Key Facts

Hereditary haemochromatosis (HH) is the most common autosomal recessive genetic disorder in Northern Europeans. Early diagnosis and treatment with venesection prevents organ damage and normalises life expectancy.

Epidemiology

C282Y homozygosity prevalence: ~1 in 200 in Northern European populations (1 in 8-10 are carriers). Clinical penetrance is lower than genetic prevalence (~30% of homozygotes develop clinically significant disease). Male predominance for clinical disease (4:1) — menstruation/pregnancy protect women.

Aetiology

• HFE gene (chromosome 6): C282Y mutation (most common, >90% of clinical HH), H63D, S65C
• Non-HFE haemochromatosis: rare — juvenile (HJV, HAMP genes), transferrin receptor 2 (TfR2), ferroportin disease

Pathophysiology

HFE protein normally regulates hepcidin production by hepatocytes. Hepcidin is the master regulator of iron homeostasis — it inhibits ferroportin (iron exporter) on enterocytes and macrophages. In HH, defective HFE leads to inadequate hepcidin production → unregulated iron absorption from the gut (2-3× normal) → progressive iron accumulation in parenchymal cells of liver, pancreas, heart, pituitary, joints, skin → oxidative damage → organ dysfunction.

Early Disease (Often Asymptomatic)

• Fatigue, lethargy
• Arthralgia (often first symptom — 2nd/3rd MCP joints)
• Abnormal iron studies on routine testing

Established Disease

• Liver: hepatomegaly, raised LFTs, cirrhosis (15× HCC risk)
• Pancreas: diabetes mellitus ("bronze diabetes")
• Heart: dilated or restrictive cardiomyopathy, arrhythmias (iron deposits in myocardium)
• Skin: bronze/grey pigmentation (melanin + iron deposition)
• Joints: arthropathy — especially 2nd/3rd MCP joints; chondrocalcinosis (pseudogout)
• Pituitary: hypogonadotropic hypogonadism (loss of libido, erectile dysfunction, amenorrhoea)
• Other: hypothyroidism

Red Flags

• Rapidly deteriorating liver function (HCC in cirrhotic HH)
• Heart failure symptoms (cardiomyopathy)
• New diabetes + hepatomegaly + skin pigmentation (classic but late triad)

Bloods

• Transferrin saturation: best screening test; >45% warrants HFE genotyping
• Serum ferritin: indicates iron stores; >300 μg/L (men) or >200 μg/L (women) suggests iron loading; >1000 μg/L = high risk of cirrhosis
• HFE genotyping: C282Y/C282Y = diagnostic of HH; C282Y/H63D = compound heterozygote (lower risk)
• LFTs: may be normal early; raised in advanced disease
• Fasting glucose/HbA1c: diabetes screening
• Testosterone, LH, FSH: hypogonadism screening (men)
• TFTs: hypothyroidism

Imaging

• *MRI liver (T2/R2)**: quantifies hepatic iron concentration non-invasively — increasingly used
• *Cardiac MRI (T2)**: if cardiac involvement suspected — quantifies myocardial iron
• USS abdomen: liver assessment, HCC screening if cirrhotic
• FibroScan: fibrosis assessment

Special Tests

• Liver biopsy: NOT routinely needed if HFE positive with ferritin <1000 and normal LFTs; indicated if: ferritin >1000, abnormal LFTs, uncertainty about fibrosis stage — shows hepatocellular iron deposition (Perls Prussian blue stain), grade and stage
• Joint X-rays: chondrocalcinosis (2nd/3rd MCPs — hook-like osteophytes), pseudogout

Non-pharmacological

• Venesection (phlebotomy): first-line treatment
  • Induction: 500 mL (1 unit) weekly until ferritin <50 μg/L and transferrin saturation <50%
  • Maintenance: venesection every 2-4 months to maintain ferritin 50-100 μg/L
  • Well-tolerated; improves fatigue, liver function, skin pigmentation, cardiac function
  • Does NOT improve established arthropathy, diabetes, or hypogonadism (irreversible)
• Dietary: avoid iron supplements, vitamin C supplements (enhances iron absorption), excessive red meat; limit alcohol (synergistic liver toxicity)
• Family screening: all first-degree relatives of confirmed HH should have iron studies and HFE genotyping

Pharmacological

• Iron chelation: desferrioxamine, deferasirox — only if venesection not possible (anaemia, poor venous access); rarely needed in HH
• Testosterone replacement: for hypogonadism (if not reversed by venesection)
• Diabetes management: standard (insulin often required)

Surgical/Interventional

• HCC surveillance: USS ± AFP every 6 months in all cirrhotic HH patients
• Liver transplantation: for decompensated cirrhosis or HCC meeting criteria
• Joint replacement: for end-stage arthropathy

Referral Criteria

• Hepatology referral: all confirmed HH with iron overload for venesection programme
• Blood service: many centres run venesection through blood transfusion services
• Genetics counselling for family screening
• Transplant assessment if cirrhosis develops

With early venesection (before cirrhosis), life expectancy is normal. If cirrhosis develops, 5-year survival is ~65% (15× HCC risk despite venesection). Venesection improves: fatigue, liver function, skin pigmentation, cardiac function. Venesection does NOT improve: arthropathy, diabetes, hypogonadism (established damage is irreversible). HCC can still occur after venesection in cirrhotics — surveillance essential. Liver transplant outcomes are slightly worse than for other indications (cardiac iron loading).

Venesection Protocol

Organ Involvement and Reversibility