Skip to main content
Public beta This website is in public beta – please give your feedback.
Primary Care

Presentation: Patient with iron overload (suspected hereditary haemochromatosis)

Hereditary haemochromatosis is an autosomal recessive condition leading to increased iron absorption, its accumulation in the body (biochemical penetrance) and resulting in multiorgan damage (clinical penetrance).

At a glance:

  • Hereditary haemochromatosis (HH) is an autosomal recessive genetic condition that may lead to a build-up of iron in the body. HH is one of the most common genetic conditions in northern European – particularly Celtic – populations.
  • Iron overload is defined as transferrin saturation >45% and serum ferritin >200 ug/L in women and transferrin saturation >50% and serum ferritin >300 ug/L in men without an alternative explanation (such as inflammatory conditions).
  • Among those who are homozygous for C282Y variants 20% of men and 10% of women develop multiorgan damage (in particular, liver, pancreas and bones). Progression of organ damage can be prevented if treatment is commenced early.
  • Alert! Early symptoms are non-specific and may include joint pains, lethargy, weight loss and low libido.

Example clinical scenario

A 45-year-old man attended with fatigue and joint pains. An initial blood test revealed abnormal liver function test results (raised AST). Further blood tests revealed a ferritin level of 1,500 micrograms per litre (ug/l), a transferrin saturation of 52% and a normal CRP.

Identifying those at risk of a genetic condition

  • Flags for an underlying genetic diagnosis of haemochromatosis include:
    • an affected first-degree relative;
    • biochemical or clinical features of iron overload; and/or
    • exclusion of other causes of high ferritin.
  • HH is an autosomal recessive condition caused by pathogenic variants in the HFE gene leading to excessive absorption of iron.
  • Iron overload is defined as transferrin saturation >45% and serum ferritin >200 ug/L in women and transferrin saturation >50% and serum ferritin >300 ug/L in men without an alternative explanation (such as inflammatory conditions).
  • There are two common pathogenic variants (C282Y and H63D) with high carrier frequency in White northern European populations, especially in those with Celtic heritage.
  • HH has variable disease expression: presentation may be non-specific and many individuals never develop clinical features.
  • In the UK population, 1 in 150 are estimated to be homozygous for C282Y variants; individuals with this genotype are at most risk of iron overload. Other genotypes have a much lower penetrance; individuals are much less likely to develop iron overload and rarely develop complications.
  • Males are more likely to develop clinical features than females because women lose iron through menstruation.
  • Early symptoms are non-specific and may include joint pains, lethargy, weight loss and low libido.
  • Features of iron build-up in tissue can include ‘bronze diabetes’ (cirrhosis of the liver, diabetes mellitus and skin pigmentation), arthritis and heart failure.

What should you do next?

  • Blood tests should be undertaken to confirm iron overload and exclude other causes of high ferritin such as inflammation or acute illness: ferritin and fasting transferrin saturation, FBC, LFTs and CRP.
  • Iron overload is treated by venesection. Refer the patient to haematology and/or hepatology/gastroenterology as per local clinical pathways.
  • Individuals of European origin with unexplained iron overload defined as transferrin saturation >45% and serum ferritin >200 ug/L in women or transferrin saturation >50% and serum ferritin >300 ug/L in men are eligible for genomic testing.
  • If a diagnosis is confirmed, genomic testing can be offered to:
    • first-degree relatives (parents, siblings and adult children);
    • partners, if required to determine offspring risk; and
    • children over the age of 15 or 16 years only (the age at which genomic testing is offered to children may vary geographically), as children are rarely affected in early life.
  • Refer to the National Genomic Test Directory under testing criteria R95.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
  • Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

Resources

For clinicians

References:

For patients

↑ Back to top
  • Last reviewed: 31/03/2025
  • Next review due: 31/03/2026
  • Authors: Dr Imran Rafi
  • Reviewers: Professor Guru Aithal, Dr Asma Hamad, Dr Kate Tatton-Brown, Dr Johanna Wong

Related articles