Haemochromatosis

At a glance

• HFE haemochromatosis is autosomal recessive iron overload from low hepcidin. In Australia, people of northern European ancestry carry it most: about 1 in 200 are C282Y homozygous and about 1 in 7 to 1 in 8 carry one C282Y copy.
• Genotype isn't disease. Penetrance is low, especially in women, who lose iron through menstruation and pregnancy.
• Diagnose with transferrin saturation first, then ferritin, then HFE. Liver biopsy is rarely needed.
• Venesection before cirrhosis gives a normal life expectancy. Cirrhosis brings a lifelong HCC risk.
• Every diagnosis triggers cascade testing of adult first-degree relatives.

Classification

Type	Gene	Features
HFE (type 1)	HFE C282Y homozygous	Over 90% of cases in Australia. Presents in middle age, men earlier
Juvenile (type 2)	HJV (2A), HAMP (2B)	Severe overload before 30: cardiomyopathy and hypogonadism dominate
Type 3	TFR2	Similar to HFE, rare
Ferroportin disease (type 4)	SLC40A1, autosomal dominant	Loss-of-function form: high ferritin with normal transferrin saturation, macrophage iron, anaemia with venesection
Secondary	None	Transfusion (thalassaemia, MDS), ineffective erythropoiesis, excess iron supplements or infusions, chronic liver disease

Porphyria cutanea tarda isn't a cause of secondary iron overload. It is associated with HFE variants and iron, which trigger it, and venesection treats it.

Pathophysiology

• Hepcidin, made by the liver, blocks ferroportin on enterocytes and macrophages. HFE mutations lower hepcidin, so ferroportin stays open.
• Duodenal absorption and macrophage iron release rise. Transferrin saturates first, then non-transferrin-bound iron loads the liver, pancreas, heart, pituitary and joints.
• Total body iron is normally 3 to 4 g. Symptomatic patients often carry over 20 g.
• Ferroportin loss-of-function disease traps iron in macrophages, which explains the normal saturation.

Recognition

Most cases are now found on routine iron studies, or now through Lifeblood's routine donor ferritin testing, before organs are damaged.

• Early, vague: fatigue, arthralgia, raised ALT.
• Joints: arthropathy of the 2nd and 3rd MCP joints ("iron fist", hook-like osteophytes), wrists, hips and knees, with chondrocalcinosis and pseudogout. Under 60 with CPPD, screen for haemochromatosis (see gout and pseudogout).
• Liver: hepatomegaly, fibrosis, cirrhosis, HCC.
• Endocrine: diabetes ("bronze diabetes"), hypogonadotrophic hypogonadism (low libido, erectile dysfunction, amenorrhoea), osteoporosis.
• Skin: slate-grey or bronze pigmentation.
• Heart: dilated or restrictive cardiomyopathy and arrhythmia, mostly in juvenile forms.
• Infection: Vibrio vulnificus (raw shellfish), Yersinia and Listeria thrive on free iron.

Pitfall: the full classic triad of cirrhosis, diabetes and bronze skin is now rare. Waiting for it misses the treatable phase.

Investigations

Reading iron studies

Hyperferritinaemia is common, and fewer than 10% of cases are iron overload (MJA 2025).

Ferritin	Transferrin saturation	Likely meaning
High	45% or more	Iron overload possible: test HFE
High	Under 45%	Inflammation, alcohol, MASLD or metabolic syndrome, liver injury, malignancy, CKD, thyrotoxicosis. Ferroportin disease if persistent and unexplained
Normal	45% or more	Early HFE haemochromatosis (especially young or female), or a non-fasting sample
Low	Low	Iron deficiency (see iron deficiency anaemia)

• Repeat abnormal studies fasting, in the morning, at least 6 weeks after an acute illness. Transferrin saturation swings with meals and the time of day.
• Look for non-iron causes in parallel: alcohol history, CRP, LFTs, lipids, HbA1c, liver ultrasound. The MASLD note and alcohol-related liver disease note cover these patterns.

HFE testing

• Test for C282Y and H63D when saturation is 45% or more with raised ferritin, or when a first-degree relative is affected.
• MBS criteria: raised transferrin saturation or ferritin on repeated samples, or a first-degree relative with haemochromatosis, C282Y homozygosity or compound heterozygosity. Testing outside these criteria isn't rebated.
• EASL 2022 diagnosis: C282Y homozygosity plus saturation over 45% and ferritin over 200 µg/L in premenopausal women, or saturation over 50% and ferritin over 300 µg/L in men and postmenopausal women. These are diagnostic thresholds in a known homozygote; the single 45% cut-off (MJA 2025) is the screening step that decides who gets HFE testing.
• Other genotypes with high saturation and ferritin need proof of hepatic iron (MRI or biopsy) before you call it haemochromatosis. Refer for non-HFE gene testing if overload is confirmed.

Measuring liver iron and fibrosis

• MRI liver iron concentration (R2 or T2* methods; FerriScan was developed in Perth) is the non-invasive standard when the genotype doesn't explain the picture or ferritin is confounded. A normal liver iron concentration excludes overload.
• Fibrosis staging decides follow-up. In C282Y homozygotes, ferritin under 1000 µg/L with normal ALT and no hepatomegaly makes cirrhosis very unlikely.
• Ferritin over 1000 µg/L, raised ALT, low platelets or hepatomegaly: assess with transient elastography. Liver biopsy only when non-invasive tests disagree.
• Screen for complications: HbA1c or fasting glucose, testosterone and gonadotrophins in men with symptoms, bone density, and ECG and echo if there are cardiac symptoms or very high iron.

Pitfall: treating a ferritin of 900 µg/L in a heavy drinker with transferrin saturation of 30% as haemochromatosis. Saturation is the gatekeeper.

Management

Venesection

• Indicated in C282Y homozygotes (or confirmed non-HFE overload) with raised ferritin. Homozygotes with normal ferritin need yearly iron studies, not venesection.
• Induction: remove about 450 to 500 mL (200 to 250 mg of iron) weekly or fortnightly as tolerated. Check haemoglobin before each one; AASLD advises against a fall of more than 20% from the previous level.
• Target ferritin under 50 µg/L in induction, checked every 4 to 12 venesections, then under 100 µg/L in maintenance (EASL 2022). Maintenance usually means 2 to 4 venesections a year.
• Don't overshoot into iron deficiency. If haemoglobin falls or ferritin drops well below 50 µg/L, space out or pause venesection.
• Australian Red Cross Lifeblood runs a therapeutic venesection program. Eligible patients donate with a doctor's request form, and their blood can be transfused.
• Erythrocytapheresis removes more iron per session and suits patients who tolerate it, but needs apheresis access.
• Chelation (deferasirox, desferrioxamine) is for secondary overload or patients who can't have venesection, such as those with anaemia or severe heart failure. Its PBS listing covers transfusional iron overload.

What improves

Usually improves	Usually doesn't
Fatigue and malaise	Arthropathy (may worsen)
Skin pigmentation	Established cirrhosis and its HCC risk
Raised ALT and early fibrosis	Hypogonadism
Cardiac function	Insulin-dependent diabetes
Glucose control, partly

Lifestyle

• Limit alcohol, and abstain with fibrosis or cirrhosis. Alcohol and iron add to each other's liver injury.
• Avoid iron and vitamin C supplements, and avoid raw shellfish.
• No strict low-iron diet is needed; venesection removes far more iron than diet adds.
• Treat coexisting MASLD and metabolic risk.

Complications and follow-up

• HCC: risk rises steeply with cirrhosis. Offer 6-monthly ultrasound (with or without AFP) for advanced fibrosis (F3) or cirrhosis, continuing after iron depletion. Varices screening follows the cirrhosis note.
• Diabetes: venesection makes HbA1c falsely low: it stimulates erythropoiesis, so the mean age of circulating red cells falls and there is less time for glycation. Monitor with glucose readings, CGM or fructosamine.
• Arthropathy: analgesia, physiotherapy and joint replacement. It's the commonest cause of persisting disability after treatment.
• Cardiomyopathy: cardiac MRI T2* in juvenile forms or very high iron. Chelation may be added to venesection.

Family screening and genetics

• Offer adult first-degree relatives (siblings, parents, children) iron studies and HFE testing. Siblings of a homozygote have a 1 in 4 chance of being homozygous.
• For children of a homozygote, test the other parent first. If that parent carries no C282Y, the children can be at most heterozygous. Testing of children is usually deferred to adulthood.
• Heterozygotes (C282Y or H63D) don't develop clinically significant overload on their own and need no treatment.
• HealthIron (Melbourne, NEJM 2008) followed C282Y homozygotes for about 12 years: iron-overload-related disease developed in 28% of men and 1% of women, mostly in those with ferritin over 1000 µg/L.
• Haemochromatosis Australia supports patients and provides family letters for cascade testing.

Special populations

• Pregnancy: iron demands usually halt accumulation. Venesection is generally paused. Avoid routine iron supplements unless iron deficiency is proven.
• Women present a decade or more later than men, often after menopause.
• Older people: venesection is still worthwhile with high ferritin, but watch for anaemia and postural symptoms.
• Liver transplant cures the liver defect for HFE disease; outcomes are worse if cardiac iron or HCC is present.

Pitfalls

• Diagnosing haemochromatosis from ferritin alone, without fasting transferrin saturation.
• Testing for HFE in someone with high ferritin and normal saturation, where MASLD, alcohol or inflammation is the cause.
• Venesecting a heterozygote or an H63D homozygote with metabolic hyperferritinaemia.
• Forgetting fibrosis assessment when ferritin is over 1000 µg/L, and stopping HCC surveillance once ferritin normalises.
• Trusting a falling HbA1c during venesection.
• Missing ferroportin disease (dominant inheritance, normal saturation, poor venesection tolerance) or juvenile haemochromatosis in a young adult with heart failure and hypogonadism.
• Not offering cascade testing to siblings.