Alteraciones del metabolismo del hierro. Homocigosis H63D

Abstract

BACKGROUND. Hereditary hemochromatosis is the leading genetic cause of iron overload. The C282Y mutation in the HFE gene is the most common polymorphism associated with this disorder; however, the substitution of a histidine for aspartate at amino acid 63 (H63D) may also play an important role in the disease. The methodological differences between studies of patients carrying the H63D mutation preclude generalization of the results. The current data argue both for and against an association between the H63D mutation and hemosiderosis. Given the high value of early diagnosis in preventing iron overload‒related damage, identifying the role of the H63D mutation in disease pathogenesis is highly important. We therefore tested the hypothesis that individuals who are homozygous for the H63D HFE mutation have an increased risk of developing iron overload compared to individuals with the wild-type allele. AIMS. Main objective: To analyze the effect of homozygous H63D polymorphism on iron metabolism. In particular, we investigated the extent to which this mutation predisposes carriers to develop significant liver disease secondary to iron overload. Secondary objectives: - To compare iron metabolism-related data between homozygous H63D, homozygous C282Y, and wild-type subjects. -To evaluate the effect of other hyperferritinemia-related factors on the results. METHODS. This observational analytical study included 445 subjects who were referred from 1994 through 2012 for suspicion of iron overload or due to a family history of hemochromatosis. The study was approved by our hospital’s Clinical Research Ethics Committee, and data were obtained from the medical records and laboratory database. Genetic analyses were performed using allele-specific polymerase chain reaction amplification, and statistical analyses were performed using SPSS version 20.0. RESULTS. Genetic testing revealed that 192 of the 445 subjects were homozygous for the H63D allele, 109 were homozygous for the C282Y allele, and the remaining 144 were wild-type. Among homozygous H63D patients, the mean ± standard deviation ferritine concentrations and IST values were 372.1± 385 mg/dl and 42.4± 19.1 %, respectively. Older patients, had higher ferritin concentrations, indicating a trend towards gradual increase over time. Serum iron, AST, ALT, bilirubin, and GGT values were all within normal ranges. Twenty-one patients had increased parenchymal iron levels (estimated by biopsy or magnetic resonance), and seven presented signs of cirrhosis with portal hypertension. Compared to the homozygous C282Y patients, H63D group presented lower ferritin levels, lower IST values, and a lower prevalence of parenchymal iron overload. The subjects with wild-type alleles had higher ferritin levels than the homozygous H63D patients, but similar IST values, iron deposition, and portal hypertension prevalence. With respect to possible confounding variables, the wild-type subjects had the highest prevalence of non-inherited hyperferritinemia-related factors, confirming a secondary origin of iron overload in this group. CONCLUSIONS. H63D homozygosity is related to increased levels of ferritin. In the absence of other clinical conditions related to secondary hemosiderosis, the presence of H63D HFE homozygosity is not sufficient for determining clinically significant iron overload in most of the cases. When assessing patients who are homozygous for the H63D allele and present with analytical and/or histological evidence of iron overload, other hyperferritinemia-related factors should be investigated first.