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Stem
A 52-year-old man of Irish descent presents with a 6-month history of fatigue, loss of libido and progressive pain in the second and third metacarpophalangeal joints of both hands. His wife has noticed his skin "turning bronze". He drinks 30 units of alcohol per week. Examination reveals slate-grey pigmentation over sun-exposed areas, hepatomegaly (4 cm below costal margin), testicular atrophy and bony swelling of the 2nd/3rd MCP joints. Investigations show: ALT 78 U/L, AST 92 U/L, fasting glucose 9.4 mmol/L, ferritin 1640 micrograms per litre, transferrin saturation 78 percent.
Questions
a) What is the most likely diagnosis and which two screening tests pointed to it? What confirmatory test would you request? (3 marks)
Diagnosis: hereditary haemochromatosis, likely HFE Type 1. Screening tests: fasting transferrin saturation 78 percent (over 45 percent) and serum ferritin 1640 micrograms per litre (over 300). Confirmatory test: HFE genotyping (expect C282Y homozygosity).
b) Outline the pathophysiology in three sentences. (2 marks)
Mutant HFE protein fails to up-regulate hepcidin in response to iron load, leaving ferroportin unopposed on enterocytes and macrophages. Unregulated duodenal absorption rises from 1-2 mg to 3-6 mg daily, with no excretion mechanism, so iron accumulates at about 1 g per year. Free iron drives Fenton chemistry (Fe²⁺ + H₂O₂ → hydroxyl radical), peroxidating membranes and damaging DNA in hepatocytes, cardiomyocytes, beta-cells, synoviocytes and pituitary gonadotrophs.
c) Describe the definitive management with specific parameters (drug, dose, target, monitoring). (3 marks)
Therapeutic venesection (phlebotomy) is first-line: remove one unit (450-500 mL) weekly or fortnightly, removing about 200-250 mg iron per session. Monitor haemoglobin before each session (postpone if under 110 g/L) and ferritin every 4-8 weeks. Target ferritin 50-100 micrograms per litre (avoid under 20), then maintenance one venesection every 2-4 months. Lifestyle: stop alcohol, avoid iron, vitamin C and raw shellfish. Begin 6-monthly liver ultrasound plus alpha-fetoprotein for hepatocellular carcinoma surveillance (he has signs of cirrhosis risk).
d) List two irreversible complications despite treatment and explain the screening obligation for relatives. (2 marks)
Irreversible: arthropathy and hypogonadotropic hypogonadism (also diabetes often irreversible). All first-degree relatives (siblings and children) must be offered HFE genotyping plus fasting transferrin saturation and ferritin — pre-symptomatic C282Y homozygotes should be followed and venesected if iron loading develops.