Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives

Abstract

Liver fibrosis is the pathological deposition of extracellular matrix rich in fibrillar collagen within the hepatocytes in response to chronic liver injury due to various causes. As the condition advances, it can progress to cirrhosis, the late stages of which are irreversible. Multiple pathophysiological mechanisms and cell types are responsible for the progression of liver fibrosis and cirrhosis. Hepatic stellate cells and myofibroblast activation represent a key event in fibrosis. Capillarization of liver sinusoidal endothelial cells further contributes to extracellular matrix deposition and an increase in portal pressure. Macrophages and neutrophils produce inflammatory cytokines and participate in activating hepatic stellate cells. Although initially believed to be irreversible, early stages of fibrosis are now found to be reversible. Furthermore, advances in noninvasive imaging and serum studies have changed and improved how cirrhosis can be evaluated and monitored. Although there are currently no specific approved therapies to reverse liver fibrosis, management of underlying diseases has been found to halt the progression, and to an extent, even reverse liver fibrosis, preventing further liver injury and cirrhosis-related complications.

Keywords: cirrhosis; hepatic stellate cells; liver fibrosis; reversibility.

Figure 1

Pathogenesis of fibrosis. The pathogenesis of fibrosis involves the activation of various cell types in response to injurious stimuli and the subsequent interplay between them. Some ways this is accomplished are cytokine release leading to HSC activation and extracellular matrix deposition, and neutrophil and macrophage activation leading to inflammation via cytokine release.

Figure 2

Target checkpoints in fibrosis progression. This figure details various checkpoints that can be intercepted to halt progression of liver fibrosis. Possible interceptions include decreasing production of TGF-beta and other inflammatory cytokines, inducing the apoptosis of activated HSCs and the dissolution of formed extracellular matrix proteins.

Figure 3

Liver zonation and susceptibility. This figure describes liver zonation, detailing functions and disease susceptibility particular to the centrilobular, intermediate, and periportal zones.

Figure 4

Mechanism of action of Resmetirom. Resmetirom is a partial THR-beta agonist. It promotes beta-fatty acid oxidation in the liver, reducing fat content in the liver. The activation of THR-beta reduces levels of intrahepatic triglycerides. Figure created by Rukam Mahawa MBBS, Sreeja Moolamalla MBBS.

Figure 5

Mechanism of action of obeticholic acid. Obeticholic acid is a Farsenoid X receptor (FXR) agonist that, once bound, triggers a cascade leading to reduced bile production in the liver. It also facilitates bile removal by inducing FGF19 release and inhibiting CYP7A1 gene expression. Figure created by Rukam Mahawa, MBBS, and Sreeja Moolamalla, MBBS.