Smoking and NASH: A hidden message from the GREACE trial
Authors: Megha Babu, Navin Paul
Journal: Journal of Hepatology (2011)

Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver diseaseJournal of HepatologyVol. 54Issue 4PreviewAlthough many predictors of disease severity of nonalcoholic fatty liver disease (NAFLD) have been proposed, studies of the potential effects of specific environmental exposures on human NAFLD are lacking. Smoking increases insulin resistance. Given the pathophysiological role of insulin resistance in NAFLD, characterization of the influence of smoking in NAFLD is warranted. The aim of this paper was to study the potential association between cigarette smoking and advanced fibrosis in NAFLD. Full-Text PDF Reply to: "Smoking and NASH: A hidden message from the GREACE trial"Journal of HepatologyVol. 56Issue 1PreviewWe appreciate the interest shown in our work by Drs. Babu and Paul. In their Letter to the Editor, they comment on a higher frequency of smoking reported by Athyros et al. among patients in the GREACE trial with presumed NAFLD compared to patients with normal liver tests [1]. Interestingly, a previous study by Suzuki et al. also reported an association between current smoking and increase in serum ALT in subjects with presumed NAFLD [2]. Drs. Babu and Paul point out that, fitting with our earlier report [3], a history of smoking was more frequent among subjects in the GREACE trial with presumed NAFLD compared to those with normal liver tests, and that in addition, current smoking was more frequent among subjects with presumed NAFLD compared to subjects with normal liver tests. Full-Text PDF Open AccessSmoking and non-alcoholic steatohepatitis (NASH): The GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) trialJournal of HepatologyVol. 57Issue 2PreviewAs the authors of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) trial [1], we appreciate the comments made by Babu et al. [2] and Zein et al. [3] regarding the role of smoking on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). A few comments may be of interest. Full-Text PDF Open Access The article by Zein et al. in the April issue of this Journal adds to a growing body of evidence that tobacco use may be linked to progression of non-alcoholic fatty liver disease (NAFLD) [[1]Zein C.O. Unalp A. Colvin R. Liu Y.C. McCullough A.J. Nonalcoholic Steatohepatitis Clinical Research Network. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease..J Hepatol. 2011; 54: 753-759Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. However, while there was an association between the degree of fibrosis and tobacco use among the 1091 patients studied, the authors mention that they could not, surprisingly, find an association between NASH and current tobacco use. Another recent trial may provide some data regarding this.Athryos and colleagues recently used a post-hoc analysis of the GREACE trial to demonstrate that statins were safe for use in patients with elevated liver enzymes and presumed NAFLD [[2]Athyros V.G. Tziomalos K. Gossios T.D. et al.Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.Lancet. 2010; 376: 1916-1922Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar]. However, the authors of that trial seem to have overlooked data that suggest an association between smoking and presumed NAFLD. A review of the baseline characteristics in the GREACE trial shows a large difference in the number of current and past smokers between patients with normal and abnormal liver tests. Forty six out of 437 patients (10.3%) with abnormal liver tests were current smokers, as compared to 51/1163 with normal liver tests (4.4%). In addition, 146/437 (33.4%) with abnormal liver tests were past smokers as compared to 290/1163 (24.9%) with normal liver tests.Using this data, we were able to calculate the odds-ratio (OR) that a current smoker has abnormal liver tests compared to a life-time non-smoker to be 3.03 (95% confidence interval 1.98–4.6). Similarly, the odds-ratio for a past smoker having abnormal liver tests compared to a lifetime non-smoker is 1.69 (95% confidence interval 1.32–2.16) and a patient with any history of smoking developing abnormal liver test is 1.88 (95% confidence interval 1.51–2.37). These data show a higher risk for current smokers to have abnormal liver tests as compared to past smokers.The GREACE trial lacked liver biopsies to confirm a diagnosis of NAFLD, and relied on abnormal liver tests and abdominal ultrasound to make a diagnosis of presumed NAFLD. However, the authors had carefully excluded other causes of liver disease. The fact that about 90% of those with abnormal liver tests had co-existent metabolic syndrome lends further support to the presumption that the patients studied likely had NAFLD.As compared to the NASH CRN study, the GREACE study included a larger number of overall patients (1091 vs. 1600), although there were less NASH patients (1091 vs. 437). More importantly, the GREACE trial had a comparator group with normal liver tests, which was lacking in the NASH CRN study. This may have been the reason why the GREACE trial was able to pick up a difference, although the percentages of current smokers were similar in the two trials (9.5% in NASH CRN vs. 10.3% in the GREACE trial). The fact that we compared current smokers to lifetime non-smokers also likely increased the odds-ratio, and similar analysis of the NASH CRN data may yield comparable results.Thus, there appears to be strong current evidence to support a role for smoking in the development and progression of NAFLD. We agree with Zein et al. that smoking cessation should be recommended to those patients suspected to have NAFLD.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The article by Zein et al. in the April issue of this Journal adds to a growing body of evidence that tobacco use may be linked to progression of non-alcoholic fatty liver disease (NAFLD) [[1]Zein C.O. Unalp A. Colvin R. Liu Y.C. McCullough A.J. Nonalcoholic Steatohepatitis Clinical Research Network. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease..J Hepatol. 2011; 54: 753-759Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. However, while there was an association between the degree of fibrosis and tobacco use among the 1091 patients studied, the authors mention that they could not, surprisingly, find an association between NASH and current tobacco use. Another recent trial may provide some data regarding this. Athryos and colleagues recently used a post-hoc analysis of the GREACE trial to demonstrate that statins were safe for use in patients with elevated liver enzymes and presumed NAFLD [[2]Athyros V.G. Tziomalos K. Gossios T.D. et al.Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.Lancet. 2010; 376: 1916-1922Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar]. However, the authors of that trial seem to have overlooked data that suggest an association between smoking and presumed NAFLD. A review of the baseline characteristics in the GREACE trial shows a large difference in the number of current and past smokers between patients with normal and abnormal liver tests. Forty six out of 437 patients (10.3%) with abnormal liver tests were current smokers, as compared to 51/1163 with normal liver tests (4.4%). In addition, 146/437 (33.4%) with abnormal liver tests were past smokers as compared to 290/1163 (24.9%) with normal liver tests. Using this data, we were able to calculate the odds-ratio (OR) that a current smoker has abnormal liver tests compared to a life-time non-smoker to be 3.03 (95% confidence interval 1.98–4.6). Similarly, the odds-ratio for a past smoker having abnormal liver tests compared to a lifetime non-smoker is 1.69 (95% confidence interval 1.32–2.16) and a patient with any history of smoking developing abnormal liver test is 1.88 (95% confidence interval 1.51–2.37). These data show a higher risk for current smokers to have abnormal liver tests as compared to past smokers. The GREACE trial lacked liver biopsies to confirm a diagnosis of NAFLD, and relied on abnormal liver tests and abdominal ultrasound to make a diagnosis of presumed NAFLD. However, the authors had carefully excluded other causes of liver disease. The fact that about 90% of those with abnormal liver tests had co-existent metabolic syndrome lends further support to the presumption that the patients studied likely had NAFLD. As compared to the NASH CRN study, the GREACE study included a larger number of overall patients (1091 vs. 1600), although there were less NASH patients (1091 vs. 437). More importantly, the GREACE trial had a comparator group with normal liver tests, which was lacking in the NASH CRN study. This may have been the reason why the GREACE trial was able to pick up a difference, although the percentages of current smokers were similar in the two trials (9.5% in NASH CRN vs. 10.3% in the GREACE trial). The fact that we compared current smokers to lifetime non-smokers also likely increased the odds-ratio, and similar analysis of the NASH CRN data may yield comparable results. Thus, there appears to be strong current evidence to support a role for smoking in the development and progression of NAFLD. We agree with Zein et al. that smoking cessation should be recommended to those patients suspected to have NAFLD. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.