ALD presents as a broad spectrum of disorders, ranging from simple fatty liver to more severe forms of liver injury, including alcoholic hepatitis (AH), cirrhosis, and superimposed hepatocellular carcinoma (HCC) (). Fatty liver, an early response to alcohol consumption, develops in most (more than 90%) heavy drinkers, with early-mild steatosis in zone 3 (perivenular) hepatocytes; it can also affect zone 2 and even zone 1 (periportal) hepatocytes when liver injury is more severe. Interestingly, only about 30% of heavy drinkers develop more severe forms of ALD, such as advanced fibrosis and cirrhosis. In patients with underlying ALD and heavy alcohol intake, episodes of superimposed AH may occur. In severe cases and in patients with liver cirrhosis, AH leads to severe complications related to liver failure and portal hypertension and has high short-term mortality.
Figure 1 Spectrum of ALD, risk factors, and comorbidity. More than 95% of heavy drinkers develop fatty liver, but only up to 35% of this population develops more severe forms of ALD, including fibrosis, alcoholic hepatitis, cirrhosis, and HCC. Many risk factors (more ...)
The fact that only about 35% of heavy drinkers develop advanced ALD indicates that other factors are involved. Several risk factors for ALD have been identified (). These include sex, obesity, drinking patterns, dietary factors, non-sex-linked genetic factors, and cigarette smoking ().11-13
Female sex is a well-documented risk factor for susceptibility to ALD; the increased risk among women likely results from lower levels of gastric alcohol dehydrogenase, a higher proportion of body fat, and the presence of estrogens. Obesity represents another important risk factor that accelerates fibrosis progression and the development of cirrhosis in ALD.14,15
Experimental studies indicate that the synergistic effects of obesity and alcohol abuse involve the endoplasmic reticulum response to cell stress, type I macrophage activation, and adiponectin resistance.16
Daily or near-daily heavy drinking, begun at an early age, increases the risk of the development of severe forms of ALD compared with episodic or binge drinking.17
Genetic factors might also influence susceptibility to advanced ALD, but little data are available. Variations in genes that encode antioxidant enzymes, cytokines and other inflammatory mediators, and alcohol-metabolizing enzymes could have a role.13
Also, recent studies indicate that variations in patatin-like phospholipase domain-containing protein 3 (PNPLA3
) affect development of alcoholic cirrhosis in white alcoholic subjects.18-20
Despite the strong link between the PNPLA3
polymorphisms and fatty liver diseases, deletion of this gene did not affect obesity-associated fatty liver or levels of liver enzymes in mice fed a high-fat diet.21
Further studies are required to clarify the role of PNPLA3
variants in the pathogenesis of ALD.
Finally, long-term alcohol drinking has synergistic effects with hepatitis virus B or C and/or human immunodeficiency virus infection, nonalcoholic fatty liver disease, and disorders such as hemochromatosis to accelerate progression of liver diseases. For example, many patients with viral hepatitis consume alcohol, which accelerates progression of liver fibrosis, cirrhosis, and HCC, likely via multiple mechanisms.22,23
A greater understanding of the interaction between alcohol and these comorbid factors could help us design better therapies for the treatment of chronic liver disease.