Elsevier

Clinics in Liver Disease

Volume 4, Issue 1, 1 February 2000, Pages 211-228
Clinics in Liver Disease

HEMOCHROMATOSIS

https://doi.org/10.1016/S1089-3261(05)70104-5Get rights and content

The association of cirrhosis with diabetes mellitus and bronze skin pigmentation was first recognized more than a century ago, when the term hemochromatosis (HC) was given to the condition. Hereditary hemochromatosis, also previously described as genetic or idiopathic hemochromatosis, is now known to result from an inborn error of iron metabolism leading to inappropriately increased iron absorption from the diet. The discovery of the hemochromatosis gene (HFE) and the observation that a single missense mutation, leading to a cysteine-to-tyrosine substitution at position 282 (Cys282Tyr or C282Y), is responsible for most cases of hereditary hemochromatosis have led to rapid advances in the field of iron metabolism. Although the basic defect is still not fully elucidated, much is known about the sequence of events leading to iron overload symptomatic disease, and rational effective therapy is available.

Section snippets

DEFINITIONS, CAUSES, AND CLASSIFICATION OF IRON OVERLOAD

States of iron overload in the human can result from several disorders, some inherited and some acquired, and may be classified accordingly.

Nomenclature for Iron Overload States

  1. 1

    Hereditary hemochromatosis

  • A

    HFE-associated hereditary hemochromatosis

    • C282Y homozygosity

    • C282Y/H63D compound heterozygosity

  • B

    Non– HFE-associated hereditary hemochromatosis

  • C

    Juvenile hemochromatosis

  • D

    Autosomal dominant hemochromatosis

  • E

    Acquired iron overload

    • A

      Iron-loading anemias

      • Thalassemia major

      • Sideroblastic anemia

      • Chronic

PATHOPHYSIOLOGY OF IRON OVERLOAD

A detailed account of iron metabolism is beyond the scope of this article, but newer concepts of iron metabolism and iron absorption resulting from the discovery of HFE and its functions are summarized. Iron balance is regulated by iron absorption,20 which in turn is reciprocally regulated by the level of body iron stores.22 In hereditary hemochromatosis (HHC), the enhanced net absorption of 3 to 4 mg/d results in the accumulation of 500 to 1000 mg of iron/y during adult life. Increased

Prevalence and Mode of Inheritance

HFE-associated hereditary HC is an inherited autosomal recessive trait and is the most common inherited liver disease in Europeans (Table 1). Studies using biochemical markers of iron overload conducted in Australia,48 South Africa,53 Italy, and the United States77 have found a very high prevalence, between 0.22% and 0.95%. Reliance on biochemical expression infers complete phenotypic expression in affected individuals. In a screening study of more than 3000 subjects in Busselton, Western

OTHER CAUSES OF HEREDITARY HEMOCHROMATOSIS

A list of causes of iron overload with organ damage is given at the beginning of this article. Clearly, because the C282Y mutation has only recently been identified, understanding is continuing to evolve. With 16 of 75 (21%) Italian patients with HHC shown not to have the C282Y mutation, Carella et al19 have presented evidence for a second cause of hemochromatosis linked to the HLA-A locus. Worwood et al86 also describe six patients with HHC who lack the C282Y mutation. They suggest that other

ROLE OF THE HEREDITARY HEMOCHROMATOSIS MUTATIONS AND IRON IN OTHER DISEASES

In addition to the direct complications of tissue iron excess that occur as manifestations or complications of HHC, increased body iron stores have been implicated in the pathogenesis of several other disease states.

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      Genetic iron overload is found in hereditary hemochromatosis (HH), a genetic disorder that affects up to 1 in 250 individuals of European descent and has a carrier rate of between 10% and 15%.12 It is characterized by excessive dietary iron absorption in the small intestine.13 The excess iron is stored in the parenchymal cells of major tissues, primarily the liver, heart, pancreas, pituitary, and joints, where its accumulation eventually leads to severe tissue damage.14,15

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    Address reprint requests to Lawrie W. Powell, PhD, MD, The Queensland Institute of Medical Research, The Bancroft Centre, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia 4029, e-mail: [email protected]

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