Cell Injury and Adaptation

Dr. Sayed Abdel Raheem

Cell injury

Dr. Sayed Abdel Raheem

Cell injury

Causes of cell injury

1- Hypoxia:
- It is the most common cause of cell injury
- It is the lack of oxygen content of tissue with inability of cells to synthesize
ATP from aerobic oxidation
- Hypoxia is due to either:
- Ischemia: as in cases of atherosclerosis, thrombosis and embolism
- Cardiopulmonary failure
- Decreased oxygen carrying capacity of blood: as in cases of anemia

2- Infection:
- Due to bacteria, viruses, parasites and fungi
- Mechanism: either
- Direct effect of organisms on cells
- Production of toxins
- Host immune response

3- Immunologic reaction:
Such as in
- Hypersensitivity reaction
- Auto-immune diseases

4- Chemical causes:
- Drugs
- Poisons
- Pollution
- Occupational disease: asbestosis, silicosis, carbon monoxide poisoning
- Social lifestyle: alcohol intake, I.V drug abuse

5- Physical causes:
- Trauma
- Burns
- Radiation
- Forest bite

Dr. Sayed Abdel Raheem

Cell injury

6- Nutritional causes:
- Inadequate calorie intake: marasmus, kwashiorkor, and anorexia
nervosa
- Excess calorie intake: obesity
- Vitamin deficiency: vit. A, B, D, E, K
- Hypervitaminosis

7- Congenital disorders:
-Inborn errors of metabolism

Cellular changes during cell injury

a- Cellular response to injury:
- Adaptation
- Reversible cell injury
- Irreversible cell injury and death (necrosis and apoptosis)

b- Cellular response to injury depends on:

i - The type of injury
ii- Duration including pattern of injury
iii- Severity and intensity of injury
iv- Type of injured cell
v- Metabolic state of cells
vi- Ability of cells to adapt

c- Critical intracellular systems susceptible to injury:

i- DNA
ii- Cell membrane
iii- ATP production
iv- Protein synthesis

Dr. Sayed Abdel Raheem

Cell injury

Cell Injury
1- Reversible Cell Injury:
Cloudy swelling
Hydropic degeneration
Fatty changes

2- Irreversible Cell Injury:

Necrosis
Apoptosis

Mechanism of reversible cell injury

i- Decreased ATP production: by oxidative phosphorylation
ii- Decreased Na pump via cell membrane resulting in:
- Influx of Na and water
- Efflux of K
- Swelling of endoplasmic reticulum
- Swelling of cell (hydropic swelling)

Dr. Sayed Abdel Raheem

Cell injury

iii- Switch to glycolysis resulting in:

- Depletion of cytoplasmic glycogen
- Increased lactic acid production
- Decreased intracellular PH

iv- Decreased protein synthesis: due to detachment of ribosomes from

rough endoplasmic reticulum

Mechanism of irreversible cell injury

i- Severe membrane damage:
- Membrane damage results in massive intracellular influx of calcium
- Efflux of intracellular proteins and enzymes into circulation

ii- Marked mitochondrial dysfunction:

- Mitochondrial swelling
- Damage of oxidative phosphorylation pathway with lack of ATP production

Dr. Sayed Abdel Raheem

Cell injury

iii- Rupture of lysosomes:

- Release of lysosomal enzymes into cytoplasm
- Activation of acid hydrolases followed by autolysis
The hallmark of irreversible injury is membrane damage
The end result of irreversible injury is cell death

Nuclear changes:
- Pyknosis: condensation of nuclear chromatin
- Karyorrhexis: nuclear fragmentation
- Karyolysis: dissolution of nucleus

Dr. Sayed Abdel Raheem

Cell injury

Pyknosis: shrinkage, Hyperchromasia: increased nuclear staining,

Karyorrhexis: nuclear fragmentation

Necrosis
Definition: localized tissue death in living body
Types:
i- Coagulative necrosis:
- Most common type
- Most often due to ischemia
- Due to denaturation and coagulation of proteins within cytoplasm
- Microscopically, there is loss of cellular details with preservation of
cellular outlines (City of ghosts)
- Common in most organs, including heart, liver, spleen, and kidney

ii- Liquefactive necrosis:

- Cellular destruction by hydrolytic enzymes
- Due to autolysis (release of proteolytic enzymes by injured cells) and
heterolysis (release of proteolytic enzymes from inflammatory cells)
- Occurs in abscess and brain infarcts
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Dr. Sayed Abdel Raheem

Cell injury

Kidney, infarction, gross and microscopic

Lung infarction

Cerebral infarct

Dr. Sayed Abdel Raheem

A- Normal myocardium

Cell injury

B- Myocardium with coagulation necrosis

iii- Caseous necrosis:

- Combination of coagulation and liquefaction necrosis
- Grossly, soft, friable, yellowish and cheese-like
- Characteristic for granulomatous diseases like tuberculosis

iv- Fat necrosis:

- Caused by action of lipases on fatty tissue as in acute hemorrhagic
pancreatitis or trauma to fatty organs like breast

v- Fibrinoid necrosis:
- Necrotic connective tissue resembling fibrin
- Microscopically, has eosinophilic homogenous appearance
- It occurs in acute immnuologic injury as in hypersensitivity type II&III,
and rheumatic myocarditis

vi- Gangrenous necrosis:

- Gangrene means necrosis followed by putrefaction
- Dry gangrene, microscopic pattern is coagulative necrosis
- Wet gangrene, microscopic pattern is liquefactive necrosis

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Dr. Sayed Abdel Raheem

Cell injury

Caseous necrosis, TB

Fat necrosis, enzymatic, omentum in acute pancreatitis

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Dr. Sayed Abdel Raheem

Cell injury

Fibrinoid necrosis

Dry gangrene, big toe

Apoptosis
Definition:
- It is a programmed cell death without inflammatory response
- Only affects single cell or small groups of cells
Morphological changes:
- Cell shrinks in size and has dense eosinophilic cytoplasm
- Nuclear chromatin condensation followed by fragmentation
- Formation of cytoplasmic blebs
- Breakdown of cell into fragments (apoptotic bodies)
- Phagocytosis of apoptotic bodies by adjacent cells or macrophages
- Lack of inflammatory response

Regulator genes of apoptosis:

- bcl-2 (inhibits apoptosis by:
- Prevents release of cytochrome C from mitochondria
- Binding pro-apoptosis protease activating factor
- p 53 (stimulates apoptosis) by:
- Elevated by DNA injury and inhibition of cell cycle
- If DNA repair is impossible, p53 stimulates apoptosis
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Dr. Sayed Abdel Raheem

Cell injury

Physiologic examples of apoptosis:

-Removal of cells during Embryogenesis
- Endometrial shedding during menstrual cycle
- Thymus after puberty
- Post Inflammatory Clean-up

Pathological examples of apoptosis:

- CD8+ T cell-mediated killing of virally infected cells (Councilman
bodies in Viral hepatitis)
- Cystic fibrosis, duct obstruction and atrophy of pancreatic cells
- Tumor cells
- Toxic effect on cells, e.g., chemicals, pathogens

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Dr. Sayed Abdel Raheem

Cell injury

Skin apoptosis (arrow)

Apoptosis of epidermal cells. The apoptotic cells with intensely eosinophilic

cytoplasm and small, dense nuclei

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Dr. Sayed Abdel Raheem

Cell injury

Cellular adaptive responses to injury

Atrophy
Definition:
Decrease of size of cell or organ after its full development

Causes:
- Immobilization, decrease of workload or disuse of an organ
- Ischemia, as in atherosclerosis
- Lack of hormonal or neural stimulation such as breast and uterus after
menopause and in paralysis
- Malnutrition
- Aging
Microscopically, small shrunken cells with lipofuscin granules
E/M, decrease intracellular components and autophagosomes

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Dr. Sayed Abdel Raheem

Cell injury

Kidneys, normal (left) and ischemic atrophy (right) - gross, cut surfaces

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Dr. Sayed Abdel Raheem

Cell injury

Hypertrophy
Definition:
Increase of size of an organ due to increase of size of its cells

Causes:
- Increase mechanical demand:
- Physiologic: striated muscles of athletes and weight lifters
- Pathologic: left ventricle of heart in hypertension
- Increased endocrine stimulation:
- Gravid uterus
- Lactating breast
Hypertrophy is mediated by growth factors, cytokines, increased
expression of genes, and increased protein synthesis
Hypertrophy and hyperplasia often occurs together

Benign prostatic hyperplasia

Heart, very thick ventricular wall

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Dr. Sayed Abdel Raheem

Cell injury

Hyperplasia
Definition:
Increase of an organ due to increase of number of its cells

Causes:
- Physiologic causes:
- Compensatory, such as after partial hepatectomy
- Hormonal such as breast after puberty
- Antigenic stimulation such as lymphoid tissue in inflammation
- Pathologic causes :
- Endometrial hyperplasia
- Prostatic hyperplasia
Hyperplasia is mediated by growth factors, cytokines, and increased
expression of proto- oncogenes, increased DNA synthesis, and cell division

Benign prostatic hyperplasia, lining epithelium showing papillary

projections

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Dr. Sayed Abdel Raheem

Cell injury

Metaplasia
Definition:
Reversible change of one cell type to another cell type in response to
irritation to tolerate environmental stresses

Examples:
- Epithelial metaplasia:
- Bronchial epithelium replaced by stratified squamous epithelium due to
irritation and smoking
- Urinary bladder epithelium replaced by stratified squamous epithelium
due to bilharziasis and urinary stones
- Gall bladder epithelium replaced by stratified squamous epithelium due
to gall bladder stones
- Mesenchymal metaplasia:
- Muscle tissue undergoes chondroid and osseous metaplasia in myositis
ossificans
Under persistent stress, metaplasia can progress to dysplasia and
eventually result in cancer

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Dr. Sayed Abdel Raheem

Cell injury

Lung, squamous metaplasia

Barrett esophagus

Dysplasia
Definition:
Abnormal proliferation of cells characterized by variation of size, shape and
arrangement

Examples:
- Cervical intraepithelial neoplasia (CIN):
- It occurs in cervix of uterus due to chronic irritation
- It is graded as:
- CIN grade I: affects inner 1/3 of epithelial lining
- CIN grade II: affects inner 2/3 of epithelial lining
- CIN grade III: affects whole thickness of epithelial lining
Other examples of dysplasia, as actinic keratosis of skin and oral
leukoplakia
Dysplasia is not a cancer but may progress to cancer (pre- neoplastic)
severe dysplasia (dysplasia grade III) is considered as carcinoma in situ

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Dr. Sayed Abdel Raheem

Cell injury

Normal epithelium

Severe dysplasia

Intracellular accumulations
Lipids:
- Triglycerides: such as fatty change of liver
- Cholesterol and LDL: such as atherosclerosis and xanthomas

Fatty change
Definition:
It is a form of reversible cell injury characterized by accumulation of fat in
non-fatty tissue

Sites:
Liver, kidney, heart, muscles

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Dr. Sayed Abdel Raheem

Cell injury

Fatty change of liver

Causes:
1- Excess intake of fat and carbohydrates
2- Specific liver diseases such as viral hepatitis
3- Starvation
4- Diabetes mellitus
5- Deficiency of lipotropic factors as cholin and methionine

Gross:
The liver is enlarged, yellow, soft, and greasy, due to accumulation of fat
in the hepatocytes

Microscopic:
Hepatocytes contain large vacuoles with compressed nucleus atone side

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Dr. Sayed Abdel Raheem

Cell injury

Fatty liver

fatty change (steatosis)

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Dr. Sayed Abdel Raheem

Cell injury

Proteins:
- Russel bodies:
Intracytoplasmic accumulation of immunoglobulines in cases of
Rhinoscleroma
- Councilman bodies: in cases of viral hepatitis
- Proximal renal tubular epithelium in protienuria

Glycogen:
- In cases of glycogen storage disease

Exogenous pigments:
- Anthracosis: deposition of carbon particles in interstitial tissue of lung
due to inhalation of carbon particles
- Tattooing
- Ingestion of lead resulting in gingival lead line

Russel bodies

Councilman Bodies, in viral hepatitis

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Dr. Sayed Abdel Raheem

Cell injury

Anthracosis of the lung

Endogenous pigments:
Lipofuscin:
Peri -nuclear yellow-brown pigment deposition in cases of brown atrophy
of the heart
Melanin:
Black-brown pigment deposition in skin in cases of navi and melanoma
Hemosidrin:
Golden-yellow-brown pigment, such as in cases of hemorrhage, heart
failure cells in cases of CVC of lung
Bilirubin:
Such as in jaundice and kernicterus (deposition of bilirubin in basal
ganglia) of newborn

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Dr. Sayed Abdel Raheem

Cell injury

Lipofuscin granules in cardiac myocyte: A, light microscopy (deposits

indicated by arrows), and B, electron microscopy (note the perinuclear,
intralysosomal location)

Hemosiderin granules in liver cells, A, H&E section showing goldenbrown, finely granular pigment. B, Prussian blue reaction, specific for iron

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Dr. Sayed Abdel Raheem

Cell injury

Liver: green yellow discoloration

Intracellular of bilirubin

Hyaline change
Definition:
Non-specific term used to describe any intra- or extracellular alteration that
has homogenous pink and structurless on H&E stains

Examples of intracellular hyaline:

- Russel bodies in rhinoscleroma
- Mallory bodies in liver in cases of alcholism
- Renal tubules in cases of protienuria

Examples of extracellular hyaline:

- Arteriolar wall in cases of hyaline arteriolosclerosis
- Amyloidosis
- Hyaline membrane disease of newborn
- Corpora amylacea in benign prostatic hyperplasia

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Dr. Sayed Abdel Raheem

Cell injury

Hyalinosis of blood vessels of spleen

Pathological calcification
Definition:
Abnormal deposition of calcium salts in areas other than bone and teeth

A- Dystrophic calcification:
Definition:
It is abnormal deposition of calcium phosphates in necrotic and dead tissue

Examples:
- Psammoma bodies: laminated calcified bodies in cases of meningiomas,
papillary carcinoma of thyroid and ovary
- Traumatic fat necrosis of beast
- Enzymatic fat necrosis in cases of acute hemorrhagic pancreatitis
- Atherosclerotic plaques
- Monkberg medial calcific sclerosis

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Dr. Sayed Abdel Raheem

Cell injury

Dystrophic calcification: calcium deposits in degenerated valve leaflet

Chronic pancreatitis, main duct is dilated and filled with calcified material

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Dr. Sayed Abdel Raheem

Cell injury

B-Metastatic calcification:
Definition:
Precipitation of calcium salts in normal tissues due to hypercalcaemia

Causes:
- Hyperparathyroidism
- Parathyroid adenoma
- Renal failure
- Para- neoplastic syndrome
- Vitamin D intoxication
- Milk- alkalie syndrome
- Sarcoidosis
- Paget disease
- Multiple myeloma
Location of calcification in interstitial tissue of stomach, kidneys, lungs and
blood vessels

Calcification, metastatic, kidney

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Dr. Sayed Abdel Raheem

Cell injury

Amyloidosis
Definition:
It is a group of diseases characterized by deposition of proteinaceous
material in extracellular spaces with pressure atrophy of these cells

Stains of amyloidal material:

a- H&E stains: appears homogenous pink and structureless
b- Congo red stain: appears orange red
c. Apple green birefringence under polarized light

Composition of Amyloid:
1. 90% non-branching fibrillary protein
2. 10% non fibrillary pentagonal substance called Amyloid P (AP)
component
3. Glycosaminoglycans (heparin sulfate)

Systemic Types of Amyloidosis

1. Primary amyloidosis:
Type of amyloid: AL (amyloid light chain)
Plasma cell disorders (multiple myeloma, B-cell lymphomas
Amyloid deposited in git, heart, tongue, larynx, bladder and peripheral
nerves

2. Secondary (Reactive) amyloidosis:

Type of amyloid: AA (amyloid associated protein)
Inflammation and neoplasia
Rheumatoid arthritis , system lupus erythematosus,TB,osteomyelitis,
Crohn, s disease, cancer
Amyloid deposited in liver, kidneys, spleen, lymph nodes and adrenals

3. Familial Mediterranean fever:

Type of amyloid: AA
Fibrillary protein: serum amyloid A (SAA)
Autosomal recessive disease
Recurrent inflammation, fever, and polyneuropathies

4. Hemodialysis-associated amyloidosis:
Type of amyloid: beta 2 microglobulin
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Dr. Sayed Abdel Raheem

Cell injury

Fibrillary protein microglobulin

Affects 70% of patients on haemodialysis
Amyloid deposited in joints, synovium, and tendon sheath

Localized Types of Amyloid

1. Senile cerebral amyloidosis (Alzheimer disease)

Type of amyloid: beta 2 amyloid protein

Fibrillary protein: amyloid precursor protein (I3APP)
Found in Alzhiemer plaques and in cerebral vessels
The gene for APP is located on chromosome 21

2. Senile cardiac amyloidosis

Type of amyloid: TTR (transthyretin)

Fibrillary protein: transthyretin
Men> 70 years old
May cause cardiomyopathy, heart failure, and arrythmias

3. Endocrine type
Medullary carcinoma of the thyroid (procalcitonin)
Adult-onset diabetes (amylin)
Pancreatic islet cell tumors (amylin)

Clinical Features
1. Distribution of disease in systemic forms

a. Kidney
. Most commonly involved organ
. Nephrotic syndrome
. Progressive renal failure

b. Heart
. Restrictive cardiomyopathy
. Low voltage EKG
. Cardiac arrhythmias and CHF

c. Hepatospleenomegaly

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Dr. Sayed Abdel Raheem

Cell injury

d. Gastrointestinal tract
. Tongue enlargement
. Malabsorption

2. Diagnosis: biopsy of the rectal mucosa, gingival, or the abdominal fat

pad

3. Prognosis: the prognosis of systemic amyloidosis is poor

Kidney, amyloidosis

Thyroid, medullary carcinoma

Cerebral amyloid

apple green birefringence

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