Haemochromatosis
On this page
Direct answer
Cirrhosis, diabetes, bronze skin pigmentation and hypogonadism — the classic tetrad of "bronze diabetes" — with a distinctive arthropathy of the second and third metacarpophalangeal joints, signal hereditary haemochromatosis: autosomal recessive iron overload, most often from C282Y homozygosity in the HFE gene, with increased dietary absorption depositing iron in liver, pancreas, heart, joints, skin and pituitary. Screening is by transferrin saturation above 45 per cent with a raised ferritin, and treatment is therapeutic phlebotomy.
What you must remember
- Genetics: autosomal recessive; C282Y homozygosity accounts for most classic cases in people of northern European descent; H63D and S65C variants contribute milder risk; non-HFE causes and secondary iron overload (transfusion-dependent anaemias, dyserythropoiesis) complete the differential.
- Screening and diagnosis: transferrin saturation above 45 per cent prompts ferritin and genetic testing; MRI quantifies liver iron non-invasively; liver biopsy (Perl's Prussian blue stain) shows gradeable iron and assesses fibrosis, traditionally offered when ferritin is very high or liver tests abnormal.
- Clinical features: fatigue and arthropathy (second and third MCP joints first, then wrists, hips, knees) often precede organ disease; hepatomegaly and cirrhosis with hepatocellular carcinoma risk; bronze or slate-grey pigmentation; diabetes from pancreatic deposition; dilated cardiomyopathy and arrhythmia; hypogonadotrophic hypogonadism from pituitary iron.
- Treatment: weekly or twice-weekly phlebotomy of about 500 mL (roughly 250 mg of iron each) until ferritin falls to around 50 to 100 nanograms per mL, then maintenance phlebotomy two to four times a year; erythrocytapheresis or chelation (deferasirox) when phlebotomy is not tolerated or anaemia coexists.
- Advice: avoid iron supplements, vitamin C with meals (enhances absorption), raw shellfish (Vibrio vulnificus risk) and alcohol; screen first-degree relatives with transferrin saturation, ferritin and genotype.
- Prognosis: phlebotomy started before cirrhosis and diabetes restores a near-normal life expectancy; established cirrhosis carries hepatocellular carcinoma risk even after iron depletion, requiring surveillance ultrasound and alpha-fetoprotein.
- Ferritin is an acute-phase reactant — confirm true overload with transferrin saturation and clinical context before depleting iron.
A middle-aged man with sugar, stiff hands and tan
A 55-year-old presents with new diabetes, fatigue, grey-bronze pigmentation and painful stiff second and third metacarpophalangeal joints; his ferritin is 1,400 nanograms per mL. The screening question decides the work-up: transferrin saturation, not ferritin alone, because ferritin is an acute-phase reactant and metabolic syndrome or inflammation raise it without overload — his saturation is 62 per cent, above the 45 threshold, so HFE genotyping follows and returns C282Y homozygosity (H63D and S65C contribute milder risk; transfusional overload is the secondary differential with normal genes). MRI quantifies liver iron, and biopsy with Perl's Prussian blue is reserved for very high ferritin or abnormal liver tests. Survey the deposition systematically: hepatomegaly progressing to cirrhosis with hepatocellular carcinoma risk, pancreatic diabetes, dilated cardiomyopathy and arrhythmia, hypogonadotrophic hypogonadism from pituitary iron, and the arthropathy that often precedes everything. Treatment is phlebotomy of about 500 mL weekly until ferritin falls to 50 to 100, then maintenance two to four times yearly; erythrocytapheresis or deferasirox when phlebotomy is not tolerated. Counsel against iron supplements, vitamin C with meals, raw shellfish (Vibrio vulnificus) and alcohol, and screen first-degree relatives. Depletion before cirrhosis restores near-normal life expectancy; established cirrhosis still requires ultrasound and alpha-fetoprotein surveillance.
Where students slip
Three confusions recur. The ferritin-only diagnosis: a raised ferritin in metabolic syndrome or inflammation is not overload, and the transferrin saturation above 45 per cent is the test that opens the pathway — the exam plants an isolated ferritin precisely to catch it. The arthropathy misread as rheumatoid: haemochromatotic arthropathy has hook-like osteophytes on the metacarpal heads with normal inflammatory markers, not an erosive picture. And hereditary versus secondary: transfusional overload loads the reticuloendothelial system first with normal HFE genes. The single-liners recycle dependably — autosomal recessive inheritance, HFE C282Y on chromosome 6, bronze diabetes, second and third MCP joints, phlebotomy targets of 50 to 100 — with family screening as the viva add-on.
Frequently asked questions
What is the inheritance and gene of hereditary haemochromatosis?
Autosomal recessive, most commonly due to homozygous C282Y mutation of the HFE gene on chromosome 6.
What screening test suggests iron overload?
Transferrin saturation above 45 per cent, followed by serum ferritin and HFE genetic testing.
Which arthropathy is characteristic?
Pain and bony swelling of the second and third metacarpophalangeal joints with hook-like osteophytes, not an erosive rheumatoid picture.
What is the treatment of choice?
Therapeutic phlebotomy — about 500 mL weekly until ferritin reaches roughly 50 to 100 nanograms per mL, then maintenance phlebotomy for life.
Why avoid raw shellfish and vitamin C?
Shellfish carry Vibrio vulnificus, to which iron-loaded patients are uniquely susceptible; vitamin C enhances dietary iron absorption.
Does phlebotomy reverse established cirrhosis?
No — it halts progression, but cirrhotic patients still need lifelong hepatocellular carcinoma surveillance.