Pathology chapters
Cell injury, ischaemia, hypoxia and necrosis
The causes of cell injury, how hypoxia and ischaemia damage cells, the signs of reversible and irreversible injury, and the six morphological types of necrosis with the organs and diseases they occur in.
- Hypoxia (low oxygen) is the commonest cause of cell injury; ischaemia (low blood flow) is worse because it also stops nutrients and waste removal.
- Reversible injury shows cellular swelling and fatty change; the hallmarks of irreversible injury are severe mitochondrial damage and membrane damage (with nuclear changes: pyknosis, karyorrhexis, karyolysis).
- Coagulative necrosis (solid organs, infarcts except brain), liquefactive (brain, abscesses), caseous (TB), fat (pancreatitis, breast), fibrinoid (vasculitis, malignant hypertension), gangrenous (limbs, gut).
On this page
Overview
Cells constantly adjust to stress. If the stress is too great, the cell is injured. Mild injury is reversible; severe or prolonged injury leads to cell death, by necrosis or apoptosis (see apoptosis).
Causes of cell injury
- Oxygen deprivation (hypoxia): the commonest cause.
- Physical agents: trauma, heat, cold, radiation, electricity.
- Chemicals and drugs: poisons, alcohol, drug overdose (paracetamol).
- Infections.
- Immune reactions (autoimmunity, allergy).
- Genetic defects.
- Nutritional imbalance (deficiency or excess).
Hypoxia vs ischaemia
- Hypoxia: reduced oxygen supply (anaemia, CO poisoning, lung disease, heart failure). Glycolysis can continue.
- Ischaemia: reduced blood flow. Oxygen and nutrients (glucose) fall, and waste products build up. Ischaemia damages tissue faster and more severely than hypoxia alone.
Ischaemia is worse than hypoxia because anaerobic glycolysis also stops (no glucose supply) and toxic metabolites accumulate.
Mechanisms of cell injury
- ATP depletion: the Na+/K+ pump fails → sodium and water enter → cell swelling; anaerobic glycolysis → lactic acid → low pH; protein synthesis falls (ribosomes detach).
- Mitochondrial damage: less ATP, leakage of cytochrome c (triggers apoptosis), formation of free radicals.
- Calcium influx: activates enzymes that damage membranes, proteins and DNA.
- Free radicals (reactive oxygen species): damage lipids (lipid peroxidation), proteins and DNA. Important in reperfusion injury, radiation, chemical injury and inflammation.
- Membrane damage: loss of selective permeability; lysosomal enzymes leak and digest the cell.
- DNA and protein damage.
Reperfusion injury
When blood flow returns to ischaemic tissue, damage can worsen: new oxygen produces free radicals, calcium floods in, and inflammatory cells arrive. Seen after thrombolysis or angioplasty for myocardial infarction.
Reversible cell injury
| Change | Features |
|---|---|
| Cellular (hydropic) swelling | The earliest change; pale, swollen cell with clear vacuoles; from failure of ion pumps |
| Fatty change (steatosis) | Lipid vacuoles in cells that metabolise fat: liver (alcohol, obesity, diabetes), heart, kidney |
| Others | Blebbing of the plasma membrane, mitochondrial swelling, dilated endoplasmic reticulum, ribosome detachment, myelin figures |
If the cause is removed, the cell recovers.
Irreversible injury and necrosis
The two key signs of the "point of no return":
- Inability to restore mitochondrial function (no ATP even after reperfusion).
- Severe membrane damage (plasma and lysosomal membranes).
Mitochondrial dysfunction and membrane damage mark irreversible injury.
Necrosis is cell death with membrane rupture, leakage of contents and inflammation. It is always pathological.
Microscopic features
- Cytoplasm: more eosinophilic (pink), glassy, vacuolated.
- Nucleus:
- Pyknosis: shrinkage and darkening.
- Karyorrhexis: fragmentation.
- Karyolysis: fading of the nucleus as DNA is digested.
Leaked cell enzymes in the blood are used as markers of injury: troponin (heart), ALT and AST (liver), CK (muscle).
Types of necrosis
| Type | Features | Typical sites |
|---|---|---|
| Coagulative | Proteins denature; tissue architecture is preserved for days ("ghost outlines") | Infarcts of the heart, kidney, spleen (all solid organs except the brain) |
| Liquefactive | Tissue is digested into a liquid mass by enzymes | Brain infarcts; abscesses (bacterial and fungal infections, pus) |
| Caseous | Cheese-like, white, friable; amorphous pink debris surrounded by a granuloma | Tuberculosis (and some fungal infections) |
| Fat necrosis | Fat destroyed by lipases; fatty acids combine with calcium (saponification), chalky white areas | Acute pancreatitis; trauma to the breast (traumatic fat necrosis) |
| Fibrinoid | Immune complexes and fibrin deposit in vessel walls; bright pink smudgy appearance | Vasculitis, malignant hypertension, rheumatic fever |
| Gangrenous (clinical term) | Coagulative necrosis of a limb or gut; dry (arterial occlusion) or wet (with bacterial infection and liquefaction); gas gangrene (Clostridium perfringens) | Diabetic foot, peripheral arterial disease, strangulated bowel |
Brain infarcts show liquefactive necrosis; infarcts of other solid organs show coagulative necrosis.
Caseous necrosis is classic for TB, but it is not unique to it (some fungal infections, such as histoplasmosis, can cause it).
Clinical relevance
Myocardial infarction
How it happens: blockage of a coronary artery causes ischaemia; irreversible damage begins after about 20–30 minutes of severe ischaemia.
What you see: coagulative necrosis; troponin rises in the blood. Early reperfusion saves muscle but may cause reperfusion injury.
Fatty liver
How it happens: alcohol, obesity and diabetes.
What you see: an enlarged, yellow liver; reversible if the cause is removed.
Expect: the commonest cause of injury, hypoxia vs ischaemia, the earliest reversible change, hallmarks of irreversible injury, nuclear changes (pyknosis, karyorrhexis, karyolysis), and matching each type of necrosis to its organ or disease (heart = coagulative, brain = liquefactive, TB = caseous, pancreas = fat, vasculitis = fibrinoid).
Quick revision
- Hypoxia: commonest cause; ischaemia is worse (no glucose, waste builds up).
- Reversible: cell swelling (earliest), fatty change.
- Irreversible: mitochondrial and membrane damage.
- Nucleus: pyknosis, karyorrhexis, karyolysis.
- Coagulative: heart, kidney, spleen. Liquefactive: brain, abscess. Caseous: TB.
- Fat: pancreatitis, breast. Fibrinoid: vasculitis, malignant hypertension.
Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).
FAQ
What is the commonest cause of cell injury?
Hypoxia (oxygen deprivation).
Which type of necrosis occurs in a brain infarct?
Liquefactive necrosis.
What type of necrosis is seen in tuberculosis?
Caseous necrosis, surrounded by granulomatous inflammation.
What are the features of irreversible cell injury?
Failure to restore mitochondrial function and severe damage to cell membranes, with nuclear changes of pyknosis, karyorrhexis and karyolysis.