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Alcohol Consumption and Risk of Liver Cirrhosis

A Systematic Review and Meta-Analysis

Roerecke, Michael PhD1,2; Vafaei, Afshin PhD1; Hasan, Omer S.M. BA1,2; Chrystoja, Bethany R. BSc1,2; Cruz, Marcus BSc3; Lee, Roy BSc3; Neuman, Manuela G. PhD3,4; Rehm, Jürgen PhD1,2,5–8

American Journal of Gastroenterology: October 2019 - Volume 114 - Issue 10 - p 1574–1586
doi: 10.14309/ajg.0000000000000340

OBJECTIVES: To systematically summarize the risk relationship between different levels of alcohol consumption and incidence of liver cirrhosis.

METHODS: MEDLINE and Embase were searched up to March 6, 2019, to identify case–control and cohort studies with sex-specific results and more than 2 categories of drinking in relation to the incidence of liver cirrhosis. Study characteristics were extracted and random-effects meta-analyses and meta-regressions were conducted.

RESULTS: A total of 7 cohort studies and 2 case–control studies met the inclusion criteria, providing data from 2,629,272 participants with 5,505 cases of liver cirrhosis. There was no increased risk for occasional drinkers. Consumption of one drink per day in comparison to long-term abstainers showed an increased risk for liver cirrhosis in women, but not in men. The risk for women was consistently higher compared to men. Drinking ≥5 drinks per day was associated with a substantially increased risk in both women (relative risk [RR] = 12.44, 95% confidence interval [CI]: 6.65–23.27 for 5–6 drinks, and RR = 24.58, 95% CI: 14.77–40.90 for ≥7 drinks) and men (RR = 3.80, 95% CI: 0.85–17.02, and RR = 6.93, 95% CI: 1.07–44.99, respectively). Heterogeneity across studies indicated an additional impact of other risk factors.

DISCUSSION: Alcohol is a major risk factor for liver cirrhosis with risk increasing exponentially. Women may be at higher risk compared to men even with little alcohol consumption. More high-quality research is necessary to elucidate the role of other risk factors, such as genetic vulnerability, body weight, metabolic risk factors, and drinking patterns over the life course. High alcohol consumption should be avoided, and people drinking at high levels should receive interventions to reduce their intake.

1Institute for Mental Health Policy Research, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada;

2Dalla Lana School of Public Health (DLSPH), University of Toronto, Toronto, Ontario, Canada;

3In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada;

4Department of Pharmacology and Toxicology, Faculty of Medicine and Global Health, University of Toronto, Toronto, Ontario, Canada;

5Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;

6Institute for Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany;

7Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;

8Campbell Family Mental Health Research Institute, CAMH, Toronto, Canada.

Correspondence: Michael Roerecke, PhD. E-mail:

SUPPLEMENTARY MATERIAL accompanies this paper at

Received November 21, 2018

Accepted June 26, 2019

Online date: August 20, 2019

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Alcohol is a major risk factor for liver disease in general and for liver cirrhosis in particular (1–3). In fact, about half of the liver cirrhosis burden of morbidity and mortality would disappear in a world without alcohol (4). Mortality from liver cirrhosis has been on the rise in the United States (5) and Europe (6), more so in women than in men. Alcohol consumption is partly responsible, but liver disease is increasingly recognized as a multifactorial disease process (6).

The importance of alcohol in the etiology of liver disease has led to the establishment of different codes for categories of liver diseases, which are considered to be primarily caused by alcohol. Thus, the International Classification of Diseases (ICD-10 [7]) recognizes several forms of alcoholic liver disease (ICD-10, K70), sometimes considered stages (8) that range from relatively mild and reversible alcoholic hepatic steatosis (fatty liver) (K70.0) and alcoholic hepatitis (K70.1), to alcoholic fibrosis and sclerosis of the liver (K70.2), and further to severe and irreversible stages such as alcoholic liver cirrhosis (K70.3) and alcoholic hepatic failure (K70.4). Alcohol consumption, in particular heavy use over time, has been found crucial in the etiology and progression of these diseases (1,9,10). However, liver diseases are multifactorial, and alcohol use may play a role in the progression of all types of cirrhosis (11). Even one drink per day may have an effect on the incidence of liver cirrhosis (12). For a scientific review of all liver cirrhosis, it is therefore crucial to include both alcoholic and nonalcoholic liver cirrhosis when examining the impact of alcohol use.

Most of the epidemiological literature to date has dealt with the level of drinking and incidence or mortality of liver cirrhosis (13). It followed the epidemiological tradition of the early studies of Lelbach and others (14,15), who, based on studies in people with alcohol use disorders, postulated a clear association between the volume of alcohol use and liver cirrhosis (1). This association was corroborated in more rigorous studies (1,13,16). It remains to be determined, however, whether a threshold for alcohol-related damage to the liver exists or whether any amount of alcohol increases the risk for liver cirrhosis, which has been discussed recently (17–19). In fact, the last meta-analysis on the topic is now more than 10 years old and found some evidence for a protective association at low levels of alcohol intake in men (13). Furthermore, several large-scale studies have been published since then (20–22).

The present review provides an overview of the current knowledge on the dose–response relationship between alcohol consumption and risk of liver cirrhosis in comparison to abstainers, with particular consideration given to the effects of study design and sex, and other subgroups where data were available. As noted above, our review was not restricted to alcoholic liver cirrhosis.

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Search strategy and selection criteria

Following the MOOSE guidelines (23), we conducted a systematic electronic literature search using MEDLINE and Embase from inception to March 6, 2019, for keywords and MeSH terms relating to alcohol consumption, liver cirrhosis, and observational studies (see Table, Supplementary Digital Content 1, Additionally, we searched reference lists of identified articles and published meta-analyses and reviews. Inclusion criteria were as follows:

  1. cohort and case–control studies examining sex-specific association between average alcohol consumption and liver cirrhosis
  2. analyses were adjusted for age at baseline
  3. data for at least 2 quantitatively defined categories of average alcohol consumption in relation to nondrinkers, or data for former drinkers in relation to long-term abstainers were reported
  4. more than 50 cases of liver cirrhosis occurred.

We did not apply language restrictions. At least 2 reviewers independently excluded articles based on title and abstract or full-text and abstracted the data. Any discrepancies were resolved in consultation with a third reviewer.

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Data extraction

From all relevant articles, we extracted authors' names, year of publication, country, year(s) of baseline examination, follow-up period, setting of the study, study design, assessment of liver cirrhosis, age (range, mean or median) at baseline, sex, number of observed liver cirrhosis cases among participants by drinking group, number of total participants by drinking group, specific adjustment or stratification for potential confounders, and adjusted relative risks (RRs) and their confidence intervals (CIs) or standard errors. Risk estimates by sex were treated as independent samples. Where necessary, RRs within studies were recalculated to contrast alcohol consumption categories against nondrinkers (24).

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Exposure and outcome assessment

Consolidating exposure measures across primary studies involved a two-step process. First, among drinkers, we converted reported alcohol intake categories in primary studies into an average of pure alcohol in grams per day (g/d) using the midpoints (mean or median) of reported drinking group categories. For open-ended categories, we added 3 quarters of the second highest category's range to the lower limit of the open-ended category of alcohol intake if the mean was not reported. Standard drinks vary by country, with one standard drink containing approximately 8–14 g of pure alcohol (25). We used reported conversion factors when standard drinks were the unit of measurement to convert all measures to grams per day. Then, for the reporting of our analyses, we considered categories with a mean of up to 12 g of pure ethanol as one standard drink for a global representation. Qualitative descriptions, such as “social” or “frequent” drinkers, with no clear total alcohol intake in grams per day were excluded. When current nondrinkers were the reference group (i.e., including both long-term abstainers and former drinkers), we adjusted risk estimates for the effect of former drinking compared to long-term abstention, based on the pooled risk for former drinking from 2 studies included in this review to avoid the sick quitter effect. Long-term abstainers were defined as people who stated that they never consumed alcohol (20), people who stated that they never, or almost never, drank alcohol in the past (26), or when people who had greatly decreased their consumption in the last 10 years were excluded from nondrinkers (27). The logRR for former drinkers in comparison to current non-drinkers (RRformer drinkers = 2.52) was multiplied by the mean fraction of former drinkers among current nondrinkers (0.23) and added to the respective logRRs of current drinking groups from primary studies used in our analysis when current nondrinkers was the reference group.

Liver cirrhosis due to known etiology such as alcohol and unspecified liver cirrhosis were defined as in the primary studies, which included ICD codes for liver cirrhosis (ICD-7: 581; ICD-8: 571; ICD-10: K70, K73, K74) and unspecified liver cirrhosis (ICD-8: 571.9, 456.0, 785.3; ICD-10: I85.0, I85.9, K74.6, R18.9). Because we aimed to estimate the RR in comparison to abstainers, we excluded several studies (28,29) that focused only on alcoholic liver cirrhosis (or included alcoholism in addition to liver cirrhosis in the outcome) (30), which, by definition, cannot occur in lifetime abstainers.

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Quality assessment

Most quality scores are tailored for meta-analyses of randomized trials of interventions (31–33) and many criteria do not apply to epidemiological studies examined in this study. Additionally, quality score use in meta-analyses remains controversial (34–36). As a result, study quality was enhanced by including quality components, such as study design, measurement of alcohol consumption and liver cirrhosis, adjustment for age in our inclusion and exclusion criteria, and further by investigating potential heterogeneity in several sensitivity analyses. We used the most adjusted RR reported and the most comprehensive data available for each analysis and gave priority to estimates where lifetime or long-term abstainers were used as the risk reference group.

In a formal risk of bias analysis, we used the Cochrane Risk-of-Bias Tool for Non-Randomized Studies (ROBINS-I [37]) to assess risk of bias in primary studies. We rated the evidence for the association between alcohol consumption and incidence of liver cirrhosis based on the Grading of Recommendations Assessment, Development and Evaluation approach (38).

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Statistical analyses

In categorical analyses using standard drinks (12 g pure alcohol) as the exposure measure, RRs were pooled with inverse-variance weighting using DerSimonian–Laird random-effect models to allow for between-study heterogeneity (39). Small-study bias was examined using Egger's regression-based test (40). Variation in the effect size because of heterogeneity between studies was quantified using the I2 statistic (41).

Using studies that reported data for 4 or more alcohol intake groups, we conducted 2-stage restricted cubic spline regression analysis in multivariate meta-regression models, taking into account the variance–covariance matrix for risk estimates derived from one reference group (42,43) to test for nonlinear dose–response relationships in relation to long-term abstainers. All meta-analytical analyses were conducted on the natural log scale in Stata Statistical Software, version 14.2.

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In total, out of 2,977 identified references, 385 articles were retrieved in full-text. Of these, 7 cohort and 2 case–control studies fulfilled our inclusion criteria (Figure 1). Four studies were conducted in the United States (26,27,44,45), 2 in Italy (46,47), and one each in China (22), the United Kingdom (21), and Denmark (20). In total, data from 2,629,272 participants (579,592 men and 2,049,680 women) and 5,505 cases of liver cirrhosis (2,196 men and 3,309 women) were used in the analyses. All cohort studies included liver cirrhosis mortality as the outcome. The 2 case–control studies investigated first-time diagnosis of symptomatic liver cirrhosis in comparison to lifetime abstainers (Table 1). The study by Liu et al. contributed 2,078 liver cirrhosis cases from the National Health Service Million Women Study linked to death and morbidity registries (21). The proportion of nondrinkers varied widely, from 0.002% (lifetime abstainers) among men in the Danish study by Askgaard et al. (20) to 80% (current abstainers) in the study of women from the American Cancer Society I cohort by Garfinkel et al. (44). All cohort studies used a one-time measurement of alcohol consumption as the baseline alcohol intake, whereas the 3 case–control studies from Italy assessed lifetime alcohol consumption retrospectively. All but one cohort study were rated to be of moderate quality mainly because of the one-time measurement of alcohol consumption at baseline (cohort studies) and the observational study design (see Table, Supplementary Digital Content 2, One cohort study (44) had potential serious bias because the results were adjusted only for age.

Figure 1

Figure 1

Table 1-a

Table 1-a

Table 1-b

Table 1-b

Table 1-c

Table 1-c

The pooled proportion of former drinkers among current abstainers (20,26) was 23%, and the pooled RR for liver cirrhosis in comparison to long-term abstainers was 2.56 (95% CI: 0.93–6.79). Figure 2 displays the RRs for liver cirrhosis in cohort studies by alcohol intake in reference to long-term abstainers after current abstention at baseline was adjusted for the proportion and risk in former drinkers. Alcohol consumption beyond occasional drinking, which showed a similar risk compared to long-term abstainers, was associated with increasing risk for liver cirrhosis (Figure 2) with a pooled RR of 10.70 (95% CI: 2.95–38.78) for consumption of 7 drinks or more per day. However, all drinking categories showed substantial heterogeneity across studies (I2 between 70 and 98%, all P-values < 0.001), resulting in large CIs. We restricted analyses of small-study effects and influential studies to drinkers of 1 or 2 drinks per day for both sexes because of the small number of studies identified. We found no statistical evidence for small study bias for drinkers of 1 or 2 drinks per day (P = 0.94), the funnel plot showed similar results (see Figure, Supplementary Digital Content 1, None of the studies had an overly large impact on the pooled estimates (see Figure, Supplementary Digital Content 2,

Figure 2

Figure 2

Results for men and women are shown separately in Figures 3 and 4, respectively. Across all consumption levels, RRs in women were higher, reaching RR = 24.58 (95% CI: 14.77–40.90) for ≥7 drinks. Although consumption of 1–2 drinks was associated with a substantially elevated risk for liver cirrhosis in women, this was not the case in men. However, these results need to be interpreted with caution because of the small number of studies available. Four cohort studies (20,21,26,27) in women were adjusted for age, body mass index (BMI) or waist circumference, and smoking. The relationship was similar to the main analysis with an elevated and linearly increasing risk for consumption of one drink and beyond (see Figure, Supplementary Digital Content 3,

Figure 3

Figure 3

Figure 4

Figure 4

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, 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,

Figure 5

Figure 5

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Subgroup analyses

One cohort study (21) showed that although the risk in smokers was higher than in never-smokers, the risk of liver cirrhosis by alcohol intake increased in never-smokers similar to current smokers, indicating that smoking is a confounder but not an effect modifier. In another report (48) from the case–control studies by Corrao et al., it was shown that the relationship between alcohol and liver cirrhosis in all participants was similar to participants without serum hepatitis B virus surface antigen and/or positive anti-hepatitis C virus status. One of the case–control studies (46) included in our main analysis also showed that the risk for liver cirrhosis was greatest in drinkers who drank heavily for 10 or 20 years, but not for 30 years, indicating potentially a survivor bias. Similarly, the same study (46) reported risk by age (≤60 years and >60 years), showing that the risk increase was stronger in younger participants for both sexes. The cohort study by Askgaard et al. (20) reported results by frequency of drinking days adjusted for weekly alcohol intake. In men, there was an increased risk for daily drinking in comparison to drinking on 2–4 days per week (RR = 2.25, 95% CI: 1.68–3.00). In women, the RR was 1.28 (95% CI: 0.82–2.02). Results from the UK Million Women Study (49) showed that among drinkers daily drinking in comparison to nondaily drinking (RR = 1.61, 95% CI: 1.40–1.85) and drinking with meals in comparison to drinking outside of meals (RR = 0.69, 95% CI: 0.62–0.77) were associated with incidence of liver cirrhosis. These associations were similar in strata of BMI, smoking status, and type of alcoholic beverage. Women who both drank daily and outside of meals had a 2.47 (95% CI: 1.96–3.11) increased risk for liver cirrhosis with adjustment for amount and type of beverage (49).

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.

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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.

An investigation of Midspan cohorts (65) in Scotland indicated that BMI modifies the effect of alcohol consumption on liver disease, with obese participants being more susceptible to the harms from alcohol consumption than participants with lower BMI. An analysis of the Million Women Study (66) confirmed that BMI and alcohol consumption interact in development of liver cirrhosis, in particular at alcohol intake of more than 150 g/wk and BMI above 30. Potential interaction with drinking patterns seem possible (62). The effect of smoking in relation to alcohol consumption on liver cirrhosis is not clear. Several studies have reported an effect independent of alcohol consumption (21,67) and no clear effect (68,69). Meta-analyses of the association of coffee consumption and risk for liver disease consistently show a decreased risk (70,71). Potential interaction with alcohol consumption should be explored. Liver cirrhosis severity may also play a role. Another analysis from the series of case–control studies from Italy showed the risk increase from alcohol consumption was characterized by a threshold effect at approximately 150 g/d, and a smaller risk at higher consumption for asymptomatic liver cirrhosis than for symptomatic liver cirrhosis. In other reports including the same participants (69,72), it was shown that hepatitis B virus and HCV infection were risk factors independent from alcohol consumption. The role of nutrient intake is unclear. Several nutrients were investigated in reports from the Italian case–control studies. Possible interaction effects were observed for dietary intake of lipids (73), vitamin A (74), and iron (74). However, larger sample sizes are required to detect an effect with sufficient power. More and higher quality epidemiological studies are needed to reach firm conclusions about confounding and interaction effects of these risk and protective factors in men and women (51).

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).

In comparison to our earlier meta-analysis (13), the strengths of this meta-analysis lie in its clear definition of the outcome, and its methodological rigor. For example, we excluded studies with insufficient number of cases or adjustment (77) and provide an examination of age, drinking patterns, and type of beverage where data were available. This strength came at a cost—some of the most well-known studies in the field, which were limited to subcategories of liver cirrhosis, had to be excluded (28,29), which was crucial to quantify the risk of liver cirrhosis in comparison to abstainers, which by definition cannot develop alcoholic liver cirrhosis.

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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Guarantor of the article: Michael Roerecke, PhD.

Specific author contributions: M.R. designed the study, and oversaw and conducted the literature review, data extraction, statistical analysis, data interpretation, article preparation, article review, and correspondence. J.R. and M.G.N. contributed to the design and data interpretation, article preparation, and article review. A.V., O.S.M.H., B.R.C., M.C., and R.L. contributed to the literature review, article preparation, and article review. All authors contributed to the final article and approved the final version. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all of the data and the final responsibility to submit for publication.

Financial support: Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health under Award Number R21AA023521 to M.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The sponsor of the study (NIAAA) had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The authors collected the data and had full access to all of the data in the study. The authors also had final responsibility for the decision to submit the study results for publication.

Potential competing interests: M.R. and J.R. report grants from the National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), during the conduct of the study. J.R. reports grants and personal fees from Lundbeck and D&A Pharma outside of this work. A.V., O.S.M.H., B.R.C., M.C., R.L., and M.G.N. report no conflicts of interest.

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Study Highlights


  • ✓ Alcohol is involved in all types of liver disease, and high alcohol consumption is associated with high disease risk.
  • ✓ Prior systematic evidence syntheses have included inconsistent definitions of alcohol exposure and liver cirrhosis.
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  • ✓ The risk for incidence of liver cirrhosis for former drinkers in comparison to long-term abstainers was 3-fold.
  • ✓ With any alcohol consumption, the risk for liver cirrhosis increased exponentially among women; among men, the risk increased beyond consumption of one drink or more per day.
  • ✓ Drinking daily and outside of meals increases the risk for liver cirrhosis at any given level of overall alcohol intake. Several other risk factors for liver cirrhosis may modify the association of alcohol with liver cirrhosis, such as genetics, age, BMI, metabolic risk factors, and others.
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