Analysis of hereditary haemochromatosis and clinical correlations in the elderly

[摘要] ENGLISH ABSTRACT:Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease wherethe accumulation of iron in parenchymal organs may lead to diabetes, heart failure, livercirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures arenot taken. HH is often not considered as a cause of these conditions, particularly not in theelderly where the background frequencies of type II diabetes, osteoarthritis and heartfailure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH inapproximately 80% of affected individuals worldwide, has been linked to a raisedincidence of malignancies of the colon and rectum, stomach and the haematologicalsystem. One of the highest carrier-frequencies (116) in the world for this mutation has beenreported in the South-African Afrikaner population, resulting in C282Y-homozygosity inapproximately 1 in every 115 people in this group.A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotypeassociation studies. Their clinical presentation was denoted, biochemical iron-statusdetermined and HFE genotyping performed. Either an increase or decrease in survival, orboth, were proposed, depending on possible gender effects. HH has been positivelyassociated with various cancer types, but may also protect against iron-deficiency anaemiawhich is by far the most frequent cause of anaemia in the older person. This study has led to the following findings:1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population(similar in males and females), which is slightly lower than the 1/6 reported in youngeradults from the same population. Only one C282Y homozygote and two C282YIH63Dcompound heterozygotes were detected, all of them female.2. The prevalence of diabetes, heart disease, arthropathy or a combination of theseconditions did not differ significantly in C282Y heterozygotes and the mutationnegativegroup.3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma wasdetected compared with two cases with rectal- and seven with colonic malignancies in153 mutation-negative individuals. The single female C282Y homozygote identifiedsuffered from both rectal and colon carcinoma and died approximately 6 months ago asa consequence of her colon malignancy.4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly inthe elderly where a variety of factors that may influence the levels are often present inelderly individuals. This may be due to ageing alone or as a result of multiple comorbidities.5. Serum ferritin levels were lower than expected in elderly subjects with mutationC282Y and compound heterozygotes with both C282Y and H63D, which may berelated to a variable penetrance of the HFE gene mutations. It is possible that variationin other genes exist that confer protection against iron-loading by gene-geneinteraction. The probability that environmental factors (e.g. a low iron diet) are moreimportant in this respect cannot be excluded, although this is considered less likely inthe light of the fact that the same trend was observed in all mutation-positive elderlyindividuals. It is therefore highly likely that C282Y -positive subjects with significantiron loading have died before reaching their seventies, particularly since none of themales included in this study were homozygous or compound heterozygous for themutations analysed.In conclusion, possession of a mutant HFE gene does not appear to confer a survivaladvantage in old age, neither does it seem that mutation carriers with significant ironloadingare overlooked by the medical fraternity. Further investigations are warranted toshed more light on the contributions of gene-gene and gene-environment interaction in theclinical manifestation of Hll, and how these processes can be manipulated to prevent thesymptoms of this largely underdiagnosed disease.

[发布机构] Stellenbosch University