Haemochromatosis

Condition

Autosomal recessive — 1 in 10 people are carriers, 1 in 200 homozygous. More common in patients of northern European descent.

Genotype/risk:

• Homozygous C282Y — high risk of hereditary haemochromatosis (HHC, ~50%).
• Compound heterozygous C282Y/H63D — milder form of HHC.
• Homozygous H63D — unlikely to develop clinical HHC.
• Heterozygous C282Y or H63D alone — do not usually cause HHC; consider another diagnosis.

Secondary iron overload from chronic haemolysis and multiple transfusions is termed haemosiderosis, a distinct entity.

History and examination

Most patients are asymptomatic. Some have extreme lethargy, abdominal discomfort, polyuria and polydipsia, arthralgia, erectile dysfunction, loss of libido, increasing skin pigmentation, and joint symptoms.

Signs: hepatomegaly; very tanned skin; cardiac arrhythmias; joint swelling; testicular atrophy.

Investigations

Increased serum transferrin saturation (>45%) plus increased serum ferritin. Genetic studies — HFE gene, C282Y and/or H63D mutation. CT, MRI, or FerriScan can show increased iron deposition in the liver.

Consider repeating fasting iron studies, FBC and film, ESR, CRP, LFTs, and fasting BGL to rule out alternative diagnoses (FBC and ESR should be normal in haemochromatosis). If ferritin is isolated and raised without elevated transferrin saturation, consider other causes: infection, inflammation, alcohol use, liver disease (including hepatitis B/C, fatty liver disease), malignancy, metabolic syndrome, endocrine disorder (diabetes, thyroid disease, Addison’s disease), renal disease, anaemia from causes other than iron deficiency, or a blood disorder (e.g. porphyria).

Interpreting results:

Ferritin	Transferrin saturation	What to do
>200µg/L (F), >300µg/L (M)	<45%	Non-specific, non-iron-overload-related elevation — consider other causes of raised ferritin
>200µg/L (F), >300µg/L (M)	≥45%	Suggests possible iron overload — investigate further with HFE gene testing
>1000µg/L	—	Suggests iron overload; very high ferritin in patients with haemochromatosis makes end-organ damage more likely

Homozygous C282Y confirms HHC and explains the elevated ferritin. Compound heterozygous (C282Y/H63D) confirms HHC and may explain the elevated ferritin. Heterozygous C282Y or homozygous H63D alone don’t usually cause HHC — consider another diagnosis.

Management

Refer to gastroenterology if: LFTs are abnormal, ferritin >1000µg/L, signs of chronic liver disease (e.g. hepatomegaly), or comorbid alcohol dependency. Refer to gastroenterology or haematology if there’s significant diagnostic uncertainty.

Therapeutic venesection if HHC (homozygous C282Y or compound heterozygote C282Y/H63D) and raised ferritin (>200µg/L F, >300µg/L M):

• Iron unloading phase — one or two venesections of 500mL/week until excess iron stores are removed (unlikely to be tolerated at that frequency — do at least monthly). Check Hb before venesection and maintain >120g/L; oral B12 and folate supplements may be needed if Hb is falling. Check ferritin every 4–6 venesections; continue at the tolerated frequency until ferritin is 50–100µg/L.
• Maintenance phase — regular venesection to maintain ferritin 50–100µg/L, typically 3–4 times/year for men and non-menstruating women, 1–2 times/year for other women. Check ferritin every 6–12 months.

Advise the patient to avoid: iron supplements; vitamin C supplements; excessive alcohol consumption. Screen first-degree relatives with fasting iron studies plus HFE gene testing.

Practical note: Lifeblood’s therapeutic donation pathway lets haemochromatosis patients’ venesected blood be used therapeutically for others — worth mentioning to patients, as it can improve motivation and compliance with the venesection schedule.