Clinical and biochemical expression of the genetic abnormality in idiopathic hemochromatosis

Abstract

The pattern of transmission of the predisposing alleles of idiopathic hemochromatosis was traced in 111 members of 12 pedigrees by typing for the A and B alleles of the HLA complex. The 12 probands were assigned the status of homozygotes. Other family members were grouped according to their HLA typing into one of three categories independent of their iron stores: homozygotes who shared two haplotypes with the proband; heterozygotes who shared one haplotype; and normals who lacked both haplotypes. Clinical manifestations of iron loading were prevalent in male homozygotes and absent in heterozygotes and normals. The results of tests of iron metabolism were compared with age- and sexmatched controls. Abnormalities in 12 probands and 6 discovered homozygotes were characterized by a significant increase in mean serum iron, a decrease in serum transferrin, an increase in both transferrin saturation, and serum ferritin. Similar but less marked abnormalities were found in 25% of 69 heterozygotes with the exception that mean serum ferritin was normal. In 24 normal family members a slight increase in mean serum iron and transferrin saturation was detected, but mean serum ferritin was normal. Radioiron absorption in relation to the respective serum ferritin concentration measured in selected subjects was markedly increased in 10/10 homozygotes, moderately increased in 5/14 heterozygotes and within the control range in 2/2 normals. In summary, phenotypic expression of hemochromatosis was characterized by increased serum iron, decreased transferrin, increased serum ferritin, and iron absorption relative to serum ferritin in both homozygous males and females, but a major degree or iron loading with clinical features was only prevalent in homozygous males. Partial biochemical expression of the disorder in some heterozygotes was associated with an increase in iron absorption and a minor degree of iron loading in the absence of clinical manifestations.