Original article
The Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis

https://doi.org/10.1016/j.cgh.2006.07.009Get rights and content

Background & Aims: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes. Methods: Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated. Results: C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 μg/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes. Conclusions: C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.

Section snippets

Patients

Ninety-one C282Y/H63D probands were referred for clinical assessment either at The Royal Brisbane and Women’s Hospital or The Canberra Hospital in Australia. These subjects were ascertained over a 25-year period, although most were established over the past 15 years.15 However, all subjects were genotyped after the cloning of the HFE gene in 1996. Fifty-two subjects were diagnosed incidentally at health checks (males:females, 32:20); 24 presented because of lethargy (males:females, 19:5). The

Clinical Expression and Patient Demographics

Table 1 depicts the symptoms and signs on presentation of the C282Y/H63D probands compared with C282Y homozygous probands. The most common symptom in both compound heterozygous and homozygous probands was joint pain. The frequency was significantly higher in both male and female C282Y homozygous probands when compared with male and female compound heterozygous probands (P < .001 and .018, respectively). The most common sign in compound heterozygous probands was hepatomegaly in males (9.7%) and

Discussion

This study has characterized a large cohort of referred subjects with compound heterozygosity for the major HFE mutations (C282Y/H63D) and compares the findings with a cohort of C282Y homozygous subjects referred to the same 2 centers over the same period. C282Y/H63D subjects had a high prevalence of biochemical expression but lesser degrees of iron overload compared with C282Y homozygous subjects, as assessed by the HIC and mobilizable body iron levels. Moreover, these values fall short of the

References (38)

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    Citation Excerpt :

    For this reason, HFE-related HC should not be viewed as a simple monogenic disorder but rather as the complex result of the interplay of environmental, lifestyle, and still unidentified genetic cofactors.1 Regarding the compound p.Cys282Tyr and p.His63Asp heterozygosity, compelling evidence exists that this genotype per se is characterized by minimal or no clinical penetrance.65,66 Thus, it cannot be considered diagnostic for HC,14 but at most as a susceptibility factor that can be associated with mild-to-moderate IO only in case of digenic inheritance67 (see below) or when other predominant causes of liver disease are present, namely nonalcoholic fatty liver disease (NAFLD), alcohol, or hepatitis C virus (HCV).

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Supported by the National Institutes of Health (grant 5ROIDK057648-04 to L.W.P., G.A.R., G.J.A., and V.N.S) and the National Health and Medical Research Council of Australia (339400 to L.W.P., G.A.R., G.J.A., and V.N.S.).

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