Biochemical expression of heterozygous hereditary hemochromatosis

Abstract

Background: Hereditary hemochromatosis (HH) is a common autosomal recessive disease caused by an iron overload. Two mutations (C282Y and H63D) on the responsible HFE gene have been described. HH heterozygotes may have a slight iron overload that does not cause clinical disease. Compound heterozygosity may be associated with higher iron stores than C282Y heterozygosity. We studied biochemical iron parameters in HH C282Y and compound heterozygotes without a clinically significant iron overload. Methods: Data on hemoglobin, hematocrit, mean corpuscular volume, serum ferritin, serum iron, transferrin, and transferrin saturation were obtained from 40 C282 wild type controls (irrespective of H63D genotype), 61 C282Y heterozygotes, and 18 compound (C282Y/H63D) heterozygotes without clinical iron overload disease. Results: Serum ferritin levels were significantly higher in female HH heterozygotes, particularly in compound heterozygotes, than in normal women. In male heterozygotes, no difference in serum ferritin was found. We found higher mean serum iron and transferrin saturation levels in male and female HH heterozygotes than in normal controls, the highest in the group of compound heterozygotes. Conclusions: Mean serum ferritin (only in women), serum iron, and transferrin saturation are highest in compound heterozygotes and lowest in controls. C282Y heterozygotes seem to be an intermediate group between compound heterozygotes and the normal population.

Introduction

Hereditary hemochromatosis (HH) is a common autosomal recessive disease caused by an iron overload. It is caused by inappropriately high iron absorption from the gut that leads to iron deposition in various organs, resulting in impaired function of these organs, e.g. liver cirrhosis, diabetes mellitus, or cardiac failure [1], [2], [3]. Diagnosis is made by laboratory investigations (a high serum ferritin and transferrin saturation) and by liver biopsy, which shows an elevated hepatic iron concentration, and hemosiderin deposits characteristically appearing first in the hepatocytes in the periportal area [1], [2], [3]. The gene responsible for HH–HFE – situated on the short arm of chromosome 6, was recently discovered [4]. Most but not all patients with HH are homozygous for a mutation of this gene, resulting in a cysteine instead of a tyrosine at position 282 (C282Y) [4], [5], [6]. The significance of another mutation found in the HFE gene, the substitution of a histidine for aspartic acid at position 63 (H63D), is unclear [4], [7]. After genotyping of HH patients became available, some patients with clinical symptoms of HH appeared to be heterozygous for the C282Y mutation; they were identified as compound heterozygotes (i.e. C282Y/H63D heterozygotes) or were even missing both HFE mutations, indicating a different molecular defect [7], [8], [9], [10]. Results from earlier studies in which HH heterozygotes were identified by HLA typing may be unreliable as iron overload could have been caused by non-HFE-linked disease modalities [11], [12], [13], [14]. It has been suggested that the heterozygosity of the C282Y mutation protects young women from iron deficiency [15]. Compound heterozygosity is probably associated with higher iron stores than C282Y heterozygosity [7], [8], [9], [10], [16]. Recently, heterozygous HH has been identified as an independent risk factor for cardiovascular mortality and myocardial infarction [17], [18]. Long-term exposure to small amounts of iron may play a role in atherogenesis and ischemia/reperfusion damage by catalyzing free radical formation [19], so even minimally increased iron stores in heterozygous HH could be detrimental and might explain the increased cardiovascular risk in heterozygous HH. We studied conventional biochemical iron parameters in Dutch HH C282Y and compound heterozygotes without a clinically significant iron overload who would need phlebotomy treatment and we compared them with the iron parameters of a control group containing subjects with wild type HFE (H63D heterozygotes and H63D homozygotes) also without a clinically significant iron overload.