Ferroportin disease: pathogenesis, diagnosis and treatment

Abstract

Ferroportin Disease (FD) is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (FPN) gene. It represents one of the commonest causes of genetic hyperferritinemia, regardless of ethnicity. FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting. The hallmark of FD is marked iron accumulation in hepatic Kupffer cells. Numerous FD-associated mutations have been reported worldwide, with a few occurring in different populations and some more commonly reported (e.g. Val192del, A77D, and G80S). FPN1 polymorphisms also represent the gene variants most commonly responsible for hyperferritinemia in Africans. Differential diagnosis includes mainly hereditary hemochromatosis, the syndrome commonly due to either HFE or TfR2, HJV, HAMP, and, in rare instances, FPN1 itself. Here, unlike FD, hyperferritinemia associates with high transferrin saturation, iron-spared macrophages, and progressive parenchymal cell iron load. Abdominal magnetic resonance imaging (MRI), the key non-invasive diagnostic tool for the diagnosis of FD, shows the characteristic iron loading SSL triad (spleen, spine and liver). A non-aggressive phlebotomy regimen is recommended, with careful monitoring of transferrin saturation and hemoglobin due to the risk of anemia. Family screening is mandatory since siblings and offspring have a 50% chance of carrying the pathogenic mutation.

Figure 1.

Biology of ferroportin and postulated pathobiology of Ferroportin Disease (FD). (A) Structure-function relationship of iron-export ferroportin activity. (B) Putative mechanisms of hepcidin binding to FPN and its degradation. (C) Postulated basis for FD. (Upper panel) In cells undergoing relatively low iron flux, such as enterocytes, the product of the FPN wild-type allele is able to reach the plasma membrane and export iron. For clarity, mutated FPN1 was not depicted at the cell surface: based on previous in vitro work, it has been postulated that some mutant FPN1 can still reach the cell surface and preserve some iron-transport competence, but this is still controversial. (Lower panel) In cells undergoing high iron turnover, such as macrophages, increased requests for iron export impose high demands on FPN traffic leading to a ‘traffic jam’ within the endocytic/plasmamembrane and degradation compartments and inappropriately low wild-type allele product targeting to the cell membrane. (D) Postulated effect of FPN mutations that affect formation of the intracellular gate and access to the iron binding site.

Figure 2.

The basis for abnormal iron transfer into the bloodstream in Ferroportin Disease as opposed to FPN-associated hereditary hemochromatosis.

Figure 3.

The different stages and outcomes of “iron retention” in Ferroportin Disease versus “iron accumulation” in FPN1-associated hemochromatosis (HC). Liver histology pictures are reproduced with the permission of Sabelli et al.

Figure 4.

Diagnostic algorithm for Ferroportin Disease and hereditary hyperferritinemia. ACD/AI: anemia of chronic disease/anemia of inflammation. *Gaucher disease may present with or without siderosis depending on the disease stage. **Advanced ACD/AI may also present with siderosis at MRI (usually spleen and bone marrow).

Figure 5.

Abdominal magnetic resonance imaging (MRI) pattern of Ferroportin Disease (FD). MRI scans. T2*-weighted gradient-echo sequences were used to detect iron accumulation. (A) Normal subject. (B) FD. (C) FD after completion of phlebotomy program (note that excess iron is still detectable in the liver and spine in spite of normal serum ferritin and transferrin saturation levels). (D) Ferroportin-associated hereditary hemochromatosis: iron accumulation involves only the liver and spares the spleen and spine (arrows).