EASL Clinical Practice Guidelines

Risk factors for disease progression in alcoholic liver disease

Risk factors for fibrosis progression in ALD have been evaluated in two types of approaches: (1) comparisons of the prevalence of risk factors in patients with and without fibrotic ALD; (2) longitudinal evaluation using sequential histology. Risk factors for fibrosis progression can be thought of as host and environmental or genetic and non-genetic. Non-genetic or environmental factors that potentially modulate the development of ALD include the amount and type of alcoholic beverage, the duration of abuse and patterns of drinking. Gender, ethnicity, coexisting conditions such as metabolic syndrome, iron overload, and infection with chronic hepatitis viruses are important genetic or host factors, respectively (Fig. 1). Increasingly, the contribution of host genetic factors to the risk of ALD is being acknowledged.

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Fig. 1
Natural history of alcoholic liver disease (ALD). The spectrum of ALD is comprised of steatosis, steatohepatitis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Both environmental and genetic factors are known to modify the progression of ALD (adapted from [2] with permission from the American Gastroenterological Association). View Large Image | View Hi-Res Image | Download PowerPoint Slide

There is a clear dose-relationship between the amount of alcohol and the likelihood of developing ALD. Alcoholic steatosis can be found in 60% of individuals who drink >60 g of alcohol per day and the risk of developing cirrhosis is highest in those with a daily consumption of above 120 g of alcohol per day [[86], [87]]. However, lower daily amounts of alcohol may also lead to significant liver injury in some individuals. The consumption of >40 g of alcohol per day increases the risk of progression to liver cirrhosis to 30% in patients with uncomplicated alcoholic fatty liver, and to 37% in those with established alcoholic fibrosis [65]. Whether the type of alcoholic drink consumed, e.g. wine as opposed to beer or hard liquor, impacts the risk of ALD is still debated [[88], [89]] and it is unclear whether the effect of different beverages on disease risk is direct or related to confounding factors, such as diet. Patterns of drinking vary substantially among patients with ALD and may influence the risk of ALD. While earlier studies indicated that binge drinking increases the risk of ALD [[90], [91]], data from a recent prospective, single-center study suggested that recent increases in liver-related mortality in the UK are the result of daily or regular heavy drinking rather than due to episodic or binge drinking [92]. Drinking outside meals increases the risk of ALD compared to drinking only together with meals [[87], [93]]. However, data on whether drinking patterns affect the likelihood of ALD evolution are sparse and information on alcohol consumption is largely restricted to total amounts [16]. A number of studies have also shown that caffeine intake appears to protect against cirrhosis in heavy drinkers, with a clear inverse dose–response effect [[94], [95], [96]]. However, the mechanism behind this correlation is unknown.

Studies in humans have demonstrated that women are more susceptible towards the hepatotoxic effects of alcohol, and develop ALD more quickly than men when daily alcohol consumption is equal [[86], [97], [98], [99], [100]]. The pathophysiology behind this increased sensitivity to alcohol is not yet fully understood, but is probably related to oestrogens and their synergistic impact on oxidative stress and inflammation [101]. In addition, women drinking equal amounts of alcohol exhibit higher blood ethanol levels than men. This difference is possibly due to higher gastric alcohol dehydrogenase levels resulting in a faster first-pass metabolism of alcohol in men [102] or to a lower volume of distribution for alcohol in women compared with men.

There are notable differences in the prevalence of ALD and associated mortality among different ethnic groups [[103], [104], [105]]. The highest mortality rates of alcoholic cirrhotics for men are found in white Hispanics, followed by black non-Hispanics, white non-Hispanics, and black Hispanics. In women, the order is black non-Hispanics, white Hispanics, white non-Hispanics, black Hispanics [106]. However, it remains unclear whether ethnic differences in rates of alcoholic cirrhosis and ALD are due to genetic differences or differences in the amount and type of alcohol consumed or related to differences in socioeconomic status and access to medical care.

The most significant, diet-related risk factor for fibrosis progression appears to be obesity, with several studies showing that obesity is the single most important risk factor determining the risk of cirrhosis in heavy drinkers [[107], [108]]. The synergy between obesity and heavy alcohol intake presumably reflects similar mechanisms of disease for both ALD and non-alcoholic fatty liver disease, along with the direct fibrogenic effects of expanded larger mass of adipose tissue (via high levels of noradrenaline, angiotensin II and leptin, and low levels of adiponectin).

Numerous case-control, cross-sectional, and cohort studies have unequivocally shown that coexistence of alcohol misuse and chronic hepatitis C virus infection leads to an acceleration of liver injury [[109], [110], [111], [112], [113]]. From these data it can be concluded that individuals with chronic hepatitis C who drink more than 30–50 g per day increase their risk of developing fibrosis approximately 4-fold. However, one study has even quantified the risk of cirrhosis as 30 times greater in patients with hepatitis C who consume alcohol to excess [114].

Iron in liver biopsies has also been associated with fibrosis in ALD [108] and increased mortality in alcoholic cirrhosis [115]. Elevated serum iron indices are not uncommon in ALD patients, more so than in alcohol misusers without liver disease [115]. However, there is no clear association with the C282Y HFE gene mutation. Some studies have described an association with the H63D mutation [[116], [117]]. Certainly alcohol and iron can act synergistically to produce oxidative stress and thus potentiate progressive liver damage.

Studies of twins have indicated the importance of genetic susceptibility to ALD, demonstrating that monozygotic twins have a higher concordance rate for alcohol-related cirrhosis than dizygotic twins [[118], [119]]. Such studies suggest that genetic factors may represent up to 50% of an individual's susceptibility to ALD. In an attempt to identify possible genetic modifiers of the risk of ALD, a large number of hypothesis-driven, candidate gene case control studies have been performed. These compared the allelic and/or genotypic frequencies of certain genetic variants (i.e. single nucleotide polymorphisms; SNP) between alcoholic cirrhosis and alcoholics without liver disease or healthy controls. In the majority of publications, chosen candidate genes were those associated with alcohol metabolism, fibrogenesis/fibrolysis, or with the inflammatory response. A meta-analysis reviewed studies on associations between SNPs in genes coding for alcohol and aldehyde dehydrogenases, and cytochrome P450 2E1 and retrieved 50 case control studies between 1990 and 2004 [120]. While there were significant associations between certain genetic variants and the risk of alcoholism, no overall association of any of the tested SNPs with alcoholic cirrhosis was detected. Studies on a possible association between ALD and genetic variation of the antioxidant response, cytokines, and others also failed to robustly confirm any of the genetic variants as risk factors for ALD in independent cohorts [121]. However, recently, two candidate gene case control studies in alcoholics found a significant association between the risk of alcoholic cirrhosis and carriage of genotype PNPLA3 rs738409 (GG) in Mestizo subjects [122] and Caucasians [123].

Suggestions for future studies

  1. Large genome-wide association studies should identify the genetic determinants implicated in individual susceptibility to develop ALD.
  2. The interaction between environmental and genetic factors should be investigated.
  3. Additional studies are required to identify the factors influencing disease regression after drinking cessation and long-term outcome in abstinent patients.