Cyanide Poisoning and Types of Insults

Types of Insults

• Chemical: drugs (e.g. paracetamol overdose), alcohol, cigarette smoke, and many more
• Infections: Eukaryotes (Fungi, Protozoa), Prokaryotes (Bacteria, Rickettsiae, Chlamydiae), Viruses (DNA, RNA)
• Physical: direct physical effects (e.g. extreme heat or cold, sudden changes in pressure, electrical currents)
• Immune: Humoral and Cell-mediated
• Nutrition: dietary insufficiency and excess

Principle Structural Targets for Cell Damage

• Cell membranes: Plasma membrane, Organellar membranes
• DNA
• Proteins: Structural, Enzymes
• Mitochondria: oxidative phosphorylation

Cell Injury and Necrosis

• Ischemic and Hypoxic Injury: ischemia is the most common cause of cell injury in clinical medicine
• Ischemia vs. Hypoxia: in ischemia, energy generation by anaerobic glycolysis stops due to the cut-off of blood supply, whereas in hypoxia, energy generation can continue
• Ischemia injures tissues faster than hypoxia

Hypoxia and Ischemia

• Loss of ATP Generation: failure of many energy-dependent systems of the affected cell
• Failure of ion pumps: leading to cell swelling, influx of Na+ and Ca++, and exit of K+
• Anaerobic Glycolysis: depletion of glycogen stores with accumulation of lactic acid
• Reduction in Protein Synthesis: altered metabolism leading to abnormal accumulations

Pathogenesis of Cell Injury - Hypoxia

• Reversible:
  • Loss of ATP
  • Failure of Na/K pump
  • Anaerobic metabolism
  • Increased lactic acid and phosphate
  • Clumped nuclear chromatin
  • Reduced protein synthesis
• Irreversible:
  • Massive intra-cytoplasmic calcium accumulation
  • Activation of multiple degradative enzymes
  • Lethal cell damage

Cellular Swelling (Hydropic Change)

• Affected hepatocytes are distended by accumulated water, imparting cytoplasmic pallor
• Histologic appearance of hepatic fatty change: lipid accumulates in hepatocytes as vacuoles with clear appearance on H&E staining

Consequences of Ischemia

• Irreversible injury and necrosis: associated with severe swelling of mitochondria and lysosomes, extensive damage to plasma membranes, and widespread leakage of cellular enzymes into the extracellular space
• Massive influx of calcium into the cell may occur
• Death is mainly by necrosis, but apoptosis also occurs

Detection of Tissue-Specific Necrosis

• Leakage of intracellular proteins through damaged cell membranes into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples
• Examples: cardiac muscle (creatine kinase and troponin), hepatocytes (transaminases)
• Measurement of serum levels is used clinically to assess damage to these tissues

Pathogenesis of Cell Injury - Non-Ischaemic

• Reduced ATP synthesis/mitochondrial damage
• Loss of calcium homeostasis
• Disrupted membrane permeability
• Free radicals

Free Radicals

• Highly reactive, unstable chemicals
• Associated with cell injury in many settings, including chemicals/drugs, reperfusion injury, inflammation, irradiation, oxygen toxicity, and carcinogenesis
• Free radical generation occurs by cellular injury

Cell Injury and Death

• Occurs when the limits of adaptive capability are exceeded
• Cell injury is divided into reversible and irreversible (cell death)
• Reversible cell injury occurs when the injurious agent is mild or short-lived
• Irreversible cell injury occurs when the injury becomes severe and the cell cannot recover

Factors Influencing Severity of Injury

• Type and severity of injurious agent
• Duration of exposure
• Type of affected cells (e.g. neurons, myocardial cells, hepatocytes, skeletal muscles, epidermis, fibroblasts)
• Susceptibility of cells to injury varies, with neurons being highly susceptible to ischemic damage and skeletal muscles being less susceptible