Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

Abstract

Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.

Figure 1.. Functions of the hepatic extracellular matrix (ECM) that contribute to inflammation.

The ECM plays multiple roles that contribute to the regulation of inflammation and injury in the liver. These roles are related to adhesion, structure, presentation of signaling molecules and/or receptors, storage of signaling molecules, and sensing. Figure modified with permission from Dolin and Arteel [11].

Figure 2.. Roles of hepatic stellate cells in ALD.

Hepatic stellate cells and other types of fibrogenic cells are present and/or activated in early and late-stage ALD. Main functions include the secretion of ECM and growth factors (GF), the latter often being bound to ECM for long-term storage. While the disease-promoting role of HSC/fibroblast in advanced disease, leading to decreased liver function and increased risk for HCC, are increasingly established, their role in early disease remain poorly understood and could also include protective functions that either promote regeneration or protect from injury.

Figure 3.

The liver lobule consists of the diffusion dominated canalicular zone and the flow augmented network of interlobular ducts [57,58]. When the canalicular network is compromised in chronic liver disease, new ducts infiltrate into the diffusion dominated zone to support the clearance of bile acids. While this process may ameliorate cholestasis, the new ducts may also induce the formation of fibrotic streets, although a causal relationship still has to be analyzed.

Figure 4.. Genetic loci modulating risk for onset and progression of ALD.

Both risk-increasing and protective loci with different effect sizes have been identified.