Hemochromatosis type 4 or ferroportin disease is an autosomal dominant form of primary iron overload which occurs in adults. An affected individual has a 50% chance of passing the disorder to offspring. Ferroportin binds with hepcidin to regulate export of iron from cells. Defective ferroportin is postulated to interfere with this function.
Ferroportin disease usually has features distinct from HFE hemochromatosis. There is an early increase in serum ferritin despite a low or normal transferrin saturation. Progressive iron accumulation occurs in organs especially the liver and spleen and reticuloendothelial macrophages. The pattern of iron accumulation in the liver is distinct when examined under the microscope. These patients may be hard to venesect as a borderline anemia with low tolerance to phlebotomy may occur. Venesection may have to consist of smaller units taken over a longer time.
However as more patients with ferroportin disease have been diagnosed the disorder has been shown to be clinically diverse. Some patients can present with a disorder similar to HFE hemochromatosis with high transferrin saturation and loading of iron in parenchymal tissues. Current thinking is that mutations in different regions of the ferroportin gene may cause different functional abnormalities.
The ferroportin gene SLC40A1 (SLC11A3) is located on chromosome 2q32. The first descriptions of the disorder were in 1999 and the first identification of mutations was in 2001 in Dutch and Italian patients with the N144H and A77D mutations respectively. A previously described iron overload disorder in a Solomon Islander was subsequently shown to be a N144T mutation. The most common mutation is probably the Val 162 deletion which has been found widely in persons of different ethnicity from countries as diverse as the United Kingdom, Sri Lanka, Australia, Italy and Greece. Other mutations have been described in Chinese and Japanese patients and Canadian patients of Scandinavian origin. Ferroportin disease appears to be the most common form of iron overload after HFE hemochromatosis. It is possible that ferrroportin disease is actually the most common form of iron overload but undiscovered in the majority of patients worldwide as they do not have access to testing. A ferroportin mutation Q248H has been implicated as a possible cause of African Iron Overload, but this is not proven. Different presentations may occur at different ages for the same patient. It has been shown that transferrin saturation for the Val 162 deletion and to a lesser extent the A77D mutation rises as the patient ages.
Recent work using magnetic resonance imaging has shown differences associated with ferroportin mutations. A classic or common form characterized by liver, spleen and bone macrophage iron retention was shown to occur in patients carrying the A77D, G80S and Val 162 deletion ferroportin variants. A rarer non-classic form associated with liver iron overload but normal spleen and bone marrow iron content was noted in patients with the N144H mutation. Interestingly, in treated patients with the classic form, the spleen and the spine showed appreciable iron accumulation even when serum ferritin was normal and liver iron content low.