In both men and women, there was no evidence for a nonlinear dose–response relationship on the log scale (P = 0.24 and 0.27, respectively, see Table, Supplementary Digital Content 4 and 5, http://links.lww.com/AJG/B250). However, the number of studies available was low, resulting in little power to detect nonlinearity.
The 2 case–control studies with liver cirrhosis morbidity as the outcome yielded smaller risks associated with alcohol consumption, with 1–4 drinks showing no risk increase compared to lifetime abstainers (pooled RR = 1.19, 95% CI: 0.58–2.43, Figure 5). Risks for consumption of 5–8 and 9–13 drinks were associated with large heterogeneity with one study (47) showing substantial risk increases for both men and women, whereas the other study (46) showed no or marginally statistically significant risk increases for either men or women (see Figure, Supplementary Digital Content 6 and 7, http://links.lww.com/AJG/B250).
Given the observational nature of the studies included in this report, we rate the evidence for a causal effect of alcohol consumption and risk for liver cirrhosis as moderate. However, the dose–response relationship in addition to established biological pathways confirmed in randomized controlled trials (50) gives rise to high confidence in a causal dose–response relationship. There was no clear indication for a threshold effect, but we rate the quality of the evidence as low because of imprecision and the small number of studies reporting sex-specific RRs for low levels of drinking.
We conducted a systematic review and various meta-analyses on alcohol consumption and risk of liver cirrhosis. Contrary to previous analyses (13), we found overall no protective effects at any level of drinking when compared to long-term abstainers, and a steadily increasing dose–response relationship in women, and some evidence for a threshold effect in men. However, risks varied widely and the analysis of case–control studies showed no risk increase for consumption of 1–4 drinks per day. The high risk for heavy drinkers found in our meta-analysis of cohort studies is in line with previous research on risk for liver cirrhosis in people with alcohol use disorders (11,51,52). The pooled RRs from case–control studies were much smaller; however, the more recent case–control study (47) corresponds with the risks found in people with alcohol use disorder. One of the cohort studies and one of the case–control studies reported very small RRs compared to the other studies. The reasons for this are unclear, although some outliers are to be expected in any statistical analysis.
Additionally, many studies were not well adjusted and of generally moderate methodological quality, mostly related to potential bias due to confounding and selection bias. Although the increase in risk was stronger in women, CIs were large and overlapped with those for men. Stronger effects in women are supported by studies in people with alcohol use disorder with or without liver cirrhosis (53,54), and higher hepatotoxicity. Although there is no doubt that heavy alcohol consumption is one of the main risk factors for liver cirrhosis, the large heterogeneity observed indicates that the multifactorial nature of development of liver cirrhosis has not been reflected in the epidemiological literature. Liver cirrhosis has a complex and not fully understood etiology, and the contributory role of other risk factors for liver cirrhosis, such as BMI, metabolic syndrome, diabetes, drinking frequency and outside of meals, and others, at any given level of alcohol intake over the life course, needs more attention in both research and prevention efforts.
Although several important confounders have been identified and should be adjusted for in epidemiological studies, it is likely that some of them are in fact effect modifiers that impact the risk associated with alcohol consumption. Most important here is genetic vulnerability. Twin studies have shown a 3-fold higher disease concordance between monozygotic twins and dizygotic twins, but the genetic case–control studies have not yet led to conclusive results (55). Genetic vulnerability is seen as the major reason why only a minority of very heavy drinkers develop liver problems. With respect to other potential effect modifiers, it seems that the drinking frequency modifies the risk for liver cirrhosis associated with a given total weekly alcohol intake with fewer drinking days being associated with lower risk supporting the notion of a “liver holiday” (56–58). A report from the Singapore Chinese Health Study (59) showed that among daily drinkers, consumption of even one drink a day was associated with a RR = 2.72 (95% CI: 0.98–7.50) for liver cirrhosis in comparison to nondrinkers. In more recent years, patterns of drinking, especially binge drinking, were introduced as potentially important for the etiology and progression of liver cirrhosis (60,61). However, evidence is limited and inconclusive at this point (62,63). Future research should include standard measures on patterns of drinking, such as measures of irregular heavy drinking in addition to average volume of drinking and drinking frequency, to test hypotheses about such patterns, and to determine whether there is a positive effect of abstinence days (64). The consumption of mostly wine, as opposed to beer or liquor, has been shown to modify the risk for alcoholic liver cirrhosis in some studies (29,58); however, as the UK Million Women Study showed (49), this may be explained by the consumption of alcohol with meals, which is more common in wine drinkers than consumers of other types of alcohol.
Other limitations of this review are based on the underlying literature. First, the number of original articles was limited. This is surprising given the fact that the majority of liver cirrhosis cases would not exist in a counterfactual scenario without alcohol. Second, the quality of the contributions was limited. Because of the small number of studies published, we were unable to investigate in detail the role of many study design characteristics, such as adjustment for potential confounders, follow-up length, race/ethnicity, and others that may play a role in the development of liver cirrhosis. Low response rates and inclusion criteria in primary studies, such as participants in screening programs, may limit the generalizability of our findings. Although self-reported alcohol consumption is generally reliable (75), it may result in underestimation of the real consumption. No cohort study measured alcohol consumption more than once, thus opening the research to measurement and regression dilution bias, and underestimation of the real effect (76). Although the 2 case–control studies from Italy were able to assess lifetime drinking retrospectively, these types of studies are prone to recall bias, and categories of alcohol consumption were large, and adjustments for other risk factors for liver cirrhosis were minimal. Again, even with similar methodology in the same country, the 2 studies observed large differences in risk for liver cirrhosis for a given total alcohol intake. One possibility for the difference in risk observed between cohort and case–control studies is because of the difference in outcome assessment (mortality vs morbidity).
What are the clinical conclusions of this study? The exponential dose–response curve on the RR level indicates that the highest levels of average volume of alcohol consumption confer exponentially higher risks and should be avoided (78). For people at the high end of this trajectory, the risk for liver cirrhosis is very high (16), and reductions of the highest levels are associated with the highest health gains (79). This can be achieved on the individual level in 2 ways: first, the trajectory toward these levels should be interrupted early and more than once. This should best be done at the general practitioner level with screening and brief interventions or treatment (80); however, screening for unhealthy alcohol use is still not conducted routinely (81,82). Second (79), to prevent liver cirrhosis and subsequent complications including death in people with continued high consumption, it is most important to reduce high levels, even if the new drinking level are still high, and even if the patients still qualify for alcohol use disorders. Of course, the larger the reduction from a given level, the larger the reduction of RR, but it should be taken into consideration that any reduction of high volume drinking will be beneficial (83). Finally, there are alcohol control policy measures. Measures like increase in price by taxation (84) or restrictions in availability have historically shown to impact on liver cirrhosis deaths (85). Thus, the current high impact of alcohol consumption on liver cirrhosis is avoidable, and both individual interventions in the health care sector and alcohol control policies can contribute to reduce this impact.
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