Patho

• The four aspects of a disease

  • Cause (etiology)
  • The biochemical and molecular mechanisms of its development (pathogenesis)
  • The structural alterations induced in the cells and organs of the body (morphologic changes – gross and microscopic)
  • The functional consequences of these changes (clinical manifestations)
• Etiology or Cause

  • Genetic (e.g. inherited mutations and disease-associated gene variants, or polymorphisms)
  • Acquired (e.g. infectious, nutritional, chemical, physical)
• Most diseases are multifactorial and arise from the effects of various external triggers on a genetically susceptible individual
• Pathogenesis

  • Sequence of cellular, biochemical, and molecular events that follow the exposure of cells or tissues to an injurious agent
  • Link from cause to the expression of the disease
  • Sequence of molecular, biochemical, and cellular events that lead to the development of disease
  • Pathogenesis explains how the underlying etiologies produce the morphologic and clinical manifestations of the disease
• Morphologic Changes

  Structural alterations in cells or tissues that are either characteristic of a disease or diagnostic of an etiologic process
• Clinical Manifestations

  The end results of changes in cells and tissues are functional abnormalities that lead to the symptoms and signs of disease, as well as its progression
• Homeostasis

  The normal cell is able to handle physiologic demands, maintaining a steady state
• Adaptations

  • An increase in the size (hypertrophy) and functional activity of cells
  • Increase in cell number (hyperplasia)
  • A decrease in the size and metabolic activity of cells (atrophy)
  • A change in the phenotype of cells (metaplasia)
• When the stress is eliminated, the cell can return to its original state without having suffered any harmful consequences
• If the limits of adaptive responses are exceeded or if cells are exposed to damaging insults, deprived of critical nutrients, or compromised by mutations that affect essential cellular functions, a sequence of events follows that is termed cell injury
• Causes of Cell Injury

  • Oxygen deprivation or hypoxia
  • Physical Agents
  • Chemical Agents and Drugs
  • Infectious Agents
  • Immunologic Reactions
  • Genetic Derangements
  • Nutritional Imbalances
• Oxygen deprivation or hypoxia

  Reduces aerobic oxidative respiration; reduced blood flow (ischemia), cardiorespiratory failure, and decreased oxygen-carrying capacity of the blood, as in anemia or carbon monoxide poisoning or after severe blood loss
• Physical Agents

  Include mechanical trauma, extremes of temperature, radiation, and electric shock
• Chemical Agents and Drugs

  Arsenic, cyanide, or mercury
• Infectious Agents

  Viruses, bacteria, parasites
• Immunologic Reactions

  Autoimmune diseases
• Genetic aberrations

  An extra chromosome, or single base pair substitution
• Nutritional Imbalances

  Protein-calorie deficiencies, Deficiencies of specific vitamins, and diets high in certain lipids
• Features of Reversible Cell Injury

  • Cellular swelling
  • Fatty change
• Cell injury - reversible up to a certain point, but if the stimulus persists or is severe enough from the beginning, the cell suffers irreversible injury and ultimately undergoes cell death
• Phenomena characterizing irreversibility

  • The inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation)
  • Profound disturbances in membrane function
• Principal pathways of cell death

  • Necrosis
  • Apoptosis
• Necrosis

  • Denaturation of cellular proteins
  • Unable to maintain membrane integrity and their contents often leak out, a process that may elicit inflammation in the surrounding tissue
  • Local inflammation
  • Enzymatic ingestion of lethally injured cell
  • Necrotic cells show increased eosinophilia in H & E stains
• Nuclear changes in necrosis

  • Karyolysis – basophilia of chromatin may fade
  • Pyknosis – nuclear shrinkage and increased basophilia
  • Karyorrhexis – pyknotic nucleus undergoes fragmentation
• Patterns of Tissue Necrosis

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

  • A form of necrosis in which the architecture of dead tissues is preserved for a span of at least some days
  • Firm texture
  • Injury denatures not only structural proteins but also enzymes and so blocks the proteolysis of dead cells
  • A localized area of coagulative necrosis is called an infarct
• Liquefactive necrosis


  • Characterized by digestion of the dead cells, resulting in transformation of the tissue into a liquid viscous mass
  • Seen in focal bacterial or, occasionally, fungal infections
  • The necrotic material is frequently creamy yellow because of the presence of dead leukocytes (pus)
  • Hypoxic death of cells within the central nervous system often manifests as liquefactive necrosis
• Gangrenous necrosis


  • Involves multiple tissue planes
  • Caseous necrosis (cheese-like) – derived from friable white appearance of the area of necrosis
  • Encountered most often in foci of tuberculous infection
  • Necrotic area appears as a structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinctive inflammatory border (granuloma)
• Fat necrosis

  • Refers to focal areas of fat destruction
  • Typically results from release of activated pancreatic lipases into the substance of the pancreas, as in acute pancreatitis
  • Released lipases split triglyceride esters contained within fat cells
  • The fatty acids combine with calcium to produce grossly visible chalky-white areas (fat saponification)
• Fibrinoid necrosis

  • Usually seen in immune reactions involving blood vessels
  • Antigen-antibody complexes, together with plasma proteins, result in a bright pink and amorphous appearance in H&E stains ("fibrinoid" or fibrin-like)
• Apoptosis

  • A pathway of cell death that is induced by a tightly regulated suicide program
  • Activated intrinsic enzymes degrade the cells' genomic DNA and nuclear and cytoplasmic proteins
  • Cells break up into fragments, called apoptotic bodies, which contain portions of the cytoplasm and nucleus
  • Plasma membrane remains intact
  • Dead cell and its fragments are rapidly devoured before the contents leak out
  • Does not elicit an inflammatory reaction
• Apoptosis in Physiologic Situations

  • Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed
  • Mechanism to maintain a constant number of various cell populations in tissues (endometrial cell breakdown during the menstrual cycle, ovarian follicular atresia in menopause, regression of the lactating breast after weaning, death of host cells that have served their useful purpose (neutrophils in an acute inflammatory response))
• Apoptosis in Pathologic Situations

  • Eliminates cells that are injured beyond repair without eliciting a host reaction (DNA damage after radiation and cytotoxic anticancer drugs, in HIV infections or viral hepatitis, atrophy in parenchymal organs after duct obstruction)
• Morphologic features that characterize cells undergoing apoptosis

  • Cell shrinkage
  • Chromatin condensation
  • Formation of cytoplasmic blebs and apoptotic bodies
  • Phagocytosis of apoptotic cells or cell bodies, usually by macrophages
• In healthy cells, phosphatidylserine is present on the inner leaflet of the plasma membrane, but in apoptotic cells this phospholipid "flips" out and is expressed on the outer layer of the membrane, where it is recognized by several macrophage receptors
• Two distinct pathways of apoptosis

  • Intrinsic (Mitochondrial) Pathway of Apoptosis
  • Extrinsic (Death Receptor-Initiated) Pathway of Apoptosis
• Intrinsic (Mitochondrial) Pathway of Apoptosis

  • Responsible for apoptosis in most physiologic and pathologic situations
  • Results from increased permeability of the mitochondrial outer membrane with release of death-inducing (pro-apoptotic) molecules into the cytoplasm
  • BCL family of proteins control the release of pro-apoptotic proteins
  • Anti-apoptotic proteins - BCL2, BCL-XL, and MCL1
  • Pro-apoptotic proteins - BAX and BAK
  • Regulated apoptosis initiators - BAD, BIM, BID, Puma, and Noxa that can initiate apoptosis when unregulated and activated
• Extrinsic (Death Receptor-Initiated) Pathway of Apoptosis

  • Initiated by engagement of plasma membrane
  • Death receptors – members of the TNF receptor family
  • Type 1 TNF receptor (TNFR1) and a related protein called Fas (CD95)
• Other Mechanisms of Cell Death

  • Necroptosis
  • Pyroptosis
  • Ferroptosis
• Necroptosis

  Shares aspects of both necrosis and apoptosis