. WBC casts can also be seen with actue interstitial nephritis, which often
presents with low-grade fever and findings of acute kidney injury (urinary symptoms are not present)

Metabolic acidosis (11939)

Acute ischemic colitis, due to embolic disease related to his atrial fibrillation. The ischemic bowel undergoes anaerobic
metabolism, causing lactate accumulation in the blood that leads to an anion gap metabolic acidosis. Acidosis stimulates
renal ammoniagenesis, a process by which renal epithelial cells metabolize glutamine, generating ammonium and
bicarbonate. Ammonium ions are transported into the tubular fluid and excreted in the urine while peritubular
capillaries absorb bicarbonate, which functions to buffer acids in the blood.

Atheroembolism (810)

Invasive vascular procedure can be complicated by atheroembolic disease, which may involve the kidneys, GI tract, CNS
and the skin. Light microscopy shows a partially or completely obstructed arterial lumen with needle-shaped cholesterol
clefts within the atheromatous embolous.

(15250)
Atheroembolic disease typically occurs after an invasive vascular procedure due to mechanical dislodgement of
atherosclerotic plaque, resulting in the showering of cholesterol-rich microemboli into the circulation. Needle-shaped
cholesterol clefts in affected vessels are diagnostic. Commonly involved organs include the kidneys (eg, acute kidney
injury), skin (eg, blue toe syndrome, livedo reticularis), GI tract (eg, bleeding, infarction) and CNS (eg, stroke, amaurosis
fugax)

Acute kidney injury

(7624)

Prerenal Acute tubular necrosis

Mechanism Decreased renal perfusion (eg, Renal ischemia (eg, hemorrhage,
hypovolemia, CHF) sepsis) or nephrotoxins (eg,
aminoglycosides, radiocontrast)
Findings
BUN/creatinine ratio Typically >20 Typically ~10-15
Fractional excretion of sodium <1% >2%
Urine osmololity >500 mOsm/kg ~300 mOsm/kg
Microscopy Hyaline cast Muddy brown casts

Acute Renal Failure types:

- Prerenal: caused by decreased renal perfusion; the nephrons remain intact and tubular function is preserved.
Etiologies include volume loss (eg, hemorrhage), low-output states (eg, myocardial infarction, CHF), or systemic
vasodilation (Eg, sepsis)
- Intrinsic: caused by tubular epithelial or glomerular dmg; resorptive capacity is lost. Etiologies include acute
tubular necrosis (due to renal ischemia or nephrotoxins) or glomerular diseases (eg, glomerulonephritis,
nephrotic syndrome)
- Postrenal: caused by urinary tract obstruction with normal nephrone capacity. Etiologies include bilateral calculi,
enlarged prostate, or a renal tumor in an individual with a sole functional kidney

(885)
Ischemic kidney injury predominantly affects the renal medulla, which has low blood supply even under normal
conditions. The most metabolically active segments of the nephron are particularly vulnerable, including the terminal
(straight) portion of the proximal tubule and thick ascending limb of the loop of Henle.

ATN is characterized histologically by flattening of the tubular epithelila cells with loss of the brush border and
subsequent cell necrosis and denudation of the tubular basement membrane. Muddy brown casts consisting of
sloughed and degenerated tubule cells are pathognomonic for ATN. Px have increased serum creatinine, a blood urea
nitrogen/serum creatinine ratio <20 (indicating intrinsic renal pathology), and oliguria.
Stages of acute tubular necrosis (886)
Initiation stage (24-36 hrs) Tubular injury resulting from:
- Ischemia (eg, hemorrhage, acute MI, sepsis, shock)
- Cytotoxins (eg, radiologic contrast agents,
aminoglycosides, myoglobin)
Maintenance stage (1-3 weeks) Oliguric renal failure (decrease GFR, decrease urine output,
fluid overload)
Increase creatinine/BUN, increase potassium, metabolic
acidosis
Recovery phase (months) Gradual increase in urine output, leading to high-volume
diuresis
Continued impairment of renal tubular function, resulting
in electrolyte wasting (decrease potassium, magnesium,
phosphorus, calcium)

(1053) when ATN is associated with multiorgan failure, renal fx may be permanently impaired; in such px, foci of
interstitial scarring can be seen on light microscopy.

Acute tubular necrosis due to nephrotoxins (15227)

Common nephrotoxins - Antibiotics: aminoglycosides (eg, gentamicin), vancomycin
- Antivirals: cidofovir, foscarnet
- Other: IV radiocontrast dye, cisplatin, heme pigment
Histology - Tubular epithelial necrosis with casts obstructing the tubular lumens and rupture of
basement membrane
- Extensive involvement of the proximal tubules
Presentation - BUN/creatinine ration <20:1, FENa>2%
- Muddy brown granular casts, low urine osmolality
- Oliguria or polyuria, +/- electrolyte abnormalities
Aminoglycosides are filtered across the glomerulus and concentrate within the proximal renal tubules, where they
impair lysosomal fx, protein synthesis and mitochondrial activity, leading to acute tubular necrosis (ATN)

Manifests within 1 week of therapy initiation

Renal papillary necrosis (834)

Abrupt-onset gross hematuria in an otherwise healthy px with a family hx of sicle cell disease suggests RPN due to
underlying sickle cell trait. Conditions associated with RPN include:

- Sickle cell disease or trait: sickled cells cause obstruction of small kidney vessels, predisposing to ischemia
- Analgesic nephropathy: many NSAID inh RBF by decreasing prostaglandin synthesis and vasoconstricting the
afferent arterioles. Certain analgesics can cause ischemia in px predisposed to renal hypoperfusion
- DM: Diabetic metabolic abnormalities (eg, nonenzymatic glycosylation) cause changes in vascular walls, leading
to renal vasculopathy and subsequent hypoperfusion
- Pyelonephritis and urinary tract obstruction: the edematous interstitium of the pyelonephritic kidney
compresses the medullary vasculature, leading to ischemia. In this px, acute pyelonephritis is unlikely in the
absence of fever or costovertebral angle tenderness

Gray-white or yellow necrosis of the distal two-thirds of the renal pyramids is seen macroscopically and corresponds
microscopically to coagulation necrosis with preserved tubule outlines; cortical surface scars can develop subsequently
as inflammatory foci are replaced by fibrous depressions. Symptoms are due to sloughed papillae (sometimes visible in
urine as tissue flecks) and include dark or bloodyurine and colicky flank pain (due to ureteral obstruction)

Urinary incontinence (8249)

Urge incontinence, or overactive bladder syndrome, is caused by uninhibited bladder contractions (detrusor instability).
It results in sense of urgency accompanied by an involuntary loss of urine. If behavioral therapy alone is unsuccessful,
pharmacologic therapy with an antimuscarinic drug (targeting M3 receptors) can help improve symptoms. These agents
should be used with caution in the elderly, as they may cause confusion and functional decline.

Diuretics (1533)
Loop diuretics (685)

The most commonly used first line agents, work by inh Na/K/2Cl symporters in the ascending limb of the loop of Henle.
Inh of similar symporters in the inner ear is believed to cause ototoxicity (tinnitus, vertigo, hearing impairment, or
deafness). It usually occurs with higher dosages, preexisting CKD, rapid IV admn or when used in combination with other
ototoxic agents (aminoglycosides, alicylates, cisplatin)

(6475) on audiogram, a subclinical loss of response to high frequencies occurs in 74-100% of px receiving cumulative
cisplatin doses of 200 mg/m2. Approximately 6% of px receiving cisplatin develop clinical hearing loss, with children
particularly at risk.

ACE inhibitors (696)

ACE inh reduce angiotensin II levels and cause efferent arteriole dilation, thereby decreasing the glomerular pressure
and filtration rate. This can precipitate acute renal failure in px with reduced intrarenal perfusion pressure at baseline
(eg, renal artery stenosis, congestive heart failure, hypovolemia)

(693) ACE inh can cause significant first-dose hypotension in px with volume depletion (eg, from diuretic use) or heart
failure. To reduce the risk of first-dose hypotension, ACE inh therapy should be initiated at low dosages. Significant
hypotension is most likely to occur with px with high plasma renin activity, such as those with volume depletion (eg,
from diuretic use [hydrochlorothiazide in this px]) or heart failure.

(690) ACE inh block the effect of ACE, decreasing angiotensin II and aldosterone levels. By decreasing angiotensin II
levels, ACE inh directly interrupt negative feedback loops, thereby increasing renin and angiotensin I levels. ACE is also
responsible for the breakdown of bradykinin; ACE inh therefore increase bradykinin levels.
Differential dx of urinary incontinence (10962)
Etiology Symptoms
Stress - Decrease urethral sphincter tone Leakage with coughing, lifting and sneezing
- Urethral hypermobility
Urge Detrusor hyperactivity Sudde, overwhelming urge to urinate
Overflow - Impaired detrusor contractility Incomplete emptying & persistent involuntary dribbling
- Bladder outlet obstruction

More prevalent in women:

- External urethral sphincter injury is common during vaginal child birth

- Post menopausal women have estrogen deficiency, which can cause laxity and weakness of pelvic floor support
- Other risk factors: obesity, co-morbidities (eg, diabetes, stroke) and genituourinary surgery (eg, hysterectomy)

Ureter blood supply (1680)

The blood supply to the proximal ureter comes from branches of the renal artery. At the distal ureter, arterial blood
supply arises from the superior vesical artery. In between, the arterial supply to the ureter is anastomic and highly
variable, with possible afferent branches from the gonadal, common and internal iliac, aorta and uterine arteries.

Ureter injury (1804)

The urters pass posterior to the ovarian (gonadal) vessels within the retroperitoneum and anterior to the
common/external iliac arteries to reach the true pelvis. Within the true pelvis, the ureters lie anterior to the internal iliac
artery and medial to the ovarian vessels. The uterine artery crosses over the anterior surface of the urter (“water under
the bridge”)

Prerenal azotemia

Hypovolemia induced (15207)

Hypovolemia (eg, excessive diuresis) can cause acute kidney injury due to reduced renal blood flow (prerenal azotemia).
Urine sodium and fractional excretion of sodium levels are low, and the BUN/creatinine ratio is elevated. In severe cases,
acute tubular necrosis can occur and cause an intrinsic renal injury pattern (ie, high urine sodium, normal
BUN/creatinine ratio) with muddy brown casts on urianalysis

(15209) hypovolemia triggers a variety of compensatory mechanisms to improve tissue perfusion. These include
activation of the renin-angiotensin-aldosterone system (resulting in increased aldosterone and endothelin release),
increased vasopressin release, and increased sympathetic tone

NSAIDS (15229)

Prostaglandins also help maintain renal perfusion by dilating the afferent arteriole, particularly in px with intravascular
volume depletion (eg, CHF, diarrhea, excessive diuresis) or CKD. In such px, increased prostaglandin synthesis is
necessary to preserve renal blood flow and maintain GFR. In at-risk px , inh of afferent dilation with NSAIDs results in
reduced glomerular filtration and prerenal azotemia with elevations in creatinine and BUN (ration >20:1)

NSAID-induced acute kidney injury is often dx incidentally on lab tests performed for other reasons and px are generally
asymptomatic. Urinanalysis is typically bland without proteinuria, hematuria, or casts. Prolonged NSAID use can cause
CKD (analgesic nephropathy) due to papillary necrosis and chronic interstitial nephritis.
Reproductive

Female Reproductive System & Breast

HPV (11929)

The oncogenic capability of HPV is dependent on its ability to integrate into the host genome and subsequently produce
viral proteins E6 and E7, which interact with cell cycle regulatory proteins p53 and Rb, respectively. E6 binds p53, leading
to its ubiquination and subsequent proteasomal degradation. Without p53, the cell is unable to halt cell growth to repair
damaged DNA or trigger apoptosis when DNA is dmged beyond repair. Similarly, E7 binds Rb and displaces bound
transcription factors, promoting unregulated DNA replication and cyclin-mediated cell cycling. The collective effects of
E6 and E7 lead to inhibiton of cell cycle regulation and evasion of apoptosis, consequently increasing malignant
potential.

Contraceptives (879)

Urinary incontinence (11820)

Stress urinary incontinence is defined as involuntary urine loss with increased intraabdominal pressure. Pelvic floor
strengthening (eg, Kegel exercises) targets the levator ani to improve support around the urethra and bladder.

Mullerian anomalies (1831)

Failed lateral fusion of the paramesonephric ducts can result in various anomalies. Incomplete lateral fusion of the upper
segments can result in a bicornuate uterus characterized by an indentationo in the center of the fundus. Complete lack
of fusion can lead to utedine didelphys (double uterus and cervix). Failed involuation of the paramesonephric ducts can
result in a longitudinal uterine septum.

Epithelia of the female reproductive tract (2056)

Organ Type Key features
Ovary Simple cuboidal (eg, germinal) - Rapidly proliferate to repair ovulatory surface defects
Fallopian tube Simple columnar - Ciliated cells transport egg/embryo
- Damage can cause infertility, hydrosalpinx, ectopic
pregnancy
Uterus Simple columnar (eg, - Stratum fuctionalis sloughs off during menstruation
endometriuem) - Prolonged estrogen exposure prevents shedding,
resulting in hyperplasia/malignancy
Cervix Ectocervix: stratified squamous - Cervical glands secret mucus:
non-keratinized Thin and watery during ovulation
Mucus plug in pregnancy
Endocervix: simple columnar HPV infection predisposes to cervical malignancy
Vagina Stratified squamous non- - Maintain acidic environment to prevent infection
keratinized

Accessory nipple (8904)

Are the most common congenital breast anomaly resulting from failed regression of the mammary ridge in utero. They
are usually asymptomatic but can become tender along with breast tissue during times of hormonal fluctuation.

Twinning (8406)

Dizygotic twins result from fertilization of 2 oocytes by 2 different sperm and always have 2 amnions and 2 chorions. In
contrast, monozygotic twins arise from the fertilization of a single oocyte. Monozygotic twinning may occur at different
stages of embryogenesis, which affects the organization of the fetal membranes: dichorionic/diamnionic (days 0-4),
monochorionic diamniotic (days 4-8), monochorionic monoamniotic (days 8-12), and monochorionic monoamniotic
conjoined twins (>13 days)

Mullerian aplasia (ie, Mayer-Rokitansky-Kuster-Hauser syndrome) (1809)

Have no upper vagina (eg, short vagina) and variable uterine development. These px are 46, XX females with normal
ovaries and secondary sexual characteristics.

Androgen insensitivity syndromes (6455)

Ureter injury (11781)

The urter can be injured during hysterectomy due to its close proximity to the uterine structures. The distal ureter may
be severed during ligation of the uterine vessels because the ureter passes inferior and lateral to the uterine artery at
the level of the internal cervical os prior to entering the bladder (eg, “water under the bridge”)

Ovarian Torsion (11901)

Ovarian torsion typically involves twisting of the infundibulopelvic ligament, often due to the weight of a large adnexal
mass. The resulting occlusion of the blood and nerve supply to the ovary results in severe acute pelvic pain and ovarian
ischemia.

The ovary is suspended posterolaterally to the uterus by the uteor-ovarian ligament and receives its blood supply
through the vessls that traverse the infundibulopelvic ligament (eg, suspensory ligament of the ovary)

The mesosalpinx is the portion of the broad ligament that connects the fallopian tubes to the pelvic sidewall

The round ligament maintains the anteflexion of the uterus

The uterosacral ligament connects the posterior aspect of the uterus to the anterior portion of the sacrum

Ovarian vein thrombosis (11920)

Thrombosis risk is markedly increased during pregnancy and puerperium due to Virchow’s triad:

- Stasis from pregnancy-related venous dilation and compression of the IVC and iliac veins by the gravid uterus
- Physiologic increases in factors VII, VIII, and X, as well as von Willebrand factor and fibrinogen (to protect from
hemorrhage during miscarriage or childbirth)
- Endothelial dmg due to uterine infection or intrapartum vascular trauma.

Symptoms include fever and localized abd or flank pain. Most thrombosis is right-sided and can extend to the IVC;
however, left ovarian vein thrombosis can extend to the left renal vein.
Hydatidiform mole (791)
Type Complete Partial
Clinical features - Vaginal bleeding - Vaginal bleeding
- Enlarged uterus inconsistent with dates - Crampy abdominal pain
- Extremely high beta-hCG levels that can case: - Normal uterine size
.hyperemesis gravidarum - Normal to high beta-HCG
.pre-eclampsia levels
.hyperthyroidism
.theca-lutein cysts
Pathologic features - Diffuse trophoblastic proliferation &edematous - Some enlarged villi with focal
chorionic villi (“bunch of grapes”appearance) trophoblastic proliferation
- No fetal/embryonic tissue - Fetal/embryonic tissue
present
Karyotype 46, XX or XY 69, XXX or XXY
(Paternal DNA only) (maternal & paternal DNA)
Immunochemistry p57-negative p57-positive
Risk of gestational 15-30& <5%
trophoblastic
neoplasia

Intraductal papilloma (11890)

Is a proliferation of papillary cells in a cyst wall or duct that may contain focal atypia. It is the most common cause of
bloody nipple discharge and typically presents without breast masses or skin changes.

Estrogen synthesis (1560)

Estradiol, the predominant estrogen in the human body, is primarily derived from androgens. Androgens and
progesterone are synthesized from cholesterol in the theca interna cells under the influence of LH. Androgens released
from the theca interna cells migrate into the nearby granulosa cells, which contain the enzyme aromatase. Aromatase
converts the androgens into estradiol. This reaction is stimulated by FSH.

Gallstones and pregnancy (68)

Estrogen-induced cholesterol hypersecretion and progesterone-induced gallbladder hypomotility are responsible for the
increased incidence of cholelithiasis in women who are pregnant or using OCPs

Labor (11888)

Immediately prior to delivery, estrogen stimulates upregulation of gap junctions between individual myometrial smooth
muscle cells. An increase in gap junction density at delivery heightens myometrial excitability. Gap junctions consist of
aggregated connexin proteins (Eg, connexin-43) that allow passage of ions between myometrial cells.

Estrogen also increases expression of uterotonic (Eg, oxytocin) receptors, which mediate calcium transport through
ligand-activated calcium channels. The combination of an increase in gap junction density and uterotonic receptors
results in coordinated, synchronous labor contractions.

Postpartum hemorrhage (11908)

Postpartum hemorrhage is an obstetrical emergency. Bilateral ligation of the internal iliac artery can decrease uterine
blood flow and control postpartum hemorrhage that is unresponsive to medical management (eg, uterine massage,
uterotonic medications). The uterus has collateral blood flow from the ovarian arteries, which is sufficient to maintain
uterine function after internal iliac ligation.

Anesthesia

(1739)

Important landmarks for a PN block include the ischial spines and sacrospinous ligament. The ischial spines are bony
protrusions located posterolateral to the vaginal sidewall. The sacrospinous ligament is a firm band that runs medially
and posteriorly from the ischial spine to the sacrum. When admn a PN block, the ischial spines should be palpated
intravaginally, and the anesthetic should be injected medially in very close proximity to the ischial spine through the
sacrospinous ligament

Other important structures include the internal pudendal artery and inferior gluteal artery, which run medial to the PN.
Inadvertent injection into these vessels can lead to hematoma or arrhythmia from IV infiltration of local anesthetics (eg,
lidocaine).

Ectopic pregnancy (334)

In an ectopic pregnancy, the uterine specimen would reveal decidualized endometrium only, consistent with dilated,
coiled endometrial glands and vascularized edematous stroma. These changes occur in the luteal phase of the menstrual
cycle, under the influence of progesterone, as the endometrium prepares for implantation. Embryonic and trophoblastic
tissue will be absent from the uterus.

Maternal serum alpha-fetoprotein screening (342)

Elevated Decreased
- Open neural tube defects (eg, anencephaly, open - Aneuploidies (eg, trisomy 18 & 21)
spina bifida
- Ventral wall defects (eg, omphalocele,
gastroschisis)
- Multiple gestation
AFP is synthesized by the fetal liver, GI tract, and yolk sac (early gestation only), and levels increase with gestational age.

Vs. tabacco use during pregnancy increases the risk of fetal growth restriction (FGR) and placental insufficiency.
Decreased estriol levels, not AFP levels, are associated with placental abnormalities and FGR.

Preecampsia (1914)
Gestational trophoblastic disease

Complete mole (1830)

- Has no fetal structures

- Composed entirely of large, edematous and disordered chorionic villi
- Appear grossly as clusters of vesicular structures “bunch of grapes”
- Typically presents with pelvic pain and vaginal bleeding
- Uterus larger than expected
- Beta-hCG markedly elevated due to trophoblastic hyperplasia
- U/S: central heterogenous mass with multiple cystic areas and classically described as a “swiss chese” or
“snowstorm”
 - Risks: extremes of maternal age, prior molar pregnancy, prior miscarriage, or infertility

Vs. partial molar pregnancies 69, XXX or 69, XXY, typically contain fetal tissue and normal placental villi intermixed with
hydropic villi

Polyhydramnios (337)
Fibroadenoma breast (1109)

Histologically, fibroadenomas are characterized by a benign-appearing cellular or myxoid stroma that encircles
epithelium-lined glandular and cystic spaces. The lesions have a well-defined border but may compress and distor the
surrounding glandular epithelium. As women age, the epithelium atrophies and the stroma becomes more hyalinized

Breast cancer (581)

(1762) HER2/ERBB2 is a member of the epidermal growth factor receptor family. It is overexpressed in 20%-30% of
breast cancers. HER2 is a transmembrane glycoprotein with tyrosine kinase activity that acts to increase cell
proliferation. It is present in diminutive amounts in normal breast and ovarian cells. In breast cancer, HER2
overexpression (positivity) is associated with poorly differentiated, rapidly growing tumors. Clinically, HER2 status is used
to predict therapeutic response to anti-HER2 monoclonal antibodies (eg, trastuzumab)

Ovarian cancer

Teratoma (11652)

One of the most common subtypes of ovarian germ cell tumors (which occur most frequently in females age 10-30).
Based on their histologic differentiation, teratomas are divided into mature and immature types. Mature teratomas of
the ovaries are usually benign and contain cell lines of >1 germ layer. A diversity of tissues, including hair follicles, skin,
teeth, bones, and other tissues, can be seen on histologic examination.
Infertility (207)

Failure of ovulation (eg, anovulation in polycystic ovary syndrome) is a common cause of infertility. Tx options include
the admn of drugs that act like FSH and LH. Menotropin (human menopausal gonadotrophin) therapy mimics FSH and
triggers the formation of a dominant ovarian follicule. When the follicle appears mature, exogenous human chorionic
gonadotropin (hCG) is admn. The alpha subunit of hCG is structurally similar to LH and therefore simulates the LH surge
by inducing ovulation.

Septic abortion (11961)

Typically presents with fever, abd pain, uterine tenderness, and/or foul-smelling discharge after pregnancy termination.
Common offending pathogens include S. aureus and E. coli due to seeding of the uterine cavity during instrumentation.
Tx includes broad spectrum antibiotics and prompt surgical evacuation to remove the nidus of infection and prevent
severe complications such as sepsis, multi-organ failure, and death. Long-term complications include synechiae
(adhesions) in the uterine cavity that can lead to secondary amenorrhea and infertility (Ashermann syndrome)

Opioids (1255)

Neonatal abstincence syndrome

Pathophysiology - Withdrawal from transplacenal opiates de to maternal drug use
Clinical manifestations - Neurologic: irritability, hypertonia, jittery movements, seizrues (rare)
- GI: diarrhea, vomiting, feeding intolerance
- Autonomic: sweating, sneezing, pupillary dilation
Tx - Opioid therapy (eg, morphine, methadone)

PCO (2095)

- Does not wish to become pregnant: dual estrogen-progestin OCP

 - Desire fertility: clomiphene: is an estrogen receptor modulator that decreases negative feedback inh on the
hypothalamus by circulating estrogen, thereby increasing gonadotropin production

Turner syndrome (256)

Streak ovaries, amenorrhea, and infertility are the gynecologic complications of Turner syndrome. In addition px with TS
usually have short stature, webbed neck, shield chest, and low posterior hairline. Bicuspid aortic valve is the most
common cardiac comorbidity

(339) posterior neck mass is most likely a cystic hygroma, and the bilateral extremity swelling is consistent with
lymphedema. These findings in the context of diminished femoral pulses (suggestive of coarctation of the aorta) in a
newborn girl are classic for Turner syndrome. Turner syndrome is characterized by a 45, X karyotype due to loss of
paternal chromosome X. both cystic hygromas and lymphedema occur due to abnormalities of lymphatic outflow in
Turner syndrome. The swelling decreases with age.

(7489) Px with Turner syndrome have a variable degree of ovarian dysgenesis. The ovaries usually appear
underdeveloped and atrophic (“streak gonads”) due to in utero degeneration of the ovarian follicles with replacement
by fibrotic tissue.

(8292) a nonstenotic bicuspid aortic valve manifests with an aortic ejection sound, which is an early systolic, high-
frequency click heard over the right second interspace. As the valve calcifies, it may result in progressive valvular
dysfunction, manifesting with aortic stenosis or regurgitation and associated murmurs. Px with a bicuspid aortic valve
are susceptible to infectious endocarditis due to abnormal leaflet structure and turbulent flow.

Malignant ovarian neoplasms (1837)

Histologic type Dx Key features
Epithelial *presents Serous cystadenocarcinoma - Most common ovarian CA
increase CA-125, but - Often bilateral
also endometriosis - Histology: psammoma bodies
Mucinous cystadenocarcinoma - Pseudomyxoma peritonei
- Mucin-producing epithelial cells
Germ cell Dysgerminoma - Adolescents
- Increase B-hCG, increase LDH
- Histology: “fried egg cells”
Endodermal sinus (yolk sac) - Increase AFP
- Aggressive
- Schiller-Duval bodies resemble glomeruli
Stroma (sex cord) Granulosa cell - Increase estrogen (eg, endometrial hyperplasia,
postmenopausal bleeding)
- Increase inhibin
- Histology: call-exner bodies, coffee bean nuclei
Sertoli-leydig - Increase androgens (eg, hisurtism,
clitoromegaly)

Sertoli leydig cell ovarian tumor (1928)

Typically px as a large adnexal mass with amenorrhea and virilization (eg, hirsutism, clitoromegaly, deeper voice).
Virilization occurs due to increased testosterone secretion by this rare sex cord-stromal tumor. Px with this neoplasm
are usually young women, and it is histopathologically similar to sertoli cell testicular neoplasms. Microscopic
examination of these tumors shows hollow or solid tubules lined by round sertoli cells and surrounded by a fibrous
stroma.

Granulosa cell tumor of the ovary (1158)

Clinical features - Large, unilateral adnexal mass
- Increase estrogen (endometrial hyperplasia, precocious puberty)
- Increase inhibin
Histology - Call-exner bodies (cuboidal granulosa cells in a rosette pattern with coffee bean nuclei)
- Yellow theca cells with lipid

VS. Struma ovarii is a germ cell tumor of the ovary that can cause hyperthyroidism by secreting thyroxine.
Histopathology of this tumor reveals mature thyroid tissue.

Epithelial ovarian CA (578)

Amenorrhea (1839)

The underlying pathophysiology of functional hypothalamic amenorrhea (FHA)

The decrease in leptin inh pulsatile gonadotropin-releasing hormone (GnRH) release from the hypothalamus, causing
decreased pituitary LH and FSH secretion, low circulating estrogen levels, and amenorrhea.

Teratogenic

Vitamin A (6443)
Is highly teratogenic, particulary in the first trimester, when organogenesis primarily occurs. Potential complications
include spontaneous abortion and fetal defects (eg, microcephaly, cardiac anomalies, early epiphyseal closure, growth
retardation). For this reason, oral retinoid acid (eg, isotretinoin) for acne tx is contraindicated in pregnancy.

Male reproductive

Erectile dysfunction (11800)

The prostatic plexus lies within the fascia of the prostate and innervates the corpus cavernosa of the penis, which
facilitates penile erection. As a result, prostatectomy or injyry to the prostatic plexus can cause erectile dysfunction.

Inhibin (1902)

Steroidogenic factor-1 (SF-1) is a nuclear receptor that regulates the transcription of several genes involved in
steroidogenesis, sexual development, and reproduction. Mutations of SF-1/NR5A1 cause a wide variety of phenotypic
features in males and females, including genital malfomrations and Sertoli cell failure. Selective impairment in Sertoli cell
function would cause decreased production of inhibin and lead to increased FSH levels, as well as infertility due to
impaired sperm production. However, the leydig cells are unaffected, so no changes in testosterone or LH levels would
be expected/

Gonadal arteries (11658)

The gonadal arteries arise from the abd aorta slightly below the renal arteries. Each gonadal artery courses obliquely
downward and laterally within the retroperitoneal space near the psoas major muscle. The right gonadal artery travels
in front of the inferior vena cava and behind the ileum, whereas the left gonadal artery courses behind the left colic and
sigmoid arteries and iliac colon. After crossing anteriorly over the ureter, the gonadal arteries run parallel to the external
iliac vessels and eventually traverse the inguinal canal to supply the testes via the spermatic cord.

(6556) Androgen-binding protein (ABP) is synthesized by the Sertoli cells of the seminiferous epithelium and secreted
into the seminiferous tubule lumen. ABP maintains the high local concentration of testosterone necessary for normal
sperm production and maturation.

Scrotum (8326)

Due to its intra-abd origin, lymphatic drainage of the testis is to the para-aortic lymph nodes. In contrast, lymph drainage
from the scrotum goes into the superficial inguinal lymph nodes.

Hydrocele (1827)

A communicating hydrocele results when serous fluid accumulates within the tunica vaginalis in the setting of a patent
processus vaginalis. It presents as a painless swelling that transilluminates on examination

(419) communicating hydroceles and indirect inguinal hernias are caused by an incomplete obliteration of the processus
vaginalis. The resultant connection between the scrotum and abd cavity can allow for fluid leakage (hydrocele) or the
passage of abd contents (indirect inguinal hernia)

BPH (811)
Increased hydrostatic force is needed to overcome the obstruction, causing hypertrophy of the bladder wall musculature
and dilation of the ureters, renal pelvis and calyces (hydronephrosis). If left untreated, urinary reflux can lead to
significant pressure-induced parenchymal atrophy with scarring and eventual CKD.

(1737)

(658) finasteride is an anti-androgen that inh the action of 5-alpha-reductase. This enzyme is responsible for peripheral
conversion of testosterone to its active metabolite, DHT. DHT has a much higher affinity for the testosterone receptor
and mediates the majority of testosterone effects, including development of male external genitalia and prostate
enlargement. Finasteride counteracts these effects of DHT and is used for tx for BPH.

Px with androgenetic alopecia have higher levels of 5-alpha-reductase and a higher quantity of androgen receptors.
Thus, reducing the 5-alpha-reductase level with finasteride is also useful for treating androgenetic alopecia.

(14797) microscopic or gross hematuria can sometimes arise in px with BPH due to the formation of new, friable blood
vessels in the area of prostatic hyperplasia. Further examination with cystoscopy is generally warranted to rule out other
(potentially life-threatening) causes of hematuria such as bladder cancer and urinary calculi. Cystoscopy in those with
BPH often shows increased detrusor wall trabeculations due to detrusor muscle hypertrophy (to generate increased
pressure to overcome urethral obstruction)

Treatment (14818)

First line: tamsulin

Second: 5-alpha reductase inhibitor (eg, finasteride, dutasteride). These medications block conversion of testosterone to
dihydrotestosterone (which has a higher affinity for the testosterone receptor and mediates the majority of
testosterone effects); the excess testosterone is then converted to estrogens (eg, estradiol) by aromatase, leading to
gynecomastia.

Testicular cancer (15828)

Epidemiology - Age 15-35
- Risk factors: family history, cryptorchidism
Types - Germ cell tumors (95%): seminomatous or nonseminomatous (embryonal carcinoma,
yolk sac, choriocarcinoma, teratoma, mixed)
 - Sex cord – stromal tumors: Sertoli cell, Leydig cell
Manifestations - Unilateral, painless testicular mass
- Dull ache in lower abdomen
Diagnosis - Examination: firm, ovoid mass
- Elevated tumor markers (AFP, beta-hCG, LDH)
- Scrotal U/S

Nonseminomatous germ cell tumors are composed of partially differentiated germ cells, which often retain the ability to
secret human chorionic growth hormone and alpha-fetoprotein (serum tumor markers). Serum lactate dehydrogenase,
a marker of tissue injury and cell turnover, is also frequently increased.

Prostate cancer (11747)

CA of the pelvis, including the prostate, spread to the lumbosacral spine via the vertebral venous plexus, which in turn
communicates with a number of veous networks, including the prostatic venous plexus.

Testicular cancer (624)

hCG has a structure similar to TSH. Px with testicular germ cell tumors or gestational trophoblastic disease may develop
very high serum hCG concentrations, which can stimulate TSH receptors and cause paraneoplastic hyperthyroidism.

Klinefelter (343)

Caused by meiotic nondisjunction -> 47, XXY

Variants: 46, XY/47, XXY mosaicism and 48, XXXY (higher numbers of X chromosomes are more likely to have more
severe manifestations).

- Hyalinization and fibrosis of the seminiferous tubules -> small, firm testes; azoospermia + leydig cell dysfunction
-> testosterone deficiency + FSH, LH levels increased secondary to gonadal failure
- testosterone def -> eunuchoid body habitus: tall stature + gynecomastia + facial and body hair is sparse
- Mild intellectual disability is seen in some patients. Psychosocial abnormalities (eg, lack of insight, poor
judgment)

Prostate cancer

(209) leuprolide is a gonadotropin-releasing hormone agonist that causes a transient increase in pituitary LH secretion,
which leads to a rise in testosterone levels. However, continuous use of leuprolide suppresses LH release and leads to a
decrease in testosterone production.

Tx (657)
Sexual differentiation (1449)

The SRY gene on the Y chromosome codes for the testes-determining factor, which differentiates the primitive gonads
into testes. Sertoli cells produce anti-Mullerian hormone, which causes regression of the Mullerian ducts and suppresses
female internal reproductive organ development. Leydig cells produce testosterone, differentiating Wolffian ducts into
internal male reproductive organs. Dihydrotestosterone is required for differentiation of the external male genitalia.

Hypospadias (1870)

Differentiation and development of the external genitalia occurs during weeks 8-15 of gestation. In the female the
urethral (urogenital) folds do not fuse and ultimately form the labia minora. In the male, the urethral folds fuse to form
the ventral aspect of the penis and the penile raphe, which serve as the anterior wall of the urethra. Incomplete fusion
of these folds results in an abnormal opening of the urethra at a location proximal to the distal tip of the glans penis.

VS. epispadias is an abnormal opening of the urethra on the dorsal surface of the penile shaft that results from faulty
positioning of the genital tubercle in the fifth week of gestation.

Kartagener syndrome (664)

Primary ciliary dyskinesia results from an AR mutation in the proteins responsible for normal flagellar and ciliary
structure and fx (eg, dynein, assembly proteins). Clinical manifestations include situs inversus, chronic sinusitis,
bronchiectasis and infertility

Respiratory

Respiratory resistance (481)

Pulmonary auscultation examination findings (7614)

Pleural effusion (15420)

Pleural effusions that develop due to pressure changes (eg, heart failure, cirrhosis, nephrotic syndrome) are typically
transudative, whereas those that develop due to inflammation and consequent increased vascular membrane
permeability (eg, infection, malignancy, rheumatologic disease), are typically exudative

The Light criteria are used to differentiate transudative and exudative pleural effusions and aid in the differential
diagnosis. Transudative effusions have a low fluid-to-serum ratio of total protein and LDH and low absolute levels of
LDH.

Pneumothorax (490)

Primary spontaneous pneumothorax occurs in px without preexisting pulmonary disease when a large change in the
alveolar or intrapleural pressure results in a break in the visceral (eg, ruptured superficial bleb) pleura and air trapping
between the pleural spaces.
Aspiration pneumonia (1745)

Due to gravity, supine px typically aspirate into the posterior segments of the upper lobes and superior segments of the
lower lobes. Px who are upright (or semirecumbent) tend to aspirate into the basilar segments of the lower lobes.
Aspirated material is more likely to travel down the right main bronchus

Thoracocentesis (844)
Should be performed above the 8th rib in the midclavicular line, the 10 th rib along the midaxillary line and the 12 th rib
along the posterior scapular or paravertebral line.

Respiratory physiology (1386)

The binding of O2 to hb increases the affinity for binding of subsequent O2 molecules (cooperative binding). In the lungs,
the binding of O2 to hb drives the release of H+ and CO2 from hb (Haldane effect). In the peripheral tissues, high
concentrations of CO2 and H+ facilitate O2 unloading from Hb (Bohr effect)

Work of breathing (8260)

Respiratory mucosa (480)

(536) larger particles become trapped by mucus secretions in the trachea, bronchi, and proximal bronchioles; these
trapped particles are swept upward toward the pharynx by the collective beating of ciliated cells. the finest particles
(<2microm) can travel past the highly ciliated airways into the respiratory bronchioles and alveoli, where they are
phagocytized by alveolar macrophages.

Pulmonary function test (1919)

Lung transplant rejection (534)

Type Onset Etiology Pathophysiology
Hyperacute Min to hrs Preformed host antibodies to Neutrophilic infiltration with fibrinoid necrosis with
donor ABO or HLA hemorrhage and ischemia (“white graft” reaction)
Acute <6 months Cell-mediated response to Perivascular (small lung vessels) & submucosal
mistmatched donor HLA (bronchiole) lymphocytic infiltrates which can expand
to include the alveolar walls
Typically caused by a cell-mediated immune response
 to donor HLA
Chronic Months or years Chronic, low-grade, cell- Submucosal inflammation -> granulation, scarring &
mediated response to HLA bronchiolitis obliterans (subsequent ingrowth of
antigens granulation tissue into the lumen leads to airway
obstruction and obliteration)
Px usually present with slowly worsening dyspnea and
dry cough that begins months or years after
transplantation.
Lung examination may reveal end-expiratory squeaks
or pops and spirometry typically demonstrates airflow
limitation (obstructive pattern) with a drop in FEV1

VS. restrictive allograft syndrome, a less common type of chronic lung transplant rejection, can result in fibrotic changes
to the pleurae. However, pulmonary function tests would reveal a restrictive (reduced FVC), not obstructive pattern

Neonatal respiratory distress syndrome (800)

Phosphatidylcholine (also known as lecithin) is a component of pulmonary surfactant and sphingomyelin is a common
membrane phospholipid. A commonly used measure of fetal lung maturity is the amniotic fluid lecithin/sphingomyelin
(L/S) ratio. The amniotic fluid concentration of lecithin approximately equals that of sphingomyelin until the middle of
the 3rd trimester, at which point mature type II pneumocytes begin secreting surfactant. The lecithin concentration then
increases sharply while the sphingomyelin level remains unchanged. By 35 weeks gestation, the L/S ratio averages 2:1 or
higher, indicating lung maturity.

(479) the lamellar bodies of type II pneumocytes sotre and release pulmonary surfactant into the fluid layer lining the
inner surfaces of alveoli. The major function of surfactant is to reduce surface tension in this fluid layer, and so a
surfactant deficiency can cause alveolar atelectasis, as seen in neonatal respiratory distress syndrome

Neonatal respiratory distress syndrome (799)

Temporary local hyperoxia in the retina is thought to induce changes that cause upregulation of proangiogenic factors
such as vascular endothelial growth factor (VEGF) upon return to room air ventilation. Retinal vessel proliferation
(neovascularization) and possible retinal detachment with blindness may result. This complication of neonatal
respiratory distress syndrome is referred to as retinopathy of prematurity or retrolental fibroplasia.

AAT deficiency

Associated with early-onset emphysema

AAT is a protein that inh several proteolytic enzymes released by inflammatory cells (particularly neutrophil elastase),
thereby reducing tissue dmg from the inflammatory cascade. The emphysema in AAT deficiency typically develops in a
panacinar pattern

- Increased total lung capacity as the lungs hyperinflate

- Decreased FEV1/FVC ratio
- Decreased DLCO (diffusing capacity of CO) due to destruction of alveoli and adjoining capillary beds

ARDS (6423)

Is characterized by hypoxemia and bilateral pulomonary edema in the absence of HF. It is most common with px with
severe systemic illness, trauma, or pulmonary injury. Injury to alveolar pneumocytes and pulmonary endothelium leads
to an inflammatory response resulting in increased capillary permeability, intraalveolar fluid accumulation, and hyaline
membrane formation.

(485)

Pancreatitis is a major risk factor for ARDS as it results in the release of large amounts of inflammatory cytokines and
pancreatic enzymes into the circulation, which leads to infiltration of neutrophils into the pulmonary interstitium and
alveolar spaces. Diffuse injury to the alveolar epithelium and pulmonary microvascular endothelium results in a leaky
alveolocapillary membrane and significant pulmonary edema.

ARDS is typically characterized by progressive hypoxemia refractory to O2 therapy and diffuse interstitial edema in the
absence of cardiogenic causes. Dung the first 1-6 days, interstitial and intraalveolar edema, inflammation and fibrin
deposition cause the alveoli to become lined with waxy hyaline membranes. These membranes consist of fibrin exudate
and inspissated protein-rich edema fluid mixed with the remnats of necrotic epithelial cells.

Pulmonary Arterial Hypertension (PAH) (14847)

Due to primary change in the pulmonary arteries, termed PAH, results from proliferative vasculopathy of the pulmonary
arteriolar smooth muscle which may occur in the setting of hereditary genetic mutation (BMPR2 mutation is most
common), connective tissue disease, or HIV infection.

Endothelin is a potent vasoconstrictor that also promotes smooth muscle cell proliferation; it is typically found in high
concentrations in px with PAh and it is an important target of therapy for the smooth muscle proliferation and alleviate
vasoconstriction to lower pulmonary arterial pressure and improve dyspnea in px with PAH

(15199)
 - Progressive dyspnea
- Exertional angina/syncope
- Most commonly in young women

PE:

- Loud pulmonic component (P2) of S2, caused by forceful pulmonic valve closure in the setting of high pulmonary
arterial pressure
- Concentric right ventricular hypertrophy -> accentuated impulse palpated at the left sternal border (left
parasternal lift due to right ventricular heave)

Right-sided heart failure eventually develops, but because left ventricular function remains intact, there is an absence of
pulmonary edema in pulmonary arterial hypertension

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD) (6480)

Results from cyclooxygenase inh leading to diversion of arachidonic acid down the 5-lipoxygenase pathway and
increased production of leukotrienes. Some px with underlying asthma, particularly those with nasal polyps and chronic
rhinosinusitis are susceptible to NERD.

Asthma (169)

Lung hyperinflation and bronchial inflammation are suggestive of uncontrolled asthma. Chronic inflammation, composed
mainly of eosinophils, helper T cells and mast cells causes airway remodeling (ie, bronchial wall thickening, increased
smooth muscle, which further worsens airway obstruction and asthma symptoms. Corticosteroids reduce airway
inflammation and are used for both chronic asthma management (inhaled admn) and acute exacerbations (systemic
admn).

(6508) mast cells and eosinophils release cystenyl-containing leukotrienes (leukotriene C4, D4, and E4) that trigger
bronchospasm, bronchial mucus secretion and bronchial edema. Cysteinyl leukotriene receptor antagonists (eg,
montelukast, zafirlukast) block these leukotriene-mediated effects to improve asthma symptoms.

(1925)

Intermittent respiratory symptoms in a px with a normal chest x-ray, sputum eosinophils and reduced FEV1 suggest
asthma. Common asthma triggers include exercise, cold air, respiratory infection and exposure to inhaled allergens (eg,
dust mites, cockroages, pet dander, mold, pollen)

(527) in response to allergic stimuli, these cells secret IL-5, a critical cytokine for eosinophilic activation, recruitement
and prolonged survival in the bronchial mucosa. TH2 cells also synthesize IL-4, which stimulates IgE formation by plasma
cells

Tx:

Cromolyn (171)

Cromolyn and nedocromil inh mast cell degranulation and prevent release of preformed chemical mediators. These
medications do not influence bronchial constriction directly; therefore, they are typically used to prevent acute attacks,
rather than to tx acute exacerbations. Even though these drugs are less efficacious than inhaled glucocorticoids, they are
very effective prophylactic agents for xp with seasonal symptoms, aspirin hypersensitivity, and exercise-induced asthma.
Vs. the anti-IgE antibody, omalizumab, inh IgE binding to mast cells, preventing mast cell degranulation. Omalizumab is
used in some px with severe, persistent asthma to lower IgE levels and reduce allergen-induced bronchial constriction.

Vs. glucocorticoids, inh phospholipase A2 synthesis -> inh the release of these downstream mediators, decreasing airway
hyperresponsiveness and inflammation

Vs. ziuleton: selective inh of lipoxygenase pathway that leads to decreased formation of leukotrienes. Zafirlukast and
montelukast are leukotriene receptor antagonists. These agents are typically used for chronic asthma prophylaxis.

(523) The eosinophilic granules predominantly contain major basic protein, which, once released, acts as a potent
antihelminthic toxin. Major basic protein also dmgs epithelial and endothelial cells and is a major cause of chronic lung
dmg in asthma.

(663) bronchial challenge testing is a highly sensitive but nonspecific measure that can help exclude a dx of asthma. A
provocative stimulus (typically aerosolized methacholine) is admn at increasing concentrations to induce
bronchoconstriction. Px with asthma ar ehyperresponsive to this stimulus and experience a decline in FEV1 at lower
doses than nonasthmatics.

Neuromuscular blockers (1212)

Train-of-four (TOF) stimulation is used during anesthesia to assess the degree of paralysis induced by NMJ blocking
agents. A peripheral nerve is stimulated 4 times in quick succession and the muscular response is recorded. The height
of each bar represents the strength of each twitch; higher bars indicate the activation of increasing numbers of
individual muscle fibers (myocytes).

When a nondepolarizing NMJ blocker (eg, vecuronium) is admn, competitive inhibition of postsynaptic acetylcholine
receptors at the motor endplate prevents some of these fibers from activating, decreasing the strength of the twitch.
TOF stimulation shows a progressive reduction in each of the 4 responses (fading pattern) as a result of less
acetylcholine being released with each subsequent impulse (due to the additional effect of presynaptic acetylcholine
receptor blockade). In contrast, depolarizing blockers (eg, succinylcholine) initially function by preventing repolarization
of the motor endplate and show equal reduction of all 4 twtiches during TOF stimulation (phase 1 blockade). The
responses remain equal because the presypanaptic acetylcholine receptor stimulation helps to mobilize presynaptic
acetylcholine vesicles for release. Persistent exposure to succinylcholine results in eventual transition to phase II
blockade as the acetylcholine receptors become desensitized and inactivated (ie, functionally similar to nondepolarizing
blockade).
Succinylcholine is commonly admn for rapid-sequence intubation due to its rapid onset (<1 min). the duration of action
is determined by its metabolism by plasma cholinesterase and is typically <10 min. however, some patients are
homozygous for an atypical plasma cholinesterase, which breaks down succinylcholine more slowly. In these patients,
the paralysis can last for hrs and they must be maintained on mechanical ventilation until spontaneous respirations
resume.

Succinylcholine (8481)

Succinylcholine is a depolarizing NMJ blocking agent, like acetylcholine, attaches to the nicotinic acetylcholine receptor
(nAChR) and depolarizes the NMJ end plate. Unlike acetylcholine, succinylcholine is not degraded by
acetylcholinesterase, resulting in continuous stimulation of the endplate (reflected by initial transient fasciculations).
However, the sodium channels surrounding the end plate rapidly become inactivated and cannot reopen until the end
plate, resulting in development of flaccid paralysis (phase 1 block). Eventually, with continued admn of succinylcholine,
the continuous depolarization of the endplate gives way to gradual repolarization as the nAChR becomes desensitized to
the effects of succinylcholine. This is termed phase II block and is similar to non-depolarizing blockade.

Because the nAChR is a nonselective cation channel, its opening not only allows sodium influx but also potassium
release. Exaggerated hyperkalemia and life-threatening arrhythmias can occur in px with crush or burn injuries,
denervating injuries or diseases (eg, quadriplegia and Guillain-Barre syndrome), and myopathies, these pathologic states
cause up-regulation of muscle nAChRs and/or rhabdomyolysis, which can result in the release of large amount of
potassium when succinylcholine is admn. In these px, non-depolarizing agents such as vecuronium or rocuronium are
better choices.

Interstitial lung disease (1543)

Presents:

- Progressive dyspnea
- Fine crackles
- Clubbing
- Diffuse reticular opacities

Causes: pulmonary fibrosis with thickening and stiffening of the pulmonary interstitium ->causes increased lung elastic
recoil + airway widening due to increased outward pulling (radial traction) by the surrounding fibrotic tissue -> decrease
in airflow resistance leads to supernormal expiratory flow rates

PFT: (restrictive lung disease)

- Reduced TLC + VC + IC + FRC + RV

 - Reduced FVC + FEV1 (however the FEV1/FVC ratio is typically normal or increased as FEV1 decreases less than
FVC [due to airway widening relative to the low lung volumes])
- Fibrosis causes a reduction in the diffusion capacity of CO

Interstitial lung diseases (6476)

Etiology - Drug-induced: amiodarone, bleomycin,
methotrexate
- Connective tissue disease: RA, SLE, systemic
sclerosis
- Environemental: silica, talc, fungi, animal proteins
(ie, bird fancier’s lung)
- Cryptogenic: idiopathic pulmonary fibrosis
Clinical presentation - Progressive dyspnea, dry cough, fatigue
- Fine crackles during late inspiration, possible
digital clubbing
- Extrapulmonary signs of systemic disease (eg, skin
thickening, butterfly rash_
Lab/imaging - Chest x-ray: reticular or nodular opacities
- Chest CT: fibrosis or honeycombing
- PFTs: increase FEV1/FVC; decrease DLCO, decrease
TLC

Smoking cessation (8754)

Varenicline is a partial agonist of nicotinic ACh receptors. It can assist px with cessation of tabacco use by reducing
withdrawal cravings and attenuating the rewarding effects of nicotine.

Important respiratory tract infections in children (1667)

Clinical illness Presentation Common etiologic agents
Nasopharyngitis (common cold) Nasal congestion & discharge, - Rhinovirus
sneezing, cough & sore throat - Influenza virus
- Coronavirus
Laryngotracheitis (croup) Upper respiratory tract symptoms - Parainfluenza virus
followed by hoarseness, barking
cough, stridor & respiratory distress
Diphteria Sore throat, cervical - Corynebacterium diphtheria
lymphadenopathy, coalescing
pseudomembrane
Epiglottitis Sore throat, dysphagia, drooling & - H. influenza
respiratory distress
Bronchiolitis Upper respiratory tract symptoms - Respiratory syncytial virus
followed by wheezing, cough &
respiratory

Hypoxemia (1526)

Etiologies of hypoxemia (1526)

Normal alveolar to arterial gradient Elevated alveolar to arterial gradient
- Hypoventilation - Right to left shunt
Obesity hypoventilation syndrome, Cardiac septal defects, pulmonary edema
neuromuscular disorder - Ventilation/perfusion mismatch
 - Low inspired fraction of oxygen Pulmonary embolism, chronic obstructive lung disease
High altitude - Impaired diffusion
Interstitial lung disease

*Hypoxemia in the setting of a normal A-a gradient indicates that both the alveolar and the arterial partial pressure of
oxygen (PO2) are low.

Obesity hypoventilation syndrome: characterized by chronic fatigue, dyspnea, difficulty concentrating and evidence of
hypoventilation (PaCO2>45 mmHg while awake). It is one of the important causes of hypoxemia with a normal alveolar
to arterial oxygen gradient.

Pulmonary embolism

(1981)

PE occludes or significantly reduces blood flow to a portion of the pulmonary parenchyma, resulting in increased dead
space ventilation and redistribution of pulmonary blood flow away from the affected segments. This leads to increased
V/Q mismatch in the remainder of the lungs with consequent hyoxemia.

Stimulation of the central respiratory drive occurs in response to dyspnea and inflammatory mediators released by
ischemic pulmonary tissue. Hyperventilation does not significantly improve arterial oxygenation because, as hb is nearly
fully saturated with O2 in areas of normal V/Q ratio, there is little capacity for high V/Q regions to increase blood O2
content much further. In contrast, CO2 removal is more directly dependent on ventilation, and high V/Q regions have
large capacity to exhale additional CO2. Therefore, the hyperventilation elads to hypocapnia and respiratory alkalosis.
The serum HCO2 level remains normal in the acute phase, but metabolic compensation with renal bicarbonate loss
occurs after approximately 48 hrs.

(529) large emboli lodge in the pulmonary artery bifurcation (“saddle emboli”) and may cause severe hypotension or
sudden cardiac death, whereas smaller emboli occlude peripheral pulmonary arterial branches. In most cases,
pulmonary emboli are multiple, with the lower lobes involved more often than the upper lobes. Low-moleuclar-weight
heparin (eg, enoxaparin) is preferred in most px due to proven efficacy and relatively low risk of adverse effects.

(12184)

A V/Q scan is a nuclear medicine study that uses a radioactive tracer placed in both inhaled gas and the bloodstream to
visualize areas of ventilation and perfusion in the lung. In px with PE, ventilation is preserved but the embolus prevents
adequate blood perfusion to the affected areas of the lung. Therefore, the most definitive dx finding for PE on V/Q scan
is a large area showing a perfusion defect without ventilation defect (mismatched perfusion defect).

Vs. matched ventilation and perfusion defects

May result from chronic lung abnormalities (Eg, airway inflammation or obstruction, atelectasis) that lead to localized
areas of poor ventilation with corresponding hypoxic vasoconstriction, or they may represent a PE that happens to be in
an area of poor ventilation. These results are often inconclusive and necessitate additional testing to confirm or rule out
PE

Vs. ventilation defect without perfusion defect

Is suggestive of conditions that lead to acute alveolar filling (eg, pneumonia, pulmonary edema)
(1538)

The IVC courses through the abdomen and inferior thorax in a location anterior to the right half of the vertebral bodies.
Th erenal veins join the IVC at the level of L1/L2, and the common iliac veins merge to become the IVC at the level of L5.
IVC filters are placed in px with DVT who have contraindications to anticoagulation therapy.

(476) CT pulmonary angiography is typically the imaging modality of choice, however, V/Q scans are helpful in evaluating
px in whom angiography is contraindicated (eg, contrast allergy, renal failure).

V/Q scans are 2 part studies that compare regional ventilation and perfusion. The initial phase uses a radiolabeled
aerosol that is inhaled and delivered throughout the tracheobronchial tree. The second phase uses an IV tracer that is
distributed throughout the pulmonary vasculature. V/Q mismatch occurs when alveoli are ventilated but not perfused
(ie, a defect in the perfusion phase). This pattern can be seen in diseases that increase physiologic dead space, including
pulmonary embolism (asi n this patient) and malignancies that obstruct arterial blood flow

Saddle pulmonary embolism (1880)

Saddle pulmonary embolism straddles the bifurcation of the main pulmonary artery. Venous thromboembolism (ie,
pulmonary embolism or DVT) arises due to the Virchow triad of endothelial injury, venous stasis and a hypercoagulable
state. Malignancy causes a hypercoagulable state and is a strong risk factor for venous thromboembolism.

Oxygen (1527)
Bronchiectasis

Digital clubbing (820)

Pathophysiology:

In disease associated with right-to-left shunts (eg, cyanotic congenital heart disease), it is thought to be caused by a
failure of platelet precurosrs to fragment completely into platelets within the pulmonary circulation. The result is an
increase in peripheral circulation of megakaryocytes and platelet clumps. These impact in the fingers and toes and
release platelet-derived growth factor and vascular endothelial growth factor (promoters of vascularity). This results in
increased fibrovascular proliferation, leading to clubbing of the fingers and toes. Elevated levels of prostaglandin E2
(which activates platelets via the EP3 receptor) have also been implicated in the pathogenesis of digital clubbing

ARDS (1579)

Is caused by injury of the pulmonary epithelium and/or endothelium, and occur most often due to sepsis or pneumonia.
Cytokines recruit neutrophils to the lung tissue, which cause capillary dmg and leakage of protein-rich fluid into the
alveoli. Later, cellular proliferation and collagen deposition occurs, and in some px, this leads to irreversible pulmonary
fibrosis.

It can occur due to direct pulmonary trauma (eg, pulmonary contusions, inhaled irritants) or indirect nonpulmonary
insults (eg, sepsis, burns, pancreatitis)

Progression:

- Exudative phase: inflammatory cytokines (eg, TNF, IL-1, IL-6) activate the pulmonary endothelium and recruit
neutrophils to the lung tissue, which release inflammatory mediators. Resultant endothelial dmg leads to
increased capillary permeability and leakage of protein-rich fluid into the alveolar space. Organization of the
edema and cellular debris leads to the formation of hyaline membranes
- Proliferative phase: one to two weeks later, endothelial cells, pneumocytes, and fibroblasts proliferate in
attempts to repair the damaged lung; collagen is deposited and scarring may occur. Edema is reabsorbed
 - Fibrotic phase: in a minority of px, excessive collagen deposition leads to irreversible pulmonary fibrosis and
pulmonary HTA.

Obesity related restrictive disease (11900)

Obesity, particularly morbid, central obesity, can cause a pattern of extrinsic restrictive pulmonary function tests. The
most common indicator of obesity-reltaed disease is a reduction in expiratory reserve volume and functional residual
capacity, but forced expiratory volume in 1 second, forced vital capacity and total lung capacity are also typically
decreased.

Sudden Infant death syndrome (310)

The adverse effects of secondhand smoke exposure include an increased risk of low birth weight, asthma, middle ear
disease, and sudden infant death syndrome (SIDS). Up to half of all SIDS cases are due to tabacco exposure, likely from
imapried arousal and abnormal CV responses to stimuli

COPD

COPD exacerbation (14925)

Triggers - Viral infection: rhinovirus, influenza, parainfluenza
- Bacterial infection: H. influenzae, Moraxella catarrhalis, S. pneumonia
- Air pollution, pulmonary embolism
Clinical presentation - Increased dyspnea &/or cough
- Change in sputum color or quality
PE - Increased RR, wheezing
- Pursed lip breathing with prolonged expiration
Dx - Arterial blood gas: hypoxemia, CO2 retention
- Chest x-ray: hyperinflation & flattened diaphragm

(521)
Air trapping and airway obstruction in COPD reduce both forced expiratory volume in 1 sec (FEV1) and FVC on
pulmonary function testing. Because the decrease in FEV1 is more profound, the FEV1/FVC ratio is also reduced, which is
the hallmark of obstructive lung disease on PFT. Air trapping raises functional residual capacity, causing respiration to
occur at higher baseline lung volume. The residual volume (RV) is increased. TLC is also increased.

(13402) most chronic obstructive pulmonary disease exacerbations are triggered by viral or bacterial upper respiratory
infections, with rhinovirus, influenza virus, H. influenzae, Moraxella catarrhalis and S. pneumonia being among the most
common causes

(1583) PaCO2 is the major stimulator of respiration in healthy individuals; even a slight increase in PaCO2 stimulates
central chemoreceptors and triggers increased ventilation. In px with chronic obstructive pulmonary disease, the
response to PaCO2 is blunted and hypoxemia can contribute to respiratory drive. Peripheral chemoreceptors are
primarily responsible for sensing arterial partial pressure of oxygen (PaO2) and can be suppressed with oxygen admn

(1521) causes air trapping and hyperinflation; consequently, these px breathe at higher baseline lung volumes (higher
functional residual capacity). The absolute volume of air in the lungs that is not respired (residual volume) increases
substantially, as does the fraction of air in the lungs that is not involved in respiration (residual volume/total lung
capacity ratio).

(12141) supplemental oxygen admn in px with chronic obstructive pulmonary disease can lead to increased CO2
retention (oxygen-induced hypercapnia), resulting in confusion and depressed consciousness. The major cause is
reversal of hypoxic pulmonary vasoconstriction, which increases physiologic dead space as blood is shunted away from
well-ventilated alveoli.

(2100) Asthma and COPD exacerbation are the most frequent causes of pulsus paradoxus in the absence of significant
pericardial disease (pericardial effusion or constrictive pericarditis). There is a small normal variation in intrathoracic
pressure with respiration, which drops 2-5 mmHG below the atmospheric pressure during inspiration. In px with severe
asthma or COPD exacerbation, this drop in intrathoracic pressure becomes greatly exaggerated and is transmitted to
extrathoracic structures. This leads to an excessive drop in bp with inspiration that is detected as pulsus paradoxus.

(12082) The primary cell lines that are increased in COPD are neutrophils, macrophages, and CD8+ T lymphocytes. These
cells release enzymes and proteases, such as neutrophil elastase, that cause alveolar dmg, reduced ciliary motion and
increased mucus secretion by goblet cells.

(119) expectorated sputum cultures are often contaminated by normal oral flora. The growth of Candida albicans a
normal commensal of the GI tract and skin, almost always indicates oral contamination rather than true pulmonary
infection.

(15212) multiple large subpleural blebs consistent with severe emphysema. Emphysema most commonly develops due
to chornic exposure to cigarette smoke via the following mechanisms:

- Inflammation and leukocyte infiltration: alveolar macrophages release inflammatory cytokines (eg, TNF) and
recruit neutrophils and CD8_ T lymphocytes to the alveolar tissue
- Protease-antiprotease imbalance: inflammatory cells release tissue-destructive proteases (eg, elastase) often in
the setting of decreased production of antiproteases due to genetic predisposition or outright genetic mutation
(Eg, alpha-1 antitrypsin deficiency)
- Oxidative stress: cigarette smoke and chronic inflammation increase exposure to reactive oxygen species that
impart further tissue damage.
The ongoing tissue dmg leads to loss of alveolar elasticity and consequent alveolar distension. In severe cases, large air
spaces (>1 cm in diameter) called subpleural blebs can form, mostly in the lung apex. These subpleural blebs can
sometimes rupture leading to a spontaneous pneumothorax

(525) chronic bronchitis is characterized by increased mucus secretion and bronchial wall thickening with consequent
narrowing of the bronchial lumen. Bronchial gland hyperplasia in the submucosa is the major contributor to bronchial
wall thickening. The severity of this change can be measured by the Reid index.

The Reid index is a pathologic tool that measures the ratio of the thickness of the submucosal glands to the thickness of
the bronchial wall between the epithelial basement membrane and the bronchial cartilage. A normal reid inde is 0.4.
Higher values correlate with increased duration and severity of chronic bronchitis

Tx:

Beta-adrenergic agonists (2100)

Produces relaxation of bronchial smooth muscle by stimulating the beta-2-adrenergic receptor, this receptor is Gs
protein-coupled receptor that activates adenylyl cyclase and increases intracellular cAMP concentrations.

Ipratropium (170)

An anticholinergic agent and derivative of atropine, tx obstructive lung disease by blocking ACh at muscarinic receptors,
which prevents bronchoconstriction and reduces mucus secretion from tracheobronchial submucosal glands.

Community acquired pneumonia (531)

Step-wise inflammatory response:

1. Congestion (day 0-2) – neutrophils respond to bacterial components (eg, peptidoglycan) by releasing cytokines
that increase the permeability of the pulmonary capillary endothelium, which allows circulating immune cells to
more easily migrate to the area. Increased capillary permeability also leads to the accumulation of erythrocytes
and abundant proteinaceous fluid in the alveolar space, resulting in the affected lobe becoming heavy and red.
2. Red hepatization (day 2-4) – the proteinaceous fluid transforms into fibrin strands, resulting in a confluent
exudate of fibrin, neutrophils and erytrhocytes. On gross examination, the lobe appears liver-like: red, firm and
airless
3. Gray hepatization (day 4-7) – red cell disintegration along with increased leukocyte infiltration causes the lung to
appear gray rather than red. Neutrophils being to be replaced by macrophages that begin the repair process.
4. Resolution (>7 days) – macrophages secrete digestive enzymes that liquefy the fibrinous exudate, which is
reabsorbed, expectorated, or phagocytized by macrophages. The lung parenchyma regains its normal
appearance by approximately 3 weeks.

(1910) neutrophil myeloperoxidase is responsible for the green color of pus and sputum in bacterial infections. It is a
blue-green heme-based pigmented molecule contained within the azurophilic granules of neutrophils and catalyzes the
production of hypochlorous acid from chloride and hydrogen peroxide during the phagocytic respiratory burst.

Acute phase reactants (14921)

Are proteins whose serum concentrations change by >25% during periods of inflammation. Several APRs have diagnostic
and prognostic utility and can be interpreted on the basis of serum concentrations:
 - Postivie APRs (serum levels rise in acute inflammatory states) include fibrinogen, C-reactive protein, ferritin,
hepcidin, ceruloplasmin, haptoglobin, vWf and complement. The ESR (the time required for erythrocytes to
settle from suspension) is an indirect measure of positive APRs
- Negative APRs (serum levels fall in acute inflammatory states) include albumin, transferrin and transthyretin
(prealbumin)

Procalcitonin, a precursor of calcitonin produced by monocytes and the C cells of the thyroid, is a unique APR that has a
positive and negative properties. Levels rise in response to bacterial toxins and fall in response to viral infections, and
therefore levels can suggest the etiology of community-acquired pneumonia.

CREST syndrome (825)

- Calcinosis
- Raynaud’s phenomenon
- Esophageal dysmotily
- Sclerodactyly
- Telangiectasia

Both diffuse and limited forms of systemic sclerosis variants develop due to increased deposition of collagen in tissues.
Collagen deposition is thought to be triggered by increased proliferation and accumulation of monoclonal T cells in the
affected tissues that secrete a variety of cytokines (especially TGF-beta), which increase production of collagen and
extracellular matrix proteins by fibroblasts. All tissues can be affected, but the earliest dmg is seen in small arterioles and
capillaries. Microvascular injury of pulmonary arterioles leads to narrowing of the lumen and increased pressure in
pulmonary cicrculation. It leads to hypertrophy of RV, with subsequent development of right-sided congestive heart
failure.

(340) CREST syndrome (limited scleroderma) manifests with calcinosis, Raynaud’s phenomenon, esophageal dysmotility,
sclerodactyly and telangiectasias. Anti-centromere antibodies are found in about 40% of px with CREST syndrome. Anti-
DNA topoisomerase I (Scl-70) antibodies are highly specific for systemic sclerosis.

Idiopathic pulmonary fibrosis (15126)

Progressive dyspnea, dry cough, digital lubbing and crackles on examination has signs of an interstitial lung disease. The
histologic findings of patchy lymphoplasmacytic infiltrates, focal fibroblastic proliferation, areas of dense fibrosis and
honeycombing, and hyperplasia of type 2 pneumoncytes are highly suggestive of idiopathic pulmonary fibrosis (IPF).

IPF is a chronic, progressive fibrotic lung disease thought to be due to recurrent episode of lung injury and disordered
healing. Persistent inflammation likely triggers excessive activity of growth factors normally involved in wound healing,
including transforming growth factor-beta (TGF-Beta), platelet-derived growth factor (PDGF), fibroblastic growth factor
(FGF), and vascular endothelial growth factor (VEGF). This leads to increased fibroblast activity, myofibroblast formation,
and collagen production, which contribute to pulmonary fibrosis. Pirfenidone is an antifbrotic agent that inh TGF-beta;
another tx option is nintedanib, a tyrosine kinase inh that inh PDGF, FGF, and VEGF. Although neither drug is curative,
these therapies have been shown to slow progressive fibrosis in px with IPF.

Sarcoidosis

Common features of sarcoidosis (877)

Epidemiology - Young adults
- African americans
Clinical - Constitutional symptoms
 - Cough, dyspnea & chest pain
- Extrapulmonary findings
. skin lesions
. anterior/posterior uveitis
. Lofgren syndrome
Imaging - Bilateral hilar adenopathy
- Pulmonary reticular infiltrates
Laboratory - Hypercalcemia/hypercalciuria
- Elevated serum ACE level
Pathology - Biopsy showing noncaseating granulomas that stain negative for fungi & acid-fast bacilli

(214) mass effect symptoms + recurrent hypercalcemia (caused by excessive calcitriol formation by activated
macrophages) 6 months after the discontinuation of glucocorticoid therapy, this presentation suggests active sarcoidosis
with involvement of the hypothalamus (neurosarcoidosis). Although sarcoidosis classically causes noncaseating
granulomas involving the lungs, lymph nodes, and skin, granulomas can form in any tissue. The release of prolactin is
under inhibitory control by dopamine secretion from the hypothalamus. Disruption of dopaminergic pathways or
blockade of dopamine D2 receptors can cause hyperprolactinemia.

(796)

Activated macrophages can ectopically prodce ACE and 1-alpha-hydroxylase (increases production of 1, 25-
dihydroxycholecalciferol, the active form of vit D). this results in high ACE levels and hypercalcemia commonly seen in px
with sarcoidosis.

(797)

Sarcoidosis is thought to result from a dysregulated cell-mediated immune response to an unidentified antigen, which
causes the formation of granulomas. Cell-mediated immunity is driven by the Th1 subtype of CD4+ helper T cells.
Activated antigen-presenting cells produce IL-12, which stimulates the differentiation of Th1 cells. Th1 cells secrete IL-2
and IFN-gamma. IL-2 stimulates the autocrine proliferation of Th1 cells and ufther Th1 recruitment. IFN-gamma activates
macrophages, promoting granuloma formation. Activated macrophages and T cells also produce TNF alpha, further
assisting in leukocyte recruitment and granuloma maintenance.

(795)

Often presents in young African American women with the insidious onset of respiratory symptoms (eg, cough, dyspnea,
chest pain) accompanied by fatigue, fever and weight loss. The characteristic histopathologic feature is non-caseating
granulomas, which consist of aggregates of epithelioid macrophages and multinucleated giant cells.
Vs. Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) usually presents with chronic rhinosinusitis,
asthma, and peripheral eosinophilia. The granulomas seen with Churg-Strauss syndrome typically have eosinophilic
infiltration and prominent areas of necrosis

Vs. Desquamative interstitial pneumonia, idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis are
associated with cigarette smoking and typically present with the insidious onset of progressive dyspnea and chronic
cough. However, non-caseating granulomas are not characteristic of these conditions

Vs. Systemic sclerosis is a multisystemic disorder that results in progressive collagen deposition and fibrosis of the skin
and visceral organs (eg, GI tract, lungs, kidneys, CV) Pulmonary involvement often leads to dyspnea and chronic cough;
however, non-caseating granulomas are not characteristic

Vs. small cell carcinoma is a highly malignant lung cancer that is strongly associated with smoking. Histopathologic
features include small cells with scant cytoplasm, granular nuclear chromatin (“salt-and-pepper” pattern), and indistinct
nuclei. Necrosis is typically extensive.

(1147) cough + night sweats + bilateral hilar adenopathy -> sarcoidosis

Systemic inflammatory disease characterized by noncaseating granulomas (non-necrotic aggregates of epithelioid

macrophages and multinucleated giant cells)

Any organ can be affected, however, the lungs (eg, reticular/nodular infiltrates), lymph nodes (eg, hilar adenopathy),
skin (erythematous rash) and eyes (eg, anterior uveitis) are often involved. In addition to pulmonary symptoms (Eg,
cough, chest pain, dyspnea), constitutional symptoms (including fever, weight loss, fatigue, night sweats, and
arthralgias) are common

Lung cancer (554)

Type of tumor Incidence Location Clinical manifestation

Adenocarcinoma 40-50% Peripheral - Clubbing
 - Hypertrophic
osteoarthropathy
Squamous cell carcinoma 20-25% Central Hypercalcemia
Necrosis & cavitation
Small cell carcinoma 10-15% Central Cushing syndrome
SIADH
Lambert-Eaton syndrome
Large cell carcinoma 5-10% Peripheral Gynecomastia
galactorrhea

Adenocarcinoma:

- Most common lung cancer in the general population, women, and nonsmokers
- Risk factors:
Environmental exposures (eg, radon, second-hand smoke) and underlying lung disease
- Certain molecular alterations are seen more commonly in nonsmokers; these “driver mutations” are the thought
be responsible for the development of the malignancy and include epidermal growth factor receptor (EGFR)
mutations and ALK gene rearrangements.
- PS: KRAS mutations, another driver in the formation of adenocarcinoma, is seen more commonly in smokers

(564)

Adenocarcinoma arises from the alveolar epithelium and is characterized by invasive cells with abundant cytoplasm and
eccentrically placed nuclei that form irregular glandular elements; mucin production is common.

Small cell carcinoma of the lung (555)

Superior vena cava syndrome (565)

Intrathoracic spread of bronchogenic carcinoma may lead to compression of the superior vena cava, causing impaired
venous return from the upper part of the body. Signs and symptoms include dyspnea, facial swelling and dilated
collateral veins in the upper trunk

VS. pancoast tumor, arise at the lung apex and frequently cause shoulder pain due to compression of the brachial
plexus. The cervical sympathetic ganglia are also commonly involved, leading to Horner’s syndrome (ptosis, miosis and
anhydrosis). SVC syndrome can sometimes occur with Pancoast tumors, but shoulder pain and Horner’s syndrome are
more frequent manifestations.

Common paraneoplastic syndromes associated with lung cancer (1921)

Endocrine - Syndrome of inappropriate antidiuretic hormone
- Parathyroid hormone-related protein secretion
(hypercalcemia)
- Ectopic ACTH production (Cushing syndrome)
Neurologic - Lambert-Eaton myasthenic syndrome
- Paraneoplastic cerebellar degeneration
Musculoskeletal - Hypertrophic osteoarthropathy (clubbing)

Alpha1 antitrypsin deficiency (400)

Is a serine protease inh that regulates the activity of elastase in the lung. Inherited deficiency of AAT leads to alveolar
destruction and panacinar emphysema; in addition, accumulation of improperly folded AAT proteins in hepatocytes can
lead to liver dysfunction and cirrhosis in some px.

Metabolic acidosis (2101)

Lactic acidosis may result from overproduction and/or impaired clearance of lactic acid. End-organ hypoperfusion in
septic shock impairs tissue oxygenation and decreases oxidative phosphorylation, leading to a buildup of NADH and
shunting of pyruvate to lactate following glycolysis. Hepatic hypoperfusion during sepsis also contributes to the
accumulation of lactic acid as the liver is the primary site of lactate clearance (via conversion back into glucose)

Obstructive sleep apnea (11845)

Stimulation of the hypoglossal nerve using an implantable nerve stimulator causes the tongue to move forward slightly,
increasing the anteroposterior diameter of the airway. Studies with these devices have shown a reduction in the number
of obstructive events during sleep.

Cystic fibrosis (802)

Different types of mutations:

Most common: (70%) is a 3 base pair deletion of phenylalanine at amino acid position 508. This mutation causes
impaired post-translational processing (Eg, improper folding and glycosylation) of CFTR, which is detected by the
endoplasmic reticulum. As a result, the abnormal protein is targeted for proteasomal degradation, preventing it from
reaching the cell surface. (certain drugs (eg, lumacaftor) can partially correct this folding defect, leading to expression of
functional CFTR)

Other les common mutations:

- Decreased production of functionally normal CFTR (eg, reduced messenger RNA or protein stability) often causes
a milder form of the disease with normal sweat chloride levels that may not be diagnosed until adulthood
- Mutations impairing chloride ion conduction through CFTR also result in CF. however, they are less common
than the F508 which produces a functional protein that retains the ability to transport chloride ions
- Mutations causing premature termination of the transmembrane protein (eg, nonsense, frameshift) also lead to
a complete absence of membrane-bound CFTR as the truncated protein is typically recognized and degraded.
These mutations are more common in the Ashkenazi Jewish population
- CFTR is an ATP-gated chloride channel activated by cAMP-mediated phosphorylation. Mutations that reduce the
ability of the channel to open can also cause CF. the F508 mutation, in addition to preventing proper trafficking
to the cell surface, also reduces the regulatory effects of ATP and cAMP on channel opening.

(1514) The CFTR protein is a transmembrane ATP-gated chloride channel.

(6492) electrolyte differences in the body fluids of px with CF develop due to tissue-specific variation in the functioning
of the CF transmembrane conductance regulator gene. In the sweat glands, mutated CFTR prevents salt reabsorption,
producing sweat that has higher levels of sodium and chloride. In the respiratory epithelium, mutated CFTR causes thick
viscid secretions that are low in both sodium and chloride.

(1939) px with CF produce eccrine sweat with higher-than-normal concentrations of sodium and chloride. Exposure to
high temperature or exercise can lead to hyponatremia and hypochloremia due to excessive sodium chloride loss
through sweat; therefore, salt supplementation is recommended

(805) Tx for CF:

Lumacaftor and ivacaftor are CFTR-modulating medications that can potentially help px with CF by restoring CFTR
proteins to the membrane and also by enhancing protein function (eg, chloride transport) at the membrane,
respectively. The combination of these 2 medications in px with homoxygous F508 mutations has been shown to
improve predicted forced expiratory volume (FEV) and decrease rates of pulmonary exacerbations

(806) pancreatic insufficiency -> deficiency of fat soluble vitamins

Avitaminosis A in particular may contribute to squamous metaplasia of the epithelial lining of pancreatic exocrine ducts,
which are already injured and predisposed to squamous metaplasia by inspissated mucus. When a deficiency state
exists, the epithelium undergoes squamous metaplasia to a keratinizing epithelium.
(803) Inspissated mass (dehydrated meconium) in the distal ileum -> meconium ileus (very specific finding for CF)

Only 10%-20% of infants

Hirschsprung vs meconium ileus

Hirschsprung disease Meconium ileus
Associated disorder Down syndrome CF
Typical level of obstruction Rectosigmoid Ileum
Meconium consistency Normal Inspissated
“Squirt sign” Positive Negative

Vitamin K deficiency (710)

Px with CF are also at risk for vit K deficiency due to malabsorption of fat-solueble vitamins

Can result in life-threatening bleeding diathesis, such as intracranial hemorrhage and profuse bleeding from the GI tract,
umbilicus and surgical sites. Def is prevented by IM supplementation at birth

CF vs primary ciliary dyskinesia (807)

Hb properties (1414)
Carbonic anhydrase activity within erythrocytes forms bicarbonate from CO2 and H2O. Many of the bicarbonate ions
diffuse out of the RBC into the plasma. To maintain the electrical neutrality chloride ions diffuse into the RBC to make
their place. This process is called “chloride shift,” and it is principal cause of high RBC chloride content in venous blood.

Aspiration syndromes (532)

Lung abscess (1446)

Px with alcoholism are at increased risk for lung abscess due to the aspiration of oral flora during periods of
unconsciousness. Lung abscesses tend to be polymicrobial; they are usually composed of anaerobic oral flora
(Bacteroides, Prevotella, Fusobacterium, and Peptostreptococcus) and aerobic bacteria. Clindamycin provides coverage
against both anaerobic and aerobic organisms and has been traditionally used in the tx of lung abscess. Clindamycin
binds to the bacterial 50S ribosomal subunit and disrupts bacterial protein synthesis (macrolides operate in similar
fashion)

(532) Infections are most common in dependent areas of the right lung because the right bronchus is straighter than the
left bronchus; aspiration that occurs in the upright position usually leads to an abscess in the basal segment of the right
lower lobe, whereas aspiration that occurs while supine often causes abscess in the posterior segment of the right upper
lobe or the superior segment of the right lower lobe.

Chronic bronchitis (524)

Thickened bronchial walls, lymphocytic infiltration, mucous gland enlargement, and patchy squamous metaplasia of the
bronchial mucosa are features of chronic bronchitis. Tabacco smoking is the leading cause of chronic bronchitis.

Alveolar hyperventilation (528)

Can result from a ventilation-perfusion mismatch that causes decrease of O2 and CO2 exchange (eg, pneumonia or
pulmonary embolism). The resultant hypoxemia stimulates peripheral chemoreceptors and increases the respiratory
drive above normal levels. This leads to excessive CO2 excretion by the lungs, resulting in hypocapnia. However,
hypoxemia persists since the blood flowing through highly oxygenated lung cannot absorb extra O2 to compensate for
the hypoxemic blood returning from poorly oxygenated regions. This causes an increased alveolar-arterial oxygen
gradient, which can be tx with oxygen and by correcting the underlying disease process. Without treatment, persistent
tachypnea will lead to eventual respiratory muscle fatigue, hypoventilation and hypercapnia.

Lung nodule (552)

The most common benign lung tumor is a hamartoma (also called pulmonary chondroma). Hamartomas usually present
as incidental findings on chest x-ray, with the appearance of a well-defined coin lesion with “popcorn calcifications.” A
hamartoma is an excessive growth of a tissue type native to the organ of involvement. The lung is the most common
location. Lung hamartomas often contain islands of mature hyline cartilage, fat, smooth muscle and clefts lined by
respiratory epithelium.

Mesothelioma (15370)

Histologically, mesothelioma can appear as cuboidal or flattened cells (epithelium-like) or spindle cells (stromal-like).
Immunohistochemistry is an important diagnostic marker; nearly all cases of mesothelioma will stain positive for
cytokeratins and many will also typically stain positive for calretinin. Electron microscopy usually shows polygonal tumor
cells with numerous long, slender microvilli and abundant tonofilaments

Asbestos

(553)

Inhalation of fine asbestos fibers causes epithelial cell injury, activation of macrophages, and chronic interstitial
inflammation and fibrosis

Major clinical manifestations:

- Pleural disease includes pleural effusions and pleural plaques. Pleural plaques are a hallmark of asbestos
exposure that ypically caffect the parietal pleural along the lower lungs and diaphragm. The plaques are
composed of discrete circumscribed areas of dense collagen that frequently become calcified
- Asbestosis is characterized by progressive pulmonary fibrosis that is most predominant in the lower lobes and by
the presence of asbestos bodies (golden-brown beaded rods with translucent centers)
- Bronchogenic carcinoma is the most common malignancy associated with asbestos exposure. Smoking and
asbestos exposure have a synergistic effect on the development of lung carcinoma, increasing the risk from 6-
fold in nonsmoking patients with asbestos exposure to 60-fold in asbestos-exposed px who smoke regularly
- Malignant mesothelioma is a rare malignancy of the pleura for which asbestos is the only known environmental
risk factor. It is less common than bronchogenic carcinoma in asbestos-exposed px. However, mesothelioma is
more specific for heavy asbestos exposure.

VS. direct- acting alkylating agents and benzene exposure are associated with acute leukemias, which occur due to
malignant proliferation of hematopoietic stem cells.

(669)
Occupational exposure:

- Insulation manufacturing and application

- Shipbuilding
- Drywall workers

(15335)

Pleural plaques (focal thickening and calcification of the parietal pleura) and lower lung fibrosis, consistent with
pleuropulmonary asbestosis. Asbestosis is a pneumoconiosis that occurs with inhalation of asbestos fibers (hydrated
magnesium silicates), typically in px with occupational exposure (eg, insulation installation, shipbuilding, pipe work). Px
are typically asymptomatic for 20-30 years after initial exposure; dyspnea, cough and fatigue are common presenting
symptoms.

CT radiography in asbestosis demonstrates bilateral parenchymal fibrosis, most predominant in the lower lungs;
honeycombing and upper lung involvement occur in advanced disease. Pleural disease is common and includes pleural
plaques, diffuse pleural thickening, or benign pleural effusions. Histopathology typically demonstrates diffuse interstitial
fibrosis in association with ferruginous bodies (golden brown, rod or fusiform-shaped fibers coated with iron protein
complexes). Asbestos fibers can be differentiated from other ferruginous bodies (eg, carbon, talc) by their translucent
fiber core.

VS. birefringent silicate particles are seen in silicosis, which typically presents with innumerable nodules that
predominate in the upper lungs; egg-shell calcifications of the hilar lymph nodes may also be seen. Pleural plagues are
unexpected.

VS. carbon-laden macrophages are seen in coal workers pneumoconiosis. Gross pathology demonstrates black coal
nodules distributed throughout the upper lungs.
Silicosis (670)

In silicosis, internalized silica particles impair macrophage fx by disrupting phagocytosis and promoting apoptosis. This
increases the risk of mycobacteria infection (particularly tb)

(668) histologically, silicosis is characterized by birefringent silicate particles within dense, whorled collagenous nodules
surrounded by dust-laden macropahges. Silicosis is often initially asymptomatic but can present with dyspnea on
exertion and productive cough, typically 10-20 years after initial exposure. Radiography varies based on disease
progression; simple silicosis typically demonstrates numerous small, rounded nodules predominant in the upper lobes
that may rarely coalesce to form mass-like upper lobe fibrosis (progressive massive fibrosis). Calcification of the rim of
hilar nodes (eggshell calcification) may also be seen

Dermatology

Melanoma (7707)

BRAF is a protein kinase involved in activating the signaling pathways of melanocyte proliferation. BRAF mutation V600E
(valine -> glutamic acid), seen in 40%-60% of px with melanoma, leads to greatly increased activation of the signaling
pathways for melanocyte growth, survival and metastasis

Vemurafenib, a potent inh of mutated BRAF, has significant anti-tumor effects with improved survival and long-term
outcomes in advanced stage V600E-postiive melanoma px. The presence of this BRAF mutation in this px’s tissue sample
most likely indicates a dx of metastatic melanoma.

Keloid (11738)
Transforming growth factor-beta is critical for fibroblast migration, proliferation and connective tissue synthesis.
Increased TGF-beta activity is responsbiel for the hypertrophic/keloid scarring and fibrosis of the lung, liver and kidney
that occur with chronic inflammation

Psoriasis (1116)

Psoriatic arthiritis is an inflammatory disorder affecting the synovium and often the insertion of tendons and ligamets
(ie, enthesopathy). It typically manifest as asymmetric oligoarthritis or symmetric polyarthritis (resembling rheumatoid
arthritis) that often affects the distal interphalangal joints. In severe cases, px can develop an aggressive and destructive
arthritis mutilans. The risk is increased in px who are B27 positive

(14677) IL-12 and IL-23 are produced by activated T cells and play a prominent role in the pathogenesis of psoriasis.

(15408) minor trauma can often precipitate the formation of lesions (Koebner phenomenon)

(8569) the epidermal cell layer superficial to the dermal papillae may be thinned and contain dilated blood vessels,
which can lead to pinpoint bleeding when the scale is removed (Auspitz sign)

First line tx:

- Corticosteroids (eg, diflorasone)

- Vit D analgos (eg, calcipotriene, calcitriol)
Vit D analogs activate the vit D receptor, a nuclear transcription factor, resulting in inh of T-cell and
keroatinocyte proliferation and stimulation of keratinocyte differentiation

Actinic keratosis (1993)

- Small, scaly, erythematous lesions with a sandpaper texture occurring on sun-exposed areas
- Light microscopy:
Hyperkeratosis (hyperplasia of the stratum corneum)
Parakeratosis (retention of nuclei in the stratum corneum)
Atypical keratinocytes with pleomorphic nuclei and multiple mitoses

Hair loss (1725)

Androgenetic alopecia is the most common cause of hair loss in both males and females. The pattern and severity of the
baldness depend on both hormonal (circulating androgens) and genetic factors and vary between males and females.
The condition is polygenic with variable expressivity.

Common medical conditions with polygenic inheritance

- Androgenetic alopecia
- Epilepsy
- Glaucoma
- HTA
- Ischemic heart disease
- Schizophrenia
- DM type II

(1726) In particular, follicular hair growth is strongly influenced by dihydrotestosterone, which is produced by
conversion from testosterone by 5-alpha-reductase. 5-alpha-reductase inhibitors (eg, finasteride) can minimize
progression if used early in the course of hair loss.
Pemphigus vulgaris (2065)

An autoimmune bullous disease characterized by painful flaccid bullae and erosions of the skin and mucosal
membranes. Any mucosal site can be involved, but the oral mucosa is the most common. The bullae are structurally
weak and often rupture prior to presentation, with only erosions remaining. The bullae spread laterally when pressure is
applied on top (Asboe-Hansen sign), and new blisters may form with gentle traction or rubbing (Nikolsky sign).

The underlying pathophysiology of PV involves autoantibodies directed against desmosomes, specifically desmogleins 1
and 3, which disrupt cohesion of keratinocytes. Biopsy of an active PV lesion will show intraepithelial cleavage with
detached keratinocytes (acantholysis), retained keratinocytes along the basement membrane, and an eosinophilic
inflammatory infiltrate. Direct immunofluorescence of unaffected skin adjacent to PV lesions will show epidermal
intercellular IgG and C3 deposits. Circulating autoantibodies against desmoglein are present in many px and can aid dx.

VS. autoantibodies against cutaneous basement membrane proteins are characteristic of epidermolysis bullosa acquisita
(forms tense acral bullae) and cicatricial pemphigoid (causes chronic conjunctivitis and scarring)

VS. no known cutaneous diseases result from connexin autoimmunity, but connexin defects do underlie some specific
forms of palmoplantar keratoderma or deafness-associated ichthyosis

VS. autoantibodies against hemidesmosomal proteins cause bullous pemphigoid, in which the bullae are usually tense
and remain intact as the entire epidermis separates from the dermis (no intraepithelial cleavage). In addition, mucosal
involvement is less common and Nikolsky sign is usually negative

VS. autoantibodies against tissue transglutaminase result in dermatitis herpetiformis and celiac sprue

Sunburn (1477)

UV rays dmg DNA primarily through formation of abnormal covalent bonds between adjacent thymine or cytosine
residues (pyrimidine dimers). The presence of pyrimidine dimers interferes with base recognition during transcription
and replication, and DNA mutations can result if the dmg is not repaired. Pyrimidine dimers are removed by nucleotid
excision repair. In this process, a specific endonuclease complex detects abnormalities in the DNA structure caused by
the formation of DNA photoproducts. The endonuclease complex then nicks the damaged strand on both sides of the
pyrimidine dimer, and the defective region is excised. DNA polymerase synthesizes new DNA in the place of damaged
DNA, and DNA ligase seals the final remaining nick.

Urticarial (11852)

A number of medications (opioids, radiocontrast agents and some antibiotics [eg, vancomycin]), can induce IgE-
independent mast cell degranulation by activation of protein kinase A and PI3 kinase. This results in release of several
mediators, including histamine, bradykinin, heparin and a number of enzymes and chemotactic factors. Common
symptoms include diffuse itching and pain, bronchospasm and localized swelling

Erythema multiforme (11662)

This px’s rash is consistent with EM, an acute inflammatory disorder that can involve the skin of the extremities, face,
trunk and neck. Severe cases (EM major) can also affect oral mucous membranes and the tongue. The appearance of EM
can vary, but px typically develop erythematous, round papules that eveolve into target lesions with a dusky central
area, a dark red inflammatory zone surrounded by a pale ring, and an erythematous halo in the lesion’s periphery.

EM represents a cell-mediated immune process, with an inflammatory infiltrate predominated by cytotoxic

CD8+lymphocytes. EM is most frequently associated with infections (especially herpes simplex virus and mycoplasma)
and may be due to an immune response against antigens deposited in the skin. EM can also be seen in association with
certain medications (eg, sulfonamides), malignancy and collagen vascular disease.

(15695) although HSV is the most common trigger, respiratory tract infections due to Mycoplasma pneumonia (eg, low-
grade fever, headache, fatigue, cough, wheezes) frequently cause EM in children.

EM develops when circulating pathogens are phagocytosed by peripheral mononuclear cells and are brought to the
epidermis,where DNA fragments are transferred to keratinocytes via direct cell-to-cell spread (facilitated by
upregulation of adhesion molecules). Pathogen-specific cytotoxic T-eclls then recognize foreign antigens produced by
keratinocytes and initiate an inflammatory cascade that results in epithelial dmg.

Lymphedema (1937)

Chronic lymphedema is a risk factor for the development of cutaneous angiosarcoma, also known as Stewart-Treves
syndrome. Radical mastectomy with axillary lymph node dissection is a classic predisposing procedure, although any
form of chronic lymphedema can be implicated. Histopathologicaly, angiosarcoma will show infiltration of the dermis
with slit-like abnormal vascular spaces. The prognosis for px with angiosarcoma is poor because the tumor is usually
widespread by the time of diagnosis. There is controversy regarding use of the term angiosarcoma vs.
lymphangiosarcoma, as it appears that this entity arises from blood vessels rather than from lymphatic vessels.

Androgenic steroids (7585)

Anabolic steroids (eg, methyltestosterone) are androgens

Pathophysio of acne:

1. Follicular epidermal hyperproliferation

2. Excessive sebum production
3. Inflammation
4. Propionibacterium acnes

After conversion to dihydrotestosterone, androgens promote both follicular epidermal hyperproliferation and excessive
sebum production. Other drugs known to cause aceniform eruptions include epidermal growth factor receptor inhibitors
and lithium

Effects of androgen abuse (1901)

Tinea (15579)

Tinea corporis presents with round or ovoid lesions with a raised, scaly border and central clearing. Trichophyton
rubrum is the most common cause and infects keratinized matter in the stratum corneum of the superficial epidermis
but does not invade the dermis and subcutaneous tissues.

Treatment (836)

Terbinafine is used for tx of dermatophytosis. If inh synthesis of fungal membrane ergosterol by suppressing the enzyme
squalene epoxidase.

Melanoma (1113)
melanoma often has an early horizontal growth phase with low metastatic potential followed by a nodular, vertical
growth phase with a significantly increased risk of metastasis. Depth of invasion (Breslow thickness) is the most
important prognostic indicator in malignant melanoma.
Dermatitis herpetiformis (1111)

Is characterized by erythematous pruritic papules, vesicles, and bullae that appear bilaterally and symmetrically on the
extensor surfaces (eg, elbows, knees), upper back and buttocks. The term “herpetiformis” refers to the resemblance of
the clustered vesicular lesions to those seen in herpes simplex virus infections. Histologically, dermatitis herpetiformis is
characterized by microabscesses containing fibrin and neutrophils at the dermal papillae tips. The overlying basal cells
become vacuolated, and coalescing blisters form at the tips of the involved papillae.

The pathogensis of DH involves the formation of IgA antibodies against gliadin (a protein unique to the gluten portion of
wheat) or a gliadin/tissue transglutaminase complex in the intestine. These antibodies appear to cause clinical disease
by cross-reacting with epidermal transglutaminase. DH is strongly associated with celiac disease, which is characterized
by increased intraepithelial lymphocytes, a variable loss of villus height, and crypt hyperplasia, leading to clinical
feautres of malabsorption (eg, steatorrhea).

Melanocytic nevus (11502)

1. Junctional nevi: are characterized by aggregates of nevus cells limited to the dermoepidermal junction. They
typically appear as flat, black- to brown- pigmented macules with darker coloration in the center than the
periphery and preserved skin markings.
2. Compound nevi form as the aggregates of nevus cells extend into the dermis. Compound nevi are raised papules
with uniform brown to tan pigmentation. This px’s lesion is a compound nevus as it has both dermal and
epidermal involvement
3. Intradermal nevi are considered to be older lesions in which the epidermal nests of nevus cells have been lost.
The remaining dermal nevus cells lose tyrosinase activity and produce little to no pigment. Intradermal nevi are
skin- to tan- colored, dome-shaped, and sometimes pedunculated.
Cherry angioma (826)

Cherry hemangiomas are small, red, cutaneous papules common in aging adults. They do not regress spontaneously and
typically increase in number with age. Light microscopy of these lesions shows proliferation of capillaries and post-
capillary venules in the papillary dermis.

VS. acrochordons (skin tags) are pedunculated outgrowths of normal skin. They are typically seen in areas of friction (eg,
neck, axilla, inframammary, groin) of patinwts with obesity and diabetes mellitus

VS. cavernous hemangiomas consist of dilated vascular spaces with thin-walled endothelial cells. They present as soft
blue, compressible masses up to a few centimeters in size. They may appear on the skin, mucosa, deep tissues, and
visversa. When cavernous hemangiomas appear on the skin, they are most frequently based in the dermis. Cavernous
hemangiomas of the brain and viscera are associated with von Hippel-Lindau disease.

(11627) cavernous hemangiomas are vascular malformations that occur most commonly within the brain parenchyma;
they carry an increased risk of intracerebral hemorrhage and seizure.

VS. cystic hygromas are comprised of lymphatic cysts lined by a thin endothelium. These beign tumors are often present
at birth and are most commonly located on the posterior neck and lateral chest wall. Cystic hygromas are frequently
found in neonates with Turner syndrome and Down syndrome

VS. spider angiomas constis of a bright red central papule surrounded by several outwardly radiating vessels that blanch
with pressure and refill centrifugally upon release. They are associated with increased estrogen states (eg, pregnancy,
cirrhosis, oral contraceptive use, estrogen supplement use)

VS. superficial (also known as infantile, capillary or strawberry) hemangiomas appear during the first weeks of life. They
initially grow rapidly and then frequently regress spontaneously by late childhood. They are bright red when near the
epidermis and more violasceous when deeper.

Cavernous hemangiomas (12283)

Cavernous hemangiomas are vascular malformations that frequently involve the deeper tissues of the body, such as the
liver and brain. Gross examination of hemangiomas reveals a “mulberry-like” appearance due to their purple vascular
clusters. Histologically, they are composed of abnormal, dilated blood vessels with a thin adventitia lacking elastic fibers
and smooth muscle. The reduced structural support gives them a tendency to leak, causing recurrent hemorrhage.

Most px are asymptomatic, although hemangiomas in the brain may cause neurologic deficits and seizures due to
compression of the surrounding tissue and irritation from recurrent bleeding. Surgical resection is indicated for lesions
causing intractable epilepsy or progressive neurologic deficits.

Glomus tumor (467)

A bluish neoplasm occurring underneath the nail bad may be either a glomus tumor (glomangioma) or a subungual
melanoma. Both are rare dx. Melanomas are composed of melanocytes, which have the function of pigmentation.

A glomangioma is a tumor of the modified smooth muscle cells of a glomus body. Glomus bodies are numerous small,
encapsulated neurovascular organs found in the dermis of the nail bed, the pads of the fingers and toes and the ears.
Each glomus body is composed of an afferent arteriole connected to a richly innervated, muscular arteriovenous
anastomosis, which is then connected to an efferent vein. Modified smooth muscle cells are arranged in layers around
these vascular channels. The role of the glomus body is to shunt blood away from the skin surface in cold temperatures
in order to prevent heat loss, and to direct blood flow to the skin surface in hot environments to facilitate the dissipation
of heat.

Granulomatous inflammation (8334)

Granulomas are characterized by aggregates of activated macrophages that assume an epithelioid appearance. They are
often surrounded by a rim of lymphocytes that synthesize cytokines responsible for continued macrophage activation.
Multinucleated giant cells, derived from fusion of several macrophages, can also be found in granulomas. Activated TH1
CD4+ cells secret interferon-gamma, which activates macrophages. Macrophages, in turn, secret TNF alpha, which
results in further macrophage maturation and formation of the granuloma. The granuloma serves to wall off the
offending agent. However, the agent is not always eradicated, as certain pathogens are resistant to killing (eg, tb).
Persistent granulomatous inflammation with subsequent fibrosis can cause organ dysfunction, which is seen in a number
of granulomatous diseases.

Aging (1860)

UVB wavelengths are predominatly absorbed in the upper dermis and contribute to sunburn and increased risk of
malignancy. UVA wavelengths penetrate deeper into skin and cause photoaging. UVA produces ROS, which activate
multiple inflammatory cell-surface receptors and nuclear transcription factors. This leads to decreased collagen fibril
production, along with upregulation of matrix metalloproteinases (including collagenases) that subsequently degrade
type I and III collagen and elastin. There is an increased crosslinking of collagen, with deposition of collagen breakdown
products.

Ehlers-danlos syndrome (1245)

Deficiency in procollagen peptidase, the enzyme that cleaves terminal propeptides from procollagen in the extracellular
space. Impaired propeptide removal results in the formation of soluble collagen that does not properly crosslink -> joint
laxity, hyperextensible skin, fragile tissue with easy bruising and poor wound healing.

Seborrheic keratosis (1112)

Is a common, tan or brown, epidermal tumor occurring in middle-aged or elderly individuals. It has a variable
appearance from nearly fat macules to raised, wart-like lesions, ranging in size from a few millimeters to centimeters. SK
typically has a velvety or greasy surface and well-demarcated border, and is often described as having a “stuck-on”
appearance. On microscopic examination, the lesions of SK are composed of small cells resembling basal cells, with
variable pigmentation, hyperkeratosis (thickening of the stratum corneum), and keratin-containing cysts.

The etiology of SK is not fully understood; however, it is frequently associated with activiating mutations of the
fibroblast growth factor receptor 3. SK itself is benign, but rapid onset of numerous SKs (Leser-Trelat sign) is often
associated with an internal malignancy (eg, gastric adenocarcinoma), possibly due to overproduction of insulin-like
growth factor 1 and other cytokines.

Scabies (13911)

Topical permethrin: blocks mite neurotransmission by impairing voltage-gated sodium channels

Oral ivermectin: antiparisitic agent that binds chloride ion channles in invertebrate nerve and muscle cells

Miscellaneous

Developmental milestones during toddlerhood

Age Gross motor Fine motor Language Social/cognitive
12 - Stands well - 2 finger princer - Says first words - Separation anxiety
months - Walks first grasp (other than - Follows 1-step
steps mama and commands with
independently dada) gestures
- Throws a ball
18 - Runs - Builds a tower of 2- - 10- to 25- word - Understands
months - Kicks a ball 4 cubes vocabulary “mine”
- Removes clothing - Identifies >1 - Begins pretend
body parts play
2 years - Walks - Builds a tower of 6 - Vocabulary >50 - Follows 2-step
up/down stairs cubes words commands
with both feet - Copies a line - 2-word phrases - Parallel play
on each step - Begins toilet
- Jumps training
3 years - Walks - Copies a circle - 3-Word - Knows age/gender
up/down stairs - Uses utensils sentences - Imaginative play
with - Speech 75%
alternating feet intelligible
- Rides tricycle
4 years - Balances & - Copies a cross - Identifies colors - Cooperative play
hops on 1 foot - Speech 100%
intelligible
5 years - Skips - - copies a square - Counts to 10 - Has friends
- Catches ball - Ties shoelaces - 5-word - Completes toilet
with 2 hands - Dresses/bathes sentences training
independently
- Prints letters

Pharyngeal arches (1691)

Tuberous sclerosis (6)

Renal angiomyolipoma is a benign tumor composed of blood vessels, smooth muscle and fat. These tumors can be dx
with an abd CT scan as the radiodensity of fat is less than that of water.

Angiomyolipomas are associated with tuberous sclerosis. In px with bilateral renal angiomyolipomas, the incidence of
tuberous sclerosis is 80-90%. Tuberous sclerosis is an autosomal dominant condition characterized by cortical tubers and
subependymal hamarotmas in the brain, with consequent seizures and cognitive disability. Cardiac rhabdomyomas,
facial angiofibromas, and leaf-shaped patches of skin lacking pigment (ash-leaf patches) can also occur.

(543)
Seafood poisoning (8352)
Tetrodotoxin (puffer fish) Binds to Na+ channels, inh Na+ influx and preventing action potential
Saxitoxin (dinoflagellates in “red tide”) conduction
Ciguatoxin (exotic fish, Moray eel) Binds to the Na+ channel, keeping it open and causing persistent
Batrachotoxin (South American frogs) depolarization

Arsenic poisoning (841)

Cyanide poisoning (1254)

Cyanide poisoning (1415)

Inh cytochrome C oxidase in the mitochondria -> severe lactic acidosis and death due to cells switching to anaerobic
metabolism

Presents: reddish sin discoloration, tachypnea, headache and tachycardia, often caccompanied by nausea/ vomiting,
confusion and weakness. Symptoms develop rapidly and can quickly progress to seizures and cardiovascular collapse.

Tx: nitrites are oxidizing agents that are effective in tx cyanide poisoning due to their ability to induce
methemoglobinemia, methemoglobin contains ferric (Fe3+) rather than ferrous iron (Fe2+). Cyanide binds to ferric iron
more avidly than to mitochondrial cytochrome enzymes, diminishing cyanide’s toxic effect.
Embryo (8702)

Ectoderm Surface ectoderm - Lens & cornea

- Inner ear sensory organs, olfactory epithelium
- Nasal & oral epithelial linings, salivary glands
- Epidermis, sweat & mammary glands
Neural tub - Brain & spinal cord
- Posterior pituitary, pineal gland
- Retina
Neural crest - Neural ganglia, adrenal medulla
- Schwann cells; pia & arachnoid mater
- Aorticopulmonary septum & endocardial cushions
- Branchial archs (bones & cartilage)
- Skull bones
- Melanocytes
Mesoderm - Muscles (skeletal, cardiac & smooth)
- Connective tissue, bone & cartilage
- Serosal linings (eg, peritoneum)
- CV & lymphatic system
- Spleen & hemopoietic cells
- Kidney & ureters, interal genitalia
- Adrenal cortex
Endoderm - GI tract, liver, pancreas
- Lungs
- Thymus, parathyroids, thyroid follicular cells
- Middle ear epithelium
- Bladder & urethra
- Parafollicular (C) cells

DiGeorge syndrome/velocardiofacial syndrome (34)

(8532) DiGeorge syndrome causes an extreme deficiency in the number of mature T lymphocytes, leading to poor
development of the lymph node paracortex. In contrast, agammaglobulinemia causes an absence of B cells, preventing
primary lymphoid follicles and germinal centers from forming in the lymph node cortex.

Theophylline poisoning (172)

In low to moderate doses, methylxanthines cause mild cortical arousal and insomnia, much like caffeine. Acute
theophylline intoxication results in nausea.vomiting, abd pain, diarrhea, cardiac arrhythmias, and seizures. Seizures are
the major cause of mobidity and mortality in the theophylline intoxication. Tachyarrhythmias are the other major
concern but usually do not cause QT prolongation.

Tx of theophylline:

- Activated charcoal to reduce GI absorption

- Beta blockers: are the drugs of choice for theophylline-induced cardiac tachyarrhythmias
- Theophilline-induced seizures are difficult to tx, but benzos and barbiturates are the most effective agents

Holoprosencephaly (352)

A developmental field defect describes multiple malformations that occur secondary to an embryonic disturbance in an
adjoining group of cells. Holoprosencephaly is a developmental field defect characterized by a spectrum of fetal
anomalies due to incomplete division of the forebrain (prosencephalon)

Risk factors:

- genetic (eg, trisomy 13, sonic hedgehog gene mutations)

- environmental (eg, maternal alcohol use) factors

Poisoning & environmental exposure

Aspirin poisoning (1544)

acute salicylate intoxication typically presents with nausea/vomiting, confusion, dizziness, tinnitus (eg, buzzing sound),
fever, and tachypnea within several hours after ingestion. Two different acid-base abnormalities are characteristic

- respiratory alkalosis: occurs first as salicylates directly stimulate the medullary respiratory center, resulting in
increased ventilation and loss of CO2 in the expired air
- anion gap metabolic acidosis begins to develop about 12 hrs later as high concentrations of salicylates increase
lipolysis, uncouple oxidative phosphorylation, and inh the citrict acid cycle. This results in the accumulation of
organic acids in the blood (eg, ketoacids, lactate, pyruvate), which bind bicarbonate, thereby increasing the
calculated anion gap.

Aging (862)

Normally, in accommodation, when focusing on near objects (Eg, reading), ciliary muscle contraction relaxes the zonular
fibers, allowing the lens to become more convex so the image focuses on the retina.

Starting around age 40-50, almost all individuals develop an inability to focus on near objects. In this condition, called
presbyopia, progressive denaturation of lens proteins and changes in lens curvature cause the lens to become less
elastic and lose its accommodating power. This causes the image of near objects to focus behind the retina. Conversely,
in myopia (increased eye axial length), the image focuses in front of the retina. Therefore, presbyopia can compensate
for myopia by displacing the image backward, so that it focuses on the retina. Px with mild myopia often note
improvement with age as presbyopia develops. In px without myopia, presbyiopia manifests with difficulty reading fine
print and the need to hold objects farther in order to see them clearly.