What are the genetic subtypes of hereditary hemochromatosis?
HHC results from mutations in one of several genes involved in regulation of iron homeostasis:
• Classic/HFE-related (type I): the HFE gene is located on chromosome 6 near the HLA-A locus and is responsible for most cases of HHC (approximately 80% of cases in the United States). HFE protein is mainly expressed in crypt enterocytes of the duodenum, where it regulates brush border iron transport from the gut lumen. HFE is also found in Kupffer cells in the liver and regulates hepcidin production via unknown mechanisms. A single G→A mutation in the HFE gene, resulting in tyrosine substitution for cysteine at position 282 (C282Y), is found in almost all (>90%) of the patients with type I HHC. Less common mutations are aspartate substitution for histidine at position 63 (H63D) and substitution of serine by cysteine at position 65 (S65C). Over 80% of patients with type I HHC are homozygous for the C282Y gene mutation (type IA). Most of the remaining patients with type I HHC are compound heterozygotes (C282Y/H63D [type IB] or C282y/S65C [type IC]) and only 1% patients are homozygous for H63D. Patients with type I HHC who are not homozygous for C282Y will have overall milder disease which tends to occur only when an associated comorbidity exists (e.g., alcoholism). The HFE gene mutations result in hepcidin deficiency. This deficiency is responsible for excessive expression of FPN at the cell surface which results in increased iron egress, especially from macrophages and enterocytes. This causes increased plasma iron and increased transferrin saturation leading to increased levels of nontransferrin-bound iron that is taken up by hepatic, pancreatic, endocrine, cardiac, and other parenchymal cells.
• Juvenile-type HHC (type II): caused by a mutation of the hemojuvelin ( HJV ) gene on chromosome 1 (type IIA) or the hepcidin antimicrobial peptide ( HAMP ) gene on chromosome 19 (type IIB). HJV is the major modulator of hepcidin expression. A mutation in either gene means that hepcidin levels remain low, leading to excess iron export from enterocytes and macrophages via FPN into serum. Patients develop symptoms by the age of 20 years.
• Transferrin receptor 2-related (type III): due to a mutation in this receptor (TFR2), the uptake of transferrin-bound iron is altered and hepcidin expression is low providing a false signal that iron stores are low.
• FPN-related HHC (type IV): FPN gene mutation causes insensitivity to hepcidin. Hepcidin is not able to cause internalization and degradation of the mutated FPN protein on cell surfaces. Consequently, FPN accumulates at the cell surface allowing excess release of iron from enterocytes and macrophages into serum.
