Natural History and Cofactors of Alcoholic Liver Disease

Genes Influencing Alcohol Metabolism

Allelic variants of the genes encoding alcohol dehydrogenase (ADH) and aldehyde dehydrogenase 2 (ALDH2) produce alcohol-metabolizing and acetaldehyde-metabolizing enzymes, respectively, with variable activity. The genetic variants influence the prevalence of alcohol dependence and modify susceptibility to liver damage. Because of differences in the capacity to metabolize alcohol to acetaldehyde, it has been considered that individuals with more active ADH1B*2 and ADH1C*1 alleles are at increased risk of developing alcoholic liver injury because of a higher acetaldehyde exposure, but the results from several studies are inconsistent because of ethnic variability in the populations studied and ADH1B*2 being a rare allele in Caucasians. A large study of 876 Caucasians failed to detect a significant association between ADH1C variants and alcoholic cirrhosis. In a Japanese cohort the presence of the ADH1B*2 allele was associated with greater risk of cirrhosis than was seen for the ADH1B*1 allele among alcoholic men (although the ADH1B*2 allele is protective against alcoholism per se ).

Less is known about the effect of the ADH1B*3 allele on responses to alcohol. This allele has been found in African Americans, Afro-Trinidadians, and Native American Mission Indians. From these relatively small studies it appears that individuals having this allele have somewhat increased rates of alcohol metabolism and are at reduced risk of developing alcohol dependence or abuse but may have a greater risk of alcoholic liver injury if they do drink heavily. The ALDH2*2 variant is dominant and results in production of an enzyme with low activity, resulting in accumulation of high levels of acetaldehyde during drinking. Acetaldehyde is a reactive molecule linked to liver injury, and is responsible for the Asian flush reaction. The ALDH2*2 allele is strongly protective against alcoholism and alcohol-related organ disease.

In rodents, ALDH2-deficient mice are resistant to alcohol-induced steatosis but prone to inflammation and fibrosis by way of malondialdehyde-acetaldehyde adduct-mediated paracrine activation of IL-6 in Kupffer cells An ALDH2*2 -linked susceptibility to ALD was not confirmed in alcoholics. In addition to ADH, alcohol can be metabolized by CYP2E1. CYP2E1 is an inducible enzyme, and its activity can increase up to 20-fold following continuous alcohol consumption. There are several polymorphic loci within the human CYP2E1 gene with two mutations in linkage disequilibrium giving rise to c1 and c2 alleles. The CYP2E1*5 (c2) allele is associated with approximately 10-fold higher messenger RNA, protein, and enzyme activity than the c1 allele and could cause a higher exposure of the liver to acetaldehyde and ROS. One study found that the cumulative lifetime alcohol intake of patients with ALD who were heterozygous for the c2 allele was almost half that of patients with ALD homozygous for the wild-type allele, suggesting that it confers increased sensitivity to alcohol. Several studies have looked for an association between a promoter region polymorphism of the CYP2E1 gene and ALD, with no consistent results emerging in any population. In summary, there is ample evidence linking polymorphisms of alcohol-metabolizing enzyme genes with the risk of alcoholism/alcohol dependence; there is growing evidence that the more active ADH1B alleles (*2 and *3) are associated with increased risk of ALD in patients who drink heavily.

Cytokine-Related Genes and Endotoxin Receptor

Cytokines and endotoxin are known to be involved in the pathogenesis of ALD, suggesting that variants of these genes might explain genetic susceptibility to ALD. CD14 acts as a coreceptor along with toll-like receptor 4 (TLR4) for the detection of bacterial lipopolysaccharide in the portal bloodstream. A C/T polymorphism is present at position −159 in the CD14 promoter region, with the TT genotype associated with increased levels of soluble and membrane CD14. In a study of 442 men with valid-alcohol consumption data, the T allele was found to be associated with advanced ALD; that is, with AH (odds ratio [OR], 2.48; p = 0.018) and especially with cirrhosis (OR, 3.45; p = 0.004) but not with fatty liver, periportal fibrosis, or bridging fibrosis. The overall age-adjusted risk for cirrhosis was 3.08 ( p = 0.01) for the carriers of the CT genotype and 4.17 ( p = 0.005) for the homozygous TT genotype. These results suggest that the T allele confers increased risk of alcoholic liver damage. In particular, TT homozygotes are at a high risk of developing cirrhosis. However, in another study looking at the polymorphism of the CD14 coreceptor, TLR4, there was no association between ALD and possession of the Asp299Gly polymorphism in the TLR4 gene.

The most convincing association between ALD and the genetic variant of a cytokine has been reported for a promoter-region polymorphism in interleukin-10 (IL-10). A variant C/A polymorphism at position −627 in the IL-10 promoter has been associated with decreased IL-10 secretion and reporter gene transcription. The allele frequencies for the substitutions at position −627 (C>A) in the IL-10 promoter were determined in 287 heavy alcohol drinkers with biopsy-proved advanced ALD, 107 heavy alcohol drinkers with no evidence of liver disease or steatosis only on biopsy, and 227 local healthy volunteers. At the polymorphic position, 50% of patients with advanced ALD had a least one A allele compared with 33% of controls ( p < 0.0001) and 34% of alcohol drinkers with no or mild disease ( p = 0.017). This study showed a strong association between possession of the A allele and ALD. Lastly, a possible genetic link between a rare polymorphism at position −238 in the tumor necrosis factor α (TNF-α) promoter and ALD was studied in 150 patients with biopsy-proven ALD and 145 healthy volunteers. An excess of this allele was found in patients with ALD with an OR of 3.5 for alcoholic cirrhosis and an OR of 4 for AH compared with controls.