A 69-year-old woman has had worsening congestive heart failure along with arthritis resembling pseudogout for the past 6 years. On examination her skin has a slate-grey color, her heart rate is irregular, her liver span is increased, and her spleen is palpable. Laboratory studies show an elevated hemoglobin A1c and increased serum ferritin. A mutation involving which of the following genes is most likely to be present in this woman?
Answer: C Hepcidin
Although most cases of hereditary hemochromatosis result from mutations of the HFE gene, some cases may occur from mutations of genes encoding for transferrin receptors, hemojuvelin, and rarely hepcidin. However, the main regulator of iron absorption is the protein hepcidin and all the genetic causes of hereditary hemochromatosis are associated with reduced hepcidin levels. Ordinarily the liver increases hepcidin production when iron stores are adequate, preventing release of iron from intestinal enterocytes and macrophages.
The PiZZ genotype, and to a lesser extent the PiSZ and PiMZ genotypes, are associated with hepatic damage from α-1-antitrypsin deficiency. ATP7B gene mutations are present with Wilson disease, a disorder of copper metabolism.
Mutations of HNF1 are seen with maturity onset diabetes of the young (MODY) and can lead to appearance of hepatic adenomas. UDP-glucuronyl transferase 1 (UGT1) is involved with hepatic conjugation of bilirubin, and mutations can lead to hyperbilirubinemia.