Iron and the liver: Update 2008

Hepcidin is synthesized by hepatocytes. Hepcidin binding to ferroportin, an iron transporter located at the basolateral part of enterocyte and macrophage membranes, results in internalization and degradation of ferroportin, and then in decreasing cellular iron egress which, in turn, leads to decrease systemic iron bioavailability and, then, to decreased parenchymal iron stores and to increased macrophagic iron stores. Tf, transferrin.

Schematic presentation of pathways regulating transcription of the hepcidin gene [1]. The bone morphogenic protein (BMP) pathway involves a complex consisting of BMP receptors I and II (BMPR-I and BMPR-II), GPI-anchored hemojuvelin (HJV) and BMPs which activate SMAD 1, 5 and 8 phosphorylation. Phosphorylated SMADs 1, 5 and 8 bind to SMAD 4 and then migrate into the nucleus where they activate hepcidin transcription [2]. The STAT 3 pathway is activated through JAK1/2 by the binding of IL-6 to its receptor at cell surface. Whether STAT 3 acts on hepcidin transcription only directly or also through the SMAD complex remains to be elucidated [3]. The complex associating transferrin (Tf), transferrin receptor 1 (TfR-1) and HFE as well as the binding of holotransferrin to transferrin receptor 2 (TfR-2) could also lead to hepcidin transcription by several putative mechanisms. Solid lines: known pathways – dotted lines: hypothetic pathways. From Anderson et al. [13].

Schematical patho-physiology of parenchymal iron-overload in haemochromatosis. Defective production, regulation or effect of hepcidin related to mutations in the HFE, hemojuvelin, transferrin receptor 2 or hepcidin gene (as roughly indicated by a cross) opens iron egress from intestinal and macrophagic cells. This results in increased iron influx into plasma and, then, in increased transferrin (Tf) saturation and in the production of a special form of iron, non-transferrin-bound iron (NTBI), which is avidly taken up by parenchymas.

Natural course, phenotype and penetrance of C282Y homozygosity. A 5-stage classification was recently proposed by the French Haute Autorité de Santé (HAS) [84] as the basis for its clinical recommendations on the management of HFE haemochromatosis: stage 0 corresponds to unexpressed genetic predisposition, stage 1 to increased transferrin saturation (>45%) only, stage 2 to increase in both transferrin saturation and serum ferritin (>200μg/L in women and >300μg/L in men), stage 3 to symptoms resulting in impaired functional prognosis (chronic fatigue and arthralgias) and stage 4 to organ damage with life-threatening disorders, especially diabetes, cardiomyopathy, liver cirrhosis and hepatocellular carcinoma (HCC). The approximate percentage of patients at each stage (%) clearly indicates incomplete penetrance of C282Y homozygosity.