Globally, the incidence of liver cirrhosis (LC) has shown an increasing trend in females and a stabilized trend in males in recent years (1), with certain areas such as the Eastern Mediterranean Region, African Region and South-East Asia, having an increasing trend of LC in females and males. Other areas had an increasing trend only in males, such as the European Region, and only in females, such as the Region of the Americas. In addition, although death and disability-adjusted life years (DALY) global rates of LC decreased from 1990 to 2019, the number of deaths and DALYs and the proportion of all global deaths due to LC have increased (2), being ranked the 8th most common non-communicable disease cause of death globally in 2019 (1). With alcohol use being a key risk factor in the progression and mortality of LC (3), particularly among females (4, 5), efforts should be made to develop alcohol control policies and prevention measures to address this concerning public health problem.

There is evidence that a dose-response relationship between alcohol consumption and LC exists (6–8) and, at the same level of alcohol consumption, females seem to have a higher risk of developing LC than males (7). By studying how the dose-response relationship varies by cause of LC and by fatal vs non-fatal events in females and males (9), we will have strong evidence to inform policy makers and prevention experts on whether most of their efforts should be directed to the general population level or targeted towards females and males by their levels of alcohol use. For instance, if the risk curves are more linear, a general population approach will yield better results, whereas with more exponential risk curves targeted approaches should be recommended (10). Consequently, there is a need to have global, updated, and precise risk curves on the association of alcohol consumption and LC in females and males from which we can identify the meaningful risk increases for each sex. Accordingly, our aim was to quantify the dose-response relationship on alcohol use and the risk of LC by sex using meta-analysis and meta-regression models, and to identify the differences between females and males in the risks of morbidity and mortality due to LC.

A total of 24 studies were included in the analysis ( Figure 1 ); 13 of the studies provided results for females and 19 provided results for males. Table 1 presents the studies’ characteristics. There were collectively 2,112,476 females and 924,853 males, and a total of 4,301 and 4,231 cases of LC for females and males respectively. The majority of studies were cohort studies (67%). In total, 10 studies (42%) provided results for LC morbidity, 11 studies (46%) were mortality studies, and three studies (12%) presented their results with both morbidity and mortality combined. As for the type of LC, 20 studies provided data including all causes of LC, two studies for alcohol-related LC, one study for HCV-induced LC, and one study for alcohol-related LC and HCV-induced LC combined. In the risk-of-bias assessment, 10 studies had a moderate score, six studies had a serious score, and eight studies had a critical score.

A non-linear dose-response curve was identified for both females and males. The restrictive cubic spline model (17) was the model that best fit our data (for reasoning on the selection of the model see Supplementary Material 4 ). For the same amount of alcohol use, females presented a higher relative risk of LC than males ( Figure 2 ). For both curves, the risk of LC increased with the average number of grams of alcohol consumed daily. Table 2 presents the RRs and the risk ratios of females vs males. The risk ratio was not constant, first increasing in value and then decreasing as the level of alcohol consumption became higher.

We identified several statistically significant differences in the overall meta-regression model (for full model results and estimates, see Supplementary Material 5 ). We obtained a significantly higher LC risk for females than for males (beta=-0.0319, se=0.00407; estimate for the interaction between sex and dose of alcohol consumption with female as reference). In addition, mortality studies presented a significantly higher risk compared to morbidity studies. Based on the quality scores obtained in the risk assessment, studies with serious and critical scores presented a higher risk compared to studies with moderate scores. Finally, we identified a significant steeper slope in HCV-related studies compared to all-cause LC and a steeper slope in all-cause LC compared to alcohol-related LC, this latter not being statistically significant.

In addition, we identified a higher risk for morbidity outcomes in females compared to males and a significantly higher risk for mortality due to LC in females compared to males ( Figure 3 , for full model results, see Supplementary Material 6 ). We also tested the interaction of morbidity and mortality stratified by sex (for full model results, see Supplementary Material 7 ). In females, we did not identify statistically significant differences between morbidity studies and mortality studies. For males, mortality studies presented a significantly higher risk compared to morbidity studies.

In our sensitivity analysis, we excluded the study by Liu and colleges (18) which provided four estimate points with the corresponding weights: 14%, 14%, 15%, 13% in the restrictive cubic splines model in the overall dose-response relationship for females. When we ran the analysis with the study excluded, the shape of the curve attenuated but there were still statistically significant differences compared to males (see Supplementary Material 8 ) and there were no changes in the significance and direction of the regression weights for the other variables studied.

Differences in the risk of LC conditional on alcohol use between females and males have been identified, showing that, for females, the same level of alcohol consumed presents a higher risk of LC than for males as well as a higher mortality risk of LC, irrespective of the cause of LC. Our study is the most comprehensive and presents the most up to date estimates currently available. These results are consistent with previous reviews published (6, 7), which identified an increasing dose-response relationship in females. Our review identified six additional studies for females and 13 additional studies for males compared to the most recent review (7) mainly due to the inclusion of additional biological pathways of LC. In addition, it was not restricted to studies of all causes of LC combined, and thus we had the necessary power to study the impact of other variables. Importantly, the dose-response curves for females accelerate quickly, characterized by a non-linear curve with a more exponential relationship before flattening out.

The basis for this difference may partly be explained by differences in alcohol pharmacokinetics and pharmacodynamics between females and males (45, 46). Females generally have a relatively lower total water content and are generally smaller than males, resulting in higher blood alcohol concentrations for the same amount of ingested alcohol. Frezza et al. (47), confirmed this theory and identified that females also present a lower rate of alcohol dehydrogenase activity in the gastric mucosa, consequently producing a higher bioavailability of alcohol when lower doses of alcohol are consumed and a longer time period during which these levels are elevated. Thus, the activity of gastric metabolism is decreased in dependent alcohol use and sex differences are less apparent in heavy drinkers (48). In addition, estrogens are involved in alcohol-related liver damage by increasing the susceptibility of Kupffer cells to endotoxins (49). When activated, Kupffer cells release cytokines and produce hepatic inflammation, playing a role in hepatotoxicity after alcohol exposure (50). In contrast, when estrogen is blocked in animal models, the alcohol-related injury is attenuated (51). Therefore, Kupffer cells are an additional key element in the sex differences in liver injury caused by alcohol use.

The gender-gap that historically existed in the level of alcohol consumption between men and women is narrowing, with women increasing their consumption, including a notable increase in high-risk drinking (52). This phenomenon is a concerning public health problem which can consequently lead to adverse health effects. Additionally, gender-related differences in alcohol use regarding drinking patterns and problematic drinking (53), have been decreasing as the newest generations are being exposed to a social, economic and cultural homogenization (54). Knowing the unique risk that alcohol has for women, increases in their consumption are concerning and efforts should be directed to build awareness for this issue. More specifically for LC, prevention campaigns should take into consideration that females incur more than twofold risks of LC compared to males at all levels of alcohol consumption, with the excess risk of females being highest at 60 grams of pure alcohol per day.

In addition, given the quick acceleration of risk curves in females, targeted approaches directed to females in the health-care system seem promising. This is especially true with the apparent gender-gap in today’s clinical practice, since women are not routinely asked about their alcohol use (4, 5). In general, alcohol assessment during healthcare visits is key to the early identification of harmful alcohol use as well as for quickly conducting brief interventions or referrals for specialty treatment. Brief interventions and alcohol use disorder treatment have been shown to be effective and relatively cost effective in decreasing consumption (55, 56), and thus in reducing the risk for LC. One study reported that men have a higher rate of accessing healthcare prior to being diagnosed with alcohol-related LC than women, but they are less likely to receive interventions or referrals than women (57). Nevertheless, women report having less social support for treatment engagement when dealing with alcohol use disorders (58). To formulate effective and accessible prevention and treatment options, these factors should be taken into account.

There are some limitations to our study that should be considered. First, we performed a meta-analysis based on an underlying literature search. Therefore, the evidence is limited to the research available and there is a longstanding and consistent history of poor measurement of alcohol use in epidemiological studies due to social desirability bias (underreporting) resulting from survey data. Also, there was a lack of data regarding the causes of LC, which leads us to be cautious when interpreting the differences identified between underlying causes of LC. Nevertheless, the same differences were identified in a wider analysis that included studies with both sexes combined. In addition, females accounted for more than twice the subjects and cases than males, and the study conducted by Liu and colleagues (18) represented more than half of the weight in our analysis. This large prospective study had a relatively high-quality methodology and, although the dose-response curve attenuated when we excluded this study from our analysis, we did not find differences in the direction of the curves or in beta-coefficients for other variables. As for the interpretation of the risk of bias score, although more than half of our studies received a serious or critical score, this was mainly because they did not include a time-variant confounding variable, which left us without a single article with a low bias score, and many articles with scores of serious and critical bias. Finally, alcohol use is often measured by self-report, which may lead to bias, although it has been shown to be valid overall (59).

By using a systematic and standardized methodology we were able to quantify the dose-response relationships in females and males and identify the differences in both curves and according to the outcomes. The higher risk observed in females, both in the progression of and mortality due to LC, calls for action. In primary care, unless alcohol use is screened for systematically, women´s drinking tends to be overlooked (60). Early identification of excessive alcohol use should be a regular practice in health-care facilities to properly diagnose and treat at-risk individuals and prevent further progression in individuals with lower levels of consumption (61).

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Conceptualization: CP and JR. Methodology: LL-F, JR, HJ and AT. Data curation: LL-F, HJ, KP, AL, CB, CP and AT. Formal analysis: LL-F, HJ and AT. Funding acquisition, CP. Investigation: LL-F, KP, AL, CB, CP and JR. Project administration: CP. Resources: CP and JR. Software: LL-F, JR, HJ and AT. Supervision: CP and JR. Validation: JR and HJ. Visualization: LL-F and AT. Writing—original draft, LL-F and JR. Writing—review and editing: all authors. All authors have read and agreed to the published version of the manuscript. All authors contributed to the article and approved the submitted version.

Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Numbers R01AA028009 and R01AA028224. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

We would like to thank Ms. Astrid Otto for referencing and copyediting the text.

Author AL reported grants from Swiss National Science Foundation (SNSF) during the conduct of the study.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.