The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for<unk>  is HFE on chromosome 6, which codes for hepcidin, a protein that participates in the regulation of iron absorption. The HFE gene has three often observed genetic variants: * rs1799945, c.187C>G, p.His63Asp (H63D); * rs1800562, c.845G>A, p. Cys282Tyr (C282Y); * rs1800730, c.193A>T, p.Ser65Cys (S65C). The worldwide prevalence rates for H63D, C282Y and S65C (minor allele frequencies) are 10%, 3% and 1% respectively. The C282Y allele is a transition point mutation from guanine to adenine at nucleotide 845 in HFE, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid. Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for<unk>  and puts them greatly at risk of storing excess iron in the body. Homozygosity for the C282Y genetic variant is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D variants, so-called compound heterozygotes, results in clinically evident iron overload. Considerable debate exists regarding the penetrance—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes. Most males homozygous for HFE C282Y show at least one manifestation of iron-storage disease by middle age. Individuals with the relevant genetic variants may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage. The H63D variant is just a gene polymorphism, and if there are no other changes, it may not have clinical significance. In a 2014 study, H63D homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up. As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload. Besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous H63D variant is significantly higher in elite endurance athletes comparing to ethnically-matched controls, and is associated with high V̇O2max in male athletes. . Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease. Penetrance differs between populations. Disease-causing genetic variants of the HFE gene account for 90% of the cases of non-transfusion iron overload. This gene is closely linked to the HLA-A3 locus.
Hereditary haemochromatosis
Hemochromatosis type 4
Juvenile hemochromatosis
Haemochromatosis type 3
Aceruloplasminemia
Non-alcoholic fatty liver disease
Familial cirrhosis
Wilson's disease