Hajiaghamohammadi AA et al. 1. Background Nonalcoholic fatty liver Disease (NAFLD) occurs in non- alcoholic persons or in whom with little consumption. It is estimated that 20-40 percent of population of west countries and 5 to 30 percent of population in Asia and Oceania are afflicted with this disease (1, 2). The histologi- cal characteristic of NAFLD is accumulation of macro ve- sicular lipid similar to liver disease due to chronic con- sumption of alcohol. Fatty liver and steatohepatitis are two histological conditions for this disease. Liver histolo- gy in this disease is indistinguishable from alcoholic hep- atitis and includes balloon degeneration, hepatocytes necrosis, and fibrosis. Currently there are no comprehen- sive and acceptable staging and grading system for this disease. Pathogenesis of NASH is not well-understood but often the presence of two damages from which the first damage leads to accumulation of lipids in liver and steatosis and the second damage to inflammation and fibrosis is an accepted mechanism. Resistance to insulin is likely the reason for the first damage in most patients, while oxidative stress and lipid peroxidation or damage by inflammatory cytokines are considered as responsible for the second damage (3). In regard to the treatments of NAFLD, currently there is no consensus, similar to other aspects of this disease. One of the treatments proposed is active essence of silybun marianum plant known as sily- marin. Four different mechanisms of action in silymarin and silibinin are recognized: (1) as antioxidants, scaven- gers, and regulators of intracellular content of glutathi- one; (2) as cell membrane stabilizers and permeability regulators; (3) as promoters of ribosomal RNA synthesis, stimulating liver regeneration; and (4) as inhibitors of stellate hepatocyte transformation into myofibroblasts. Metformin is a biguanide, approved as a hypoglycemic therapy in patients with type 2 diabetes mellitus. This agent improves sensitivity to insulin by reducing hepatic glucose production, reducing lipolysis in adipose tissue, increasing peripheral glucose uptake by liver, skeletal muscle and adipose tissue, and inhibiting intestinal glu- cose absorption (4-8). Pioglitazone is an orally adminis- tered insulin-sensitizing thiazolidinedione agent devel- oped for the treatment of type two diabetes mellitus. Pioglitazone activates nuclear PPAR-γ, which leads to in- creased transcription of genes encoding various proteins regulating glucose and lipid metabolisms (8-10). 2. Objectives The aim of this study was to compare effectiveness of si- lymarin, pioglitazone, and metformin in improving insu- lin sensitivity and some biochemical markers in NAFLD. 3. Patients and Methods 3.1. Participants This study was conducted in Qazvin, Iran. Sixty six pa- Treatment of Non Alcoholic Fatty Liver Disease tients (males = 42 and females = 24) who were presented in Endocrinology and Metabolism clinic of Boo’ali Hos- pital, Qazvin University of Medical Sciences from 2010 to 2011 were studied. Patients suffered from NAFLD (Mean age = 32.62 years, SD = 6.4 years) and their trial profileis shown in Figure 1. Some characteristics and parameters of participants are shown in Table 1. All participants provided written informed consent before enrolment and all responses were kept confidential. The ethics re- view board of Qazvin University of Medical Science ap- proved the study. Inclusion criteria were infliction with NAFLD Confirmed by performing liver sonography and increased levels of liver enzymes AST and ALT. All tests and sonographies were conducted in one center. In ad- dition to obtaining complete history on taking alcohol and drugs, the tests related to autoimmune hepatitis and virus markers were also applied for all patients. Patients having history of alcohol consumption, diabetes, chronic liver disease, use of drugs such as statin, fibrate, NSAID, and those with positive results for tests of autoimmune hepatitis and virus markers (HBS antigen. HCV antibody) were excluded from the study. 3.2. Procedure First we categorized patients in two groups (24 females and 42 males) and randomly allocated patients into three intervention groups using 22 blocks A, B, C (ABC, ACB, etc.) of Balanced Blocked Randomization method. Group one was treated by pioglitazone 15 mg/day, group two by met- formin 500 mg/d, and group three by silymarin 140 mg/d. All drugs were administered in the form of pills. Patients in each group took one pill daily for two months. Serum insulin assessment was performed by MONOBAND kits manufactured in USA. Other biochemical elements were assayed PARS-AZMOON manufactured DIASYS Germa- ny Company. In order to compare effects of drugs, the weight, FBS, serum Insulin level, serum cholesterol and triglyceride levels, AST, ALT, Body Mass Index (BMI), and Homeostasis Model Assessment index for Insulin Resis- tance (HOMA-IR) were measured in three groups before and after drug administration. Recruitment (n= 66) Stratiﬁed (n= 66) 42 males 24 females Randomization (n= 42) Randomization (n= 24) piognl=it2a2zone mentf=o2r2min n=22 silymarin Figure 1. The Trial Profile of Patients Who Completed Follow Up 2 Hepat Mon. 2012;12(8):e6099