Liver fibrosis: Pathophysiology and clinical implications

Abstract

Liver fibrosis is a clinically significant finding that has major impacts on patient morbidity and mortality. The mechanism of fibrosis involves many different cellular pathways, but the major cell type involved appears to be hepatic stellate cells. Many liver diseases, including Hepatitis B, C, and fatty liver disease cause ongoing hepatocellular damage leading to liver fibrosis. No matter the cause of liver disease, liverrelated mortality increases exponentially with increasing fibrosis. The progression to cirrhosis brings more dramatic mortality and higher incidence of hepatocellular carcinoma. Fibrosis can also affect outcomes following liver transplantation in adult and pediatric patients and require retransplantation. Drugs exist to treat Hepatitis B and C that reverse fibrosis in patients with those viral diseases, but there are currently no therapies to directly treat liver fibrosis. Several mouse models of chronic liver diseases have been successfully reversed using novel drug targets with current therapies focusing mostly on prevention of myofibroblast activation. Further research in these areas could lead to development of drugs to treat fibrosis, which will have invaluable impact on patient survival. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology K E Y W O R D S chirrosis, clinical stages of liver fibrosis, hepatic stellate cells, hepatocellular carcinoma, liver fibrosis 1 | INTRODUCTION Liver fibrosis is a clinically significant finding that has major impact on patients' morbidity and mortality. Many liver diseases, including Hepatitis B, C, and fatty liver diseases, cause ongoing hepatocellular damage leading to liver fibrosis. Fibrosis is the single histopathologic feature with the greatest impact on mortality (Stal, 2015). It eventually leads to cirrhosis, which is plagued by other complications including hepatocellular carcinoma (HCC) and liver failure, leaving liver transplant as the only therapy. New medications to treat hepatitis C may halt the progression of fibrosis, but currently no definitive treatment for fibrosis exists. Liver fibrosis involves multiple cellular mechanisms. Current models for liver fibrosis show an injury driven response from the hepatic cells which release CC motif chemokine ligand 2 (CCL2), also known as monocyte chemoattractant

The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis

“…When stimulated by a viral infection, excessive alcohol intake, toxic substances, or other detrimental factors, morphologic changes occur and HSCs will transform into myofibroblasts, which express the main components of α-SMA and the ECM, and promote the formation of liver fibrosis. 25 Recent studies have shown that PPAR-γ and GATA6 are necessary for inactivation of human HSCs and regression of liver fibrosis in mice. 26 , 27 PPAR-γ inhibits HSC activation, proliferation, and increases ECM production.…”

“…These processes involve chemotactic neutrophils, induction of autoimmune responses, and direct activation hepatic macrophages and HSCs. 1 , 25 Fatty cirrhosis has a common histologic feature. That is, the cause of steatosis of liver cells is repeated attacks of the same cause.…”

LECT2, A Novel and Direct Biomarker of Liver Fibrosis in Patients With CHB

“…Epidemiological studies have reported that the staging of liver fibrosis is positively linked with significant clinical complications, and an increased liver fibrosis stage is related to higher mortality than in patients without liver fibrosis (Berumen et al, 2021).…”

“…This is the first report that aimed to figure out the association between the expression of LECT2 and the severity of liver fibrosis. Epidemiological studies have reported that the staging of liver fibrosis is positively linked with significant clinical complications, and an increased liver fibrosis stage is related to higher mortality than in patients without liver fibrosis ( Berumen et al, 2021 ). Besides, the development of histopathology often precedes any overt clinical features and it is usually difficult to find in time in the clinic.…”

“…The worse prognosis of patients with CHB has been related to an aggravated liver fibrosis progression ( Dulai et al, 2017 ), and the guidelines of CHB had mentioned that it is an indication for antiviral therapy once patients have been diagnosed with moderate and above fibrosis ( Terrault et al, 2018 ). Considering the significant impact of liver fibrosis, it is very necessary for the progression of liver fibrosis to be accurately described as soon as possible ( Revill et al, 2019 ; Berumen et al, 2021 ).…”