Inherited Disorders of Iron Overload

Abstract

Dietary iron absorption and systemic iron traffic are tightly controlled by hepcidin, a liver-derived peptide hormone. Hepcidin inhibits iron entry into plasma by binding to and inactivating the iron exporter ferroportin in target cells, such as duodenal enterocytes and tissue macrophages. Hepcidin is induced in response to increased body iron stores to inhibit further iron absorption and prevent iron overload. The mechanism involves the BMP/SMAD signaling pathway, which triggers transcriptional hepcidin induction. Inactivating mutations in components of this pathway cause hepcidin deficiency, which allows inappropriately increased iron absorption and efflux into the bloodstream. This leads to hereditary hemochromatosis (HH), a genetically heterogenous autosomal recessive disorder of iron metabolism characterized by gradual buildup of unshielded non-transferrin bound iron (NTBI) in plasma and excessive iron deposition in tissue parenchymal cells. The predominant HH form is linked to mutations in the HFE gene and constitutes the most frequent genetic disorder in Caucasians. Other, more severe and rare variants are caused by inactivating mutations in HJV (hemojuvelin), HAMP (hepcidin) or TFR2 (transferrin receptor 2). Mutations in SLC40A1 (ferroportin) that cause hepcidin resistance recapitulate the biochemical phenotype of HH. However, ferroportin-related hemochromatosis is transmitted in an autosomal dominant manner. Loss-of-function ferroportin mutations lead to ferroportin disease, characterized by iron overload in macrophages and low transferrin saturation. Aceruloplasminemia and atransferrinemia are further inherited disorders of iron overload caused by deficiency in ceruloplasmin or transferrin, the plasma ferroxidase and iron carrier, respectively.

Keywords: HFE; aceruloplasminemia; ferroportin; hemochromatosis; hemojuvelin (HJV); hepcidin; hypotransferrinemia; transferrin receptor 2 (TFR2).

Figure 1

Dynamics of systemic iron balance. Plasma transferrin delivers iron to bone marrow erythroblasts and to other tissues. It contains a very small (~0.1%) but highly dynamic fraction of body iron that turns over >10 times/day to meet the iron need for erythropoiesis (20–30 mg/day). The transferrin iron pool is primarily replenished with iron recycled from hepatic and splenic macrophages during erythrophagocytosis of senescent red blood cells. Duodenal enterocytes absorb dietary iron and release small amounts (1–2 mg/day) to compensate for non-specific losses. Hepatocytes store excess of body iron, which can be mobilized to plasma under iron deficiency. Iron efflux to plasma from macrophages, enterocytes or hepatocytes is negatively regulated by hepcidin, a liver-derived peptide hormone that binds to the iron exporter ferroportin and promotes its degradation.

Figure 2

Iron and inflammatory signaling to hepcidin. Increases in serum or tissue iron promote transcriptional induction of hepcidin via the BMP/SMAD signaling pathway. Key upstream events are an increase in transferin saturation and the secretion of BMP6, and to a lesser extent BMP2 from liver sinusoidal endothelial cells. BMP6 binds to type I and II receptors on the surface of hepatocytes. With the critical aid of auxiliary factors, such as HJV, HFE, and TfR2, this leads to phosphorylation of regulatory SMAD1/5/8, recruitment of SMAD4, and translocation of the complex to the nucleus for binding to the hepcidin promoter. TfR2 likely operates as plasma iron sensor; TfR1 is thought to mediate uptake of transferrin-bound iron but can also negatively affect iron signaling by sequestering HFE. Iron signaling to hepcidin is negatively regulated by the serine protease matriptase-2 (TMPRSS6), which cleaves and inactivates components of the signaling complex. The major inflammatory signaling pathway to hepcidin involves IL-6, which binds to IL-6 receptors on hepatocytes. This promotes dimerization of the receptors and activation of associated JAK1/2, which in turn phosphorylate STAT3. Subsequently, phospho-STAT3 dimerizes and translocates to the nucleus for binding to the hepcidin promoter.