Alcohol intake is still among the leading causes of death and health impairments in the world. Indeed, in 2020, 1.03 billion males (35.1% of the male global population aged ≥ 15 years) and 312 million females (10.5% of female global population aged ≥ 15 years) consumed alcohol in amounts exceeding the non-drinker equivalent (NDE) [1], the latter being defined as the level of alcohol consumption at which the risk of health loss for a drinker is equivalent to that of a non-drinker. Epidemiological data further suggest that in 2020, ~1.78 million [95% uncertainty interval (UI) 1.39–2.27] of global deaths among males aged 15–49 years were related to alcohol intake [1]. Furthermore, ~5.1% of the global burden of disease and injury is attributable to alcohol consumption [1–3]. The liver is among the organs thought to be most vulnerable with respect to heavy alcohol intake and resulting damage [4]. Herein heavy alcohol use is mostly defined as 3 and more standard drinks per day for women (~40 g of ethanol per day for women) and 4 and more standard drinks per day for men (~50–60 g of ethanol per day for men) [5]. Indeed, it has been shown that ~27.3% of the deaths attributed to cirrhosis in men and 20.6% of deaths attributed to cirrhosis in women are related to alcohol consumption [6, 7] and that a daily intake of 31–60 g of ethanol may already increase the odds by 10.9% to develop liver diseases [8–10]. However, it has also been reported that not only the amounts of ethanol consumed may impact the development of alcohol-related liver diseases (ALD) but that also the type of alcoholic beverage consumed may impact the development of liver damage. Starting from this background, the aim of the present review is to summarize findings regarding the role of different alcoholic drinks with a focus on non-distilled drinks on the development of ALD and to highlight some of the underlying molecular mechanisms.

Studies suggest that the amounts of ethanol consumed vary considerably between different geographical regions [1, 2]. For instance, in North America, but also many European and Asian countries as well as Russia, intake of ethanol ranges from 10–13 L per person per year, whereas in the Eastern Mediterranean Region and across North Africa, alcohol consumption is reported to be markedly lower with being even close to zero in some countries [2]. Similar to the findings regarding total amounts of ethanol consumed, intake of different alcoholic beverages also varies considerably among different regions and even more so countries [2]. Indeed, when regarded globally, hard spirits are the type of alcoholic drink consumed the most (~44.8%), while wine accounts for ~11.7% of the ingested alcohol and beer for ~34.3% [2]. However, when being stratified by regions, in the South East Asian Region, hard spirits account for ~87.9% of the consumed alcohol-containing beverages, while beer and wine only contribute 10.2% and 1.9%, respectively, to the overall alcohol intake [2]. In contrast, in the European Region, hard spirits only make up for 27.2% of the consumed ethanol while wine and beer contribute to 29.8% and 40.0%, respectively, of the consumed ethanol [2] (see also Figure 1). There are also considerable differences found in the consumption pattern within the different regions. For instance, while in France and Italy, ~60% of the consumed alcoholic drinks are consumed as wine and herein especially red wine, in Germany, Austria, and the Czech Republic, wine only accounts for ~30% of the ingested alcoholic drinks. In these countries, epidemiological data suggests that beer intake contributes to ~54% of the ingested alcohol [2].

ALD comprise a wide spectrum of diseases ranging from simple steatosis (fatty liver) to alcoholic hepatitis (AH), alcoholic liver fibrosis (ALF), and cirrhosis as well as in some cases, even hepatocellular carcinoma (HCC, for overview see [6] and see Figure 2). However, results of epidemiological studies suggest that only about 25–35% of chronic heavy drinkers develop severe forms such as AH or cirrhosis [11]. Thus, ALD can be classified as asymptomatic or early ALD [fatty liver and alcoholic steatohepatitis (ASH)] or advanced ALD (defined as AH, cirrhosis, and its complications such as ascites, portal hypertension-related bleeding, hepatic encephalopathy, sepsis, multi-organ dysfunction, and HCC) [5, 12].

The alcohol-attributable burden of disease is usually assessed under the assumption that the type of alcoholic drink consumed does not matter. Risk relations so far are mostly based on doses of raw ethanol consumed and patterns of use rather than in terms of the type of alcoholic drink ingested (for overview also see [31, 32]). And while many epidemiological studies suggest that alcohol intake affects disease development in a dose-response manner following a J-shaped curve [33, 34], results of some epidemiological studies assessing the effects of alcohol on the development of ALD also suggest that herein the type of alcoholic beverage consumed e.g., whether a person is a wine, beer, or spirits drinker or maybe a “mixed consumer” might be important, too. For instance, in the study of Mitchell et al. [35], enrolling subjects with a mean daily alcohol intake of 20 g over the last 18 years, it was reported that exclusive wine drinkers especially when consuming wine in a non-binge pattern, had lower mean fibrosis stages and lower odds of advanced fibrosis [odds ratio (OR) 0.20, 95% confidence interval (CI) 0.06–0.60, P = 0.01] when compared to lifetime abstainers. Interestingly, in this study, similar effects were not found for beer drinkers, further suggesting that not only the absolute amount of alcohol ingested but also the type of beverage consumed (e.g., wine, beer, or spirits) may impact the effect of alcohol consumption on the liver. However, when interpreting the data of the study of Mitchell et al. [35], one has to consider, that alcohol doses consumed were rather moderate than high. Still, somewhat in line with these findings, a study conducted on 219,279 Norwegian men also reported that wine consumption was associated with a reduction of the hazard ratio (HR; HR 0.68, 95% CI 0.46–1.00) for liver-related mortality [36]. Similar effects were not reported for the consumption of hard spirits and beer, respectively; however, again average alcohol intake was rather moderate than high. Indeed, wine drinkers consumed 1.07 units/day while spirit and beer drinkers consumed 1.25 units/day and 1.17 units/day, respectively, and intake differed between wine, beer, and spirit drinkers (here: 1 unit = ~17 g ethanol). Results of the Danish Cancer, Diet, and Health study (1993–2011) also suggest that men whose alcohol consumption mainly consisted of wine had a lower HR than men who drank no or little alcohol as wine [37]. Indeed, in this study, it was shown that in men who drank 14–28 drinks/week, the HR compared to those drinking little, some, and mostly wine, respectively, was 7.47 (95% CI: 1.68; 33.12), 3.12 (95% CI: 1.53; 6.39), and 1.69 (95% CI: 0.79; 3.65) [37]. Others, studying 43,242 Swedish men, also reported a trend toward a reduced risk for severe liver disease in men consuming > 50% of alcohol as wine (HR 0.79, 95% CI 0.48–0.102, P = 0.06); however, the trend was no longer found when a multivariable model was applied [38]. In the study of Stokkeland et al. [39], it was reported that women with alcoholic liver cirrhosis have consumed 14,010 drinks during their lifetime compared to 27,440 drinks in women with alcohol dependence without liver cirrhosis. Interestingly, in the same study, women with alcohol dependence without alcohol cirrhosis were reported to have consumed 11,350 glasses of beer while those with alcohol cirrhosis had only drunk 1,611 glasses of beer. Similar differences in drinking patterns were not found in men or in wine and spirits [39]. Ye et al. [40] in 2011 also reported differences regarding beverage-specific effects on cirrhosis mortality rates in the US. In earlier studies of Kerr et al. [41], they performed a pooled cross-sectional time series analysis of per capita total alcohol, beer, wine, and spirits consumption and all-cause cirrhosis mortality with data from Australia, Canada, New Zealand, the United Kingdom, and the United States, and found an association of cirrhosis mortality with spirit consumption rather than with beer or wine intake. Indeed, in this study, it was reported that a 1 L increase in spirits consumption is associated with a 35.2% increase in cirrhosis mortality rate. Results of a recent prospective cohort study of UK Biobank participants excluding abstainers and individuals with previous cancers, liver cirrhosis, and stroke as well as myocardial infarcts suggested that spirit drinking as well as beer and cider drinkers were at higher risk of liver cirrhosis (spirits: HR 1.48; 95% CI 1.08–2.03; beer/cider: 1.36; 95% CI 1.06–1.74) compared to red wine drinkers after adjusting for the average weekly alcohol consumption [42]. Interestingly, while lowering the relative risk (RR) of all-cause mortality, consuming alcohol with food, it did not have an association with the risk of liver cirrhosis. In this study, it was also shown, that daily alcohol intake was associated with a higher liver cirrhosis risk with no further distinguishment regarding type of alcoholic drink [42]. Results of a recently published analysis focusing on the Mediterranean diet and fatty liver risk in overweight older Italians revealed that individuals with a fatty liver index > 60 had a higher intake of wine [43] and consumed alcohol at a higher percentage over an extended period of time. These data further suggest that wine consumption and herein especially at higher levels may also confer adverse effects on the liver. In the prospective UK Million Women Study, no differences between the type of alcoholic beverage consumed e.g., wine vs. all other alcoholic beverages with respect to the incidence of liver cirrhosis was found. However, the number of women who only consumed beer without spirits intake was low and the intake of the latter was often afflicted with confounders like smoking or living in a deprived area [44]. Interestingly, in this study, women who usually consumed their alcoholic drinks with a meal had a lower RR (RR 0.69, 95% CI 0.62–0.77; P < 0.0001) for cirrhosis than those who consumed alcohol without a meal despite comparable total alcohol intake between both strata [44]. Differences between the latter study and the others discussed above might have resulted from gender-specific differences. Indeed, in most other studies, no or only a limited number of women were enrolled often prohibiting a valid assessment of the impact of different alcoholic beverages on the development of ALD in women. Taken together, further studies are needed to settle the question if consumption of non-distilled alcoholic drinks like beer and wine and distilled alcoholic beverages like vodka, whiskey, and schnapps impacts the liver differently. For overview of average alcohol consumption in studies discussed in this chapter see Table 1. Also, it has to be kept in mind that regardless of the outcome of these studies, the main ingredient in the alcohol-attributable burden is ethanol. Indeed, while some compounds found in non-distilled alcoholic beverages may even bear some beneficial effects on the liver (e.g., xanthohumol and iso-α-acids derived from hops and found in beer, or resveratrol found in red wine, see below), other organs may not benefit from these compounds.

As summarized above, even when consumed chronically at elevated amounts, non-distilled alcoholic beverages, and herein especially red wine, seem to bear less harm to the liver than the consumption of spirits. Next to other well-studied factors involved in the development and progression of ALD e.g., changes in lipid metabolism and the production of ROS resulting from the metabolization of ethanol as well as a hepatic overload of iron (for overview see [45]), several possible mechanisms are discussed that may add to this ‘less’ harmful effect of non-distilled alcoholic beverages on the liver. For instance, it has been shown that moderate wine drinkers appear to be at lower risk to become heavy drinkers [46, 47], which may add to the explanation of some of the reported beverage-specific morbidity and mortality findings. Furthermore, both wine and beer are not only composed of ethanol but due to their production process contain also marked amounts of secondary plant compounds like polyphenols and side products produced during fermentation (for overview see Tables 2 and 3, and [48–51]). However, it needs to be kept in mind when interpreting data from epidemiological and experimental studies that not only ripeness and quality as well as the growing region of barely and hop but also grapes used for beer and wine production, respectively, may influence considerably the contents of secondary plant compounds in the end product but also that the production process may vary considerable between breweries and wineries in different regions of the world. In the following, results of some experimental studies focusing on effects of wine and beer in the context of the development of ALD are summarized. Also, some possible molecules and molecular mechanisms underlying the less damaging effects of these non-distilled alcoholic beverages are highlighted (findings also summarized in Figure 5).

While the study of the effect of alcohol intake on the development of liver diseases and associated molecular mechanisms has been the focus of many experimental, clinical, and epidemiological studies, reliable and unbiased data assessing the effect of different alcoholic drinks e.g., non-distilled vs. distilled alcoholic beverages are still limited. Indeed, some older and some more recent studies suggest that the intake of non-distilled alcoholic beverages and herein especially the intake of red wine may affect the liver differently than the consumption of hard spirits. However, studies also suggest that drinking pattern, gender, and whether or not the alcoholic drink is consumed with or without a meal may affect the effects of the alcohol drink of the liver. The impact of the different factors but also the compounds involved in the different effects of non-distilled alcoholic beverages vs. distilled alcoholic drinks on the liver have not yet been clarified. Accordingly, there is a need for studies with large and clinically well-characterized patients as well as validated assessment tools of alcohol intake to address the above-mentioned research questions. Along with these human studies, further experimental studies using doses of compounds found in alcoholic beverages achievable with a “normal” alcohol intake in humans are warranted to determine molecular mechanism underlying the different effects of alcoholic beverages on the liver but maybe also other organs. Still, even when results of cell cultures and rodents studies as well as some epidemiological studies suggest that effects of non-distilled and distilled alcoholic beverages may markedly differ with respect to liver health, it needs to be kept in mind that in other organs and the central nervous system these differences may not be prevalent, and that effects of ethanol regarding dependence and mental alteration may not be affected by the compounds found to be beneficial for the liver.