Alcohol-associated liver disease

Abstract

Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.

Figure 1. Spectrum of ALD, risk factors, and comorbidities.

Almost all individuals who drink heavily (90%–95%) develop steatosis; some of them may develop more severe forms of ALD, including alcohol-associated steatohepatitis (ASH), cirrhosis, and hepatocellular carcinoma (HCC). Some patients with underlying ALD develop acute alcohol-associated hepatitis (AH) with the typical clinical syndrome jaundice. AH is often referred to as a severe form of AH that has a high short-term morality. ASH is diagnosed based on histology, while AH is diagnosed based on clinical symptoms. Many risk factors promote the development of the severe forms of ALD. Alcohol intake and comorbid factors synergistically promote the progression of ALD. Adapted with permission from Gastroenterology (4).

Figure 2. Pathogenesis of and interorgan crosstalk contribution to ALD.

Excessive alcohol intake directly induces hepatocellular damage via multiple mechanisms. The crosstalk with several other organs, including brain-liver, gut-liver, and adipose-liver crosstalk, also contributes to ALD pathogenesis. Excessive alcohol consumption profoundly affects the immune system and immune cells, which also contributes to ALD progression. ABD, alcohol-associated bowel disease; AUD, alcohol use disorder; DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; FFA, free fatty acid.

Figure 3. Inflammation in ALD.

Alcohol-associated steatohepatitis (ASH) is characterized by hepatic infiltration of a large number of inflammatory cells, with predominant neutrophil and macrophage infiltration. Kupffer cells are activated at the early stage of ALD but are markedly reduced in the late stages of ALD, such as cirrhosis. ALD is also associated with infiltration of a significant number of T cells, but their subtypes and functions have not been well characterized. ALD, especially severe AH, is associated with infiltration of B cells and massive antibody deposition. The subsets and functions of inflammatory cells will be likely identified by single-cell and spatial transcriptomics and multiplex immunofluorescent staining analysis over the coming years. ASH is also associated with elevation of a large number of proinflammatory cytokines, chemokines, and adhesion molecules, which have overlapping functions and synergistically promote liver inflammation.