Q1 LONG ANSWER 10M ★ High-yield

Define cell injury. Describe its causes and mechanisms. Add a note on reversible and irreversible injury.

Pathology · 2nd Professional — Para-Clinical

Definitions

Cell injury results when a cell is stressed beyond its capacity to adapt, or is exposed to an inherently damaging agent.

Term	Meaning
Reversible injury	Functional and structural changes that recover if the stimulus is removed
Irreversible injury	The "point of no return" is passed and the cell dies
Necrosis	Pathological cell death with loss of membrane integrity, enzymatic digestion and inflammation
Apoptosis	Programmed, energy-dependent death of single cells without inflammation

Causes of Cell Injury

Hypoxia and ischaemia — the commonest cause. Ischaemia is worse than pure hypoxia, since it removes substrate as well as oxygen
Physical agents — trauma, extremes of temperature, radiation, electric shock
Chemical agents and drugs — poisons, alcohol, paracetamol, even hypertonic glucose or salt
Infections — viruses, bacteria, fungi, parasites
Immunological reactions — hypersensitivity and autoimmunity
Genetic defects — enzyme deficiencies, abnormal proteins
Nutritional imbalance — deficiency and excess alike
Ageing — cellular senescence

Mechanisms of Cell Injury

Ischaemia — oxygen supply falls → Oxidative phosphorylation stops; ATP falls → Na+/K+ ATPase fails → sodium and water enter → cellular swelling → Anaerobic glycolysis → lactic acid → pH falls → chromatin clumps → Ribosomes detach from the rough endoplasmic reticulum → protein synthesis falls → Calcium enters the cytosol → activates phospholipases, proteases, endonucleases and ATPases → membrane damage — mitochondrial, lysosomal and plasma membranes → irreversible injury and necrosis

Mechanism	Consequences
ATP depletion	Failure of ion pumps, swelling, loss of protein synthesis
Mitochondrial damage	Loss of ATP; formation of the mitochondrial permeability transition pore; leakage of cytochrome C, which triggers apoptosis
Influx of calcium	Activates degradative enzymes; the central event in irreversibility
Reactive oxygen species	Lipid peroxidation, protein oxidation, DNA damage
Membrane defects	Loss of osmotic balance; lysosomal enzyme release with autodigestion
Protein misfolding and DNA damage	Activation of apoptosis

Reversible and Irreversible Injury Compared

Feature	Reversible	Irreversible
Cell swelling	Present	Present, marked
Mitochondria	Swollen, with amorphous densities	Large dense amorphous deposits
Plasma membrane	Blebbing, loss of microvilli	Frank defects and rupture
Nucleus	Chromatin clumping	Pyknosis, karyorrhexis, karyolysis
Lysosomes	Intact	Rupture with autodigestion
Leakage of enzymes	Absent	Present — the basis of cardiac troponin, transaminases, amylase

CLINICAL PEARL

Two features mark the point of no return: irreparable mitochondrial dysfunction and profound membrane damage. Swelling is reversible, but once the membranes fail the cell cannot restore its ionic gradients however much oxygen is restored. This is why the timing of reperfusion decides how much myocardium survives.

Morphology of Reversible Injury

Cellular (hydropic) swelling — the first manifestation of almost all injury; the organ is pale, heavy and turgid
Fatty change (steatosis) — accumulation of triglyceride, chiefly in the liver, heart and kidney
On light microscopy — vacuolation, eosinophilia, swelling

Free Radical Injury

Generated by normal respiration, radiation, drug metabolism, transition metals (Fenton reaction) and nitric oxide
Chief species — superoxide, hydrogen peroxide and the hydroxyl radical, the last being the most damaging
Damage by lipid peroxidation of membranes, cross-linking of proteins, and DNA strand breaks
Removed by superoxide dismutase, catalase, glutathione peroxidase, and by antioxidants such as vitamins A, C and E
Clinically important in reperfusion injury, chemical toxicity (carbon tetrachloride, paracetamol), oxygen toxicity, inflammation and ageing

Applied Aspects

Myocardial infarction — irreversible injury begins after about 20–30 minutes of total ischaemia; troponin rises within 3–4 hours and is the marker of choice
Reperfusion injury — restoring blood flow paradoxically worsens damage through a burst of free radicals, calcium overload and neutrophil influx
Paracetamol poisoning — the toxic metabolite NAPQI depletes glutathione; treated with N-acetylcysteine, which replenishes it
Ischaemic preconditioning — brief episodes of ischaemia protect against a later prolonged one, a phenomenon exploited in cardiac surgery
Different cells tolerate ischaemia differently — neurones die within 3–5 minutes, myocardium in 20–30 minutes, fibroblasts survive hours; this dictates the urgency of resuscitation
Carbon tetrachloride is the classic experimental hepatotoxin, converted by cytochrome P450 to a free radical that destroys the endoplasmic reticulum within minutes
Enzyme leakage is the basis of most diagnostic tests — troponin and CK-MB for myocardium, ALT and ast for liver, amylase and lipase for pancreas; the enzyme identifies the tissue and the level suggests the extent
Hypothermia protects by lowering metabolic demand, which is why cardiac surgery is performed with the patient cooled and why drowning in cold water carries a better prognosis
Cyanide and carbon monoxide cause histotoxic hypoxia — oxygen reaches the cell but cannot be used; the arterial oxygen saturation may look normal
Chemical injury acts by two routes — directly, as with mercuric chloride binding sulphydryl groups, or after metabolic conversion to a toxic metabolite, as with paracetamol and carbon tetrachloride
Heat shock proteins are induced by stress and refold damaged proteins, and are among the cell's first defences against injury

All questions in General Pathology: Cell Injury, Adaptation & Cell Death

Every Pathology chapter →