Synopsis
Confirm clinically meaningful hereditary iron overload, distinguish reactive hyperferritinaemia and use safe venesection, organ assessment and family testing.
- Classic HFE haemochromatosis is an autosomal recessive disorder of inappropriately increased intestinal iron absorption, most strongly associated with C282Y homozygosity.
- Penetrance is incomplete: a genotype confers risk, while biochemical and clinical iron overload determine organ threat and treatment need.
- Transferrin saturation rises early and is central to recognising iron loading; ferritin estimates stores but also rises with inflammation, alcohol, metabolic liver disease and malignancy.
- Repeat iron studies in a clinically stable state and assess CRP, alcohol, metabolic health, blood count and liver tests before ordering or interpreting HFE testing.
- HFE genotyping follows current NHS genomic eligibility and should not be used as indiscriminate population screening.
- Liver fibrosis, diabetes, hypogonadism, cardiomyopathy, arrhythmia, MCP arthropathy and skin pigmentation represent clinically expressed disease.
- MRI can quantify hepatic iron and help separate primary iron loading from reactive ferritin elevation; biopsy is now reserved for unresolved diagnosis or staging.
- Therapeutic venesection is first-line for confirmed iron overload, initially frequent and later maintenance-based, with haemoglobin and ferritin safeguards.
- Venesection can prevent or improve some hepatic and endocrine complications but established arthropathy and cirrhosis may not reverse.
- HCC surveillance continues in people with cirrhosis even after iron depletion, and adult first-degree relatives should receive informed cascade assessment.
Key red flags
Hepatomegaly, raised aminotransferases, fibrosis or cirrhosis occurs with an iron-loading phenotype, often amplified by alcohol or metabolic steatosis.
Unexplained cardiomyopathy, conduction disease or arrhythmia with substantial iron loading requires prompt cardiology and specialist iron assessment.
Investigation priorities
Identify persistent excess circulating iron availability.
Management branches
Ferritin is elevated on routine or symptom-led blood testing.
- Review infection, inflammation, alcohol, metabolic risk, transfusions, supplements, malignancy and kidney or liver disease and obtain CRP, full blood count and liver tests.
- Measure transferrin saturation and repeat indices when clinically stable if results are borderline or discordant.
- Request HFE testing through current genomic criteria when biochemical iron loading remains unexplained, and refer marked loading or abnormal liver tests to hepatology.
- Use MRI iron and fibrosis assessment, reserving broader genetic testing or biopsy for specialist evaluation of non-HFE or mixed phenotypes.
Key medicines
Therapeutic venesectionA typical induction removes approximately 500 mL of blood weekly or fortnightly, but use a smaller volume or longer interval for low body mass, older age or comorbidity and follow the current BSH and local ferritin and haemoglobin targets.Check haemoglobin and clinical tolerance before each procedure and avoid venesection during instability or significant anaemia. Replace fluid where needed, investigate unexpected haemoglobin decline and do not use an arbitrary schedule after depletion.
Iron chelationA specialist may select deferasirox, desferrioxamine or another chelator at its current BNF and commissioning regimen only when significant overload cannot be managed by venesection; this is uncommon and may be off-label for HFE disease.Renal, hepatic, gastrointestinal, auditory, ocular and marrow toxicity vary by agent and require product-specific baseline and serial monitoring. Chelation should not be offered merely for reactive ferritin elevation.