Expression of hemochromatosis in homozygous subjects. Implications for early diagnosis and prevention

This study looks at expression of genetic hemochromatosis in the homozygous and heterozygous states. Two hundred nine subjects in 40 families with confirmed hemochromatosis and clear evidence of HLA linkage in symptomatic individuals were studied prospectively for up to 24 yr. The study group consisted of 40 probands, 51 subjects sharing two HLA haplotypes with affected relatives (putative homozygotes), 98 putative heterozygotes, and 20 putative normal homozygotes. Forty-eight of 51 subjects predicted to be homozygous showed increased hepatic iron stores as assessed by liver biopsy and quantitative phlebotomy. If not evident initially, this developed in 1-8 yr. In the 3 subjects predicted by HLA typing to be homozygous but in whom there was no progressive iron accumulation, results of studies using another chromosome 6 genetic marker (Factor 13 A subunit) were consistent with chromosomal recombination, presumably separating one hemochromatosis allele from the HLA markers. No heterozygous subject developed overt hemochromatosis during the period of follow-up, although 1 showed evidence of iron overload at initial assessment. Genetic recombination is again thought to have separated the hemochromatosis allele from the HLA markers here. The present findings favor a location of the hemochromatosis locus telomeric to HLA-A. It is concluded that, in this population, hemochromatosis is apparently always HLA linked, and homozygous subjects will develop iron overload in the absence of chromosomal recombination or blood loss.