EXAM STRATEGY & IMPORTANT QUESTIONS GUIDE

Causes of Cell Injury:
1. Hypoxia / Ischaemia — most common; ↓ ATP → Na/K pump fails.
2. Physical agents — trauma, extremes of T, radiation, electric shock.
3. Chemical agents — drugs, alcohol, poisons (CCl₄, paracetamol), heavy metals.
4. Infectious agents — bacteria, viruses, fungi, parasites.
5. Immunological — hypersensitivity reactions, autoimmunity.
6. Genetic — inborn errors of metabolism, sickle cell.
7. Nutritional — deficiency (PEM, Vit) or excess (obesity).
8. Ageing.

Pathogenesis — 4 Key Targets:
1. Cell membrane damage → loss of selective permeability; Ca²⁺ influx → activates phospholipases, proteases, endonucleases.
2. Mitochondrial damage → ↓ ATP → anaerobic glycolysis → lactic acidosis; release of cytochrome c → apoptosis.
3. Ribosome damage → ↓ protein synthesis.
4. Nuclear / DNA damage → mutations, apoptosis.
Final common pathway — free radicals (ROS), ↓ ATP, Ca²⁺ overload, membrane damage.

Adaptive Changes:

Adaptation	Change	Stimulus	Example
Atrophy	↓ cell size + number	Disuse, denervation, ↓ blood supply, aging, ↓ hormone	Muscle wasting post-fracture, senile brain atrophy
Hypertrophy	↑ cell size	↑ workload, hormonal	Cardiac muscle in HTN, uterus in pregnancy, biceps in weight-lifter
Hyperplasia	↑ cell number	Hormonal / compensatory	Breast in pregnancy, liver after hepatectomy, BPH
Metaplasia	One mature cell → another mature type	Chronic irritation	Bronchial squamous metaplasia in smokers; Barrett's oesophagus (squamous → columnar)
Dysplasia	Disordered cell growth (size, shape, orientation)	Pre-malignant; HPV, smoking	Cervical dysplasia (CIN), bronchial dysplasia

Morphology of Reversible Injury:
• Cell swelling (hydropic change) — failure of Na/K pump.
• Fatty change (steatosis) — TG accumulation (liver).
• Intracellular accumulations — water, lipid, protein, pigment.
• Mitochondrial swelling, ribosomal detachment (RER).

Cell Death — Two Types:
1. Necrosis 🔊 — pathological; always accompanied by inflammation; ATP-independent.
Types:
• Coagulative — most common (MI, ischaemia).
• Liquefactive — brain, abscesses.
• Caseous — tuberculosis ("cheesy").
• Fat — pancreatitis, trauma to breast.
• Fibrinoid — immune vasculitis.
• Gangrenous — limb, bowel (ischaemic).
2. Apoptosis 🔊 — programmed cell death; ATP-dependent; no inflammation.
Features: cell shrinkage, chromatin condensation, fragmentation into apoptotic bodies, phagocytosis.
Pathways: intrinsic (mitochondrial, cyt c → caspase-9 → caspase-3) + extrinsic (death-receptor, Fas → caspase-8 → caspase-3).
Physiological: embryonic development, menstrual cycle. Pathological: cancer (too little), HIV (too much).

Acidosis, Alkalosis & Electrolyte Imbalance (brief):
• Acidosis — blood pH < 7.35; respiratory (↑ CO₂, COPD) or metabolic (↑ H⁺, diabetic ketoacidosis, renal failure, lactic acidosis).
• Alkalosis — pH > 7.45; respiratory (hyperventilation) or metabolic (vomiting — loss of HCl, alkali overdose).
• Electrolytes: Hyponatraemia (Na < 135), Hypernatraemia (> 145), Hypokalaemia (K < 3.5 → arrhythmia), Hyperkalaemia (> 5.5 → cardiac arrest).

Clinical Signs (Celsus + Virchow):
Five cardinal signs:
1. Rubor — redness (vasodilation).
2. Tumor — swelling (exudate).
3. Calor — heat (↑ blood flow).
4. Dolor — pain (bradykinin, PG, nerve endings).
5. Functio laesa — loss of function.

Types of Inflammation:
Acute — rapid onset (seconds-minutes); short duration (days); mainly neutrophils; exudate prominent; resolves by restitution.
Chronic — > 2 weeks; mononuclear infiltrate (lymphocytes, macrophages, plasma cells); fibrosis + tissue destruction; examples TB, RA.
Granulomatous — subtype of chronic; epithelioid cells + Langhans giant cells; TB, leprosy, sarcoidosis, fungal.

Mechanism of Acute Inflammation:
1. Vascular changes:
• Transient vasoconstriction → prolonged vasodilation → ↑ blood flow → redness, heat.
• ↑ Vascular permeability → plasma leakage → oedema; via endothelial contraction (histamine), retraction, direct injury, transcytosis.
• Stasis — slowed blood flow; concentration of cells.
2. Cellular events — Leucocyte migration:
(i) Margination — WBCs roll along vessel wall.
(ii) Rolling — selectins (E, P).
(iii) Adhesion — integrins on WBC bind ICAM / VCAM.
(iv) Diapedesis / Transmigration — WBC squeezes between endothelial cells.
(v) Chemotaxis — directed migration toward chemoattractants (C5a, IL-8, LTB₄, bacterial peptides).
(vi) Phagocytosis + killing — recognition (opsonins: IgG, C3b) → engulfment → phagosome + lysosome → bacterial killing by ROS (NADPH oxidase → O₂⁻, H₂O₂, HOCl via myeloperoxidase).

Mediators of Inflammation:
Cell-derived:
• Histamine — mast cells; vasodilation + ↑ permeability.
• Serotonin — platelets.
• Prostaglandins — COX pathway (PGE₂ pain, fever).
• Leukotrienes — LOX pathway (LTB₄ chemotaxis, LTC/D/E₄ bronchoconstriction).
• Cytokines — TNF-α, IL-1 (fever, acute phase), IL-6, IL-8 (chemokine), IFN-γ.
• NO, ROS, lysosomal enzymes, PAF.
Plasma-derived:
• Complement (C3a, C5a — anaphylatoxins + chemotactic; C3b — opsonin; MAC C5b-9 — lysis).
• Kinin system — bradykinin (pain, vasodilation).
• Clotting system — fibrin, fibrinopeptides.

Outcomes of Acute Inflammation:
1. Complete resolution (restitution).
2. Healing by fibrosis (scarring).
3. Abscess formation.
4. Progression to chronic inflammation.

Wound Healing in Skin (Basic Principles):
Primary intention (clean surgical wound):
Minutes: clot forms (fibrin).
24 h: neutrophils + epidermal regeneration starts.
Day 3: macrophages + granulation tissue.
Day 5: collagen III; epithelium restored.
Weeks-months: collagen I remodelling; scar matures.
Secondary intention (large wounds, ulcers): more granulation tissue, more scar, wound contraction by myofibroblasts, longer healing.
Phases:
1. Haemostasis (minutes) — platelet plug + fibrin clot.
2. Inflammation (day 0-3) — neutrophils then macrophages clean debris.
3. Proliferation (day 3-21) — granulation tissue (fibroblasts + new capillaries); re-epithelialisation.
4. Remodelling / Maturation (weeks-months) — collagen I replaces III; wound tensile strength reaches ~80 % of original.
Factors that impair healing: diabetes, steroid use, infection, poor blood supply, malnutrition (especially Vit C), foreign body, age.

Classification (JNC 8 / ACC-AHA 2017):

Category	Systolic (mmHg)	Diastolic (mmHg)
Normal	< 120	< 80
Elevated	120-129	< 80
Stage 1 HTN	130-139	80-89
Stage 2 HTN	≥ 140	≥ 90
Hypertensive Crisis	> 180	> 120

Types: Primary / Essential (95 %) — no identifiable cause; Secondary (5 %) — renal (stenosis, CKD), endocrine (Conn's, Cushing's, phaeochromocytoma), coarctation of aorta, drugs (OCP, steroids, NSAIDs), pregnancy.

Pathogenesis:
BP = CO × TPR. Any factor raising CO or TPR raises BP.
Key mechanisms:
• ↑ RAAS activity — renin → Ang II (vasoconstriction + aldosterone → Na/H₂O retention).
• ↑ Sympathetic tone — stress, obesity, sleep apnoea.
• ↑ Na⁺ retention — ↑ blood volume.
• Endothelial dysfunction — ↓ NO; ↑ endothelin.
• Genetic + environmental (salt, obesity, alcohol, smoking, stress).
• Vascular remodelling — hyalinisation, hypertrophy → ↑ TPR.

Clinical Features:
Often asymptomatic ("silent killer"). Symptoms when severe: headache (early morning), dizziness, palpitations, nosebleeds (epistaxis), blurred vision, chest pain, shortness of breath.
Target organ damage: heart (LVH, CHF, MI), brain (stroke, TIA, hypertensive encephalopathy), kidney (nephrosclerosis, CKD), eye (retinopathy - papilloedema, cotton wool spots, AV nicking), aorta (dissection, aneurysm).

Complications:
• Coronary artery disease → MI.
• Heart failure (LVH → LVF).
• Stroke — ischaemic / haemorrhagic.
• Hypertensive encephalopathy.
• CKD / end-stage renal disease.
• Aortic dissection / aneurysm.
• Retinopathy → blindness.
• Accelerated / malignant HTN (> 180/120 with end-organ damage — emergency).

Types:
By chamber:
• Left-sided HF — most common; pulmonary congestion (dyspnoea, orthopnoea, PND, pink frothy sputum).
• Right-sided HF — systemic congestion (peripheral oedema, raised JVP, hepatomegaly, ascites).
• Biventricular (often LHF → RHF = cor pulmonale).
By function:
• Systolic (HFrEF) — ↓ ejection fraction (< 40 %), contractility defect.
• Diastolic (HFpEF) — preserved EF but stiff ventricle fails to fill; elderly, HTN.
NYHA Classes I-IV — functional grading based on symptoms with activity.

Etiology:
• Hypertension (commonest long-term cause).
• Coronary artery disease / MI.
• Valvular heart disease (mitral / aortic).
• Cardiomyopathy (dilated, hypertrophic, restrictive).
• Congenital heart defects.
• Arrhythmias (AF).
• Anaemia, thyrotoxicosis, pregnancy, ↑ output states.

Pathophysiology (Compensatory Mechanisms - initially helpful, later harmful):
1. Frank-Starling mechanism — ↑ preload → ↑ stretch → ↑ contraction.
2. Neurohumoral activation — ↑ sympathetic (↑ HR, contractility, vasoconstriction); ↑ RAAS (Na + water retention + vasoconstriction); ↑ ADH.
3. Ventricular remodelling — hypertrophy (concentric in pressure overload; eccentric in volume overload); dilation; fibrosis.
4. ↑ BNP / ANP — natriuretic response (diagnostic marker: BNP > 100 pg/mL).
Eventually compensations fail → frank pump failure → congestion.

Clinical Features:
Left-sided HF:
• Exertional dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea (PND).
• Cough with pink frothy sputum (pulmonary oedema).
• Fatigue, weakness.
• Bibasal crackles on auscultation.
• S3 gallop rhythm.
Right-sided HF:
• Peripheral pitting oedema (ankles, sacral).
• Raised jugular venous pressure (JVP).
• Hepatomegaly, ascites.
• Nocturia.
• Anorexia, nausea.

Investigations + Drugs (brief):
ECG, CXR (cardiomegaly, Kerley B lines), echocardiography (EF), BNP/NT-proBNP, electrolytes.
Treatment: ACE-I / ARB, β-blockers (bisoprolol, carvedilol), diuretics (loop), mineralocorticoid antagonists (spironolactone), SGLT2-i (dapagliflozin), ARNI (sacubitril-valsartan); digoxin in select cases.

Atherosclerosis vs Arteriosclerosis:
Arteriosclerosis — general "hardening" of arteries with age (↑ stiffness, ↓ elasticity). Includes:
• Atherosclerosis (plaque).
• Mönckeberg's medial calcification.
• Arteriolosclerosis (hyaline / hyperplastic, seen in HTN + DM).
Atherosclerosis — specific disease: build-up of lipid-rich atheromatous plaque in tunica intima of large + medium arteries.
Pathogenesis (response-to-injury hypothesis):
1. Endothelial injury (HTN, smoking, hyperlipidaemia, diabetes).
2. LDL accumulation + oxidation in intima.
3. Monocytes recruited → become macrophages → engulf oxLDL → foam cells.
4. Foam cells + T cells → fatty streak.
5. Smooth muscle migration + proliferation; collagen deposition.
6. Fibrous cap with lipid core = mature plaque.
7. Plaque rupture → thrombosis → acute coronary syndrome.

Angina Pectoris:
Chest pain from transient myocardial ischaemia without necrosis.
Types:
• Stable angina — predictable; induced by exertion; relieved by rest / nitroglycerine; fixed atheromatous stenosis > 70 %.
• Unstable angina — at rest or increasing frequency; plaque rupture with partial occlusion; emergency (acute coronary syndrome).
• Prinzmetal / variant — coronary spasm; at rest; ST elevation transient.
Features: crushing retrosternal pain radiating to left arm / jaw / back, worsens with exertion, relieved by rest + GTN.

Myocardial Infarction (MI):
Irreversible necrosis of myocardium due to prolonged ischaemia (> 20-30 min).
Etiology: coronary atherosclerotic plaque rupture → platelet aggregation → thrombotic occlusion.
LAD most commonly involved (~50 %) — anterior MI; RCA → inferior; LCx → lateral.
Types:
• STEMI — transmural (full-thickness); ST elevation; total occlusion.
• NSTEMI — subendocardial; ST depression + T inversion; partial occlusion.
Clinical features: severe crushing chest pain > 30 min, not relieved by rest/GTN; sweating, nausea, vomiting, dyspnoea, sense of impending doom; pallor, cold clammy skin.
Diagnosis:
• ECG — ST changes, Q waves.
• Troponin I / T — most specific; ↑ by 3-6 h, peaks 24 h, lasts 10-14 d.
• CK-MB — rises 4-6 h, peaks 24 h, normalises 72 h.
Complications: arrhythmia (VF — early death), cardiogenic shock, ventricular rupture, septal defect, mitral regurgitation, aneurysm, thrombus, pericarditis (Dressler's, 2-10 wks post), heart failure.
Treatment: MONA-BASH (Morphine, O₂, Nitrates, Aspirin + Beta-blocker + ACE-I + Statin + Heparin) + reperfusion (primary PCI < 90 min, or thrombolysis — streptokinase, tPA).

Asthma — Pathophysiology:
Chronic inflammatory airway disease; reversible airflow obstruction + bronchial hyper-responsiveness.
Triggers: allergens (dust mite, pollen, pet dander), exercise, cold air, infection, drugs (aspirin, β-blockers), occupational, stress.
Pathogenesis (Type I hypersensitivity, atopic asthma):
1. Allergen exposure → IgE production by B cells (under Th2 influence — IL-4, IL-5, IL-13).
2. IgE binds mast cells.
3. Re-exposure → allergen crosslinks IgE → mast cell degranulation.
4. Release of histamine, leukotrienes, prostaglandins, PAF, tryptase.
5. Early response: bronchoconstriction + oedema + mucus hypersecretion.
6. Late response (4-8 h): eosinophil infiltration (major basic protein, ECP) → airway inflammation + hyper-responsiveness.
7. Chronic inflammation → airway remodelling (goblet cell hyperplasia, smooth muscle hypertrophy, subepithelial fibrosis).
Clinical features: episodic wheeze, cough (often nocturnal), shortness of breath, chest tightness. Triggered by cold air, exercise, viral URI, NSAIDs.
Signs: polyphonic wheeze, prolonged expiration, accessory muscle use, tachycardia.
Investigations: spirometry (↓ FEV₁, ↓ FEV₁/FVC < 0.7, > 12 % + 200 mL reversibility post-bronchodilator); PEFR diurnal variation > 20 %; IgE + eosinophils ↑.
Treatment: SABA (salbutamol) reliever + ICS (budesonide) controller + LABA + LTRA (montelukast) + biologicals (omalizumab anti-IgE; mepolizumab anti-IL-5).

COPD — Pathophysiology:
Progressive, mostly irreversible airflow limitation.
Two overlapping phenotypes:
• Chronic bronchitis — productive cough ≥ 3 months/year for ≥ 2 years (blue bloater — cyanosis, obese).
• Emphysema — destruction of alveoli, loss of elastic recoil (pink puffer — thin, dyspnoeic).
Etiology: smoking (main), air pollution, occupational (dust), α1-antitrypsin deficiency (young non-smokers).
Pathogenesis:
1. Irritant inhalation → macrophages + neutrophils recruited.
2. Release of proteases (elastase, MMPs).
3. Imbalance of proteases vs antiproteases (α1-AT).
4. Elastin destruction → alveolar wall destruction (emphysema).
5. Mucus hypersecretion + goblet cell hyperplasia (chronic bronchitis).
6. Airway remodelling; small-airway narrowing.
7. Loss of radial traction → expiratory flow limitation + air trapping → hyperinflation.
Clinical features:
• Chronic productive cough.
• Progressive dyspnoea (exertional first).
• Wheeze.
• Weight loss (emphysema).
• Barrel chest, pursed-lip breathing.
• Cor pulmonale in late stage.
Diagnosis: post-bronchodilator FEV₁/FVC < 0.7 (fixed); CXR — hyperinflation, flat diaphragm, ↑ AP diameter.
Treatment: stop smoking (most important); LABA + LAMA (tiotropium); ICS; oxygen (if hypoxic); pulmonary rehabilitation; vaccines.

Asthma vs COPD:

Feature	Asthma	COPD
Age of onset	Young / child	> 40 y, smoker
Reversibility	Reversible	Mostly irreversible
Cause	Allergy + hyperreactivity	Smoking + pollution
Cells	Eosinophils, mast, Th2	Neutrophils, macrophages, CD8
Pattern	Episodic	Progressive
Response to bronchodilator	Good (> 12 %)	Poor
Response to steroids	Excellent	Variable
Nocturnal symptoms	Prominent	Less

Acute Kidney Injury (AKI):
Definition (KDIGO): rise in serum creatinine ≥ 0.3 mg/dL in 48 h OR ≥ 1.5× baseline in 7 d OR urine output < 0.5 mL/kg/h for 6 h.
Classification by cause:
• Prerenal (55-60 %) — ↓ renal perfusion; hypovolaemia (haemorrhage, dehydration, diarrhoea), heart failure, sepsis, renal artery stenosis, NSAIDs, ACE-I.
• Intrinsic / Intrarenal (35-40 %) — renal parenchymal damage; acute tubular necrosis (ischaemic or toxic — aminoglycosides, contrast), glomerulonephritis, interstitial nephritis.
• Postrenal (5 %) — urinary tract obstruction; BPH, stones, pelvic tumour.
Phases: Initiation → Oliguric (< 400 mL/day, lasts 1-2 wks) → Diuretic → Recovery.
Clinical features: oliguria, nausea, vomiting, fluid overload, hyperkalaemia (arrhythmia), metabolic acidosis, uraemic encephalopathy.
Investigations: ↑ creatinine + urea; electrolytes; urinalysis; ultrasound (postrenal); fractional excretion of Na (FeNa < 1 prerenal, > 2 ATN).

Chronic Kidney Disease (CKD):
Definition: GFR < 60 mL/min/1.73 m² for ≥ 3 months OR structural damage regardless of GFR.
Stages (KDIGO): 1 (> 90), 2 (60-89), 3a (45-59), 3b (30-44), 4 (15-29), 5 (< 15, ESRD).
Common causes:
1. Diabetes mellitus (commonest, ~45 %).
2. Hypertension (~25 %).
3. Glomerulonephritis.
4. Polycystic kidney disease.
5. Chronic pyelonephritis, obstructive uropathy.
Pathophysiology: nephron loss → remaining nephrons hyperfiltrate → glomerular hypertension → progressive fibrosis (RAAS + TGF-β) → further nephron loss → ESRD.
Clinical features (Uraemic syndrome):
• Nausea, vomiting, anorexia.
• Fluid retention → oedema, hypertension.
• Anaemia (↓ EPO from kidney).
• Hyperkalaemia, metabolic acidosis.
• Mineral-bone disease (↓ 1,25-Vit D + ↑ PO₄ + ↑ PTH → renal osteodystrophy).
• Pruritus, uraemic frost, pericarditis, encephalopathy, peripheral neuropathy.
• ↑ CV risk (leading cause of death in CKD).
Management: control BP (< 130/80; ACE-I/ARB), control DM, diet (low-salt, low-K, low-P), erythropoietin + iron, phosphate binders + Vit D, dialysis (stage 5), renal transplant (definitive).

AKI vs CKD:

Feature	AKI	CKD
Onset	Hours-days	Months-years
Duration	< 3 months	> 3 months
Kidney size (USG)	Normal / enlarged	Small, shrunken (usually)
Reversibility	Often reversible	Usually irreversible
Anaemia	Rare	Common
Renal osteodystrophy	Absent	Present in advanced
Common causes	Hypovolaemia, sepsis, drugs	Diabetes, HTN

Classification (by MCV):
• Microcytic (MCV < 80 fL) — IDA, thalassaemia, anaemia of chronic disease, sideroblastic.
• Normocytic (MCV 80-100) — acute blood loss, haemolytic, chronic disease, aplastic, CKD.
• Macrocytic (MCV > 100) — megaloblastic (B12, folate), liver disease, hypothyroid, alcohol.

1. Iron Deficiency Anaemia (IDA):
Cause: ↓ dietary iron (infancy, vegetarian), blood loss (menstruation, GI — peptic ulcer, hookworm, cancer), malabsorption, ↑ demand (pregnancy, growth).
Features: fatigue, pallor, koilonychia (spoon nails), glossitis, angular stomatitis, pica (pagophagia — ice eating), Plummer-Vinson (dysphagia + oesophageal web).
Lab: ↓ Hb, ↓ MCV, ↓ MCH (microcytic hypochromic); ↓ serum Fe; ↓ ferritin (most specific); ↑ TIBC.
Treatment: oral ferrous sulphate (60 mg elemental Fe tds); parenteral iron (sucrose) if severe / poor absorption; treat underlying cause.

2. Megaloblastic Anaemia:
Cause: ↓ B12 or folate → impaired DNA synthesis → nuclear-cytoplasmic asynchrony in bone marrow.
B12 deficiency:
• Causes: pernicious anaemia (autoimmune — anti-IF, anti-parietal cell), ileal resection, terminal ileal disease, gastrectomy, strict vegan diet, fish tapeworm.
• Features: megaloblastic anaemia + neurological symptoms (subacute combined degeneration — paraesthesiae, ataxia, dementia), glossitis, lemon-yellow skin.
Folate deficiency:
• Causes: poor diet, malabsorption, pregnancy, alcohol, drugs (MTX, phenytoin), haemolysis.
• Features: megaloblastic anaemia without neurological signs. Causes neural tube defects in fetus.
Lab: ↑ MCV, hypersegmented neutrophils (> 5 lobes), low serum B12 / folate; ↑ homocysteine + MMA (B12 only).
Treatment: B12 IM hydroxocobalamin lifelong (PA); oral folate 5 mg; periconceptional folate 400 µg/day.

3. Sickle Cell Anaemia:
Cause: autosomal recessive point mutation — β-globin Glu6→Val → HbS. Common in African, Middle Eastern, Indian populations (heterozygote carrier protects against falciparum malaria).
Pathophysiology: low O₂ / acidosis / dehydration → HbS polymerises → distorts RBC into sickle shape → haemolysis + microvascular occlusion (vaso-occlusion).
Features: chronic haemolytic anaemia + recurrent painful crises (bone, chest, abdomen), stroke, priapism, leg ulcers, splenic auto-infarction (functional hyposplenism → infections), acute chest syndrome, retinopathy.
Diagnosis: Hb electrophoresis (HbS band); sickling test; prenatal diagnosis.
Treatment: hydroxyurea (↑ HbF, ↓ crises), folate, analgesia, transfusion, penicillin prophylaxis + vaccines (for pneumococcus), bone marrow transplant (curative).

4. Thalassaemia:
Cause: autosomal recessive; ↓ synthesis of α (α-thal) or β (β-thal) globin chain → imbalanced globin synthesis → ineffective erythropoiesis + haemolysis.
β-Thalassaemia:
• Major (Cooley's) — homozygous; severe transfusion-dependent anaemia from 3-6 m; skeletal deformities (frontal bossing, maxillary hypertrophy — "chipmunk facies"); hepatosplenomegaly; hair-on-end skull X-ray; iron overload from repeated transfusions.
• Minor (trait) — heterozygous; mild anaemia; resembles IDA (but ferritin normal).
α-Thalassaemia: variable severity based on number of α-genes deleted (0-4); hydrops fetalis (all 4 deleted); HbH disease (3 deleted).
Lab: microcytic hypochromic anaemia; target cells, basophilic stippling; Hb electrophoresis — ↓ HbA + ↑ HbF + HbA₂ in β-thal.
Treatment: regular transfusions + iron chelation (deferoxamine / deferasirox) to prevent iron overload; folate; splenectomy; bone marrow transplant.

5. Haemophilia:
Cause: X-linked recessive deficiency of clotting factor.
• Haemophilia A — Factor VIII deficiency (commonest, 80 %).
• Haemophilia B (Christmas) — Factor IX.
• Haemophilia C — Factor XI (autosomal).
Features: affects males; carrier females; spontaneous / post-trauma bleeding; haemarthroses (joint — knee); muscle haematomas; prolonged bleeding after cuts; intracranial haemorrhage (severe).
Lab: prolonged aPTT; normal PT + bleeding time + platelets; specific factor assay.
Treatment: recombinant Factor VIII / IX; desmopressin (DDAVP — mild A); tranexamic acid for mucosal bleeding; avoid aspirin + IM injections.

Definition & Diagnostic Criteria (ADA):
• Fasting plasma glucose ≥ 126 mg/dL, OR
• 2-h OGTT ≥ 200 mg/dL (with 75 g glucose), OR
• Random glucose ≥ 200 + symptoms, OR
• HbA1c ≥ 6.5 %.
Prediabetes: FPG 100-125; HbA1c 5.7-6.4 %.

Type 1 DM (IDDM — 5-10 %):
• Autoimmune destruction of pancreatic β-cells → absolute insulin deficiency.
• Genetic predisposition (HLA-DR3/DR4) + environmental trigger (viral).
• Anti-GAD, anti-islet, anti-insulin antibodies.
• Onset: usually childhood / young adult; lean.
• Presents with polyuria, polydipsia, polyphagia, weight loss, ketoacidosis.
• Requires insulin for life.

Type 2 DM (NIDDM — 90-95 %):
• Insulin resistance + progressive β-cell failure.
• Multifactorial — obesity, sedentary life, genetic, age > 40.
• Peripheral tissues don't respond to insulin; initially pancreas compensates → eventually exhausts.
• Often insidious; discovered on screening; obese patient.
• Managed with diet + exercise + oral hypoglycaemics; some need insulin.
Acanthosis nigricans — pigmented velvety neck folds — marker of insulin resistance.

Type 1 vs Type 2:

Feature	Type 1	Type 2
Prevalence	5-10 %	90-95 %
Onset	Young (< 30 y)	> 40 y (now younger due to obesity)
Body habitus	Lean	Obese
Pathogenesis	Autoimmune β-cell destruction	Insulin resistance + β-cell failure
HLA	HLA-DR3 / DR4	No association
Antibodies	Anti-GAD, anti-insulin +	Absent
C-peptide	Very low	Normal / ↑ early, ↓ late
Ketoacidosis	Common	Rare (HHS more typical)
Treatment	Insulin always	Diet/exercise + oral drugs ± insulin

Complications:
Acute:
• Diabetic ketoacidosis (DKA) — Type 1; insulin absent; ↑ lipolysis → ketones; Kussmaul breathing, fruity breath, dehydration, coma.
• Hyperosmolar hyperglycaemic state (HHS) — Type 2; glucose > 600 + osmolality > 320 without ketoacidosis; severe dehydration.
• Hypoglycaemia (from treatment).
Chronic (after 10+ years of poor control):
Microvascular:
• Diabetic retinopathy — non-proliferative (microaneurysms, dot-blot haemorrhages, cotton-wool spots) → proliferative (neovascularisation) → blindness. Leading cause of blindness in working-age adults.
• Diabetic nephropathy — glomerular thickening + mesangial expansion → microalbuminuria → overt proteinuria → ESRD. Kimmelstiel-Wilson nodules on biopsy.
• Diabetic neuropathy — peripheral (stocking-glove sensory loss), autonomic (orthostatic hypotension, gastroparesis, ED), mononeuropathy.
Macrovascular:
• Accelerated atherosclerosis → coronary artery disease (2-4× risk), stroke, peripheral arterial disease.
• Diabetic foot (neuropathy + ischaemia + infection → ulcer + gangrene → amputation).
Others: ↑ infections, cataracts, glaucoma, skin infections, NASH, cognitive decline.

1. Hyperthyroidism (Thyrotoxicosis):
Causes:
• Graves' disease (80 %) — autoimmune; TSH-receptor antibody (TRAb / TSI) stimulates thyroid.
• Toxic multinodular goitre.
• Toxic adenoma (hot nodule).
• Thyroiditis (painful subacute de Quervain's; painless post-partum).
• Factitious (L-thyroxine abuse).
• TSH-secreting pituitary adenoma (rare).
Clinical Features (↑ BMR + sympathetic):
• Weight loss despite ↑ appetite, heat intolerance, sweating.
• Palpitations, tachycardia, atrial fibrillation.
• Tremor, anxiety, insomnia, hyperreflexia.
• Warm moist skin, fine hair; diarrhoea; oligomenorrhoea.
• Graves' specific: diffuse goitre (bruit), exophthalmos (proptosis), lid lag, pretibial myxoedema.
Lab: ↓ TSH (suppressed), ↑ free T₃ + T₄; TRAb + in Graves'; radioactive iodine uptake — ↑ diffuse (Graves') / focal (adenoma).
Treatment: antithyroid drugs (carbimazole, methimazole, PTU — in pregnancy), radioactive iodine I-131, thyroidectomy. β-blockers for symptoms. Graves' orbitopathy — steroids.
Thyroid storm — life-threatening thyrotoxicosis crisis with fever, severe tachycardia, heart failure — emergency (PTU + β-blocker + steroid + Lugol's iodine).

2. Hypothyroidism:
Causes:
• Hashimoto's thyroiditis (commonest in iodine-sufficient regions) — autoimmune; anti-TPO + anti-Tg antibodies.
• Iodine deficiency (commonest globally).
• Post-thyroidectomy / radioiodine therapy.
• Drugs (amiodarone, lithium, ATD).
• Secondary (pituitary failure — ↓ TSH).
• Congenital (cretinism).
Clinical Features (↓ BMR):
• Weight gain despite poor appetite, cold intolerance, fatigue.
• Bradycardia, constipation, hoarse voice.
• Dry coarse skin, hair loss (lateral eyebrows), periorbital puffiness.
• Depression, slow thinking, memory loss.
• Menorrhagia; reduced libido; infertility.
• Myxoedema (severe hypothyroid) — non-pitting oedema, myxoedema coma (hypothermia + hypoglycaemia + coma).
• Cretinism (congenital) — dwarfism, mental retardation, umbilical hernia, protruding tongue.
Lab: ↑ TSH (primary), ↓ free T₄; anti-TPO + in Hashimoto's.
Treatment: lifelong levothyroxine (L-T₄) 1.6 µg/kg/day; monitor TSH.

3. Goitre:
Enlargement of thyroid; can occur with hyper, hypo, or euthyroid state.
Types:
• Simple (endemic) goitre — iodine deficiency; diffuse enlargement in most of population.
• Multinodular (toxic or non-toxic).
• Graves' (diffuse, soft, bruit).
• Hashimoto's (firm, diffuse).
• Solitary nodule (adenoma / carcinoma).
Complications of large goitre: tracheal compression (stridor), dysphagia (oesophageal compression), SVC obstruction, recurrent laryngeal nerve compression (hoarseness).

1. Epilepsy:
Definition: recurrent unprovoked seizures due to excessive synchronous cortical discharge.
Types (ILAE):
• Focal (partial) — one hemisphere; simple (awareness preserved) or complex (impaired awareness).
• Generalised — both hemispheres; tonic-clonic (grand mal), absence (petit mal), myoclonic, atonic.
• Status epilepticus — seizure > 5 min or repeated without recovery (emergency).
Pathophysiology: imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmission; abnormal Na⁺ / Ca²⁺ channel function; cortical "epileptogenic focus".
Causes: idiopathic, structural (tumour, trauma, stroke, AVM), metabolic (hypoglycaemia, hyponatraemia), infection (meningitis), drugs + withdrawal, febrile convulsions (children).
Drugs: Phenytoin, carbamazepine, valproate, lamotrigine, levetiracetam, topiramate (focal + generalised). Ethosuximide for absence. Diazepam / lorazepam for acute.

2. Parkinson's Disease (PD):
Definition: progressive neurodegenerative disorder; loss of dopaminergic neurons in substantia nigra pars compacta; basal ganglia dysfunction.
Pathology: Lewy bodies (α-synuclein aggregates) in remaining nigral neurons.
Cardinal features (TRAP):
• Tremor (resting, "pill-rolling", 4-6 Hz, unilateral).
• Rigidity (cogwheel, lead-pipe).
• Akinesia / bradykinesia (slow initiation; masked face; micrographia; shuffling gait).
• Postural instability (falls, stooped posture).
Other: depression, cognitive decline (dementia in advanced), constipation, autonomic dysfunction.
Drugs: Levodopa + carbidopa (cornerstone); dopamine agonists (pramipexole, ropinirole); MAO-B inhibitors (selegiline, rasagiline); COMT inhibitors (entacapone); amantadine (NMDA); anticholinergics (tremor).
Advanced: deep brain stimulation of subthalamic nucleus.

3. Stroke (Cerebrovascular Accident):
Definition: sudden neurological deficit from disturbed cerebral blood supply lasting > 24 h (if < 24 h = TIA).
Types:
• Ischaemic (80 %) — thrombotic (atherosclerosis in situ) or embolic (cardiac — AF, valve disease, endocarditis); middle cerebral artery most commonly affected.
• Haemorrhagic (20 %) — intracerebral (HTN, AVM, tumour) or subarachnoid (ruptured berry aneurysm).
Risk factors: HTN (biggest), age, smoking, DM, dyslipidaemia, AF, carotid stenosis, obesity, oral contraceptive.
Clinical features: sudden unilateral weakness (hemiplegia), facial droop, dysphasia, dysarthria, visual deficit, ataxia. Haemorrhagic often has headache + vomiting + ↓ consciousness.
FAST: Face drooping, Arm weakness, Speech difficulty, Time to call emergency.
Diagnosis: non-contrast CT (rule out bleed), MRI (better for ischaemia early).
Treatment (ischaemic): alteplase (tPA) within 4.5 h / thrombectomy within 6 h; long-term aspirin + clopidogrel + statin + BP control + treat AF (anticoagulation).
Haemorrhagic: BP control, reverse anticoagulation, surgical evacuation / coiling.

4. Alzheimer's Disease:
Definition: progressive neurodegenerative disease; commonest cause of dementia (60-70 %); late-onset (> 65 y).
Pathology:
• Extracellular amyloid (Aβ) plaques (β-amyloid from APP cleavage by β + γ secretase).
• Intracellular neurofibrillary tangles (hyperphosphorylated tau protein).
• Cortical + hippocampal atrophy.
• ↓ Acetylcholine (degeneration of basal nucleus of Meynert).
Risk factors: age, APOE-ε4 allele, Down syndrome (extra APP gene), family history, head injury, cardiovascular disease.
Clinical stages: mild (forgetfulness, word-finding difficulty) → moderate (disorientation, inability to perform daily tasks, personality change) → severe (non-verbal, incontinent, bedridden).
Hallmarks:
• Early — short-term memory loss (hippocampus affected first).
• Later — language, visuospatial, executive deficits.
• Sundowning, wandering, behavioural symptoms.
Diagnosis: clinical + MMSE / MoCA; MRI (hippocampal atrophy); CSF Aβ₄₂ ↓, tau ↑; PET amyloid scan.
Drugs: cholinesterase inhibitors (donepezil, rivastigmine, galantamine); memantine (NMDA antagonist) for moderate-severe.
Other: lecanemab, aducanumab (anti-amyloid antibodies — newer).

Types:
• Gastric ulcer (GU) — in stomach; older patients; pain worsens with food.
• Duodenal ulcer (DU) — commonest (~80 %); first part of duodenum; younger; pain relieved by food; 2-3 h post-meal.
Ulcers are ≥ 5 mm in diameter and reach submucosa (distinguishes from erosion).

Pathophysiology — Imbalance of Aggressive vs Defensive Factors:
Aggressive (↑ in PUD):
• Gastric acid (H⁺).
• Pepsin.
• H. pylori (urease-producing bacteria; damages mucus layer; induces inflammation).
• NSAIDs (↓ PG synthesis → ↓ mucus + HCO₃⁻; direct toxicity).
• Alcohol, smoking, stress.
• Zollinger-Ellison syndrome (gastrinoma → ↑↑ acid).
Defensive (↓ in PUD):
• Mucus layer.
• Bicarbonate.
• Mucosal blood flow.
• Prostaglandins (PGE₂, PGI₂).
• Epithelial renewal.
H. pylori — responsible for 90 % of DU and 70-80 % of GU. Mechanism: urease → NH₃ from urea → neutralises local acid → survives; damages mucus; produces CagA + VacA toxins; induces chronic gastritis.

Clinical Features:
• Epigastric pain — burning, gnawing.
• DU: 2-3 h post-meal, relieved by food / antacid, nocturnal (wakes patient 1-2 am).
• GU: worsened by food; weight loss.
• Nausea, bloating, heartburn.
• Haematemesis (coffee-ground vomiting), melaena if bleeding.
• Perforation — sudden severe pain, rigid abdomen, shock (surgical emergency).
• Gastric outlet obstruction — vomiting.
• Malignant transformation — only GU (not DU).

Diagnosis + Treatment (brief):
• Upper GI endoscopy (gold standard) + biopsy (especially GU — rule out cancer).
• H. pylori tests: urea breath test, stool antigen, CLO test on biopsy.
Treatment:
• PPIs (omeprazole, pantoprazole) 4-8 weeks.
• H. pylori triple therapy: PPI + clarithromycin + amoxicillin (or metronidazole) × 14 days.
• Stop NSAIDs; switch to selective COX-2 (celecoxib) + PPI cover.
• H₂ blockers (ranitidine, famotidine), sucralfate, misoprostol (PG analogue).
• Lifestyle: avoid alcohol, smoking, NSAIDs.

Jaundice — Classification:
1. Prehepatic (Haemolytic): excessive RBC breakdown → ↑ unconjugated bilirubin. Causes: haemolytic anaemia, malaria, G6PD, sickle cell, incompatible transfusion, HDN.
2. Hepatic (Hepatocellular): liver cell damage. Causes: viral hepatitis, drugs (paracetamol, INH), alcohol, cirrhosis, Wilson's, haemochromatosis, congenital — Gilbert's (mild ↓UGT), Crigler-Najjar (severe UGT deficiency), Dubin-Johnson (↓ MRP2).
3. Posthepatic (Obstructive): obstruction to bile flow → ↑ conjugated bilirubin. Causes: gallstones (commonest), pancreatic head carcinoma, cholangiocarcinoma, stricture, PBC, PSC.

Feature	Prehepatic	Hepatic	Posthepatic
Bilirubin	↑ unconj	↑ both	↑ conj
Urine bilirubin	Absent	+	++
Urobilinogen	↑↑	↑	↓ / absent
Stool	Dark	Normal / pale	Pale (clay)
ALT / AST	Normal	↑↑↑	Slight ↑
ALP	Normal	Slight ↑	↑↑↑
Itching	No	Mild	Severe

Viral Hepatitis (A-E):

Type	Virus	Transmission	Incubation	Chronicity
A (HAV)	ssRNA picorna	Faeco-oral (contaminated food/water)	15-45 d	Never chronic; self-limiting
B (HBV)	dsDNA hepadna	Parenteral, sexual, vertical	30-180 d	5-10 % adults; 90 % neonates
C (HCV)	ssRNA flavi	Parenteral (transfusion, IVDU)	14-160 d	80 % chronic → cirrhosis / HCC
D (HDV)	ssRNA delta	Parenteral; needs HBV (co- or super-infection)	Similar to HBV	Only with HBV
E (HEV)	ssRNA hepe	Faeco-oral (contaminated water)	15-60 d	Self-limiting; severe in pregnancy (20 % mortality)
F (uncertain)	Not well characterised	—	—	—

Clinical phases (common): Prodromal (malaise, anorexia, nausea) → Icteric (jaundice, dark urine, pale stool, tender hepatomegaly) → Recovery.
Serology (HBV): HBsAg (active); anti-HBs (immunity); HBeAg (replication); anti-HBc IgM (acute); anti-HBc IgG (past); HBV DNA (viraemia).
Complications: fulminant hepatitis (massive necrosis → ALF), cirrhosis, hepatocellular carcinoma.
Prevention: HAV + HBV vaccines; universal precautions; screening blood; safe sex.
Treatment: Mostly supportive; HCV — direct-acting antivirals (sofosbuvir + velpatasvir) — curative > 95 %; HBV — tenofovir, entecavir.

Alcoholic Liver Disease (ALD):
Spectrum of progressive damage:
1. Alcoholic fatty liver (steatosis) — reversible; ↑ TG deposition in hepatocytes; asymptomatic / mild hepatomegaly.
2. Alcoholic hepatitis — active inflammation; Mallory-Denk bodies; fever, jaundice, tender hepatomegaly; mortality 20-50 %.
3. Cirrhosis — irreversible fibrosis + regenerative nodules → portal hypertension (ascites, oesophageal varices, splenomegaly, hepatic encephalopathy), liver failure.
Lab: AST/ALT ratio > 2 (classic), GGT ↑, macrocytic anaemia (↓ folate), ↑ MCV, ↓ albumin, ↑ PT.
Treatment: absolute abstinence (only modifiable); nutrition (thiamine, folate); steroids in severe hepatitis; liver transplant in ESLD (must be abstinent 6 months).

1. Rheumatoid Arthritis (RA):
Definition: chronic, symmetrical, erosive autoimmune polyarthritis predominantly affecting small peripheral joints; female : male = 3:1; peak 30-50 y.
Pathogenesis:
• Genetic (HLA-DR4, DR1) + environmental (smoking) trigger.
• Autoantibodies — Rheumatoid factor (RF, anti-IgG IgM) + anti-CCP (more specific).
• Activation of CD4 T cells → cytokines (TNF-α, IL-1, IL-6) → synovial cell proliferation.
• Formation of pannus — inflammatory synovial tissue that erodes articular cartilage + bone.
• Osteoclast activation → bone erosion.
Clinical features:
• Symmetrical polyarthritis of small joints (PIP, MCP, wrist); classic sparing of DIP.
• Morning stiffness > 1 h.
• Swan-neck deformity, boutonnière, ulnar deviation at MCPs.
• Extra-articular: rheumatoid nodules, Sjögren's, anaemia, vasculitis, pulmonary fibrosis, pericarditis, Felty's syndrome (RA + splenomegaly + neutropaenia).
Lab: RF +, anti-CCP + (more specific), ↑ ESR/CRP, normochromic normocytic anaemia; X-ray — periarticular osteopenia, erosion, joint space narrowing.
Treatment: DMARDs (methotrexate first-line; sulfasalazine, hydroxychloroquine, leflunomide); biologicals (anti-TNF — infliximab, etanercept, adalimumab; anti-IL-6 — tocilizumab; anti-B-cell — rituximab); JAK inhibitors (tofacitinib); NSAIDs + steroids for symptom relief.

2. Osteoporosis:
Definition: metabolic bone disease with ↓ bone mass + disruption of micro-architecture → ↑ risk of fragility fractures.
DEXA T-score: Normal > −1; Osteopenia −1 to −2.5; Osteoporosis ≤ −2.5; Severe osteoporosis ≤ −2.5 with fracture.
Types:
• Type I (post-menopausal) — ↓ estrogen → ↑ osteoclast activity; vertebral crush + Colles' fractures.
• Type II (senile, > 70 y) — both sexes; hip + vertebral fractures.
• Secondary — Cushing's, hyperthyroidism, hyperparathyroidism, steroid use, immobilisation, malabsorption, CKD, hypogonadism.
Pathogenesis: imbalance in bone remodelling — resorption (osteoclasts) > formation (osteoblasts). Peak bone mass at 25-30 y, then loss (~0.5 %/year; 2-3 %/year in post-menopause first 5 y).
Clinical features: silent until fracture. Common fractures: vertebral (height loss, kyphosis — "dowager's hump"), hip (increased mortality), distal radius (Colles').
Diagnosis: DEXA scan; FRAX risk calculator; biochemical markers (osteocalcin, CTX).
Treatment: Calcium (1200 mg/d) + Vit D (800 IU/d). Bisphosphonates (alendronate, risedronate, zoledronate — inhibit osteoclast). Denosumab (anti-RANKL mAb). Teriparatide (recombinant PTH — stimulates bone formation). Raloxifene (SERM). HRT for post-menopausal symptoms. Weight-bearing exercise.

3. Gout:
Definition: inflammatory arthritis due to deposition of monosodium urate crystals in joints, from hyperuricaemia (> 7 mg/dL ♂, > 6 ♀).
Causes of hyperuricaemia:
Overproduction: HGPRT deficiency (Lesch-Nyhan); ↑ PRPP synthase; chemotherapy (tumour lysis); high-purine diet (red meat, organ meat, seafood, beer).
Under-excretion: CKD, diuretics (thiazide), low-dose aspirin, alcohol, acidosis.
Clinical features:
• Acute — sudden excruciating monoarthritis (classically 1st MTP — podagra); often at night; precipitated by alcohol, meat, surgery, trauma.
• Chronic — tophi (urate deposits in ear, tendons, joints); erosive arthropathy.
• Uric acid nephrolithiasis + urate nephropathy.
Diagnosis: joint fluid aspirate — negatively birefringent needle-shaped urate crystals under polarised light (gold standard); ↑ serum uric acid (may be normal in acute attack); X-ray "punched out" erosions.
Treatment:
• Acute: NSAIDs (indomethacin), colchicine, glucocorticoids.
• Prophylaxis: xanthine oxidase inhibitors — allopurinol, febuxostat (↓ uric acid production); uricosurics — probenecid (↑ excretion); pegloticase / rasburicase (uricase enzyme, severe).
• Lifestyle: avoid alcohol + high-purine foods; hydrate; weight loss.

Definition:
Cancer (malignant neoplasm) — uncontrolled, invasive + metastatic growth of cells.
Neoplasm = "new growth" — can be benign or malignant.
Tumour = swelling; common synonym for neoplasm.

Classification:
A. Based on behaviour:
• Benign — slow, localised, encapsulated, well-differentiated, not invasive/metastatic; suffix "-oma" (adenoma, fibroma).
• Malignant — rapid, invasive, poorly differentiated, metastasises.
B. Based on tissue of origin:
• Carcinoma — from epithelium (80-90 %). Subtypes: squamous cell, adeno-, basal cell, transitional.
• Sarcoma — from mesenchyme (bone, muscle, fat, blood vessels). Osteosarcoma, liposarcoma, leiomyosarcoma.
• Leukaemia — haematopoietic; ALL, AML, CLL, CML.
• Lymphoma — lymphoid; Hodgkin's + Non-Hodgkin's.
• Myeloma — plasma cells.
• Melanoma — melanocytes.
• Mixed / blastoma (embryonal — retinoblastoma, nephroblastoma).
C. Grading: degree of differentiation (G1 well → G4 undifferentiated).
D. Staging (TNM): T = Tumour size, N = lymph Node, M = Metastasis; stages I-IV.

Etiology (Carcinogens):
1. Chemical:
• Tobacco (lung, oral, bladder) — 30 % of cancers.
• Alcohol (oral, oesophageal, liver).
• Aflatoxin B₁ (fungal — liver cancer).
• Asbestos (mesothelioma, lung).
• Aniline dyes (bladder).
• Benzene (leukaemia).
• Vinyl chloride (liver angiosarcoma).
2. Physical:
• Radiation — UV (skin — BCC, SCC, melanoma); ionising (thyroid, leukaemia).
• Chronic irritation (Marjolin's ulcer — SCC in chronic scar).
3. Biological (viruses + microbes):
• HPV — cervical, anal, oropharyngeal.
• HBV + HCV — hepatocellular carcinoma.
• EBV — Burkitt's lymphoma, nasopharyngeal Ca.
• HTLV-1 — T-cell leukaemia.
• H. pylori — gastric cancer + MALT lymphoma.
• HHV-8 — Kaposi's sarcoma.
4. Genetic:
• Oncogenes (activated) — RAS, MYC, HER2/neu.
• Tumour suppressor genes (inactivated) — p53, RB1, BRCA1/2, APC.
• DNA repair gene defects — Lynch syndrome, Xeroderma pigmentosum.
• Familial cancers — familial adenomatous polyposis (APC), retinoblastoma (RB1), BRCA breast/ovarian.
5. Hormonal: Estrogen (breast, endometrial); testosterone (prostate).
6. Diet + Lifestyle: high fat (colon); low fibre; obesity; processed meats.

Pathogenesis (Multi-step Carcinogenesis):
Cancer arises through accumulation of mutations (typically 5-10) over years:
1. Initiation — non-lethal DNA damage (mutation in a normal cell) by a carcinogen.
2. Promotion — proliferation of initiated cells driven by promoters (hormones, growth factors).
3. Progression — accumulation of further mutations → genetic instability → autonomous growth + invasion.
Hanahan-Weinberg Hallmarks of Cancer (8):
1. Self-sufficiency in growth signals (oncogenes).
2. Insensitivity to anti-growth signals (tumour suppressors).
3. Evasion of apoptosis (p53 loss, BCL-2).
4. Limitless replicative potential (telomerase).
5. Sustained angiogenesis (VEGF).
6. Tissue invasion + metastasis (↓ E-cadherin, ↑ MMPs).
7. Reprogramming of energy metabolism (Warburg effect — aerobic glycolysis).
8. Evasion of immune destruction (PD-L1).
Metastasis: detachment → invasion of basement membrane (MMP) → entry into vessel (intravasation) → survival in circulation → extravasation → colonisation of distant organ. Common metastasis sites: lung, liver, bone, brain.

1. Tuberculosis (TB):
Causative agent: Mycobacterium tuberculosis — aerobic, acid-fast bacillus; slow-growing (doubling 18 h).
Transmission: aerosol droplets (cough).
Pathogenesis:
• Inhaled bacilli → phagocytosed by alveolar macrophages.
• Bacilli replicate inside macrophage (evades killing due to cell wall lipids — mycolic acid).
• T-cell-mediated immunity → granuloma formation (epithelioid cells + Langhans giant cells + caseating necrosis).
• Primary complex (Ghon focus + hilar LN = Ghon complex) usually heals.
• Latent TB — dormant bacilli persist; 5-10 % lifetime reactivation risk.
• Active TB — post-primary (reactivation); commonly in apex of lung (high O₂).
Clinical features: chronic cough > 3 weeks, haemoptysis, fever (evening, low-grade), night sweats, weight loss, fatigue.
Extra-pulmonary: TB meningitis, bone/spine (Pott's disease), lymph node (scrofula), GU, abdominal, miliary TB.
Diagnosis: sputum AFB microscopy (Ziehl-Neelsen stain), culture (Löwenstein-Jensen medium — 6 weeks), GeneXpert (MTB/RIF PCR), CXR (apical cavitation), Mantoux (tuberculin) skin test, IGRA.
Treatment (DOTS):
• Intensive phase: HRZE — Isoniazid + Rifampicin + Pyrazinamide + Ethambutol × 2 months.
• Continuation phase: HR × 4 months.
• MDR-TB (INH + RIF resistant) — prolonged (18-24 m) with second-line (fluoroquinolones, bedaquiline, linezolid).
• Prevention: BCG vaccine (neonatal).

2. Typhoid Fever (Enteric Fever):
Causative agent: Salmonella typhi (and paratyphi A, B, C) — Gram-negative bacillus.
Transmission: faeco-oral; contaminated food/water; humans are only reservoir.
Pathogenesis:
• Ingested bacilli → small intestine (Peyer's patches) → invade M cells → mesenteric LN → multiply.
• Bacteraemia (1st week) → systemic seeding — liver, spleen, bone marrow, gallbladder.
• Secondary bacteraemia (2nd week) → sustained fever + rose spots.
• Intestinal ulceration (3rd week) at Peyer's patches → bleeding, perforation.
Clinical features (staircase / step-ladder pattern):
• Week 1: gradually rising fever (step-ladder), headache, malaise, constipation (later diarrhoea).
• Week 2: high continuous fever, rose spots (blanching rash on trunk), splenomegaly, hepatomegaly, relative bradycardia, coated tongue.
• Week 3: complications — intestinal haemorrhage, perforation (life-threatening), pneumonia, encephalopathy.
• Week 4: recovery (if untreated) or death.
Carriers: chronic faecal + urinary carriers; gallstones harbour bacilli.
Diagnosis: blood culture (gold standard) in week 1; stool + urine culture week 2-3; Widal test (serology); bone marrow culture most sensitive.
Treatment: Ceftriaxone (IV) or azithromycin (PO); fluoroquinolones (resistance emerging); supportive.
Prevention: typhoid vaccine (Ty21a oral, Vi polysaccharide IM); safe water + food; sanitation.

3. Leprosy (Hansen's Disease):
Causative agent: Mycobacterium leprae — obligate intracellular acid-fast bacillus; cannot be cultured in vitro; grown in armadillo / mouse footpad.
Transmission: prolonged close contact (respiratory droplets + nasal secretions); very low contagiousness.
Incubation: 2-5 years (range 6 months - 20 y).
Clinical spectrum (Ridley-Jopling):
• Tuberculoid (TT) — strong cell-mediated immunity; few hypopigmented anaesthetic skin patches; thickened peripheral nerves; few bacilli (paucibacillary).
• Lepromatous (LL) — poor immunity; multiple symmetric skin nodules + plaques (leonine facies, madarosis — eyebrow loss); nasal collapse; many bacilli (multibacillary).
• Borderline forms (BT, BB, BL) between extremes.
Nerve involvement: peripheral nerves (ulnar, peroneal) thickened + tender; anaesthesia; motor weakness (claw hand, foot drop); trophic ulcers.
Diagnosis: skin smear for AFB (slit-skin smear); biopsy of skin / nerve; clinical (any one of — hypopigmented anaesthetic patch, thickened nerve, AFB positive).
Treatment (WHO Multi-Drug Therapy — MDT):
• Paucibacillary: Rifampicin + Dapsone × 6 months.
• Multibacillary: Rifampicin + Dapsone + Clofazimine × 12 months.
• Reactions: Type 1 (reversal, upgrading — steroid); Type 2 (ENL — thalidomide + steroid).

1. AIDS (Acquired Immunodeficiency Syndrome):
Cause: HIV — ssRNA retrovirus; HIV-1 (global), HIV-2 (West Africa).
Transmission: sexual (unprotected), parenteral (needles, transfusion), perinatal (mother-child — vaginal delivery + breast-milk).
Pathogenesis:
• Virus binds CD4 + co-receptors CCR5 / CXCR4 on T-helper cells, macrophages, dendritic cells.
• Reverse transcriptase converts RNA → DNA.
• Integrase inserts DNA into host genome (provirus).
• Viral replication → lysis of CD4+ T cells.
• Progressive ↓ CD4 count → immunodeficiency → opportunistic infections + malignancies.
Clinical stages:
1. Acute retroviral syndrome (2-4 weeks post-infection) — flu-like illness; very high viraemia.
2. Clinical latency (median 8-10 years) — asymptomatic; gradual ↓ CD4.
3. AIDS — CD4 < 200 /µL or AIDS-defining illness. Opportunistic infections: Pneumocystis jirovecii pneumonia, TB, toxoplasmosis, cryptococcal meningitis, CMV retinitis, candida oesophagitis. Malignancies: Kaposi's sarcoma (HHV-8), Non-Hodgkin's lymphoma, cervical Ca (HPV).
Diagnosis: ELISA (screening — 4th generation detects p24 antigen + antibodies); confirmatory Western blot; CD4 count; viral load (PCR).
Treatment: Antiretroviral Therapy (ART) — combination of 3 drugs from 4 classes: NRTI (zidovudine, tenofovir), NNRTI (efavirenz), protease inhibitor (lopinavir), integrase inhibitor (dolutegravir), entry inhibitors (enfuvirtide).
Modern first-line: Tenofovir + Lamivudine + Dolutegravir.
Prevention: condom, PrEP (tenofovir + emtricitabine), PEP, safe blood, antenatal screening, needle exchange.

2. Syphilis:
Cause: Treponema pallidum — spirochete (spiral); not visible by light microscopy; dark-field.
Transmission: sexual contact; transplacental (congenital syphilis).
Stages:
• Primary (3-90 d after exposure) — painless chancre (genital ulcer with indurated base, clean) + regional lymphadenopathy; heals in 3-6 weeks.
• Secondary (6 weeks - 6 months) — systemic: maculopapular rash (palms + soles), condyloma lata, lymphadenopathy, fever, sore throat, weight loss, mucous patches, patchy alopecia.
• Latent — asymptomatic but serology positive (early < 1 y; late > 1 y).
• Tertiary (years later, ~30 %) — gummas (soft granuloma), cardiovascular (aortic aneurysm, aortitis), neurosyphilis (tabes dorsalis — ataxia + loss of proprioception, general paresis — dementia), Argyll-Robertson pupil (accommodates but doesn't react to light).
• Congenital syphilis — stillbirth, frontal bossing, saddle nose, Hutchinson's teeth, interstitial keratitis, deafness.
Diagnosis:
• Non-treponemal (screen): VDRL, RPR — detects cardiolipin antibodies; sensitive but not specific (false + in SLE, pregnancy).
• Treponemal (confirm): FTA-ABS, TPHA — specific.
• Dark-field microscopy of chancre — live spirochetes.
Treatment: Benzathine penicillin G 2.4 M units IM single dose (primary/secondary/early latent); 3 doses weekly for late latent / tertiary. Doxycycline if penicillin-allergic.
Jarisch-Herxheimer reaction — flu-like reaction within 24 h of first dose due to release of endotoxin from dying spirochetes.

3. Gonorrhoea:
Cause: Neisseria gonorrhoeae — Gram-negative intracellular diplococcus ("kidney-bean shaped" within neutrophils).
Transmission: sexual contact; neonatal (ophthalmia neonatorum — at birth through infected birth canal).
Clinical features:
• Males: urethritis (purulent discharge, dysuria; 2-7 day incubation); epididymitis; prostatitis.
• Females: often asymptomatic; endocervicitis with discharge; can ascend to PID, salpingitis → infertility, ectopic pregnancy, tubo-ovarian abscess, Fitz-Hugh-Curtis syndrome (perihepatitis).
• Pharyngeal + rectal: depending on sexual practice.
• Disseminated gonococcal infection — fever, skin rash, tenosynovitis, septic arthritis.
• Ophthalmia neonatorum — neonatal conjunctivitis (48-72 h after birth) → blindness if untreated.
Diagnosis: Gram stain of discharge (Gram-negative intracellular diplococci in neutrophils); culture on Thayer-Martin medium; NAAT (PCR — most sensitive).
Treatment:
• Current: Ceftriaxone 500 mg IM + Azithromycin 1 g PO (dual therapy to combat resistance + cover Chlamydia co-infection).
• Ophthalmia prophylaxis: erythromycin eye drops at birth.
• Contact tracing + partner treatment essential.

Inflammatory Bowel Disease (IBD):
Chronic relapsing immune-mediated inflammation of GI tract. Two main types:

Feature	Crohn's disease	Ulcerative colitis
Location	Anywhere mouth-anus; terminal ileum most common	Colon + rectum only; continuous from rectum
Depth	Transmural	Mucosal + submucosal
Pattern	Skip lesions	Continuous
Histology	Non-caseating granulomas	Crypt abscesses
Smoking	Worsens	Protective
Fistulae/strictures	Common	Rare
Cancer risk	Some	Higher

Rx: 5-ASA (mesalamine — UC), steroids, immunomodulators (azathioprine), biologicals (infliximab, adalimumab — anti-TNF), surgery.

Meningitis:
Types:
• Bacterial — emergency. Adults: S. pneumoniae, N. meningitidis. Neonates: GBS, E. coli, Listeria. Children: H. influenzae (if unvaccinated).
• Viral (aseptic) — enteroviruses (most common), HSV, mumps.
• Fungal — cryptococcus (in HIV).
• TB — chronic; basal meningitis.
Triad: fever + headache + neck stiffness. Also: photophobia, vomiting, altered mental state, Kernig + Brudzinski signs, petechial rash in meningococcal.
Diagnosis: lumbar puncture CSF — bacterial (↑↑ neutrophils, ↓ glucose, ↑↑ protein); viral (lymphocytes, normal glucose, mildly ↑ protein); TB (lymphocytes, ↓↓ glucose, ↑↑ protein + cobweb).
Rx: empirical ceftriaxone + vancomycin ± ampicillin (Listeria cover); dexamethasone to reduce neuro-sequelae; acyclovir (HSV); amphotericin (crypto).

Urinary Tract Infection (UTI):
Classification:
• Lower — cystitis (bladder), urethritis.
• Upper — pyelonephritis (kidney).
Causative agents: E. coli (> 80 %), Klebsiella, Proteus, Enterococcus, S. saprophyticus (young women), Pseudomonas (catheter-associated).
Risk factors: female (short urethra), sexual activity, pregnancy, catheter, diabetes, stones, BPH, VUR.
Clinical features:
• Cystitis: dysuria, frequency, urgency, suprapubic pain, haematuria.
• Pyelonephritis: fever, flank pain, nausea, costovertebral angle tenderness.
Diagnosis: urine dipstick (leucocyte esterase + nitrites); microscopy (pus cells, RBC); culture (> 10⁵ CFU/mL = significant).
Treatment: nitrofurantoin / fosfomycin / TMP-SMX (uncomplicated cystitis); fluoroquinolones + ceftriaxone for pyelonephritis; treat underlying cause.