Hereditary Hemochromatosis


Hemochromatosis 1

  • Autosomal recessive
  • Clinical manifestations usually appear after age 30-40, earlier in men than women
  • Hereditary: mutation is the HFE (C282y or H63D) gene on chromosome 6
  • Secondary iron overload: ineffective erythropoiesis: thalassemia or sideroblastic anemia
  • Risk factors: male and alcohol -> ↓ phenotypic expression if homozygous C282yY)
  • Overtime, excess iron -> hydroxyl free radicals -> fibrosis in the involved organs
  • Organs affected: Liver, pancreas, heart, joints, skin, thyroid, gonads, hypothalamus


Clinical presentation:

Clinical triad: skin pigmentation, cirrhosis, and diabetes

  • Most: initially asx
  • Fatigue, weakness, wt loss
  • Liver: cirrhosis (MCC of death) (higher risk of HCC), hepatoma
  • Heart: restrictive cardiomyopathy, CHF, arrhythmias
  • Pancreas: DM “bronze-diabetes” -> due to iron deposition in pancreas
  • Joints: arthritis in 2nd + 3rd MCP, hips, knees caused by pseudogout (CPDD)
  • Gonads: hypogonadism -> impotence (erectile dysfunx), amenorrhea, loss of libido
  • Hypothyroidism
  • Pan hypopituitarism
  • Skin: hyperpigmentation (suntan, bronze-like)



  • ↑↑ serum iron + serum ferritin (>300 mg\L)
  • ↑ transferrin saturation (>45%)
  • ↓ total iron-binding capacity (TIBC)
  • Gold standard: liver biopsy: determines hepatic iron conc (>71 mmol\g is highly suggestive)
  • MRI of the liver + HFe (C282y) gene testing -> spares liver biopsy
  • ECG: conduction defects
  • Echo: dilated or restrictive cardiomyopathy

Hemochromatosis 4



  • Treatment of choice: repeated phlebotomies (improves survival if started early):
    • Induction phase: weekly venesection of 1 unit of blood = 500 mL = 250 mg of iron until serum ferritin = 50 mg\L (may take 2 yrs)
    • Maintenance phase: followed by maintenance phlebotomy less frequently (every 1-4 mo) as needed to keep ferritin levels < 50 mg\L


  • If phlebotomy is inappropriate (anemia or hypoproteinemia) -> chelating therapy: deferoxamine (removes 10-20 mg of iron\d)
  • Treat complications (CHF, DM. hypothyroidism, arthritis)
  • Hemochromatosis 5Liver transplant if advanced\cirrhosis
  • Screen very 6 mo for HCC by US


Types of hereditary hemochromatosis:

  • HFE related hemochromatosis (type 1) [AR]: C282Y, H63D, other HFE mutations
  • Non-HFE related hemochromatosis:
  • Juvenile hemochromatosis (type 2) [AR]: presents early in life (10-30 yr), more rapid and severe course
    • Type 2A: hemojuvelin mutations
    • Type 2B: hepcidin mutations
  • Transferrin receptor 2 hemochromatosis (type 3) [AR]
  • Ferroprotien diseases (type 4) [AD]: loss of FPN activity -> accumulation of iron in macrophages -> ↑ serum ferritin, mild anemia (low avalabilty of iron) -> don’t tolerate phlebotomy


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