Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial Amir Anushiravani a , Niloufar Haddadi b , Maedeh Pourfarmanbar b and Vahid Mohammadkarimi c Introduction Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is becoming the most frequent indication of liver transplantation. Cardiovascular disease is the main cause of death in these patients. There is no Food and Drug Association-approved medication for NAFLD patients. We aimed to provide more robust evidence on the use of medications that are inexpensive and available, namely, metformin, silymarin, pioglitazone, and vitamin E, for treating NAFLD. Materials and methods We conducted a randomized double-blinded, placebo-controlled trial on 150 consecutive patients with NAFLD who were assigned to five groups: lifestyle plus placebo, metformin 500 mg/day, silymarin 140 mg/day, pioglithasone 15 mg/day, and vitamin E 400 IU/day, all for 3 months. Anthropometric and biochemical variables were measured at baseline and 3 months later. Results The mean age of the patients was 47.0 ± 9.1 (range: 18–65) years and the sex distribution was 73 (48.7%) women and 77 (51.3%) men. Patients in all groups showed a significant improvement in anthropometric parameters such as waist circumference and BMI. There was no statistically significant difference in alanine transaminase and aspartate transaminase in the control group after treatment (P = 0.51, 0.18, respectively); however, both liver enzymes decreased significantly in the other groups. Discussion and conclusion This randomized double-blinded placebo-controlled clinical trial suggested a significant benefit of silymarin, pioglitazone, and vitamin E in improving liver aminotransferases in patients with NAFLD after only 3 months, without exerting any specific side effects. Eur J Gastroenterol Hepatol 31:613–617 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. Introduction The prevalence of obesity has increased globally in the last decades. A 10–60% increase has been observed in the US population in the last three decades and is considered a major factor for the increase in nonalcoholic fatty liver disease (NAFLD) [1]. Obesity and NAFLD have been increasing in Iran and other developing nations, with a Western diet and physical inactivity as the main causes. The prevalence of NAFLD and nonalcoholic steatohepa- titis (NASH) in Iran has been estimated to be over 30% and about 3%, respectively [2]. It is becoming the most frequent indication for liver transplantation worldwide. NAFLD is defined as the presence of liver steatosis in histology or on an imaging after excluding secondary causes such as medications, excess alcohol consumption, and chronic hepatitis C. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and NASH. There is no hepatocellular injury in NAFL, whereas NASH involves hepatocyte injury with inflam- mation, with or without fibrosis [3]. NAFLD is a multisystem disease, increasing the risk of type 2 diabetes mellitus (T2DM), cardiovascular disease, and chronic kidney disease [4]. Even though liver-related mortality is increased 10-fold in patients with NAFLD, the main cause of death is cardiovascular disease [5]. Lifestyle modification is the primary therapy for patients with NAFLD who are overweight. The role of weight loss in lean patients has no evidence to support it. A sustained weight loss of about 7% can reverse the hepatic inflammation and fibrosis [6]. However, some patients will not achieve these goals or cannot maintain them. Despite decades of research, there is no Food and Drug Association-approved drug for treating NAFLD [7]. Most experts restrict treatment to those with NASH and advanced disease or those at high risk of liver cirrhosis [8]. NAFLD is the hepatic manifestation of the metabolic syndrome, where insulin resistance plays a major role. We studied two drugs that improve hepatic and peripheral insulin sensitivity: metformin and pioglitazone. Metformin decreases hepatic lipogenesis, gluconeogenesis, and glucose reabsorption from the intestines [9]. Pioglitazone, a per- oxisome proliferator-activated receptor-γ agonist, increa- ses the levels of plasma adiponectin, which exerts an anti-inflammatory and antifibrotic effect [10]. Oxidative stress is one of the main causes of NAFLD and vitamin E serves an anti-inflammatory function [11]. Silymarin is extracted from an ancient medicinal plant called ‘milk a Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, b Department of Internal Medicine, International Brach of Shiraz University of Medical Sciences and c Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Correspondence to Vahid Mohammadkarimi, MD, Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz 7187914678, Iran Tel: + 98 917 704 3855; fax: + 98 713 647 4316; e-mail: vahid.mohammadkarimi@gmail.com Received 8 December 2018 Accepted 10 January 2019 European Journal of Gastroenterology & Hepatology 2019, 31:613–617 Keywords: fatty liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity ’ Original article 0954-691X Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001369 613 Copyright r 2019 Wolters Kluwer Health, Inc. 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