Hereditary Hemochromatosis

 

• Background

  Pathophysiology

  • Mutation in HFE on chromosome 6p, 90% due to the C282Y polymorphism.
  • Leads to ↓hepcidin synthesis → ↑iron absorption and ↑release from erythrophagocytosis → iron levels 10 x normal.
  • Damages liver, joints, anterior pituitary, pancreas, heart, and thyroid.

  Epidemiology

  • Commonest congenital metabolic disease in the UK.
  • Autosomal recessive inheritance. 1/15 northern Europeans are carriers with 1/250 homozygous. But there is low penetrance, with only ~50% of homozygotes having abnormal iron studies and <10% having symptoms.
  • Symptom onset usually in middle-age for men, but 10 years later and less likely in women.

• Signs and symptoms

  A-J:

  • Anterior pituitary damage. Leads to hypogonadism.
  • Bone disease: osteoporosis.
  • Chronic liver disease: hepatomegaly, cirrhosis. Latter contributes to hypogonadism.
  • Dilated or restrictive cardiomyopathy.
  • Excess iron.
  • Fatigue
  • Grey skin, though initially may be bronze. Usually generalised but especially affects the face, neck, extensors, hands, lower legs, and genitals.
  • Hypothyroidism
  • ↓Insulin due to pancreatic damage. HH also known as 'bronze diabetes'.
  • Joint pain due to chondrocalcinosis. Especially affects 2nd/3rd MCP and PIP.

• Investigations

  Iron studies:

  • ↑Ferritin, ↑iron, and ↓TIBC (total iron binding capacity). TIBC is a proxy measure of transferrin, and is ↓ as most is already bound.
  • Rule out other causes of ↑ferritin: inflammation (CRP), alcoholism, metabolic syndrome (BP, BMI, lipids, glucose), anaemia.
  • (Iron ÷ TIBC) x 100 = transferrin saturation (TSAT). TSAT >45% in HH. May also be raised in asymptomatic carriers.

  Genetic testing if ↑TSAT:

  • HFE genotyping confirms diagnosis.
  • If +ve, screen 1st-degree relatives.
  • If -ve but suspicion remains high, consider liver MRI and/or liver biopsy to assess iron content and fibrosis.

  Test for effects if clinically indicated:

  • Bloods: LFT, glucose, TFT, LH/FSH/testosterone.
  • Imaging: liver MRI, joint X-ray, DEXA, ECG, echo.

• Management

  Conservative treatment if normal serum ferritin and asymptomatic:

  • Lifestyle changes: avoid iron and vitamin C supplements, minimize alcohol.
  • Annual monitoring with serum ferritin and TSAT.
  • Hepatitis A and B vaccination.

  Iron reduction if ↑serum ferritin or symptomatic:

  • Remove 1 unit per week until ferritin is mildly low, then maintain with less frequent venesection e.g. 1 unit every 3-6 months for life. Note that this may lead to falsely low HbA1c levels.
  • 2nd-line: iron chelation with desferrioxamine.

  Liver transplantation for those with decompensation.

• Complications and prognosis

  • Normal life expectancy if no cirrhosis or diabetes at diagnosis.
  • HCC risk: 5% in men, 1% in women.
  • Other causes of death: cirrhosis, heart failure, diabetes.