Iron and liver fibrosis: Mechanistic and clinical aspects

Abstract

Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.

Keywords: Cirrhosis; Hepatic stellate cells; Iron; Liver fibrosis; Liver pathologies.

Figure 1

Intercellular network of events in fibrosis. The figure shows the interactions between hepatocytes, Kupffer cells and hepatic stellate cells that initiate and drive fibrosis progression. The pool of pro-fibrogenic and pro-inflammatory mediators include C-C motif chemokine ligand 5, macrophage inflammatory proteins 1 and 2, monocyte chemoattractant protein-1, tumor necrosis factor alpha, transforming growth factors alpha and beta, platelet-derived growth factor, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase, and protein adducts of malondialdehyde and 4-hydroxynonenal. HNE: Hydroxynonenal; HSC: Hepatic stellate cell; MDA: Malondialdehyde; NF-κB: Nuclear factor kappa B; RBCs: Red blood cells; ROS: Reactive oxygen species; TFR1: Transferrin receptor 1; αSMA: Alpha smooth muscle actin; ECM: Extracellular matrix; TGF-β: Transforming growth factors beta.

Figure 2

Schematic of mechanistic cross-connection between the transforming growth factor beta pathway and bone morphogenetic protein signaling. Shared signalling components between transforming growth factor beta (TGF-β) (fibrosis-related) and bone morphogenetic protein (iron-related) pathways have been shown in hepatic stellate cells and hepatocytes. Previous study demonstrated TGF-β-induced hepcidin expression in human macrophages, while Chen et al[44] showed that this occurred through TGF-β-RII/RI in mouse and human hepatocytes via the non-canonical pathway involving small mothers against decapentaplegic protein-1/5/8 phosphorylation. ALK: Activin receptor-like kinase; BMPR: Bone morphogenetic protein receptor; HFE: High iron protein; HSC: Hepatic stellate cell; mHJV: Membrane-bound hemojuvelin protein; P: Phosphorylation; SMAD: Small mothers against decapentaplegic protein; TFR: Transferrin receptor; TGF-β-R: Transforming growth factor receptor.