Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment

Abstract

An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. These cells produce extra-cellular matrix that results in liver fibrosis. In a normal situation, fibrogenesis is a wound healing process that preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This process takes many years and is often asymptomatic. Therefore, patients usually present themselves with end-stage liver disease e.g., liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Currently, only a minority of patients with liver fibrosis are identified to be at risk and hence referred for treatment. This is not only because the disease is largely asymptomatic, but also due to the fact that currently liver biopsy is still the golden standard for accurate detection of liver fibrosis. However, performing a liver biopsy harbors some risks and requires resources and expertise, hence is not applicable in every clinical setting and is unsuitable for screening. Consequently, different non-invasive diagnostic tools, mainly based on analysis of blood or other specimens or based on imaging have been developed or are in development. In this review, we will first give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. This serves as the basis for the subsequent discussion of the current and future diagnostic biomarkers and anti-fibrotic drugs.

Keywords: NAFLD; liver biopsy; liver fibrosis; liver stiffness; non-invasive assessment.

Figure 1

Overview of evolution of NAFLD related fibrogenesis on clinical, cellular, and histological level. On the clinical level NAFLD starts of as simple steatosis (NAFL). The abnormal amount of liver fat triggers inflammation by infiltrating immune cells and secretion of cytokines. This is called non-alcoholic steatohepatitis or NASH which can cause liver fibrosis. On cellular level, quiescent hepatic stellate cells (HSCs) are activated by immune cell infiltration and hepatocyte injury due to inflammation. The activated HSC transdifferentiates into collagen producing myofibroblasts furthermore the myofibroblasts trigger HSC progenitor proliferation and activation. Another consequence of the immune cell infiltration and hepatocyte injury is apoptosis of hepatocytes, leading to the release of damage-associated patterns (DAMPs). DAMPs also activate hepatic progenitor cells. Both the myofibroblasts and HSCs will start producing collagen. On a histological level, first fat accumulates in the liver (A). This leads to the infiltration of immune cells (B) and ballooning and eventually liver fibrosis occurs (C). Histological pictures courtesy of Dr. P. Van Eyken, pathologist, Ziekenhuis Oost-Limburg, Genk, Belgium.