Synopsis of Pathology Anoop N
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PART 1
1General Pathology
2

Cell Injury, Cell Death and AdaptationsChapter 1

 
CELLULAR RESPONSE
Cellular response to stress/stimuli is shown in Figure 1.1.
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Fig. 1.1: Cellular response
 
CELLULAR ADAPTATIONS
  1. Cellular adaptations are reversible changes in size, number, phenotype, metabolic activity or function of cells in response to changes in the environment.
  2. Physiological:
    1. Response to normal stimulation by hormones or endogenous chemical mediators.
  3. Pathological:
    1. Response to environmental stress, which helps them to escape from injury.
 
Hypertrophy
  1. Increase in size of the cells.
  2. Resulting in increased size of the organ.
  3. Increased amount of structural proteins and organelles.
  4. Physiological:
    1. Uterine enlargement during pregnancy (hypertrophy + hyperplasia).
    2. Breast enlargement during lactation.
  5. Pathological:
    1. Cardiac hypertrophy in HTN and AS.
    2. Cardiac hypertrophy is due to:
      • Mechanical—stress
      • Trophic—α-adrenergic stimulation.
 
Hyperplasia
  1. Increase in number of cells.
  2. Resulting in hypertrophy of the organ.
  3. Physiological:
    1. Breast glands during puberty and pregnancy (hormonal).
    2. Liver regrowth after a part is resected (compensatory).
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  4. Pathological:
    1. Endometrial hyperplasia after menstruation (hormonal).
    2. Wound healing (due to growth factors).
 
Atrophy
  1. Decrease in cell size.
  2. Loss of intracellular substance.
  3. Atrophied cells have diminished function.
  4. Sometimes, accompanied by autophagy.
  5. Decreased protein synthesis and increasse protein degradation.
  6. Causes may be:
    1. Decreased work load.
    2. Denervation.
    3. Decreased blood supply.
    4. Malnutrition.
    5. Senility.
    6. Pressure.
    7. Decreased functioning.
  7. Seen in cancer cachexia.
 
Metaplasia
  1. Reversible change of one adult cell type by another.
  2. Metaplasia is in order to withstand certain conditions.
 
Epithelial Metaplasia
  1. Squamous metaplasia:
    1. Columnar epithelium of respiratory tract is replaced by stratified squamous epithelium in cigarette smoking.
  2. Intestinal metaplasia:
    1. Stratified squamous epithelium of esophagus replaced by columnar epithelium in C/c gastric reflux.
 
Mesenchymal Metaplasia
  1. Osseous metaplasia.
    1. Bone in fibrous tissues.
      • In arterial wall
      • Myositis ossificans.
  2. Cartilaginous metaplasia:
    1. Cartilage deposit in fracture healing.
 
SUBCELLULAR ALTERATIONS
  1. Autophagy—self-eating by lysosomal enzymes.
  2. Hypertrophy of SER.
  3. Mitochondrial alterations.
  4. Cytoskeletal abnormalities—loss of integrity, cell mobility, phagocytosis, etc.
 
NECROSIS
  1. Irreversible cell injury.
  2. Resulting from degenerative actions of enzymes.
  3. The enzymes are either from self-lysosomes or from lysosomes of leukocytes.
 
Morphology
  1. Increased eosinophilic staining to the cells.
  2. Cytoplasm become vacuolated and appears moth-eaten.
  3. Large phospholipid masses called myelin figures that are derived from damaged cell membranes.
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  4. These myelin figures may get degraded into fatty acids and become calcified to form calcium soaps.
  5. Marked dilatation of mitochondria, damage of cell membrane, lysosomal disruption, etc. can be seen.
  6. Nuclear changes:
    1. Karyolysis—digestion of DNA.
    2. Pyknosis—nuclear shrinkage.
    3. Karyorrhexis—fragmentation of pyknosed nuclei.
 
Classification
 
Coagulative Necrosis
  1. Basic architecture is maintained for some days.
  2. Denaturation of all proteins.
  3. Its own lysosomal enzymes are also denatured.
  4. Later digested by leukocytes.
  5. For example, all infarcts except that in brain.
 
Liquefactive Necrosis
  1. The tissue get converted into liquid viscous mass.
  2. The tissue is digested completely.
  3. Sometimes, the material will be creamy yellow-pus.
  4. Certain bacterial and fungal infections. For example, brain infarcts.
 
Gangrenous Necrosis
  1. Due to ischemia.
  2. Usually lower limb is affected.
  3. Actually this is a type of coagulative necrosis.
  4. Wet gangrene—dry gangrene + bacterial infection.
 
Caseous Necrosis
  1. Friable yellow white (cheesy like) appearance.
  2. Complete distortion of the architecture.
  3. Within a well-defined border (granuloma). For example, TB.
 
Fat Necrosis
  1. Focal areas of fat destruction.
  2. Calcified to produce chalky white areas.
  3. Necrotic fat cells with calcium deposits and surrounded by an inflammatory border. For example, acute pancreatitis.
 
Fibrinoid Necrosis
  1. Commonly seen in immune complex-mediated vasculitis.
  2. These complexes along with fibrin deposits form the fibrinoid necrosis. For example, PAN.
 
MECHANISMS OF CELL INJURY
  1. Adenosine triphosphate ATP depletion (Fig. 1.2).
  2. Mitochondrial damage (Fig. 1.3).
  3. Increased Ca2+ influx (Fig. 1.4).
  4. Defects in membrane permeability (Fig. 1.5).
  5. Accumulation of reactive O2 species (Fig. 1.6).
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    1. Antioxidant mechanisms:
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  6. Damage to DNA and proteins (Fig. 1.7).
 
APOPTOSIS
Tightly regulated suicide program by activating the degrading enzymes.
 
Causes
 
Physiologic Situations
  1. Programed destruction of cells during embryogenesis.
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    Fig. 1.2: ATP depletion
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    Fig. 1.3: Mitochondrial damage
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    Fig. 1.4: Increased Ca2+ influx
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    Fig. 1.5: Defects in membrane permeability
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  2. Involution of hormone-dependant tissues upon hormone deprivation.
  3. In proliferating cell populations.
  4. After completion of their work.
  5. Elimination of self-reactive T-cell clones.
  6. Cell death by cytotoxic T cells.
 
Pathologic Situations
  1. DNA damage.
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    Fig. 1.6: Accumulation of reactive O2 species
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    Fig. 1.7: Damage to DNA proteins
  2. Accumulation of misfolded proteins (results in ER stress).
  3. Certain infections.
  4. Atrophy due to duct obstruction.
  5. Deprivation of GFs.
 
Morphology
  1. Round or oval masses.
  2. Eosinophilic cytoplasm.
  3. Karyorrhexis of nucleus.
  4. Later, those cells get shrinked to form cytoplasmic buds and fragmented into apoptotic bodies.
  5. The cell membrane will be usually intact.
    *FLIP—a caspase antagonist.
 
Mechanisms
  1. Intrinsic/mitochondrial pathway is shown in Figure 1.8.
  2. Extrinsic/death receptor pathway is shown in Figure 1.9.
  3. Final common pathway and clearing mechanism is shown in Figure 1.10.
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Fig. 1.8: Intrinsic/mitochondrial pathway
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Fig. 1.9: Extrinsic/death receptor pathway
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Fig. 1.10: Final common pathway and clearing
 
INTRACELLULAR ACCUMULATIONS
 
Pathways
  1. Normal or increased production of a normal substance, but decreased removal. For example, fatty change in liver.
  2. Normal or abnormal substance accumulates due to defect in packaging, transportation, etc. For example, α1-antitrypsin deficiency.
  3. Decreased degrading enzymes. For example, glycogen storage diseases.
  4. Ingestion of indigestible materials. For example, pneumoconiosis, silicosis, etc.
 
Fatty Change (Steatosis)
  1. Accumulation of TAGs in parenchymal organs.
  2. Mostly in liver.
  3. Also in heart, skeletal muscle, kidney, etc.
    1. Fatty liver
      • Alcohol abuse and DM associated obesity are the most important causes
      • Hepatotoxins decrease fatty acid oxidation
      • Decreased fatty acid oxidation, decreased mobilization of fat from liver and increased mobilization of fat from periphery are the important pathways leading to fatty liver.
        Morphology
      • Bright yellow, soft and enlarged
      • Firstly small fat vacuoles around nucleus
      • Then large fat globules and peripheral nucleus
      • At last ruptures and form fatty cysts.
    2. Fat in heart
      • Prolonged moderate hypoxia causes anemia and focal fat droplets
      • Appear as yellow bands within brown colored muscle tissue—thrush breast appearance.
 
Cholesterol Accumulation
  1. Macrophages get filled with membrane bound lipid vacuoles and forms foam cells. For example, in atherosclerosis.
  2. A cluster of foam cells beneath the skin and tendons is called xanthoma.
 
Proteins
  1. Mallory bodies: Eosinophilic hyaline inclusions within the cytoplasm of degenerating hepatocytes in alcoholic liver disease—contains intermediate filaments.
  2. Russell bodies: Round eosinophilic inclusions within the RER of plasma cells and is composed of new Ig.
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Glycogen
  1. See glycogen storage diseases in the Chapter 7 (Genetic and Pediatric Diseases).
 
Pigments
  1. Lipofuscin.
    1. Wear and tear pigment.
    2. Insoluble brownish yellow granular material.
    3. Intracellularly accumulates in the heart, liver and brain.
    4. Produced after lipid peroxidation of membranes.
    5. Causes brown atrophy of heart.
    6. PAS stain is used and will give a brown color.
  2. Carbon.
    1. Mainly in the lung (anthracosis).
  3. Melanin.
    1. In freckles and in dermal macrophages.
    2. Masson-Fontana stain is used.
  4. Iron.
    1. Hemosiderosis and hemochromatosis.
  5. Human granulocytic anaplasmosis.
    1. In alkaptonuria.
    2. Produces ochronosis.
  6. Bilirubin.
    1. In jaundice.
 
CALCIFICATION
 
Dystrophic Calcification
  1. Occurring in the dead and decaying tissues.
  2. There is no derangements in calcium metabolism.
  3. Normal levels of serum calcium. For example, in atheromas (advanced cases), in aged or damaged heart valves.
  4. Seen as fine white granules felt as gritty deposits.
  5. These are microscopically seen as intracellular or extracellular basophilic deposits.
  6. Sometimes, tuberculous LNs may also get involved.
  7. Occurs as two processes:
    1. Initiation—in mitochondria and in membrane-bound vesicles.
    2. Propagation—depends on other factors too.
  8. The end product is calcium phosphate.
  9. Extracellular initiation in membrane-bound vesicles.
  10. Intracellular initiation in mitochondria.
  11. Propagation depends on Ca2+ and PO4– concentration, mineral inhibitors, collagen content, etc.
 
Metastatic Calcification
  1. Occur in normal tissues.
  2. Derangement in the calcium metabolism.
  3. Causes are:
    1. Increased parathyroid hormone (1° or 2°).
    2. Increased bone destruction.
    3. Vitamin D intoxication and sarcoidosis.
    4. Renal failure—causes 2° hyperparathyroidism.
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  4. Usually in vasculature of kidneys, lungs and gastric mucosa.
  5. White granules with gritty feeling.
  6. Nephrocalcinosis is common finding.
 
AGING
  1. Aging is a result of progressive decline in the proliferative capacity and lifespan of cells and continuous exposure to exogenous factors that cause cellular and molecular damage.
  2. The causes are:
    1. DNA damage.
    2. Decreased replication.
    3. Decreased GFs.
    4. Decreased regenerative capacity.
    5. Lifestyle.
    6. Diseases.
 
Mechanism
The mechanism of aging is shown in Figure 1.11.
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Fig. 1.11: Mechanism of aging