Reply to: “Protective effects of moderate alcohol consumption on fatty liver: A spurious association?”
Authors: Akio Moriya, Yoshiaki Iwasaki, Souhei Ohguchi, Kazuhide Yamamoto
Journal: Journal of Hepatology (2015)

Roles of alcohol consumption in fatty liver: A longitudinal studyJournal of HepatologyVol. 62Issue 4PreviewNon-alcoholic fatty liver disease (NAFLD) is the most common liver disease not only in the Western world [1,2] but also in Asia [3,4]. NAFLD is strongly associated with obesity and other metabolic syndrome-related conditions [2,3] and can progress to the severe form of NAFLD, i.e., non-alcoholic steatohepatitis, resulting in the development of liver cirrhosis, liver failure, and hepatocellular carcinoma [5–7]. A recent report indicated that insulin resistance and weight gain are predictors of NAFLD incidence, whereas weight reduction is a predictor of NAFLD remission [8]. Full-Text PDF Protective effects of moderate alcohol consumption on fatty liver: A spurious association?Journal of HepatologyVol. 62Issue 5PreviewWe read with interest Moriya and colleagues’ [1] paper on the longitudinal role of alcohol intake in relation to fatty liver. We were somewhat surprised by their findings and overall conclusion that light-to-moderate and even higher alcohol intake protects against developing fatty liver over time. They point out that several other studies also allege that moderate consumption is associated with a lower risk of non-alcoholic fatty liver disease (NAFLD) but acknowledge in their introduction that the apparent protective effects may be spurious associations induced by confounding factors. Full-Text PDF Open Access We would like to thank Bell et al. for their comments regarding our recently published article [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, Taniguchi H, et al. Roles of alcohol consumption in fatty liver: A longitudinal study. J Hepatol 2015;62:921–927.Google Scholar]. They suggested some possible concerns to be considered carefully. Concerning the possibility that non-drinkers may not always be lifetime abstainers, it was difficult to separate former drinkers from lifetime abstainers based on the questionnaire used in the study. We recognized this limitation and pointed it out in our previous study [[2]Moriya A. Iwasaki Y. Ohguchi S. Kayashima E. Mitsumune T. Taniguchi H. et al.Alcohol consumption appears to protect against non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2011; 33: 378-388Crossref PubMed Scopus (85) Google Scholar], although we were unable to do so in our recent article due to limited space. It is likely that drinkers are advised to stop drinking because of fatty liver. Actually, 4% of men and 15% of women drinking at baseline abstained by the end of the follow-up. However, we have data regarding the changes in drinking habits during the observation period; the longitudinal analysis with the generalized estimating equation can partly take the changes in the drinking status into account. Bell et al. also suggested that lifetime abstainers might have had poor health status. Although we cannot rule out the possibility that such bias may distort the results, the participants of our study were generally healthy enough to work and we suppose that the number of those who had health problems earlier in their life-course, if any, was small enough not to affect the statistical analyses. We cited some articles that suggest the possible mechanisms of the inverse association between alcohol consumption and fatty liver [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, Taniguchi H, et al. Roles of alcohol consumption in fatty liver: A longitudinal study. J Hepatol 2015;62:921–927.Google Scholar]. Bell et al. also expressed concerns regarding them. Observational studies may have similar limitations; however, we also cited an experimental study in mice [[3]You M. Considine R.V. Leone T.C. Kelly D.P. Crabb D.W. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice.Hepatology. 2005; 42: 568-577Crossref PubMed Scopus (226) Google Scholar], which is supposed to be free from those limitations. We cited some more such articles in our previous study [[2]Moriya A. Iwasaki Y. Ohguchi S. Kayashima E. Mitsumune T. Taniguchi H. et al.Alcohol consumption appears to protect against non-alcoholic fatty liver disease.Aliment Pharmacol Ther. 2011; 33: 378-388Crossref PubMed Scopus (85) Google Scholar], although due to limited space we were unable to cite all of these in our current article. Additionally, Bell et al. mentioned the causal relationship between alcohol consumption and obesity. However, this association was not observed in our cohort and rather the reverse was noted; for example, in men, the body mass index values were significantly lower in the drinkers than in the current non-drinkers (23.4 ± 2.9 kg/m2 vs. 23.8 ± 3.2 kg/m2, p <0.001) and the prevalence of obesity was lower in the drinkers than in the current non-drinkers (26.4% vs. 32.5%, p <0.001). Therefore, there appears to be no rationale concerning overadjustment bias in our study. However, we re-calculated the odds ratio for fatty liver in each category of the average weekly alcohol consumption in men without adjusting for obesity and found similar results to those obtained after adjusting for obesity, suggesting that there was almost no impact of taking obesity into consideration on the results in our cohort (Fig. 1A). We thank Bell et al. for presenting their data of the Whitehall II prospective cohort study demonstrating an association between a higher alcohol intake and greater odds of fatty liver using the fatty liver index (FLI) [[4]Bedogni G. Bellentani S. Miglioli L. Masutti F. Passalacqua M. Castiglione A. et al.The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol. 2006; 6: 33Crossref PubMed Scopus (1496) Google Scholar]. To compare their results with ours, we again re-calculated the odds ratio for fatty liver in a similar manner to the analysis by Bell et al.; that is, we analyzed with drinking 0.1–69.9 g/week as reference and adjusted for age, smoking status, and regular exercise. As shown in Fig. 1B, the non-drinker category had a higher risk for fatty liver than drinking 0.1–69.9 g/week. Since the non-drinker group was a mixture of former drinkers and lifetime abstainers, it is difficult to discuss further concerning this relationship. On the other hand, higher levels of alcohol intake were not associated with greater odds of fatty liver in our cohort; it was different from the results by Bell et al. We are not sure whether the discrepancy is due to the difference in ethnicity or in the modality to assess fatty liver. Ultrasonography is more reliable than FLI in assessing fatty liver, since FLI was developed to predict the presence of fatty liver diagnosed on ultrasonography [[4]Bedogni G. Bellentani S. Miglioli L. Masutti F. Passalacqua M. Castiglione A. et al.The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol. 2006; 6: 33Crossref PubMed Scopus (1496) Google Scholar]. Further studies in different ethnicities with ultrasonographic assessment would be warranted. Finally, we have not stated the safety of alcohol consumption for all individuals nor encouraged alcohol consumption. In our paper, we simply described the evidence obtained from a longitudinal analysis showing that alcohol consumption is inversely associated with fatty liver in a major part of the general population. However, it is hard to claim a causal relationship between alcohol consumption and fatty liver, since our study was observational and not interventional. Moreover, although we hypothesize that alcohol may have a somewhat protective effect against fatty liver within a certain threshold and that this threshold may differ in each person, at present, we cannot specify what distinguishes individuals who develop fatty liver as a result of alcohol consumption from those who do not. The authors declare that they have no conflicts to disclose regarding funding or other conflicts of interest with respect to this manuscript.