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Dr. Jalal Introduction to Pathology Dr. Jalal Cellular adaptation

Cores of pathology: Physiologic adaptations; usually represent responses of cells to
normal stimulation by hormones or endogenous chemical mediators
▪ Etiology Example\ the hormone-induced enlargement of the breast and uterus
during pregnancy.
▪ Pathogenesis. (sequence of events at the organ  molecular levels,
from initial stimulus to the ultimate expression of the disease. Pathologic adaptations; are responses to stress that allow cells to
modulate their structure and function and thus escape injury.
▪ Morphologic changes. (Macro --& microscopical changes).
1. Atrophy (smaller cells)
▪ Signs & symptoms. (Functional changes)
▪ Shrinkage in the size of the cell by the loss of cell substance is known
Causes of Cell Injury: as atrophy.
1. Oxygen Deprivation [O2 insufficiency (↓PO2)] ▪ Some of these stimuli are physiologic (e.g., the loss of hormone
▪ This is a common cause of cell death. stimulation in menopause) and others pathologic (e.g., denervation).

A. Hypoxia - lack of O2 results in decreased aerobic respiration. ▪ Atrophy results from decreased protein synthesis and increased
protein degradation in cells.
B. Ischemia - lack of O2 & metabolic substrates.
▪ Ischemia ("ischemic hypoxia“) Loss of arterial blood flow. 2. Hypertrophy (bigger cells)
2. Physical Agents
▪ Hypertrophy is an increase in the size of cells resulting in increase in
▪ Extremes of temperature – burns, deep cold
the size of the organ.
3. Chemical Agents and Drugs
▪ Hypertrophy and hyperplasia can also occur together.
▪ Poisons – arsenic, cyanide, or mercuric salts
▪ Occupational hazard – asbestos ▪ The massive physiologic enlargement of the uterus during pregnancy
occurs as a consequence of estrogen-stimulated smooth muscle
4. Infectious Agents
hypertrophy and smooth muscle hyperplasia.
5. Immunologic Reactions
▪ The striated muscle cells in both the skeletal muscle and the heart
6. Genetics Derangements can undergo only hypertrophy.

7. Nutritional Imbalances ▪ Examples of pathologic cellular hypertrophy include the cardiac

▪ Anorexia nervosa and Metabolic diseases – Diabetes enlargement that occurs with hypertension or aortic valve disease.

Ibrahim Ismail Mustafa

3. Hyperplasia (more cells) 4. Metaplasia (different type of cells)
▪ Hyperplasia is characterized by an increase in cell number. ▪ Is a reversible change in which one adult cell type (epithelial or
▪ Hyperplasia can be physiologic or pathologic. mesenchymal) is replaced by another adult cell type.

● Types of physiologic hyperplasia: ▪ Epithelial metaplasia is exemplified by the squamous change that
occurs in the respiratory epithelium in habitual cigarette smokers.
• Hormonal hyperplasia;
The normal ciliated columnar epithelial cells of the trachea and
▪ For example, The proliferation of the glandular epithelium of the bronchi are widely replaced by stratified squamous epithelial cells.
female breast at puberty and during pregnancy.
▪ In reflux esophagitis, the normal stratified squamous epithelium of
• Compensatory hyperplasia; occurs when a portion of the tissue is the lower esophagus may undergo metaplastic transformation to
removed or diseased. gastric-type columnar epithelium.

▪ For example, when a liver is partially resected, mitotic activity in the ▪ Metaplasia may also occur in mesenchymal cells as an adaptive
remaining cells begins as early as 12 hours later, eventually restoring response. For example, bone is occasionally formed in soft tissues,
the liver to its normal weight. particularly in foci of injury.

Pathologic hyperplasia: are caused by excessive hormonal or

growth factor stimulation. Reversible cell injury
▪ For example, after a normal menstrual period there is a burst of ▪ Two main morphologic patterns of reversible cell injury are cellular
uterine epithelial proliferation that is normally tightly regulated by swelling and fatty change.
stimulation through pituitary hormones and ovarian estrogen and by
Cellular swelling; is the result of failure of energy-dependent ion
inhibition through progesterone.
pumps in the plasma membrane, leading to an inability to maintain
▪ If the balance between estrogen and progesterone is disturbed, ionic and fluid homeostasis.
endometrial hyperplasia ensues, a common cause of abnormal
menstrual bleeding. Fatty change; Occurs in hypoxic injury and various forms of toxic
or metabolic injury, and is manifested by the appearance of small or
large lipid vacuoles in the cytoplasm.

▪ It occurs mainly in cells involved in and dependent on fat metabolism,

such as hepatocytes and myocardial cells.
 Lec 3 1. Coagulative Necrosis
Dr. Zheen Necrosis
• Coagulative Necrosis is the most common type of necrosis.
Morphology of Necrotic Cells
• Mostly caused by sudden cessation of blood flow (ischaemia)
Cytoplasmic changes: • The organs commonly affected are the heart, kidney, and spleen
● Increased Eosinophilia of cytoplasm: (except the brain).
▪ loss of RNA (basophilia)
▪ denatured cytoplasmic protein bind tightly to eosin Grossly
● Myelin figure (EM): • The affected tissues take on a firm texture
▪ Large, whorled phospholipid mass (phospholipid precipitate) • Preservation of structure
Nuclear changes: ▪ A wedge-shaped kidney infarct (yellow).
▪ Pyknosis (shrinkage & ↑ basophilia)
▪ Karyorrhexis (Fragmentation of pyknotic nuclei)
▪ Karyolysis (fading of chromatine –DNAase effect) Microscopically
• The hallmark of coagulative necrosis is the conversion of normal cells
into their ‘tombstones’ (i.e. outlines of the cells are retained so that
the cell type can still be recognised but their cytoplasmic and nuclear
details are lost).

[[Kidney infarct exhibiting coagulative necrosis, with loss of nuclei and

Pyknosis Karyorrhexis & Karyolysis clumping of cytoplasm but with preservation of basic outlines of glomerular
and tubular architecture]]
2. Liquefactive Necrosis 3. Caseous Necrosis

• Liquefactive or colliquative necrosis occurs commonly due to • Caseous means “cheese-like,” referring to the friable yellow-white
bacterial or fungal infections. appearance of the area of necrosis.

• It occurs due to degradation of tissue by the action of powerful • Is encountered most often in foci of tuberculous infection & certain
hydrolytic enzymes. fungal infections (as Histoplasmosis).

• For obscure reasons, hypoxic death of cells within the central • All the cells in the area die & surrounded by inflammatory cells
nervous system (brain) often evokes liquefactive necrosis. (granulomatous inflammation).

• Whatever the pathogenesis, the dead cells are completely digested,

transforming the tissue into a liquid viscous mass.
Grossly
Grossly • A tuberculous lung with a large area of
caseous necrosis [containing yellow-white
• The affected area is soft with liquefied centre
(cheesy) debris]
containing necrotic debris. Later, a cyst wall is
formed.

Microscopically
Normal brain Liquefactive necrosis
• The necrosed foci are structureless, eosinophilic, and contain
granular debris.

• Granulomatous inflammatory reaction.

• Microscopically, the cystic space contains necrotic cell debris and

macrophages filled with phagocytosed material.
4. Fat Necrosis 5. Fibrinoid Necrosis

• Refers to focal areas of fat destruction • Fibrinoid necrosis is characterised by deposition of fibrin-like
material in the walls of arteries.
• Occurring at two anatomically different locations, these are:
Acute pancreatitis • It is encountered in various examples of immunologic tissue injury
Traumatic fat necrosis (breast) (e.g. in immune complex vasculitis), arterioles in hypertension, peptic
• But morphologically similar lesions. ulcer, etc.

• There is liberation of lipases.

\

• Lipase releases free fatty acid from the local lipids (membranes,
Fibrinoid necrosis in an artery
triglyceride).

• FFA combine with Ca to produce salt “soaps” (saponification)

E Gross appearance Microscopic appearance

Microscopically
Grossly • The wall of the artery shows a circumferential bright pink area of
necrosis with protein deposition and inflammation.
• Foci of Fat necrosis with saponification in the mesentry.

• The areas of white chalky deposits represent calcium soap formation

at sites of lipid breakdown
6. Gangrenous necrosis Free radicals
• It is not a distinctive pattern of cell death, but the term is still • Free radicals are chemical species with a single unpaired electron in
commonly used in clinical practice. an outer orbital. Free radicals are extremely unstable
• It is due to an obstruction in the supply of blood (Ischemia) to an • Single free radicals initiate chain reactions which destroy large
area of body resulting in coagulative necrosis (Dry gangrene). numbers of organic and inorganic molecules
• When bacterial infection is superimposed, coagulative necrosis is • The most important free radicals are probably those derived from
modified by the liquefactive action of the bacteria and the attracted oxygen called Reactive oxygen species (ROS). Ex: superoxide (O-.2);
leukocytes (resulting in so-called wet gangrene). hydroxyl radical (OH.); hydrogen peroxide (H2O2) and Nitric oxide (NO)

• The different types of ROS are produced by two major pathways:

Dry gangrene on the right Wet gangrene on the left
▪ ROS are produced normally during the reduction-oxidation (redox)
reactions
▪ ROS are produced in phagocytic leukocytes, mainly neutrophils &
macrophages

• Free radicals may be generated in the following ways:

1. The absorption of radiant energy (e.g., ultraviolet light, x-rays).
Ionizing radiation can hydrolyze water into hydroxyl (•OH) and
hydrogen (H•) free radicals.
2. Enzymatic metabolism of exogenous chemicals (carbon tetrachloride)
Outcomes of Necrosis: 3. Inflammation, in which free radicals are produced by leukocytes

• Free Radical Defense:

1. Inflammation & resolution\\ occurs if the injury is mild & the tissue 1- Spontaneous decay.
has the power to proliferate. 2- Antioxidants
2. Inflammation & organization (fibrosis)\\ occurs if the injury is 3- Free radical scavenging systems.
severe &/or the tissue do not have the power to proliferate. • Free-radical effects:
3. Dystrophic calcification\\ deposition of Ca++ salts in necrotic tissue. 1. Oxidation of fatty acids in membranes ("lipid peroxidation").
\ 2. Cross-linking of proteins. (protein denaturation)
3. Genetic mutations (DNA depolymerization)
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Dr. Zheen
Apoptosis Morphological Features of Apoptosis:

● Involvement of single cells or small clusters of cells

Apoptosis in Physiologic Situations:
● Cell shrinkage
• Serves to eliminate cells that are no longer needed and to maintain ● Chromatin condensation and fragmentation.
a constant number of cells of various types in tissues.
● Formation of cytoplasmic blebs and apoptotic bodies.
Programmed cell destruction during embryogenesis & development
● Phagocytosis of apoptotic bodies by adjacent healthy cells or
Involution of hormone-dependent tissues upon hormone deprivation macrophages.
▪ Endometrial cells (menstrual cycle) ● Lack of inflammation.
Cell loss in proliferating cell populations
Features of Necrosis and Apoptosis
▪ Skin

Elimination of cells that have served their useful purpose

▪ Post-inflammatory clean up (neutrophils)

Cell death induced by cytotoxic T-cells to eliminate harmful cells

▪ Viral infected or tumor cells

Elimination of potentially harmful self-reactive lymphocytes

Apoptosis in Pathologic Conditions:

• Apoptosis eliminates cells that are genetically altered or injured

beyond repair and does so without eliciting a severe host reaction.

DNA damage
▪ Radiation, cytotoxic anticancer drugs

Cell injury in certain infections.

▪ Viral infections

Pathologic atrophy in parenchymal organs after duct obstruction.

▪ Pancreas, parotid gland
Lec 5 Intracellular Accumulations of Proteins
Dr. Shatha Cellular accumulations
Intracellular Accumulations of Lipids ● Microscopically → eosinophilic glassy hyaline changes:
(Triglycerides & Cholesterol) ● Accumulation of protein droplets in proximal renal tubule in renal
disease with heavy protein leakage across the glomerular filter
♦ Steatosis (fatty change): (Nephrotic syndrome)
▪ Abnormal accumulation of triglycerides within parenchymal cells
(especially hepatocytes) ● Absorption of protein causing hyaline droplets
▪ Fatty liver in chronic alcoholism in proximal epithelial cells in the kidney.

● Fatty change; Masses of altered intermediate filaments\\ Example:

1. Excessive entry of FFA into the liver (starvation, obesity). ▪ Mallory bodies in alcoholic liver and Russel bodies.
2. Metabolic disease (Diabetes mellitus). ● Intermediate filaments (flexible scaffold):
3. Decreased fatty acid oxidation (hypoxia). ▪ Keratin in epithelial cells [for example in liver cells]
4. Increased esterification of fatty acid to triglycerides (alcohol). ▪ Desmin in muscle cell.
5. Decreased apoprotein synthesis (CCl4 &protein malnutrition). ▪ Vimentin in connective tissue cell.
6. Impaired lipoprotein secretion from the liver (alcohol). ▪ Glial filaments in astrocytes.

● Microscopically, Lipids are YELLOW grossly and WASHED out (CLEAR) ● Defects in protein folding;
▪ E.g: Aggregation of abnormal folded protein - amyloidosis
● So needs Special stains: Sudan IV, Oil red

Intracellular Accumulations of Glycogen

Cholesterol and Cholesterol Esters:
● Atherosclerosis: ● Microscopically; clear vacuole (PAS = Periodic acid shiff reagent-
▪ Accumulation of cholesterol in: pink violet in color)
- Macrophage (foam cell).
- Smooth muscle cells of aorta and arteries. Diabetes mellitus;
▪ Disorder of glucose metabolism
▪ Glycogen accumulate in epithelial cells of renal tubules, liver cells,
beta-cells of the islets of Langerhans and heart muscle cells.
● Cholesterolosis:
Glycogen storage disease (Glycogenosis);
▪ Accumulation of foam cells in the lamina propria of
gallbladder. ▪ Genetic diseases
▪ Defect of enzymes in the synthesis or breakdown of glycogen
accumulation cell injury death.
 Pigmentations ● Melanin – [melas = black]

● Pigments are colored substances either: ▪ In melanocytes formed by oxidation of tyrosine to

1. Exogenous; (tattoo, Anthracosis) dihydroxyphenylalanine by tyrosinase enzyme.
2. Endogenous; they all look the same, (hemosiderin, melanin, bile,
● Hemosiderin
lipofucsin) in that they are all golden yellowish brown in microscope.
▪ Aggregates of ferritin micelles (iron + apoferritin = ferritin)
Exogenous pigments;
▪ Hemosiderosis: Excess of hemosiderin granules in mononuclear
▪ Carbon (anthracosis)
phagocytes without organ dysfunction.
▪ Coal dust (pneumoconiosis)
▪ Globin → biliverdin (green bile) → bilirubin (red bile).
● Lung; pick up by alveolar macrophages  regional lymph nods 
blackening the tissues of the lungs (anthracosis) ▪ Heme → ferritin → Hemosiderine.

Anthracosis: Carbon - laden macrophages (black exogenous pigment) ▪ Hemochromatosis: Excess of hemosiderin granules in mononuclear
phagocystic system & paranchymal cells causing organ dysfunction
(liver fibrosis, DM, heart failure).
Hemosiderin granules in liver cells
A. golden-brown,finely granular pigment B. Prussian blue reaction, specific for iron

Endogenous pigment
● Lipofuscin – aging pigment (fucus = brown)
▪ Composed of phospholipid-protein complex (lipid peroxidation).
▪ Brown-yellow pigment accumulated as the atrophic and dying cells ● Jaundice
undergo autophagocytosis.
▪ Yellowish discoloration of skin & sclera due to deposition of bilirubin
▪ Harmless, with sign of free radical injury & lipid peroxidation, seen in pigment.
aging patients, severe malnutrition & cancer cachexia.

Bile pluges
Lipofuscin
in liver of
(wear & tear) patient with
pigments in obstructive
cardiac myocytes jaundice
 Pathologic Calcification Metastatic calcification;
● Reflects deranged calcium metabolism, in contrast to dystrophic
▪ Abnormal deposition of calcium salts together with smaller amount
calcification, and is associated with increase serum calcium level &
of Mg++, Fe++ & other minerals in tissues other than osteoid or enamel.
systemic deposition of Ca++ salts in interstitial tissue of:
Dystrophic calcification; ▪ Gastric mucosa
● Refers to local deposition of calcium salts in necrotic or degenerate ▪ Kidney
tissues, whatever the type of necrosis, in spite of normal serum Ca++. ▪ Lungs
▪ Area of tissue necrosis ▪ Systemic arteries
▪ Aging or damage heart valve ▪ Pulmonary veins
▪ Atherosclerosis ● Metastatic calcification – Hypercalcemia;
▪ Single necrotic cell 1. Increased secretion of parathyroid hormone
2. Destruction of bone tissue secondary to;
▪ Primary tumor of bone marrow (multiple myeloma, leukemia),
▪ or diffuse skeletal metastasis (breast cancer).
Aortic valve, gross,
, (calcified aortic stenosis) 3. Vitamin D-related intoxication
4. Renal failure
5. Excessive intake of calcium & absorbable antacids as milk or calcium
carbonate.

This is dystrophic calcification in the wall of the stomach. At the far left is “Metastatic calcification” in the lung of a patient with a very high serum
an artery with calcification in its wall calcium level (hypercalcemia).