Diagnosis and treatment of hereditary hemochromatosis: an update

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Date: Aug. 2013
Publisher: Expert Reviews Ltd.
Document Type: Report
Length: 11,669 words
Lexile Measure: 1520L

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Author(s): Pushpjeet Kanwar 1 , Kris V Kowdley [*] 2



C282Y mutation; ferritin; hemochromatosis; hepcidin; HFE; iron overload; penetrance


Hereditary hemochromatosis (HH) is an inherited autosomal recessive iron overload disorder resulting in the failure of the normal hepcidin response to body iron stores, leading to increased duodenal absorption of dietary iron [1-3] . The increased iron enters the plasma and may be deposited in various target organs and may lead to clinical signs and symptoms [4] .

Our understanding of this condition has grown significantly since the initial description of advanced HH as 'bronze diabetes' by Trousseau [5] in 1865, to the discovery of the role of iron metabolism in its pathogenesis by Sheldon [6] in 1935, to the identification of the C282Y mutation in HFE as responsible for most cases of HH in 1996 [7] and most recently to the recognition of a central role of hepcidin in the regulation of iron absorption and pathogenesis of HH [2,3,8] . The current classification system for HH has categorized this disorder into four types [301] . The most common is type 1 or classical HH which is associated with a homozygous cysteine to tyrosine missense mutation in HFE gene. Since HFE -associated hemochromatosis (type 1) is the most common form of inherited iron overload, we will focus primarily on type 1 but will also review the current status of the understanding of types 2-4 HH.

Epidemiology & pathophysiology

Evidence from multiple studies has shown that the prevalence of C282Y homozygosity is approximately one out of 250 in populations of predominantly Northern European descent [9-11] . The presence of mutations in a large proportion of patients with phenotypic HH was initially reported by Feder et al . in 1996 [7] . These authors reported that the C282Y and H63D mutations in the HFE gene (located on the short arm of chromosome 6) were present in most patients (especially those of North European origin); the most common pattern was homozygosity for the C282Y mutation with a small portion carrying the C282Y/H63D compound heterozygous genotype. These missense mutations are characterized by replacement of cysteine with tyrosine at position 282 (C282Y) and histidine with aspartic acid at position 63 (H63D) respectively. The mean prevalence of the C282Y allele varies based on multiple screening studies and is approximately 6% [12] . Among Irish individuals, the prevalence of C282Y is >10%, while the frequency varies from 5-10% in most other Northern European countries [13,14] . It is less frequent (~1-5%) in Southern Europe [14,15] and extremely rare in nonwhite populations [16] . The H63D allele carrier frequency is between 10-20% [14] and has lower geographical variability.

The C282Y homozygosity prevalence among Caucasian populations in Northern Europe is approximately 1:200-1:300 [17] while the prevalence of C282Y/H63D compound heterozygotes, based on multiple studies, is approximately 2% [18] . Approximately 90% of individuals with HH are C282Y homozygotes while 5% or less are C282Y/H63D compound heterozygotes [19,20] .

The widespread prevalence of the C282Y mutation in populations in Northern Europe has led to much speculation as to the possible survival advantage that may...

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Gale Document Number: GALE|A341859527