Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage. Signs and symptoms
Symptoms vary greatly between individuals with type 4 hemochromatosis. This difference in symptoms is likely due to the different types of SLC40A1 mutations patients may have. In general, signs and symptoms of type 4 hemochromatosis are caused by excess iron in cells, which leads to tissue damage. The damage is largely due to iron-catalyzed oxidative reactions. Iron can exchange electrons with a variety of substrates, which can lead to generation of reactive oxygen species. This can lead to oxidative stress, lipid peroxidation, and DNA damage, which may result in cell death. Two main forms of hemochromatosis type 4 exist (A and B), and the symptoms of these forms are distinct from one another.Type 4A hemochromatosis typically has milder symptoms than other types of hemochromatosis. Individuals with type 4A hemochromatosis tend to have hyperferritinemia (elevated ferritin in the blood plasma) and low saturated transferrin levels. These individuals are likely to have liver and spleen iron overload, primarily in Kupffer cells and other macrophages.
When hepcidin binds ferroportin, ferroportin is phosphorylated, endocytosed, tagged with ubiquitin, and degraded. More than 39 mutations to the SLC40A1 gene have been identified in patients with type 4 hemochromatosis. The misregulation of ferroportin in type 4 hemochromatosis can involve a failure of ferroportin to be properly expressed at the cell membrane, or it can involve a failure of ferroportin to respond to negative regulation by hepcidin.Hemochromatosis type 4A is characterized by impaired iron export in cells. Reticuloendothelial macrophages are most affected. Iron accumulates preferentially in Kupffer cells, which are located in the liver, and serum ferritin increases; less iron is available for circulating transferrin, a protein that binds iron and transports it through the bloodstream to cell receptors. This means that, while iron is trapped in certain types of tissues, it cannot be transported to tissues where it is needed. The accumulation of iron in tissues due to impaired iron export can lead to increasing transferrin iron saturation and liver parenchymal iron overload in advanced stages of the disease. More ferritin is produced to suppress oxidative cell damage, although the amount of ferritin that cells can accumulate is limited.Hemochromatosis type 4B is characterized by abnormal iron release from macrophages and enterocytes because the mutant ferroportin is resistant to the hepcidin protein, which serves a regulatory function in wild-type ferroportin. Intestinal iron absorption and release of iron from macrophages is increased. Thus, this form of the disease leads to elevated transferrin saturation levels. Systemic iron overload results, and liver iron deposition is primarily in the hepatocytes.