Haemochromatosis

🧭 When to suspect

Genetic (hereditary) haemochromatosis is an autosomal recessive disorder of iron metabolism in which deficient activity of the iron-regulating hormone hepcidin drives unregulated intestinal iron absorption, with slow iron deposition in the liver, pancreas, heart, joints, skin and gonads. It is the commonest single-gene disorder in people of Northern European (especially Celtic) ancestry, and the great majority of clinically significant cases are homozygous for the C282Y variant of the HFE gene.

Penetrance is low: although roughly 1 in 150–200 people of Northern European descent are C282Y homozygous, only about 1 in 5 men and 1 in 10 women with that genotype ever develop organ damage. Early symptoms are vague and easily attributed to ageing, so the discipline is simple – suspect it, then prove it biochemically.

Consider haemochromatosis in adults with persistent unexplained fatigue ("tired all the time", TATT), arthralgia (classically the 2nd and 3rd metacarpophalangeal [MCP] knuckle joints), erectile dysfunction or loss of libido, amenorrhoea, unexplained raised liver enzymes, or an incidentally elevated ferritin – and in any first-degree relative of a confirmed case.

The first-line tests are fasting transferrin saturation (TSAT) and serum ferritin. Iron overload – and eligibility for HFE genetic testing under the National Genomic Test Directory (R95) – is defined as follows, in the absence of another explanation:

TSAT is the percentage of transferrin that is carrying iron, calculated as (serum iron ÷ total iron-binding capacity [TIBC]) × 100. A ferritin > 1000 µg/L signals a high risk of cirrhosis and warrants urgent specialist referral. Secondary iron overload (e.g. from repeated transfusions or chronic haemolytic anaemias) is managed differently and falls outside this article.

Source: British Society for Haematology · EASL 2022 · NHS Genomics Education