Systemic Pathology SAQsMaster Revision Vault

a) Hypertensive heart disease

(i) Gross morphology: concentric left-ventricular hypertrophy; increased heart weight (often >500 g); LV free-wall thickness >1.5–2 cm; reduced chamber size early, dilatation late; left atrial enlargement.

(ii) Microscopic: myocyte hypertrophy with enlarged rectangular "box-car" nuclei; increased cell diameter; interstitial and perivascular fibrosis.

(iii) Chronic complications: congestive cardiac failure; arrhythmias/atrial fibrillation; ischaemic heart disease; sudden cardiac death.

b) Four causes of dysphagia: oesophageal carcinoma; peptic strictures; achalasia; oesophageal webs/rings (or extrinsic compression / GERD).

c) Oesophageal carcinoma

(i) Predisposing factors: tobacco smoking; alcohol; very hot beverages / dietary nitrosamines (Barrett's oesophagus/GERD for adenocarcinoma).

(ii) Macroscopic: polypoid/fungating, ulcerating or diffusely infiltrating mass; SCC mid-oesophagus, adenocarcinoma lower third. Microscopic: SCC — nests of malignant squamous cells with keratin pearls and intercellular bridges; adenocarcinoma — malignant glands with mucin.

a) Pathogenesis: sequela of rheumatic fever following pancarditis from Group A β-haemolytic streptococcal infection. Cross-reactive immune response between host and streptococcal antigens (antigenic mimicry) → autoimmunity → destruction of endocardium at valves (esp. mitral) → valvular heart disease.

b) Morphology: Aschoff bodies with Anitschkow cells; "bread-and-butter" pericarditis; fibrin vegetations on valves (verrucae); MacCallum's plaques on the left atrium; sub-endocardial thickening with wrinkling of the posterior wall.

c) Complications: chronic disease is dominated by mitral stenosis → left atrial enlargement → atrial fibrillation → mural thrombus and systemic thromboembolism (e.g. stroke); pulmonary venous congestion and pulmonary hypertension → right-sided and congestive cardiac failure; infective endocarditis on the deformed valves; recurrent rheumatic activity; sudden cardiac death. (Aortic involvement may add left-ventricular hypertrophy, angina and syncope.)

1. Hypoplastic left heart syndrome — underdeveloped left heart affecting mitral valve, left ventricle and aorta
2. Tetralogy of Fallot — VSD, pulmonary stenosis, overriding aorta, right-ventricular hypertrophy
3. Transposition of the great arteries — aorta and pulmonary artery switched
4. Tricuspid atresia — undeveloped tricuspid valve impairing flow between RA and RV
5. Total anomalous pulmonary venous connection — pulmonary veins not connected to the left atrium

a) Inflammation of the peritoneum due to infection with M. tuberculosis, usually from spread of the pathogen (e.g. haematogenous, lymphatic).

b) Clinical features: colicky abdominal pain; ascites; fever; weight loss; night sweats; general malaise.

Morphological variants: wet (ascitic) type, with exudative ascites; dry (plastic/adhesive/fibrous) type, with caseating granulomas, adhesions and matting of viscera; encysted (loculated) type, with localised fluid collections.

Note: autoimmune gastritis targets the body/fundus oxyntic mucosa, destroying parietal cells, so it causes achlorhydria and loss of intrinsic factor. It does NOT cause acid-related ulcers or heartburn (the original card described peptic ulcer disease). The correct features follow.

1. Fatigue and pallor: pernicious (megaloblastic) anaemia. Anti-parietal-cell and anti-intrinsic-factor antibodies → loss of intrinsic factor → vitamin B12 malabsorption in the terminal ileum.

2. Neurological symptoms (paraesthesiae, sensory ataxia, subacute combined degeneration): B12 deficiency damages the dorsal columns and lateral corticospinal tracts.

3. Atrophic glossitis (smooth, sore, beefy-red tongue): epithelial effect of B12 deficiency.

4. Achlorhydria with hypergastrinaemia: parietal-cell loss removes acid feedback → G-cell and ECL-cell hyperplasia, predisposing to gastric neuroendocrine (carcinoid) tumours and an increased risk of gastric adenocarcinoma.

1) WHO histological classification: tubular; papillary; mucinous; poorly-cohesive (including signet-ring cell) carcinoma; mixed. (Lauren classification divides it into intestinal and diffuse types.)

2) Aetiology of the main classes: Intestinal type — chronic H. pylori gastritis progressing through atrophic gastritis → intestinal metaplasia → dysplasia; diet high in nitrates/smoked/salted foods. Diffuse type — CDH1 (E-cadherin) mutation; weaker environmental link.

3) Gross, early vs advanced: Early gastric cancer — carcinoma confined to mucosa/submucosa (irrespective of nodal status); protruding, superficial or excavated. Advanced — extends beyond the submucosa into muscularis and beyond; fungating/polypoid, ulcerating or infiltrating (Borrmann types); diffuse infiltration produces the rigid "linitis plastica" (leather-bottle) stomach.

Dr Okemwa's marking scheme (Anatomic Pathology) — excerpts:

1a(i) Etiology: primary/idiopathic, genetic (APOL1 risk variants), or secondary/acquired (HIV-associated, heroin, obesity, sickle cell, reduced nephron mass; hypertension is a weaker adaptive cause). 1a(ii) Morphology: based on renal biopsy — cellular variant and collapsing variant.

1b(i) Direct immunofluorescence for membranous GN: granular subepithelial IgG and C3 along the capillary loops (PLA2R-positive in primary membranous). 1b(iii) Proteomics for renal amyloidosis: laser microdissection with mass spectrometry to type the amyloid protein (AL, AA or ATTR); Congo red is the confirmatory stain, not proteomics.

1b(ii) Indirect immunofluorescence for crescentic glomerulonephritis: patient serum is layered onto a substrate and bound antibody detected with a fluorescent anti-human immunoglobulin; it identifies circulating autoantibodies - anti-GBM antibodies (linear pattern) or ANCA (pauci-immune) - and so helps classify the crescentic (rapidly progressive) GN.

1c) Ulcerative colitis versus Crohn disease

Three similarities: both are chronic idiopathic inflammatory bowel diseases; both present with bloody diarrhoea and abdominal pain and follow a relapsing-remitting course; both carry extra-intestinal manifestations (arthritis, uveitis, skin lesions) and an increased colorectal cancer risk.

1d) Colonic adenocarcinoma - morphologic and molecular sequence: the classic adenoma-carcinoma sequence. Morphologically: normal mucosa → aberrant crypt foci → adenomatous polyp (tubular → tubulovillous → villous) with increasing dysplasia → invasive adenocarcinoma. Molecularly: APC loss (initiation) → KRAS mutation → loss of 18q (SMAD) → TP53 loss, driving progression to carcinoma. (The microsatellite-instability / mismatch-repair pathway is an alternative route.)

Note: the original card carried only Dr Okemwa's excerpts for 1a and part of 1b; parts 1b(ii), 1c and 1d have been added here as worked model answers - verify against Robbins.

Causes of dysphagia: mechanical — carcinoma, peptic strictures, webs/rings, extrinsic compression; motility — achalasia, scleroderma, diffuse oesophageal spasm.

Malabsorption syndrome: impaired absorption of nutrients across the small-bowel mucosa; causes — coeliac disease, tropical sprue, Whipple's disease, chronic pancreatitis, Crohn's; features — steatorrhoea, weight loss, deficiency states.

Classification of polyps (2 examples each): non-neoplastic — hyperplastic (hyperplastic, inflammatory), hamartomatous (juvenile, Peutz–Jeghers); neoplastic — adenomatous (tubular, villous adenoma).

Oesophageal carcinoma: risk factors — smoking, alcohol, hot drinks, Barrett's oesophagus; complications — obstruction, tracheo-oesophageal fistula, haemorrhage, aspiration, metastasis.

Two pathways of colorectal cancer: (1) APC/β-catenin adenoma–carcinoma sequence (chromosomal-instability pathway); (2) microsatellite-instability pathway (DNA mismatch-repair defect / Lynch syndrome).

a) Causes: H. pylori infection; NSAIDs; gastric hyperacidity (e.g. Zollinger–Ellison syndrome); smoking; stress.

b) Location: first part of the duodenum (commonest); lesser curvature of the gastric antrum.

c) Gross morphology: small (usually <2 cm), round-to-oval, sharply "punched-out" defect with a clean base and smooth, non-heaped (regular) margins — in contrast to the heaped-up, irregular edges of malignant ulcers.

d) Complications: haemorrhage; perforation; penetration into adjacent organs; obstruction (pyloric stenosis); rare malignant transformation (gastric ulcers).

Definition: a breach in the mucosa of the alimentary tract extending through the mucosa into the submucosa.

Mucosal defence (pre-epithelial barrier): a mucus–bicarbonate layer. Surface foveolar cells secrete mucin forming an "unstirred" protective layer that prevents direct contact of food particles and impedes diffusion of ions and pepsin. Surface epithelial cells secrete bicarbonate into the mucus, buffering luminal H⁺ and creating a pH gradient (≈1–2 at the luminal surface rising to 6–7 at the epithelial surface).

Sites: duodenal ulcer — first part of the duodenum (anterior > posterior); gastric ulcer — lesser curvature at the body/antrum border.

Clinical presentation: epigastric gnawing/burning pain, worse at night and 1–3 hours after meals; nausea, vomiting, bloating, belching, weight loss; referred back pain. Complications: haemorrhage; perforation; obstruction (oedema/scarring) with cramps, intractable vomiting or pain.

Gastroduodenal artery is the source of bleeding in duodenal ulcer; left gastric artery in gastric ulcer. Urea breath test confirms eradication of H. pylori.

A. Colon adenomas

(i) Classification (WHO, by architecture):

• Tubular adenoma — >75% tubular glands; usually small and pedunculated (commonest)
• Villous adenoma — >50% villous/finger-like fronds; usually large and sessile; highest malignant potential
• Tubulovillous adenoma — mixed (25–75% villous)
• (Serrated group: sessile serrated lesion, traditional serrated adenoma). Graded by dysplasia: low- vs high-grade.)

(ii) Risk factors for malignant transformation: large size (>1–4 cm); villous architecture; high-grade dysplasia. (Also multiplicity, sessile shape.)

(iii) Familial polyposis syndromes: Familial adenomatous polyposis (FAP, APC mutation); Gardner syndrome (FAP variant). (Turcot syndrome also acceptable.)

(iv) Clinical features: often asymptomatic (found on screening); rectal bleeding / occult blood → iron-deficiency anaemia; change in bowel habit; mucous diarrhoea (villous adenoma → secretory losses, hypokalaemia); abdominal pain or obstruction if large.

B. Carcinoma of the cervix

(i) Control — screening & vaccination: screening detects and treats pre-invasive lesions (CIN) before invasion — Pap (cervical cytology), HPV DNA testing, and VIA (visual inspection with acetic acid) in low-resource settings; treat CIN with cryotherapy/LEEP. Vaccination against high-risk HPV (bivalent/quadrivalent/nonavalent covering types 16 & 18) given to girls ~9–14 yr before sexual debut.

(ii) Aetiology: persistent high-risk HPV infection (types 16 & 18 most important). Cofactors: multiple sexual partners, early coitarche, smoking, immunosuppression (HIV), high parity, other STIs.

(iii) Pathogenesis: HPV infects immature squamous/metaplastic cells of the transformation zone → viral integration → E6 oncoprotein degrades p53 and E7 inactivates Rb → loss of cell-cycle control, resistance to apoptosis, genomic instability → progressive dysplasia (CIN 1 → 2 → 3 / carcinoma in situ) → invasive squamous cell carcinoma once the basement membrane is breached.

(iv) Complications: vaginal haemorrhage; fistulae (vesicovaginal, rectovaginal); ureteric obstruction → hydronephrosis → renal failure/uraemia (common cause of death); direct spread to bladder/rectum/pelvic wall; lymphatic and haematogenous metastasis; recurrent infection.

(v) Clinical presentation (added; asked as a subheading in EOY 2016/17): often asymptomatic early or detected on screening; post-coital bleeding; intermenstrual or postmenopausal bleeding; blood-stained or foul-smelling vaginal discharge; later, pelvic or lower-back pain, urinary or bowel symptoms and leg oedema from local invasion, and features of distant metastasis.

(a) Coeliac sprue (gluten-sensitive enteropathy)

Pathogenesis: immune-mediated enteropathy triggered by gliadin (from gluten in wheat/barley/rye) in genetically predisposed individuals (HLA-DQ2/DQ8). Gliadin is deamidated by tissue transglutaminase (tTG) → presented to CD4+ T cells → Th1 response (IFN-γ) and CD8+ intraepithelial-lymphocyte-mediated epithelial injury; B-cell response produces anti-tTG, anti-endomysial and anti-gliadin antibodies. Net effect → villous atrophy and malabsorption.

Clinical features: chronic diarrhoea, steatorrhoea, bloating, weight loss, failure to thrive (children); malabsorption sequelae — iron/folate deficiency anaemia, osteopenia, bleeding (vit K); dermatitis herpetiformis (itchy vesicular rash). Adults may be silent/atypical.

Morphologic features (duodenal/proximal jejunal biopsy): villous atrophy (blunting/flattening), crypt hyperplasia, increased intraepithelial lymphocytes (>25/100 enterocytes), lamina-propria plasma-cell and lymphocyte infiltrate (Marsh grading). Reverses on a gluten-free diet.

(b) Rheumatic heart disease

(i) Pathogenesis: a sequela of rheumatic fever — an immune-mediated (type II hypersensitivity) reaction ~2–3 weeks after Group A β-haemolytic streptococcal pharyngitis. Molecular mimicry: antibodies and CD4+ T cells against streptococcal M protein cross-react with cardiac antigens (myosin, valve glycoproteins) → pancarditis.

(ii) Gross morphology: acute — small verrucae (vegetations) along valve closure lines; MacCallum plaques in the left atrium. Chronic — leaflet thickening, commissural fusion, shortened/fused chordae tendineae giving "fish-mouth"/"buttonhole" mitral stenosis; mitral valve most affected, then aortic. Microscopy: Aschoff bodies with Anitschkow ("caterpillar") cells.

(iii) Complications: valvular stenosis/regurgitation (esp. mitral stenosis) → left atrial enlargement, atrial fibrillation, mural thrombi and systemic embolism; congestive cardiac failure and pulmonary hypertension; infective endocarditis on deformed valves; sudden cardiac death.

a) Risk factors — Hereditary: family history of pancreatic cancer; hereditary breast/ovarian cancer (BRCA2 families). Non-hereditary: cigarette smoking; high-fat diet.

b) Pancreatic carcinoma — Gross: poorly circumscribed, grey-white firm masses; dense stromal fibrosis. Histology: perineural and angiolymphatic invasion; aggressive deeply infiltrating cell clusters.

c) Tumour markers: CA 19-9; CEA.

d) Alcoholic hepatitis: Mallory–Denk bodies; hepatocyte ballooning; neutrophilic infiltration; focal hepatocyte necrosis; fatty change.

1) Causes: gallstones and alcohol (commonest); also hypertriglyceridaemia; hypercalcaemia; trauma / post-ERCP; drugs; mumps and other infections; ischaemia.

2) Gross: oedematous, swollen pancreas; grey-white areas of parenchymal necrosis; chalky-white foci of fat necrosis (saponification); haemorrhage. Microscopic: enzymatic (proteolytic) necrosis of acinar parenchyma; fat necrosis with calcium (basophilic) deposits; acute neutrophilic inflammatory infiltrate; vascular thrombosis and haemorrhage.

3) Complications: pancreatic pseudocyst; abscess; ARDS; DIC; shock; hypocalcaemia; progression to chronic pancreatitis; diabetes mellitus.

i) Clinical: insidious progressive dyspnoea; cough and wheeze; significant weight loss; hyperventilation with reduced FEV1/FVC; recurrent infections.

ii) Classification: centriacinar (proximal acinus/respiratory bronchioles affected, distal spared); panacinar (uniform enlargement from respiratory bronchioles to alveoli); paraseptal (distal acinus involved, centre normal); paracicatricial (irregular, associated with scarring).

iii) Gross: pale voluminous lungs obscuring the heart (panacinar); deep-pink less-voluminous lungs (centriacinar); enlarged cystic air spaces forming bullae (paraseptal).

iv) Microscopic: dilation of air spaces and destruction of septal walls in the involved acinus.

a) Clinical presentation: chronic productive cough (± haemoptysis); low-grade fever and night sweats; weight loss; malaise.

b) Gross features: apical (upper-lobe) cavitary lesions; caseous necrosis; surrounding fibrosis and calcification; cavitation from liquefied caseous material.

c) Histological morphology: caseating granulomas — a central zone of caseous necrosis surrounded by epithelioid histiocytes, Langhans multinucleate giant cells and a rim of lymphocytes.

(a)(i) Definition: an occupational disease is a chronic ailment/pathological condition arising from exposure to hazards or risk factors in the workplace or occupational environment.

(ii) Categories + examples:

• Occupational lung disease (pneumoconioses) — silicosis (silica), asbestosis (asbestos), coal-worker's pneumoconiosis
• Occupational cancers — mesothelioma (asbestos), bladder cancer (aniline dyes), leukaemia (benzene)
• Occupational skin disease — contact dermatitis (chemicals)
• Occupational infections / poisoning — hepatitis B (health workers), lead poisoning (battery workers)

(iii) Contributing factors + examples: chemical agents (solvents, lead, mercury); physical agents (noise → deafness, radiation, vibration, heat); biological agents (TB, HBV in health workers); ergonomic/mechanical (repetitive strain, poor posture); host factors (age, pre-existing disease, lack of protective equipment).

(iv) Causes of environmental disease + examples: air pollution (particulate matter/smog, tobacco smoke → respiratory disease); water/soil chemical contamination (lead, arsenic, industrial effluent).

(b)(i) Definition: pneumonia is inflammation of the lung parenchyma (alveoli/interstitium), usually infective (bacterial, viral, fungal), producing consolidation.

(ii) Clinical features: fever/chills, productive cough (purulent/rusty sputum), pleuritic chest pain, dyspnoea/tachypnoea, tachycardia; signs of consolidation (dullness to percussion, bronchial breathing, crepitations); cyanosis if severe.

(iii) Pathologic stages (lobar pneumonia):

Types of chronic obstructive airway disease: chronic bronchitis; emphysema; bronchial asthma; bronchiectasis; (small-airway disease / bronchiolitis).

Bronchiectasis

Causes: bronchial obstruction (tumour, foreign body, mucus plugging); severe or recurrent infection (childhood measles, pertussis, TB, necrotising pneumonia); congenital / hereditary (cystic fibrosis, primary ciliary dyskinesia / Kartagener syndrome, immunodeficiency); allergic bronchopulmonary aspergillosis; connective-tissue disease.

Types: localised (obstructive) versus diffuse; morphologically cylindrical, varicose, or saccular / cystic.

Gross: permanent dilatation of bronchi and bronchioles, most severe in the lower lobes; airways dilated up to four times normal and traceable almost out to the pleura; lumina filled with mucopurulent secretions.

Microscopic: intense acute and chronic inflammation of the bronchial and bronchiolar walls with desquamation and ulceration of the lining epithelium; squamous metaplasia of residual epithelium; fibrosis of the wall and peribronchiolar tissue; abscess formation in chronic cases.

a) Differential diagnosis

• Benign: fibroadenoma; phyllodes tumour (consider for a large or rapidly growing lump); breast cyst; fat necrosis; breast abscess
• Malignant: invasive ductal carcinoma (NST, commonest); invasive lobular carcinoma; carcinoma with Paget's disease; medullary and mucinous carcinoma

b) Risk factors

• Age (40) and female sex
• Genetic mutations such as BRCA1
• Obesity
• Positive family history
• Early menarche

c) Diagnostic routine & specialised tests

• Routine: fine-needle aspiration biopsy; core biopsy; excision biopsy
• Specialised: ancillary IHC prognostic markers; radio-imaging for metastases

a) Risk factors: female sex and increasing age; BRCA1/BRCA2 mutations; positive family history; early menarche / late menopause; nulliparity; obesity; prolonged oestrogen exposure.

b) Histological subtypes: in situ — DCIS, LCIS; invasive — invasive ductal carcinoma (NST, commonest), invasive lobular, medullary, mucinous and tubular carcinoma.

c) Laboratory diagnosis & tumour markers: triple assessment — clinical exam, imaging (mammography/ultrasound), FNAC/core biopsy; receptor status ER/PR and HER2 and Ki-67 on histology; CA 15-3 for follow-up.

d) Clinical presentation: painless hard breast lump; nipple retraction or bloody discharge; skin dimpling / peau d'orange; axillary lymphadenopathy.

a) Hydatidiform mole (grape-like vesicles + markedly elevated hCG).

b) Thin-walled mass with "grape-like" vesicles; swollen oedematous villi. Microscopy: villi enlarged with central cavitation; complete mole — villi covered by trophoblastic proliferation; partial mole — only a fraction of villi enlarged with normal-appearing proliferation.

c) Complications: invasive mole; choriocarcinoma (about 2% of complete moles); persistent gestational trophoblastic disease; theca-lutein cysts; early pre-eclampsia and hyperthyroidism.

Karyotype: complete mole is diploid 46XX, entirely androgenetic, with no fetal parts and diffuse trophoblast proliferation; partial mole is triploid (69XXY), with fetal parts and focal proliferation.

1. Germ-cell tumours derived from GCNIS (germ cell neoplasia in situ; most common, young adults): seminoma; embryonal carcinoma; post-pubertal yolk-sac tumour; choriocarcinoma; post-pubertal teratoma; mixed germ-cell tumours.

2. Germ-cell tumours NOT derived from GCNIS: spermatocytic tumour (older men, indolent; the modern WHO no longer classes this as a seminoma); prepubertal-type teratoma and yolk-sac tumour.

3. Sex cord-stromal tumours: Leydig-cell; Sertoli-cell; granulosa-cell.

4. Mixed germ-cell/sex-cord-stromal: gonadoblastoma.

5. Haematolymphoid: lymphoma (commonest testicular tumour in men over 60).

Modern WHO backbone: split germ-cell tumours into GCNIS-derived versus non-GCNIS-derived. Spermatocytic tumour and gonadoblastoma were misplaced in the original card.

a) Pathogenesis of abnormal placentation: failure of the second wave of trophoblastic invasion → maternal spiral arteries retain their muscular walls and remain narrow, high-resistance vessels (inadequate remodelling) → placental hypoperfusion/ischaemia → release of anti-angiogenic factors (sFlt-1, soluble endoglin) → systemic maternal endothelial dysfunction → hypertension, proteinuria and oedema.

b) Microvascular features: endothelial cell swelling; fibrinoid necrosis of vessel walls; "acute atherosis" (lipid-laden macrophages in the wall of decidual/spiral arteries); thrombosis and reduced luminal diameter.

c) Organs affected (gross / histology):

• Placenta: infarcts, retroplacental haematoma / increased syncytial knots, villous ischaemia.
• Kidney: swollen / glomerular endotheliosis (swollen endothelial cells occluding capillary lumina).
• Liver: subcapsular haemorrhage / periportal fibrin deposition, haemorrhage and necrosis.
• Brain: oedema and petechial haemorrhages / fibrinoid necrosis of vessels, microinfarcts.
• Heart: petechial haemorrhages / subendocardial necrosis.

a) Age: peak 2–5 years (children under 5).

b) Clinical presentation: large, unilateral abdominal/flank mass; haematuria; hypertension; abdominal pain; occasionally fever.

c) Gross: large, solitary, well-circumscribed, soft tan-grey mass with areas of necrosis/haemorrhage. Histology: classically triphasic — blastemal (sheets of small blue cells), epithelial (abortive tubules and glomeruli) and stromal components.

d) Genetic abnormality: WT1 gene mutation on chromosome 11p13; associated syndromes — WAGR, Denys–Drash, Beckwith–Wiedemann.

1a) Cervical cancer: risk factors — HPV 16/18 infection, early sexual debut, multiple sexual partners, smoking, immunosuppression (HIV). Common histologic type — squamous cell carcinoma. Prevention — primary: HPV vaccination, barrier contraception; secondary: Pap-smear / VIA screening, HPV-DNA testing.

1b) Solitary thyroid nodule: screening/labs — TSH and free T4/T3, thyroid ultrasound, FNAC, radioisotope scan. DDx — colloid nodule, follicular adenoma, papillary carcinoma, thyroid cyst. Papillary carcinoma histology — branching papillae with fibrovascular cores; "Orphan-Annie-eye" clear/ground-glass nuclei; nuclear grooves and pseudo-inclusions; psammoma bodies. Spread — lymphatic (to cervical nodes).

1c) Benign nodular prostatic enlargement (gross): enlarged prostate (mainly transitional zone); nodular, firm, rubbery cut surface; compression/narrowing of the prostatic urethra; may show cystic spaces exuding milky fluid.

a) Forms: tuberculous meningitis; parenchymal tuberculoma (mass lesion); Pott's disease (spinal/vertebral TB).

b) Thick yellow exudate especially above the optic chiasm and around cranial nerves; tuberculomas and tuberculous granulomas. Microscopy: granulomas with a caseating core surrounded by epithelioid histiocytes (from macrophages that engulfed M. tuberculosis).

c) CSF: clear, forms webs on standing; raised protein; raised leukocytes (predominantly lymphocytes, unlike pyogenic bacteria); low glucose; raised intracranial pressure.

d) Diagnosis: CSF for ZN (acid-fast) or auramine stain and mycobacterial culture; nucleic-acid amplification (GeneXpert MTB/RIF) for rapid diagnosis and rifampicin resistance; CSF adenosine deaminase (ADA) as an adjunct. Gram stain does not demonstrate M. tuberculosis.

a) Injury or pathology to the vascular system supplying the brain that alters its normal function.

b) Classification — Ischaemic stroke: large-artery atherosclerosis (~30%); cardiac embolism (~20–30%); small-vessel disease (~20%); remainder from dissection, vasculitis, hypercoagulable states. Haemorrhagic stroke: intracerebral haemorrhage (~70%); subarachnoid haemorrhage (~30%).

c) Gross: infarcted areas; swelling/oedema; haemorrhage. Microscopic: neuronal injury; gliosis; red neurons; chromatolysis.

a) Meningioma — dural-based benign tumour.

b) Gross: well-defined, lobulated, attached to dura mater. Microscopy: whorls of cells; psammoma bodies (calcifications); spindle-shaped cells.

c) Presentations: severe headaches; vomiting; visual disturbances. Brain findings: papilloedema; herniation of brain structures; hydrocephalus.

a) Classification: viral (e.g. enteroviruses); fungal (e.g. Cryptococcus neoformans); parasitic (e.g. Taenia solium); bacterial (e.g. Neisseria meningitidis, Haemophilus influenzae); non-infective (e.g. malignant).

b) TB meningitis — Gross: ventricular dilatation from raised ICP and CSF obstruction; thickened meninges (exudates, granulomas); brain atrophy. (Microscopic and CSF findings continue in the source — caseating granulomas; lymphocytic CSF with high protein, low glucose.)

Marking scheme excerpts: Contusion — superficial haemorrhagic bruises on the brain. Lacerations — tears in brain parenchyma associated with fractures. Intracranial haemorrhages — extradural/epidural (between skull and dura, with skull fractures), subdural (between dura and brain, from torn bridging veins), subarachnoid and intracerebral. Diffuse axonal injury — from acceleration–deceleration forces, seen microscopically. Diffuse vascular injury — haemorrhagic spots around vessels.

2b(i) Histologic types of thyroid neoplasms: benign - follicular adenoma; malignant - papillary carcinoma (commonest, ~80%), follicular carcinoma, medullary carcinoma (parafollicular C cells, secretes calcitonin), and anaplastic (undifferentiated) carcinoma (elderly, highly aggressive); also thyroid lymphoma.

Papillary thyroid carcinoma — Gross: focal, cystic, solid, calcified lesion. Microscopic: papillae, psammoma bodies, ground-glass ("Orphan Annie") nuclei, nuclear features.

2a) Cerebrovascular disease: brain dysfunction resulting from an abnormality of its blood supply — ischaemic or haemorrhagic.

2b) Modifiable stroke risk factors: hypertension; smoking; diabetes mellitus; hyperlipidaemia; obesity/physical inactivity; atrial fibrillation.

2c) Haemorrhagic stroke: presentation — sudden severe headache, vomiting, focal neurological deficit and reduced consciousness. Causation — hypertension (rupture of Charcot–Bouchard microaneurysms); ruptured berry aneurysm; arteriovenous malformation; cerebral amyloid angiopathy; anticoagulation.

2d) Four stages of lobar pneumonia:

• Congestion: heavy, red, boggy lung; vascular congestion, alveolar oedema fluid, scattered neutrophils and many bacteria.
• Red hepatization: red, firm, airless liver-like lobe; alveoli packed with neutrophils, red cells and fibrin.
• Grey hepatization: greyish-brown, dry surface; red cells disintegrate leaving a persistent fibrinosuppurative exudate.
• Resolution: exudate enzymatically digested and resorbed or coughed up; normal architecture restored.

Histological subtypes (gliomas — most common primary brain tumours): astrocytomas; oligodendrogliomas; ependymomas.

Clinical features: headaches, seizures; posterior-fossa ependymomas present with hydrocephalus from obstruction. Complications: brain haemorrhage; brain herniation; coma.

Modern WHO 2021 CNS classification is molecularly integrated: adult diffuse gliomas are grouped as IDH-mutant astrocytoma (grades 2 to 4), IDH-mutant 1p/19q-codeleted oligodendroglioma (grades 2 to 3), and glioblastoma (IDH-wildtype, grade 4). Pilocytic astrocytoma is grade 1 (KIAA1549-BRAF fusion). Grade may be assigned on molecular features alone, e.g. CDKN2A/B homozygous deletion denotes grade 4.

i) Definition: a sustained rise in the pressure inside the cranial cavity above the normal range (adult, supine roughly 7 to 15 mmHg), occurring when the volume of brain, CSF, blood or a mass lesion increases within the rigid non-expansile skull (Monro-Kellie doctrine), once compensatory mechanisms are exhausted.

ii) Four features on the brain:

• Flattening and widening of the gyri with narrowing of the sulci
• Cerebral oedema: a heavy, swollen brain with compressed/slit-like ventricles
• Herniation syndromes: subfalcine (cingulate), transtentorial (uncal), and tonsillar (cerebellar tonsils through the foramen magnum)
• Secondary (Duret) haemorrhages in the midbrain and pons from downward brainstem displacement

(Also acceptable: papilloedema at the optic disc, hydrocephalus.)

a) Aetiological organisms

• Bacterial: Streptococcus pneumoniae, Neisseria meningitidis (also Haemophilus influenzae type b; group B streptococcus / E. coli in neonates)
• Viral: enteroviruses (echovirus/coxsackie), herpes simplex virus (also mumps virus, HIV)
• Fungal: Cryptococcus neoformans, Candida albicans (also Histoplasma, Aspergillus)

b) CSF findings

c) CNS conditions in HIV/AIDS (any five): cryptococcal meningitis; cerebral toxoplasmosis; progressive multifocal leukoencephalopathy (JC virus); CMV encephalitis / ventriculitis; primary CNS lymphoma (EBV-driven); HIV-associated neurocognitive disorder / HIV encephalitis; tuberculous meningitis.

i) Interpretation: severe anaemia (Hb 6.3 g/dL) with a raised MCV (118 fL) — a macrocytic anaemia; WBC and platelets are normal.

ii) Differential diagnosis: megaloblastic — vitamin B12 deficiency, folate deficiency; non-megaloblastic — alcohol/chronic liver disease, hypothyroidism, myelodysplastic syndrome.

iii) Investigations: peripheral blood film (macro-ovalocytes, hypersegmented neutrophils); serum B12 and folate; reticulocyte count; bone-marrow aspirate (megaloblastic change); LDH and bilirubin (ineffective erythropoiesis); intrinsic-factor / parietal-cell antibodies; thyroid and liver function tests.

b) WBC changes in chronic HIV/AIDS: lymphopenia (especially CD4 T cells) with a reversed CD4:CD8 ratio; leukopenia and neutropenia; atypical/reactive lymphocytes; progression to pancytopenia in advanced disease.

a) Causes

• Thalassaemia
• Iron deficiency anaemia
• Lead poisoning
• Sideroblastic anaemia

b) Salient features — History: fatigue, palpitations, tinnitus, generalised oedema, tachycardia. Signs: glossitis, koilonychia, conjunctival pallor.

c) Haematological investigations

• Peripheral blood smear — hypochromic microcytic cells
• Haemoglobin electrophoresis — abnormal Hb in thalassaemia
• Perls' Prussian-blue stain of bone marrow — increased iron stores in sideroblastic anaemia
• Serum ferritin — reduced in iron deficiency
• Blood toxin screen — for lead poisoning

a) Differentials

• Acute haemolytic transfusion reaction (mismatched blood group) — most likely
• Febrile non-haemolytic transfusion reaction
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload (TACO)
• Bacterial contamination

b) Specimen & tests

• Blood — for crossmatching
• Blood — culture for bacteria
• Blood — reticulocyte count (increased)
• Blood — direct antiglobulin (Coombs) test
• Urine for free haemoglobin (haemoglobinuria)
• Blood — mast cell tryptase (allergic reaction)

a) Acute lymphoblastic leukaemia (ALL) — 65% blasts on film with cytopenias (anaemia, thrombocytopenia, neutropenia).

b) Clinical features

• Anaemia: fatigue, weakness, pallor, dyspnoea
• Thrombocytopenia: bleeding gums, epistaxis, petechiae, easy bruising
• Neutropenia: increased infection risk (respiratory, sinus)
• Hepatosplenomegaly

c) Mandatory tests

• Bone-marrow aspiration — hypercellular marrow with blasts >20%
• Immunophenotyping — TdT positive in ALL; markers CD3 (T-cell), CD19/CD20 (B-cell)
• Cytogenetics — abnormalities including t(9;22)

d) Principles of treatment

• Combination chemotherapy in phases: induction, consolidation, then maintenance
• CNS-directed prophylaxis with intrathecal chemotherapy (the CNS and testes are sanctuary sites)
• Supportive care: transfusion, antimicrobial prophylaxis, tumour-lysis prevention, nutrition
• Allogeneic stem-cell transplant for high-risk or relapsed disease
• Psychosocial support

a) Easy fatigability & exertional dyspnoea (low Hb/RBC → poor oxygen delivery); recurrent infections — oral thrush, pneumonia, meningitis (low WBC); bruises/petechiae & epistaxis (low platelets → impaired primary haemostasis).

b) Differentials: bone-marrow failure (BMF); acute myeloid leukaemia (AML).

c) Investigations

• Bone-marrow aspirate — BMF: marrow replaced by adipose, lack of cells; AML: large numbers of immature myeloblasts
• Peripheral film — BMF: general lack of all cell lines, no abnormal cells; AML: immature cells with Auer rods in cytoplasm
• Cytochemical staining — BMF: no abnormalities; AML: may stain positive (Sudan Black, lysozyme)

d) Management (BMF): support — blood/whole-blood/packed-cell transfusion, antibiotics for infection; treatment — bone-marrow transplant; antiviral therapy if infection-related (e.g. HIV).

a) Raised WBC (infection/leukaemia); normal differential ratio; low Hb; low platelets; prolonged bleeding time (impaired primary haemostasis — platelet issue); prolonged PT and aPTT (intrinsic and extrinsic pathway deficiency). Differentials: disseminated intravascular coagulation (DIC); systemic lupus erythematosus.

b) Tests: peripheral film; prothrombin time (common pathway); fibrinogen assay; fibrin-degradation products (FDPs); immunofluorescence for antinuclear antibodies.

c) DIC pathophysiology: procoagulant factors enter the blood triggering coagulation cascades (a common complication of postpartum haemorrhage) → circulating thrombin → thrombi enter renal circulation and occlude vessels → renal tubular necrosis → ↓GFR from reduced perfusion → acute kidney injury.

d) Other conditions giving a similar coagulation picture (prolonged PT/aPTT with thrombocytopenia): severe liver disease; vitamin K deficiency; massive transfusion; sepsis; thrombotic microangiopathies (TTP/HUS) and HELLP syndrome.

i) Interpretation: low haemoglobin consistent with anaemia (macrocytic); WBC normal (4–11); platelets normal (150–450); MCV high.

ii) Differentials: iron-deficiency anaemia; vitamin B12 deficiency; haemolytic anaemia; folate deficiency; chronic kidney disease; myelodysplastic syndrome.

iii) Investigations: peripheral film; bone-marrow aspirate; serum ferritin (low in IDA); serum iron (low); serum transferrin (high); TIBC (increased). Note: for a macrocytic picture, serum B12/folate would be the key confirmatory tests — the source list leans toward iron studies.

i) Hereditary spherocytosis — pallor (anaemia); swollen fingers (splenomegaly); jaundice (haemolysis); family history (older sister affected → genetic).

ii) Investigations: direct Coombs test — negative (distinguishes from autoimmune haemolytic anaemia); peripheral smear — spherocytes and increased reticulocytes; Hb electrophoresis — rule out haemoglobinopathies; osmotic fragility test — increased; genetic testing.

iii) Complications: haemolytic crises; pigment gallstones; aplastic crisis (parvovirus B19); splenomegaly; folate deficiency. (Auto-splenectomy is a feature of sickle cell disease, not spherocytosis: in HS the spleen enlarges.)

a) Differentials: acute haemolytic transfusion reaction (mismatch); sepsis/bacterial contamination.

b) Samples: blood for full haemogram; blood cultures; the transfusion product for screening and crossmatch.

c) Tests: complete blood count; blood cultures; blood grouping and crossmatch; further coagulation studies.

i) Complaints: fever; malaise; weight loss; anorexia; recurrent infections; easy shortness of breath; night sweats.

ii) Examination: splenomegaly; hepatomegaly; testicular enlargement (if male); pallor; lymphadenopathy.

iii) Mandatory tests: (transcription continues from the source — full blood count/peripheral film, bone-marrow aspirate, immunophenotyping, cytogenetics are the standard set).

iv) Blood products: packed red cells and platelets.

i) Interpretation: low platelets, low WBC, low haemoglobin. Basis: pancytopenia. Clinical features: easy gum bleeding; easy fatigability; shortness of breath; frequent recurrent infections.

ii) Investigations: peripheral blood film (and bone-marrow examination as the key next step).

a) Interpretation: low Hb (7 g/dL) — severe anaemia; low RBC and low HCT/PCV; raised MCV (104 fL) — macrocytic picture; normal WBC and platelets.

b) Possible diagnosis: macrocytic anaemia, most likely megaloblastic (vitamin B12 and/or folate deficiency).

c) Further tests / interpretation: peripheral blood film (macro-ovalocytes, hypersegmented neutrophils); serum B12 and folate assays; reticulocyte count; bone-marrow aspirate (megaloblastic erythropoiesis); anti-intrinsic-factor antibodies; raised LDH and unconjugated bilirubin support ineffective erythropoiesis.

1) Vascular birth defects with haematological features: large vascular tumours/malformations that trap and consume blood elements — e.g. kaposiform haemangioendothelioma and tufted angioma causing the Kasabach–Merritt phenomenon; giant congenital haemangiomas.

2) Main haematological features: consumptive thrombocytopenia; microangiopathic haemolytic anaemia (fragmented red cells); consumptive coagulopathy with low fibrinogen (DIC-like picture).

3) Classification of lymphatic and venous birth defects: lymphatic malformations — macrocystic, microcystic and mixed (e.g. cystic hygroma); venous malformations — localised or segmental (e.g. blue-rubber-bleb naevus, malformations in Klippel–Trénaunay syndrome).

a) Three likely causes: sickle cell disease; G6PD deficiency; thalassaemia — inherited haemolytic anaemias that are prevalent in malaria-endemic coastal Kenya. Chronic red-cell haemolysis produces anaemia plus unconjugated hyperbilirubinaemia (jaundice) from early childhood.

b) Further features / complications: pallor and fatigue; hepatosplenomegaly; scleral jaundice; pigment gallstones; vaso-occlusive crises with dactylitis and bone pain (SCD); growth retardation; leg ulcers; aplastic and splenic-sequestration crises; increased susceptibility to infection.

c) Lab tests / findings: FBC (anaemia); blood film (sickle cells, target cells, Howell–Jolly bodies); reticulocytosis; Hb electrophoresis (HbSS / HbF); sickling test; G6PD assay; raised unconjugated bilirubin and LDH with low haptoglobin; negative direct antiglobulin test (non-immune haemolysis).

3a) 52-year-old female: (i) Interpretation — severe anaemia (Hb 6.3) with raised MCV (118 fL) = macrocytic anaemia; normal WBC and platelets. (ii) DDx — megaloblastic (B12 or folate deficiency); non-megaloblastic (alcohol/liver disease, hypothyroidism, myelodysplasia). (iii) Investigations — blood film (macro-ovalocytes, hypersegmented neutrophils); serum B12 and folate; reticulocytes; bone-marrow aspirate; anti-intrinsic-factor antibodies; LDH/bilirubin.

3b) Suspected congenital bleeding disorder (6-year-old boy): full blood count and platelet count; peripheral blood film; prothrombin time (PT); activated partial thromboplastin time (APTT); bleeding time; specific coagulation-factor assays (VIII and IX for haemophilia A/B); von Willebrand factor assay; mixing studies to detect inhibitors; genetic testing.

4a) Mandatory tests on donor blood: ABO and Rh(D) grouping; red-cell antibody screen; HIV; hepatitis B surface antigen (HBsAg); hepatitis C antibody; syphilis (VDRL/TPHA); malaria screen (in endemic areas); HTLV where indicated; donor haemoglobin/haematocrit.

4b) Classification and lab diagnosis of leukaemias: classify by rate (acute vs chronic) and lineage (lymphoid vs myeloid) — AML, ALL, CML, CLL. Laboratory diagnosis: FBC (variable/raised WBC, anaemia, thrombocytopenia); blood film (blasts, Auer rods in AML); bone-marrow aspirate (>20% blasts defines acute leukaemia); cytochemistry (myeloperoxidase / Sudan black for myeloid, PAS / TdT for lymphoid); immunophenotyping by flow cytometry (CD markers); cytogenetics (e.g. Philadelphia chromosome t(9;22) in CML).

Congenital haemolytic anaemias: classified by the site of defect — membrane (hereditary spherocytosis, hereditary elliptocytosis); enzyme (G6PD deficiency, pyruvate-kinase deficiency); haemoglobin (sickle cell disease, thalassaemia). Lab tests — peripheral blood film, osmotic-fragility test, G6PD assay, Hb electrophoresis.

40-year-old man with very low Hb, platelets and WBCs (pancytopenia): differentials — aplastic anaemia; acute leukaemia; megaloblastic anaemia; marrow infiltration; hypersplenism. Key investigations — peripheral blood film and bone-marrow examination.

a) Most likely diagnosis: sickle cell disease. The recurrent infections (functional hyposplenism predisposing to encapsulated organisms), haemolytic jaundice, low Hb and an affected sibling (autosomal-recessive inheritance) fit an inherited haemolytic anaemia.

b) Differential diagnosis: G6PD deficiency; thalassaemia major; hereditary spherocytosis; autoimmune haemolytic anaemia.

c) Laboratory tests / expected findings: FBC (anaemia); blood film (sickle cells, target cells, Howell–Jolly bodies); Hb electrophoresis (HbSS); sickling test; reticulocytosis; raised unconjugated bilirubin and LDH; G6PD assay to exclude the differential.

a) Types of blood donors: voluntary non-remunerated (safest); family/replacement donors; paid/commercial donors; autologous donors; directed donors; apheresis donors.

b) Changes in blood cells (incl. reticulocytes): reticulocytosis (increased marrow output in haemolysis or after blood loss); reticulocytopenia (marrow failure); anisocytosis and poikilocytosis; polychromasia; left shift; toxic granulation of neutrophils in infection.

c) Indications for bone-marrow examination from the film: unexplained cytopenias (especially pancytopenia); blasts or abnormal cells on the film; suspected leukaemia, lymphoma or myeloma; a leucoerythroblastic picture; disease staging; unexplained anaemia not responding to treatment.

3a) 46-year-old male: (i) Interpretation — low Hb (7.9), low MCV (60 fL) and low MCH (20 pg) = microcytic hypochromic anaemia, with a raised WBC (leucocytosis); platelets normal. (ii) DDx — iron-deficiency anaemia (chronic blood loss, e.g. GI malignancy given age and weight loss); anaemia of chronic disease; thalassaemia trait; sideroblastic anaemia. (iii) Investigation — blood film; serum ferritin, iron, TIBC and transferrin saturation; faecal occult blood / endoscopy; Hb electrophoresis; CRP.

3b) Haemophilia vs ITP: Haemophilia — coagulation-factor deficiency (VIII/IX): prolonged APTT, normal PT, normal platelets and bleeding time; deep bleeds (haemarthroses, muscle haematomas). ITP — immune platelet destruction: low platelet count, prolonged bleeding time, normal PT/APTT; mucocutaneous bleeding (petechiae, purpura); increased megakaryocytes on marrow.

4a) National Blood Transfusion Service structure & blood-bank function: a national coordinating centre with regional/satellite transfusion centres; functions span donor recruitment and mobilisation, blood collection, mandatory testing (grouping and transfusion-transmissible-infection screening), processing into components, storage and distribution. The blood bank performs grouping, antibody screening, component storage, cross-matching, safe issue of blood and haemovigilance.

4b) Role of compatibility testing (cross-matching): confirms donor–recipient compatibility to prevent haemolytic transfusion reactions — ABO/Rh grouping of donor and recipient, antibody screening, and the cross-match itself (major: recipient serum against donor cells; minor: donor serum against recipient cells) performed through immediate-spin, 37 °C incubation and antihuman-globulin (Coombs) phases.

Case I — isolated anaemia + jaundice

a) Differential: haemolytic anaemia (anaemia + jaundice with normal WBC and platelets → isolated red-cell destruction, i.e. pre-hepatic/haemolytic jaundice). Causes: autoimmune haemolytic anaemia; inherited — sickle cell disease, thalassaemia, G6PD deficiency, hereditary spherocytosis.

b) Salient history: onset/duration and family history (inherited haemolysis); drug/food triggers (G6PD — antimalarials, fava beans); dark urine (haemoglobinuria); recent infection; anaemia symptoms; pregnancy; prior transfusions; features of SLE/autoimmune disease.

c) Investigations + expected findings:

• FBC + peripheral film — anaemia; spherocytes/schistocytes/sickle cells; polychromasia
• Reticulocyte count — raised (marrow compensation)
• Serum bilirubin — raised unconjugated (indirect)
• LDH raised; haptoglobin low/absent
• Direct antiglobulin (Coombs) test — positive in autoimmune haemolysis
• Urine — raised urobilinogen ± haemoglobinuria
• Hb electrophoresis; G6PD assay; osmotic fragility — per suspected cause

d) Blood product: cross-matched packed red blood cells (least-incompatible/closely cross-matched units if autoimmune).

e) Late (~1 week) adverse events: delayed haemolytic transfusion reaction (anamnestic antibody response); post-transfusion purpura / alloimmunisation. (Transfusion-associated GVHD and iron overload are later still.)

Case II — menorrhagia + prolonged bleeding time and APTT

a) Causes of prolonged APTT: haemophilia A (FVIII deficiency); haemophilia B (FIX deficiency); von Willebrand disease; heparin therapy; lupus anticoagulant/antiphospholipid. (Also FXI/FXII deficiency, DIC, liver disease, vitamin K deficiency.)

b) Most likely cause: von Willebrand disease — the combination of a prolonged bleeding time (defective platelet adhesion) and prolonged APTT (low FVIII carried by vWF), with menorrhagia in a young female, is classic. Haemophilia would prolong APTT but not the bleeding time and is X-linked (rare in females).

c) Confirmatory tests: vWF antigen (reduced); vWF activity / ristocetin cofactor assay (reduced); factor VIII level (reduced); ristocetin-induced platelet aggregation and vWF multimer analysis.

d) Principles of management: desmopressin (DDAVP) to release vWF/FVIII (type 1); vWF/FVIII concentrate for severe/type 3 or major bleeds; antifibrinolytics (tranexamic acid) for mucosal bleeding/menorrhagia; hormonal control of menorrhagia (combined OCP); avoid aspirin/NSAIDs; patient education and genetic counselling.

f) Blood products (Hb 6, symptomatic): packed red cells for the anaemia, plus a vWF-containing factor concentrate — or cryoprecipitate (contains fibrinogen, FVIII and vWF) — to correct the bleeding tendency; tranexamic acid as adjunct.

a) Causes of splenomegaly (child):

• Infections — malaria (endemic in Kenya), visceral leishmaniasis (kala-azar), typhoid, EBV (infectious mononucleosis)
• Haemolytic anaemias — sickle cell disease, thalassaemia, hereditary spherocytosis
• Haematological malignancy — acute leukaemia (ALL), lymphoma
• Portal hypertension (hepatic/portal-vein pathology)
• Storage disorders — Gaucher, Niemann–Pick

b) Laboratory investigations:

• FBC + differential — cytopenias (hypersplenism), blasts (leukaemia)
• Peripheral blood film — malaria parasites, sickle cells, blasts, spherocytes
• Reticulocyte count
• Malaria rapid test + thick/thin films
• Hb electrophoresis (sickle/thalassaemia)
• Bone-marrow aspirate — leukaemia, Leishmania amastigotes, storage cells
• LFTs + coagulation screen (portal hypertension/liver disease)
• Abdominal ultrasound — spleen size, portal vein, liver
• Blood cultures / serology (typhoid, EBV); HIV test
• LDH, bilirubin (markers of haemolysis)

a) Differential diagnosis (macrocytic anaemia): megaloblastic — vitamin B12 deficiency, folate deficiency; non-megaloblastic — alcohol/liver disease, hypothyroidism, myelodysplastic syndrome, reticulocytosis from haemolysis or bleeding, drugs (hydroxyurea, methotrexate).

b) Confirmatory follow-up tests:

• Peripheral blood film — macro-ovalocytes and hypersegmented neutrophils (megaloblastic); target cells (liver)
• Reticulocyte count — low (megaloblastic) vs high (haemolysis/bleeding)
• Serum vitamin B12, serum and red-cell folate
• If B12 low: anti-intrinsic-factor and anti-parietal-cell antibodies (pernicious anaemia)
• Bone-marrow aspirate — megaloblastic change or MDS features (ring sideroblasts, dysplasia)
• LFTs and TSH (liver, thyroid causes)
• LDH and bilirubin — raised with ineffective erythropoiesis
• Cytogenetics if MDS suspected

c) Initial investigation of suspected haemolysis:

• FBC + reticulocyte count — reticulocytosis
• Peripheral film — schistocytes, spherocytes, sickle cells, bite cells
• Serum unconjugated bilirubin — raised
• LDH — raised
• Haptoglobin — reduced/absent
• Direct antiglobulin (Coombs) test — autoimmune haemolysis
• Urine — urobilinogen, haemoglobinuria, haemosiderinuria
• Confirmatory per cause — Hb electrophoresis, G6PD assay, osmotic fragility

a) Other relevant observations:

• Clinical: age; fever/infection, weight loss, night sweats, bleeding, bone pain; lymphadenopathy, hepatosplenomegaly, pallor, gum hypertrophy
• Rest of the FBC — haemoglobin (anaemia?), platelets (thrombocytopenia?), red-cell indices
• The white-cell differential — which lineage is raised (neutrophils, lymphocytes, eosinophils, blasts)?
• Presence of immature cells/blasts on the film
• Reactive (infection, inflammation, steroids, splenectomy) vs neoplastic (leukaemia) cause
• Drug history (steroids, G-CSF), recent infection

b) Immediate follow-up tests:

• Peripheral blood film — morphology, blasts, Auer rods, left shift, smudge cells
• Repeat FBC with differential
• Bone-marrow aspirate and trephine biopsy — cellularity, blast %
• Immunophenotyping / flow cytometry — lineage (myeloid vs lymphoid, CD markers)
• Cytochemistry — myeloperoxidase, Sudan black, PAS
• Cytogenetics / molecular — t(9;22) BCR-ABL (CML), t(15;17) (APL)
• Blood cultures, CRP if a reactive/infective cause is suspected
• LDH, uric acid, renal function — tumour-lysis risk
• Coagulation screen — DIC (especially in acute promyelocytic leukaemia)

a) Likely complaint: mucocutaneous bleeding - easy bruising; recurrent epistaxis; prolonged bleeding from minor cuts, dental work or surgery; menorrhagia (the likely cause of her anaemia); gum bleeding; plus symptoms of anaemia (fatigue, dyspnoea, palpitations).

b) Physical findings: pallor of anaemia; ecchymoses / bruises of varying age; petechiae uncommon; haemarthrosis characteristically absent (unlike haemophilia) except in severe type 3; tachycardia; features of iron deficiency (koilonychia, glossitis, angular stomatitis).

c) Haematological investigations: FBC (low Hb, microcytic if iron-deficient) and peripheral film; bleeding time prolonged; platelet count usually normal; PT normal; APTT normal or prolonged (from low factor VIII); von Willebrand factor antigen (vWF:Ag) reduced; vWF activity / ristocetin cofactor (vWF:RCo) reduced; factor VIII level reduced (vWF stabilises it); ristocetin-induced platelet aggregation (RIPA); vWF multimer analysis to type the disease.

d) Treatment: desmopressin (DDAVP) to release stored vWF/FVIII (type 1); vWF-containing factor VIII concentrate for severe type 3 or major surgery; antifibrinolytics (tranexamic acid) for mucosal bleeding and menorrhagia; combined oral contraceptive for menorrhagia; iron supplementation for the anaemia; avoid aspirin and NSAIDs.

a)i) Findings: normal Hb, WBC and platelets; normal PT; an isolated, markedly prolonged APTT points to an intrinsic-pathway factor defect (factor VIII, IX or XI). The painful swollen joint is a haemarthrosis. Picture suggests an inherited factor deficiency.

a)ii) Differentials: haemophilia A (factor VIII deficiency); haemophilia B (factor IX deficiency, Christmas disease). (Also factor XI deficiency.)

a)iii) Further history: family history of bleeding (X-linked, affected maternal male relatives); prolonged bleeding after circumcision or injury; recurrent joint or muscle bleeds; drug history.

a)iv) Investigations + expected findings: mixing study (APTT corrects with normal plasma, indicating factor deficiency not an inhibitor); factor VIII and factor IX assays (one markedly reduced); vWF assay (normal, to exclude vWD); genetic testing.

b) Blood components:

• i) Packed red cells and platelet concentrate (symptomatic anaemia plus severe thrombocytopenia)
• ii) Fresh frozen plasma (multiple clotting-factor deficiency of liver failure), with platelets if thrombocytopenic
• iii) Desmopressin or a vWF/FVIII concentrate; if a product is needed, cryoprecipitate (source of vWF/FVIII)
• iv) Packed red cells given slowly with diuretic cover / in small aliquots to avoid volume overload in heart failure

c) Transfusion-reaction lab workup: clerical / bedside check of patient identity and unit; return the unit and giving set to the lab; repeat ABO/Rh grouping and crossmatch on pre- and post-transfusion samples; direct antiglobulin test (DAT/Coombs); FBC; plasma free haemoglobin and serum bilirubin (haemolysis); LDH and haptoglobin; urinalysis for haemoglobinuria; coagulation screen (DIC); blood cultures of patient and unit (bacterial contamination); renal function (acute kidney injury).

i) Most likely diagnosis: sickle cell disease (Hb SS) - an endemic coastal region, chronic haemolytic jaundice with pallor, recurrent painful vaso-occlusive crises, and dactylitis (hand-foot syndrome), which is the classic early childhood presentation.

ii) Further history: family history / sickle trait in parents; age at first symptoms; frequency and triggers of crises (infection, cold, dehydration); previous transfusions and hospital admissions; episodes of splenic sequestration; jaundice; growth and development; vaccination and penicillin prophylaxis.

iii) Investigations + likely findings: FBC (normocytic normochromic anaemia, Hb ~6 to 9 g/dL) with reticulocytosis; peripheral film (sickle cells, target cells, Howell-Jolly bodies from hyposplenism, nucleated RBCs); sickling test / sodium metabisulphite (positive); Hb electrophoresis or HPLC as the confirmatory test (HbS band, no HbA, raised HbF); raised unconjugated bilirubin and LDH with low haptoglobin (haemolysis); for management - G6PD screen, iron studies, renal and hepatic function, blood group and crossmatch, and an infection screen during crises.

i) Interpretation: severe macrocytic anaemia (Hb 4.5, MCV 116) with mild leucopenia and thrombocytopenia, i.e. a macrocytic anaemia with early pancytopenia, typical of megaloblastic anaemia.

ii) Two likely causes: vitamin B12 deficiency (pernicious anaemia); folate deficiency. (Also myelodysplasia.)

iii) Clinical features: pallor with fatigue and dyspnoea; mild jaundice (ineffective erythropoiesis); glossitis / angular stomatitis; in B12 deficiency, peripheral neuropathy or subacute combined degeneration; easy bruising and infections from the cytopenias.

iv) Investigations + expected findings: peripheral film (oval macrocytes, hypersegmented neutrophils, pancytopenia); reticulocyte count (low); serum B12 and red-cell folate assays; bone-marrow aspirate (hypercellular, megaloblastic erythropoiesis, giant metamyelocytes); anti-intrinsic-factor and anti-parietal-cell antibodies; raised LDH and unconjugated bilirubin; OGD for atrophic gastritis if pernicious anaemia is suspected.

Note: reading red-cell indices to place an anaemia is the single most repeated skill in this question set - see also the macrocytic cases q1, q27, q49, q66, q96.

a) Burkitt's lymphoma.

b) Lab tests: tissue biopsy; flow cytometry; specialised staining.

c) Microscopic features: starry-sky appearance; high mitotic figures; sheets of monotonous uniform lymphoid cells with high N:C ratio; high cell density with small non-cleaved cells.

d) Mutations: translocation of chromosome 8 and 14; translocation of chromosome 8 and 22.

IHC (added; source garbled): CD20 positive (B-cell); CD10 positive; BCL6 positive; Ki-67 proliferation index approaching 100%; BCL2 negative.

a) Burkitt's lymphoma (African/endemic).

b) Mass usually on the mandible; extranodal presentation; may involve abdominal viscera (endemic). A peripheral B-cell neoplasm often driven by Epstein–Barr virus (EBV, Herpesviridae). Seen in children and the young.

c) Infiltration by lymphoid cells with rounded nuclei and several nucleoli; high mitotic index; numerous apoptotic cells; "starry-sky" pattern from macrophages engulfing apoptotic debris.

d) Subtypes: African (endemic); sporadic; HIV-associated.

e) Mutation: translocation of the MYC gene on chromosome 8 → increased MYC protein production.

a) Two main groups: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). NHL is subdivided by the lymphocyte involved (B-cell or T-cell) and other features.

b) Basis: cell type/origin; morphology; genotype; clinical features; response to treatment.

A. Meningitis

(i) Aetiological causes:

• Bacterial (pyogenic): neonates — E. coli, Group B Streptococcus, Listeria; children/adults — N. meningitidis, S. pneumoniae, H. influenzae
• Viral (aseptic): enteroviruses, mumps, HSV
• Fungal: Cryptococcus neoformans (esp. HIV)
• Mycobacterial: M. tuberculosis (chronic)
• Non-infective: chemical, malignant (carcinomatous)

(ii) Gross & microscopic (pyogenic): gross — purulent exudate over the meninges filling the sulci and (pneumococcal) base of brain; congested, swollen brain; cloudy CSF. Microscopic — neutrophil-rich exudate in the subarachnoid space; congested/dilated meningeal vessels; vasculitis/thrombosis may occur; organisms on Gram stain.

(iii) CSF findings: turbid appearance; raised pressure; neutrophilic pleocytosis; raised protein; low glucose (< ⅔ of blood glucose); positive Gram stain and culture.

B. Hodgkin lymphoma

(i) Morphologic features: diagnostic Reed–Sternberg cells — large binucleate/bilobed cells with prominent eosinophilic "owl-eye" nucleoli, on a reactive background of lymphocytes, eosinophils, plasma cells and histiocytes. Variants: mononuclear Hodgkin cell; lacunar cells (nodular sclerosis); popcorn/L&H cells (lymphocyte-predominant). Nodal architecture effaced; contiguous spread.

(ii) Types (WHO): Classical HL — nodular sclerosis (commonest), mixed cellularity (EBV-associated), lymphocyte-rich, lymphocyte-depleted (worst prognosis). Plus nodular lymphocyte-predominant HL (NLPHL).

(iii) Immunophenotype: classical RS cells CD15+, CD30+, PAX5 weak+, CD45−, usually CD20− (LMP1/EBV+ in mixed cellularity). NLPHL popcorn cells CD20+, CD45+, CD15−, CD30−.

a) i) Comment: hyponatraemia (Na 130); hyperkalaemia (K 5.4); markedly raised urea (19.4) and creatinine (301) — i.e. azotaemia/renal impairment.

ii) Diagnosis: acute kidney injury (likely acute tubular necrosis from post-traumatic hypovolaemia ± rhabdomyolysis). Reasons — raised urea and creatinine with hyperkalaemia following major trauma.

iii) Other tests: urinalysis; urine sodium and osmolality (pre-renal vs intrinsic); creatine kinase (rhabdomyolysis); arterial blood gas; calcium and phosphate; hourly urine output; renal ultrasound (to exclude obstruction).

b) i) Acid–base disturbance: metabolic acidosis (low pH 7.26, low HCO₃⁻ 13) with partial respiratory compensation (low PCO₂ 31).

ii) Anion gap = Na⁻ − (Cl⁻ + HCO₃⁻) = 136 − (105 + 13) = 18 mmol/L — a raised anion gap; i.e. high-anion-gap metabolic acidosis.

iii) Causes (MUDPILES): methanol; uraemia; diabetic ketoacidosis; paraldehyde; iron/isoniazid; lactic acidosis; ethylene glycol; salicylates.

Note: the specific result values on this page were not legible in the source scan, so only the interpretive framework can be given.

a) Describe the results / abnormality: comment systematically on each analyte against its reference interval, stating the direction and magnitude of any deviation.

b) Possible cause: relate the pattern of abnormal analytes to the most likely underlying pathology (e.g. an endocrine, renal or hepatic cause depending on which values are deranged).

c) Follow-up urine and blood tests: targeted confirmatory tests — paired serum and urine measurements of the relevant analyte, plus function tests of the implicated organ system.

d) Other utilities of the test: its roles beyond diagnosis — screening, monitoring of treatment response, and prognostication.

a) Chronic kidney disease from long-standing hypertension (hypertensive nephrosclerosis), with secondary hyperparathyroidism. The raised PTH, raised ALP (renal osteodystrophy) and low calcium point to a chronic rather than acute process; acute-on-chronic injury is possible.

b) Acid–base: metabolic acidosis — low pH, low bicarbonate, normal PCO₂.

c) High PTH: low calcium triggers compensatory PTH secretion to restore calcium.

d) Urinalysis: high creatinine/urea, RBC casts, WBC casts, proteinuria.

e) Plasma: elevated inflammatory markers (ESR, CRP); elevated magnesium.

a) Type 2 diabetes mellitus — age 51 with risk factors (elevated total cholesterol, low HDL).

b) Atherogenic lipids: elevated total cholesterol, low HDL, high triglycerides — the raised TG/cholesterol accelerate atheroma formation while low HDL removes less, further accelerating it.

c) Additional tests:

• Fructosamine — glycaemic control
• U/E/Cr — kidney damage
• Microalbumin — microalbuminuria
• OGTT — confirm diagnosis
• Fasting blood sugar — confirm diabetes

a) Urinalysis: glucose (blood glucose exceeds renal reabsorption threshold); ketone bodies (ketogenesis from lipid utilisation); protein/albumin (nephropathy in prolonged diabetes).

b) Cause: type 1 diabetes mellitus — early age of onset with hyperglycaemia (type 1a autoimmune destruction of islet β-cells; type 1b idiopathic).

c) Tests: fasting blood glucose (expected >7.0 mmol/L); OGTT (2-hr value markedly elevated); HbA1c (diagnostic if ≥6.5%; also indicates chronicity).

a) Hepatocellular carcinoma secondary to cirrhosis from viral hepatitis B — markedly raised AFP; HBsAg-positive active infection; low albumin (reduced synthetic function).

b) Severe hypervolaemic (dilutional) hyponatraemia: cirrhosis causes splanchnic vasodilatation with secondary hyperaldosteronism and ADH release → avid water and sodium retention with ascites. Urine sodium is characteristically LOW (avid renal retention), and very low in hepatorenal syndrome. This is a true dilutional hyponatraemia, not pseudohyponatraemia.

c) Loss of gluconeogenesis — the damaged liver cannot generate glucose from glycogenolysis, fats and proteins → hypoglycaemia.

d) Cirrhosis with lesion(s); mixed/conjugated hyperbilirubinaemia from impaired excretion of conjugated bilirubin (cirrhosis) and reduced conjugation by tumour cells.

a) Renal mechanisms: (1) reabsorption of filtered bicarbonate and generation of new bicarbonate in the proximal tubule; (2) excretion of H⁺ as titratable acid (buffered by phosphate) and as ammonium (NH₄⁺) in the distal nephron.

b) Severe vomiting: loss of gastric HCl produces a hypochloraemic metabolic alkalosis. Accompanying volume depletion drives avid Na⁺ (and HCO₃⁻) reabsorption and increased H⁺ secretion, so the kidney excretes acid urine despite the alkalosis (paradoxical aciduria), which maintains it. Hypokalaemia further promotes H⁺ secretion.

i) Predisposing factors: dehydration (concentrated urine); diet (high salt, animal protein, oxalate); family history; obesity; medical conditions (hyperparathyroidism, gout, UTIs).

ii) Biochemical tests: urinalysis (blood, crystals, infection); electrolyte profile (e.g. calcium); creatinine (kidney function); uric acid (24-hr urine); stone analysis (composition).

a) Acute myocardial infarction leading to heart failure — greatly elevated cTnI (myocardial infarct) and NT-proBNP (ventricular stress in heart failure).

b) AST: raised because AST is released from necrotic myocardium (cardiac muscle is rich in AST); it was historically used as a cardiac marker. The normal ALT confirms the source is not hepatocellular.

c) Tests: lipid profile (hyperlipidaemia — CAD risk); renal function tests (kidney disease/hypertension risk); OGTT (diabetes — mortality risk factor).

d) Raised NT-proBNP: heart failure; ventricular stress/strain conditions.

• α1 region: α1-antitrypsin (low in panacinar emphysema and liver disease); α1-antichymotrypsin; α1-acid glycoprotein (orosomucoid, an acute-phase protein); α1-fetoprotein; HDL/α-lipoprotein
• α2 region: haptoglobin (binds free haemoglobin; low in intravascular haemolysis); α2-macroglobulin (raised in nephrotic syndrome); ceruloplasmin (copper transport; low in Wilson disease)

Note: albumin migrates as its own band before α1 and is not an alpha-region protein; CRP runs in the gamma region. Both were miscategorised in the original card.

a) CSF biochemistry — viral vs bacterial meningitis:

• Acute viral: clear appearance; normal or mildly raised protein; normal glucose; lymphocytic pleocytosis; normal/mildly raised opening pressure.
• Acute bacterial: turbid/cloudy; markedly raised protein; low glucose (<50% of serum); neutrophilic pleocytosis; raised opening pressure.

b) Contraindications to lumbar puncture: raised intracranial pressure / space-occupying lesion (risk of coning); coagulopathy or thrombocytopenia; local skin/soft-tissue infection at the puncture site (also cardiorespiratory instability).

a) Factors affecting reference intervals: age; sex; ethnicity/race; physiological state (e.g. pregnancy); diet; diurnal (time-of-day) variation; posture; and the analytical method used.

b) Measures of central tendency: mean; median; mode.

c) Removal of outliers: statistical exclusion methods — Dixon's Q test; Tukey's rule (values beyond 1.5 × IQR from the quartiles); or excluding values more than 3 standard deviations from the mean.

Exocrine function: serum amylase and lipase (raised in acute pancreatitis; lipase is more specific); faecal elastase-1 (low in chronic pancreatic insufficiency); 72-hour faecal fat (steatorrhoea); faecal chymotrypsin; the secretin-cholecystokinin stimulation test (direct measure of duct and enzyme output).

Endocrine function: fasting glucose, HbA1c and OGTT (islet/beta-cell function); C-peptide.

Note: the source answer was cut off on the scan; these are the standard tests, to be verified against notes.

a) Screening serology for viral hepatitis: anti-HAV IgM; HBsAg; anti-HCV; anti-HEV IgM.

b) If HBsAg positive — monitoring tests (with justification): HBsAg (persistence beyond 6 months indicates chronicity); HBeAg (marker of active replication and high infectivity); anti-HBe (seroconversion, falling infectivity); HBV-DNA viral load (quantifies replication and response to therapy); anti-HBc IgM (acute) versus IgG (established/past); serial ALT to track hepatocellular activity.

c) Chronic hepatitis B markers present: HBsAg positive >6 months; anti-HBc IgG; HBeAg or anti-HBe; detectable HBV-DNA.

a) Type of hyperbilirubinaemia: conjugated (direct) hyperbilirubinaemia — both total and direct bilirubin are raised.

b) Likely clinical diagnosis: a cholestatic/hepatocellular jaundice — the raised direct bilirubin with raised ALP indicates cholestasis, while the low albumin points to impaired hepatic synthetic function (chronic hepatocellular disease).

c) Reasons: conjugated bilirubin is water-soluble and appears in urine; raised ALP reflects cholestasis; low albumin reflects reduced hepatic protein synthesis.

d) Expected urine findings: dark urine with bilirubinuria; urobilinogen variable (reduced in obstruction, raised in hepatocellular disease).

e) Two confirmatory tests: full liver-function panel (ALT/AST, GGT) and abdominal ultrasound (± viral hepatitis serology).

Pancreatic secretion is regulated by neural and hormonal mechanisms over three phases (cephalic, gastric, intestinal):

• Neural (cephalic phase): the sight, smell and taste of food trigger vagal (parasympathetic) stimulation → an enzyme-rich secretion.
• Secretin: released from duodenal S cells in response to acidic chyme → stimulates ductal cells to secrete a watery, bicarbonate-rich fluid that neutralises acid.
• Cholecystokinin (CCK): released from duodenal I cells in response to fats and amino acids → stimulates acinar cells to secrete digestive enzymes and causes gallbladder contraction.
• Gastrin (gastric phase) also contributes to enzyme secretion.

5a) Trauma electrolytes: (i) Comment — hyponatraemia (Na 130), hyperkalaemia (K 5.4), grossly raised urea (19.4) and creatinine (301) = azotaemia. (ii) Diagnosis — acute kidney injury (post-traumatic ATN ± rhabdomyolysis); reasons: raised urea/creatinine with hyperkalaemia after trauma. (iii) Other tests — urinalysis, urine Na/osmolality, creatine kinase, ABG, calcium/phosphate, urine output, renal ultrasound.

5b) ICU blood-gas: (i) Disturbance — metabolic acidosis (low pH 7.26, low HCO₃⁻ 13) with partial respiratory compensation (low PCO₂ 31). (ii) Anion gap = 136 − (105 + 13) = 18 mmol/L (raised → high-anion-gap metabolic acidosis). (iii) Six causes (MUDPILES): methanol, uraemia, diabetic ketoacidosis, paraldehyde, iron/isoniazid, lactic acidosis, ethylene glycol, salicylates.

Causes (by stone type): calcium oxalate/phosphate stones (hypercalciuria, hypercalcaemia, hyperoxaluria) — commonest; struvite stones (urea-splitting infections, e.g. Proteus); uric-acid stones (hyperuricaemia/gout, acidic urine); cystine stones (cystinuria).

Risk factors: low fluid intake / dehydration; recurrent urinary infection; hyperparathyroidism; gout; diet high in oxalate, animal protein or salt; immobilisation; family history.

Complications: urinary obstruction and hydronephrosis; infection (pyelonephritis); haematuria; renal colic; chronic kidney disease/renal failure.

a) Renal regulation of acid–base: (1) reabsorption of filtered bicarbonate and generation of new bicarbonate in the proximal tubule; (2) excretion of H⁺ as titratable acid (buffered by phosphate) and as ammonium (NH₄⁺). In severe vomiting, loss of gastric HCl produces a metabolic alkalosis; the volume depletion that accompanies it drives avid Na⁺ (and HCO₃⁻) reabsorption and H⁺ secretion, giving the characteristic paradoxical aciduria that maintains the alkalosis.

b) Endocrine causes of hypertension + tests:

• Phaeochromocytoma → plasma/urine metanephrines and catecholamines.
• Cushing's syndrome → dexamethasone suppression test, 24-h urinary free cortisol.
• Conn's syndrome (primary hyperaldosteronism) → aldosterone:renin ratio, serum potassium.
• Hyperthyroidism → TSH and free T4.
• Acromegaly → IGF-1, growth-hormone/OGTT suppression.

a) Tests to confirm/exclude AMI (with expected findings): cardiac troponin I or T — the most sensitive and specific marker, rising 3–6 h after injury and peaking at ~24 h (raised confirms myocardial injury); CK-MB — rises 3–6 h and normalises by 48–72 h, useful for re-infarction (raised); myoglobin — earliest but non-specific.

b) Three tests for underlying risk: fasting lipid profile (total cholesterol, LDL, HDL, triglycerides); fasting glucose / HbA1c (diabetes); high-sensitivity CRP (or homocysteine).

a) Metabolic syndrome — biochemical findings: raised fasting glucose (impaired fasting glucose or frank diabetes); dyslipidaemia (raised triglycerides, low HDL cholesterol); raised fasting insulin (insulin resistance). These accompany the clinical criteria of central obesity and hypertension.

b) Post-hepatic (obstructive) jaundice: markedly raised conjugated (direct) bilirubin; markedly raised ALP and GGT; mildly raised ALT/AST; urine — dark, bilirubin present, urobilinogen absent/reduced; stool — pale (reduced stercobilinogen); prolonged prothrombin time that corrects with vitamin K.

Context: total pancreatectomy → loss of islet β-cells → no insulin (C-peptide undetectable at 0.01) → new insulin-dependent diabetes presenting as diabetic ketoacidosis (hyperglycaemia, Kussmaul breathing, dehydration, hypotension).

A(i) Sodium, creatinine, urea: Na⁺ raised (150) — hypernatraemia from osmotic (glucose) diuresis and dehydration. Urea (18) and creatinine (160) both raised, with urea disproportionately high → pre-renal acute kidney injury from hypovolaemia (osmotic diuresis, vomiting, hypotension, poor perfusion); the raised urea:creatinine ratio supports a pre-renal/dehydration cause.

A(ii) Acid–base: high-anion-gap metabolic acidosis (pH 7.05, HCO₃⁻ 5) with respiratory compensation (pCO₂ 15 from Kussmaul breathing). Cause: ketoacidosis from insulin deficiency (accumulation of ketone bodies).

A(iii) Anion gap = (Na⁺ + K⁺) − (Cl⁻ + HCO₃⁻) = (150 + 5.9) − (105 + 5) = 45.9 mmol/L (≈40 if K omitted). Markedly raised (normal ~8–16) → confirms high-anion-gap metabolic acidosis from unmeasured anions (ketones).

A(iv) Urine: glycosuria (RBS exceeds the renal threshold); ketonuria; high specific gravity (dehydration) ± casts if AKI.

A(v) Potassium: raised (5.9, hyperkalaemia) — acidosis drives H⁺ into cells in exchange for K⁺ moving out; insulin deficiency prevents cellular K⁺ uptake; AKI reduces renal excretion. Note: total-body potassium is actually depleted (osmotic-diuresis losses) and will fall sharply once insulin and fluids are started — monitor closely.

B(i) Diagnosis: acute myocardial infarction. Reasons — markedly raised hs-Troponin I with a rise-and-fall pattern (peak ~day 3), raised CK-MB (>2×), in a patient with chest pain. The characteristic troponin kinetics are diagnostic of acute MI.

B(ii) NT-proBNP: released by ventricular myocardium in response to wall stretch/volume overload. Its rise from 310 to 658 (above reference) indicates developing left-ventricular dysfunction / early heart failure as a complication of the infarct (ventricular remodelling).

B(iii) Serial hs-Troponin: to demonstrate the rise-and-fall (delta) that distinguishes acute MI from chronic troponin elevation (e.g. CKD, chronic heart failure), to help when the first sample is early/borderline, and to gauge infarct size or detect re-infarction.

B(iv) Modifiable risk factors here: atherogenic dyslipidaemia — very high triglycerides (7.33) and low HDL (0.79). (Others modifiable in general: smoking, hypertension, diabetes, obesity, inactivity, diet.)

B(v) Tests for complications: NT-proBNP/BNP (heart failure); renal function (cardiorenal); serial troponin (re-infarction); electrolytes K⁺/Mg²⁺ (arrhythmia risk); glucose/HbA1c and lipid profile (risk factors). LFTs for statin monitoring.

(a)(i) Bence Jones protein (free monoclonal immunoglobulin light chains, seen in multiple myeloma):

• Classic heat test (historical): urine heated to ~40–60°C precipitates the protein, which redissolves on boiling (~100°C) and reappears on cooling — unreliable.
• Definitive: urine protein electrophoresis with immunofixation on a concentrated urine sample identifies the monoclonal light chain (κ or λ); serum free light-chain assay is complementary.
• Note: the standard urine dipstick does not detect Bence Jones protein (it detects albumin, not light chains).

(ii) Characteristics of plasma proteins: synthesised mainly by the liver (except immunoglobulins — plasma cells); amphoteric, carrying a net negative charge at physiological pH (so they migrate in an electric field); diverse functions — oncotic pressure and transport (albumin), transport (transferrin), immunity (immunoglobulins), clotting (fibrinogen), plus enzymes and hormones; vary in size/molecular weight; total plasma protein ~60–80 g/L with albumin the most abundant.

(iii) Serum protein electrophoresis (alkaline pH ~8.6) separates five bands from anode (+) to cathode (−): albumin (largest peak), α₁-globulins (α₁-antitrypsin), α₂-globulins (haptoglobin, α₂-macroglobulin, ceruloplasmin), β-globulins (transferrin, C3, β-lipoprotein) and γ-globulins (immunoglobulins IgG/IgA/IgM).

(b) Neonatal jaundice. Baby A shows unconjugated hyperbilirubinaemia (total 142.7, direct only 7.7 → indirect ≈135). Baby B shows conjugated hyperbilirubinaemia (total 385, direct 318).

(i) Clinical detection: jaundice becomes visible once serum bilirubin exceeds ~34–50 µmol/L (>2–3 mg/dL); in neonates skin jaundice is usually apparent above ~85 µmol/L (~5 mg/dL).

(ii) Two possible causes: (1) haemolytic disease of the newborn (ABO/Rh incompatibility, G6PD) → unconjugated pattern (Baby A) — also physiological or breast-milk jaundice; (2) biliary atresia / obstructive (or neonatal hepatitis, choledochal cyst, sepsis, galactosaemia) → conjugated pattern (Baby B).

(iii) ALT/AST/ALP/GGT (values given for Baby A): all sit within or near their reference ranges (ALT 23, AST 27, ALP 124 [ref ≤128; ALP is physiologically higher in infants due to bone growth], GGT 50) — so they are not deranged. This fits a pre-hepatic/unconjugated (haemolytic) cause, which does not injure hepatocytes (would raise ALT/AST) or bile ducts (would raise ALP/GGT). In a conjugated/obstructive picture like Baby B, one would instead expect raised GGT and ALP.

(iv) Urine dipstick: Baby A (unconjugated/haemolytic) — bilirubin negative (unconjugated bilirubin is albumin-bound, insoluble and not filtered) with raised urobilinogen (more bilirubin is conjugated, excreted and reabsorbed). Baby B (conjugated/obstructive) — bilirubin positive (conjugated bilirubin is water-soluble and filtered → dark urine) with reduced/absent urobilinogen if the obstruction is complete.

i) Causes of hypoglycaemia (any three): insulinoma (autonomous insulin secretion by a pancreatic beta-cell tumour); exogenous insulin or sulfonylurea (therapeutic, factitious or overdose); adrenal insufficiency (Addison disease, cortisol deficiency) or hypopituitarism; severe liver disease (impaired gluconeogenesis and glycogenolysis); alcohol (inhibits gluconeogenesis); sepsis; non-islet-cell tumours secreting IGF-2.

ii) Biochemical tests + reasons:

• Plasma insulin and C-peptide taken during hypoglycaemia: high insulin with high C-peptide indicates endogenous excess (insulinoma or sulfonylurea); high insulin with low C-peptide indicates exogenous insulin
• Sulfonylurea screen: distinguishes drug-induced hyperinsulinism from an insulinoma
• Serum cortisol (with a short Synacthen test): excludes adrenal insufficiency as a cause

(Also useful: proinsulin, beta-hydroxybutyrate - suppressed in insulin excess - and a laboratory glucose to confirm true hypoglycaemia, i.e. Whipple triad.)

The choice depends on the likely primary site. Three useful markers, with reasons:

• CEA (carcinoembryonic antigen): raised in colorectal carcinoma (also gastric and pancreatic); supports diagnosis, aids staging, and monitors for recurrence after resection
• AFP (alpha-fetoprotein): raised in hepatocellular carcinoma and germ-cell (yolk-sac) tumours; helps identify a hepatic primary and monitor treatment response
• CA 19-9: raised in pancreatic and biliary (cholangiocarcinoma) tumours; supports diagnosis and monitors response and recurrence

(Also acceptable with reasons: CA-125 for ovarian, PSA if prostate, beta-hCG for germ-cell tumours.) Markers support diagnosis and monitor disease; they are not diagnostic on their own because they lack specificity.

i) Type: obstructive (post-hepatic / cholestatic) jaundice - a predominantly conjugated (direct) hyperbilirubinaemia with markedly raised ALP and GGT but near-normal transaminases (a cholestatic, not hepatocellular, pattern).

ii) Differentials: carcinoma of the head of the pancreas; cholangiocarcinoma; choledocholithiasis (a stone in the common bile duct); periampullary carcinoma.

iii) Tumour markers + reasons: CA 19-9 (raised in pancreatic and biliary carcinoma, supporting a malignant obstructive cause); CEA (raised in pancreaticobiliary and metastatic GI adenocarcinoma, complements CA 19-9).

iv) Urine findings: dark urine with raised conjugated bilirubin (bilirubinuria, positive on dipstick); urobilinogen absent or reduced (obstruction blocks bile flow to the gut). Stools are clinically pale.

a) Causes of hypernatraemia (a water deficit relative to sodium):

• Pure water loss or reduced intake: impaired thirst or no access to water (elderly, unconscious), fever and high insensible loss
• Renal water loss: diabetes insipidus (cranial or nephrogenic), osmotic diuresis (hyperglycaemia, mannitol)
• GI water loss: osmotic diarrhoea, vomiting
• Sodium excess: hypertonic saline or sodium bicarbonate infusion, primary hyperaldosteronism / Cushing syndrome, salt poisoning

b) Clinical features (mainly neurological, from cellular dehydration and brain shrinkage): thirst; lethargy, weakness, irritability and restlessness; confusion progressing to drowsiness, seizures and coma; muscle twitching and hyperreflexia; features of the cause (polyuria and polydipsia in diabetes insipidus); signs of volume depletion (dry mucous membranes, reduced skin turgor, tachycardia, hypotension); in severe or rapid cases, intracranial (subdural) haemorrhage from tearing of bridging veins.

a) Immunopathogenesis: H. pylori colonises the gastric mucus layer — urease neutralises gastric acid, flagella provide motility and adhesins anchor it to the epithelium. Virulence factors CagA and VacA injure epithelial cells and trigger both innate (neutrophils, macrophages) and adaptive (Th1/Th17) immune responses. Released cytokines (IL-8 recruits neutrophils; TNF, IL-1) drive a chronic active gastritis and disturb acid regulation, producing peptic ulceration. Persistent inflammation leads to atrophic gastritis → intestinal metaplasia → dysplasia, raising the risk of gastric adenocarcinoma and MALT lymphoma.

b) Other laboratory tests: rapid urease (CLO) test on biopsy; urea breath test; stool antigen test; serology for anti-H. pylori antibodies; histology with Giemsa or Warthin–Starry stain; and culture.

Primary vs secondary immune response: the primary response is slow (5–10-day lag), of lower magnitude, IgM-predominant (then IgG) and of lower affinity; the secondary response is rapid, of higher magnitude, IgG-predominant, of higher affinity (affinity maturation) and longer-lasting — driven by immunological memory.

Cells of the secondary response: memory B cells (rapidly differentiate into antibody-secreting plasma cells); memory helper (CD4) T cells (provide co-stimulation and cytokine help); plasma cells (secrete high-affinity IgG).

ELISA principle & procedure: antigen is adsorbed onto the plate; patient serum is added and specific antibody binds; after washing, an enzyme-labelled anti-human antibody is added; a substrate is then added and the resulting colour change (optical density) is proportional to the amount of bound antibody.

Interpretation: the rise from a pre-booster OD of 0.3 to a post-booster OD of 1.5 indicates a brisk secondary (anamnestic) antibody response, i.e. good immunological memory.

Toxoid vs immune globulin: tetanus toxoid is an inactivated toxin used for active immunisation — it stimulates the person's own long-lasting antibody production; tetanus immune globulin supplies preformed antibodies (passive immunisation) giving immediate but short-lived protection.