Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease

Abstract

Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition, we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Alcohol and the mechanisms of liver disease

“…Multiple visceral organs are faced with injury induced by alcohol metabolism with metabolites of alcohol being distributed systematically via circulation 2 . As the primary catabolic site of alcohol, liver takes on the heaviest burden of tissue injury by excessive alcohol consumption 3 …”

“…2 As the primary catabolic site of alcohol, liver takes on the heaviest burden of tissue injury by excessive alcohol consumption. 3 Liver disorders with the background of excessive alcohol intake are specifically categorized as a disease entity Alcohol-associated liver disease (ALD), featured with alcohol metabolism oriented hepatic pathological progress and encompassing a spectrum of diseases including asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis (AH) and its complications. 4 ALD is annually responsible for roughly 3 million liver-related mortality and contributes to over 70% of newly diagnosed liver cirrhosis in liver transplantation waiting list.…”

Neutrophil subsets in noncancer liver diseases: Cellular crosstalk and therapeutic targets

“…γδ T cells promote the expansion and accumulation of neutrophils in psoriatic arthritis [6]. Moreover, regulatory neutrophils are (LSEC) dysfunction, and hepatic stellate cell (HSC) activation contribute to the pathogenesis of ALD [13]. Additionally, hepatic ischemia-reperfusion injury (IRI) is caused by insufficient oxygen supply and immune attack after blood flow recovery [14].…”

“…Moreover, alcohol‐associated liver disease (ALD) is a complex disorder caused by excessive alcohol consumption. The innate immune response, liver sinusoidal endothelial cell (LSEC) dysfunction, and hepatic stellate cell (HSC) activation contribute to the pathogenesis of ALD [13]. Additionally, hepatic ischemia‒reperfusion injury (IRI) is caused by insufficient oxygen supply and immune attack after blood flow recovery [14].…”

The pre-mRNA alternative splicing regulated by SRPK2: A new player in alcohol-associated liver disease?

“…spectrum of liver pathologies that span from hepatic steatosis to steatohepatitis, which may eventually progress to cirrhosis and HCC. [1] While alcoholinduced hepatic steatosis is reversible on abstinence of alcohol, mounting evidence indicates that chronic hepatic steatosis promotes hepatocyte lipotoxicity, inflammation, and progression of ALD. [2] Hence, an in-depth understanding of the mechanisms by which alcohol regulates lipid metabolism in the pathogenesis of ALD is critical for the development of novel therapeutic strategies against ALD.…”