Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes

Abstract

Alcoholic liver disease (ALD) develops in approximately 20% of alcoholics, with a higher prevalence in females. ALD progression is marked by fatty liver and hepatocyte necrosis, as well as apoptosis, inflammation, regenerating nodules, fibrosis, and cirrhosis 1. ALD develops via a complex process involving parenchymal and non-parenchymal cells, as well as recruitment of other cell types to the liver in response to damage and inflammation. Hepatocytes are damaged by ethanol, via generation of reactive oxygen species and induction of endoplasmic reticulum stress and mitochondrial dysfunction. Hepatocyte cell death via apoptosis and necrosis are markers of ethanol-induced liver injury. We review the mechanisms by which alcohol injures hepatocytes and the response of hepatic sinusoidal cells to alcohol-induced injury. We also discuss how recent insights into the pathogenesis of ALD will affect treatment and management of patients.

Caspase Inhibition Prevents Tumor Necrosis Factor-α–Induced Apoptosis and Promotes Necrotic Cell Death in Mouse Hepatocytes in Vivo and in Vitro

“…2,4,28,29 As a result, pharmacologic inhibition of caspase activity has been considered as a potential therapeutic approach for treating liver diseases with excessive apoptosis such as alcoholic liver disease. 28,30 TNF-aemediated apoptosis has been well documented to play a central role in acute and chronic liver injuries.…”

“…A liver cell can die in many different ways, but caspase-dependent apoptosis and caspase-independent necrosis are thought to be the predominant cell death pathways that contribute to liver injury. 1,2 Apoptosis can be activated by two distinct pathways: the intrinsic mitochondrial pathway and the extrinsic death-receptor pathway. In the liver, the activation of extrinsic death-receptoremediated apoptotic pathway by tumor necrosis factor (TNF)-a and Fas ligand is one common pathway to cause acute liver injury.…”

“…In the liver, the activation of extrinsic death-receptoremediated apoptotic pathway by tumor necrosis factor (TNF)-a and Fas ligand is one common pathway to cause acute liver injury. 1,2 TNF-a is a pleiotropic cytokine that is up-regulated in a number of stressful conditions that result in liver injury. One of the well-established animal models to study TNF-ae induced hepatocyte apoptosis and liver injury is co-injection of mice with lipopolysaccharide (LPS) and D-galactosamine (GalN).…”

“…Caspase-8 further cleaves Bid and the truncated Bid translocates to mitochondria to trigger the mitochondrial intrinsic pathway, resulting in the release of mitochondrial cytochrome c and second mitochondria-derived activator of caspase, which further amplifies the apoptotic signals to ensure apoptosis induction. 1,2,4 In addition to apoptosis, hepatocytes can also die by necrosis, which is characterized by swollen cells, permeabilized plasma membrane and is often accompanied by inflammation in vivo. 5 Although necrosis has previously been considered an uncontrolled cellular process without caspase activation, recent evidence indicates that necrosis can also be highly regulated, a process referred to as necroptosis or programed necrosis.…”

Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

“…Despite the massive economic and health burden of alcoholic cirrhosis, little development in therapeutic strategy has been made for patients with this severe malady due to incomplete understanding in the mechanism and pathogenesis of alcoholic liver disease (ALD) (1,3). ALD represents a broad spectrum of hepatic pathology ranging from simple steatosis (fatty liver) to severe forms of liver injury, such as steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC) (1).…”