A Review of Liver Fibrosis and Emerging Therapies

Abstract

With the increasing burden of liver cirrhosis, the most advanced stage of hepatic fibrosis, there is a need to better understand the pathological processes and mechanisms to target specific treatments to reverse or cease fibrosis progression. Antiviral therapy for hepatitis B and C has effectively treated underlying causes of chronic liver disease and has induced fibrosis reversal in some; however, this has not been targeted for the majority of aetiologies for cirrhosis including alcohol or nonalcoholic steatohepatitis. Fibrosis, characterised by the accumulation of extracellular matrix proteins, is caused by chronic injury from toxic, infectious, or metabolic causes. The primary event of fibrogenesis is increased matrix production and scar formation mediated by the hepatic stellate cell, which is the principal cell type involved. Experimental models using rodent and human cell lines of liver injury have assisted in better understanding of fibrogenesis, especially in recognising the role of procoagulant factors. This has led to interventional studies using anticoagulants in animal models with reversal of fibrosis as the primary endpoint. Though these trials have been encouraging, no antifibrotic therapies are currently licenced for human use. This literature review discusses current knowledge in the pathophysiology of hepatic fibrosis, including characteristics of the extracellular matrix, signalling pathways, and hepatic stellate cells. Current types of experimental models used to induce fibrosis, as well as up-to-date anticoagulant therapies and agents targeting the hepatic stellate cell that have been trialled in animal and human studies with antifibrotic properties, are also reviewed.

Preclinical Long-term Magnetic Resonance Imaging Study of Silymarin Liver-protective Effects

“…We observed meaningful correlations between MRI-based values and the levels of several biomarkers. Carbon tetrachloride (CCl 4 ) is frequently used to induce liver failure, [40][41][42] but liver function occasionally occurs when CCl 4 administration is stopped. 42 Conversely, TAA damage persists for more than 2 months after withdrawal, and induces pathological characteristics similar to human chronic liver dysfunction.…”

“…Carbon tetrachloride (CCl 4 ) is frequently used to induce liver failure, [40][41][42] but liver function occasionally occurs when CCl 4 administration is stopped. 42 Conversely, TAA damage persists for more than 2 months after withdrawal, and induces pathological characteristics similar to human chronic liver dysfunction. TAA-induced liver injury models are thus more suitable than CCl 4 for longitudinal studies.…”

Nrf2/HO‐1, NF‐κB and PI3K/Akt signalling pathways decipher the therapeutic mechanism of pitavastatin in early phase liver fibrosis in rats

“…This process typically takes decades (about 20–30 years), although it can advance quickly, as in the case of biliary atresia, drug‐induced liver damage, HIV/HCV coinfection, or HCV infections following liver transplantation 18 . A great deal of work has been done to understand the pathophysiology of fibrosis, which has led to the identification of prospective targets for antifibrotic drugs that could either slow down or reverse fibrosis 19 …”

“…18 A great deal of work has been done to understand the pathophysiology of fibrosis, which has led to the identification of prospective targets for antifibrotic drugs that could either slow down or reverse fibrosis. 19 Pitavastatin is a cholesterol-lowering agent (statin) that was approved in 2009. It is also one of the foundations for treating and preventing atherosclerotic cardiovascular disease.…”

The Material World of 3D‐Bioprinted and Microfluidic‐Chip Models of Human Liver Fibrosis

“…[ 30 ] In rodents, fibrosis is usually induced chemically by the administration of carbon tetrachloride or thioacetamide or surgically by bile duct ligation. [ 31 ] However, animal models still fail to precisely replicate the human disease. While the onset of the disease in animals takes several weeks and, in some cases, may be reverted when the inducing agent is removed, in the clinical setting, advanced liver disease takes years or even decades to develop and it is not reversible.…”