Introduction

There is now incontrovertible evidence that early diagnosis and therapy of hemochromatosis prevents virtually all manifestations of the disorder and results in normal life expectancy. In contrast, unrecognized and untreated hemochromatosis leads to hepatic cirrhosis, hepatocellular carcinoma, and other lethal complications. A statistically significant increase in risk among heterozygotes for hemochromatosis has been demonstrated: for colorectal polyps in each sex; for colorectal cancer, diabetes mellitus, and hematologic malignancy in men; and for gastric cancer in women. Heterozygotes for hemochromatosis with co-existing hematologic disorders such as idiopathic refractory sideroblastic anemia, hereditary spherocytosis, pyruvate kinase deficiency or sporadic porphyria cutanea tarda may develop iron overload sufficient to cause overt organ damage. In addition, the identification of a putative heterozygote provides the opportunity to conduct studies of family members to identify individuals who are homozygous for the disorder. Thus early identification of homozygotes and heterozygotes for hemochromatosis is an important clinical challenge. This chapter provides a review of methods for determination and prevalence estimation of hemochromatosis heterozygosity including kinship and HLA analysis, population surveys, and statistical mixture modeling of transferrin saturation data. Criteria used for hemochromatosis screening studies are reviewed and suggestions for screening based on transferrin saturation are discussed.

Determination of heterozygosity

Kinship and HLA analysis

Hemochromatosis is the most common autosomal recessive disorder in Caucasian populations. For pedigree analyses based on HLA typing of index subjects and family members, three different genotypes, determined by a onelocus, two-allele model, have been proposed: homozygous normal; heterozygous for the hemochromatosis allele; and homozygous for the hemochromatosis allele.