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

Alissa Walsh, Jeannette L. Dixon, Grant A. Ramm, David G. Hewett, Douglas J. Lincoln, Gregory J. Anderson, V. Nathan Subramaniam, Julian Dodemaide, Juleen A. Cavanaugh, Mark L. Bassett, Lawrie W. Powell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1403-1410
Number of pages8
JournalClinical Gastroenterology and Hepatology
Issue number11
Publication statusPublished - Nov 2006
Externally publishedYes


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