genpath

• PATHOLOGY

  The study (logos) of disease (pathos)
• Pathology


  The scientific foundation for ALL of medicine, bridging the basic sciences and clinical medicine
• 4 aspects of disease / core of pathology

  • Cause (etiology)
  • Mechanism of development (pathogenesis)
  • Biochemical & structural changes (molecular & morphologic changes)
  • Functional consequences (clinical manifestations)
• Cellular Responses to Stress & Noxious Stimuli

  • Adaptations of cellular growth and differentiation

  
• Adaptations


  Reversible changes in response to alterations in the cellular environment
• Adaptations


  • Changes in size, number, phenotype, metabolic activity, and functions of cells
• Hypertrophy


  Increase in the size of cells, leading to increase in organ size due to synthesis of one or more structural components of the cells
• Cells capable of division respond to stress by undergoing both hypertrophy and hyperplasia, while non-dividing cells only undergo hypertrophy
• Hypertrophy


  Can be physiologic or pathologic, induced by increased functional demand or stimulation by hormones and growth factors
• Most common stimulus for muscle hypertrophy is increased workload
• Hypertrophy results from increased production of cellular proteins, induced by linked actions of mechanical sensors, growth factors, and vasoactive agents
• Hypertrophy reaches a limit beyond which enlargement of muscle mass is no longer able to compensate for the increased burden, and can progress to functionally significant cell injury if the stress is not relieved
• Hyperplasia


  Increase in the number of cells in an organ or tissue, leading to increased organ/tissue mass
• Hyperplasia frequently occurs with hypertrophy and may be triggered by the same stimulus
• Types of physiologic hyperplasia

  • Hormonal hyperplasia
  • Compensatory hyperplasia
• Pathologic hyperplasia


  Caused by excesses of hormones or growth factors acting on target cells, providing fertile soil in which cancerous proliferation may eventually arise
• Atrophy


  Reduced size of an organ or tissue, leading to decreased size and number
• Types of atrophy


  • Physiologic atrophy (seen in normal development)
  • Pathologic atrophy (decreased workload, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, pressure)
• Metaplasia


  Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type
• Influences that predispose to metaplasia may initiate malignant transformation in metaplastic epithelium

  
• Examples of metaplasia


  • Columnar to squamous (respiratory tract, smoking)
  • Squamous to columnar (Barrett esophagus)
  • Connective tissue metaplasia (formation of cartilage, bone, or adipose tissue in areas that do not contain mesenchymal elements, e.g. myositis ossificans following intramuscular hemorrhage)

  
• Reversible cell injury


  • Reduced oxidative phosphorylation, depletion of energy stores (ATP), cellular swelling caused by changes in ion concentrations and water influx

  
• Types of cell death


  • Necrosis (always a pathologic process)
  • Apoptosis (serves many normal functions, not necessarily associated with cell injury)

  
• Causes of cell injury


  • Oxygen deprivation
  • Physical agents
  • Chemical agents and drugs
  • Infectious agents
  • Immunologic reactions
  • Genetic derangements
  • Nutritional imbalances
• Morphologic changes in cell injury


  • Irreversible biochemical changes may cause cell death, typically preceding ultrastructural, light microscopic, and gross changes

  
• Features of reversible injury (light microscopy)


  • Cellular swelling
  • Fatty change

  
• Ultrastructural changes in reversible cell injury

  • Plasma membrane alterations (blebbing, blunting, loss of microvilli)
  • Mitochondrial changes (swelling, amorphous densities)
  • Dilation of the endoplasmic reticulum (with detachment of polysomes, myelin figures)
  • Nuclear alterations (with disaggregation of granular and fibrillar elements)

  
• Necrosis


  Denaturation of intracellular proteins, enzymatic digestion of injured cell, inability to maintain membrane integrity, leakage of contents often eliciting surrounding inflammation

  
• Morphological features of necrosis


  • Increased eosinophilia
  • Loss of RNA
  • Denatured cytoplasmic proteins
  • Glassy appearance
  • Loss of glycogen particles
  • Vacuolated cytoplasm, moth-eaten appearance
  • Myelin figures
  • Nuclear changes (karyolysis, pyknosis, karyorrhexis)

  
• Patterns of tissue necrosis


  • Coagulative necrosis
  • Liquefactive necrosis
  • Gangrenous necrosis
  • Caseous necrosis
  • Fat necrosis
  • Fibrinoid necrosis
• Mechanisms of cell injury


  • Depletion of ATP, mitochondrial damage, influx of calcium and loss of calcium homeostasis, accumulation of oxygen-derived free radicals (oxidative stress), defects in membrane permeability, damage to DNA and proteins

  
• Apoptosis


  Programmed cell death, serving many normal functions and not necessarily associated with cell injury

  
• Physiologic situations of apoptosis


  • Programmed destruction of cells during embryogenesis
  • Involution of hormone-dependent tissues upon hormone withdrawal
  • Cell loss in proliferating cell populations
  • Elimination of potentially harmful self-reactive lymphocytes
  • Death of host cells that have served their useful purpose (end of immune response)

  
• Pathologic situations of apoptosis


  • DNA damage
  • Accumulation of folded proteins
  • Cell death in certain infections
  • Pathologic atrophy in parenchymal organs after duct obstruction

  
• Morphologic features of apoptosis


  • Cell shrinkage
  • Chromatin condensation
  • Formation of cytoplasmic blebs and apoptotic bodies
  • Phagocytosis of apoptotic cells or cell bodies, usually by macrophages

  
• Biochemical features of apoptosis


  • Activation of caspases
  • DNA and protein breakdown
  • Membrane alteration and recognition by phagocytes
• Comparison of features between necrosis and apoptosis


  • Cell size, nucleus, plasma membrane, cellular contents, adjacent inflammation, physiologic or pathologic role

  
• Disorders associated with dysregulated apoptosis include defective apoptosis and increased cell survival (permits survival of abnormal cells, failure to eliminate potentially harmful cells and dead cells), and increased apoptosis and excessive cell death (neurodegenerative disease, ischemic injury, death of virus-infected cells)

  
• Autophagy


  Process in which a cell eats its own contents, a survival mechanism activated by cellular stresses like nutrient deprivation
• Types of intracellular accumulations

  • Abnormal metabolism (normal endogenous substance produced at normal/increased rate but removal is inadequate)
  • Protein folding, transport (abnormal endogenous substance accumulates due to misfolding or transport defect)
  • Lysosomal storage (abnormal endogenous/exogenous substance accumulates due to defective lysosomal enzyme)
  • Infiltration (abnormal exogenous substance accumulates)