Reply:
Authors: Winston Dunn, Jeffrey B. Schwimmer
Journal: Hepatology (2008)

We appreciate Dr. Fujita's enthusiasm for our recent publication and the interesting questions he presents. What is the most important predictor of nonalcoholic fatty liver disease (NAFLD)? What is the protective mechanism of modest wine drinking? How should physicians advise their patients based on this new information? The multivariate analysis we reported was not designed to look for the strongest predictor of NAFLD. Because there are social, demographic, and lifestyle factors that differ between nondrinkers and modest wine drinkers, the main multivariate model was used to correct for these confounders. Subsequent multivariate models were created to explore potential pathways. For example, the effect of modest wine drinking was considered to be independent of metabolic syndrome features, because the odds ratio for suspected NAFLD remained unchanged after correction for these metabolic syndrome features. The multivariate models, however, were not designed as predictive models, such that nonsignificant variables were not removed by backward elimination process. If one does such an analysis, insulin sensitivity as measured by QUICKI has the highest Wald F-statistics using the laboratory cut-point while race has the highest F-statistics using the healthy cut-point. These findings must be interpreted in the context that any variable that correlates closely with NAFLD but loosely with elevated alanine aminotransferase would be underappreciated by such a predictive model. Modest wine drinkers compared to nondrinkers had fewer metabolic syndrome features such as low high-density lipoprotein (HDL) cholesterol and high triglyceride, which was significantly associated with suspected NAFLD. However, the presence of HDL and triglyceride in multivariate model 2 and 3 did not attenuate the adjusted odds ratio, suggesting that the pathway of modest wine drinking is independent of conventional measures of lipid trafficking. In addition to metabolic syndrome features, Dr. Fujita pointed out that wine may be associated with level of C-reactive protein (CRP), which is associated with nonalcoholic steatohepatitis in patients with NAFLD.1 In additional analysis of our data, mean CRP level is slightly but significantly lower in modest wine drinkers (0.39 mg/dL, standard deviation of 0.60 mg/dL) than nondrinkers (0.49 mg/dL, standard deviation of 0.72 mg/dL). However, adding CRP into the multivariate model does not attenuate the odds ratio. Although the mechanisms of how modest wine drinking may protect against NAFLD cannot be revealed through a cross-sectional epidemiological study, the body of literature offers some clues. Modest alcohol consumption has been reported to prevent diabetes and improve insulin resistance.2-4 Nonalcohol components of wine has been shown to lower serum triglyceride.5, 6 Both alcohol7, 8 and nonalcohol wine components5, 6 have been shown to increase serum HDL. The Copenhagen Center for Prospective Population Study demonstrated that wine drinkers, compared to other drinkers of equal amount, were less likely to develop cirrhosis.9 In our study, modest drinkers pooled together had lower prevalence of suspected NAFLD than nondrinkers. However, modest wine drinkers had lower prevalence of suspected NAFLD than modest beer, liquor, or mixed drinkers. Therefore, we too speculate that the nonalcohol components of wine such as polyphenols and flavonoids are likely to play a major role, but the alcohol component may also contribute to the overall beneficial effect. Finally, how should physicians advise their patients about modest wine drinking? Rarely are physicians' recommendations driven by a single study. A search of PubMed for "wine AND cardiovascular disease" yields 1213 references; despite this number, however, there remains controversy in the application of modest alcohol for cardiovascular health.10, 11 In contrast, a search for "wine AND nonalcoholic fatty liver disease" yields only one reference.12 If a physician recommends modest alcohol to patients for cardiovascular protection, these data suggest that wine up to one serving per day is the best choice from a liver standpoint. As for a recommendation to prevent NAFLD, the data are provocative, but more information is needed to form the basis of solid clinical evidence. Thus, the role of modest wine for the prevention of NAFLD is a new question in need of a carefully derived answer. The Goldilocks Principle states that something must fall within certain margins, as opposed to reaching extremes. For wine, the difficulty is one of defining these margins. How much is too little? How much is too much? How much is just right? Not everyone should be advised to drink wine. As has been demonstrated in studies on cardiovascular protection, the potential for benefit is most relevant to those individuals at risk for NAFLD.13, 14 Patients with a substance abuse history, viral hepatitis,15 or iron overload16 should not be advised to drink wine. For those patients that may benefit from wine, how much wine should they drink? While the threshold for harm has been well studied,13, 17 the therapeutic window for protection remains unclear. The optimum dose for preventing NAFLD may be different than for preventing cardiovascular disease. Unlike the decision-making process for eating a bowl of porridge, the current study has created more questions than answers. Winston Dunn M.D.*, Jeffrey B. Schwimmer M.D. , * Division of Gastroenterology, Department of Medicine, University of California, San Diego, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego.