Current experimental perspectives on the clinical progression of alcoholic liver disease

Abstract

Chronic alcohol abuse is an important cause of morbidity and mortality throughout the world. Liver damage due to chronic alcohol intoxication initially leads to accumulation of lipids within the liver and with ongoing exposure this condition of steatosis may first progress to an inflammatory stage which leads the way for fibrogenesis and finally cirrhosis of the liver. While the earlier stages of the disease are considered reversible, cirrhotic destruction of the liver architecture beyond certain limits causes irreversible damage of the organ and often represents the basis for cancer development. This review will summarize current knowledge about the molecular mechanisms underlying the different stages of alcoholic liver disease (ALD). Recent observations have led to the identification of new molecular mechanisms and mediators of ALD. For example, plasminogen activator inhibitor 1 was shown to play a central role for steatosis, the anti-inflammatory adipokine, adiponectin profoundly regulates liver macrophage function and excessive hepatic deposition of iron is caused by chronic ethanol intoxication and increases the risk of hepatocellular carcinoma development.

Fig. 1.

Schematic representation of the role of cytokines in the altered lipid metabolism caused by ethanol. It is proposed that alcohol alters, via cytokines (e.g., TNF-α), the balance between esterification and lipolysis in adipocytes of the periphery, which leads to an increased release of fatty acids. Furthermore,TNF-α may decrease the β-oxidation of fatty acids and increase lipogenesis in the liver, resulting in an intracellular lipid accumulation. TG: triglycerides, FFA: free fatty acids, MTTP: microsomal triglyceride transfer protein, VLDL: very low density lipoprotein, ApoB: apolipoprotein B, PPARγ: peroxisome proliferator activated receptor γ, SREBP-1c: sterol regulatory element binding protein, TNF-α, tumor necrosis factor.

Fig. 2.

Transforming growth factor (TGF-β) signaling is highly activated in human liver samples from patients with alcoholic liver disease. The picture shows a representative immunostaining for phosphorylated Smad2 in liver tissue from a patient with alcoholic steatohepatitis (ASH; sample on the right). A high percentage of nuclei-stained positive for activated Smad2 (dark nuclei) imply highly active TGF-β signal transduction. A control liver tissue (sample on the left) was from a patient with gall stone and showed mainly p-Smad2-negative nuclei. Magnification: 400×.

Fig. 3.

Schematic summary of the molecular mechanisms underlying the progression of alcoholic liver disease. CYP2E1: cytochrome P450 2E1, PAI-1: plasminogen activator inhibitor-1, TNF-α: tumor necrosis factor-α, ROS: reactive oxygen species, TGF-β: transforming growth factor-β, HCC: hepatocellular carcinoma; NADPH: reduced forms of nicotinamide adenine dinucleotide phosphate.