General Pathology [ CELL INJURY]

Cell response to injury: Morphological & functional changes of cells following stress
Stressful conditions: Hypoxia, Infections, physical, or chemical changes

The Outcome of injury depends on : Type of tissue - Type of injury – duration of

injury

• Reversible injury (with mild/moderate injury, recovery is possible)

• Irreversible injury (with severe persistent injury → cell death necrosis &
apoptosis)
• Accumulations & tissue deposits (In some types of tissues, in certain
situations , tissue cannot utilize certain types of substances that accumulate
in tissue or cells)
• Adaptations (Accommodation by new steady state to maintain viability &
function)

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Reversible & Irreversible injury

Causes:
• Hypoxia (decrease oxygen supply )
o Ischemia , heart failure
o Anemia, or heart diseases
• Infections : viral – bacterial – fungal – parasitic …etc.
• Immunological: Ag-Ab reaction, Autoimmune
• Physical: e.g. Tempreture- truma – Radiation
• Chemicals: Acids – Alkalis – Poisons – drugs
• Genetic disorders
• Nutritional : protein deficiency (marasmus, Kwashiorkor) – excess fat

Factors affecting reposnse to injury:

Type of injury (severity & duration)
Type of cells (labile – stable – permanent)

Skeletal muscle resists hypoxia for 2-3 hours, Cardiac muscle resists for 20-30 minutes

Mechanism of cell injury

• Lack of ATP
• Defective membrane permeability (Na-K pump failure)
• Mitochondrial injury
• Release of Reactive oxygen species (Free Radicals)
• Increased intracellular Calcium
• Activation of damaging enzymes

CAFÉ MAP
CAlcium influx
Free radicals
Enzymes

Mitochondrial damage
ATP depletion
Pump failure

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General Pathology [ CELL INJURY]

Mechanism of cell injury

↓ ATP → Defective cell membrane transport (Na-K pump failure) →

↑ intracellular Sodium (Na) → water influx → Cell Swelling & organelles swelling
mitochondria damage (appear as amorphous deposits or vacuoles ) :
• Release of free radicals (Active oxygen metabolites) → damage of
proteins, lipid, & DNA
• Release of Cytochrome C → activation of apoptosis
• ATP depletion

↓ ATP → Calcium influx → ↑ intracellular Ca → activate damaging enzymes:

o ATPase → more ATP loss

o Protease→ damaged proteins & neucleoprotein
o Caspase → Cell apoptosis
o Phospholipase →
▪ membranes damage:→Myline figures :
• Phagocytosed
• Bind with Ca → saponification
▪ Release of intracellular enzymes to blood (e.g. CK ,& troponins in
myocardial infarction ,& AST, or ALT in liver diseases)
▪ Mitochondrial & lysosomal damage
o Endoneucleaese → damage of neucleus, DNA, RNA
▪ Pyknosis(condensation)
▪ Karyorhexis(fragmented)
▪ Karyolysis (dissolution)

↓ ATP → Anaerobic glycolysis → lactic acidosis→ activates enzymatic digestion

Points of no return: The critical phenomena that lead to irreversible changes are
permanent Mitochondrial dysfunction & cell membrane damage.

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General Pathology [ CELL INJURY]

Reversible injury
Hydropic degeneration
(cloudy swelling)

Definition: Reversible cell injury, with intracellular water vacuoles

Causes: causes of cell injury (enumerate) , but mild for short duration

Pathogenesis:
Hypoxia → Loss of ATP → Failure of sodium pumps → Sodium & water influx → Cell swelling

Site: highly specialized organs (e.g. Liver, & kidney)

Gross:
- Size : swollen
- Surface : smooth
- Cut section : bulging
- Color : pale bloodless (compressed capillaries)
- Consistency : Soft

Microscopic:
• Cells: Swollen – intact membrane – cytoplasmic vacuoles (swollen ER)
• Stroma: compressed capillaries

E/M (ultrastructure):
• Cell swelling
• Blebs at the surface
• Loss of microvilli in some epithelial cells
• Ribosomes are detached
• Loose intracellular attachment
• Mitochondria & ER are swollen
• Chromatin clumping

Fate:
If the cause is removed → cells return to normal
If not → necrosis

Clinical:
Liver → hepatomegaly and jaundice due to occlusion of bile canaliculi
Intestine → diarrhea

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General Pathology [ CELL INJURY]

Irreversible injury

NECROSIS
Definition: Death of group of cells inside living tissue, directly, or following
degeneration. Necrosis is surrounded by inflammation.

Pathological picture:
- Cytoplasm: eosinophilia (due to loss of RNA & denaturated proteins)
- Neucleus: Pyknosis– Karyorhexis – Karyolysis

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General Pathology [ CELL INJURY]

Morphological Types of necrosis:

1- Coagulative necrosis:

- The most common type of necrosis

- Tissue resembles "Boiled meat"
- Cause: Hypoxia is the most common , mainly ischemia
- Gross: dead area is " firm", and "pale "
- Microscopic:
Cellular details are lost
architecture is preserved in early stage (Fibrous stroma resists hypoxia,
but later , inflammatory cells lead to lysis of architecture)
- e.g. : Myocardial infarction (MI), Renal infarction

2- Caseation necrosis:

- Tissue resembles Casine "Cheese"

- occur in Tuberculosis (T.B.)
- Cause: Hypersensitivity against T.B. bacteria → tissue caseation
- Gross: dead area is "soft cheesy, granular", and "yellowish white"
- Microscopic: tissue became structureless homogenous , with granular
areas + granuloma of TB (discussed in Chapter: granuloma)

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3- Liquifactive necrosis:
Cause:

1- Proteolytic enzymes in Abscess

2-Brain infarction

3-Liquifactive enzymes of amoeba (Amoebic abscess)

Gross: dead area is "liquified", and "yellowish "

Microscopic:

tissue became structureless homogenous (complete liquefaction) → cystic

change or cavitation ,Surrounded by inflammatory cells & macrophage
Surrounded by fibroblasts or glial cells (in CNS) & new capillaries
(discussed in Chapter: inflammation)

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4- Fat necrosis: It is necrosis of "Fat cells" in adipose tissue

1- Traumatic Fat necrosis

Trauma of subcutaneous fat, → lead to ruptured fat cells→ and deposition of

calcium salts in the area of fat necrosis→ giving hard palpable mass.

in case of hard mass in the breast of young female, traumatic fat necrosis should
be taken in consideration before diagnosis of cancer breast.

2-Enzymatic Fat necrosis

Acute pancreatitis → release of lipase → fat cell necrosis in omentum → release of

fatty acids (FA) → FA binds with intracellular Ca → Calcium soaps (Saponification)

- Gross: dead area is "firm chalky", and "white "

- Microscopic: - Injured fat cells (shadows of fat cells)
-Calcification (basophilic in color)
- inflammatory cells and giant cells

5- Fibrinoid necrosis: Deposition of fibrin-like material

- Autoimmune vasculitis (e.g. polyarteritis nodosa)
- Arterioles in malignant hypertension
- Aschoff nodule (in rheumatic fever)
Microscopic: homogenous eosinophilic deposit in the wall

N.B. Autolysis: means damage of cell by its own lysosomal enzymes mainly postmortem

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Fate of necrosis

- Inflammation: All types of necrosis initiates inflammatory reaction

- Regeneration
- Fibrosis: depends on type of tissue and severity of injury
- Capsulation: fibrosis around the periphery of necrotic area
- Calcification: deposition of calcium salts inside dead tissue
- Putrefaction (Gangrene) : if infected with certain types of bacteria

Autophagy:
Elemination of intracellular components (e.g.organelles) by the internal
lysosomal system.

Autophagy occurs in case of cellular stress (e.g. Hypoxia, starvation or aging)

Autophagy could be physiological, or pathological

Autophagy vacuoles containing damaged lipids are called (Lipofuscin)

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General Pathology [ CELL INJURY]

Apoptosis

Definition: Coordinate death of single cell or group of cells, by energy-

dependant programmed pathway. Not accompanied by inflammation

Causes:
- Physiological (mainly Hormonal or growth factor deprivation)
o Menstruation , hormonal-induced apoptosis of endometrium
o Embryogenesis, absence of some embryonic structures
o Thymus atrophy

- Pathological (disease-induced) 3 H + 3 C
o HCV → Liver cell apoptosis (councilman body)
o HLA mismatch → graft rejection by Cytotoxic T cells
o Hypoxia and radiation
o Chemotherapy → tumor cell apoptosis
o Cancer prostate (after orchiectmy)
o Cerebral apoptosis (in Alzheimer)

Mechanism:

Extrinsic:
Expression of FAS receptors on cell → bind with FAS-L on
CD8-lymphocytes→ activation of caspases (caspase 8) →
apoptosis

Intrinsic (mitochondrial): mediated by regulation of Bcl2

family genes→ activation of Bax & bak,
inhibition of Bcl → Bax is forming mitochondrial channels → increased mitochondrial
permeability → release of cytochrome C →
activation of caspases 9 → apoptosis

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Morphological changes :
- Cell shrink in size & convoluted
- Condensation of chromatin or fragmented
- Condensed organelles
- Cell divides into smaller apoptotic bodies
- Apoptotic bodies are phagocytosed

Necrosis Apoptosis

Definition Cell death with damaged cellular content Programmed cell death

causes Pathological injury Physiological or pathological

group of cells Single cell or group of cells

mechanism Controlled by ATP depletion Controlled by genes, enzymes and

hormones

microscopic -large cell -Small cell

-damaged membrane -intact membrane with blebs
- damaged organelles & lysosome -condensed organelles
-damaged neucleues -condensed chromatin
Molecular Libration of lysosomal enzymes Gene regulation
changes Fee radicals Bcl2 , Bax, P53
Lack of ATP and FAS
inflammation present absent
fate (enumerate) phagocytosis

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 General Pathology [ CELL INJURY]

Gangrene
Massive tissue necrosis, followed by putrefaction

Putrefaction: Breakdown of dead tissue by saprophytic bacteria → realease of H2S

(offensive gas) → formation of Iron Sulphide (black color)

Dry gangrene
Gangrene Caused by arterial occlusion (e.g. Thrombus) → followed by tissue dryness
(mummification) → then putrefaction e.g. Senile dry gangrene of the foot

Pathogenesis:

• Ischemia (P.F. : Atherosclerosis, & H.F.)

• Tissue necrosis & inflammatory edema
• Dryness (mummification)
o Edema is drained by lymphatics, and veins.
o Evaporation of tissue fluid. No more fluid supply (ischemia)
• Putrefaction & spread
• Line of demarcation
o Putrefaction stop at the area with good blood supply
o The red line separating healthy tissue from putrefied tissue
• Granulation tissue
o Healing starts from line of demarcation → extend distally
• Line of separation
o The line separating GT from remaining unhealed putrefied tissue
• Self separation (amputation)
o The remaining dead tissue begin to separate spontaneously leaving conical stump

Ischemia Necrosis Mumification Putrefaction Demarcation Separation

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Dry gangrene Moist gangrene

Arterial occlusion Arterial occlusion in moist areas
Atherosclerosis – Burger -Reynaud Moist tissue (mouth, cervix)
Aetiology Intestine (strabgulation)
D.M. (excess inflammation & fluid)
Bed sores (arterial & venous compression)
Ischemia prsent present

Edema present more

Mummification present No mummification

Putrefaction and spread Slow Rapid

Line of demarcation present No line of demarcation

Line of separation Present No line of separation

Self separation present No self separation

Complications Mild Toxemia (sapremia) Rapid spread

Severe Toxemia (sapremia)

Gas gangrene
Putrefaction of muscles , through infection of deep wounds

Aetiology:

1. Infected deep wounds by anerobic Cholestridia from soil

2. Infected wound during colon surgery

Pathogenesis :

3. Muscle necrosis + Hemolysis → Red dead muscle

4. Putrefaction → extensive gas (H2S) accumulation + Black

swollen muscle

5. Excessive gas → Crepitation

Fate : Severe toxemia

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 General Pathology [ CELL INJURY]

Hylinosis
Microscopic change in tissue proteins, which became glassy, homogenous &
eosinophilic.

1. Extracellular hyalinosis (CAPS)

1. Chronic Glomerulonephritis : hyalinosis of glomeruli
2. Arteriolosclerosis : in benign hypertension
3. Prostate: Corpora amylacea in prostatic hyperplasia
4. Scar : hylainosis of collagen in old scar

2. Intracellular hyalinosis: (4 P)
• Plasma cell → accumulated Ig → Russel body
• Parenchyma of liver (in alcoholism)→ alteration of intermediate
filaments → Mallory body
• Proximal convoluted tubules (in proteinurea)→ reabsorption of
protein → Hyaline bodies
• Pneumonia, or Diphteria : → Toxemia → Abdominal muscle injury
→ Lactic acidosis → hyaline change of muscle proteins → homogenous
pink & loss of striations → (Zenker's degeneration)

Mucoid changes Myxoid changes

Intracellular Accumulation of mucinous material Extracellular Accumulation of mucinous
(glycoprotein) in epithelial cells material (glycoprotein) in connective tissue

Catarrhal inflammation Myxoid changes in tumors

Mucoid Carcinoma
Muco-Cele Myxoedema

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Fatty changes
Definition: Reversible cell injury, showing neutral fat (triglycerides) accumulation
Causes: causes of cell injury, Mostly: hypoxia, bacterial toxins, chemicals
Sites: Liver (most common) – Heart - Kidney

causes of fatty liver

• Hyperlipidemia (Congenital – Obesity – DM – Alcohol the most common)
• Drugs & toxins (CCL4, Steroides)
• Diseases (H.F. – Anemia – TB)

Pathogenesis of fatty liver

Alpha G. phosphate
Protein
estrification Lipoprotein
Normally: Fatty T.G.
Acids LDL, VLDL
Oxidation
Ketone

In Fatty changes:

• Increased F.A. intake, or synthesis → T.G.

• Increased F.A. estrification → T.G.
• Decreased F.A. oxidation → increased F.A. → T.G.
• Decreased protein carriers → T.G. accumulation
• Decreased Lipoprotein excretion

Gross:
- Size : enlarged with tense capsule
- Surface : smooth with rounded borders
- Cut section : bulging and greasy
- Color : Yellow
- Consistency : Soft Greasy

Microscopic:
- Cells: swollen , intact membrane, with clear cytoplasmic vacuoles
(microvesicular steatosis) → large single vacuole (macrovesicular)→
signet ring cells
- Ruptured fat cells → Fat cyst & lipogranuloma
- Staining: SudanIII, IV, black , Osmic acid , Oil red

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Fatty changes of the Heart

Diffuse fatty change Patchy (focal) fatty change
Severe Mild
In cases of Toxemia , severe hypoxia In case of Anemia
Yellow in color Yellow & brown (Tabby cat/ tiger skin)

Fatty infiltration
Accumulation of fat inside connective tissue due to obesity or chronic diseases.
(e.g. Heart , pancreas

Cholesterol deposition:
• Macrophages (in old hemorrhage or necrosis)→ foam cells
• Atherosclerosis (in macrophages 'foam cells' inside arterial wall)
• Xanthoma (in macrophage of Skin in cases of hyperlipidemia)

Cholesterolosis: accumulation of cholesterol in G.B. epithelium

Melanin pigment
Tyrosine→ converted into brown melanin (by tyrosinase enzyme)→
engulphed by macrophage (melanophores)

Hyper pigmentation
o Generalized
▪ Chloasma: butterfly color in face and breast (estrogen-progestron)
▪ Adisson's: due to increased ACTH, MSH
o Localized Patchy
▪ Sun Freckle
▪ Melanocyte tumors (nevus- melanoma)

Hypo pigmentation
o Generalized Albinism : congenital 'autosomal-recessive' tyrosinase deficiency
o Localized Patchy
▪ Leukoderma which is congenital or secondary to Syphilis or Leprosy
▪ Vetiligo which is an autoimmune dis.

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Glycogen
In D.M.: due to abnormal glucose metabolism
Glycogen storage disease: genetic, metabolic
disease. Accumulation of glycogen in Liver, muscle, and
heart. Cells show clear cytoplasm , stained with Best’s
carmine

Hemosiderosis
Ferretin accumulates inside tissue macrophages (yellowish brown) → stains blue with Perl
or Prussian blue
No tissue damage

Localized Hemosiderosis Generalized hemosiderosis

• Skin hemorrhage (bruise)
green billiverdin → brown hemosedrin
• Hemolysis

• Repeated transfusion
• Lung congestion → macrophage engulf
hemosedrin → H.F. cells • Increased Iron intake
(brown induration of lung) Engulfed by macrophage of Liver,
spleen, B.M., & L.N.

Hemochromatosis
Accumulation of iron in parenchymatous tissue → leading to tissue damage

1ry Hemochromatosis 2ry hemochromatosis

(bronzed D.M.)
Increased iron absorption (autosomal dominant)
→deposition in
Prolonged generalized hemosidrosis
• Pancreas → DM
• Liver → pigmented cirrhosis
• Skin → bronzed color

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Exogenous Pigments
• Tatoo (Indian ink → engulfed by macrophage)
• Anthracosis (Black Carbon deposition e.g. smoking, pollution → engulfed
by lung macrophages → black color in lung and hilar L.N.)

Lipofuscin pigment (Lipochrome)

Definition: Yellowish brown Intracellular, Lipid-derived pigment, due to cell aging
(waer and tear)
Pathogenesis: lipid peroxidation + waste products →accumulated in lysosomes
Brown atrophy of the heart :
• Cause: Senility (aging) - Starvation - Chronic ischemia
• Gross: Reduced size, tortious coronaries, absent
pericardial fat, thin brown muscle
• Microscopic: cell size: reduced , cytoplasm: yellow
brown pigment around nucleus,

Pathological Calcification
Pathological deposition of calcium salts in tissues other than bone and teeth.

Gross:
• Color : white
• Consistency: Hard granular, or chalky

Micro: Basophilic in color, intracellular or extracellular

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Dystrophic calcification Metastatic calcification

Tissue Dead tissue, Degenerated tissue Normal tissue

Serum Ca Normal (9-11) Elevated > 11

Dead: Elevation of serum calcium :

• Necrosis (……)
• Necrotic cancer 1-Increased absorption:
• Dead fetus
Causes and • ↑ Vitamin D(e.g. sarcoidosis)
• Dead parasites and ova macrophage activate v. D precursor
sites • Blood thrombus • ↑ Ca (milk alkali syndrome)
• Blood hematoma
2-Increased bone resorption:
Degenerated: P A S S
• Psammoma bodies • ↑ Parathyroid
1ry – 2ry to R.F. – parathyroid like proteins
• Atherosclerosis & monkeberg
• Bone tumors (multiple myeloma)
• Scar
• Stroma of tumors • Immobilization
Serum Ca → deposits in alkaline tissues

• Renal tubular membrane

• Gatsric mucosa
• Alveolar wall
• Blood vessels
rarely synovium

Mechanism • Increased intracellular Ca Increased serum calcium and phosphate

• Increased intracellular
phosphate

Calcium phosphate stones

Psammoma bodies : Rounded laminated bodies , seen in some tumors

(Menengioma – Papillary carcinomas)

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General Pathology [ CELL INJURY]

Adaptation
Adaptations are almost reversible changes (except in connective tissue metaplasia) .
These changes occur in number, size, function, or type of cell.
They are physiological to adapt hormonal or chemical changes. Or Pathological to
adapt harmful situations.

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1.Atrophy
Decreased size of organ due to decreased size and/or number of cells in well-formed
organ or tissue
• Physiological
o Lymphoid tissue in thymus after puberty
o Lymphoid tissue, & appendix in old age
o Brain & Heart atrophy in old age
o Atrophy of ovaries after menopause

• Pathological
o Ischemic atrophy (chronic ischemia)→ tissue atrophy
o Pressure atrophy e.g. Aortic aneurism → atrophy of vertebral bodies
(discs are spared)
o Neurogenic e.g. wasting of muscle in motor neuron injury)
o Disuse atrophy (fractured limb → immobilization → muscle atrophy)
o Hormonal (e.g.Pitutary diseases with lack of TSH → thyroid atrophy)
o Nutritional protein deficiency (e.g. lack of protein in marasmus →
muscle atrophy)
o Morphology:
Decreased cell size – decreased organelles
(mitochondria, ER, myofilaments) –autophagy
vacuoles (e.g. lipofuscin)

Aplasia :
Failure of differentiation and development of cells which
remains rudimentary. e.g. Aplastic anemia

Agenesia:
Failure of organ formation (complete absence)

N.B. In Apoptosis, number of cells is reduced , wich may lead to organ atrophy

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2.Hypertrophy
Increased size of organ due to increased size of cells
(Mostly in non-dividing permanent cells)
• Physiological
o Pregnancy → uterine smooth muscle hypertrophy
o Exercise → muscle hypertrophy

• Pathological
o Hypertension, valve diseases → cardiac hypertrophy
o Pyloric stenosis → gastric hypertrophy
o Compensatory in one kidney after nephrectomy of
the other one.
o Urethral obstruction → bladder hypertrophy

Morphology: Increased cell size – Increased nuclear size

3.Hyperplasia
Increased size of organ due to increased number of cells
Site: Labile & stable cells (cells with mitotic ability), NOT in permanent cells

• Physiological
o Breast (during lactation) , Uterine muscle
(pregnancy)
• Pathological
o Compensatory : e.g. Liver (partial hepatectomy)
, Kidney (nephrectomy)
o Hormonal :
▪ Mammary hyperplasia (fibrocystic
disease)
▪ Endometrial hyperplasia
▪ Prostatic hyperplasia
▪ Thyroid hyperplasia in Goiter (elevated
TSH)
▪ Bone marrow ,following blood loss (erythropoietin)
o Reactive Hyperplasia :L.N. hyperplasia following infection
o Chronic Irritation : urothelial hyperplasia in bilharziasis (Brunn's nest)

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Brunn’s nest

N.B. Hyperplasia may occur with hypertrophy in some cases (e.g. pregnant uterus)
It is precancerous in some pathological cases (endometrial, mammary)

Hyperplasia Neoplasia (Tumor)

Initiated by a cause (stimulus) Multi-factorial
Self-limited Uncontrolled
-Reversible (after removal of the cause) Irreversible

4.Metaplasia
Transformation of a cell into another type of differentiated cell within limits
mechanism: Abnormal stimuli (Irritant) → Reprogramming of stem cells → new type
• Epithelial metaplasia
o Squamous metaplasia
▪ Smoking → metaplasia of Bronchi in chronic bronchitis
▪ Shistozoma → metaplasia in urinary Bladder
▪ Stones → metaplasia of urinary bladder or gall Bladder
▪ In Chronic nasal polyp
▪ Endocervix in Chronic Cervicitis

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General Pathology [ CELL INJURY]

o Columnar metaplasia
▪ Eosophagous : Barret's eosophagitis in case of GERD
▪ Stomach: Intestinal metaplasia in Chronic gastritis
▪ Bladder: Cystitis cystic → cystitis glandularis

• Mesenchymal metaplasia
o Osseous
▪ Myositis ossification in muscle
▪ Ossification of calcified areas
▪ Ossification of tumor stroma
o Cartilagenous metaplasia of Splenic capsule (in splenomegaly)
o Myloid metaplasia in case of blood loss (extramedullary
hematopoesis)

Cartilaginous
metaplasia

Osseous metaplasia

Myeloid metaplasia

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Cell aging
Factors affecting aging
• Internal (Telomere length)
• Envirnomental (Inhaled pollution)
• Diet (obesity , alcohol)
• Diseases (Atherosclerosis, hypertension, DM)
Mechanism
• After fixed number of cell divisions → telomerase inhibition → Shortening of
telomere gene
• Arrest of cell cycle → No regeneration (stem cell arrest)
• Accumlation of DNA damaging factors (e.g.Free radicals) → Cell Senescence
(Aging)

In cancer cells : Active telomerase gene → protection of telomere → No cell Aging

27 Dr. Abdelrahman Khalifa, M.D., Phd.