Hereditary hemochromatosis is an autosomal recessive disorder that results from a mutated hemochromatosis (HFE [human factors engineering]) protein.
In the bloodstream, iron binds to transferrin, forming diferric transferrin. Iron is released from transferrin when the compound binds with the transferrin receptor on the basolateral surface of hepatocytes. It is at this location where the HFE protein normally binds to the transferrin receptor, and the iron is brought into the cell along with the deactivated transferrin receptor. The association between the HFE protein and the transferrin receptor reduces the affinity of the transferrin receptor for diferric transferrin, resulting in a decreased release of iron from the iron-transferrin complex.
It is unclear exactly how the mutated form of HFE leads to an iron overload state. One theory is that mutated HFE has a conformation change in its structure that prevents the transferrin receptor from entering the hepatocyte. The receptor therefore stays active, and continues to bind to diferric transferrin and release iron, leading to iron overload.
Studies have classified HFE-associated hereditary hemochromatosis as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues, causing multiple organ damage and failure.
Liver transplantation (LT) has been determined to be a key treatment for HFE-related hereditary hemochromatosis to correct reduced hepatic hepcidin secretion. In a study of 18 patients who underwent LT, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; P< 0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at 1 and 5 years, respectively, and was was similar to that of patients who received LT for other causes.
Hemochromatosis is the clinical expression of iron-induced end-organ injury; in hereditary hemochromatosis, the clinical disorder is linked to a genetic cause. Three mutations in the HFE gene have been implicated. The first involves a G→A mutation at nucleoside 845, leading to a cysteine to tyrosine substitution at amino acid position 282 (C282Y). The second mutation involves a G→C substitution at nucleotide 197, leading to a histidine to aspartic acid substitution at amino acid position 63 (H63D). The third mutation involves an A→T mutation at nucleotide 193, leading to a serine to cysteine substitution at amino acid position 65 (S65C).
The most penetrant of these mutations is the C282Y defect; C282Y homozygotes account for up to 90% of clinical cases of hereditary hemochromatosis. By contrast, H63D and S65C homozygosity typically cause only mild disease or no clinical consequences.