HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype‐stratified cohort study of hemochromatosis in Australian women

Abstract

Background and Aim Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably due to the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild-types) as comparison groups. Methods A sample of the Melbourne Collaborative Cohort Study (MCCS) was selected for the “HealthIron” study (n=1,438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. Results For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), p < 0.001) during the first ten years post menopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between pre- and post-menopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 µg/L post-menopause, but the projected SF did not increase the risk of iron-overload related disease. Conclusions These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity.

Haemochromatosis: a clinical update for the practising physician

“…Symptoms usually develop earlier in men than women, most commonly in the fourth to fifth decades of life. In women, clinical symptoms usually appear post‐menopause, due to iron loss during menstruation, pregnancy and lactation offsetting the increased absorption of iron during this time …”

“…Treatment should be tailored to the clinical scenario of the individual patient. Abnormal SF levels for a menstruating woman likely differ to that of a male if both age and weight are considered . Most consensus statements or guidelines agree to initiate treatment early.…”

“…On the other hand, the incidence of iron overload‐related disease in people carrying the homozygous mutation is less than 30% for men and 1% for women . This is partly due to environmental factors, including physiological blood loss, as well as the interaction of other genetic factors . Novel research is exploiting next‐generation sequencing techniques to identify these disease modifying‐genes that may close the gap in knowledge about incomplete penetrance of the C282Y substitution.…”

Utility of hepatic or total body iron burden in the assessment of advanced hepatic fibrosis in HFE hemochromatosis

“…A sub-analysis of our data for the prediction of F2-F4 fibrosis demonstrated that the accuracy of HIC is similarly improved by the addition of age, albeit to a lesser degree (Supplementary Table S1). The more significant influence of duration of exposure in women could be related to gender-related differences in rates of iron accumulation during adult life, that is, women have lower HIC levels prior to menopause with an exponential increase following menopause in women 21 .…”

The Allele Frequency of the HFE gene mutation H63D (rs1799945) and Its Relationship to a Hereditary Hemochromatosis Diagnosis in Metabolic Nutrition Students at Virginia Tech

“…15,16 Also, this population was relatively young (20-23 years of age). Typically, signs and symptoms of HH do not appear until around 40 to 60 years of age, meaning that this population might be too young to have severe enough symptoms of HH to warrant testing for a diagnosis.…”