Alcohol and Liver Disease

Alcohol and Liver Disease

Critique 269 – Global prevalence, incidence, and outcomes of alcohol related liver diseases: a systematic review and meta‑analysis – September 2023

In general terms, the risk of alcohol-related liver disease (ARLD) increases with how much you drink and how often you drink. Liver disease can take the form of fatty liver disease, alcoholic hepatitis and alcoholic cirrhosis.

A definitive threshold below which alcohol intake will not cause liver disease has not been established, but levels of around 20-30 g/day for men and 10-15 g/day for women are unlikely to cause ARLD in most individuals. As both quantity and frequency of influences the risk of ARLD, regular heavy drinkers and alcohol dependent drinkers are at risk of and die from ARLD at a much higher rate than the general population.

This extensive systematic review and meta‑analysis summarises the usually small-scale studies on ARLD to describe the ARLD population (Niu et al., 2023). Accordingly, it provides insight in the global prevalence of ARLD which is currently estimated at 4.8%, and the role of factors influencing the disease such as gender, ethnicity, tobacco smoking, obesity, and chronic viral hepatitis C. The relationship between ARLD prevalence or incidence and alcohol consumption data in a specific country were, however, not investigated.

For the detailed critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

Critique 245:  Effects of different patterns of alcohol consumption on risk of mortality, major cardiovascular events, cirrhosis, and cancer —  25 January 2021

This study was designed to determine factors that affect the pattern of alcohol consumption (including the frequency of consumption, type of beverage, with or without food, etc.), rather than just the reported average amount of alcohol, related to all-cause mortality, major cardiovascular events-MACE (MI/stroke/cardiovascular death), accidents/injuries, liver cirrhosis, all-cause and alcohol-related cancer incidence.  It was based on a large prospective cohort study of UK Biobank (UKB) participants and included more than 300,000 subjects; outcomes were ascertained over a 9-year median follow-up period.  Non-drinkers and only occasional drinkers were excluded from the analyses, so this paper does not judge the effects of light or moderate drinking versus not drinking, but only the effects of the pattern of reported alcohol consumption among regular drinkers.

The study showed that in comparison with subjects who consumed red wine more than 50% of the time (the reference group) there were lower risks of many adverse outcomes than among consumers of more than 50% of the time of spirits; the latter had 25% greater risk of all-cause mortality, 31% greater risk of MACE, and 48% higher risk of liver cirrhosis after controlling for total weekly alcohol consumption and relevant confounders.  In comparison with red-wine drinkers, consumers of beer/cider showed an 18% higher risk for all-cause mortality, 16% higher risk of MACE, and 36% higher risk of liver cirrhosis.   There were no statistically significant differences in outcomes between white wine drinkers and red wine drinkers.

Consumption of alcohol with food, versus not with food, showed a 10% (CI 2%-17%) lower risk of all-cause mortality.  While consumers reporting alcohol consumption 3-4 days/week had lower risk of some adverse outcomes than subjects reporting intake on only 1-2 days/week, for some reasons subjects reporting daily or near-daily intake had an increased risk of liver cirrhosis, probably related to under-reporting by some heavy drinkers.

Forum members agree with the conclusions of this study as reported in the Authors’ Abstract: “Red wine drinking, consumption with food and spreading alcohol intake over 3–4 days were associated with lower risk of mortality and vascular events among regular alcohol drinkers, after adjusting for the effects of average amount consumed.”  The results of this well-done study emphasize how inappropriate it is to use just the total average alcohol intake when relating the consumption of alcoholic beverages to the risk of adverse health outcomes.

Reference:  Jani BD, McQueenie R, Nicholl BI, Field R, Hanlon P, Gallacher KI, Mair FS, Lewsey J.  Association between patterns of alcohol consumption (beverage type, frequency and consumption with food) and risk of adverse health outcomes: a prospective cohort study.  BMC Medicine 2021;19:8.  https://doi.org/10.1186/s12916-020-01878-2.

For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

Critique 156: The pattern of alcohol consumption and risk of cirrhosis  —  10 February 2015 

This paper, from a group of experienced investigators in Denmark using data from a large population-based cohort, attempted to judge how drinking pattern affects the risk of a subject developing alcoholic cirrhosis.  From a cohort study of 55,917 participants (aged 50–64 years), the authors calculated hazard ratios (HRs) for alcoholic cirrhosis in relation to drinking frequency, lifetime alcohol amount, and beverage type.  A total of 342 subjects developed alcoholic cirrhosis.  The authors concluded that, in men, daily drinking was associated with an increased risk of alcoholic cirrhosis as compared with less frequent consumption; they also concluded that wine consumption might be associated with a lower risk of alcoholic cirrhosis that associated with the consumption of beer or liquor.

The major concern of Forum reviewers regarding this paper was the use of a diagnosis of “alcoholic cirrhosis” to judge the effects of alcohol on the disease; this was considered a type of circular reasoning.  A diagnosis of alcoholic cirrhosis generally requires a history of alcoholism or heavy drinking, and subjects given that diagnosis would essentially be limited to those who were heavy drinkers.  Thus, it would be no surprise to find a history of heavy drinking when evaluating alcohol as an exposure.

There was also concern about the implications of the author regarding frequency of drinking.  The authors’ described in detail the relation of drinking pattern to liver cirrhosis, differentiating, in particular, effects associated with drinking daily versus drinking on 4-5, or 6 days a week.  However, Forum members were concerned that as the overall average amount of alcohol for the daily drinkers exceeded that of those drinking less frequently, it was difficult to know if it was primarily the frequency of drinking (as concluded by the authors) or the total amount of alcohol consumed by subjects. The authors stated that they wanted to “execute evidence-based counselling,” which of course is praiseworthy, but Forum members had difficulty understanding why the effect of drinking 5-6 days/week should differ much from 7 days/week, especially if the usual amount was moderate.  Indeed, the investigators state: “The mean alcohol amounts for daily drinkers were somewhat higher compared to those drinking less frequently in each category of alcohol amount, making it difficult to detangle the effect of drinking frequency and alcohol amount.”  Forum members noted that the authors conclude that “daily drinking” was associated with increased cirrhosis, but they do not state daily drinking of how many drinks, which would be especially important. The study did not provide reliable data that would support alcohol-free days during the week.

The referent group in this study was made up of subjects reporting < 0 to 14 drinks/week, which would consist of light-to-moderate drinkers, those considered to be “sensible drinkers” in most cultures.  Hence, it is no surprise that as subjects reported greater amounts of alcohol in the study, the risk of alcoholic cirrhosis increased.  No one advises people to drink more than sensible limits. Further, there was a much higher risk of of cirrhosis among “current abstainers” than in the referent group, undoubtedly indicating that the current abstainers group included many former heavy drinkers.

Overall, the Forum thought that this paper raises, but does not answer, a number of questions about the relation of alcohol to the risk of cirrhosis: (1) Is wine really less liver-toxic than beer or liquor?  (2) Should we really tell everyone to have one day each week without wine being included with their meal, or on which to avoid any alcohol?  (3)  Why is daily drinking, rather than 5 or 6 days per week dangerous for men but tends to be even slightly protective in women regarding liver disease?  Because of concerns due to problems with bias from the diagnostic approach, the probability of under-reporting of alcohol consumption, and the lack of biological plausibility, we will need further scientific data to answer these important questions.

Reference:  Askgaard G, Grønbæk M, Kjær MS, Tjønneland A, Tolstrup JS.  Alcohol drinking pattern and risk of alcoholic liver cirrhosis:  A prospective cohort study. Pre-publication.  J Hepatol (2015)   http://dx.doi.org/10.1016/j.jhep.2014.12.005.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 148:  Alcohol and liver cancer  —  24 September 2014

Hepatic cirrhosis frequently precedes the development of liver cancer, and excessive alcohol consumption is known to be one cause of cirrhosis.  The investigators in the present study carried out a meta-analysis to evaluate the association of alcohol consumption with liver cancer.  They used data from 19 prospectively studied cohorts with a large total number of cases: 4,445 incident cases and 5,550 deaths from liver cancer.

The analysis from this large study indicates that liver cancer is related to heavier alcohol intake, but not to light-to-moderate drinking (with the latter defined in this study as < 3 typical drinks per day).  The authors conclude: “This systematic review suggests a moderate detrimental role of consumption of 3 or more alcoholic drinks per day on liver cancer, and a lack of association with moderate drinking.”

Forum reviewers considered this to be a well-done analysis with appropriate statistical methodology.  While the authors were unable to test the potential effects of pattern of drinking (regular moderate versus binge drinking), the type of beverage (wine or other beverages), or potential effects of obesity (with the latter being a key factor associated with the most common type of liver disease in the US, non-alcoholic fatty liver disease), the results of this study support most other research indicating that more than moderate drinking increases the risk of cirrhosis and liver cancer.  However, the findings of no effect from what the authors considered “moderate” drinking (< 3 drinks/day, which exceeds the guidelines for most countries), also fits with another recent meta-analysis showing no increase in risk of liver cancer to be associated with light drinking.

There are many adverse health effects of heavy alcohol consumption.  Liver cirrhosis, which frequently precedes the development of liver cancer, is one such potential outcome.  On the other hand, this study suggests that moderate alcohol intake does not increase the risk of liver cancer.

Reference:  F. Turati, C. Galeone, M. Rota, C. Pelucchi, E. Negri, V. Bagnardi, G. Corrao, P. Boffetta, C. La Vecchia.  Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. Annals of Oncology 2014; advance publication; doi:10.1093/annonc/mdu020

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 080:  Modest alcohol intake is associated with less inflammation among patients with the most common type of liver disease, non-alcoholic fatty liver disease (NAFLD)   — 15 May 2012

NAFLD (non-alcoholic fatty liver disease) is the most common type of liver disease in the developed world, affecting up to one-third of the US population.  NAFLD is often associated with obesity and other parameters of the so-called “metabolic syndrome,” which is a major risk factor for the development of cardiovascular disease.  In a well-done study among subjects with NAFLD, the investigators have demonstrated that modest alcohol consumption (an average of up to 20 grams of alcohol per day and no binge drinking) is associated with less evidence of inflammation of the liver (steatohepatitis), a condition known to markedly increase the risk of progression of liver disease to cirrhosis.

Given that NAFLD and other conditions associated with the metabolic syndrome are so common, and are major risk factors for developing cardiovascular disease, the results of the present study are important.  They show that modest drinking is associated with decreased, not increased, inflammation of the liver.  Further, even among subjects with NAFLD, cardiovascular disease is a much more common cause of death than liver disease.  The authors suggest that intervention studies should be done to support their findings; if confirmed, subjects with NAFLD should not be advised to avoid all alcohol, which is the current advice usually given to such patients.

Reference:  Dunn W, Sanyal AJ, Brunt EM, Unalp-Arida A, Donohue M, McCullough AJ, Schwimmer JB.  Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD).  Journal of Hepatology 2012 (pre-publication release)

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 063: Genes modify the risk of liver disease among alcoholics  — 5 December 2011

It has been widely observed that only a small percentage of alcoholics develop cirrhosis of the liver, the most advanced form of alcoholic liver disease (ALD); the reason why all alcoholics do not develop such disease is not known.  The present study from Spain, that includes original work and a meta-analysis, evaluates whether genetic polymorphisms that determine levels of glutathione-S-transferases (GST) relate to the risk of developing ALD among alcoholics.  Alcoholics with certain genetic GST polymorphisms were found to be at significant excess risk for such liver disease in comparison with alcoholics without these polymorphisms.

As stated by the authors, the theory that these enzymes may affect risk is based on the ability of certain GST alleles to detoxify harmful ethanol metabolites in the liver by conjugating acetaldehyde and ROS to reduced glutathione.  The specific polymorphisms that they found to be associated with increased liver disease are among those that would be expected to lower the activity of the corresponding GST enzymes; this would permit higher levels of toxic metabolites of alcohol and oxidative stress to be present for longer periods of time after excessive alcohol consumption.

Some Forum reviewers thought that while the study was well done, the authors were unclear as to how these data could directly lead to “potential therapeutic targets” for liver disease in alcoholics.  Nevertheless, the original study and meta-analysis provide important data on how specific genetic factors relate to the development of liver disease among alcoholics and could theoretically lead to better strategies for the prevention and treatment of alcoholic liver disease. 

Reference:  Marcos M, Pastor I, Chamorro A-J, Ciria-Abad S, González-Sarmiento R, Laso F-J.  Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease.  Aliment Pharmacol Ther 2011;34:1159–1172.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 043:  Frequent moderate drinking of alcohol is associated with a lower risk of fatty liver disease – 23 May 2011

In a large study of men in Japan, the presence of fatty liver disease by ultrasonography showed an inverse association with the frequency of alcohol consumption; there was some suggestion of an increase in fatty liver disease with higher volume of alcohol consumed per day.  Moderate drinkers had lower levels of obesity than did non-drinkers, and both obesity and metabolic abnormalities were positively associated with fatty liver disease.

These findings support the results of a number of other recent studies showing that moderate drinking does not increase the risk of this common type of liver disease; instead, it is associated with a lower risk of its occurrence.  We agree with the implications of these studies as stated by the authors: “These results suggest that lifestyle modifications aimed at fighting central obesity and metabolic abnormalities should be the most important recommendations for the management of fatty liver.  In addition, it seems unlikely that the risk of fatty liver can be reduced by the discontinuation and/or reduction of alcohol consumption alone.”

Reference:  Hiramine Y, Imamura Y, Uto H, Koriyama C, Horiuchi M, Oketani M, Hosoyamada K, Kusano K, Ido A, Tsubouchi H.  Alcohol drinking patterns and the risk of fatty liver in Japanese men.  J Gastroenterol 2011 46:519–528.  DOI 10.1007/s00535-010-0336-z.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 028.  Changes over time in relation of social class to mortality from cirrhosis. 9 January 2011

Reference:  Crombie IK, Precious E.  Changes in the social class gradient of cirrhosis mortality in England and Wales across the 20th century.  Alcohol and Alcoholism 2011;46:80–82.

To explore the nature of the social class gradient of cirrhosis mortality in England and Wales across the 20^th century, data on male cirrhosis mortality by social class were obtained from the Registrar General’s Decennial Supplements for the years 1921–1991. This paper describes a dramatic change during the 20th century in the association between social class and mortality from liver cirrhosis.  While deaths from cirrhosis were more common among higher social classes in the early part of the century, the pattern changed so that deaths from cirrhosis were much more common among the lower social classes by the end of the century.

Suggested reasons for the lower current rates among subjects at higher social class include different patterns of alcohol consumption, with regular moderate consumption (especially of wine with meals) becoming more common with higher social class subjects while binge drinking (especially of beer and spirits) remaining more common in lower social classes.  However, a number of other factors may relate to the class differences in rates of hepatic cirrhosis, including a less healthy diet and greater rates of obesity (associated with hepatic fatty liver and cirrhosis) among lower social class subjects and social class differences in hepatitis rates.  Further, certain medications, coffee consumption, and many other lifestyle factors are associated with hepatic cirrhosis.  The actual reasons for the changes over time reported in this paper remain unclear.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 013. Greater than moderate alcohol intake increases the risk of liver cirrhosis.

27 July 2010

Reference:  Rehm J, Taylor B, Patra SM, Irving H, Baliunas D, Patra J, Roerecke M.  Alcohol as a risk factor for liver cirrhosis: A systematic review and meta-analysis.  Drug and Alcohol Review 2010,29,437–445.  DOI: 10.1111/j.1465-3362.2009.00153.x.

A new meta-analysis shows that alcohol consumption is a strong factor in the development of cirrhosis of the liver.  The study also supports the theory that there is a threshold of drinking above which the risk is increased, as some of their analyses suggest that the risk increases only with intake of more than 24 grams/day of alcohol for women (about 2 typical drinks by US standards) and 36 grams/day of alcohol for men (about 3 typical US drinks).

Despite some concerns about the approach used, our Forum agrees that the present meta-analysis supports previous studies indicating a strong role of heavy alcohol drinking in the development of cirrhosis.  The differences found by the investigators between the effects of moderate alcohol intake on cirrhosis morbidity and on cirrhosis mortality are difficult to explain, but may relate to misclassification of alcohol intake (heavy drinkers reporting less alcohol), always a problem in observational studies of the effects of alcohol.

The results related to morbidity suggest that small amounts of alcohol are not associated with an increased risk of cirrhosis, and may be associated with lower risk of disease.  Thus, the data provide evidence for a “threshold effect” of alcohol intake for the development of cirrhosis.  Limited previous data are available suggesting that wine consumption may be associated with lower risk of cirrhosis than the intake of other beverages, but essentially all studies show heavy drinking of any type of beverage increases the risk.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.