Critique 269 – Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta‑analysis
Niu X; Zhu L; Xu Y; Zhang M; Hao Y; Ma L; Li Y; Xing H
Background Alcohol-related liver disease (ARLD) is one of the major chronic liver diseases worldwide. This review aimed to describe the global prevalence, incidence, and outcomes of ARLD.
Methods Medline, Embase, The Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched from inception to May 31, 2022. The language was restricted to English or Chinese. According to the criteria, articles describing the basic characteristics of the population were selected. Two reviewers extracted the data independently.
Results A total of 372 studies were identified: 353 were used for prevalence analysis, 7 were used for incidence analysis, and 114 were used to for outcome analysis. The prevalence of ARLD worldwide was 4.8%. The prevalence in males was 2.9%, which was higher than female (0.5%). Among the ethnic groups, the percentage was highest in Caucasians (68.9%). Alcoholic liver cirrhosis comprised the highest proportion in the disease spectrum of ARLD at 32.9%. The prevalence of ascites in ARLD population was highest (25.1%). The ARLD population who drinking for > 20 years accounted for 54.8%, and the average daily alcohol intake was 146.6 g/d. About 59.5% of ARLD patients were current or former smokers, and 18.7% were complicated with hepatitis virus infection. The incidence was 0.208/1000 person-years. The overall mortality was 23.9%, and the liver-related mortality was 21.6%.
Conclusion The global prevalence of ARLD was 4.8% and was affected by sex, region, drinking years, and other factors. Therefore, removing the factors causing a high disease prevalence is an urgent requisite.
Background including previous results
The liver is the most important organ metabolizing and, therefore, detoxifying alcohol. Alcohol-related liver disease (ARLD) refers to liver damage caused by long-term excessive alcohol consumption. Alcohol causes hepatocellular damage through alcohol breakdown-associated mechanisms and malnutrition (Gao & Bataller, 2011). ARLD has a range of associated symptoms and consists of three main stages, which often overlap. These stages are: alcoholic fatty liver disease (a built up of fat in the liver); alcoholic hepatitis (inflammation of the liver characterized by rapid onset of jaundice, malaise, tender hepatomegaly, and subtle features of systemic inflammatory response); and alcoholic liver cirrhosis (severe scarring of the liver) (GBD, 2017, WHO, 2018, Rehm et al., 2017, Louvet & Mathurin, 2015).
After drinking alcohol, alcohol is absorbed in the gastrointestinal tract and transported to the liver both by a first-pass before entering the central blood circulation and by the following passes of blood circulating through the liver. The liver absorbs the alcohol and breaks it down into acetaldehyde and acetate using some very active and efficient enzymes. On average, the liver can break down 6-14 g of alcohol per hour (Stockley & Saunders, 2010). So, when one drinks in moderation, viz 10-20 g/day for women and 20-30 g/day for men over a period of several hours, the liver can detoxify such a dose during that period of time. ARLD, however, occurs when much larger quantities of alcohol are being consumed daily over longer periods of time. Regular heavy drinkers and alcohol dependent drinkers die from alcoholic liver cirrhosis at a much higher rate than the general population, as the risk for alcoholic liver cirrhosis is related to overall cumulative lifetime alcohol consumption (Lelbach 1995). Cumulative life-time alcohol consumption is the average level of drinking in grams of pure alcohol (ethanol) per day (Roerecke et al., 2019) during at least a decade of sustained heavy drinking (Szabo, 2007).
Alcohol consumption and liver disease have an exponentially increasing dose-response relationship (Roerecke et al., 2019), where both the frequency of drinking as well as the quantity of alcohol consumed influence the risk of liver disease (Kamper-Jorgensen et al., 2004, Askgaard et al., 2015). A definitive threshold below which alcohol consumption will not cause ARLD has not been established. Research suggests, however, that levels of around 20-30 g/day for men and 10-15 g/day for women are unlikely to cause liver disease in most individuals (Szabo, 2007).
ARLD is one of the major lethal outcomes of alcohol consumption, and global burden of disease from ARLD is mainly due to (premature) years of life lost rather than due to disability resulting from alcohol consumption (Rehm & Shield, 2019). ARLD deaths were estimated at some 607,000 in 2016, which is about 20% of all deaths attributed to alcohol (WHO, 2018). While the age-standardized mortality rates of alcohol-induced cirrhosis and other chronic liver diseases have declined from 5.7 deaths per 100,000 people in 1990 to 4.5 deaths in 2019, alcohol consumption per capita has risen from 5.5 L in 2005 and is projected to increase further to 7.6 L in 2030 (Zhang, 2022). Accordingly, there could be a concomitant increase in the incidence of ARLD in 2030 (Bang et al., 2015, Huang et al., 2023).
Various other factors than drinking large quantities of alcohol over extended periods of time modify the risk for ARLD. Specific genes have been identified that modify the severity of ARLD. These genes include PNPLA3, TM6SF2 and MBOAT7, which have also been implicated in lipid dysregulation (Scott & Anstee, 2018). Some lifestyle factors contributing to chronic liver disease include smoking and hepatitis viral infections, which have been analysed by the authors of this paper. The authors report that 60% of the ARLD patients were smokers and about 19% had a concurrent hepatitis virus infection.
The latter is interesting in the light of the recent COVID-19 pandemic. Recent research shows that after a spike in alcohol-related hepatitis admissions during the first summer of the COVID-19 pandemic, rates declined significantly in 2021 and returned to pre-pandemic levels (Gonzalez et al., 2023). Other risk factors for ARLD, which were not analysed by the authors, are metabolic syndrome (Pose et al., 2021), type 2 diabetes mellitus, cardiovascular disease and obesity (Theodoreson et al., 2023), as well as older age and gut microbial dysbiosis (Huang et al., 2023). Interestingly, COVID-19-associated dysbiosis has also been linked to increased intestinal permeability, which may negatively impact ARLD prognosis (Hussain et al., 2021).
With respect to the latter, a recent meta-analysis estimated the global prevalence of non-alcoholic fatty liver disease in the overweight population at about 70%, the prevalence of non-alcoholic fatty liver at about 40%, and the prevalence of non-alcoholic steatohepatitis at about 30%. Similar prevalence estimates were reported in the obese population (Quek et al., 2023). So, prevalence of the non-alcohol related liver diseases is quite high and it would have been interesting to study the effect of this risk factor as well.
Design and main outcomes
This systematic review and meta-analysis identified papers through various literature databases for English and Chinese papers on ARLD in general populations. A total of 372 studies were identified that fulfilled the inclusion criteria based on the diagnosis of ARLD with blood testing, ultrasound, imaging techniques and liver biopsies and the reporting of prevalence, incidence and outcomes of ARLD. In total, 14 countries were included. This study was extensive and resulted in a paper having 417 literature references.
Europe, the region with the highest alcohol consumption also had the highest prevalence of ARFLD, namely 5.4%, which did not differ much from the prevalence in Asia and North-America, namely 4.5% and 4.7%, respectively. However, heterogeneity between studies and between countries was large. For instance, Italy was reported to have the highest prevalence in Europe at a current per capita alcohol consumption of 7.5 L pure alcohol, whereas Portugal reported an ARLD prevalence of 1% at a per capita alcohol consumption of 12.3 L pure alcohol. These data seem contradictory and are not discussed other than in general terms that other contributing factors may play a role in the aetiology of ARLD.
Prevalence of ARLD was analysed by region, sex, study period, by race and nationality, by duration and average dose of alcohol intake and other contributing factors such as smoking and hepatitis viral infections; however, other contributing factors such as older age, obesity, type 2 diabetes mellitus and gut microbial dysbiosis were not analysed. In addition, incidence and mortality and cause of ARLD death were analysed as well.
Comments on outcomes and methodology
Data reported on gender differences in ARLD prevalence seem contradictory to overall prevalence. Male prevalence was estimated at 2.9%, which was higher than that of women, namely 0.5%. Still the overall prevalence of ARLD in the general population was estimated at a much higher 4.8%. One possible explanation may be that the papers used for the gender assessments and the overall assessment were different: overall prevalence was based on 99 studies and prevalence per gender was based on 58 studies, possibly in lower prevalence countries.
Unfortunately, the relationship between ARLD prevalence or incidence and alcohol consumption data in a specific country were not investigated. One would expect a positive association between per capita alcohol consumption, but such an association has not always been observed. For example, Swedes and Italians drink lower quantities of pure alcohol per capita (7.5 and 7.7 L/year) but have an extremely high prevalence of ARLD (14.0 and 16.1%), while the French and Portuguese drink at higher levels (11.4 and 10.4 L/year respectively), whereas the prevalence of ARLD in these two countries is only 1%. These data suggest that apart from drinking levels other risk factors play an important role in ARLD. The authors suggest that beverage type may be relevant in that respect, which is not consistent with the different prevalence in wine drinking countries such as France and Italy. This is also inconsistent with a previous observation that compared to beer and liquor, wine might be associated with a lower risk of alcoholic cirrhosis (Askgaard et al., 2015).
Noteworthy, the analysis of the causes of death in ARLD showed that mortality related to liver diseases was some 20%, about twice that of non-liver diseases. Overall mortality rate was some 24%.
Very interesting are the characteristics observed in terms of the duration of alcohol intake and the daily dose of pure alcohol consumption. Analysis of 19 studies indicated that the longer the drinking in years the higher the number of ARLD patients with the majority of the patients with a drinking history of over 20 years. Recent alcohol consumption rather than earlier in life has also been associated with risk of alcoholic cirrhosis (Askgaard et al., 2015). Moreover, analysis of 20 studies suggested that average daily alcohol consumption was up to 147 g of alcohol per day. This is an extreme amount of alcohol, which translates into a daily consumption of 14-15 Australian and European standard glasses, 10 US standard glasses and 18 UK standard glasses.
The authors correctly remarked that these high consumption levels are much higher than the excessive drinking defined by health authorities like the NIAAA. They note that there seems to be a discrepancy between the guidelines for alcohol consumption and disease prevalence in the case of ARLD. In other words, prevalence of ARLD is most likely not relevant as a risk for those that follow the guidelines. Guidelines need a safety margin on the drinking levels advised in the assumption that people will drink more than advised. However, in the case of ARLD, such a safety margin would appear to be extensive. In other words, based on these results, the risk for ARLD at moderate drinking levels may be negligible.
In general, health institutions currently do not look at incidence or prevalence of diseases associated with alcohol, but construct estimated risks for diseases. Moreover, a no-risk level seems to be acceptable, which may be hard to accept for the general population because people do usually not drink for their health but for their pleasure and relaxation. At least drinking guidelines may be too strict in terms of ARLD risk since it mainly occurs in people drinking huge quantities of alcohol for extensive periods of time. Although this paper seems to suggest that the threshold for developing ARLD may be much higher than most current drinking guidelines, the paper does not indicate where such a threshold may be.
Specific Comments from Forum Members
Forum member Keil considers that “this review paper contains inconsistencies and contradictions. The clear message is that alcohol consumption around 10-15 grams/day in women and 20-30 grams/ day in men is highly unlikely to cause ARLD.”
Forum Member Skovenborg states that “in the conclusion section the authors suggest that “by increasing alcoholic taxes and controlling the quantity and timing of alcohol sales, the harm caused by alcohol can be reduced to some extent.” If you look at the map of global prevalence of ARLD (Fig. 2) you will notice that the prevalence of ARLD in Portugal, a country that does not have excise taxes on wine and no restriction on timing of alcohol sales, is merely 1%, while the prevalence of ARLD in Sweden, a country with some of the highest excise taxes on alcoholic beverages in the world and a state monopoly with control of the timing and quantity of alcohol sales, is much higher: 14.0%.
These figures might have provoked some thoughts about the reason for the “Portuguese Paradox” and the possible effects of drinking pattern and drinking culture suggestion a kind of “cultural immunity”. A study of the contextual and psychological factors of wine and beer consumption in Portugal and in the Netherlands found that “cultural differences define Portuguese as outdoors, everyday drinkers, within a meal context, and Dutch as at home, weekend drinkers.”
The importance of drinking pattern was confirmed by the results from the prospective UK Million Women Study (Simpson et al., 2019). The incidence of cirrhosis increased with amount of alcohol consumed (≥15 drinks [mean 220 g of alcohol] vs one to two drinks [mean 30 g of alcohol] per week; RR 3·43, 95% CI 2·87–4·10; p<0·0001). About half of the participants (203 564 of 401 806) reported usually drinking with meals and, after adjusting for amount consumed, incidence of cirrhosis was lower for usually drinking with meals than not (RR 0·69, 0·62–0·77; p<0·0001; wine-only drinkers RR 0·69, 0·56–0·85; all other drinkers RR 0·72, 0·63–0·82).”
Concluding comments from Forum Members
This extensive systematic review and meta‑analysis summarises the usually small-scale studies on ARLD to describe the ARLD population and its prevalence (Niu et al., 2023). Accordingly, it provides insight in the worldwide prevalence of ARLD and the role of factors affecting the disease.
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
Henk Hendriks, PhD, Netherlands
Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia
Ulrich Keil, MD, PhD, Professor Emeritus, Institute of Epidemiology & Social Medicine, University of Muenster, Germany
Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark
Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France