Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

Abstract

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.

Altered Metabolic Profile and Adipocyte Insulin Resistance Mark Severe Liver Fibrosis in Patients with Chronic Liver Disease

“…Moreover, HCV infection is associated with alterations in glucose, lipid and amino acid metabolism, lipid synthesis and clearance and insulin resistance [4,18]. Hepatitis C virus consist of replicates principally in hepatocytes; other organs are also affected by the virus, such as muscle, adipose tissue and pancreas [11,19,20], leading to comorbidities such as type 2 diabetes, renal and cardiovascular disease and fibrosis in liver [5].…”

“…Several studies have shown that in patients with chronic liver disease (CLD) and HCV infection, insulin resistance when present affects the liver, muscle and adipose tissue by altering both glucose and lipid homeostasis [3,4]. Chronic hepatitis C (CHC) infection leads to hepatic inflammation, which stimulates liver fibrosis [5]. Moreover, HCV infection might be able to disrupt glucose and lipid metabolism via up-regulation of TNF-alfa and/or down-regulation of suppressors of cytokine signaling and protein phosphatase 2A [6] that could be implicated in hepatic and extra-hepatic IR [4].…”

“…Liver fibrosis is due to excessive accumulation of extracellular matrix proteins, including collagen [8], in response to tissue damage caused by HCV infection. Although recent advancements in direct-acting antiviral (DAA) treatment are able to eliminate viremia, very few treatment strategies can effective prevent the advancement of liver fibrosis in these patients [5]. Several lipid species, including mono-(MAGs), di-(DAGs) and tri-acylglycerol (TAGs), ceramides (CER) and lysophosphatidylcholines (LPC) are implicated in chronic inflammation with consequent effects on multiple organs [9].…”

Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis

“…NASH can regress without specific pharmacologic intervention; for example, weight loss through lifestyle modification improved NAFLD activity scores [49,50]. On the other hand, chronic inflammation induced by persistent HCV infection drives a maladaptive reparative reaction and over stimulates liver cell death and regeneration, promoting liver fibrosis and carcinogenesis [51]. Degree of fibrosis correlates closely with risk of HCC in HCV infected livers.…”

Extracellular Vesicles in Viral Replication and Pathogenesis and Their Potential Role in Therapeutic Intervention

“…HCV belongs to a family of human virus called Flaviviridae characterized by positive-sense single-stranded RNA that encodes precursor polyprotein that is cleaved into three structural proteins comprising of core protein p22 with envelope glycoprotein E1 & E2, and seven non-structural proteins that play a role in viral pathogenesis [131,134]. The chronic viral infection leads to hepatic inflammation that is associated with increased production of pro-inflammatory cytokines and chemokines from liver residential immune cells and immune cells recruited to the liver [174]. EVs are observed as major modifiers of cellular crosstalk between HCV-infected hepatocytes & immune cells [174].…”