16-13: Hemochromatosis

GENERAL CONSIDERATIONS

Hemochromatosis is an autosomal recessive disease caused in most cases by a pathogenic variant in the HFE gene on chromosome 6. The HFE protein is thought to play an important role in the process by which duodenal crypt cells sense body iron stores, and the variant gene leads to increased iron absorption from the duodenum. A decrease in the synthesis or expression of hepcidin, the principal iron regulatory hormone, is thought to be a key pathogenic factor in all forms of hemochromatosis. About 85% of persons with well-established hemochromatosis are homozygous for the C282Y variant (type 1a hemochromatosis). The frequency of the C282Y variant averages 7% in Northern European and North American White populations, resulting in a 0.5% frequency of homozygotes (of whom 38–50% will develop biochemical evidence of iron overload but only 28% of men and 1% of women will develop clinical symptoms). Polymorphisms in modifier genes have been shown to lead to a high iron phenotype. The C282Y gene variant and hemochromatosis are uncommon in Black and Asian American populations. A second genetic variant (H63D) may contribute to the development of iron overload in a small percentage (1.5%) of persons who are compound heterozygotes for C282Y and H63D (type 1b); iron overload–related disease develops in only a few patients (particularly those who have a comorbidity such as diabetes mellitus and fatty liver). H63D homozygotes do not develop hemochromatosis but may be at increased risk for amyotrophic lateral sclerosis, and carriers may be at increased risk for non-cardia gastric cancer. A third gene variant (S65C) may lead to increased serum iron and ferritin levels without clinical significance (type 1c). High serum ferritin levels are seen in hyperferritinemia cataract syndrome associated with pathogenic variants in the FTL (ferritin L-chain) gene. An uncommon juvenile-onset variant that is characterized by severe iron overload, cardiac dysfunction, hypogonadotropic hypogonadism, and a high mortality rate is usually linked to a variant gene on chromosome 1q designated HJV that produces a protein called hemojuvelin (type 2a) or, rarely, to a variant of the HAMP gene on chromosome 19 that encodes hepcidin (type 2b). Rare instances of hemochromatosis result from pathogenic variants in the genes that encode transferrin receptor 2 (TFR2) (type 3) and ferroportin (SLC40A1) (type 4a). Type 4b hemochromatosis is characterized by resistance of ferroportin to hepcidin. Mutations in other genes associated with iron regulation, including ceruloplasmin gene variants, have been identified in ...