Cell injury and inflammation
Cell injury, necrosis, apoptosis, inflammation and repair: general pathology
Cell injury, necrosis, apoptosis, acute and chronic inflammation, granulomas, abscesses and repair for FCPS Part 1, with imaging correlation. It explains which necrosis, mediator, cell or organism lies behind each classic picture.
One of the most tested topics in past papers
Reversible and irreversible injury
- The common pathway in hypoxic, toxic and burn injury is ATP depletion, followed by free radical damage and calcium influx.
- Low ATP stops the Na⁺/K⁺ pump, water enters: cell swelling (hydropic change) is the earliest light-microscopic change. Fatty change (triglyceride) is the other reversible sign.
- Irreversible injury: the decisive step is loss of membrane integrity (plasma and lysosomal membranes), with flocculent densities in mitochondria. Nuclear changes: pyknosis, karyorrhexis, karyolysis.
- Ischaemia kills faster than hypoxia alone: with flow stopped, anaerobic glycolysis also loses its glucose substrate, and lactate and H⁺ are not washed out. Myocytes die after 20–30 minutes of complete ischaemia. Ischaemia is the commonest cause of cell injury in practice.
- Reperfusion injury: oxygen radicals and calcium influx cause contraction band necrosis.
- Ischaemic acute tubular necrosis after prolonged shock: patchy necrosis of the straight proximal tubule and thick ascending limb; dead cells shed as muddy brown granular casts; oliguria with rising creatinine.
- Diffuse alveolar damage (ARDS): injured type I pneumocytes and endothelium leak protein that lines the alveoli as hyaline membranes.
- Most sensitive neurones: CA1 pyramidal cells of the hippocampus.
Adaptations
| Term | Meaning | Example |
|---|---|---|
| Atrophy | Smaller cells | Pressure atrophy of renal cortex in hydronephrosis |
| Hyperplasia | More cells | BPH driven by DHT |
| Metaplasia | One adult cell type reversibly replaced by another | Squamous in a smoker's bronchus; Barrett oesophagus; gastric metaplasia in gallbladder |
| Dysplasia | Disordered growth: variation in cell size and shape, loss of polarity; potentially reversible if mild | Cervical intraepithelial neoplasia |
Types of necrosis
| Type | Where | Appearance and imaging |
|---|---|---|
| Coagulative | Most solid organs (heart, kidney) | Outlines preserved, nuclei lost |
| Liquefactive | Brain, abscesses (e.g. infected finger cut) | Enzymes digest tissue; an old brain infarct becomes a CSF-density cavity with ex vacuo ventricular dilatation |
| Caseous | Tuberculosis | Cheesy, structureless debris with granulomatous rim |
| Fat necrosis | Pancreatitis or pancreatic surgery (enzymatic), breast trauma | Calcium soaps (hypocalcaemia); breast oil cyst |
| Fibrinoid | Malignant hypertension, any vasculitis | Bright pink, smudgy vessel wall |
| Gangrene | Limbs, bowel | Dry or wet; gas gangrene from C. perfringens alpha toxin |
- Why brain liquefies: it has little supporting collagen and much lipid; microglia (resident macrophages) and neutrophils release lysosomal enzymes that digest the dead tissue, leaving a fluid cavity.
- Infarcts: white in solid organs with end arteries; red in tissue with dual supply or venous occlusion (lung, bowel, torted testis).
Apoptosis
- Energy-dependent death of single cells: shrinkage, chromatin condensation, apoptotic bodies eaten without inflammation; membrane stays intact.
- Intrinsic pathway: cytochrome c leaves mitochondria and activates caspase-9; held in check by Bcl-2 (anti-apoptotic, overexpressed in follicular lymphoma, t(14;18)); Bax and Bak promote it. Extrinsic pathway: Fas ligand or TNF activates caspase-8. Executioner caspase-3 completes both. p53 triggers apoptosis after DNA damage.
- Examples: interdigital tissue, breast involution, hormone withdrawal, chemotherapy and radiotherapy, viral hepatitis (Councilman bodies). Cancers escape apoptosis (p53 loss, Bcl-2 gain).
Pigments and calcification
- Anthracosis: inhaled carbon inside macrophages in lungs and hilar nodes, black streaks, no fibrosis (city dwellers). Lipofuscin (wear-and-tear), haemosiderin (old haemorrhage), melanosis coli.
| Calcification | Serum calcium | Examples |
|---|---|---|
| Dystrophic | Normal | Dead or damaged tissue: TB nodes, fat necrosis, atheroma, damaged valves |
| Metastatic | High (or high phosphate) | Normal tissues: kidney (nephrocalcinosis), gastric mucosa, lung; commonest cause hyperparathyroidism and renal failure |
Acute inflammation
- Vascular events: vasodilatation, then increased permeability from endothelial gaps in venules (histamine). Exudate: protein over 30 g/L, specific gravity over 1.020, Light criteria. Transudate: low protein (about 20 g/L), specific gravity about 1.010, from raised hydrostatic or low oncotic pressure, classically congestive cardiac failure.
- Leucocyte cascade: margination, rolling (selectins), firm adhesion (β2 integrins, CD18, binding ICAM-1), transmigration (diapedesis, PECAM-1), chemotaxis (C5a, LTB4, IL-8, bacterial peptides). Chemotaxis is most marked in acute inflammation.
- Phagocytosis: opsonins are IgG and C3b. Phagocytes bind IgG through Fc receptors: the Fc portion of an antibody decides its effects (complement activation, phagocyte binding), while Fab binds antigen. Killing: NADPH oxidase makes superoxide; myeloperoxidase makes hypochlorous acid.
- Terminal complement (C5–C9) deficiency: no membrane attack complex, so recurrent Neisseria (meningococcal, gonococcal) infection.
| Mediator | Main effect |
|---|---|
| Histamine | Early permeability, vasodilatation |
| Bradykinin | Pain, permeability; inactivated by ACE in the lungs (ACE inhibitor cough and angioedema) |
| PGE2 | Vasodilatation, pain (sensitises nerve endings), fever |
| IL-1, TNF | Fever (postoperative fever), endothelial activation, early neutrophil recruitment |
| IL-8 | Main neutrophil chemokine |
| IL-6 | Acute phase proteins (CRP, fibrinogen) |
| LTC4, D4, E4 | Bronchospasm, permeability |
- Pain after a knife injury: bradykinin and prostaglandins, plus K⁺ and H⁺ from damaged cells.
- Neutrophils dominate for 1–2 days, then macrophages. In the lungs, alveolar macrophages (dust cells) are the first line of defence.
| Defect | Cause | Clue |
|---|---|---|
| Leucocyte adhesion deficiency | CD18 absent | Delayed cord separation, no pus |
| Chronic granulomatous disease | NADPH oxidase | Catalase-positive infections; abnormal NBT test |
| Chédiak–Higashi | Lysosomal trafficking | Giant granules, partial albinism |
Suppuration and abscesses
| Abscess or lesion | Organism and clue |
|---|---|
| Pyogenic liver abscess | Commonest cause E. coli, usually from a biliary source (Klebsiella in diabetics) |
| Amoebic liver abscess | Single, right lobe, anchovy sauce pus; stool often negative, so serology for Entamoeba histolytica confirms |
| Actinomycosis | Chronic jaw abscesses with sinuses; pus has yellow sulphur granules; branching Gram-positive filaments (Actinomyces israelii) |
| Brodie abscess | Subacute osteomyelitis (S. aureus): lucent metaphyseal lesion with sclerotic rim and night pain |
| Pelvic abscess | After perforated appendicitis: swinging fever, mucus diarrhoea, tenesmus, boggy anterior rectal wall |
| Progressive synergistic gangrene (Meleney) | Slowly spreading ulcer around a suture: central ulcer, purple zone, outer red zone; microaerophilic streptococci with S. aureus |
- An abscess has a liquefied centre (neutrophil proteases) and an enhancing wall of granulation tissue. A walled-off cavity needs drainage because antibiotics penetrate poorly.
Chronic and granulomatous inflammation
- Lymphocytes, plasma cells and macrophages with fibrosis; the macrophage is the central cell.
- Granuloma: epithelioid cells (activated macrophages), driven by Th1 interferon-γ, maintained by TNF-α (anti-TNF drugs reactivate TB).
| Giant cell | Nuclei | Setting |
|---|---|---|
| Langhans | Horseshoe at the periphery | Tuberculosis |
| Foreign body | Scattered | Sutures, retained swab |
| Touton | Ring with foamy rim | Xanthoma |
- Sarcoidosis: non-caseating granulomas, bilateral hilar lymphadenopathy, dry cough; granuloma macrophages make 1α-hydroxylase, giving hypercalcaemia with suppressed PTH. Heerfordt syndrome: fever, uveitis, parotid swelling and facial palsy.
- Leprosy shows the Th1 spectrum: tuberculoid has strong Th1 immunity, so granulomas contain the bacilli: few lesions, few bacilli, early nerve damage. Lepromatous has weak Th1 (Th2 bias): widespread lesions packed with bacilli in foamy macrophages.
- Visceral leishmaniasis: amastigotes (LD bodies) inside macrophages of spleen and marrow; promastigotes are seen only in culture or the sandfly.
- Giant cell arteritis: granulomatous inflammation of the temporal artery; with jaw claudication and visual symptoms, give high-dose steroids immediately, then biopsy, to save sight.
Vascular changes and repair
- Hyaline arteriolosclerosis: pink glassy thickening of arteriolar walls from plasma protein leakage and matrix excess in benign hypertension and diabetes. Malignant hypertension gives hyperplastic (onion-skin) arteriolosclerosis with fibrinoid necrosis.
- First intention: neutrophils day 1, macrophages and granulation tissue by day 3, collagen by week 1, strength about 70–80% at 3 months.
- Granulation tissue has leaky new capillaries, so scar enhances on MRI. After a transmural MI, the wall is weakest at 3–7 days.
Remember Brain dies by liquefaction, solid organs by coagulation, tuberculosis by caseation.
Exam trap Dystrophic calcification occurs with normal serum calcium; metastatic calcification needs raised calcium or phosphate.
Exam trap Tuberculoid leprosy has few bacilli because immunity is strong, not because infection is mild.
How FCPS asks about this
- Decisive step in irreversible injury: loss of membrane integrity; common feature of all injury is ATP depletion.
- Old brain infarct becoming a CSF cavity: liquefaction by microglial lysosomal enzymes.
- Anti-apoptotic protein: Bcl-2; apoptosis runs through caspases without inflammation.
- Pleural fluid protein 20 g/L, specific gravity 1.010: transudate from heart failure.
- Jaw abscesses with sulphur granules: Actinomyces israelii.
- Recurrent Neisseria infection: terminal complement (C5–C9) deficiency.
- Hilar nodes, non-caseating granulomas and hypercalcaemia: sarcoidosis.
Test yourself on this topic
5 of the 179 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 64-year-old man with a long-standing pelviureteric junction obstruction has a markedly dilated pelvicalyceal system with a renal cortex only 4 mm thick. What process has thinned the cortex?
Answer: Pressure atrophy
Prolonged back-pressure from obstruction compresses the renal parenchyma between the dilated collecting system and the capsule. Compression reduces blood flow and causes the tubular cells to shrink and be lost, a form of atrophy. Over time the kidney becomes a thin-walled sac with little functioning tissue. Hypoplasia is a developmental failure to grow, not loss of tissue that was once normal.
Pressure atrophy
- Long-standing obstruction
- Parenchyma compressed
- Cortex thins
- Ends as a sac of urine
Remember Back-pressure squeezes the kidney thin.
Exam trap Cortical thinning from obstruction can be permanent even after the obstruction is relieved.
Why the other options are wrong
- Disuse atrophy Disuse atrophy follows loss of function, as in an immobilised limb.
- Hypoplasia Hypoplasia is congenital underdevelopment.
- Coagulative necrosis Infarction would give a wedge-shaped defect.
- Apoptosis from radiation No radiation is involved.
An obese 44-year-old man with mildly raised liver enzymes has a liver biopsy showing large clear vacuoles in hepatocytes that push the nucleus to the side. What has accumulated inside these hepatocytes?
Answer: Triglyceride
Fatty change (steatosis) is a reversible form of cell injury in which triglyceride accumulates as vacuoles in hepatocytes. In obesity and insulin resistance more fatty acids reach the liver than it can oxidise or export as lipoprotein. Large single droplets displace the nucleus (macrovesicular steatosis); the fat dissolves during processing, leaving clear spaces, and stains with oil red O on frozen sections. Glycogen gives pale, not vacuolated, cytoplasm.
Hepatic steatosis
- Triglyceride in hepatocytes
- Large droplet pushes nucleus aside
- Stains with oil red O (frozen)
- Reversible injury
Remember Clear vacuoles in hepatocytes: fat.
Exam trap The fat dissolves out in routine processing, so the vacuoles look empty.
Why the other options are wrong
- Glycogen Glycogen gives pale cytoplasm without discrete vacuoles.
- Iron Iron appears as brown granules (Prussian blue positive).
- Copper Copper is shown by special stains, not clear vacuoles.
- Amyloid protein Amyloid is extracellular pink material in the space of Disse.
In one experiment, heart muscle is perfused with blood of very low oxygen content at normal flow; in another, the coronary artery is clamped so flow stops. Cells die much faster with the clamp. Why is ischaemia more damaging than hypoxia alone?
Answer: Glycolysis also loses substrate and washout
In pure hypoxia, blood still brings glucose and carries away lactate and hydrogen ions, so anaerobic glycolysis can continue producing some ATP. When flow stops, delivery of glycolytic substrate also ceases and metabolites such as lactate and H+ accumulate. The acidosis inhibits glycolysis itself, so ATP falls faster and injury becomes irreversible sooner. This is why ischaemia injures tissue more rapidly and severely than hypoxia.
Ischaemia vs hypoxia
- Hypoxia: glycolysis continues
- Ischaemia: no substrate
- Ischaemia: no washout of lactate, H+
- ATP falls faster
Remember Ischaemia removes both oxygen and the backup supply.
Exam trap Ischaemia is the commonest cause of cell injury in clinical practice.
Why the other options are wrong
- Only ischaemia lowers mitochondrial ATP Both conditions stop oxidative phosphorylation.
- Hypoxia activates protective apoptosis Apoptosis does not protect the tissue here.
- Ischaemia alone raises intracellular sodium Sodium pump failure occurs in both once ATP falls.
- Hypoxic cells switch to fatty acid oxidation Fatty acid oxidation needs oxygen.
A 25-year-old man has fever, erythema nodosum and bilateral hilar lymphadenopathy. Biopsy of an enlarged node shows tight nodules of plump cells with pale, slipper-shaped nuclei and abundant pink cytoplasm, with occasional giant cells. What are these plump cells?
Answer: Epithelioid macrophages
A granuloma is a focal collection of activated macrophages called epithelioid cells, because their abundant cytoplasm makes them resemble epithelium. Interferon-gamma from Th1 lymphocytes transforms ordinary macrophages into these cells, which may fuse into multinucleate giant cells. A rim of lymphocytes surrounds them. Non-caseating granulomas in hilar nodes of a young adult suggest sarcoidosis; caseation points to tuberculosis.
Granuloma
- Core: epithelioid macrophages
- Fusion: giant cells
- Driver: IFN-gamma from Th1
- Rim of lymphocytes
Remember Epithelioid cells are macrophages dressed as epithelium.
Exam trap Giant cells alone do not make a granuloma; epithelioid cells are essential.
Why the other options are wrong
- Plasma cells These have eccentric clock-face nuclei and make antibody.
- Reed-Sternberg cells These are large binucleate cells of Hodgkin lymphoma.
- Activated fibroblasts Fibroblasts are spindle-shaped and lay down collagen at the edge.
- Eosinophils These have bilobed nuclei with red granules.
In acute inflammation, which mediator made by cyclo-oxygenase dilates arterioles, adds to the oedema caused by histamine and bradykinin and makes pain fibres more sensitive, so that NSAIDs relieve the pain?
Answer: Prostaglandin E2
Prostaglandins E2 and I2 are formed from arachidonic acid by cyclo-oxygenase. They dilate arterioles and so potentiate the oedema produced by histamine and bradykinin, and they lower the threshold of nociceptors, making them hypersensitive to bradykinin. PGE2 also resets the hypothalamic thermostat in fever. NSAIDs block cyclo-oxygenase, which explains their analgesic, anti-inflammatory and antipyretic effects.
Prostaglandins in inflammation
- From arachidonic acid by COX
- Vasodilatation, more oedema
- Sensitise pain fibres to bradykinin
- PGE2: fever
Remember Prostaglandins amplify histamine and bradykinin.
Exam trap Thromboxane A2 is also a COX product but constricts vessels.
Why the other options are wrong
- Leukotriene B4 Made by lipoxygenase; a neutrophil chemoattractant.
- Thromboxane A2 Made by COX in platelets but causes vasoconstriction and aggregation.
- Histamine A preformed amine from mast cells, not a COX product.
- Complement C5a A complement fragment that attracts neutrophils.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: General pathology and genetics, Cell injury, inflammation and repair