Hereditary Haemochromatosis

Related Subjects: | Chronic liver disease | Cirrhosis | Alkaline phosphatase (ALP) | Liver Function Tests | Ascites Assessment and Management | Budd-Chiari syndrome | Autoimmune Hepatitis | Primary Biliary Cirrhosis | Primary Sclerosing Cholangitis | Wilson disease | Hereditary Haemochromatosis | Alpha-1 Antitrypsin (AAT) deficiency | Nonalcoholic steatohepatitis (NASH) | Spontaneous Bacterial Peritonitis | Alcoholism and Alcoholic Liver Disease |Hepatitis C

💡 Hereditary haemochromatosis (HH) is the most common inherited cause of iron overload. Early recognition and venesection treatment can prevent cirrhosis, diabetes, and cardiomyopathy.

📘 About

• Autosomal recessive disorder of excessive intestinal iron absorption → progressive iron overload.
• No regulated excretion mechanism → iron accumulates in liver, pancreas, heart, joints, skin.
• Most common cause of primary liver disease in Western populations.
• Classic triad: “Bronze diabetes” = cirrhosis + diabetes + skin pigmentation.

🧬 Genetics

• HFE gene mutation (chromosome 6).
• C282Y homozygous → high risk; C282Y/H63D compound heterozygotes milder.
• Carrier frequency: ~1 in 8 in Northern Europeans; homozygous prevalence 1 in 200.
• Incomplete penetrance: not all homozygotes develop disease.

⚠️ Aetiology & Pathology

• HFE mutation → loss of hepcidin regulation → unopposed ferroportin activity → ↑ iron absorption.
• Progressive iron deposition → hepatocyte injury, fibrosis, cirrhosis.
• Prussian Blue stain: periportal iron deposition in hepatocytes, sparing Kupffer cells.

🩺 Clinical Features

• Non-specific: fatigue, arthralgia, abdominal pain.
• Liver: hepatomegaly, cirrhosis, ↑ HCC risk.
• Pancreas: diabetes mellitus.
• Endocrine: hypogonadism, impotence, infertility.
• Cardiac: dilated/restrictive cardiomyopathy, arrhythmias, heart failure.
• Skin: slate-grey/bronze pigmentation.
• Joints: arthropathy, chondrocalcinosis (especially 2nd/3rd MCP joints).

🔎 Investigations

• Serum ferritin usually elevated (>500 micrograms/L).
• Transferrin saturation >50% (often >90%).
• Genetic testing for HFE mutations (C282Y, H63D).
• Liver enzymes (↑ ALT, AST), assess fibrosis with elastography.
• MRI T2*: quantifies iron in liver, pancreas, myocardium.
• Liver biopsy now rare - for unclear cases or staging cirrhosis.

📊 Summary Table

🚨 Complications

• Cirrhosis & hepatocellular carcinoma (HCC).
• Heart failure, arrhythmias.
• Secondary diabetes.
• Hypogonadism and infertility.

👨‍👩‍👧 Screening

• Screen patients with unexplained high ferritin + transferrin saturation.
• First-degree relatives of affected patients should undergo HFE genetic testing.
• Especially relevant in Northern European ancestry.

⚕️ Management

• Venesection (phlebotomy): weekly until ferritin 20–50 micrograms/L, transferrin saturation <50%, then lifelong maintenance every 1–3 months.
• Iron chelation (deferoxamine, deferasirox) only if phlebotomy contraindicated (e.g. severe anaemia, cardiac failure).
• Cirrhosis: HCC surveillance (US + AFP every 6 months).
• Advise avoidance of excess alcohol, iron, and vitamin C supplementation.

📚 References

• BNF – Haemochromatosis
• EASL Clinical Practice Guidelines: Haemochromatosis
• NICE – Iron overload guidance

Cases - Hereditary Haemochromatosis (HH)

• Case 1 - Classic triad 🏥: A 52-year-old man presents with fatigue, arthralgia, and bronze skin pigmentation. Bloods: ferritin 1800 micrograms/L, transferrin saturation 75%. LFTs: raised ALT/AST. Genetic testing: homozygous C282Y mutation. Diagnosis: hereditary haemochromatosis with early organ involvement. Managed with regular venesection.
• Case 2 - Diabetes and liver disease 🍬🫁: A 60-year-old man with type 2 diabetes develops hepatomegaly and features of cirrhosis. Bloods: ferritin 2400 micrograms/L, iron studies show high transferrin saturation. Fibroscan: advanced fibrosis. Diagnosis: HH with “bronze diabetes” and cirrhosis. Managed with venesection, strict alcohol avoidance, and hepatology follow-up for HCC surveillance.
• Case 3 - Cardiac involvement ❤️: A 48-year-old woman presents with palpitations, exertional dyspnoea, and ankle swelling. ECG: atrial fibrillation. Echocardiogram: dilated cardiomyopathy. Iron studies: ferritin 1600 micrograms/L, transferrin saturation 80%. Genetic test: HFE mutation. Diagnosis: HH with iron overload cardiomyopathy. Managed with venesection, cardiology input, and rhythm control.

Teaching Point 🩺: Hereditary haemochromatosis is an autosomal recessive iron overload disorder (most often HFE C282Y mutation). It causes progressive organ damage: liver (cirrhosis, HCC), pancreas (diabetes), skin (bronzing), joints (arthropathy), and heart (cardiomyopathy, arrhythmias). Diagnosis: ↑ ferritin, ↑ transferrin saturation, genetic testing. First-line treatment: regular venesection.