Kuliah 4

• Introduction to Pathology


  Field of pathology understanding the causes of disease and the changes in cells, tissues, and organs that are associated with disease and give rise to the presenting signs and symptoms in patients
• Pathologists


  • Identify changes in the gross or microscopic appearance (morphology) of cells and tissues, and biochemical alterations in body fluids
  • To make a diagnosis & guid therapy in clinical setting
• Causes of disease


  • Immunologic abnormalities
  • Genetic abnormalities (inherited and acquired)
  • Infections
  • Nutritional imbalances
  • Trauma
  • Toxins
  • Biochemical changes
• Pathogenesis


  Mechanisms of disease
• Clinical manifestations


  Signs and symptoms of disease
• Cellular responses to stress and noxious stimuli

  Cells actively interact with their environment, constantly adjusting their structure and function to accommodate changing demands and extracellular stresses
• Adaptation


  Achieving a new steady state as cells encounter physiologic or potentially injurious conditions
• Cell injury


  Develops when the adaptive capability is exceeded or if the external stress is inherently harmful or excessive
• Reversible cell injury


  Deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed
• Reversible cell injury


  • Cells and intracellular organelles typically become swollen because they take in water as a result of the failure of energy-dependent ion pumps in the plasma membrane
  • Inability to maintain ionic and fluid homeostasis
• Main morphologic correlates in reversible cell injury

  • Cellular swelling
  • Fatty change
• Other changes associated with cell injury

  • Cytoplasm may become redder (eosinophilic)
  • Plasma membrane alterations such as blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments
  • Mitochondrial changes such as swelling and the appearance of phospholipid-rich amorphous densities
  • Dilation of the ER with detachment of ribosomes and dissociation of polysomes
  • Nuclear alterations, such as clumping of chromatin
  • Myelin figures (collection of phospholipid resembling myelin sheaths from damaged cellular membranes)
• Necrosis


  Form of cell death in which cellular membranes fall apart and cellular enzymes leak out and ultimately digest the cell
• Necrosis


  • Elicits a local host reaction -> inflammation
  • Due to some underlying pathologic process (never physiologic)
  • Biochemical mechanisms vary with different injurious stimuli
  • Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples
• Morphological characteristics of necrosis

  • Cytoplasmic changes: increased eosinophilia, vacuolation, discontinuities in membranes, dilation of mitochondria, disruption of lysosomes, myelin figures
  • Nuclear changes: nuclear condensation (pyknosis), nuclear fragmentation (karyorrhexis), or nuclear dissolution (karyolysis)
• Morphologic/Gross patterns of necrosis

  • Coagulative necrosis
  • Liquefactive necrosis
  • Gangrenous necrosis
  • Caseous necrosis
  • Fat necrosis
  • Fibrinoid necrosis
• Coagulative necrosis


  Necrotic tissue that remains firm; cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears
• Liquefactive necrosis


  Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction
• Coagulative necrosis


  • Gross appearance: Hemorrhagic, roughly wedge shape
  • Microscopic appearance: Difficult to discern at this magnification
• Coagulative necrosis


  • Pulmonary infarct
• Liquefactive necrosis


  • Seen in focal bacterial and, occasionally, fungal infections because microbes stimulate rapid accumulation of inflammatory cells, and the enzymes of leukocytes digest ("liquefy") the tissue
  • Characteristic of brain infarction, abscess, pancreatitis
• Liquefactive necrosis


  • Brain infarct
  • Abscess
  • Pancreatitis
• Gangrenous necrosis


  • Coagulative necrosis that resembles mummified tissue (dry gangrene)
  • If superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene)
• Gangrenous necrosis


  • Ischemia of lower limb and GI tract
• Caseous necrosis


  • Soft and friable necrotic tissue with "cottage cheese-like" appearance
  • Combination of coagulative and liquefactive necrosis
  • Tissue architecture is completely obliterated and cellular outlines cannot be discerned
• Caseous necrosis


  • Characteristics of granulomatous inflammation due to tuberculous or fungal infection
• Fat necrosis


  • Necrotic adipose tissue with chalky-white appearance due to deposition of calcium
  • Fatty acids released by trauma or lipase join with calcium via a process called saponification
• Fat necrosis


  • Trauma to fat (e.g., breast)
  • Pancreatitis-mediated damage of peripancreatic fat
• Fibrinoid necrosis


  • Necrotic damage to blood vessel wall
  • Deposited immune complexes and plasma proteins that leak into the wall of damaged vessels produce a bright pink, amorphous appearance on H&E preparations called fibrinoid (fibrinlike)
• Fibrinoid necrosis


  • Characteristic of malignant hypertension and vasculitis
• Apoptosis


  • Pathway of cell death in which cells activate enzymes that degrade the cell's own nuclear DNA and nuclear and cytoplasmic proteins
  • The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that the fragments called apoptotic bodies, become highly "edible" → rapid consumption by phagocytes
  • The dead cell and its fragments are cleared with little leakage of cellular contents, so apoptotic cell death does not elicit an inflammatory reaction
• Physiologic conditions that cause apoptosis

  • During embryogenesis
  • Turnover of proliferative tissues (e.g., intestinal epithelium, lymphocytes in bone marrow, and thymus)
  • Involution of hormone-dependent tissues (e.g., endometrium)
  • Decline of leukocyte numbers at the end of immune and inflammatory responses
  • Elimination of potentially harmful self-reactive lymphocytes
• Pathologic conditions that cause apoptosis

  • DNA damage
  • Accumulation of misfolded proteins
  • Infections, especially certain viral infections
• Mechanisms of apoptosis


  • Intrinsic (mitochondrial) pathway
  • Extrinsic (death receptor) pathway
  • Cytotoxic CD8 T cell-mediated pathway
• Morphology of apoptotic cells

  • Nuclei show various stages of chromatin condensation and aggregation and, ultimately, karyorrhexis
  • At the molecular level, this is reflected in the fragmentation of DNA into nucleosome-sized pieces