• Hereditary hemochromatosis can damage liver, heart, pancreas, endocrine glands, bones, and joints. However clinical expression spans from a few biologic anomalies to full-blown multiorgan involvement.

• Hereditary hemochromatosis is mainly related to inappropriately deficient hepcidin secretion related to mutations in genes involved in hepcidin regulation.

• Ferroportin disease is associated with normal hepcidin secretion, but mutations in ferroportin induce loss of iron export function or resistance to hepcidin regulation.

• HFE-related hemochromatosis is the most frequent form in the white population. Genetic testing for rare forms of hereditary hemochromatosis must be guided by the clinical phenotype.

Hepcidin

Hepcidin (HAMP)3 is synthesized primarily by hepatocytes, but is also produced at lower levels by adipocytes and macrophages. This small peptide, initially identified as an antimicrobial peptide, was later shown to be the key hormone regulator of iron metabolism.4,5

Hepcidin regulates iron availability through the modulation of iron export by ferroportin: hepcidin binds to ferroportin at the membrane of enterocytes or macrophages, and causes subsequent ferroportin endocytosis and degradation, thus impairing iron export.6

Hepcidin regulation

Because of its central role in iron metabolism, hepcidin is tightly regulated by several pathways including inflammation, erythropoiesis, and body iron stores. The regulation of hepcidin according to body iron stores involves distinct pathways for long- and short-term regulation. Basal expression is regulated through a bone morphogenetic protein/Son of Mother Against Decapentaplegic (SMAD) pathway. Bone morphogenetic protein 6 plays a major role in association with its coreceptor hemojuvelin (HJV),7 and is also involved in the response of hepcidin expression to iron stores over the long term.

Regarding the short-term regulation, it is proposed to be mediated through serum transferrin saturation.8 Although the molecular mechanisms remain debated, it is proposed that HFE, TFR1, TFR2, and HJV form an iron-sensing complex at the hepatocyte membrane, with subsequent regulation of hepcidin expression.

Hepcidin deficiency

Hepcidin deficiency is the key mechanism of iron overload in HFE, HJV, HAMP, and TFR2 related hemochromatosis.9 Mutations in these genes lead to defective or inappropriately low hepatic synthesis of hepcidin for the degree of iron burden. In HFE hemochromatosis it has been demonstrated that correction of liver hepcidin secretion normalized iron metabolism, confirming the predominant role of liver.10

Relative hepcidin deficiency leads to a sustained and unregulated activity of ferroportin with two consequences: increased duodenal iron absorption, and enhanced release of iron from reticuloendothelial macrophages into the bloodstream originating from erythrophagocytosis.

The overall result is increased plasma iron concentration and increased saturation of transferrin. If the capacity of transferrin is exceeded, an abnormal physiologic form of iron appears, called nontransferrin bound iron. Nontransferrin bound iron is rapidly taken up by the liver, pancreas, and heart, and leads to pathologic parenchymal iron deposition and organ dysfunction. Moreover, if transferrin saturation exceeds 75%, labile plasma iron appears, which has a high propensity for generating reactive oxygen species that can directly damage tissues.11

Ferroportin disease

There are two types of ferroportin disease that are distinguished by the molecular mechanism involved. Type A is characterized by a loss of ferroportin activity caused by mutations in the SLC40A1 gene.12 As a consequence of the functional deficiency, macrophage iron overload results from decreased iron export. The pathologic consequence is reticuloendothelial macrophage iron loading. Type B is characterized by mutations in ferroportin, which confer “resistance” to hepcidin.13 Thus, despite an increased serum hepcidin level, ferroportin regulation is defective, resulting in constitutive ferroportin activity and a “functional” hepcidin deficiency, as in HFE hemochromatosis. The pathologic consequence is reticuloendothelial macrophage iron sparing and parenchymal iron loading in target organs.