End of Year Essays 2025Master Revision Guide

Cervical carcinoma (usually squamous cell carcinoma arising at the transformation zone) is driven by persistent high-risk HPV infection. It is largely preventable through the twin strategies of vaccination (primary prevention) and screening (secondary prevention).

i. Control - Screening

• HPV DNA testing - now the recommended primary screening test (WHO); detects high-risk HPV before cytological change.
• Cervical cytology (Pap smear) - detects dysplastic/premalignant cells (CIN); reported by the Bethesda system.
• Visual inspection with acetic acid (VIA) - cheap, single-visit "screen-and-treat"; key in low-resource settings including Kenya.
• Colposcopy + biopsy confirms abnormal screens; premalignant lesions are treated by cryotherapy, thermal ablation or LEEP before they become invasive.
• WHO "90-70-90" target: 90% girls vaccinated, 70% women screened (twice by 35 and 45), 90% of disease treated.

i. Control - Vaccination

• HPV vaccines: bivalent (16, 18), quadrivalent (6, 11, 16, 18) and nonavalent (adds 31, 33, 45, 52, 58).
• Given to girls aged 9–14, ideally before sexual debut (Kenya immunises 10-year-old girls with the quadrivalent vaccine).
• Prevents infection with the oncogenic HPV types responsible for ~70–90% of cervical cancers; most effective before HPV exposure.

ii. Etiology

• Persistent infection with high-risk HPV is the central necessary cause - chiefly HPV 16 and 18 (also 31, 33, 45, 52, 58).
• Viral oncoproteins: E6 inactivates p53 and E7 inactivates Rb, driving uncontrolled proliferation and dysplasia.
• Cofactors: early age at first intercourse, multiple sexual partners, high parity, cigarette smoking, immunosuppression (HIV), long-term combined OCP use, other STIs, and low socioeconomic status.

Why the transformation zone? The squamocolumnar junction undergoes active metaplasia, making it vulnerable to HPV-driven dysplasia. Why vaccinate before debut? The vaccine is prophylactic, not therapeutic - it cannot clear an established infection. Viva questions: "Which HPV types?"; "How do E6/E7 work?"; "Difference between CIN and invasive carcinoma?" (invasion breaches the basement membrane); "Why does HIV increase risk?"

The clue is isolated anaemia (Hb 6.2) with jaundice, normal WBC and platelets in an otherwise well young woman. This pattern points to haemolytic anaemia (increased RBC destruction with unconjugated hyperbilirubinaemia), rather than marrow failure (which would drop all lineages).

a) Differential Diagnosis

• Autoimmune haemolytic anaemia (warm AIHA) - most likely: acquired, young woman, may be primary or secondary (SLE, lymphoma, drugs).
• Hereditary haemolytic anaemia - hereditary spherocytosis or G6PD deficiency.
• (Consider also megaloblastic anaemia from B12/folate deficiency, which causes anaemia + mild jaundice via ineffective erythropoiesis.)

b) Salient History

• Drug history - methyldopa, penicillins, oxidant drugs (dapsone, primaquine, sulfonamides for G6PD).
• Family history - anaemia, jaundice, gallstones, splenectomy (hereditary spherocytosis).
• Dark/red urine (haemoglobinuria = intravascular haemolysis).
• Recent infection or fava-bean ingestion (G6PD trigger); features of SLE (rash, arthralgia) or lymphoma (fever, night sweats, weight loss, lumps).
• Diet (vegan → B12), transfusion/pregnancy history, ethnicity.

c) Investigations & Expected Findings

Two goals: confirm haemolysis and find the cause.

• Reticulocyte count - raised (appropriate marrow response).
• Peripheral blood film - polychromasia, spherocytes (AIHA/HS), bite & blister cells + Heinz bodies (G6PD), agglutination (cold AIHA), schistocytes (MAHA).
• Unconjugated (indirect) bilirubin - raised; LDH raised; serum haptoglobin low/absent.
• Direct antiglobulin test (Coombs / DAT) - positive → AIHA; negative → hereditary/non-immune cause.
• Urinalysis - raised urobilinogen; haemoglobinuria / haemosiderinuria in intravascular haemolysis.
• Cause-specific: G6PD assay, osmotic fragility / EMA-binding test (spherocytosis); ANA if SLE suspected; B12/folate if macrocytic.

d) Appropriate Blood Product

Leucodepleted, cross-matched packed red blood cells. In AIHA the autoantibody makes crossmatching difficult, so give ABO/Rh-compatible "least-incompatible" units, transfuse slowly under steroid cover and close monitoring. Correct the anaemia, not just the number.

e) Late (≈1 week) Adverse Transfusion Events

• Delayed haemolytic transfusion reaction (5–14 days) - anamnestic alloantibody, falling Hb, jaundice, fatigue.
• Transfusion-transmitted infection (viral/bacterial).
• (Also acceptable: transfusion-associated GvHD, post-transfusion purpura, alloimmunisation.)

Why jaundice is unconjugated: excess haem overwhelms hepatic conjugation. Why haptoglobin falls: it mops up free haemoglobin and the complex is cleared. Why crossmatch is hard in AIHA: the panagglutinating autoantibody reacts with all donor cells. Viva: "Intravascular vs extravascular haemolysis?"; "What does a positive DAT tell you?"; "Why give folate in chronic haemolysis?" (high RBC turnover consumes folate).

The combination of prolonged bleeding time (platelet-type defect) AND prolonged APTT (intrinsic-pathway/factor defect) in a young woman with menorrhagia is the classic footprint of von Willebrand disease - because von Willebrand factor (vWF) mediates platelet adhesion (bleeding time) and carries/stabilises factor VIII (APTT).

a) Causes of Prolonged APTT

• Haemophilia A (factor VIII deficiency)
• Haemophilia B (factor IX deficiency)
• von Willebrand disease (reduced vWF → low factor VIII)
• Heparin therapy
• Lupus anticoagulant / antiphospholipid antibody
• (Also: factor XI/XII deficiency, DIC, liver disease, vitamin K deficiency)

b) Most Likely Cause

von Willebrand disease - commonest inherited bleeding disorder, autosomal dominant, presenting with mucocutaneous bleeding (menorrhagia, epistaxis, easy bruising). It uniquely prolongs both the bleeding time and the APTT.

c) Confirmatory Tests

• vWF antigen (vWF:Ag) - quantity of vWF (reduced).
• vWF activity (ristocetin cofactor, vWF:RCo) - function of vWF (reduced).
• Factor VIII coagulant activity (FVIII:C) - reduced.
• Ristocetin-induced platelet aggregation (RIPA) and vWF multimer analysis - to type the disease (type 1/2/3).
• (Blood group - type O individuals have lower baseline vWF.)

d) Principles of Management

• Desmopressin (DDAVP) - releases endogenous vWF/FVIII from endothelium (effective in type 1).
• Tranexamic acid - antifibrinolytic for mucosal bleeding and menorrhagia.
• vWF/Factor VIII concentrate (or cryoprecipitate) - for type 3, severe or major bleeding/surgery.
• Combined oral contraceptive pill - controls menorrhagia and raises vWF.
• Avoid aspirin/NSAIDs; give iron for anaemia; genetic counselling.

f) Blood Product for Hb 6 with Symptoms

Two products for two problems: leucodepleted packed red cells to correct the symptomatic anaemia, plus a vWF/Factor VIII concentrate (or cryoprecipitate, which contains vWF, FVIII and fibrinogen) to correct the bleeding tendency and stop ongoing menorrhagia.

Why APTT is prolonged in vWD: vWF is the plasma carrier that protects factor VIII from degradation; low vWF means low FVIII. Why bleeding is mucocutaneous: platelet-adhesion defects cause mucosal bleeding (menorrhagia, epistaxis, gums), unlike the deep joint/muscle bleeds of haemophilia. Viva: "Difference between vWD and haemophilia A pattern?"; "How does a mixing study work?"; "Why is DDAVP contraindicated in type 2B?"

Splenomegaly in a child is best approached by mechanism-based categories: infective, haematological/malignant, haemolytic, congestive (portal hypertension) and infiltrative (storage). In an East-African child, chronic malaria and visceral leishmaniasis must top the list.

a) Possible Causes

• Chronic infection - malaria (hyperreactive malarial splenomegaly), visceral leishmaniasis (kala-azar), EBV, TB, schistosomiasis.
• Haematological malignancy - acute lymphoblastic leukaemia, lymphoma.
• Chronic haemolytic anaemia - sickle cell disease (early), thalassaemia, hereditary spherocytosis.
• Portal hypertension - congestive splenomegaly from chronic liver disease or portal-vein thrombosis.
• Storage / infiltrative disease - Gaucher disease, Niemann-Pick.

b) Laboratory Investigations

• Full blood count + differential + peripheral blood film - cytopenias, blasts (leukaemia), sickle cells, malaria parasites, target cells.
• Malaria microscopy / rapid diagnostic test.
• Reticulocyte count - raised in haemolysis.
• Bone marrow aspirate/trephine - leukaemic blasts, Leishmania amastigotes, Gaucher cells.
• Haemoglobin electrophoresis / sickling test - sickle cell / thalassaemia.
• Liver function tests + coagulation - chronic liver disease/portal hypertension.
• Serology - HIV, EBV, viral hepatitis, Leishmania rK39.
• Abdominal ultrasound - confirm spleen size, assess liver and portal vein; blood cultures if endocarditis suspected.

Why the spleen enlarges: work hypertrophy (clearing parasites/abnormal cells), congestion (portal hypertension), infiltration (leukaemia, storage cells) or extramedullary haematopoiesis. Hypersplenism then causes cytopenias by pooling and destroying cells. Viva: "How do you clinically confirm the mass is spleen?" (moves with respiration, notch, cannot get above it, dull to percussion, not ballotable); "Which single test would you do first?" (FBC + film + malaria smear).

Whole picture: total pancreatectomy removed the islet beta cells → absolute insulin deficiency → new-onset diabetes presenting as diabetic ketoacidosis (DKA) with dehydration and pre-renal acute kidney injury. This is pancreatogenic (type 3c) diabetes.

i. Sodium, Creatinine and Urea

• Na 150 = hypernatraemia (ref 135–145). And because the high glucose already draws water into plasma and dilutes sodium, the corrected sodium is even higher, confirming a large free-water deficit.
• Urea 18 and creatinine 160 = raised (urea ref 2.5–7.5; creatinine 60–110), with the urea rising proportionally more than creatinine → pre-renal pattern.
• Cause: severe dehydration from glucose-driven osmotic diuresis plus vomiting → hypovolaemia → pre-renal acute kidney injury and haemoconcentration.

ii. Acid-Base Imbalance

High anion gap metabolic acidosis with respiratory compensation. pH 7.05 (acidaemic), HCO₃ 5 (low, metabolic), pCO₂ 15 (low = the Kussmaul breathing blowing off CO₂ to compensate). Cause: accumulation of ketoacids (β-hydroxybutyrate, acetoacetate) in DKA.

iii. Anion Gap

Anion gap = Na − (Cl + HCO₃) = 150 − (105 + 5) = 40 mmol/L (normal 8–12). This is a markedly raised (high) anion gap, consistent with the unmeasured ketoanions of DKA.

iv. Urine Examination

• Glycosuria (glucose exceeds the renal threshold).
• Ketonuria (acetoacetate on dipstick).
• High specific gravity/osmolality reflecting dehydration.

v. Potassium

• K 5.9 = hyperkalaemia (ref 3.5–5.0).
• Cause: acidosis shifts K⁺ out of cells (H⁺/K⁺ exchange), insulin deficiency removes the drive pushing K⁺ into cells, and AKI reduces renal excretion.
• Key caveat: despite the high serum level, total body potassium is depleted (lost via osmotic diuresis and vomiting). It will fall sharply once insulin and fluids are started, so monitor and replace early.

Why Kussmaul breathing: deep, rapid respiration lowers pCO₂ to partly correct the severe metabolic acidosis. Why the AKI is pre-renal: volume depletion reduces renal perfusion, raising urea more than creatinine. Why this patient became diabetic: pancreatectomy removed insulin-producing islets. Viva: "How do you calculate anion gap?"; "Why does K⁺ fall with treatment?"; "Difference between DKA and HHS?" (HHS: higher glucose, minimal ketones, higher osmolality, older type 2).

Whole picture: chest pain plus raised cardiac injury markers (hs-troponin I and CK-MB) in a middle-aged man with a dyslipidaemic profile points to acute myocardial infarction / acute coronary syndrome, with the NT-proBNP flagging early cardiac dysfunction.

i. Likely Diagnosis

• Acute myocardial infarction (ACS).
• Reasons: typical chest pain; markedly elevated hs-troponin I (435 rising to 7266 ng/L, the most specific marker of myocardial necrosis); elevated CK-MB (53 U/L, supports recent myocardial injury); and an atherogenic dyslipidaemia (low HDL 0.79, high triglycerides 7.33, with total cholesterol and LDL still within range) providing the risk substrate.

ii. NT-proBNP Result

Elevated NT-proBNP is released from ventricular myocytes in response to wall stretch/strain. Here it signals left ventricular dysfunction / early heart failure complicating the infarct. It is a marker of ventricular strain and prognosis, not of necrosis, and rises when the damaged ventricle is under increased load.

iii. Why Serial hs-Troponin I

To demonstrate the characteristic rise and/or fall (delta) that confirms acute myocardial injury and distinguishes it from a chronically raised troponin. A single early sample can be normal because troponin takes a few hours to rise; 0h/1h or 0h/3h serial sampling improves both sensitivity and specificity and allows rapid rule-in/rule-out.

iv. Modifiable Risk Factors

• Smoking
• Hypertension
• Dyslipidaemia (high LDL, low HDL)
• Diabetes mellitus
• Obesity, physical inactivity, unhealthy diet, excess alcohol, stress

v. Biochemical Tests for Complications

• NT-proBNP/BNP - heart failure.
• Urea, electrolytes & creatinine - cardiorenal syndrome, arrhythmia risk (K⁺, Mg²⁺), contrast nephropathy.
• Glucose / HbA1c - diabetes; fasting lipids for ongoing risk; blood gas/lactate if cardiogenic shock.

Why troponin is specific: cardiac troponins I and T are unique isoforms of contractile protein released only on myocyte death. Why NT-proBNP rises after MI: the infarcted ventricle stretches, myocytes secrete proBNP which is cleaved to BNP and NT-proBNP. Viva: "Which marker rises first?" (myoglobin); "Which is most specific?" (troponin); "Why serial testing?" (delta change); "How does CK-MB help after troponin exists?" (re-infarction).

1. Polymerase Chain Reaction (PCR)

An in-vitro method that amplifies a specific DNA sequence millions of times. It requires template DNA, two primers, Taq DNA polymerase, dNTPs and a thermal cycler. Each cycle has three steps: denaturation (~94°C, strands separate), annealing (~55°C, primers bind), and extension (~72°C, polymerase synthesises new strands). Variants include reverse-transcription PCR (from RNA) and real-time/quantitative PCR.

2. Gel Electrophoresis

Separates DNA fragments by size. DNA (negatively charged) migrates through an agarose gel in an electric field toward the anode; smaller fragments travel further. Fragments are visualised under UV after staining with ethidium bromide (or a safer dye) and sized against a molecular-weight ladder.

3. Southern Blotting

Detects a specific DNA sequence. Steps: restriction-enzyme digestion → gel electrophoresis → denaturation → transfer (blotting) onto a nitrocellulose/nylon membrane → hybridisation with a labelled (radioactive or fluorescent) probe → detection. Used to detect gene rearrangements and RFLPs.

4. DNA Sequencing

Determines the exact order of nucleotides. The Sanger (chain-termination) method uses dideoxynucleotides (ddNTPs) that stop chain elongation, generating fragments read by electrophoresis. Next-generation sequencing (NGS) performs massively parallel high-throughput sequencing of whole genomes/exomes.

Other acceptable techniques: restriction fragment length polymorphism (RFLP), fluorescence in-situ hybridisation (FISH), and DNA microarrays.

Why Taq polymerase: it survives the 94°C denaturation step, so it need not be replaced each cycle. Why primers: they define the exact sequence amplified. Applications: molecular diagnosis of infections, genetic disease, cancer mutations, and paternity/forensic testing. Viva: "What does each PCR temperature do?"; "Difference between Southern and Northern blot?"; "What does a ddNTP do in sequencing?"

Monoclonal antibodies (mAbs) are identical antibodies produced by a single clone of B cells, all directed against a single epitope. They are made by hybridoma technology (Köhler and Milstein, 1975).

Production - Hybridoma Technology (stepwise)

1. Immunisation: a mouse is injected with the target antigen to stimulate an antibody response.
2. Harvest B cells: antibody-producing B lymphocytes (plasma cells) are isolated from the mouse spleen.
3. Fusion: spleen B cells are fused with immortal myeloma cells using polyethylene glycol (PEG) to form hybridomas. (The myeloma line lacks the enzyme HGPRT.)
4. Selection in HAT medium (hypoxanthine-aminopterin-thymidine): aminopterin blocks the de-novo nucleotide pathway, so only fused hybridomas (which gain HGPRT from the B cell and immortality from the myeloma) survive via the salvage pathway. Unfused myeloma cells die; unfused B cells die naturally.
5. Screening: supernatants are tested (e.g. by ELISA) for antibody of the desired specificity.
6. Cloning: positive hybridomas are cloned by limiting dilution so each culture derives from a single cell (truly monoclonal).
7. Expansion & harvest: clones are expanded in culture (or as ascites) and the monoclonal antibody is purified.

Two Applications

• Diagnostic: pregnancy tests (detect hCG), ELISA, immunohistochemistry, blood grouping, tumour-marker detection and flow cytometry.
• Therapeutic: targeted treatment, e.g. rituximab (anti-CD20, lymphoma), trastuzumab (anti-HER2, breast cancer), infliximab (anti-TNF-α, autoimmune disease).
• (Also acceptable: research/purification, and imaging/radioimmunodetection.)

Why fuse two cells: B cells make the specific antibody but die in culture; myeloma cells are immortal but make no useful antibody. The hybrid gets both properties. Why it matters clinically: mAbs give reproducible, highly specific reagents for diagnosis and precisely targeted therapy (cancer, autoimmune disease). Viva: "What is a hybridoma?"; "Why HAT medium?"; "Monoclonal vs polyclonal?"; "Give a therapeutic mAb and its target."