General Pathology
1. What this chapter covers, and how NEET PG actually tests it
General pathology is the vocabulary of every other clinical subject, which is why it is examined more heavily than its page count suggests.
The subject looks like a list of definitions. It is better understood as a set of visible fingerprints.
Almost every question gives you a morphological appearance and asks for the cause, or gives a cause and asks for the appearance. The two are linked one-to-one.
That linkage is the tool this chapter builds: name the mechanism and the morphology follows, or read the morphology backwards and the mechanism is named for you.
| Area | What the exam asks | Typical stem |
|---|---|---|
| Cell injury | Reversible or irreversible, and why | Electron microscopy findings |
| Necrosis patterns | Which organ, which cause | A described gross or microscopic appearance |
| Apoptosis | Intrinsic versus extrinsic trigger | A named protein (Bcl-2, Fas, caspase) |
| Acute inflammation | Which mediator does what | A specific vascular or cellular event |
| Chronic inflammation | Granuloma type and cause | Caseating versus non-caseating |
| Healing | First versus second intention, wound strength | A timeline in days or weeks |
| Thrombosis and infarction | Red versus white, Virchow's triad | Organ plus described infarct colour |
| Deposits | Amyloid, calcification, pigment | A stain result |
Roughly 8 to 10 questions per NEET PG paper come from pathology overall, and general pathology supplies the largest single share.
2. Cell injury and the point of no return
2.1 Adaptation comes before injury
A cell facing persistent stress first adapts. Only when adaptation is exceeded does injury begin.
Hypertrophy is an increase in cell size, used by permanent tissues that cannot divide — cardiac and skeletal muscle.
Hyperplasia is an increase in cell number, available only to tissues capable of division. The prostate and endometrium are the classic sites.
Atrophy is a decrease in cell size and number, mediated largely by the ubiquitin-proteasome pathway and autophagy.
Metaplasia is the replacement of one differentiated cell type by another better suited to the stress. Squamous metaplasia in the bronchus of a smoker is the standard example.
Metaplasia is reversible, but it is also the soil in which dysplasia grows. That is why Barrett oesophagus — glandular metaplasia of squamous mucosa — is followed endoscopically.
2.2 Reversible injury
Reversible injury has two universal features, both consequences of failing membrane pumps.
Cellular swelling occurs because the sodium-potassium ATPase fails when ATP falls, sodium enters, and water follows.
Fatty change occurs when the cell can no longer export triglyceride, and is prominent in liver, heart and kidney.
Under electron microscopy, reversible injury shows blebbing of the plasma membrane, swollen mitochondria, dispersed ribosomes and clumped nuclear chromatin.
Every one of those changes can be undone if the insult is removed.
2.3 The two irreversible events
The transition to irreversibility is defined by exactly two things: severe membrane damage, and mitochondrial permeability transition pore formation.
Once the mitochondrial pore opens, the proton gradient dissipates and ATP cannot be regenerated, no matter how quickly perfusion is restored.
Severe membrane damage allows enzymes to leak out and calcium to flood in. The clinical measurement of cardiac troponin depends entirely on this leak.
Intracellular calcium is the common executioner. It activates phospholipases that digest membranes, proteases that digest cytoskeleton, endonucleases that fragment DNA, and ATPases that waste the little remaining ATP.
Ischaemia is more damaging than pure hypoxia, because ischaemia removes substrate delivery and waste removal as well as oxygen, so anaerobic glycolysis also fails.
2.4 Free radical injury and reperfusion
Free radicals are generated by ionising radiation, drug metabolism, transition metals and the respiratory burst.
The Fenton reaction converts hydrogen peroxide to the hydroxyl radical in the presence of ferrous iron, which is why iron overload is directly cytotoxic.
Defences are superoxide dismutase, catalase, glutathione peroxidase, and the chain-breaking antioxidants vitamin E and vitamin C.
Reperfusion injury is the paradox that restoring blood flow to ischaemic tissue worsens damage, because returning oxygen fuels radical generation in cells that are already calcium-loaded.
3. Cell death: reading the pattern
3.1 Necrosis patterns each name their cause
| Pattern | Mechanism | Where it occurs |
|---|---|---|
| Coagulative | Denatured structural proteins hold the outline | Infarcts in all solid organs except brain |
| Liquefactive | Enzymatic digestion dominates | Brain infarcts, all abscesses |
| Caseous | Granulomatous, lipid-rich cell wall debris | Tuberculosis, some fungi |
| Fat | Lipase-released fatty acids bind calcium | Acute pancreatitis, breast trauma |
| Fibrinoid | Immune complexes plus fibrin in vessel walls | Vasculitis, malignant hypertension |
| Gangrenous | Clinical, not a distinct mechanism | Limbs, bowel |
Coagulative necrosis preserves the cell outline because the same acidosis that kills the cell also denatures its lysosomal enzymes, so autolysis cannot proceed.
The brain is the exception because it has little structural protein and abundant lysosomal content, so liquefaction wins there instead.
Gangrene is described as dry when coagulative necrosis predominates, and wet when bacterial infection adds liquefaction.
3.2 Apoptosis versus necrosis
Apoptosis is ATP-dependent, affects single cells, and provokes no inflammation because the membrane stays intact until fragments are phagocytosed.
Necrosis is passive, affects contiguous groups of cells, and is intensely inflammatory because contents spill out.
The intrinsic pathway is controlled by mitochondrial permeability. Bcl-2 and Bcl-xL are anti-apoptotic; Bax and Bak are pro-apoptotic. Cytochrome c release activates caspase-9.
The extrinsic pathway works through death receptors — Fas binding FasL, or TNF receptor 1 — and activates caspase-8.
Both converge on the executioner caspases, principally caspase-3.
Bcl-2 overexpression in follicular lymphoma, from the t(14;18) translocation, blocks apoptosis rather than driving proliferation. That distinction is a recurring question.
3.3 The regulated necrosis pathways
Three further pathways are now standard examinable content, and each is defined by a single molecule.
Necroptosis is caspase-independent programmed necrosis. It proceeds when caspase-8 is inhibited, allowing RIPK1 and RIPK3 to phosphorylate MLKL, which oligomerises and ruptures the membrane.
Pyroptosis is caspase-dependent and inflammatory. Inflammatory caspases, chiefly caspase-1, cleave gasdermin D, whose N-terminal fragment forms membrane pores and releases interleukin-1 beta and interleukin-18.
Ferroptosis is iron-dependent and caspase-independent, driven by peroxidation of polyunsaturated fatty acids in membrane phospholipids when glutathione peroxidase 4 activity fails.
The discriminator is straightforward: MLKL means necroptosis, gasdermin means pyroptosis, lipid peroxidation with iron means ferroptosis.
4. Acute inflammation
4.1 The vascular events in order
Transient vasoconstriction is followed by vasodilatation, then increased permeability, then stasis.
Vasodilatation of arterioles produces the heat and redness; increased permeability produces the swelling; the resulting exudate compresses nerves and, with bradykinin, produces the pain.
Increased permeability occurs by four distinct mechanisms, and the exam distinguishes them: endothelial contraction (immediate transient, histamine-mediated), direct endothelial injury (immediate sustained, as in burns), leukocyte-mediated injury, and increased transcytosis.
Stasis concentrates red cells centrally and pushes leukocytes to the vessel margin, which is what makes margination possible.
4.2 The leukocyte cascade
Margination, then rolling, then adhesion, then transmigration, then chemotaxis.
Rolling is mediated by selectins; firm adhesion by integrins. Selectins give the weak, reversible interaction; integrins give the strong one.
Leukocyte adhesion deficiency type 1 is a defect of the beta-2 integrin CD18, and presents with delayed umbilical cord separation and recurrent infections without pus.
Leukocyte adhesion deficiency type 2 is a defect in the selectin ligand sialyl-Lewis X, and is milder.
Chemotaxis is driven by C5a, leukotriene B4, interleukin-8 and bacterial N-formylated peptides.
4.3 Phagocytosis and the respiratory burst
Opsonisation by IgG and C3b massively increases phagocytic efficiency.
NADPH oxidase converts oxygen to superoxide; superoxide dismutase gives hydrogen peroxide; myeloperoxidase converts hydrogen peroxide plus chloride to hypochlorite.
Chronic granulomatous disease is NADPH oxidase deficiency, diagnosed by a failed nitroblue tetrazolium test or an abnormal dihydrorhodamine flow cytometry result.
Catalase-positive organisms cause disease in chronic granulomatous disease because they destroy the hydrogen peroxide the patient would otherwise borrow from the microbe itself.
Myeloperoxidase deficiency is much milder, and characteristically presents with candidal infection.
4.4 Mediators worth knowing precisely
| Mediator | Principal action |
|---|---|
| Histamine | Vasodilatation, immediate permeability |
| Bradykinin | Pain, permeability |
| Prostaglandin E2 | Fever, pain sensitisation, vasodilatation |
| Leukotriene B4 | Chemotaxis |
| Leukotrienes C4, D4, E4 | Bronchoconstriction, permeability |
| C3a and C5a | Anaphylatoxins; C5a also chemotactic |
| TNF-alpha and IL-1 | Endothelial activation, fever, cachexia |
| IL-6 | Acute phase protein synthesis |
| Nitric oxide | Vasodilatation, microbicidal |
Cyclooxygenase inhibition by aspirin and other non-steroidal drugs blocks prostaglandins only; corticosteroids inhibit phospholipase A2 and therefore block both prostaglandins and leukotrienes.
5. Chronic inflammation, granulomas and healing
5.1 Granuloma structure and classification
A granuloma is a collection of activated macrophages transformed into epithelioid cells, often with multinucleate giant cells and a lymphocyte cuff.
Formation requires interferon-gamma from T-helper 1 cells and interleukin-12 from macrophages, which is precisely why anti-TNF therapy reactivates latent tuberculosis.
Caseating granulomas occur in tuberculosis, histoplasmosis and other deep fungal infections.
Non-caseating granulomas occur in sarcoidosis, Crohn disease, berylliosis, foreign body reactions and cat-scratch disease.
Sarcoidosis is a diagnosis of exclusion and characteristically shows raised angiotensin converting enzyme and hypercalcaemia from macrophage 1-alpha-hydroxylase activity.
5.2 Repair: regeneration or scar
Labile tissues divide continuously (gut, skin, marrow); stable tissues divide on demand (liver, kidney, fibroblasts); permanent tissues cannot divide (neurons, cardiac and skeletal muscle).
An intact basement membrane and extracellular matrix scaffold determine whether regeneration or scarring occurs. Destroy the scaffold and even a labile tissue heals by scar.
Granulation tissue appears at around three to five days, and consists of proliferating fibroblasts, new capillaries and loose extracellular matrix.
Wound strength reaches only about 10 per cent at one week — which is when sutures are typically removed — and plateaus near 70 to 80 per cent of original strength at three months.
Collagen type III laid down early is progressively replaced by the stronger type I, a remodelling step performed by matrix metalloproteinases, which require zinc.
That zinc requirement is why zinc deficiency impairs healing, and vitamin C deficiency impairs it separately by blocking the hydroxylation of proline and lysine.
5.3 Abnormal healing
A hypertrophic scar stays within the wound boundary and may regress; a keloid extends beyond it and does not. Keloids show thick type III collagen and are commoner in darker skin.
Wound dehiscence, contracture and excess granulation tissue complete the group of local complications.
6. Haemodynamics and deposits
6.1 Thrombosis and infarction
Virchow's triad is endothelial injury, abnormal blood flow and hypercoagulability. Endothelial injury is the dominant factor in arterial thrombosis, and stasis in venous thrombosis.
Lines of Zahn — alternating pale platelet and dark red cell layers — indicate a thrombus formed in flowing blood, and so distinguish antemortem thrombus from postmortem clot.
Infarct colour is determined by the blood supply, not by the organ's identity.
White infarcts occur in solid organs with a single end-arterial supply: heart, kidney, spleen.
Red infarcts occur in tissues that are loose, dually supplied, congested, or reperfused: lung, small intestine, testis, and any reperfused infarct.
6.2 Embolism
An embolus is anything carried in the blood to a site distant from its origin, and over 95 per cent are thrombi.
Fat embolism follows long bone fracture, and its triad is respiratory distress, neurological change and a petechial rash appearing 24 to 72 hours later.
Amniotic fluid embolism presents in labour with sudden dyspnoea, cardiovascular collapse and disseminated intravascular coagulation, and fetal squames may be found in the maternal pulmonary vasculature.
Air embolism requires a substantial volume to be fatal, and decompression sickness is its dissolved-gas variant, producing the bends acutely and caisson disease chronically.
A paradoxical embolus is a venous embolus reaching the systemic circulation through a right-to-left shunt, most often a patent foramen ovale.
6.3 Shock
Shock is inadequate tissue perfusion, and the three principal categories are separated by their haemodynamic profile rather than by their cause.
| Type | Cardiac output | Systemic vascular resistance | Skin |
|---|---|---|---|
| Hypovolaemic | Low | High | Cold, clammy |
| Cardiogenic | Low | High | Cold, clammy |
| Septic (early) | High | Low | Warm, flushed |
The warm skin of early septic shock is the single most useful bedside discriminator, and it reflects nitric oxide-mediated vasodilatation rather than any difference in severity.
Cardiogenic and hypovolaemic shock are separated by the filling pressures: high in cardiogenic shock, low in hypovolaemic shock.
Shock progresses through a compensated stage, a progressive stage with lactic acidosis, and an irreversible stage in which restoring perfusion no longer helps.
6.4 Amyloid
Amyloid is any protein deposited in beta-pleated sheet configuration, which is what gives it apple-green birefringence under polarised light after Congo red staining.
AL amyloid derives from immunoglobulin light chains in plasma cell dyscrasias; AA amyloid derives from serum amyloid A in chronic inflammation.
Beta-2 microglobulin amyloid accumulates in long-term dialysis and deposits in the carpal tunnel; transthyretin amyloid causes familial and senile cardiac forms.
Abdominal fat pad aspiration is the usual screening biopsy, and rectal biopsy is an alternative.
6.5 Calcification and pigments
Dystrophic calcification occurs in dead or dying tissue with a normal serum calcium, as in atherosclerotic plaque, damaged heart valves and old tuberculous foci.
Metastatic calcification occurs in normal tissue with a raised serum calcium, as in hyperparathyroidism, vitamin D excess and bone destruction, and favours alkaline tissues such as gastric mucosa, kidney and lung.
Lipofuscin is the wear-and-tear pigment of ageing and brown atrophy, and represents undigested lipid peroxidation products.
Haemosiderin is iron storage pigment, stained blue by Perls Prussian blue.
7. Worked examples
Example 1
A 62-year-old man dies three days after a myocardial infarction. Which describes the histology?
The reasoning runs by timeline, and the timeline is driven by which cell arrives when.
Coagulative necrosis is established by 12 to 24 hours, with the cell outlines preserved but nuclei lost.
Neutrophils dominate from roughly one to three days, and macrophages from three to seven days.
At three days the answer is coagulative necrosis with a dense neutrophilic infiltrate, sitting at the transition where macrophages are just beginning to appear.
Example 2
A neonate has delayed separation of the umbilical cord and recurrent bacterial infections. Abscesses contain almost no pus. What is the defect?
The absence of pus despite bacterial infection is the discriminating detail, because pus is dead neutrophils.
Neutrophils are being produced but cannot reach the tissue, which localises the fault to the adhesion cascade rather than to phagocytosis or killing.
The defect is CD18, the beta-2 integrin chain, giving leukocyte adhesion deficiency type 1. Integrins mediate firm adhesion, without which transmigration cannot occur.
A blood count typically shows a marked neutrophilia, since the cells remain in the circulation.
Example 3
A patient on long-term haemodialysis develops bilateral carpal tunnel syndrome. A biopsy shows Congo red positive material.
Congo red positivity with apple-green birefringence identifies amyloid, so the question is only which type.
Beta-2 microglobulin is normally cleared by the kidney and is poorly removed by conventional dialysis membranes, so it accumulates over years.
Its deposition has a striking predilection for synovium and tendon sheaths, which is why the carpal tunnel is the presenting site.
8. Traps the exam sets repeatedly
Assuming all infarcts in a given organ are the same colour. Colour follows the vascular architecture and whether reperfusion occurred, so a reperfused myocardial infarct is haemorrhagic despite the heart being an end-arterial organ.
Calling every granuloma tuberculous. Caseation is what suggests tuberculosis; a non-caseating granuloma should redirect you to sarcoidosis, Crohn disease or berylliosis.
Confusing dystrophic with metastatic calcification. The serum calcium decides it, not the site.
Treating apoptosis as a form of necrosis. Apoptosis requires ATP and causes no inflammation, which is the opposite of necrosis on both counts.
Forgetting that steroids block both arms of the arachidonic acid cascade while non-steroidal anti-inflammatory drugs block only the cyclooxygenase arm.
Summary
General pathology is best approached as a set of one-to-one links between mechanism and morphology, so that reading either direction gives the other.
Reversible injury is swelling and fatty change; irreversibility begins with severe membrane damage and mitochondrial permeability transition, with calcium as the final executioner.
Each necrosis pattern names its cause: coagulative for infarcts, liquefactive for brain and abscess, caseous for tuberculosis, fat for pancreatitis, fibrinoid for immune vascular damage.
Apoptosis is ATP-dependent and non-inflammatory, controlled intrinsically by the Bcl-2 family and extrinsically by death receptors.
Among regulated necrosis pathways, MLKL identifies necroptosis, gasdermin identifies pyroptosis, and iron-dependent lipid peroxidation identifies ferroptosis.
Acute inflammation runs through defined vascular and cellular steps, with selectins mediating rolling and integrins mediating adhesion.
Granulomas require interferon-gamma and interleukin-12, which explains reactivation of tuberculosis on anti-TNF therapy; caseation separates infection from sarcoidosis and Crohn disease.
Healing depends on the surviving scaffold, reaches only 10 per cent strength at one week, and is impaired by deficiency of zinc or vitamin C.
Infarct colour follows the blood supply, amyloid is defined by beta-pleated sheet and Congo red birefringence, and serum calcium separates dystrophic from metastatic calcification.
