Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C

Abstract

At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.

Keywords: Anti-fibrotic; Biomarker; Chronic hepatitis C; Chronic liver disease; Cirrhosis; Fibrosis; Liver inflammation; Non-alcoholic fatty liver disease.

Figure 1

Anatomy of the liver and its macroscopic relationship to the intestinal tract and vasculature. Reproduced with permission of Creative Commons Attribution License from Ebaid et al[164].

Figure 2

Schematic diagram representing the relationship of the macroscopic structure of the liver with the functional hepatic lobule with hepatic venules (blue), hepatic arteriole (red), bile ductules (yellow). Reproduced with permission of Creative Commons Attribution License from Anatomy & Physiology textbook[165].

Figure 3

Schematic diagram representing functional hepatic acinus with hepatic venules (blue), hepatic arteriole (red), bile ductules (green) together with the relationship to the Space of Disse and the sinusoidal lumen. Reproduced with permission of Creative Commons Attribution License from Chouhan et al[166].

Figure 4

Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells, and Kupffer cells. A: After injury, the stellate cells become activated and secrete large amounts of extracellular matrix (ECM); B: Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and hepatocyte microvilli. Reproduced with permission from Hernandez-Gea and Friedman[37]. HSC: Hepatic stellate cells; KC: Kupffer cells.

Figure 5

Pathways of hepatic stellate cell activation including those contributing to initiation and perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals, apoptotic bodies, lipopolysaccharide, and cytokine stimuli from neighbouring cells. Perpetuation is characterised by specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and cytokine signalling. Reproduced with permission from Friedman[30]. CTGF: Connective tissue growth factor; ET: Endothelin; FGF: Fibroblast growth factor; LPS: Lipopolysaccharide; MMP: Matrix metalloproteinase; MT-1: membrane type-1, NK: Natural killer, NO: Nitrous oxide; PDGF: Platelet derived growth factor; TIMP: Tissue inhibitor of metalloproteases; TGF: Transforming growth factor; TLR: Toll like receptor; TRAIL: Tumour necrosis factor-related apoptosis-inducing ligand; VEGF: Vascular endothelial growth factor.

Figure 6

Depiction of hepatitis C virus genome structure and drug targets. NS: Non-structural.