Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker

Abstract

Liver fibrosis is a precursor of liver cirrhosis, which is associated with increased mortality. Though liver biopsy remains the gold standard for the diagnosis of fibrosis, noninvasive biochemical methods are cost-effective, practical and are not linked with major risks of complications. In this respect, serum hepcidin, has emerged as a new marker of fibrosis and cirrhosis. In this review the discussion uncovers molecular links between hepcidin disturbance and liver fibrosis/cirrhosis. The discussion also expands on clinical studies that suggest that hepcidin can potentially be used as a biochemical parameter of fibrosis/cirrhosis and target of therapeutic strategies to treat liver diseases. The debatable issues such as the complicated nature of hepcidin disturbance in non-alcoholic liver disease, serum levels of hepcidin in acute hepatitis C virus infection, cause of hepcidin disturbance in autoimmune hepatitis and hepatic insulin resistance are discussed, with potential solutions unveiled in order to be studied by future research.

Keywords: Alcohol, HCV, Hepcidin, liver fibrosis.

Fig. 1

Hepcidin expression and mode of action. BMP6, bone morphogenetic protein 6; BMPR, BMP receptor; ERFE, erythroferrone; Fe, iron; FPN, ferroportin; HAMP, hepcidin antimicrobial peptide; HFE, hemochromatosis protein; IL-6, interleukin 6; IL-6R, IL-6 receptor; JAK2, janus kinase 2; SMAD proteins, s-mothers against decapentaplegic proteins; STAT3, signal transducer and activator of transcription 3; TFR2, transferrin receptor 2. Hepcidin expression is primary regulated by iron-status, inflammation and erythropoietic drive. Iron-status induces hepcidin expression by through BMPR ligands such as BMP6. BMPR activates SMAD pathway which increases hepcidin expression through HAMP transcription. Inflammation induces hepcidin expression through cytokines like IL-6 which activates JAK2/STAT3 pathway in heptocytes. This pathway increases hepcidin expression. Erythropoiesis suppresses hepcidin expression probably through erythroferrone produced by erythrocyte precursors. Once released by hepatocytes in plasma, hepcidin reaches target cells like enterocytes and macrophages, where hepcidin induces FPN degradation. This action reduces iron efflux from cells, because FPN is the major exporter of iron out of cells

Fig. 2

Hepcidin (in)actions in normal liver and liver fibrosis. Fe, iron; FPN, ferroportin. In normal liver, hepcidin produced by heptocytes controls iron levels in plasma by preventing excessive iron absorption from enterocytes. In this way hepcidin protects liver form iron-load. But hepcidin can protect liver by inactivating hepatic stellate cells as well. In liver fibrosis low hepcidin causes high iron-load and oxidative stress. Oxidative stress and lack of hepcidin-induced supression of hepatic stellate cells induces their activation, which results in deposition of scar tissue and liver fibrosis

Fig. 3

Mechanisms behind low levels of hepcidin in liver disease. BMPR, bone morphogenetic protein receptor; C/EBP alpha, CCAAT enhancer binding protein alpha; HAMP, hepcidin antimicrobial peptide; HCV, hepatitis C virus; HFE, hemochromatosis protein; HH, hemochromatosis; HJV, hemojuvelin; IL-6, interleukin 6; InR, insulin receptor; STAT3, signal transducer and activator of transcription 3; TFR2, transferrin receptor 2; TLR4, toll-like receptor 4. Different pathogenic factors are responsible for low values of hepcidin. In HH mechanisms behind low levels of hepcidin are already known and they include defective signalling though HJV, HFE, TFR2 or through direct inhibition of HAMP gene. Alcohol inhibits hepcidin expression through its actions on C/EBP, but also indirectly through TLR4 pathway. It is believed that TLR4 mediates this action of alcohol through nonparenchymal liver cells, but the paracrine signal responsible for this effect is unknown. HCV also suppresses hepcidin expression through oxidative stress, which inhibits C/EBP and STAT3 actions on HAMP. Cholestasis, on the other hand, suppresses hepcidin expression by inhibiting IL-6/STAT3 pathway. In AILD mechanisms behind low levels of hepcidin are unknown. In hepatic insulin resistance defective insulin signaling is linked with defective hepcidin expression, partially through STAT3 pathway