Pathology: Cell injury, inflammation and repair

🩻 Cell injury, inflammation and repair. General pathology describes the small number of ways tissues respond to harm. Cells adapt, are injured reversibly, or die; tissues mount acute inflammation, which resolves, suppurates, or becomes chronic; and damage heals by regeneration or scarring. These processes explain the clinical features of almost every disease - from myocardial infarction and pneumonia to cirrhosis, TB and wound breakdown - and are core knowledge for the UKMLA and MRCP Part 1.
Your four questions: What is the injurious agent (hypoxia, toxin, infection, immune, physical, genetic, nutritional)? Is the injury reversible, and if not, which type of necrosis? Is the inflammatory response acute or chronic (granulomatous)? Can the tissue regenerate, or will it scar?

---

Cellular Adaptations

Adaptation	Definition	Physiological example	Pathological example
Hypertrophy	Increase in cell size	Skeletal muscle with exercise; uterus in pregnancy	Left ventricular hypertrophy (hypertension, aortic stenosis); bladder wall in outflow obstruction
Hyperplasia	Increase in cell number (dividing cells only)	Breast at puberty and in lactation; endometrium in the proliferative phase; liver after partial resection	Endometrial hyperplasia (unopposed oestrogen - can progress to carcinoma), benign prostatic hyperplasia, Graves' thyroid, psoriasis
Atrophy	Decrease in cell size and number	Thymus in adulthood; uterus after menopause	Disuse (immobilised limb), denervation, ischaemia (renal artery stenosis), pressure, malnutrition, loss of hormone stimulation (adrenal atrophy with long-term steroids)
Metaplasia	Replacement of one differentiated cell type by another	-	Barrett's oesophagus (squamous → columnar with goblet cells - reflux), bronchial squamous metaplasia (smoking), cervical transformation zone (columnar → squamous), urothelium → squamous (schistosomiasis, stones)

• Metaplasia is reversible if the stimulus is removed, but may progress to dysplasia and carcinoma (Barrett's → adenocarcinoma; bronchial → squamous cell carcinoma).
• Dysplasia - disordered growth with cytological atypia (nuclear enlargement, hyperchromasia, pleomorphism, increased mitoses) and loss of maturation, confined by the basement membrane; graded low or high; high-grade dysplasia throughout the full thickness = carcinoma in situ.

Reversible and Irreversible Cell Injury

• Causes: hypoxia (commonest - ischaemia, hypoxaemia, anaemia, CO poisoning), physical agents (trauma, heat, cold, radiation, electricity), chemicals and drugs (paracetamol, alcohol), infections, immune reactions, genetic defects, nutritional imbalance, ageing.
• Mechanisms: ATP depletion (failure of Na⁺/K⁺-ATPase → cell swelling), mitochondrial damage, calcium influx (activates destructive enzymes), free radicals/reactive oxygen species (reperfusion injury, radiation, paracetamol metabolite NAPQI, iron and copper), membrane damage, DNA damage.
• Reversible injury: cell swelling (hydropic change), fatty change (steatosis - liver in alcohol, obesity, diabetes; heart), membrane blebs, ribosome detachment.
• Irreversible injury (the "point of no return"): severe mitochondrial dysfunction and membrane rupture (plasma and lysosomal), nuclear changes - pyknosis (shrinkage), karyorrhexis (fragmentation), karyolysis (dissolution). Leakage of cell contents (troponin, CK, ALT) is the basis of blood tests for tissue damage.
• Ischaemia–reperfusion injury - restoring blood flow causes additional damage through free radicals, calcium overload and neutrophil influx (after PCI, thrombolysis, transplantation, compartment release, revascularisation of limbs).
• Time to irreversible injury: neurons 3–5 minutes; myocardium 20–30 minutes; kidney and liver longer; skeletal muscle and skin hours.

Types of Necrosis

Type	Mechanism and appearance	Typical sites and causes
Coagulative	Protein denaturation; cell outlines ("ghosts") preserved for days	Infarcts of solid organs - heart, kidney, spleen (not brain)
Liquefactive	Enzymatic digestion → liquid	Brain infarcts; abscesses (bacterial and fungal - neutrophil enzymes)
Caseous	"Cheese-like" amorphous debris surrounded by granulomas	Tuberculosis; some fungi (histoplasmosis)
Fat necrosis	Lipase release → fatty acids combine with calcium (saponification) - chalky white	Acute pancreatitis (hypocalcaemia), breast trauma (mimics carcinoma - lump, calcification)
Fibrinoid	Immune complexes and fibrin in vessel walls - bright pink	Vasculitis, malignant hypertension, pre-eclampsia (placenta)
Gangrenous	Clinical term: dry (coagulative - ischaemic limb) or wet (liquefactive - superadded infection); gas gangrene (Clostridium perfringens)	Limbs in peripheral arterial disease and diabetes; bowel (strangulation, mesenteric ischaemia)

• Infarcts are pale (white) in solid organs with end-arteries (heart, kidney, spleen) and red (haemorrhagic) in organs with dual blood supply or loose tissue (lung, liver, bowel), in venous occlusion (testicular torsion, ovarian torsion), and after reperfusion.

Intracellular Accumulations and Calcification

• Lipids - steatosis (liver), cholesterol in macrophages (foam cells in atheroma, xanthomas).
• Proteins - Mallory–Denk bodies (alcoholic hepatitis), Russell bodies (plasma cells).
• Glycogen - glycogen storage diseases, diabetes (renal tubules).
• Pigments: lipofuscin ("wear and tear" pigment - ageing heart, liver), haemosiderin (iron - bruises, haemochromatosis, repeated transfusions, Prussian blue stain; heart failure cells in the lungs), melanin, bilirubin (jaundice), carbon (anthracosis - lungs of city dwellers and smokers).
• Dystrophic calcification - in damaged or dead tissue with normal serum calcium: atheroma, damaged heart valves (calcific aortic stenosis), tuberculous lymph nodes, fat necrosis, tumours (psammoma bodies - papillary thyroid carcinoma, serous ovarian carcinoma, meningioma), breast microcalcification (mammography).
• Metastatic calcification - in normal tissue due to hypercalcaemia or hyperphosphataemia: CKD (calciphylaxis), hyperparathyroidism, vitamin D toxicity, sarcoidosis, malignancy; affects lungs, kidneys (nephrocalcinosis), gastric mucosa, blood vessels.

Acute Inflammation

• Definition - the rapid (minutes to days), non-specific response of vascularised tissue to injury, aimed at removing the cause and starting repair. Cardinal signs: rubor (redness), calor (heat), tumor (swelling), dolor (pain) and functio laesa (loss of function).
• Causes: infection (especially bacterial), tissue necrosis (infarction), trauma, foreign bodies, chemicals, burns, immune reactions (hypersensitivity).
• Vascular events:
  • Transient vasoconstriction, then vasodilatation (histamine, prostaglandins, nitric oxide) → redness and heat.
  • Increased vascular permeability (endothelial contraction, injury) → exudate (protein-rich fluid, specific gravity >1.020) → swelling. Contrast with transudate (low protein, from raised hydrostatic or reduced oncotic pressure - heart failure, hypoalbuminaemia).
  • Slowing of flow (stasis) → leucocyte margination.
• Cellular events (neutrophils dominate in the first 24–48 hours): margination → rolling (selectins) → firm adhesion (integrins binding ICAM-1, VCAM-1) → transmigration (diapedesis, PECAM-1) → chemotaxis (C5a, IL-8, LTB4, bacterial products) → phagocytosis (aided by opsonins - IgG, C3b) → killing (respiratory burst - NADPH oxidase, myeloperoxidase, lysosomal enzymes).
• Defects in leucocyte function: leucocyte adhesion deficiency (CD18 - delayed umbilical cord separation, recurrent infections without pus), chronic granulomatous disease (NADPH oxidase - recurrent catalase-positive infections - S. aureus, Aspergillus; abnormal neutrophil oxidative burst test), Chédiak–Higashi syndrome, myeloperoxidase deficiency; acquired - diabetes, steroids, chemotherapy, neutropenia.

Inflammatory Mediators

Mediator	Source	Main actions
Histamine	Mast cells, basophils, platelets	Vasodilatation, increased permeability (immediate) - urticaria, anaphylaxis
Prostaglandins (PGE₂, PGI₂)	COX pathway from arachidonic acid	Vasodilatation, pain and fever (PGE₂ - target of NSAIDs and paracetamol), PGI₂ inhibits platelets
Thromboxane A₂	Platelets (COX-1)	Vasoconstriction, platelet aggregation - irreversibly blocked by aspirin
Leukotrienes	Lipoxygenase pathway	LTB4 - chemotaxis; LTC4, D4, E4 - bronchospasm and permeability (asthma - montelukast blocks receptors; aspirin-exacerbated respiratory disease)
Complement	Plasma (liver)	C3a, C5a anaphylatoxins (mast cell degranulation); C5a chemotaxis; C3b opsonisation; C5b–9 membrane attack complex (lysis - Neisseria)
Kinins (bradykinin)	Plasma	Permeability, vasodilatation, pain; ACE breaks down bradykinin → ACE inhibitor cough and angioedema; hereditary angioedema (C1 esterase inhibitor deficiency)
Cytokines (TNF-α, IL-1, IL-6)	Macrophages, lymphocytes	Endothelial activation, fever, acute phase response, cachexia
Nitric oxide	Endothelium, macrophages	Vasodilatation, microbial killing; septic shock vasodilatation

• Corticosteroids inhibit phospholipase A₂ (via annexin-1) and cytokine transcription - reducing prostaglandins and leukotrienes.

Outcomes of Acute Inflammation

• Resolution - complete restoration (e.g. lobar pneumonia) when injury is limited and tissue framework is intact.
• Suppuration - pus formation (neutrophils, dead tissue, bacteria) → abscess (walled off by granulation and fibrous tissue - needs drainage; antibiotics penetrate poorly), empyema (pus in a body cavity - pleura, gallbladder).
• Organisation and fibrosis - replacement by granulation tissue then scar when there is extensive necrosis or fibrin (pleural adhesions, organising pneumonia).
• Progression to chronic inflammation - persistent cause (infection, foreign body, autoimmunity).
• Spread - cellulitis, lymphangitis (red streaks), lymphadenitis, bacteraemia and sepsis.
• Special types: serous (blisters, effusions), fibrinous (pericarditis - "bread and butter" appearance and friction rub), membranous/pseudomembranous (C. difficile colitis, diphtheria), haemorrhagic, ulceration.

Chronic and Granulomatous Inflammation

• Chronic inflammation - weeks to years; inflammation, tissue destruction and attempted repair occur simultaneously. Cells: macrophages (central), lymphocytes, plasma cells, eosinophils (parasites, allergy), fibroblasts.
• Causes: persistent infection (TB, H. pylori, hepatitis B and C, syphilis), prolonged exposure to toxins (silica, asbestos, alcohol), autoimmune disease (rheumatoid arthritis, IBD, SLE), recurrent acute inflammation (chronic cholecystitis).
• Granulomatous inflammation - a distinctive chronic pattern: aggregates of activated (epithelioid) macrophages, often with multinucleate giant cells (Langhans type in TB - nuclei in a horseshoe), surrounded by lymphocytes. Driven by Th1 cells, IFN-γ and TNF-α (anti-TNF therapy causes TB reactivation).

Caseating granulomas	Non-caseating granulomas
Tuberculosis (classically)	Sarcoidosis
Fungal infections (histoplasmosis, coccidioidomycosis)	Crohn's disease
-	Foreign bodies (sutures, talc in people who inject drugs, silicone, tattoos)
-	Berylliosis, hypersensitivity pneumonitis
-	Leprosy (tuberculoid), cat scratch disease, schistosomiasis
-	Granulomatosis with polyangiitis, giant cell arteritis, primary biliary cholangitis, de Quervain's thyroiditis, drug reactions

• Ziehl–Neelsen stain and culture for mycobacteria are essential before attributing granulomas to sarcoidosis.

Systemic Effects of Inflammation

• Fever - IL-1, IL-6 and TNF-α act on the hypothalamus via PGE₂ → raised set point.
• Acute phase response - IL-6 stimulates the liver: ↑ CRP, fibrinogen (raises ESR), serum amyloid A (chronic → AA amyloidosis), ferritin, hepcidin (anaemia of chronic disease), complement, haptoglobin; ↓ albumin, transferrin.
• Leucocytosis - neutrophilia (bacterial infection), lymphocytosis (viral infections, pertussis), eosinophilia (parasites, allergy); left shift (immature band forms); leukaemoid reaction (very high count mimicking leukaemia).
• Sepsis and septic shock - dysregulated host response: vasodilatation, capillary leak, DIC, multi-organ dysfunction (Sepsis-3 - organ dysfunction measured by SOFA; qSOFA and NEWS2 for bedside screening).
• Cachexia - TNF-α ("cachectin") and IL-6 → muscle wasting and weight loss in chronic inflammation and cancer.

Regeneration, Repair and Wound Healing

• Regeneration - replacement by the same tissue; possible in labile and stable tissues when the supporting framework (basement membrane, reticulin) is intact - e.g. liver regeneration after hepatitis A, renal tubular regeneration after acute tubular necrosis.
• Repair - replacement by granulation tissue (new capillaries - angiogenesis via VEGF; fibroblasts; macrophages; loose oedematous matrix - bleeds easily, red and granular), which matures into a fibrous scar (collagen type III → type I). Permanent tissues (myocardium after MI, CNS - gliosis) always heal by scarring.
• Myocardial infarction - timeline: 0–24 hours (coagulative necrosis, neutrophils; risk of arrhythmia); 3–7 days (macrophages remove debris - weakest point → free wall rupture, septal rupture, papillary muscle rupture); 1–2 weeks (granulation tissue); 2 months onwards (dense scar - aneurysm, Dressler's syndrome autoimmune pericarditis weeks later).
• Primary intention - clean, opposed wound edges (surgical incision): minimal granulation tissue, fine scar; epithelium bridges in 24–48 hours; wound strength about 10% at 1 week (sutures removed), about 70–80% at 3 months (never reaches 100%).
• Secondary intention - large, gaping or infected wounds: abundant granulation tissue, wound contraction by myofibroblasts, larger scar (pressure ulcers, abscess cavities left open, burns).
• Factors impairing healing: local - infection, poor blood supply (arterial disease), venous hypertension, pressure, foreign bodies, haematoma, movement, radiation damage; systemic - diabetes, malnutrition (protein, vitamin C, zinc), corticosteroids, chemotherapy, smoking, old age, obesity, anaemia, jaundice, uraemia.
• Bone fracture healing: haematoma → soft callus (granulation tissue, cartilage - 2–3 weeks) → hard callus (woven bone - 6–12 weeks) → remodelling (lamellar bone - months to years); delayed by movement, infection, poor blood supply (scaphoid, femoral neck), smoking, NSAIDs (controversial), diabetes.

Fibrosis and Abnormal Healing

• Fibrosis - excessive collagen deposition from persistent injury; TGF-β is the key profibrotic cytokine; activated myofibroblasts (hepatic stellate cells in liver).
• Examples: liver cirrhosis (diffuse fibrosis with regenerative nodules), idiopathic pulmonary fibrosis (antifibrotics - pirfenidone, nintedanib), chronic pancreatitis, CKD (glomerulosclerosis and interstitial fibrosis), systemic sclerosis, myocardial fibrosis, retroperitoneal fibrosis.
• Abnormal scars: hypertrophic scar (raised, confined to the original wound, may regress - pressure garments, silicone) versus keloid (extends beyond the wound margins, does not regress, recurs after excision; commoner in people with darker skin; earlobes, chest, shoulders - intralesional steroid).
• Contractures - excessive contraction across joints (burns); adhesions - after abdominal surgery or peritonitis → small bowel obstruction; wound dehiscence and incisional hernia (infection, obesity, raised abdominal pressure, poor technique).
• Exuberant granulation tissue ("proud flesh") - prevents re-epithelialisation.

At a Glance

Concept	Remember
Barrett's oesophagus	Metaplasia → dysplasia → adenocarcinoma
Brain infarct	Liquefactive necrosis
Heart/kidney infarct	Coagulative necrosis, pale infarct
TB	Caseous necrosis, caseating granulomas
Pancreatitis	Fat necrosis, saponification, hypocalcaemia
Malignant hypertension, vasculitis	Fibrinoid necrosis
Dystrophic vs metastatic calcification	Damaged tissue, normal Ca vs normal tissue, high Ca
Acute inflammation	Neutrophils
Chronic inflammation	Macrophages, lymphocytes, plasma cells
MI days 3–7	Rupture risk
Keloid	Beyond the wound margin, recurs

Spot the Process

• A breast lump with calcification after a seatbelt injury. → Fat necrosis (mimics carcinoma - triple assessment).
• A man with hypercalcaemia from sarcoidosis has calcification in his kidneys. → Metastatic calcification (nephrocalcinosis).
• A child with recurrent staphylococcal abscesses and Aspergillus pneumonia. → Chronic granulomatous disease (NADPH oxidase).
• New pansystolic murmur and shock 5 days after an anterior MI. → Ventricular septal or papillary muscle rupture.
• Raised scar extending onto normal skin after ear piercing. → Keloid.

Exam-style Scenarios

• Scenario. A 62-year-old with long-standing reflux has a biopsy showing columnar epithelium with goblet cells and low-grade dysplasia in the lower oesophagus. Explain and manage.
  Answer: Barrett's oesophagus (intestinal metaplasia) with low-grade dysplasia - a precursor of adenocarcinoma. Confirm by two GI pathologists; high-dose PPI; repeat endoscopy within 6 months; endoscopic eradication therapy (radiofrequency ablation) is offered for confirmed dysplasia (BSG).
• Scenario. A lymph node biopsy shows non-caseating granulomas. What must be excluded before diagnosing sarcoidosis?
  Answer: Infection - especially TB (Ziehl–Neelsen stain, mycobacterial culture and PCR) and fungi; also lymphoma (granulomatous reaction), foreign material, berylliosis (occupational history) and drug reactions. Sarcoidosis is a diagnosis of exclusion with compatible clinical and radiological features.
• Scenario. Why do patients on long-term prednisolone have poor wound healing?
  Answer: Corticosteroids suppress inflammation (fewer macrophages and cytokines), reduce fibroblast proliferation and collagen synthesis, impair angiogenesis and epithelialisation, and increase infection risk.

Key Points

• Metaplasia is reversible; dysplasia is pre-malignant but confined by the basement membrane.
• Know the six types of necrosis and their classic causes.
• Dystrophic calcification - damaged tissue; metastatic - hypercalcaemia.
• Acute inflammation: neutrophils, exudate; chronic: macrophages and lymphocytes; granulomas: epithelioid macrophages.
• Permanent tissues heal by scarring; MI rupture risk peaks at days 3–7.
• Vitamin C, zinc, protein, oxygen and blood supply are essential for healing.

Further Reading

• Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease
• Underwood's Pathology: A Clinical Approach
• Royal College of Pathologists: datasets and tissue pathways
• British Society of Gastroenterology: Barrett's oesophagus guidelines