Role of ferritin and ferroportin genes in unexplained hyperferritinaemia

A large body of evidence indicates that the level of serum ferritin parallels the concentration of storage iron within the body, regardless of the cell type in which it is stored. Elevated serum ferritin levels, in the absence of inflammation and liver disease, are currently taken to indicate increased iron stores and require further investigation to determine the site of iron overload. Until recently, the only genetic disorder with elevated serum ferritin levels known in Western countries was hereditary HLA-related HFE-related genetic haemochromatosis in Caucasians (HFE, OMIM 235200), and a high serum ferritin in apparently healthy persons was considered suggestive of this disease. In the last few years, at least two novel genetic disorders of iron metabolism presenting as unexplained hyperferritinaemia have been recognized. The first one is hereditary hyperferritinaemia/cataract syndrome (HHCS, OMIM 600886). HHCS arises from various point mutations or deletions within a protein binding sequence in the 5'-UTR of the L-ferritin mRNA that results in increased efficiency of L-ferritin translation. The second one is haemochromatosis type 4, or HFE4 (OMIM 606069), or ferroportin disease. In this latter condition, reticuloendothelial iron overload and hyperferritinaemia are caused by loss-of-function mutations in the SLC11A3 gene that mainly impair macrophage iron recycling. These genetic disorders should be taken into account in the differential diagnosis of unexplained hyperferritinaemia.