The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis

Walsh, Alissa, Dixon, Jeannette L., Ramm, Grant A., Hewett, David G., Lincoln, Douglas J., Anderson, Gregory J., Subramaniam, V. Nathan, Dodemaide, Julian, Cavanaugh, Juleen A., Bassett, Mark L. and Powell, Lawrie W. (2006) The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Clinical Gastroenterology and Hepatology, 4 11: 1403-1410. doi:10.1016/j.cgh.2006.07.009

Author Walsh, Alissa
Dixon, Jeannette L.
Ramm, Grant A.
Hewett, David G.
Lincoln, Douglas J.
Anderson, Gregory J.
Subramaniam, V. Nathan
Dodemaide, Julian
Cavanaugh, Juleen A.
Bassett, Mark L.
Powell, Lawrie W.
Title The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis
Journal name Clinical Gastroenterology and Hepatology   Check publisher's open access policy
ISSN 1542-3565
Publication date 2006-11
Sub-type Article (original research)
DOI 10.1016/j.cgh.2006.07.009
Volume 4
Issue 11
Start page 1403
End page 1410
Total pages 8
Place of publication Bethesda, MD, United States
Publisher W.B. Saunders
Language eng
Subject 110307 Gastroenterology and Hepatology
Formatted abstract
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.

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.

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.


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.
Keyword Hemochromatosis
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
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Created: Fri, 18 Dec 2009, 12:11:44 EST by Ms Lynette Adams on behalf of School of Mathematics & Physics