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Hemochromatosis is a heterogeneous group of heritable disorders that increase the risk of developing iron overload due to increased dietary absorption of iron. Most hemochromatosis is due to mutation(s) in genes that alter the expression, structure, or ferroportin binding of hepcidin, a liver polypeptide that is the central regulator of iron absorption. Deleterious mutations that cause hemochromatosis include those of the HFE, HJV, TFR2, HAMP, and SLC40A1 genes. A rare mutation in the iron-responsive element of the FTH1 gene caused hemochromatosis due to decreased ferritin heavy-chain ferroxidase activity. Because mechanisms to excrete iron are limited, some persons with hemochromatosis develop iron overload and consequent target organ injury



HFE hemochromatosis:

  • 4–10 per thousand (western European whites)

  • 4–5 per thousand (non-Hispanic whites in United States)

  • 1 in 200 (U.S. Vietnamese)

Non-HFE hemochromatosis:

Rare, based on pathogenic mutations and cases discovered in population samples



HFE hemochromatosis:

Predominantly European whites; some Native Americans, U.S. Vietnamese, Hispanics, African Americans

Non-HFE hemochromatosis:

Predominantly European whites; some Asians, Native Africans, African Americans, Japanese, Pacific Islanders


Male-to-female ratios in HFE hemochromatosis diagnosed in medical care:

  • Hemochromatosis genotype: 1:1

  • Elevated serum iron measures: 1.3:1

  • Elevated hepatic transaminase levels: 2:1

  • Diabetes mellitus: 4:1

  • Cirrhosis: 5:1

  • Primary liver cancer: 5:1


HFE hemochromatosis:

Severe iron overload typically occurs in subjects 40–60 years old but is rare before age 30 years

Non-HFE hemochromatosis:

Severe iron overload is common in children, adolescents, or young adults with HJV, TFR2, or “gain-of-function” SLC40A1 hemochromatosis


Life expectancy:

Normal in treated patients without cardiomyopathy, cirrhosis, or diabetes mellitus, and in individuals who do not develop iron overload


Mortality rate in U.S. Adults:

  • Men: 2.4/million

  • Women: 1.2/million

  • Whites: 1.9/million

  • Nonwhites: 1/million


Barton JC et al. Genet Test 2007;11:269–275

Beutler E, Felitti VJ. Arch Intern Med 2002;162:1196–1197

Witte DL et al. Clin Chim Acta 1996;245:139–200

Yang Q et al. Ann Intern Med 1998;129:946–953

Etiology and Classification

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Etiology and Classification
Frequency Transmission Penetrance Ethnicity Presentation Clinical Presentations
Hereditary Hemochromatosis Type: Classic Hereditary (HFE) Hemochromatosis
Common AR (C282Y) Low—Iron overload in <1% of heterozygotes European whites (90% have HFE C282Y) Second to fifth decades

Progressive iron overload

Advanced symptoms:

  • Liver cirrhosis

  • Diabetes

  • Hypogonadism

  • Skin pigmentation

Early symptoms:

  • Chronic fatigue

  • Joint and muscle pain

  • Decreased libido

  • Lethargy

  • Hepatomegaly

AR (H63D, S65C, E168X)
  • Iron overload, usually mild

  • Other liver disorders

AR (IVS5+1 G/A)   Vietnamese  
Hereditary Hemochromatosis Type 2A: Hemojuvelin (HJV) Hemochromatosis (Juvenile Hemochromatosis)
Uncommon AR High European whites First or second decades
  • Arthropathy

  • Hypogonadism

  • Cardiomyopathy

  • Liver fibrosis or cirrhosis

  • Fatigue (older patients)

  • Diabetes mellitus (older patients)

    With prolonged hypogonadism:

  • Osteopenia

  • Osteoporosis

Hereditary Hemochromatosis Type 2B: Hepcidin (HAMP) Hemochromatosis
Rare AR or digenic HAMP/HFE   European whites First or second decades  
Hereditary Hemochromatosis Type 3: Alternate Transferrin Receptor 2 (TFR2) Hemochromatosis
Rare AR <100% Italian and Japanese kinships Second ...

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