Hereditary Haemochromatosis
Summary
Hereditary Haemochromatosis (HH) is the most common autosomal recessive genetic disorder in Northern European populations. It is caused by mutations in the HFE gene (typically C282Y homozygosity), which leads to a deficiency of Hepcidin, the key regulator of iron absorption. Consequently, iron is absorbed uncontrollably from the gut and deposited in the liver, pancreas, heart, joints, and pituitary. If untreated, this leads to cirrhosis, diabetes ("Bronze Diabetes"), cardiomyopathy, and hypogonadism. Early diagnosis and treatment with venesection (phlebotomy) can prevent organ damage and ensure a normal life expectancy. [1,2]
Key Facts
- Genetics: Autosomal Recessive. HFE gene on Chromosome 6.
- Classic Mutation: C282Y Homozygote (accounts for 90% of clinical cases).
- Penetrance: Low. Only ~10-30% of C282Y homozygotes develop clinical iron overload. Men are affected earlier than women (menstruation/pregnancy protects women by offloading iron).
- Signs: Usually presents with non-specific Fatigue and Arthralgia. Classic "Bronze Diabetes" is a late, severe finding.
- Diagnostic Key: Transferrin Saturation (T-Sat) is the earliest and most sensitive marker (>45-50%). Ferritin is an acute phase reactant and often raised by alcohol/inflammation, making it less specific.
Clinical Pearls
The "Celtic Curse": HH is extremely common in Irish/Scottish populations (1 in 8 are carriers, 1 in 200 homozygous).
The "Iron Fist": Arthritis in the 2nd and 3rd MCP joints (Hook-like osteophytes) is pathognomonic. It can mimic Rheumatoid Arthritis but is non-inflammatory.
Vibrio Vulnerability: Patients with iron overload are uniquely susceptible to catastrophic sepsis from siderophilic bacteria like Vibrio vulnificus (raw oysters) and Yersinia.
Ferritin Trap: A high ferritin with normal T-Sat is usually NOT haemochromatosis. It is usually "Reactive Ferritin" (Alcohol, Fatty Liver, Infection, Malignancy).
Incidence
- Prevalence: 1 in 200 (Caucasians).
- Carrier Rate: 1 in 8 to 1 in 10.
- Gender: Men clinical onset 40s-50s. Women clinical onset post-menopausal (60s).
Genotypes
- C282Y / C282Y (Homozygote): Highest risk of overload.
- C282Y / H63D (Compound Heterozygote): Low risk. Rarely requires treatment.
- H63D / H63D (Homozygote): Very low risk.
The Hepcidin Axis
- Normal: Liver produces Hepcidin -> Closes "Iron Gates" (Ferroportin) in gut when iron is high.
- Haemochromatosis: HFE mutation -> Liver cannot produce Hepcidin -> Gut "Iron Gates" stay permanently open -> Unregulated absorption.
Organ Damage
- Free Iron (NTBI): Non-Transferrin Bound Iron circulates and generates free radicals (Fenton reaction).
- Fibrosis: Iron deposition triggers stellate cells in liver -> Cirrhosis.
- Beta Cells: Pancreatic islet damage -> Insulin dependent diabetes.
Early Symptoms (Reversible)
Late Signs (Irreversible)
- Hands: Inspect 2nd/3rd MCPJs for swelling/tenderness. Handshake may be painful ("Iron Fist").
- Skin: Check for tanning in non-exposed areas (axillae/groin).
- Abdomen: Palpate liver/spleen.
- Genitalia: Testicular volume.
Iron Studies (Fasting)
- Transferrin Saturation (T-Sat):
- Normal less than 45%.
- >45-50% is strongly suggestive of HH.
- Ferritin:
- Often >300 (M) / >200 (F). Can reach >1000-5000 in severe overload.
Genetic Testing
- HFE Genotype: Testing for C282Y and H63D mutations.
- Confirms diagnosis if T-Sat/Ferritin high.
Assessing Organ Damage
- LFTs: ALT often mildly elevated.
- HbA1c: Diabetes screen.
- Liver Fibrosis Assessment:
- Transient Elastography (FibroScan): Non-invasive stiffness score.
- MRI Liver (FerriScan): Quantifies Iron Concentration (LIC).
- Biopsy: Rarely needed now. Shows Perls' Prussian Blue staining.
Note: If Ferritin >1000 ug/L or abnormal LFTs, referral to hepatologist is urgent to rule out cirrhosis.
Management Algorithm
DIAGNOSIS CONFIRMED
(Homozygote + Ferritin >300)
↓
┌─────────────────────────────────────────────┐
│ INDUCTION VENESECTION │
│ - Remove 500ml blood (approx 250mg Iron) │
│ - Frequency: Weekly or Fortnightly │
│ - Monitor Hb (Check before each bleed) │
│ - Continue until Ferritin less than 50 ug/L │
└─────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────┐
│ MAINTENANCE │
│ - Venesection every 3-6 months │
│ - Target Ferritin 50-100 ug/L │
│ - Target T-Sat less than 50% │
└─────────────────────────────────────────────┘
1. Phlebotomy (Venesection)
- The mainstay of treatment. Simple, effective, cheap.
- Goal: De-iron the patient (remove excess stores) and maintain normal stores.
- Indication: Usually started if Ferritin >300 (M) / >200 (F) AND T-Sat >45%.
2. Dietary Discovery
- Avoid: Iron supplements, Vitamin C supplements (enhances absorption).
- Limit: Red meat (heme iron), Alcohol (accelerates liver damage).
- Encourage: Tea/Coffee with meals (tannins reduce iron absorption).
3. Family Screening
- Screen all first-degree relatives (Siblings, Parents, Children >18).
- Test: HFE Genetics + Iron Studies.
4. Chelation (Deferoxamine)
- Rarely used. Only for patients who cannot tolerate venesection (e.g., severe anaemia, heart failure).
- Cirrhosis: Reversible if treated early? Fibrosis can regress, cirrhosis usually permanent.
- Hepatocellular Carcinoma (HCC): 20-100x increased risk in patients with cirrhosis. Requires 6-monthly Ultrasound surveillance.
- Arthropathy: Often Does NOT improve with venesection (damage is done). May require NSAIDs or joint replacement.
- Hypogonadism: May require Testosterone replacement.
- Normal Life Expectancy: If treated before cirrhosis or diabetes develops.
- Cirrhosis: Reduces survival.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Haemochromatosis | EASL (Euro Assoc Study Liver) | T-Sat is first line screen. Homozygotes with normal ferritin do not need venesection yet (monitor annual). |
| HFE Guidelines | AASLD (American) | Target Ferritin 50-100 during maintenance. |
Landmark Knowledge
1. Discovery of HFE (1996)
- Feder et al. identified the gene, transforming diagnosis from "Liver Biopsy" to "Blood Test".
2. Penetrance Studies
- Huge population studies showed many C282Y homozygotes never get sick. Led to move away from "disease" towards "susceptibility". Treatment is based on expression (iron levels), not just genetics.
What is Haemochromatosis?
Your body has lost the ability to say "No" to iron in food. It absorbs too much. Because the body has no natural way to get rid of iron (except bleeding), it builds up in your liver and joints like rust.
Is it dangerous?
If untreated for many years, the "rust" damages the liver (scarring) and pancreas (diabetes). If caught early, it is completely manageable.
The Treatment
The treatment is ancient but perfect: Bloodletting. We take about a pint of blood (like a donation) every week for a few months. This forces your body to use the stored iron to make new blood cells, cleaning out the organs. Once levels are low, you only need to confirm 3-4 times a year.
Diet
You don't need a strict "no iron" diet, but avoid iron pills, Vitamin C pills (which boost iron), and limit red meat. Drink tea with meals (it blocks iron).
Primary Sources
- European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines for HFE Hemochromatosis. J Hepatol. 2010;53:3-22.
- Bacon BR, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328-343.
- Allen KJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221-230.
Common Exam Questions
- Gastroenterology: "Screening test of choice for HH?"
- Answer: Fasting Transferrin Saturation.
- Rheumatology: "Type of arthritis in HH?"
- Answer: Calcium Pyrophosphate Deposition (CPPD/Pseudogout) affecting 2nd/3rd MCPJs.
- Genetics: "Patient is C282Y homozygote. Probability siblings are affected?"
- Answer: Autosomal Recessive. Siblings have 25% chance (if parents are carriers) or higher depending on parental genotype (high carrier rate).
- Oncology: "Major cause of death in cirrhotic HH patients?"
- Answer: Hepatocellular Carcinoma (HCC).
Viva Points
- Hepcidin: Mechanism of action. (Binds Ferroportin -> Internalisation/Degradation -> Blocks iron exit from enterocyte).
- Reactive Ferritin: Differentiating from HH. (Check T-Sat. If T-Sat normal but Ferritin high, it's inflammation/alcohol).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.