Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients

Abstract

Background and aims: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60). Methods: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2). Results: In total, 92% of 180 eligible first degree relatives were interviewed in the ''screened'' family group and 85% of 143 eligible relatives in the ''patient'' group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the ''iron phenotype'' (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the ''screened'' and ''patient'' groups. Serious morbidity (including cirrhosis) was low in both groups of relatives. Conclusions: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.

Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

“…In contrast, participants in the large multicentre HEIRS Study were enrolled without regard to any clinical conditions. Our findings are consistent with the results of several single-centre and regional population-and primary care-based studies (15)(16)(17)(18). A recent study of first-degree relatives of patients with known C282Y hemochromatosis also found a low prevalence of clinical manifestations in family members who were C282Y homozygotes or C282Y/H63D compound heterozygotes, despite evidence of iron overload in most cases (31).…”

“…By self-identified race/ethnicity, 44% of the participants were non-Hispanic Caucasians. As previously reported (24), the frequency of homozygosity for the C282Y mutation in this group of non-Hispanic Caucasians was 4.4 per 1000 subjects; consistent with the findings of other screening studies (9,18,(25)(26)(27)(28)(29) had SF below these levels. Eighty-seven other participants with C282Y homozygosity reported they previously were told by a physician that they had hemochromatosis or iron overload, or had been treated by therapeutic phlebotomy, including 39 (45%) women and 48 (55%) men, of median age 56 years (range 25 to 83 years).…”

“…A possible interpretation of the relative lack of an increased prevalence of symptoms and signs among C282Y homozygotes in the current study may be that most homozygotes do not develop sufficient iron overload to cause symptoms and clinical manifestations (15)(16)(17)(18), even though the majority have evidence of excess iron accumulation (46). Previous studies of hemochromatosis patients (47) in referral practice settings have shown that the risk of hepatic cirrhosis in C282Y homozygotes begins to increase when SF levels rise above 1000 µg/L, but this SF level was exceeded in only 29 of 131 newly diagnosed C282Y homozygotes with elevated SF in the current study (24).…”

“…This has stimulated interest in early detection (3,13,14) and recent studies (15)(16)(17)(18)(19) have suggested that manifestations of severe iron overload are relatively uncommon in C282Y homozygotes identified by screening.…”

Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first‐degree relatives: a nationwide, population‐based study

“…Mere HFE hetero-or homozygosity may therefore not be a sufficient marker of perturbated iron distribution. In fact, siblings and twins of probands with phenotypic haemochromatosis are known to have higher levels of iron compared with those related to probands with a haemochromatosis genotype, but not phenotype [17,18], suggesting that other factors are critical for the expression of phenotypic disease. Thus, in the context of a family history of genetic haemochromatosis (GH), the observed risks of IHD among individuals heterozygous for HFE mutations may be different from those for individuals with HFE mutations detected through population screening, but the risks of IHD in the former remain unclear [19][20][21].…”