Hereditary hemochromatosis (HH) is a common genetic disease with autosomal recessive inheritance that results in iron overload and subsequent deposition into various tissues.

  • HH includes at least four types of iron overload conditions, which involve gene mutations that alter iron metabolism.
  • There is no mechanism to excrete excess iron, so the surplus is stored in tissue, including the liver, pancreas, and heart, eventually resulting in severe damage to the affected organ(s).
  • Patients are often asymptomatic, but late effects may include diabetes, liver cirrhosis, hypermelanotic pigmentation of the skin, cardiac issues, and other complications.
  • Synonym(s): bronze diabetes; Troisier-Hanot-Chauffard syndrome



  • Predominant age: Metabolic abnormality is congenital, but symptoms typically present between the 3rd and 5th decades for HH types 1, 3, and 4; type 2 juvenile hemochromatosis typically presents between the 1st and 3rd decades of life, and neonatal presentation is exceedingly rare.
  • Predominant sex: Gene frequency is equal between male and female, although clinical signs are more frequent in men.


  • Prevalence in the United States for carrying an HFE gene mutation (type 1 HH) is 5.4% for the C282Y gene and 13.5% for the H63D gene; prevalence for homozygosity is 0.3% for C282Y and 1.9% for H63D (1).
  • Type 1 accounts for >90% of HH cases in the United States and primarily occurs in people of northern European descent; ~1 in 200 white adults in the United States are C282Y homozygous (1).

Pediatric Considerations
Juvenile (type 2) HHC is rare but can present in young patients (between 1st and 3rd decades of life) with hypogonadism and cardiomyopathy.

Etiology and Pathophysiology

  • HH type 1 is caused by mutations in the HFE gene (most frequently C282Y and/or H63D), and it is the most common form of HH overall. Other variations include type 2 which is caused by mutations in either the HJV or HAMP gene, type 3 by mutations in the TFR2 gene, and type 4 by mutations in the SLC11A3 gene.
  • Types 1 to 3 involve a deficiency in an iron-regulating hormone named hepcidin, which causes increased intestinal absorption of iron through excessive expression of ferroportin (a transmembrane protein that transports iron out of the cell and into the bloodstream).
  • Type 4 is caused by an insensitivity of ferroportin to hepcidin (4a) or an inactivity of ferroportin itself (4b); the latter leads to iron accumulation within mesenchymal tissue.
  • Other rare types of HH exist as a result of different gene mutations.
  • Increased plasma iron and transferrin saturation (TS) leads to elevated levels of unbound iron, which are then absorbed into various tissue, eventually causing organ dysfunction.


  • Genetically heterogeneous disorder of iron overload; types 1, 2, and 3 are autosomal recessive; type 4 is autosomal dominant.
  • Biochemical penetrance is incomplete and expressivity is variable; in type 1 HH, the penetrance for developing clinically significant iron overload is rare, but approximately 75% of men with type 1 HH and 50% of women will have an increase in TS (with or without elevated serum ferritin [SF]) (2).
  • Factors contributing to variable expressivity include different mutations in the same gene, mitigating or exacerbating genes, and environmental factors.

Risk Factors

  • Family history
  • White men between the ages of 30 and 50 years (particularly for HFE-related HH)
  • Loss of blood, such as that which occurs during menstruation and pregnancy, delays the onset of symptoms in women
  • Alcohol consumption because it increases the absorption of iron and synergistically damages the liver along with the oxidative effects of iron

General Prevention

  • First-degree relatives of those with HH should be screened; typically, with fasting TS and ferritin levels.
  • Children of a diagnosed parent, HFE testing of the other parent is recommended with no further testing required if the results are normal.
Screening of the general population is not recommended because only a small subset of patients with HH will develop symptoms or advanced disease (2).

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