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

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)

Authors’ Abstract

Background & Aims:  Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor.  Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue.  We aimed to evaluate the association between modest alcohol drinking and non-alcoholic steatohepatitis (NASH), among subjects with NAFLD.

Methods: In a cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non-drinkers were included: participants identified as (1) drinking >20 g/day, (2) binge drinkers, or (3) non-drinkers with previous alcohol consumption were excluded.  The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression.

Results: The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to non-drinkers had lower odds of having a diagnosis of NASH (summary odds ratio 0.56, 95% CI 0.39–0.84, p = 0.002).  The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption.  Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95% CI 0.41–0.77) and ballooning hepatocellular injury (OR 0.66, 95% CI 0.48–0.92) than lifetime non-drinkers.

Conclusions:  In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis.  These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD.

Forum Comments

Background:  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.1,2  NAFLD is often associated with obesity and other parameters of the so-called “metabolic syndrome,” and is a major risk factor for the development of cardiovascular disease.  Unfortunately, due to a marked increase in obesity among the young, NAFLD is also the major cause of hepatic dysfunction in children.3   Previous research has suggested that moderate alcohol intake may not be harmful in patients with NAFLD; in fact, moderate drinking may actually reduce the risk of steatohepatitis, an inflammatory reaction within the liver that increases the risk that NAFLD will progress to the much more serious fibrotic liver disease, cirrhosis.4,5  Szabo has shown in animals that whereas heavy chronic intake increases inflammation in liver cells, light drinking has been shown to acutely reduce inflammation.6

The present study was not a testing of all of the associations of alcohol consumption with liver disease — heavy alcohol intake is well known to be a major factor in the development of cirrhosis — as subjects reporting an average of more than 20 grams of alcohol per day (about 1 ½ to 2 typical drinks) and binge drinkers were excluded.  The investigators focused, instead, on what they define as “modest” intake, versus no alcohol intake, among subjects with biopsy-proven NAFLD.  Given that NAFLD is a risk factor for cardiovascular disease, the leading cause of death throughout the developed world, and that moderate alcohol intake significantly lowers the risk of such disease, it is important to determine whether or not people with NAFLD should be advised to avoid all alcohol (as is currently the usual advice), or to be reassured that moderate intake is not harmful to their underlying liver disease.

Specific comments on the paper:  Previous papers relating alcohol intake to NAFLD have shown a reduced risk of steatohepatitis.  While an earlier study by Dunn et al5 was based on abnormal hepatic enzymes, in the present study the diagnosis of NAFLD was confirmed by liver biopsy.  The outcome of interest was demonstrated by the presence of steatosis and ballooning hepatocellular injury with a zone 3 predominance as well as lobular inflammation.  The results of this paper support the earlier findings: almost 50% less inflammatory disease among modest drinkers in comparison with lifetime abstainers.  

The present study did not find an interaction between alcohol and disease according to PNPLA3 genotypes.  However, as pointed out by a Forum reviewer, there are undoubtedly many genetic factors that affect the relation.  “For example, the HFE gene mutation status (C282Y, H63D) appears to modify alcohol’s effects and could be important.  Molecular medicine is beginning to bring predictive medicine into the clinical domain, and may explain previously unknown mechanisms.  Further, the present study did not comment on the diet of subjects, which may also modify the effects of alcohol.”  Another reviewer pointed out that “It is unfortunate that the authors did not describe the type of alcohol consumed., as polyphenols may be implicated in the regulation of inflammation and other reactive oxygen species.”

Another Forum reviewer commented: “BMI and alcohol consumption are both related to liver disease, and Hart et al found evidence of a supra-additive interaction between BMI and alcohol intake of >15 units per week.7  There seems to be a safe window for drinking 1-2 drinks per day for the large number of people with NAFLD, with evidence indicating benefits to their liver as well as to their risk of diabetes and heart disease. Randomized prospective studies are needed.”  Added another reviewer: “In this paper we have another piece of evidence that, while not conclusive, indicates that alcohol is not all bad, not even for the liver.  This supports considerable data from experiments in mice and rats, and from other human studies, showing that small amounts of alcohol may actually benefit the liver.”

Drinking guidelines for subjects with NAFLD:  It should be pointed out that the present study did not deal with outcomes among subjects drinking heavily, which is a known major risk factor for severe liver disease.  However, the results of this study support previous research suggesting that our current habit of advising the complete avoidance of any alcohol consumption for subjects with all types of liver disease may not be correct.  For the most common type of liver disease, NAFLD, data now indicate beneficial, rather than adverse, effects of moderate drinking.  This information may be especially important for the population in most developed countries, in that subjects with NAFLD are more likely to die of cardiovascular disease than of liver disease, and moderate alcohol consumption markedly reduces the risk of the former.

A gastroenterologist in our Forum concluded: “We clinical hepatologists have gone by an old recommendation for total alcohol abstinence in patients with liver disease (except, perhaps, for minor conditions such as Gilbert syndrome or hepatic cyst).  New scientific evidence about moderate drinking, as in this paper, is welcome, and may break a taboo against even small amounts of alcohol in patients with NAFLD.

References from Forum review:

1.  Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al.  Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–1395.

2.  Lazo M, Clark JM.  The epidemiology of nonalcoholic fatty liver disease: A global perspective.  Semin Liver Dis 2008;28:339-350.

3.  Barshop NJ, Francis CS, Schwimmer JB, Lavine JE.  Nonalcoholic fatty liver disease as a comorbidity of childhood obesity.  Ped Health 2009;3:271-281.

4.  Dixon JB, Bhathal PS, O’Brien PE.  Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese.  Gastroenterology 2001;121:91–100.

5.  Dunn W, Xu R, Schwimmer JB.  Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease.  Hepatology 2008;47:1947-1954.

6.  Szabo G. Moderate drinking, inflammation, and liver disease. Ann Epidemiol. 2007;17(Suppl):S49-S54. 

7.  Hart CL, Morrison DS, Batty GD, Mitchell RJ, Davey Smith G.  Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies.  BMJ 2010;340:c1240.

Forum Summary

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.

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Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:

Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona. Italy.

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark.

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA.

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway.

Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, Dept. of Cardiology, University of Arizona School of Medicine, Tucson, Arizona, USA

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA.

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia.

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK.

 David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa.