Haemochromatosis

🧭 When to suspect

Genetic (hereditary) haemochromatosis is an autosomal recessive disorder of iron metabolism.

• Deficient activity of the iron-regulating hormone hepcidin drives unregulated intestinal iron absorption.

• Iron is slowly deposited in the liver, pancreas, heart, joints, skin and gonads.

• It is the commonest single-gene disorder in people of Northern European (especially Celtic) ancestry.

• The great majority of clinically significant cases are homozygous for the C282Y variant of the HFE gene.

Penetrance is low:

• 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

• An incidentally elevated ferritin

Consider it also 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