Original articleThe Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis
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
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2022, BloodCitation 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).
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.).