Genetic testing revealed that the patient described here was homozygous for the Cys282Tyr mutation, which was not particularly surprising because this mutation is most common in patients with a Northern European ancestry. About 85% to 90% of patients of Northern European descent with HH are Cys282Tyr homozygotes.16 This mutation is almost certainly associated with increased iron absorption, though population surveys have revealed that some Cys282Tyr homozygotes do not have elevated iron stores.17 The Cys282Tyr mutation is most common in white individuals, but this mutation does not account for iron overload in nonwhite individuals, including Pacific Islanders and Asians.18 In addition, several other genes have been implicated in iron overload. The Leu490Arg and Val561Xaa mutations in the TFR2 gene have been identified in Japanese patients with hemochromatosis lacking mutations in HFE.19 Also, mutations in the HJV gene have been identified in patients with juvenile HH.20 Hepcidin is a key hormone in iron regulation.21 Its expression is decreased by mutations in HFE, TFR2, and HJV, all of which can contribute to iron overload in patients with HH. Hepcidin is a 25–amino acid peptide that was first identified in urine and plasma during a search for antimicrobial peptides.22 When there are increased iron stores in the body, HFE triggers hepcidin expression, which decreases the level of iron in the blood.21 The loss of hepcidin in upstream stimulatory factor 2 knockout mice is associated with increased intestinal iron absorption and increased circulating iron levels, akin to HH.23 Reduced hepcidin expression occurs in HH regardless of the genetic etiology. Although current treatment for HH is phlebotomy, a future treatment may be exogenous hepcidin.21
Conclusion
The homozygous Cys282Tyr mutation in the HFE gene was identified as the cause of PCT and HH in a 41-year-old woman. An understanding of iron overload has been enhanced by the identification of genes that control hepcidin, including HFE, TFR2, and HJV. Mutations in these genes are associated with reduced levels of hepcidin, resulting in iron overload observed in HH.