Haemochromatosis

Overview

•Autosomal recessive disorder of iron overload - most common genetic disorder in Northern European descent (~1 in 200)

•Caused by HFE gene mutation (chromosome 6) - most commonly C282Y homozygosity

•Mechanism: HFE mutation → reduced hepcidin → ferroportin remains active → unregulated duodenal iron absorption → progressive organ iron deposition

•Men present earlier/more severely; pre-menopausal women protected by menstrual iron loss

Presentation

•Early (non-specific): fatigue, arthralgia (2nd/3rd MCP joints - 'iron fist'), reduced libido/erectile dysfunction, abdominal pain

•Classic triad: bronze skin + diabetes mellitus ('bronze diabetes') + cirrhosis

•Cardiomyopathy - dilated, from myocardial iron deposition; arrhythmias

•Hypogonadism - pituitary iron deposition → low LH/FSH/testosterone → testicular atrophy, amenorrhoea

🧠

Mnemonic ABCDE: Arthropathy (2nd/3rd MCP), Bronze skin, Cirrhosis/Cardiomyopathy, Diabetes mellitus, Endocrine dysfunction (hypogonadism, adrenal). The 2nd/3rd MCP joint pattern is a characteristic discriminating clue.

Investigations

🥇 First-line

•transferrin saturation - most important screening test; >45% triggers genetic testing

•serum ferritin - raised in iron overload but non-specific (rises with inflammation, alcohol, diabetes, malignancy); normal ferritin essentially excludes significant iron overload

•HFE genetic testing - confirms C282Y homozygosity (or C282Y/H63D compound heterozygosity) after raised transferrin saturation

🏆 Gold standard

•liver biopsy with Perl's Prussian blue stain - quantifies hepatocyte iron and grades fibrosis; indicated if ferritin >2247 pmol/L or clinical liver involvement

🥈 Second-line

•MRI liver/heart - non-invasive iron quantification; ECG and echo if cardiac involvement suspected

⚠️

Ferritin is an acute phase reactant - raised ferritin alone is insufficient to diagnose iron overload. Always interpret alongside transferrin saturation. Genetic testing follows confirmed raised transferrin saturation, not a raised ferritin in isolation.

Management

🥇 First-line

•venesection (phlebotomy) - weekly initially until ferritin <50 µg/L, then maintenance 2-4 times/year; halts progression; reverses cardiomyopathy if early; does not reverse established cirrhosis

•If venesection not tolerated: desferrioxamine - iron chelation therapy

•Organ-specific: diabetes managed per standard guidelines; testosterone replacement for established hypogonadism; standard heart failure therapy for cardiomyopathy

•Cirrhosis: lifelong 6-monthly liver ultrasound + AFP for HCC surveillance - risk persists even after successful iron depletion

💡

Treatment before organ damage (cirrhosis or diabetes) results in normal life expectancy. Once cirrhosis is established, venesection slows but does not reverse fibrosis and HCC risk persists.

Prevention and screening

•First-degree relatives should be offered serum ferritin and transferrin saturation, followed by HFE mutation analysis if iron studies abnormal

•Siblings of a confirmed C282Y homozygote have a 25% chance of being affected

•General population genetic screening is not currently recommended given low disease penetrance