📋 Key Information Summary
- Hereditary haemochromatosis (HH) is the most common inherited iron-overload disorder in Australia, predominantly affecting individuals of Northern European descent.
- C282Y homozygosity accounts for ≥90% of clinical HH cases; C282Y/H63D compound heterozygotes have lower penetrance and variable iron loading.
- Non-HFE forms (juvenile haemochromatosis with HJV/HAMP mutations, TFR2, ferroportin disease) are rare but cause more aggressive iron overload, often presenting in the 2nd–3rd decade.
- Diagnostic workup: Transferrin saturation ≥45% is the earliest biochemical marker; serum ferritin elevation confirms iron overload; HFE genotyping is the first-line confirmatory test.
- MRI T2* is the preferred non-invasive method to quantify hepatic iron concentration; liver biopsy is reserved for cases with ferritin >1000 µg/L with abnormal LFTs or suspected advanced fibrosis.
- Therapeutic phlebotomy is the cornerstone of treatment: weekly 450–500 mL venesections until serum ferritin reaches 50–100 µg/L, then maintenance every 2–4 months lifelong.
- Iron chelation with deferasirox (Jadenu®) is indicated when phlebotomy is contraindicated (severe anaemia, heart failure, poor venous access).
- Dietary advice: avoid iron and vitamin C supplements, minimise red meat alcohol excess, and avoid raw shellfish due to Vibrio vulnificus sepsis risk.
- First-degree relative screening (parents, siblings, children) with HFE genotyping and iron studies is mandatory once an index case is identified.
- Major complications include cirrhosis, hepatocellular carcinoma (HCC), diabetes mellitus, cardiomyopathy, hypogonadism, arthropathy, and skin hyperpigmentation.
- HCC surveillance (6-monthly AFP + ultrasound) is recommended for all patients with established cirrhosis or persistently elevated ferritin >1000 µg/L.
- Arthropathy preferentially affects the 2nd and 3rd metacarpophalangeal joints (MCPJs) with characteristic hooked osteophytes — a clinically distinctive finding.
- Aboriginal and Torres Strait Islander Australians should be screened where clinically indicated, though HH prevalence is lower than in non-Indigenous Australians of European descent.
- Early detection and pre-symptomatic treatment with phlebotomy can prevent all major complications and restore normal life expectancy.
Introduction & Australian Epidemiology
Hereditary haemochromatosis (HH) is an autosomal recessive disorder of iron metabolism characterised by progressive parenchymal iron deposition leading to organ damage. Australia has one of the highest prevalence rates of HFE-related haemochromatosis globally, owing to the Celtic and Northern European ancestry of much of the population.
In Australia, approximately 1 in 200 individuals of European descent are C282Y homozygous, and roughly 1 in 8 are heterozygous carriers. However, clinical penetrance is variable — not all homozygotes develop significant iron overload or organ damage. Males are typically affected earlier and more severely than females, with clinical manifestations usually appearing between ages 40 and 60 in men and post-menopause in women.
HH was historically called "bronze diabetes" due to the combination of skin hyperpigmentation and secondary diabetes mellitus. With earlier detection through population screening and family studies, most cases are now identified before irreversible organ damage occurs.
Australian context: Haemochromatosis is the most common genetic disorder in Australians of European descent. The Australian Haemochromatosis Association estimates over 80,000 Australians may be undiagnosed C282Y homozygotes. Routine iron studies in primary care have improved detection rates significantly.
Genetics & Diagnosis
HFE Gene Mutations
The HFE gene on chromosome 6p21.3 encodes a protein that modulates hepcidin expression and thus controls systemic iron homeostasis. Two missense mutations account for the vast majority of clinical HH:
| Genotype | Prevalence (European) | Iron Overload Risk | Penetrance |
|---|---|---|---|
| C282Y homozygous | 1 in 200 | High | Variable — ~50% of males, ~20% of females develop clinical disease |
| C282Y / H63D compound heterozygous | 1 in 50 | Low–moderate | Usually mild; significant overload uncommon unless cofactors present (alcohol, metabolic syndrome) |
| H63D homozygous | 1 in 50 | Very low | Minimal clinical significance in isolation |
| C282Y heterozygous | 1 in 8 | Negligible | Carrier state; no clinical iron overload expected |
Non-HFE Haemochromatosis
Rare non-HFE forms present with more aggressive iron loading, typically in younger patients:
- Juvenile haemochromatosis (Type 2): Mutations in HJV (hemojuvelin, Type 2A) or HAMP (hepcidin, Type 2B). Presents in the 2nd–3rd decade with severe cardiomyopathy, hypogonadism, and hepatic iron overload. Ferritin often >10,000 µg/L.
- TFR2-related haemochromatosis (Type 3): Mutations in transferrin receptor 2. Phenotype similar to HFE-HH but can present earlier. Autosomal recessive.
- Ferroportin disease (Type 4): Mutations in SLC40A1 (ferroportin). Two subtypes: loss-of-function (autosomal dominant, iron loading in macrophages, raised ferritin with lower transferrin saturation) and gain-of-function (resembles classic HH). Phlebotomy may be poorly tolerated due to anaemia in the loss-of-function variant.
Diagnostic Workup
The diagnostic approach follows a stepwise algorithm:
1
Iron Studies Screening
Transferrin saturation (TSAT) ≥45% is the most sensitive early marker. Fasting sample preferred (diurnal variation). Serum ferritin reflects total body iron stores but is influenced by inflammation, liver disease, and alcohol.
2
HFE Genotyping
First-line confirmatory test for C282Y and H63D mutations. Available on MBS (Medicare). If TSAT ≥45% and ferritin elevated, proceed to HFE testing. Non-HFE gene panels available at specialised genetics laboratories (e.g., Sonic Genetics, Victorian Clinical Genetics Services).
3
Quantification of Iron Load
MRI T2* of the liver is the preferred non-invasive method for quantifying hepatic iron concentration (HIC). Validated thresholds: HIC >80 µmol/g (dry weight) indicates significant overload. Cardiac T2* MRI if cardiomyopathy suspected.
4
Liver Biopsy (Selective)
Reserved for cases with ferritin >1000 µg/L combined with abnormal LFTs, or when non-HFE haemochromatosis is suspected. Provides hepatic iron index (HII = hepatic iron concentration / age); HII >1.9 supports HH. Also stages fibrosis (Metavir / Ishak scoring).
Pitfall: Ferritin is an acute-phase reactant. Elevated ferritin with normal transferrin saturation more commonly reflects metabolic syndrome, alcoholic liver disease, or chronic inflammation rather than haemochromatosis. Always interpret ferritin in conjunction with transferrin saturation and clinical context.
Investigations Summary
MBS Available
Iron studies (ferritin, TSAT, serum iron, TIBC)
MBS Item 66120. Fasting preferred. Repeat if abnormal before proceeding to genotyping.
MBS Available
HFE genotyping (C282Y, H63D)
MBS Item 73298. Medicare rebate available when iron studies abnormal. Turnaround 1–2 weeks.
MBS Available
MRI liver (T2* for hepatic iron quantification)
Available at major radiology centres. Non-invasive alternative to biopsy. Cardiac MRI if indicated.
Specialist
Liver biopsy with hepatic iron concentration
Gastroenterologist/hepatologist referral. Indicated when ferritin >1000 + abnormal LFTs, or non-HFE suspected.
Referral
Genetic counselling
Recommended for all confirmed cases prior to family screening. Available through public genetics services or privately.
Treatment
Therapeutic Phlebotomy
Therapeutic venesection remains the cornerstone and most effective treatment for hereditary haemochromatosis. The goal is to deplete excess iron stores and then maintain ferritin at a low-normal level lifelong.
Induction Phase
Iron Depletion
Weekly venesection of 450–500 mL (equivalent to ~200–250 mg iron per session). Continue until serum ferritin reaches 50–100 µg/L. Typically requires 12–24 sessions over 3–6 months depending on initial iron load.
Setting: GP surgery, pathology collection centre, or hospital outpatient
Maintenance Phase
Lifelong Maintenance
Venesection every 2–4 months to keep ferritin between 50–100 µg/L. Frequency adjusted based on serial ferritin monitoring. Lifelong treatment is essential — stopping leads to re-accumulation.
Setting: GP surgery or Red Cross Lifeblood donation (where eligible)
Lifeblood (Red Cross) donation: Patients with HH who meet general eligibility criteria can donate blood through the Australian Red Cross Lifeblood service. This serves dual purpose — therapeutic phlebotomy and contribution to the blood supply. Blood from HH donors is now accepted for transfusion in Australia.
Iron Chelation Therapy
Chelation is reserved for patients in whom therapeutic phlebotomy is contraindicated or poorly tolerated:
- Severe anaemia (Hb <100 g/L and cannot tolerate venesection)
- Heart failure or significant cardiomyopathy
- Poor venous access
- Non-HFE haemochromatosis with rapid iron re-accumulation
Deferasirox
Jadenu® · Generic · Iron chelator (oral)
Adult dose
10–30 mg/kg PO once daily, adjusted based on ferritin trend and tolerability
Paediatric dose
Not routinely used in paediatric HH; specialist-only
Route
Oral — tablet (Jadenu®) or dispersible tablet (Exjade®)
Key monitoring
Serum creatinine (monthly), LFTs, audiometry, ophthalmology (annually)
Renal adjustment
Contraindicated if CrCl <60 mL/min (relative). Reduce dose or avoid.
Hepatic adjustment
Avoid in severe hepatic impairment (Child-Pugh C)
PBS status
Authority Required
Deferoxamine (Desferrioxamine)
Desferal® · Iron chelator (parenteral)
Adult dose
20–40 mg/kg/day SC infusion over 8–12 hours, 5–7 days/week
Route
Subcutaneous infusion (preferred) or IV infusion
Indication
Second-line or when oral chelators contraindicated. Burdensome administration.
PBS status
Authority Required
Dietary Advice
While dietary modification alone cannot treat iron overload, the following advice is recommended to minimise additional iron absorption:
- Avoid iron supplements and multivitamins containing iron.
- Avoid vitamin C supplements — ascorbic acid enhances non-haem iron absorption by 2–3 fold. Dietary vitamin C from fruit is acceptable in normal quantities.
- Limit red meat — reduce intake but complete avoidance is unnecessary.
- Limit alcohol — alcohol increases iron absorption and accelerates liver injury. Particularly avoid alcohol with meals.
- Avoid raw or undercooked shellfish — especially oysters. Vibrio vulnificus is an iron-dependent bacterium; HH patients are at markedly increased risk of fatal sepsis with Vibrio infection.
- Tea and coffee consumed with meals may reduce non-haem iron absorption.
Critical safety advice: Patients with haemochromatosis must be counselled to avoid raw shellfish (especially oysters). Vibrio vulnificus bacteraemia in iron-overloaded patients carries a mortality rate exceeding 50%. Any patient with HH presenting with fever, rigors, or cellulitis after shellfish exposure requires urgent IV antibiotics (ceftriaxone + doxycycline) and hospital admission.
First-Degree Relative Screening
Once an index case of HFE-related haemochromatosis is confirmed, cascade screening of all first-degree relatives (parents, siblings, children) is mandatory:
- HFE genotyping to identify homozygous or compound heterozygous relatives.
- Iron studies (ferritin, TSAT) at time of genetic testing.
- Genetic counselling should be offered before testing, particularly for minors.
- Children of a confirmed C282Y homozygote are obligate heterozygotes; full genotyping of the other parent is required to determine risk of homozygosity in offspring.
- Pre-symptomatic detection and early phlebotomy prevents all major complications.
Complications
Iron deposition in parenchymal organs leads to progressive tissue damage. The risk of complications correlates with the degree and duration of iron overload. Early phlebotomy before organ damage occurs can prevent all of the following complications.
Cirrhosis
Hepatic iron deposition causes progressive fibrosis and ultimately cirrhosis, which is the most serious hepatic complication. Once cirrhosis is established, it is irreversible even with adequate iron depletion. Risk factors for cirrhosis include:
- Ferritin persistently >1000 µg/L
- Concurrent alcohol excess (synergistic hepatotoxicity)
- Hepatitis B or C co-infection
- Duration of iron overload (late diagnosis)
Key threshold: Patients with ferritin >1000 µg/L have a significantly increased risk of advanced fibrosis/cirrhosis. Liver biopsy or MRI elastography should be considered to stage fibrosis in these patients.
Hepatocellular Carcinoma (HCC)
HCC risk is increased in HH patients with established cirrhosis. Importantly, HCC may also develop in non-cirrhotic livers with very high iron stores, though this is less common. Surveillance recommendations:
- 6-monthly surveillance with serum alpha-fetoprotein (AFP) and hepatic ultrasound for all patients with established cirrhosis.
- Consider HCC surveillance in non-cirrhotic patients with persistently elevated ferritin >1000 µg/L, particularly if other risk factors present (co-infection, alcohol excess).
- Surveillance should continue lifelong even after adequate iron depletion if cirrhosis has been established.
Diabetes Mellitus
Iron deposition in the pancreatic islet cells causes beta-cell damage and insulin deficiency. The term "bronze diabetes" reflects the combination of iron-related skin pigmentation and secondary diabetes. Management includes:
- Standard diabetes management per Australian guidelines (ADIPS/RACGP).
- Glycaemic control may improve with adequate iron depletion if detected early.
- If cirrhosis coexists, consider hepatogenic diabetes and adjust HbA1c interpretation accordingly.
Cardiomyopathy and Arrhythmia
Myocardial iron deposition is a feared complication, particularly in juvenile haemochromatosis and severe HFE-HH:
- Restrictive cardiomyopathy progressing to dilated cardiomyopathy and heart failure.
- Cardiac arrhythmias: Atrial fibrillation, ventricular ectopy, and potentially fatal ventricular tachycardia.
- Cardiac T2* MRI is the gold standard for myocardial iron quantification.
- Aggressive iron chelation is essential when cardiac iron overload is demonstrated. Combination therapy (deferoxamine + deferiprone) may be required.
- Cardiac involvement may be reversible with intensive chelation if detected before irreversible fibrosis.
Hypogonadism
Iron deposition in the anterior pituitary (particularly gonadotrophs) causes secondary hypogonadotropic hypogonadism:
- Males: Erectile dysfunction, decreased libido, testicular atrophy, loss of secondary sexual characteristics. Testosterone replacement may be required.
- Females: Amenorrhoea, infertility, premature menopause. Oestrogen/progesterone replacement if symptomatic.
- Other pituitary axes may be affected (growth hormone deficiency, hypothyroidism).
- Ferritin >2000 µg/L significantly increases hypogonadism risk.
Arthropathy
Iron-related arthropathy is a distinctive and common complication affecting up to 50% of patients with HH:
- Classic pattern: Involvement of the 2nd and 3rd metacarpophalangeal joints (MCPJs) — a clinically distinctive feature that should prompt consideration of HH.
- Radiographic finding: "Hooked" or "beak-like" osteophytes at the MCPJs, particularly the index and middle finger MCPJs.
- Chondrocalcinosis (pseudogout) is common — iron promotes calcium pyrophosphate crystal deposition.
- Other affected joints: wrists, knees, hips, and first metatarsophalangeal joints.
- Arthropathy is often not reversible with phlebotomy once established. Early detection and treatment is critical.
- Management: NSAIDs, intra-articular corticosteroids, physiotherapy. Phlebotomy does not improve established joint damage.
Skin Hyperpigmentation
Bronze-grey skin discolouration results from increased melanin and iron deposition in the skin:
- Most noticeable on the face, neck, extensor surfaces of forearms, lower legs, and genitalia.
- May improve with iron depletion, though permanent pigmentation can occur.
- Distinctive when combined with the other classic features (diabetes, cirrhosis, cardiomyopathy).
Reversible
Early Complications
Fatigue, arthralgia, abdominal pain, mild hepatomegaly, early skin pigmentation. These typically improve or resolve with adequate iron depletion.
Phlebotomy effective
Partially Reversible
Moderate Complications
Early cardiomyopathy, secondary diabetes, hypogonadism (may require hormone replacement), hepatomegaly with early fibrosis.
Phlebotomy + targeted management
Irreversible
Advanced Complications
Established cirrhosis, HCC, advanced arthropathy with hooked osteophytes, irreversible cardiomyopathy, permanent hypogonadism.
Phlebotomy prevents progression; organ damage persists
HCC Surveillance Protocol
Who: All patients with HH + cirrhosis; consider in non-cirrhotic HH with ferritin persistently >1000 µg/L
Test: 6-monthly serum AFP + hepatic ultrasound
Alternative: CT or MRI if ultrasound technically limited (e.g., obesity, nodular liver)
Lifelong: Surveillance continues indefinitely even after adequate iron depletion
Special Populations
Paediatric
HFE-related HH rarely presents clinically in childhood; juvenile haemochromatosis (HJV/HAMP) may present in adolescence.
Screen children of C282Y homozygotes with iron studies from age 18 (or earlier if symptomatic).
Phlebotomy volumes adjusted for weight (typically 5–7 mL/kg per session).
Deferasirox: Specialist paediatric haematology supervision required; limited data in HH specifically.
Pregnancy
Phlebotomy is contraindicated during pregnancy.
Iron studies may be normal or misleading during pregnancy due to haemodilution and physiological changes.
Resume phlebotomy post-partum when clinically appropriate.
Deferasirox: Category D — contraindicated in pregnancy. Discontinue pre-conception.
Elderly
May present with complications (cirrhosis, diabetes, cardiomyopathy) if diagnosis was delayed.
Phlebotomy well tolerated; adjust venesection volume if anaemia or cardiovascular instability.
Comorbidities may limit aggressive treatment — individualise targets.
Renal Impairment
Phlebotomy is generally safe in renal impairment (monitor for anaemia).
Deferasirox: Avoid or significantly reduce dose if CrCl <60 mL/min. Nephrotoxic risk.
Deferoxamine: Use with caution; aluminium toxicity risk in dialysis patients.
Immunocompromised
Iron overload itself impairs immune function — phlebotomy improves immune competence.
Increased susceptibility to Vibrio, Listeria, and Yersinia infections with iron overload.
Counsel rigorously regarding raw shellfish avoidance and food safety.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
📚 References
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