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Pathology studies the causes (aetiology), mechanisms of development (pathogenesis), structural changes (morphology) and clinical consequences of disease. Causes include genetic, infectious, immunological, nutritional, physical, chemical and ischaemic factors. The cell responds to stress by adapting; when adaptive capacity is exceeded the cell is injured, reversibly if the stress is removed in time or irreversibly, leading to death.

- Hypertrophy: increase in cell size (cardiac muscle in hypertension, uterus in pregnancy). Occurs in cells that cannot divide. - Hyperplasia: increase in cell number (endometrium under oestrogen, liver regeneration, benign prostatic hyperplasia); physiological or pathological, driven by growth factors, and reversible when the stimulus stops. - Atrophy: decrease in size and function (disuse, denervation, ischaemia, malnutrition, ageing); involves autophagy and the ubiquitin-proteasome pathway. - Metaplasia: replacement of one mature cell type by another (squamous metaplasia of bronchi in smokers, Barrett oesophagus with columnar cells); may progress to dysplasia and cancer. - Dysplasia: disordered growth with cellular atypia; a pre-neoplastic change.

Common mechanisms: ATP depletion, mitochondrial damage, calcium influx, reactive oxygen species and oxidative stress, membrane damage and protein misfolding. Reversible injury shows cell swelling and fatty change. Irreversible injury shows loss of membrane integrity, release of enzymes (troponin, transaminases, creatine kinase) and nuclear changes: pyknosis, karyorrhexis, karyolysis.

Necrosis: uncontrolled death with swelling and release of contents that triggers inflammation. Patterns: coagulative (ischaemia in solid organs), liquefactive (brain, abscesses), caseous (tuberculosis), fat necrosis (pancreatitis), fibrinoid (vasculitis) and gangrenous. Apoptosis: regulated, energy-dependent death with cell shrinkage and fragmentation into apoptotic bodies removed by phagocytes without inflammation; physiological (development, turnover) or pathological. Pathways: intrinsic (mitochondrial; BCL-2 family, cytochrome c, caspase-9) and extrinsic (death receptors such as Fas, caspase-8); executed by caspases. Other regulated forms: necroptosis (RIPK3, MLKL; inflammatory), pyroptosis (inflammasome, caspase-1, gasdermin), ferroptosis (iron-dependent lipid peroxidation) and autophagy (cell survival mechanism that can lead to death).

Intracellular: lipids (steatosis of the liver), proteins (Mallory bodies, alpha-1 antitrypsin), glycogen (storage diseases, diabetes), pigments (lipofuscin, melanin, haemosiderin, bilirubin). Extracellular: amyloid (misfolded proteins in beta-pleated sheets, Congo red with apple-green birefringence; AL and AA types, transthyretin), and calcification: dystrophic (in dead tissue with normal calcium levels) and metastatic (with hypercalcaemia).

1. Define metaplasia and give an example. 2. Compare necrosis and apoptosis. 3. Name the two apoptotic pathways. 4. What stain identifies amyloid? 5. Difference between dystrophic and metastatic calcification?

1. Replacement of one mature cell type by another, for example squamous metaplasia in the bronchus of smokers. 2. Necrosis: uncontrolled, swelling, inflammation. Apoptosis: regulated, shrinkage, no inflammation. 3. Intrinsic (mitochondrial) and extrinsic (death receptor). 4. Congo red (apple-green birefringence under polarised light). 5. Dystrophic occurs in damaged tissue with normal calcium; metastatic occurs in normal tissue with hypercalcaemia.

Triggers: infection, tissue necrosis, foreign bodies, immune reactions. Recognition by pattern recognition receptors (PAMPs, DAMPs) activates resident cells. Vascular events: brief vasoconstriction, then vasodilation (redness and heat) and increased vascular permeability with plasma exudation (swelling; histamine, bradykinin, leukotrienes). Cellular events: margination, rolling (selectins), firm adhesion (integrins) and transmigration of neutrophils, chemotaxis (IL-8, C5a, LTB4), phagocytosis and killing. Cardinal signs: rubor, calor, tumor, dolor, functio laesa. Outcomes: resolution, scarring, abscess formation or progression to chronic inflammation.

Mediators: vasoactive amines (histamine, serotonin), arachidonic acid metabolites (prostaglandins: vasodilation, pain, fever; leukotrienes: bronchoconstriction, chemotaxis; blocked by NSAIDs and corticosteroids), complement (C3a, C5a), kinins, coagulation system and platelet-activating factor. Cytokines: TNF, IL-1 and IL-6 (fever, acute-phase response, endothelial activation), IL-8 (neutrophil chemotaxis), IL-10 and TGF-beta (anti-inflammatory), interferons.

Fever: IL-1, TNF and IL-6 raise the hypothalamic set point through prostaglandin E2. Acute-phase response: liver production of C-reactive protein, fibrinogen (raises erythrocyte sedimentation rate), serum amyloid A and hepcidin (anaemia of chronic disease); leukocytosis. Sepsis: dysregulated host response to infection with organ dysfunction; septic shock with vasodilation, capillary leak and disseminated intravascular coagulation.

Causes: persistent infection (tuberculosis), prolonged toxic exposure, autoimmune disease. Features: macrophages, lymphocytes and plasma cells, tissue destruction, angiogenesis and fibrosis. Granulomatous inflammation: aggregates of activated macrophages (epithelioid cells, giant cells) surrounded by lymphocytes, in tuberculosis (caseating), sarcoidosis, Crohn disease and foreign body reactions.

Regeneration needs proliferating cells (labile tissues such as skin and gut; stable tissues such as liver) and an intact scaffold. Scar formation: granulation tissue (new vessels, fibroblasts, macrophages), then collagen deposition and remodelling. Healing by first intention (clean, sutured wound) and second intention (large defect, granulation and contraction). Factors that impair healing: infection, poor blood supply, diabetes, malnutrition, corticosteroids, foreign material. Complications: keloid and hypertrophic scars, dehiscence, contracture, fibrosis.

1. List the cardinal signs of inflammation. 2. How do leukocytes leave the blood vessels? 3. Which cytokines cause fever? 4. What is a granuloma? 5. Which factors impair wound healing?

1. Redness, heat, swelling, pain, loss of function. 2. Margination, rolling by selectins, adhesion by integrins and transmigration. 3. IL-1, TNF and IL-6 (via prostaglandin E2). 4. An aggregate of activated macrophages (epithelioid cells, often with giant cells) with lymphocytes. 5. Infection, poor perfusion, diabetes, malnutrition, corticosteroids, foreign material.

Haemostasis: vasoconstriction, primary haemostasis (platelet adhesion by von Willebrand factor, activation and aggregation) and secondary haemostasis (coagulation cascade generating thrombin and fibrin). Natural anticoagulants: antithrombin, protein C and S, tissue factor pathway inhibitor; fibrinolysis by plasmin. Thrombosis: Virchow triad (endothelial injury, abnormal flow, hypercoagulability). Arterial thrombi (platelet-rich, on plaque rupture) cause infarction; venous thrombi (fibrin- and red cell-rich) cause deep vein thrombosis and pulmonary embolism. Fates: propagation, embolisation, dissolution, organisation. Disseminated intravascular coagulation is widespread microvascular thrombosis with consumption of clotting factors.

Risk factors: dyslipidaemia, hypertension, smoking, diabetes, age, male sex, family history, obesity. Pathogenesis: endothelial injury, LDL entry and oxidation in the intima, monocyte recruitment and foam cell formation, smooth muscle migration and matrix production, giving fatty streaks, then fibrous plaques with a necrotic lipid core and fibrous cap. Complications: plaque rupture with thrombosis (myocardial infarction, stroke), stenosis causing ischaemia (angina, claudication), aneurysm and embolism.

1. State Virchow's triad. 2. Compare arterial and venous thrombi. 3. Describe the steps in the formation of an atheromatous plaque. 4. What complications result from plaque rupture?

1. Endothelial injury, abnormal blood flow and hypercoagulability. 2. Arterial thrombi are platelet-rich and form on ruptured plaques causing infarcts; venous thrombi are fibrin- and red cell-rich and cause DVT and pulmonary embolism. 3. Endothelial injury, LDL entry and oxidation, monocyte recruitment and foam cells, smooth muscle proliferation, fibrous plaque with lipid core. 4. Acute thrombosis with myocardial infarction, stroke or limb ischaemia.

Geroscience studies the biology of ageing. Hallmarks: genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence (stable growth arrest with a pro-inflammatory secretory phenotype), stem cell exhaustion and altered intercellular communication.

Mendelian disorders: autosomal dominant (Marfan syndrome, familial hypercholesterolaemia, Huntington disease), autosomal recessive (cystic fibrosis, phenylketonuria, sickle cell disease) and X-linked (Duchenne muscular dystrophy, haemophilia A). Chromosomal disorders: trisomy 21 (Down syndrome), Turner (45,X) and Klinefelter (47,XXY) syndromes. Complex multifactorial diseases combine genes and environment; mitochondrial diseases show maternal inheritance.

A neoplasm is an abnormal mass of tissue with uncoordinated growth that persists after the stimulus ends. Benign tumours (suffix -oma) stay localised; malignant tumours (carcinoma of epithelial origin, sarcoma of mesenchymal origin) invade and metastasise. Hallmarks of cancer: self-sufficiency in growth signals, insensitivity to growth inhibition, evasion of apoptosis, unlimited replicative potential, sustained angiogenesis, invasion and metastasis, altered metabolism, and immune evasion. Genes: proto-oncogenes become oncogenes by gain of function (for example RAS, mutated in many cancers, encodes a GTPase that stays active), tumour suppressor genes are inactivated (loss of function).

1. List four hallmarks of ageing. 2. Give one example each of autosomal dominant, autosomal recessive and X-linked disease. 3. Distinguish carcinoma from sarcoma. 4. Why is RAS an oncogene?

1. For example telomere shortening, genomic instability, senescence and mitochondrial dysfunction. 2. Huntington disease, cystic fibrosis, Duchenne muscular dystrophy. 3. Carcinoma arises from epithelium; sarcoma from mesenchymal tissue. 4. Mutant RAS remains locked in the active GTP-bound state and drives proliferation.