Protective effects of moderate alcohol consumption on fatty liver: A spurious association?
Authors: Steven Bell, Annie Britton
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 Reply to: "Protective effects of moderate alcohol consumption on fatty liver: A spurious association?"Journal of HepatologyVol. 62Issue 5PreviewWe would like to thank Bell et al. for their comments regarding our recently published article [1]. They suggested some possible concerns to be considered carefully. Full-Text PDF Open Access We read with interest Moriya and colleagues' [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015;62:921–927.Google Scholar] 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. However, their analysis is also prone to a number of biases that have been well documented in the field of alcohol epidemiology [2Fekjær H.O. Alcohol—a universal preventive agent? A critical analysis.Addiction. 2013; 108: 2051-2057https://doi.org/10.1111/add.12104Crossref PubMed Scopus (91) Google Scholar, 3Chikirzhs T. Fillmore K. Stockwell T. A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease.Drug Alcohol Rev. 2009; 28: 441-444https://doi.org/10.1111/j.1465-3362.2009.00052.xCrossref PubMed Scopus (65) Google Scholar]. Firstly, their choice of past week non-drinkers as a referent group is unsound. Past week non-drinkers include a mixture of lifelong abstainers, former drinkers (who may have quit for multiple reasons, including poor health) and infrequent drinkers. This misclassification error is known to negatively bias the health status of the aggregate group of non-drinkers and has been demonstrated to produce protective effects; studies that actively separate these distinctive non-drinking groups show none [[3]Chikirzhs T. Fillmore K. Stockwell T. A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease.Drug Alcohol Rev. 2009; 28: 441-444https://doi.org/10.1111/j.1465-3362.2009.00052.xCrossref PubMed Scopus (65) Google Scholar]. There is evidence that even if lifetime abstainers are separated from other non-drinkers they remain a poor choice of referent category for several reasons [3Chikirzhs T. Fillmore K. Stockwell T. A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease.Drug Alcohol Rev. 2009; 28: 441-444https://doi.org/10.1111/j.1465-3362.2009.00052.xCrossref PubMed Scopus (65) Google Scholar, 4Rehm J. Irving H. Ye Y. Kerr W.C. Bond J. et al.Are lifetime abstainers the best control group in alcohol epidemiology? On the stability and validity of reported lifetime abstention.Am J Epidemiol. 2008; 168: 866-871https://doi.org/10.1093/aje/kwn093Crossref PubMed Scopus (167) Google Scholar], including misclassification bias and that lifetime non-drinking may itself be indicative of poor health earlier in the life-course. Additionally, declines in consumption (including reductions to infrequent drinking) are more common amongst former heavy drinkers [[3]Chikirzhs T. Fillmore K. Stockwell T. A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease.Drug Alcohol Rev. 2009; 28: 441-444https://doi.org/10.1111/j.1465-3362.2009.00052.xCrossref PubMed Scopus (65) Google Scholar]. This is a potential source of bias, even in studies that are able to disentangle less than weekly drinkers from lifelong non-drinkers, leading to spurious beneficial effects of moderate intake being observed. Combined, these studies indicate that alleged protective effects of light-to-moderate alcohol intake should be treated with caution. Moriya and colleagues [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015;62:921–927.Google Scholar] provide many possible biological mechanisms for the protective effect they observe, ranging from insulin sensitivity to antioxidant agents. However, the association between alcohol intake and these posited mediators share the same limitations noted above with respect to combining current non-drinkers into a single aggregate group [[2]Fekjær H.O. Alcohol—a universal preventive agent? A critical analysis.Addiction. 2013; 108: 2051-2057https://doi.org/10.1111/add.12104Crossref PubMed Scopus (91) Google Scholar]. Additionally, large scale studies have shown that alcohol consumption is causally related to obesity [[5]Holmes M.V. Dale C.E. Zuccolo L. Silverwood R.J. Guo Y. et al.Association between alcohol and cardiovascular disease: mendelian randomisation analysis based on individual participant data.BMJ. 2014; 349 (Available: http://www.bmj.com/content/349/bmj.g4164)Crossref Scopus (474) Google Scholar] and that obesity is a risk factor for NAFLD [[6]Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231https://doi.org/10.1056/NEJMra011775Crossref PubMed Scopus (4204) Google Scholar]. Therefore adjustment for obesity is likely to have produced biased estimates. Adjusting for a variable on the causal pathway between alcohol intake and fatty liver is a form of over adjustment bias [[7]Schisterman E.F. Cole S.R. Platt R.W. Overadjustment bias and unnecessary adjustment in epidemiologic studies.Epidemiology. 2009; 20: 488-495https://doi.org/10.1097/EDE.0b013e3181a819a1Crossref PubMed Scopus (1238) Google Scholar] – unless controlled direct causal effects are the estimate of interest which in this case seems unlikely. This typically biases estimates towards the null. Applied in this case, one might imagine that those who consume larger amounts of alcohol are more likely to become obese [[5]Holmes M.V. Dale C.E. Zuccolo L. Silverwood R.J. Guo Y. et al.Association between alcohol and cardiovascular disease: mendelian randomisation analysis based on individual participant data.BMJ. 2014; 349 (Available: http://www.bmj.com/content/349/bmj.g4164)Crossref Scopus (474) Google Scholar] which in turn increases their odds of developing fatty liver [[6]Angulo P. Nonalcoholic fatty liver disease.N Engl J Med. 2002; 346: 1221-1231https://doi.org/10.1056/NEJMra011775Crossref PubMed Scopus (4204) Google Scholar], therefore adjustment for obesity may have attenuated the estimated effect of higher levels of alcohol on fatty liver development. While we do not have ultrasonography data to illustrate the potential impact of these biases with reference to the specific outcome used in Moriya and colleagues [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015;62:921–927.Google Scholar] paper, we have data on triglycerides, body mass index, waist circumference and γ-glutamyltransferase, which can be used to derive the fatty liver index (FLI) [[8]Bedogni G. Bellentani S. Miglioli L. Masutti F. Passalacqua M. et al.The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol. 2006; 6: 33https://doi.org/10.1186/1471-230X-6-33Crossref PubMed Scopus (1496) Google Scholar]. The FLI has been shown to be moderately associated with an increased occurrence of fatty liver on ultrasonography (scores of ⩾60). In Fig. 1 we show that amongst 3531 men participating in the two most recent data collection phases (2007–2009 and 2012–2013) of the Whitehall II prospective cohort study [[9]Marmot M. Brunner E. Cohort profile: the Whitehall II study.Int J Epidemiol. 2005; 34: 251-256https://doi.org/10.1093/ije/dyh372Crossref PubMed Scopus (554) Google Scholar], when the group of non-drinkers is decomposed further, never drinkers have similar odds of fatty liver approximately 5 years later as those consuming 0.1–69.9 grams of alcohol on a weekly basis (OR 1.05, CI 0.48–2.27) after adjustment for age, smoking status and physical activity. An increased risk is observed amongst former drinkers (OR 1.43, CI 0.93–2.19) and monthly/special occasion drinkers (OR 1.37, CI 1.08–1.73) – the two groups with the largest sources of bias present as described above. Furthermore, unlike like Moriya and colleagues [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015;62:921–927.Google Scholar], we show that higher levels of alcohol intake are associated with greater odds of fatty liver in a dose-dependent manner which is consistent with prior knowledge and current public health advice to limit alcohol intake [[10]Williams R. Aspinall R. Bellis M. Camps-Walsh G. Cramp M. et al.Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis.Lancet. 2014; 384: 1953-1997https://doi.org/10.1016/S0140-6736(14)61838-9Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar]. While it is acknowledged that Moriya and colleagues [[1]Moriya A, Iwasaki Y, Ohguchi S, Kayashima E, Mitsumune T, et al. Roles of alcohol consumption in fatty liver: a longitudinal study. J Hepatol 2015;62:921–927.Google Scholar] give a somewhat more balanced conclusion at the end of their article that the decision to drink should be tailored to an individual – this is not reflected throughout the rest of the manuscript. We illustrate that the alleged protective effect of moderate alcohol intake they describe is likely to be due to a combination of overadjustment bias and failure to appropriately stratify the current non-drinking group. As such we would recommend that it is ill-advised to take up light-to-moderate drinking to prevent fatty liver, or any other disease for that matter. SB and AB are funded by the European Research Council (ERC-StG-2012-309337_AlcoholLifecourse, PI: Britton, http://www.ucl.ac.uk/alcohol-lifecourse). The Whitehall II study is supported by grants from the Medical Research Council (K013351), British Heart Foundation (RG/07/008/23674), Stroke Association, National Heart Lung and Blood Institute (HL036310) and National Institute on Aging (AG13196 and AG034454). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. SB had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors who have taken part in this letter declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.