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The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial. 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Double-blind Randomized Placebo-controlled Clinical Trial of Omega 3 Fatty Acids for the Treatment of Diabetic Patients With Nonalcoholic Steatohepatitis Fish Oil Supplements Lower Serum Lipids and Glucose in Correlation with a Reduction in Plasma Fibroblast Growth Factor 21 and Prostaglandin E2 in Nonalcoholic Fatty Liver Disease Associated with Hyperlipidemia: A Randomized Clinical Trial Effects of Probiotics on Nonalcoholic Fatty Liver Disease in Obese Children and Adolescents Effect of Telmisartan on Histological Activity and Fibrosis of Non-alcoholic Steatohepatitis: A 1-Year Randomized Control Trial Resveratrol does not benefit patients with nonalcoholic fatty liver disease. A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH) Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study Telmisartan, a dual ARB/partial PPAR-γ agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Omega-3 Fatty acids therapy in children with nonalcoholic Fatty liver disease: a randomized controlled trial. Effects of ursodeoxycholic acid in combination with vitamin E on adipokines and apoptosis in patients with nonalcoholic steatohepatitis. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non‐alcoholic steatohepatitis A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non‐alcoholic fatty liver disease: A pilot randomized trial Effects of Oral Antidiabetic Drugs on Changes in the Liver-to-Spleen Ratio on Computed Tomography and Inflammatory Biomarkers in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Betaine for nonalcoholic fatty liver disease: Results of a randomized placebo‐controlled trial Synbiotic supplementation in lean patients with non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-controlled, clinical trial. Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non‐alcoholic fatty liver disease: A prospective randomized controlled pilot study Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial.
In a prospect i ve , r and omized , double-blind therapeutic trial , 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d . orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate ( Ietepar ) ( 96 patients ) or with undistinguishable placebo capsules ( 95 patients ) . The verum treatment effectively reduced by 25 % hepatic steatosis ( p < 0.01 ) and by 6 % hepatomegaly ( p < 0.05 ) , while placebo did not significantly reduce the disorders . Verum was also more effective than placebo on discomfort in abdominal upper right quadrant . The global efficacy of treatment was rated by the doctor " very good " or " good " in 48 % of verum treated patients and only in 17 % after placcbo ( P of difference = 9 x 10(-6 ) ) . 52 % of patients self-rated efficacy as " very good " or " good " after verum and only 34 % after placebo ( P of difference = 0.017 ) . The verum treatment provoked a significant reduction of the increased liver transaminases ( ALT , AST and gamma-GT ) while placebo was ineffective . Adverse events were recorded in 10 % of verum-treated patients and in 7 % under placebo ( no significant difference ) . In both groups the adverse events were mild and transient , did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders . In conclusion , the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis , a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective Nonalcoholic steatohepatitis ( NASH ) is increasing in prevalence and is related to underlying insulin resistance . The aim of this study was to assess the efficacy of metformin on the characteristic histopathologic lesions of NASH . This was a 12-month prospect i ve , r and omized , placebo-controlled trial comparing diet and exercise alone to diet , exercise and metformin in nondiabetic patients with insulin resistance and NASH . Patients were r and omized to either group A or B. Group A received placebo , dietary counseling , recommendations for weight loss and exercise four times per week . Group B received long-acting metformin 500 mg daily ( titrated to 1000 mg daily ) plus dietary counseling , recommendations for weight loss and exercise four times per week . Histopathology was assessed at 12 months and biopsies were scored by two pathologists who were blinded to all data . Twenty-three subjects were screened and 19 were r and omized to either group A ( n = 10 ) or group B ( n = 9 ) . Seven of the 10 subjects in group A completed the study including repeat liver biopsy while all patients in group B completed the study . Body mass index improved in both groups decreasing by 1.7 kg/m2 in group A and 0.9 kg/m 2 in group B ( not significant , control versus treatment ) . Homeostasis model assessment of insulin resistance scores improved in both groups decreasing by 1.14 in group A and 1.58 in group B ( not significant , control versus treatment ) . No significant difference in histopathology was seen between groups on follow-up liver biopsy . Metformin appeared to have little effect in improvement in liver function tests or liver histology in nondiabetic patients with insulin resistance and NASH . Decrease in BMI through diet and exercise significantly improved HOMA-IR scores , serum aminotransferases and liver histology Background Nonalcoholic fatty liver disease ( NAFLD ) is one of the most common reasons of enzyme increase in liver . In About 10 percent of patients with NAFLD , the disease progresses toward Non Alcoholic Steatohepatitis ( NASH ) and about one third of them may progress toward cirrhosis , liver dysfunction , and even hepatocellular carcinoma . Objectives According to high prevalence of NAFLD and the fact that there is no consensus on treatment of this disease , the aim of this study was to assess the effects of metformin , pioglitazone , and silymarin on treatment of NAFLD . Patients and Methods Sixty six patients with NAFLD who were presented in the Endocrinology and Metabolism clinic of Boo’ali Hospital , Qazvin , Iran , were assigned r and omly into three groups ( n = 22 ) . First group was treated by pioglitazone 15 mg/d , second group by metformin 500 mg/d , and third group by silymarin 140 mg/d . All patients underwent clinical and biochemical evaluations including weight , fasting blood sugar ( FBS ) , lipid profiles , body mass index ( BMI ) , aspartate aminotransferase ( AST ) , alanine aminotransferase ( ALT ) , and serum insulin levels in pre- and post-intervention after eight-week follow up . Results Before the treatment there was no significant difference between three groups with respect to average age , BMI and gender , FBS , lipid profile , AST , ALT , serum insulin level , and Homeostasis Model Assessment ( HOMA ) index for insulin resistance . After the intervention , a significant reduction was observed in average amount of FBS , lipid profile , ALT , AST , serum insulin level and HOMA index in three groups ( P < 0.01 ) . The most reduction in average FBS , TG , serum insulin level , and HOMA index was observed in pioglitazone group , the most reduction in average amount of cholesterol was seen in metformin group , and the most decrease in average amount of AST and ALT occurred in silymarin group . Conclusions These results suggest that all drugs are beneficial in improving biochemical indices in patients with NAFLD . Changes in AST and ALT in silymarin group were demonstrated more than that in other groups and the average difference between changes was significant between silymarin and metformin groups Background Increased exposure to intestinal bacterial products may contribute to the pathogenesis of non alcoholic steatohepatitis ( NASH ) . Bifidobacteria are predominant bacterial species in the human gut microbiota and have been considered to exert a beneficial effect on human health by maintaining the equilibrium of the resident microbiota . Aims To evaluate the effects of Bifidobacterium longum with fructo-oligosaccharides ( Fos ) in the treatment of NASH . Methods A total of 66 patients were r and omly and equally divided into two groups receiving Bifidobacterium longum with Fos and lifestyle modification ( i.e. , diet and exercise ) versus lifestyle modification alone . The following variables were assessed at −4 ( beginning of the dietary lead-in period ) , 0 ( r and omization ) , 6 , 12 , 18 , and 24 weeks : aspartate transaminase ( AST ) , alanine transaminase ( ALT ) , bilirubin , albumin , total cholesterol , high-density lipoprotein ( HDL ) cholesterol , low-density lipoprotein ( LDL ) cholesterol , triglycerides , fasting plasma glucose , insulin , C-peptide , C-reactive protein ( CRP ) , tumor necrosis factor (TNF)-α , homeostasis model assessment of insulin resistance ( HOMA-IR ) , and serum endotoxins . Liver biopsies were performed at entry and repeated after 24 weeks of treatment . Results At the end of study period , we observed that the Bifidobacterium longum with Fos and lifestyle modification group versus the lifestyle modification alone group showed significant differences in the AST −69.6 versus −45.9 IU/mL ( P < 0.05 ) , LDL cholesterol −0.84 versus −0.18 mmol/L ( P < 0.001 ) , CRP −2.9 versus −0.7 mg/L ( P < 0.05 ) , TNF-α −0.45 versus −0.12 ng/mL ( P < 0.001 ) , HOMA-IR −1.1 versus −0.6 ( P < 0.001 ) , serum endotoxin −45.2 versus −30.6 pg/mL ( P < 0.001 ) , steatosis ( P < 0.05 ) , and the NASH activity index ( P < 0.05 ) . Conclusions Bifidobacterium longum with Fos and lifestyle modification , when compared to lifestyle modification alone , significantly reduces TNF-α , CRP , serum AST levels , HOMA-IR , serum endotoxin , steatosis , and the NASH activity index UNLABELLED In uncontrolled clinical studies , ursodeoxycholic acid ( UDCA ) had a beneficial effect on  nonalcoholic steatohepatitis ( NASH ) .  However , a large controlled trial using UDCA ( 13 - 15 mg/kg/day ) was unable to confirm these results . Accordingly , a r and omized , placebo-controlled study was initiated with a high dose of UDCA ( 23 - 28 mg/kg/day ) . The allocation of patients and the evaluation of liver histology were performed according to a modified Brunt score and the nonalcoholic fatty liver disease activity score ( NAS ) . With the modified Brunt score , 185 patients with histologically proven NASH were r and omized [ intention to treat ( ITT ) ] , and 147 were treated per protocol ( PP ) . With the NAS , 137 patients were confirmed to have NASH , 48 had borderline NASH , and 1 did not have NASH . The treatment time was 18 months . At entry , the treatment groups were comparable . A second biopsy sample was obtained from 139 of 185 patients ( NAS : 107/137 ) . The primary criterion for evaluation was a change in the liver histology ; the secondary criteria were single histological variables and liver biochemistry . Significant differences in the overall histology could not be detected between the two treatment groups with the modified Brunt score ( P = 0.881 ) or NAS ( P = 0.355 ) . Only lobular inflammation improved significantly ( P for the modified Brunt score = 0.011 , P for NAS = 0.005 ) . In subgroup analyses , significant improvements in lobular inflammation were also observed in males , younger patients up to 50 years of age , slightly overweight patients , and patients with hypertension and an increased histology score . The fibrosis score did not change ( P for ITT = 0.133 , P for PP = 0.140 ) . With the exception of gamma-glutamyl transferase , UDCA did not improve laboratory data . CONCLUSION High-dose UDCA failed to improve the overall histology in patients with NASH in comparison with placebo BACKGROUND / AIMS Non-Alcoholic Steatohepatitis ( NASH ) is a chronic liver disease frequently associated with insulin resistance and type 2 diabetes mellitus ( T2DM ) . Pioglitazone reverses the metabolic and histological abnormalities of patients with impaired glucose tolerance or T2DM and NASH , but also leads to weight gain . To underst and the nature of weight gain associated with pioglitazone treatment in NASH we analyzed 35 patients who completed tests for determination of whole body fat ( WBF ) and total body water ( TBW ) .  METHODS Twenty-one patients received pioglitazone and 14 placebo in a double-blind , r and omized fashion for a period of 6 months . WBF and TBW were measured before and after treatment using DXA , a water dilution technique and bioimpedance . RESULTS Pioglitazone increased body weight ( from 93.6+/-4.2 to 96.1+/-4.5 kg , p<0.003 ) and WBF measured with DXA ( from 32.9+/-2.1 to 35.4+/-2.5 kg , p<0.002 ) while no changes were seen with placebo .  Total body water was not altered significantly either after pioglitazone ( from 45.4+/-2.3 to 45.6+/-2.7 l , p = NS ) or placebo . Muscle hydration and extracellular water were unchanged both by pioglitazone and placebo treatments . CONCLUSIONS Six months of pioglitazone  treatment in patients with NASH is associated with weight gain that is attributable to an increase in adipose tissue mass and not to water retention BACKGROUND / AIMS Despite a proposed role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis , antioxidant approaches have not been investigated sufficiently in the therapy of nonalcoholic steatohepatitis . Our aim was to determine whether vitamin E plus C therapy is effective in normalization of liver enzymes compared to ursodeoxycholic acid treatment in patients with fatty liver disease . METHODS This was an open-labeled , prospect i ve , r and omized study enrolling patients with histologically proven fatty liver disease who had chronically elevated alanine aminotransferase , despite a three-month reducing diet . Patients consuming alcohol ( more than 20 g/day ) were excluded . The patients were r and omly prescribed either oral vitamin E ( 600 IU/day ) plus vitamin C ( 500 mg/day ) or ursodeoxycholic acid ( 10 mg/kg/day ) . Patients were r and omized as two groups to receive vitamin E plus vitamin C combination ( 28 patients , 10 F ) or ursodeoxycholic acid treatment ( 29 patients , 13 F ) . RESULTS There was no significant change in body mass index before and after the treatment in both groups . At the end of six months of therapy , serum aspartate aminotransferase and aminotransferase levels significantly decreased in both treatment options . Vitamin E and C combination was more efficacious on serum aminotransferase levels than ursodeoxycholic acid , but the difference was not significant . Alanine aminotransferase decreased to normal levels in 17 of 27 ( 63 % ) and in 16 of 29 patients ( 55 % ) , respectively , in the two groups . Gamma-glutamyl transpeptidase decreased in patients receiving ursodeoxycholic acid , but no change was obtained in the vitamin-treated patients . CONCLUSIONS Vitamin E plus C combination treatment is a safe , inexpensive and effective treatment option in patients with fatty liver disease , with results comparable to those obtained with ursodeoxycholic acid . Since more effective new therapeutic options are lacking , patients with fatty liver disease should be encouraged to take vitamin E and C supplements , which are safe and affordable Background / Aim : The study was carried out to compare the efficacy of Vitamin E versus Ursodeoxycholic acid ( UDCA ) in nondiabetic nonalcoholic fatty liver disease ( NAFLD ) patients . Patients and Methods : We r and omized 250 non cirrhotic and non diabetic NAFLD patients diagnosed on ultrasound , with raised alanine aminotransferase ( ALT ) level . ( > 40 IU/L ) , to receive Vitamin E 400 mg twice a day ( Group A ) or UDCA 300 mg twice a day ( Group B ) for 52 weeks . Lifestyle modification to achieve at least 5 % weight reduction and subsequent weight control and regular exercise was advised to both groups . The primary study endpoint was normalization of ALT . Secondary endpoints were the proportion of patients with reduction in ALT , relative reduction in the NAFLD Fibrosis score ( NFS ) , symptomatic improvement and tolerability . Results : One hundred and fifty patients received UDCA as compared to 100 patients receiving Vitamin E. The treatment groups were comparable at entry with regard to age ( 44.1 vs 42.4 years ) , gender ( 67 % vs 63 % female ) , risk factors for nonalcoholic steatohepatitis , hypochondriac pain , serum liver biochemistries , and NAFLD Fibrosis score . The primary endpoint was achieved in 21 ( 14 % ) and 19 ( 19 % ) of patients in Group A and Group B , respectively ( P = 0.2 ) . The proportion of patients with reduction in ALT ( 56 % vs 63 % , P = 0.2 ) , symptomatic improvement ( 78 % vs 67 % , P= 0.058 ) , reduction in the NFS ( 44 % vs 47 % , P= 0.69 ) , and tolerability ( 98 % vs 95 % , P= 0.2 ) were similar between Group A and Group B , respectively . Conclusion : UDCA is an effective and safe alternative to Vitamin E in nondiabetic – noncirrhotic Indian NAFLD patients Nonalcoholic fatty liver disease ( NAFLD ) is reaching epidemic proportions worldwide ( 1 ) and is the most common chronic liver condition in obese patients with prediabetes or type 2 diabetes mellitus ( T2DM ) . Histologic findings range from isolated steatosis ( with no or minimal inflammation ) to severe nonalcoholic steatohepatitis ( NASH ) and variable perisinusoidal or perivenular fibrosis ( 2 ) . Patients with T2DM and NASH have the highest risk for cirrhosis and hepatocellular carcinoma ( 3 , 4 ) , and the presence of NAFLD seems to worsen microvascular and macrovascular complications of diabetes ( 57 ) . Given that most patients with T2DM have NAFLD ( 812 ) and many are at risk for NASH even if they have normal liver aminotransferase levels ( 6 , 9 , 13 , 14 ) , it is surprising that few trials have focused on this population . This distinction ( patients with NASH with vs. without T2DM ) is relevant because additional metabolic factors , such as hyperglycemia ( 15 , 16 ) , lower adiponectin levels ( 17 , 18 ) , worse dyslipidemia ( 19 , 20 ) , and more severe insulin resistance and hepatic steatosis ( 10 , 16 , 1821 ) , may account for the higher rates of severe liver disease observed in patients with T2DM ( 22 ) . Although the cause of NASH is multifactorial and treatment remains challenging ( 23 ) , a major factor is the increase in liver triglyceride content caused by chronic release of free fatty acids ( FFAs ) from insulin-resistant dysfunctional adipose tissue ( 7 , 2427 ) . Because thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic lipotoxicity in NASH ( 7 , 22 , 28 ) ( which is also a prominent feature of T2DM [ 15 ] ) , they may be more helpful for treating steatohepatitis in this population . In predominantly nondiabetic patients with NASH , several studies have reported variable degrees of histologic benefit with thiazolidinediones ( 2933 ) . In the largest study to date in patients without T2DM ( 34 ) , pioglitazone was no better than placebo for the primary outcome but was beneficial for secondary outcomes , such as resolution of NASH . However , in patients with prediabetes or T2DM , the only available r and omized , controlled trial is a relatively small proof-of-concept study ( 35 ) . This is disappointing given that there are 29.1 million adults with diabetes ( > 90 % with T2DM ) and 86 million with prediabetes ( 36 ) in the United States , many of whom are at risk for cirrhosis from NASH . Moreover , because pioglitazone may also halt the progression of prediabetes to T2DM ( 37 ) , defining its role in patients with prediabetes and NASH is critical . Finally , safety concerns about the long-term use of thiazolidinediones remain ( 38 , 39 ) ; therefore , studies with extended thiazolidinedione exposure are needed before a pioglitazone-based approach can be embraced in this population . The aim of our study was to assess the efficacy and safety of long-term pioglitazone treatment in improving liver histologic outcomes in patients with NASH and prediabetes or T2DM . Methods Design Overview This was a single-center , parallel-group , r and omized ( 1:1 allocation ) , placebo-controlled study , conducted between December 2008 ( first patient enrolled ) and December 2014 ( final data collection ) . Participants , investigators , and health care providers were blinded to treatment assignment throughout the study . The Institutional Review Board at the University of Texas Health Science Center at San Antonio ( UTHSCSA ) approved the study , and all participants provided written informed consent before enrollment . In October 2009 , while updating registry data for another study , investigators discovered that this trial , which they thought had been registered by other study personnel , was not registered . At the time of registration ( Clinical Trials.gov : NCT00994682 ) , 29 patients ( of 97 anticipated ) were enrolled in the study . None of these patients had had the follow-up metabolic measurements or liver biopsies ( primary outcome ) that were to be performed at 18 months , and no interim analyses were done before the trial was registered . A recent review of Clinical Trials.gov ( November 2015 ) revealed that the initial trial registration data erroneously stated that patients with normal glucose tolerance would be r and omly assigned to treatment or placebo . Given that the trial 's eligibility criteria required patients to have an abnormal oral glucose tolerance test ( OGTT ) result ( that is , prediabetes or T2DM ) , the investigators never planned to enroll patients with normal glucose tolerance . This error in trial registration was corrected by the principal investigator . The trial registry states that the primary end point is liver histologic outcomes ( Kleiner criteria [ 40 ] ) at 18 months , and these data are presented in Appendix Table 1 . In this article , the primary end point is defined as a reduction of at least 2 points in 2 categories of the NAFLD activity score ( NAS ) without worsening of fibrosis , an outcome that was not specified in the original registration . This end point has been accepted by investigators in this field as representing significant change in liver histologic outcomes in clinical trials involving patients with NASH ( 34 , 4143 ) . Some secondary outcomes that were assessed , such as insulin secretion , prevention of the onset of T2DM or reversal of glucose intolerance , measurement of visceral fat by magnetic resonance imaging , bone density measurement via dual-energy x-ray absorptiometry ( DXA ) , plasma measurements of bone metabolism , and molecular metabolic pathways , are not reported in this article . Appendix Table 1 . Liver Histologic Variables at Baseline and After 18 mo , Based on Observed Data * Setting and Participants Participants were recruited from the general population of San Antonio , Texas , via newspaper advertisements and from the endocrinology and hepatology clinics at UTHSCSA and the Veterans Affairs Medical Center . Persons were eligible for the trial if they had histologically confirmed NASH and either prediabetes or T2DM . All patients had a screening 2-hour OGTT to diagnose or confirm a diagnosis of prediabetes or T2DM . Prediabetes was defined as impaired fasting glucose ( 5.6 to 6.9 mmol/L [ 100 to 125 mg/dL ] ) , impaired glucose tolerance ( 7.8 to 11.1 mmol/L [ 140 to 199 mg/dL ] on an OGTT ) , or a hemoglobin A1c level of 5.7 % to 6.4 % . Exclusion criteria included use of thiazolidinediones or vitamin E ; other causes of liver disease ( 22 ) or abnormal laboratory results ( such as an aspartate aminotransferase [ AST ] or alanine aminotransferase [ ALT ] level 3 times the upper limit of normal [ ULN ] ) ; type 1 diabetes mellitus ; or severe heart , hepatic , or renal disease . Detailed inclusion and exclusion criteria are provided in the Appendix . R and omization and Interventions After initial screening ( medical history , physical examination , laboratory tests , and 75-g OGTT ) , patients began receiving placebo and were instructed by the research dietician ( C.D. ) to keep physical activity and diet constant during the run-in phase ( mean duration , 1 month ) . After completion of baseline metabolic measurements , participants were prescribed a hypocaloric diet ( 500kcal/d deficit from the calculated weight-maintaining diet ) and were r and omly assigned in a 1:1 ratio to either pioglitazone ( Actos [ Takeda Pharmaceuticals ] ) , 30 mg/d ( titrated after 2 months to 45 mg/d ) , or placebo . R and omization ( computer-generated ) and patient allocation were performed by the research pharmacist without stratification and using a block factor of 4 , which was unknown to investigators . Takeda Pharmaceuticals provided pioglitazone and placebo pills with identical physical characteristics , which were stored at the research pharmacy and dispensed in identical bottles . Outcomes and Follow-up The primary outcome was a reduction of at least 2 points in 2 histologic categories of the NAS without worsening of fibrosis after 18 months of therapy . Secondary liver histologic outcomes included resolution of NASH ; improvement in individual histologic scores ; or improvement in a combined histologic outcome , defined as a reduction in ballooning with at least a 2-point improvement in the NAS or an absolute NAS of 3 or lower ( with improvement in steatosis or inflammation ) without worsening of fibrosis . Baseline liver biopsy specimens were read by a team of experienced clinical pathologists to establish or rule out the presence of NASH and thus determine whether patients were included or excluded . At the end of the study , all biopsy specimens were reread by an experienced research pathologist ( F.T. ) , who was blinded to patient identity , intervention assignment , and pretreatment or posttreatment sequence ( 0 , 18 , or 36 months ) . Biopsy specimens were read by the research pathologist 2 times , with good to excellent intraobserver variability ( agreement > 75 % for all histologic parameters ) . Diagnosis of definite NASH was defined as zone 3 accentuation of macrovesicular steatosis ( any grade ) , hepatocellular ballooning ( any degree ) , and lobular inflammatory infiltrates ( any amount ) . The NAS was calculated as the sum of the steatosis , inflammation , and ballooning grade s from the liver biopsy , and histopathologic changes were determined by using st and ard criteria ( 44 ) . Additional secondary outcomes included the following : 1 ) fasting plasma glucose , fasting plasma insulin , FFA , hemoglobin A1c , fasting plasma lipid profile , adiponectin , and cytokeratin-18 concentrations ; 2 ) total body fat percentage , measured by DXA ; 3 ) hepatic triglyceride content , measured by magnetic resonance and proton spectroscopy ( 1H-MRS ) as previously described ( 14 , 16 , 35 , 45 ) ( baseline and 18 months only ) ; 4 ) glucose tolerance and insulin secretion on an OGTT ; 5 ) endogenous glucose production ( EGP ) , rate of glucose disappearance ( R d ) , and insulin-induced suppression of EGP and plasma FFA concentration , all measured during a euglycemic insulin clamp with tritiated glucose and indirect calorimetry ( baseline and 18 months only ) as previously reported ( Inhibition of apoptosis signal – regulating kinase 1 , a serine/threonine kinase , leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis . We evaluated the safety and efficacy of selonsertib , a selective inhibitor of apoptosis signal – regulating kinase 1 , alone or in combination with simtuzumab , in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis . In this multicenter phase 2 trial , 72 patients were r and omized to receive 24 weeks of open‐label treatment with either 6 or 18 mg of selonsertib  orally once daily with or without once‐weekly injections of 125 mg of simtuzumab or simtuzumab alone . The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies , magnetic resonance elastography , magnetic resonance imaging – estimated proton density fat fraction , quantitative collagen content , and noninvasive markers of liver injury . Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics , selonsertib groups with and without simtuzumab were pooled . After 24 weeks of treatment , the proportion of patients with a one or more stage reduction in fibrosis in the 18‐mg selonsertib group was 13 of 30 ( 43 % ; 95 % confidence interval , 26‐63 ) ; in the 6‐mg selonsertib group , 8 of 27 ( 30 % ; 95 % confidence interval , 14‐50 ) ; and in the simtuzumab‐alone group , 2 of 10 ( 20 % ; 95 % confidence interval , 3‐56 ) . Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography , collagen content and lobular inflammation on liver biopsy , as well as improvements in serum biomarkers of apoptosis and necrosis . There were no significant differences in adverse events between the treatment groups . Conclusion : These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2‐3 fibrosis . ( Hepatology 2018;67:549‐559 ) OBJECTIVE To compare the efficacy of ipragliflozin versus pioglitazone in patients with type 2 diabetes complicated by nonalcoholic fatty liver disease ( NAFLD ) . RESEARCH DESIGN AND METHODS In this open-label , r and omized , active-controlled trial , we r and omly assigned 66 patients with type 2 diabetes and NAFLD to receive ipragliflozin 50 mg ( n = 32 ) or pioglitazone 15–30 mg ( n = 34 ) orally once daily . The primary outcome was a change from baseline in the liver-to-spleen attenuation ratio ( L/S ratio ) on computed tomography at week 24 . RESULTS At week 24 , the mean ± SD L/S ratio had increased by 0.22 ( from 0.80 ± 0.24 to 1.00 ± 0.18 ) in the ipragliflozin group and 0.21 ( from 0.78 ± 0.26 to 0.98 ± 0.16 ) in the pioglitazone group ( P = 0.90 ) . Serum aspartate and alanine aminotransferase levels , HbA1c , and fasting plasma glucose were similarly reduced in the two treatment groups . Nevertheless , body weight and visceral fat area showed significant reductions only in the ipragliflozin group compared with the pioglitazone group ( P < 0.0001 and P = 0.0013 , respectively ) . There were no serious adverse events in either group . CONCLUSIONS Compared with pioglitazone , ipragliflozin exerts equally beneficial effects on NAFLD and glycemic control during the treatment of patients with type 2 diabetes complicated by NAFLD . Furthermore , ipragliflozin significantly reduced body weight and abdominal fat area OBJECTIVE Non-alcoholic fatty liver disease ( NAFLD ) is an increasingly recognized health problem . Various treatment strategies such as thiazolidinediones , metformin , lipid-lowering agents and antioxidants have been evaluated . So far , no single intervention has convincingly improved liver histology . Experience of using silymarin alone or in combination with other agents in patients with NAFLD is limited in the medical literature . The present study was conducted to evaluate the efficacy of silymarin plus vitamin E in the treatment of NAFLD . PATIENTS AND METHODS A sample of 36 patients was enrolled . The diagnosis of NAFLD was confirmed by percutaneous liver biopsy . All patients were r and omized to one of the following intervention groups : group I : treated with 2 tablets per day of silymarin plus vitamin E ( Eurosil 85 ® , MEDAS SL ) and a lifestyle modification program consisting of hypocaloric diet ( 1520 kcal , 52 % of carbohydrates , 25 % of lipids and 23 % of proteins ) and exercise for 3 months and group II ( only with the hypocaloric diet )  . Anthropometric variables as waist circumference , weight , body mass index ( BMI ) were measured . Biochemical parameters : Glucose , triglycerides , AST , ALT , GGt levels and insulin resistance ( HOMA-IR ) were determined under fasting conditions . Non-invasive NAFLD-index were applied before and after the treatments : Fatty liver index ( FLI ) , liver accumulation product ( LAP ) and NAFLD-Fibrosis score ( FS ) . RESULTS The mean age was 47.4 ± 11.2 years old ( range 18 - 67 ) ; 22 men and 14 women . In group I , 11 patients ( 61 % ) have a NAS-score > 5 and 10 ( 55.5 % ) in the group II ( NS ) . Anthropometric parameters decreased after treatment in both groups . Patients in both groups showed a decrease in GGt levels after treatment ( group I : 68 IU/L vs. 46.2 ± 27 IU/L ; p < 0.05 and group II 80.5 ± 46 IU/L vs. 50.3 ± 27 IU/L ; p < 0.05 ) . Only in group II we observed a significant decrease in AST and ALT levels . In both groups , we observed a decrease in : FLI index ( group I : 86.2 ± 19 vs. 76.9 + 20 ; p < 0.05 and in group II : 85.2 ± 18 vs. 77.5 ± 23 ; p < 0.05 ) , and NAFLD-FS index ( group I : -1.6 ± 1.8 vs. -2.1 ± 1.5 ; p < 0.05 and in group II -1 ± 1.9 vs. -1.5 ± 2.1 ; p < 0.05 ) . Patients in group I who did not get a 5 % loss of weight also displayed decreased GGt levels , and in the FLI and NAFLD-FS indexes ; whereas patients in group II without decrease of 5 % by weight showed no improvement in any of the analyzed parameters . CONCLUSIONS Treatment with silymarin plus vitamin E and a hypocaloric diet ameliorate function hepatic test , and non-invasive NAFLD index . Silymarin can be an alternative valid therapeutic option particularly when other drugs are not indicated or have failed or as a complementary treatment associated with other therapeutic programs BACKGROUND Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease in the world . Oral administration of synbiotic has been proposed as an effective treatment of NAFLD because of its modulating effect on the gut flora , which can influence the gut-liver axis . OBJECTIVE The objective was to evaluate the effects of supplementation with synbiotic on hepatic fibrosis , liver enzymes , and inflammatory markers in patients with NAFLD . DESIGN In a r and omized , double-blind , placebo-controlled clinical trial conducted as a pilot study , 52 patients with NAFLD were supplemented twice daily for 28 wk with either a synbiotic or a placebo capsule . Both groups were advised to follow an energy-balanced diet and physical activity recommendations . RESULTS At the end of the study , the alanine aminotransferase ( ALT ) concentration decreased in both groups ; this reduction was significantly greater in the synbiotic group . At the end of the study , the following significant differences [ means ( 95 % CIs ) ] were seen between the synbiotic and placebo groups , respectively : ALT [ -25.1 ( -26.2 , -24 ) compared with -7.29 ( -9.5 , -5.1 ) IU/L ; P < 0.001 ] , aspartate aminotransferase [ -31.33 ( -32.1 , -30.5 ) compared with -7.94 ( -11.1 , -4.8 ) IU/L ; P < 0.001 ] , γ-glutamyltransferase [ -15.08 ( -15.5 , -14.7 ) compared with -5.21 ( -6.6 , -3.9 ) IU/L ; P < 0.001 ] , high-sensitivity C-reactive protein [ -2.3 ( -3 , -1.5 ) compared with -1.04 ( -1.5 , -0.6 ) mmol/L ; P < 0.05 ] , tumor necrosis factor-α [ -1.4 ( -1.7 , -1.1 ) compared with -0.59 ( -0.8 , -0.3 ) mmol/L ; P < 0.001 ] , total nuclear factor κ-B p65 [ -0.016 ( -0.022 , -0.011 ) compared with 0.001 ( -0.004 , -0.007 ) mmol/L ; P < 0.001 ] , and fibrosis score as determined by transient elastography [ - 2.98 ( -3.6 , -2.37 ) compared with -0.77 ( -1.32 , -0.22 ) kPa ; P < 0.001 ] . CONCLUSIONS Synbiotic supplementation in addition to lifestyle modification is superior to lifestyle modification alone for the treatment of NAFLD , at least partially through attenuation of inflammatory markers in the body . Whether these effects will be sustained with longer treatment duration s remains to be determined BACKGROUND The aim of the present study was to compare the effects of gliclazide , liraglutide , and metformin in type 2 diabetes mellitus ( T2DM ) patients with non-alcoholic fatty liver disease ( NAFLD ) . METHODS Eighty-seven subjects were r and omized to receive liraglutide , metformin , or gliclazide for 24 weeks . Primary outcomes included HbA1c levels , intrahepatic fat ( IHF ) content , and liver function . RESULTS Both HbA1c levels and IHF content were reduced after treatment in all three groups . However , HbA1c levels were lower in the liraglutide- and metformin-treated groups than in the gliclazide-treated group , and reductions in IHF content were greater with liraglutide than with gliclazide . Liraglutide and metformin treatments reduced weight and improved liver function . Changes in IHF content were positively correlated with reductions in serum alanine aminotransferase and triglyceride levels , as well as weight . At 24 weeks , reductions in IHF content were greater in subjects with weight loss ≥5 % , changes in waistline ≤0 cm ( including decreases in waistline ) , HbA1c reductions ≥2.5 % , and HbA1c levels < 6.5 % . CONCLUSIONS In T2DM patients with NAFLD , compared with liraglutide and metformin , gliclazide result ed in less improvement in liver function , reductions in IHF content and HbA1c levels , and less weight loss ; in addition , slightly better improvements were achieved with liraglutide than with metformin BACKGROUND & AIMS Uncontrolled studies show sitagliptin , an oral DPP-4 inhibitor , may improve alanine aminotransferase and liver histology in non-alcoholic fatty liver disease ( NAFLD ) patients . We aim ed to compare sitagliptin vs. the efficacy of a placebo in reducing liver fat measured by MRI-derived proton density-fat fraction ( MRI-PDFF ) . METHODS This r and omized , double-blind , allocation-concealed , placebo-controlled trial included 50 NAFLD patients with prediabetes or early diabetes r and omized to sitagliptin orally 100mg/day or placebo for 24weeks . Primary outcome was liver fat change measured by MRI-PDFF in colocalized regions of interest within each of nine liver segments . Additional advanced assessment s included MR spectroscopy ( MRS ) for internal validation of MRI-PDFF 's accuracy , and magnetic resonance elastography ( MRE ) and FIBROSpect ® II to assess liver fibrosis . RESULTS Sitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF ( mean difference between sitagliptin and placebo arms : -1.3 % , p=0.4 ) . Compared to baseline , there were no significant differences in end-of-treatment MRI-PDFF  for sitagliptin ( 18.1 % to 16.9 % , p=0.27 ) or placebo ( 16.6 % to 14.0 % , p=0.07 ) . The groups had no significant differences for changes in alanine aminotransferase , aspartate aminotransferase , low-density lipoprotein , homeostatic model assessment insulin resistance , and MRE-derived liver stiffness . In both groups at baseline and post-treatment , MRI-PDFF and MRS showed robust correlation coefficients ranging from r(2)=0.96 to r(2)=0.99 ( p<0.0001 ) , demonstrating the strong internal validity of the findings . FIBROSpect ® II showed no changes in the sitagliptin group but was significantly increased in the placebo group ( p=0.03 ) . CONCLUSIONS Sitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD . LAY SUMMARY In a r and omized , double-blind , placebo-controlled study , the anti-diabetic drug sitagliptin was no more effective than placebo for improving liver fat and liver fibrosis in patients with non-alcoholic fatty liver disease . This study demonstrates that non-invasive magnetic resonance imaging techniques , including magnetic resonance imaging-proton density-fat fraction and magnetic resonance elastography , can be used to assess treatment response in non-alcoholic fatty liver disease clinical trials BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis , which is characterized by insulin resistance , steatosis , and necroinflammation with or without centrilobular fibrosis . Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus . METHODS We r and omly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet  ( a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight ) plus pioglitazone ( 45 mg daily ) or a hypocaloric diet plus placebo . Before and after treatment , we assessed hepatic histologic features , hepatic fat content by means of magnetic resonance spectroscopy , and glucose turnover during an oral glucose tolerance test ( [14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion ) . RESULTS Diet plus pioglitazone , as compared with diet plus placebo , improved glycemic control and glucose tolerance ( P<0.001 ) , normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels ( by 40 % vs. 21 % , P=0.04 ) , decreased alanine aminotransferase levels ( by 58 % vs. 34 % , P<0.001 ) , decreased hepatic fat content ( by 54 % vs. 0 % , P<0.001 ) , and increased hepatic insulin sensitivity ( by 48 % vs. 14 % , P=0.008 ) . Administration of pioglitazone , as compared with placebo , was associated with improvement in histologic findings with regard to steatosis ( P=0.003 ) , ballooning necrosis ( P=0.02 ) , and inflammation ( P=0.008 ) . Subjects in the pioglitazone group had a greater reduction in necroinflammation ( 85 % vs. 38 % , P=0.001 ) , but the reduction in fibrosis did not differ significantly from that in the placebo group ( P=0.08 ) . Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone ; no other adverse events were observed . CONCLUSIONS In this proof-of-concept study , the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis . Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone . ( Clinical Trials.gov number , NCT00227110 [ Clinical Trials.gov ] . ) ABSTRACT Objective “ The obesity epidemic ” has led to an increase in obesity-related conditions including non-alcoholic fatty liver disease ( NAFLD ) , for which effective treatments are in dem and . The polyphenol resveratrol prevents the development of experimental NAFLD through modulation of cellular pathways involved in calorie restriction . We aim ed to test the hypothesis that resveratrol alleviates NAFLD in a r and omised , clinical trial . Material s and methods A total of 28 overweight patients with transaminasemia and histological NAFLD were r and omised 1:1 to placebo or resveratrol 1.5 g daily for 6 months . Twenty-six participants completed the trial and underwent repeated clinical investigation , blood work , MR spectroscopy ; and 19 participants agreed to a repeat liver biopsy . Results Resveratrol treatment was generally not superior to placebo in improving plasma markers of liver injury ( primary outcome : alanine transaminase , p = 0.51 ) . Resveratrol-treated patients showed a 3.8 % decrease in liver lipid content ( p = 0.03 ) , with no difference between the two treatment arms ( p = 0.38 ) and no improvement of histological features .  Resveratrol treatment was not associated with improvements in insulin sensitivity or markers of the metabolic syndrome , except for a transient decrease in systolic BP . Microarray analysis and qRT-PCR revealed no major changes in expression profile . Also , we report a serious adverse event in a patient who developed fever and bicytopenia . Conclusions In this placebo-controlled , high-dose and long-term study , resveratrol treatment had no consistent therapeutic effect in alleviating clinical or histological NAFLD , though there may be a small ameliorating effect on liver function tests and liver fat accumulation The aim of this study was to determine if orlistat , an inhibitor of fat absorption , combined with caloric restriction in overweight subjects with nonalcoholic steatohepatitis results in weight loss and improved liver histology .  Fifty overweight subjects ( body mass index = > or=27 ) with biopsy proven nonalcoholic steatohepatitis were r and omized to receive a 1,400 Kcal/day diet plus vitamin E ( 800 IU ) daily with or without orlistat ( 120 mg three times a day ) for 36 weeks . Liver biopsies were repeated at week 36 . Twenty-three subjects in the orlistat/diet/vitamin E group and 18 in the diet/vitamin E group completed the study . The mean age was 47 + /- 9.0 ( st and ard deviation ) years and mean body mass index was 36.4 + /- 6.3 kg/m(2 ) . Four subjects were diabetic . The orlistat group lost a mean of 8.3 % body weight compared to 6.0 % in the diet plus vitamin E group ( not significant ) . Both groups also had similarly improved serum aminotransferases , hepatic steatosis , necroinflammation , ballooning , and nonalcoholic fatty liver disease activity scores . Stratified according to weight loss instead of treatment group , a loss of > or=5 % body weight ( n = 24 ) compared to < 5 % body weight ( n = 17 ) correlated with improvement in insulin sensitivity ( P = 0.001 ) and steatosis ( P = 0.015 ) . Comparing subjects who lost > or=9 % of body weight ( n = 16 ) , to those that did not ( n = 25 ) , improved insulin sensitivity ( P < 0.001 ) , adiponectin ( P = 0.03 ) , steatosis ( P = 0.005 ) , ballooning ( P = 0.04 ) , inflammation ( P = 0.045 ) , and nonalcoholic fatty liver disease activity score ( P = 0.009 ) were seen . Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score ( P = 0.03 ) . Orlistat did not enhance weight loss or improve liver enzymes , measures of insulin resistance , and histopathology . However , subjects who lost > or=5 % of body weight over 9 months improved insulin resistance and steatosis , and those subjects who lost > or=9 % also achieved improved hepatic histologic changes Background This study aim ed to evaluate the efficacy and safety of sitagliptin for treating Chinese patients with type 2 diabetes mellitus ( T2DM ) with nonalcoholic fatty liver disease ( NAFLD ) . Methods In total , 72 Chinese T2DM patients with NAFLD were divided r and omly into two groups of 36 patients each group . All 72 patients were assigned to receive either sitagliptin or diet and exercise for 52 weeks between January 2013 and December 2015 . The outcomes ’ measurements included serum levels of hemoglobin A1c , fasting plasma glucose , aspartate aminotransferase , and alanine aminotransferase . Results Seventy patients completed the study .  Sitagliptin showed greater efficacy than the diet and exercise in decreasing the hemoglobin A1c and fasting plasma glucose levels at weeks 13 , 26 , 39 , and 52 . In addition , no significant changes in the average aspartate aminotransferase and alanine aminotransferase levels were found during the 52-week follow-up in both the sitagliptin and the control groups . Conclusion The results of this study indicate that sitagliptin is an effective and safe treatment for patients with T2DM and NAFLD OBJECTIVE Hepatic steatosis is a common complication in patients with lipodystrophies and can lead to cirrhosis . There is no proven effective therapy for hepatic steatosis , but cholic acid ( CA ) , a farnesoid X receptor agonist , has previously been shown to reduce hepatic triglyceride ( TG ) content in mice and serum TG in humans . Our objective was to assess clinical efficacy and tolerability of CA therapy in patients with lipodystrophy and hepatic steatosis . DESIGN A r and omized , double-blind , placebo-controlled , crossover study . METHODS Eighteen patients with genetic or autoimmune lipodystrophies and elevated hepatic TG content participated in the study . The intervention was CA ( 15 mg/kg per day ) compared with placebo for a period of 6 months each . Hepatic TG content , the primary outcome variable , was measured with (1)H magnetic resonance spectroscopy at baseline and at 3 and 6 months during each study period . Levels of serum alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) , gamma-glutamyl transpeptidase ( GGT ) , and TG were secondary end points of the study . RESULTS Compared with placebo , CA did not reduce ( median ( interquartile range ) hepatic TG content ( 14.8 % ( 9.4 - 19.0 % ) vs 15.9 % ( 10.5 - 26.5 % ) respectively ; P=0.42 ) or serum TG ( ( 340 mg/dl ( 233 - 433 mg/dl ) vs 390 mg/dl ( 233 - 595 mg/dl ) respectively ; P=0.45 ) ) . CA therapy also did not change AST , ALT , or GGT levels . Two patients developed diarrhea and excessive flatus while taking CA and these symptoms resolved after reducing the dose of CA . CONCLUSION CA was well tolerated but did not reduce hepatic TG content in patients with lipodystrophy Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease in the world . Resveratrol is a polyphenolic compound with antioxidant capacity that shows beneficial effects on down-regulation of inflammatory mediators and metabolic disorders . We hypothesized that supplementation with resveratrol can further improve the efficacy of lifestyle modifications in the management of NAFLD . In this r and omized , double-blinded , controlled clinical trial , 50 NAFLD patients were supplemented with either a 500-mg resveratrol capsule or a placebo capsule for 12 weeks . Both groups were advised to follow an energy-balanced diet and received physical activity recommendations  . Serum liver enzymes , inflammatory markers , hepatic steatosis and fibrosis , dietary intake , anthropometric measurements , and physical activity were assessed at both baseline and the end of the study . In both groups , anthropometric measurements ( weight , body mass index , waist circumference ) , liver enzymes , and steatosis grade improved ( P < 005 ) . Resveratrol supplementation was associated with a significant reduction in liver enzyme alanine aminotransferase , inflammatory cytokines , nuclear factor κB activity , serum cytokeratin-18 , and hepatic steatosis grade , as compared with placebo supplementation ( P < .05 ) . For the treatment of NAFLD , our results showed that 12 weeks of supplementation of 500 mg resveratrol , along with lifestyle modification , is superior to lifestyle modification alone . This is at least partially due to the attenuation of inflammatory markers and hepatocellular apoptosis . More studies are needed to confirm and increase the clinical application of the present results BACKGROUND & AIMS Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease ( NAFLD ) . We herein assessed the effect of orlistat in patients with NAFLD . METHODS We performed a r and omized , double-blind , placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound ( US ) and confirmed by liver biopsy ( 40 patients ) . The patients were r and omized to receive either orlistat ( 120 mg 3 times daily for 6 months ) or placebo . All patients participated in an identical behavioral weight loss program . All patients underwent monthly evaluation by abdominal US ; liver enzyme levels , lipid profiles , insulin levels , and anthropometric parameters were monitored , and all patients underwent nutritional follow-up evaluation . Twenty-two patients underwent a second liver biopsy examination at the end of the study . RESULTS Fifty-two patients were recruited and 44 ( mean age , 47.7 y ; mean body mass index , 33 ) completed the study .  Serum glucose and insulin levels ( P<.03 ) were significantly higher in the orlistat group , which also presented a higher degree of fibrosis . Body mass index was reduced significantly in each group , with a nonsignificant difference between the groups . Serum alanine transaminase ( ALT ) levels decreased significantly in both groups , with an almost 2-fold reduction in the orlistat group ( 48 % vs 26.4 % ) . There was a statistically significant reversal of fatty liver by US only in the orlistat group ( P<.05 ) . CONCLUSIONS Orlistat improves serum ALT levels and steatosis on US in NAFLD patients , beyond its effect on weight reduction Background : Non-alcoholic steatohepatitis ( NASH ) is a clinicopathological entity that is being recognized more frequently in recent years . This study aim ed to evaluate the effects of Metformin , with and without a probiotic supplement on liver aminotransferases in patients with NASH . Methods : Sixty four patients 18 - 75 years with NASH confirmed by biopsy and histological assessment were enrolled to study . Patients were r and omized to one of the following treatments for 6 months : Group I , probiotic ( Protexin two tablets per day ) plus Metformin 500 mg two tablets per day ( Met/Pro ) , or group II , Metformin 500 mg two tablets per day plus two placebo tablet ( Met/P ) . After 6 month alanine aminotransferase ( ALT ) , aspartate aminotransferase , and ultrasound grading of NASH were assessed . Results : In group I , serum alanine aminotransferase ( ALT : 133.7 ± 70 vs. 45.2 ± 32.5 ; P < 0.00 ) , and aspartate aminotransferase activity ( AST : 123.1 ± 72 vs. 44.2 ± 33.9 ; P < 0.001 ) , and ultrasound grading of NASH ( P < 0.001 ) all decreased significantly by the end of the treatment period . In group II , while serum alanine aminotransferase ( ALT ) was not significantly reduced ( 118.4 ± 67.9 vs. 112.5 ± 68.7 ; P < 0.064 ) , aspartate aminotransferase activity ( AST : 125.3 ± 71 vs. 113.4 ± 71 ; P < 0.001 ) , and ultrasound grading of NASH did fall significantly ( P < 0.01 ) . Body mass index ( BMI ) , fasting blood sugar ( FBS ) , cholesterol , and triglyceride fell significantly in both groups . Conclusions : Probiotic combination with Metformin improves liver aminotransferases better than metformin alone in patients with NASH Aim To investigate the efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease ( NAFLD ) patients . Methods This is an open-label , r and omized , a single-center study . Sixty-four patients , with impaired glucose metabolism and elevated alanine aminotransferase for at least 6 months before enrollment and NAFLD activity score at least 5 in liver biopsy , were r and omized as group 1 and received metformin 1700 mg/day , group 2 received rosiglitazone 4 mg/day , and group 3 received a combination of metformin 1700 mg/day and rosiglitazone 4 mg/day for 12 months . Results Baseline demographic and laboratory findings were similar in all the three groups , except baseline insulin level that was significantly higher in group 1 and group 3 versus group 2 ( P<0.05 ) . Serum transaminase levels showed a significant decrease after treatment in both group 2 and group 3 . Serum & ggr;-glutamyl transpeptidase levels decreased significantly only in the group 3 . However , there was no significant change in liver tests of group 1 . Postpr and ial glucose levels showed significant decrease in all of the three groups . Homeostasis model assessment -insulin resistance was reduced significantly in only group 2 . NAFLD score was significantly decreased on follow-up biopsy of the patients in group 2 and group 3 . Fibrosis did not change significantly after the treatment . Conclusion Rosiglitazone therapy seems to be more effective in metabolic control and histological improvement in NAFLD patients with impaired glucose metabolism OBJECTIVES : Nonalcoholic fatty liver disease ( NAFLD ) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis . Its prevalence has been found to be as high as 39 % . It is estimated that up to 15 % of those affected will go on to have progressive liver disease . Currently , there is no proven therapy for NAFLD . In this study , we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD . METHODS : In all , 1,005 men and women , aged 50–70 years were r and omized to receive either a daily combination of atorvastatin 20 mg , vitamin C 1 g , and vitamin E 1,000 IU vs. matching placebo , as part of the St Francis Heart Study r and omized clinical trial . Liver to spleen ( LS ) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence . Baseline and final LS ratios were compared within treatment groups , and results were compared between the treatment and placebo groups using univariate and multivariate analyses . Mean duration of follow-up was 3.6 years . RESULTS : There were 80 patients with NAFLD at baseline . We identified baseline triglyceride levels ( odds ratio (OR)=1.003 , P<0.001 ) and body mass index ( OR=0.10 , P<0.001 ) as independent correlates of NAFLD . Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up , 70 vs. 34 % ( OR=0.29 , P<0.001 ) . CONCLUSIONS : In conclusion , atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71 % in healthy individuals with NAFLD at baseline after 4 years of active therapy Background : Non-alcoholic steatohepatitis ( NASH ) is a progressive form of nonalcoholic fatty liver disease . Several studies suggest that pentoxifylline ( PTX ) can improve the disease outcome . Objectives : We aim ed to compare the effect of pentoxifylline with placebo on liver aminotransferases and cytokines , including interleukin 6 ( IL-6 ) , tumor necrosis factor alpha ( TNF-α ) , and interleukin 8 ( IL-8 ) in patients with NASH . Patients and Methods : Thirty patients with NASH were included in the study , based on ultrasonography and 1.5-fold mean change from baseline serum levels of liver aminotransferases . Patients with NASH were r and omized to receive 1200 mg PTX ( the intervention group ) or placebo ( the placebo group ) for 6 months . The serum levels of liver aminotransferases and cytokines were compared between the intervention and placebo groups , at various time points . Results : The serum levels of liver aminotransferases were significantly reduced at 3 months and at 6 months , compared with baseline , in both groups . The serum levels of IL-6 were significantly decreased , in both groups , only at 6 months , compared with baseline . Compared to the placebo group , the serum level of TNF-α was significantly decreased in the intervention group , at 6 months . The serum level of IL-8 was increased , in both groups , after 6 months , without reaching clinical significance . There was no significant difference in serum levels of liver aminotransferases and cytokines , between intervention and placebo groups . Conclusions : Decreases in the serum levels of liver aminotransferases and cytokines , in both groups , are related to low-calorie diets and exercise , rather than PTX BACKGROUND & AIMS Obeticholic acid ( OCA ; INT-747 , 6α-ethyl-chenodeoxycholic acid ) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid , the natural agonist of the farnesoid X receptor , which is a nuclear hormone receptor that regulates glucose and lipid metabolism . In animal models , OCA decreases insulin resistance and hepatic steatosis . METHODS We performed a double-blind , placebo-controlled , proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus . Patients were r and omly assigned to groups given placebo ( n = 23 ) , 25 mg OCA ( n = 20 ) , or 50 mg OCA ( n = 21 ) once daily for 6 weeks . A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period . We also measured levels of liver enzymes , lipid analytes , fibroblast growth factor 19 , 7α-hydroxy-4-cholesten-3-one ( a BA precursor ) , endogenous bile acids , and markers of liver fibrosis . RESULTS When patients were given a low-dose insulin infusion , insulin sensitivity increased by 28.0 % from baseline in the group treated with 25 mg OCA ( P = .019 ) and 20.1 % from baseline in the group treated with 50 mg OCA ( P = .060 ) . Insulin sensitivity increased by 24.5 % ( P = .011 ) in combined OCA groups , whereas it decreased by 5.5 % in the placebo group . A similar pattern was observed in patients given a high-dose insulin infusion . The OCA groups had significant reductions in levels of γ-glutamyltransferase and alanine aminotransferase and dose-related weight loss . They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19 , associated with decreased levels of 7α-hydroxy-4-cholesten-3-one and endogenous bile acids , indicating activation of farnesoid X receptor . Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA . Adverse experiences were similar among groups . CONCLUSIONS In this phase 2 trial , administration of 25 or 50 mg OCA for 6 weeks was well tolerated , increased insulin sensitivity , and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease . Longer and larger studies are warranted . Clinical Trials.gov , Number : NCT00501592 BACKGROUND Long-chain polyunsaturated fatty acid omega-3 levels are decreased in the hepatic tissue of patients with nonalcoholic fatty liver disease .  Polyunsaturated fatty acids are negative regulators of hepatic lipogenesis and attenuate the inflammatory response in mice . AIM To investigate whether polyunsaturated fatty acid may be effective in the treatment of nonalcoholic fatty liver disease . METHODS Forty patients with nonalcoholic fatty liver disease were r and omized into two groups for treatment of 6 months duration . Group DP ( n=20 ) received an AHA recommended diet and polyunsaturated fatty acid 2g/day ; Group D ( n=20 ) received only the AHA regular diet . Outcome measurements were fatty liver assessed by abdominal ultrasound , liver aminotransferase and tumour necrosis factor-alpha serum levels , and insulin resistance assessed by HOMA(IR ) . RESULTS After 6 months of treatment , the DP group displayed a decrease in alanine aminotransferase levels ( p<0.01 ) , as well as in triglyceride levels ( p<0.01 ) , serum tumour necrosis factor-alpha levels ( p<0.05 ) and in HOMA(IR ) ( p<0.05 ) . In the D group , no significant modification was observed . In the DP group , complete fatty liver regression was observed in 33.4 % of the patients , and an overall reduction in 50 % . In contrast , no patient achieved complete regression in the D group , whereas some amount of reduction occurred in 27.7 % of the patients ; the remaining 72.2 % did not change . CONCLUSION Our results indicate that alanine aminotransferase , triglyceride and serum tumour necrosis factor-alpha levels , as well as fatty liver improved after polyunsaturated fatty acid administration Background : Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease in the world . Oral administration of symbiotic and Vitamin E has been proposed as an effective treatment in NAFLD patients . This study was carried out to assess the effects of symbiotic and /or Vitamin E supplementation on liver enzymes , leptin , lipid profile , and some parameters of insulin resistance ( IR ) in NAFLD patients . Material s and Methods : We r and omly assigned sixty NAFLD adult patients to receive ( 1 ) symbiotic twice daily + Vitamin E-like placebo capsule ; ( 2 ) 400 IU/d Vitamin E + symbiotic-like placebo ; ( 3 ) symbiotic twice daily + 400 IU/d Vitamin E ; and ( 4 ) symbiotic-like placebo + Vitamin E-like placebo for 8 weeks . Results : Symbiotic plus Vitamin E supplementation led to a significant decrease in concentrations of liver transaminase ( P ≤ 0.05 ) . Mean difference of apolipoprotein A-1 was more significant in symbiotic group compared to control . However , mean difference of apolipoprotein B100/A-1 was only significant in symbiotic group compared to control . At the end of the study , significant differences in total cholesterol ( TC ) and low-density lipoprotein cholesterol ( LDL-C ) were seen between the symbiotic plus Vitamin E and control groups ( P < 0.001 ) . Furthermore , intake of symbiotic plus Vitamin E supplements led to a significant decrease in concentrations of triglycerides ( TG ) after the intervention . Significant differences in leptin , fasting blood sugar ( FBS ) , and insulin levels were seen between the symbiotic plus Vitamin E and control groups at the end of the study ( P < 0.001 ) . In contrast , symbiotic and /or Vitamin E supplementation did not affect high-density lipoprotein cholesterol and homeostasis model assessment for IR levels . Conclusion : In our study , symbiotic plus Vitamin E supplementation was the most effective treatment in lowering liver enzymes , leptin , FBS , insulin , TG , TC , and LDL-C among NAFLD patients Introduction Non-alcoholic fatty liver disease ( NAFLD ) is a common liver disease worldwide . Experimental and small clinical trials have demonstrated that angiotensin II blockers ( ARB ) may be anti-fibrotic in the liver . The aim of this r and omised controlled trial was to assess whether treatment with Losartan for 96 weeks slowed , halted or reversed the progression of fibrosis in patients with non-alcoholic steatohepatitis ( NASH ) . Methods Double-blind r and omised-controlled trial of Losartan 50 mg once a day versus placebo for 96 weeks in patients with histological evidence of NASH . The primary outcome for the study was change in histological fibrosis stage from pre-treatment to end-of-treatment . Results The study planned to recruit 214 patients . However , recruitment was slower than expected , and after 45 patients were r and omised ( median age 55 ; 56 % male ; 60 % diabetic ; median fibrosis stage 2 ) , enrolment was suspended . Thirty-two patients ( 15 losartan and 17 placebo ) completed follow up period : one patient ( 6.7 % ) treated with losartan and 4 patients ( 23.5 % ) in the placebo group were “ responders ” ( lower fibrosis stage at follow up compared with baseline ) . The major reason for slow recruitment was that 39 % of potentially eligible patients were already taking an ARB or angiotensin converting enzyme inhibitor ( ACEI ) , and 15 % were taking other prohibited medications . Conclusions Due to the widespread use of ACEI and ARB in patients with NASH this trial failed to recruit sufficient patients to determine whether losartan has anti-fibrotic effects in the liver . Trial registration IS RCT N Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol . Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis ( NASH ) . Therefore , we aim ed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction ( MRI-PDFF ) and liver histology in patients with biopsy-proven NASH . In this r and omized , double-blind , placebo-controlled trial , 50 patients with biopsy-proven NASH were r and omized to either ezetimibe 10 mg orally daily or placebo for 24 weeks . The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments . Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed . Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF ( mean difference between the ezetimibe and placebo arms -1.3 % , P = 0.4 ) . Compared to baseline , however , end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm ( 15%-11.6 % , P < 0.016 ) but not in the placebo arm ( 18.5%-16.4 % , P = 0.15 ) . There were no significant differences in histologic response rates , serum alanine aminotransferase and aspartate aminotransferase levels , or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms . Compared to histologic nonresponders ( 25/35 ) , histologic responders ( 10/35 ) had a significantly greater reduction in MRI-PDFF ( -4.35 ± 4.9 % versus -0.30 ± 4.1 % , P < 0.019 ) . Conclusions : Ezetimibe did not significantly reduce liver fat in NASH . This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH . ( Hepatology 2015;61:1239–1250 Background and purpose Nonalcoholic fatty liver disease ( NAFLD ) is one of the causes of a fatty liver , occurring when fat is deposited ( steatosis ) in the liver not due to excessive alcohol use . It is related to insulin resistance and the metabolic syndrome . The purpose of the present study was to evaluate the impact of combination therapy with alpha-lipoic acid ( ALA ) and ursodeoxycholic acid ( UDCA ) on NAFLD . Methods Alpha-lipoic acid 400 mg/day plus UDCA 300 mg/day ( ALAUDCA ) was investigated in patients over a period of 12 months using a r and omized , placebo (PLA)-controlled study with four parallel groups . Serum concentration of gamma-glutamyl transpeptidase ( GGT ) , alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) , albumin and platelets ( PLT ) were measured at the beginning and at the end of the treatment . Moreover , the AST/ALT ratio and the NAFLD fibrosis score were examined . Results A total of 120 patients were r and omly assigned to the four groups . ALA and UDCA were safe and well tolerated in the oral daily administration only . AST , ALT , GGT ( p < 0.001 ) showed a significant difference between ALAUDCA and other three groups . Besides , NAFLD fibrosis score underlined a significant reduction ( p < 0.04 ) in the ALAUDCA group , while AST/ALT ratio presented a moderate decline ( p > 0.05 ) . Conclusion ALAUDCA therapy reduced AST , ALT , GGT values and improved NAFLD fibrosis score and AST/ALT ratio , especially in patients who were on a hypocaloric diet . These findings will be useful in patient selection in future clinical trials with ALAUDCA in long-term studies Nonalcoholic steatohepatitis ( NASH ) , a progressive form of nonalcoholic fatty liver disease , is one of the most common hepatic diseases in children . We conducted a r and omized controlled clinical trial on children with biopsy-proven NASH based on a combinatorial nutritional approach compared with placebo . Participants were assigned to lifestyle modification plus placebo or lifestyle modification plus a mix containing docosahexaenoic acid , choline , and vitamin E ( DHA-CHO-VE ) .  Forty children and adolescents participated in the entire trial . The primary outcome was the improvement of liver hyperechogenicity . Secondary outcomes included alterations of alanine aminotransferase ( ALT ) and other metabolic parameters . Furthermore , changes of serum bile acids ( BA ) and plasma fibroblast growth factor 19 ( FGF19 ) levels were evaluated as inverse biomarkers of disease severity . At the end of the study , we observed a significant decrease in severe steatosis in the treatment group ( 50 % to 5 % , p = 0.001 ) . Furthermore , although the anthropometric and biochemical measurements in the placebo and DHA-CHO-VE groups were comparable at baseline , at the end of the study ALT and fasting glucose levels improved only in the treatment group . Finally , we found that BA levels were not influenced whereas FGF19 levels were significantly increased by DHA-CHO-VE . The results suggest that a combination of DHA , VE , and CHO could improve steatosis and reduce ALT and glucose levels in children with NASH . However , further studies are needed to assess the impact of a DHA and VE combination on repair of liver damage in paediatric NASH BACKGROUND & AIMS Nonalcoholic steatohepatitis ( NASH ) is a leading cause of chronic liver disease for which there is limited therapy available . Insulin sensitizing , anti-inflammatory , and antifibrotic properties of thiazolidinediones support their use in treating NASH . We have evaluated pioglitazone in the treatment of nondiabetic patients with NASH . METHODS We r and omized 74 nondiabetic patients ( 45 men ; median age , 54 y ) with histologically proven NASH to 12 months of st and ard diet , exercise , and either placebo or pioglitazone ( 30 mg/day ) . Sixty-one patients ( 30 placebo , 31 pioglitazone ) had liver biopsies both at the beginning and the end of the study . RESULTS Compared with placebo , pioglitazone therapy was associated with an increase in weight ( mean change , -0.55 vs + 2.77 kg ; P = .04 ) and a reduction in glucose ( + 0.4 vs -0.1 mmol/L ; P = .02 ) , HbA1c ( + 0.16 % vs -0.18 % ; P = .006 ) , insulin C peptide level ( + 42 vs -78 pmol/L ; P = .02 ) , alanine aminotransferase level ( -10.9 vs -36.2 u/L ; P = .009 ) , gamma-glutamyltransferase level ( -9.4 vs -41.2 u/L ; P = .002 ) , and ferritin ( -11.3 vs -90.5 microg/L ; P = .01 ) . Histologic features including hepatocellular injury ( P = .005 ) , Mallory-Denk bodies ( P = .004 ) , and fibrosis ( P = .05 ) were reduced in patients treated with pioglitazone compared with those in the placebo group . CONCLUSIONS Pioglitazone therapy over a 12-month period in nondiabetic subjects with NASH result ed in improvements in metabolic and histologic parameters , most notably liver injury and fibrosis . Larger extended trials are justified to assess the long-term efficacy of pioglitazone in this patient group Aim . This study compared the effects of telmisartan and losartan on  nonalcoholic fatty liver disease ( NAFLD )  and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus . Methods . This was a r and omized , open-label , parallel-group comparison of therapy with telmisartan or losartan .  Nineteen hypertensive NAFLD patients with type 2 diabetes were r and omly assigned to receive telmisartan at a dose of 20 mg once a day ( n = 12 ) or losartan at a dose of 50 mg once a day ( n = 7 ) for 12 months . Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen ( L/S ) ratio , as well as several parameters of glycemic and lipid metabolism , were compared before and after 12 months . Results . The telmisartan group showed a significant decline in serum free fatty acid ( FFA ) level ( from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L ( mean ± SD ) , P = 0.005 ) and a significant increase in L/S ratio ( P = 0.049 ) evaluated by CT scan , while these parameters were not changed in the losartan group . Conclusion . Although there was no significant difference in improvement in liver enzymes  with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months , it is suggested that telmisartan may exert beneficial effects by improving fatty liver INTRODUCTION The burden of non-alcoholic steatohepatitis ( NASH ) is growing and current pharmacologic treatments are limited by side effects and inconsistent efficacy . Pilot studies suggest that pentoxifylline ( PTX ) can reduce liver injury in patients with NASH . OBJECTIVE We sought to determine the tolerability of PTX and its effect on aminotransferases and liver histology in patients with NASH . MATERIAL AND METHODS Thirty patients with biopsy proven NASH were r and omized in a 2:1 fashion to receive 1,200 mg PTX or placebo for 12 months . Metabolic parameters , aminotransferases , liver histology and hepatic gene expression changes were compared . RESULTS At baseline the groups were similar . Adverse events were mild , most frequently headache and abdominal cramps , and did not differ between groups ( p = NS ) . After 12 months , ALT and AST decreased from 92 ± 12 IU/L to 67 ± 13 IU/L and 67 ± 6 IU/L to 47 ± 6 IU/L ( p < 0.05 ) , respectively in patients treated with PTX . No significant effect was seen with  placebo . Steatosis and cellular ballooning improved in the PTX group ( p < 0.05 ) , whereas no histological feature of steatohepatitis improved with placebo . However , between groups comparison of both biochemical and histological features were nonsignificant . CONCLUSION Pentoxifylline is safe , well tolerated and improves transaminases and histology in patients with NASH when compared to baseline and may be a reasonable therapeutic modality for the treatment of NASH . However PTX failed to reduce transaminases compared to placebo and did not positively affect any of the metabolic markers postulated to contribute to NASH . Although animal data and small pilot studies in humans have suggested that PTX may be effective as a treatment for NASH , translating this therapy to clinical practice may prove challenging Aim To investigate if conjugated linoleic acid supplementation ( CLA ) affects metabolic factors and oxidative stress in non-alcoholic fatty liver disease ( NAFLD ) . Methods The study was a r and omized , controlled clinical trial conducted in specialized and subspecialized clinics of Tabriz University of Medical Sciences from January 2014 to March 2015 . 38 obese NAFLD patients were r and omly allocated into either the intervention group , receiving three 1000 mg softgel of CLA with a weight loss diet and 400 IU vitamin E , or into the control group , receiving only weight loss diet and 400 IU vitamin E for eight weeks . Dietary data and physical activity , as well as anthropometric , body composition , metabolic factors , and oxidative stress were assessed at baseline and at the end of the study . Results Weight , body composition , and serum oxidative stress , insulin , and lipid profile significantly improved in both groups , while hemoglobin A1c ( HbA1c ) levels ( P = 0.004 ) , total cholesterol to high density lipoprotein ratio ( P = 0.008 ) , low density lipoprotein to high density lipoprotein ratio ( LDL/HDL ) ( P = 0.002 ) , and alanine aminotransferase to aspartate aminotransferase ( ALT/AST ) ratio ( P = 0.025 ) significantly decreased in the intervention group . At the end of the study , fat mass ( P = 0.001 ) , muscle mass ( P = 0.023 ) , total body water ( P = 0.004 ) , HbA1c ( P < 0.001 ) , triglycerides ( P = 0.006 ) , LDL/HDL ratio ( P = 0.027 ) , and ALT/AST ratio ( P = 0.046 ) were significantly better in the CLA group than in the control group . Conclusion CLA improved insulin resistance , lipid disturbances , oxidative stress , and liver function in NAFLD . Therefore , it could be considered as an effective complementary treatment in NAFLD . Registration number : I RCT 2014020516491N1 Objective : To investigate the efficacy and safety of n-3 polyunsaturated fatty acids ( PUFA ) treatment in obese children with nonalcoholic fatty liver disease ( NAFLD ) . Methods : One hundred and eight obese ( body mass index ( BMI ) > 95th percentile for age and sex ) adolescents with NAFLD were included in the study . Mean age of the subjects was 13.8±3.9 years ( 9 - 17 yrs ) . The diagnosis of NAFLD was based on the presence of liver steatosis with high transaminases . The subjects were r and omly divided into two groups . Group 1 ( PUFA group , n=52 ) received a 1000 mg dose of PUFA once daily for 12 months and lifestyle intervention . Group 2 ( placebo group , n=56 ) received a recommended diet plus placebo and lifestyle intervention for 12 months . Insulin resistance was evaluated by homeostasis model assessment of insulin resistance ( HOMA-IR ) from fasting sample s. Results : BMI , fasting insulin levels and HOMA-IR values in both groups decreased significantly at the end of the study . In group 1 , 67.8 % of the patients had a decrease from baseline in the prevalence of steatosis ( p<0.001 ) . Frequency of elevated alanine aminotransferase ( ALT ) levels ( 39.2 % to 14.2 % ; p<0.01 ) and elevated aspartate aminotransferase ( AST ) levels ( 25 % to 17.8 % ; p=0.01 ) decreased significantly in the PUFA group . Following a 12-month diet plus placebo and lifestyle intervention treatment , 40.3 % ( 21 ) of the patients in the placebo group also showed a decrease in frequency of steatosis ( p=0.04 ) and slight decreases in frequency of elevated ALT levels ( 38.4 % to 28.8 % ; p=0.01 ) and AST levels ( 30.7 % to 28.8 % ; p>0.05 ) . Conclusion : Our results indicated that n-3 PUFA treatment is safe and efficacious in obese children with NAFLD and can improve ultrasonographic findings and the elevated transaminase levels OBJECTIVE Nonalcoholic fatty liver disease is an increasingly recognized condition that may progress to end-stage liver disease . We investigated the effects of weight reduction and ursodeoxycholic acid administration in patients with this disease . RESEARCH METHODS AND PROCEDURES A double-blind , placebo-controlled trial . Twenty-seven women with a body mass index of > 30 kg/m2 and willing to participate in the diet plan for six weeks were studied were assigned to one of two treatment groups ( ursodeoxycholic acid , n = 14 : placebo n = 13 ) . Both groups received a normal diet ( 1,200 kcal/d ) plus 1200 mg/d of ursodeoxycholic acid or placebo .  Hepatic steatosis , was assessed by abdominal ultrasound . Fasting glucose , cholesterol , triglycerides , and aminotransferases levels were determined before and after treatment . RESULTS Body mass index decreases significantly from 34.2 + /- 4.2 kg/m2 and 33.3 + /- 1.6 kg/m2 to 31.8 + /- 4.5 kg/m2 and 30.6 + /- 2.6 kg/m2 in the ursodeoxycholic acid and placebo groups , p < 0.001 . The hepatic steatosis index decreased from 2.3 + /- 0.7 to 1.0 + /- 0.6 and 2.2 + /- 0.7 to 1.1 + /- 0.7 in the ursodeoxycholic acid and placebo groups , p<0.003 . Serum AST decreased significantly from 41.2 + /- 5.6 to 34.5 + /- 3.4 in the ursodeoxycholic acid group , p < 0.001 , and from 43.6 + /- 4.2 to 35.3 + /- 2.9 in the placebo group , p < 0.001 . Serum ALT decreased from 62.9 + /- 6.5 to 44.0 + /- 3.5 in the ursodeoxycholic acid group , p < 0.001 , and from 63.5 + /- 4.5 to 44.0 + /- 3.5 in the placebo group . We did not find any differences in all variables studied between groups . CONCLUSIONS The present study shows beneficial effect of weight reduction , producing improvements in biochemical and imaging markers of liver disease BACKGROUND Non-alcoholic fatty liver disease ( NAFLD ) is considered as the hepatic manifestation of insulin resistance ( IR ) syndrome . The effect of insulin sensitizers on liver function tests and metabolic indices in NAFLD patients is a matter of debate . OBJECTIVES The aim of study was to compare the effects of two different insulin sensitizers , pioglitazone , and metformin , on liver function tests ( LFT ) , lipid profile , homeostasis model assessment -IR ( HOMA-IR ) index , and liver fat content ( LFC ) in NAFLD patients . MATERIAL S AND METHODS This double blind clinical trial was performed on patients who were referred to a gastroenterology clinic with evidence of fatty liver in ultrasonography . After excluding other causes , participants with persistent elevated alanine aminotransferase ( ALT ) levels and " NAFLD liver fat score " greater than -0.64 were presumed to have NAFLD and were enrolled . They were r and omly assigned to take metformin ( 1 g/day ) or pioglitazone ( 30 mg/day ) for four months . Fasting serum glucose ( FSG ) , ALT , aspartate aminotransferase ( AST ) , alkaline phosphatase ( ALP ) , triglyceride , cholesterol ( CHOL ) , high and low density lipoprotein ( HDL , LDL ) , HOMA-IR , and LFC were checked at the baseline , two and four months post-treatment . LFC was measured by a vali date d formula . RESULTS Eighty patients ( 68 males ) with mean age of 35.27 ( ± 7.98 ) were included . After 2 months , LFT was improved significantly in the pioglitazone group and did not change in the metformin group . After four months , both medications significantly decreased serum levels of LFT , FSG , CHOL , LDL , HOMA-IR , and LFC , and increased serum level of HDL . No statistically significant differences were seen between the two treatment groups with regard to the changes of laboratory parameters and LFC from baseline to four months post-treatment . CONCLUSIONS During the four months , the use of metformin ( 1 g/day ) and pioglitazone ( 30 mg/day ) were safe and might have equally affected LFT , HOMA-IR , lipid profile , and LFC in NAFLD patients Background There are no licensed treatments for non alcoholic fatty liver disease ( NAFLD ) in adults or children . In NAFLD , several studies have shown a benefit of omega-3 fatty acid treatment on lipid profile , insulin-sensitivity and hepatic steatosis and it has also been suggested that Vitamin D treatment has potential antifibrotic properties in liver disease . Trial Design To date , however , there are no studies that have tested the combination of Docosahexanoic acid ( DHA ) and vitamin D treatment which may benefit the whole spectrum of disease in NAFLD . Our aim therefore , was to test the effect of daily DHA ( 500 mg ) plus vitamin D ( 800 IU ) treatment , in obese children with biopsy-proven NAFLD and vitamin D deficiency , in a r and omized , double-blind placebo-controlled trial . Methods The 41/43 patients completed the study ( 18-treatment , 23-placebo ) . At 12 months : i ) the main outcome was liver histology improvement , defined by NAS ; ii ) the secondary outcome was amelioration of metabolic parameters .  Results DHA plus vitamin D treatment reduced the NAFLD Activity Score ( NAS ) , in the treatment group ( 5.4 v1.92 ; p<0.001 for baseline versus end of study ) . There was no change in fibrosis score , but a reduction of the activation of hepatic stellate cells ( HSC ) and fibrillar collagen content was noted ( 3.51±1.66 v. 1.59±1.37 ; p = 0.003 ) in treatment group . Moreover , the triglycerides ( 174.5 vs. 102.15 mg/dl ) , ALT ( 40.25 vs. 24.5 UI/l ) and HOMA-IR ( 4.59 vs. 3.42 ) were all decreased with treatment . Conclusion DHA plus vitamin D treatment improved insulin-resistance , lipid profile , ALT and NAS . There was also decreased HSC activation and collagen content with treatment Bile acid sequestrants ( BAS ) lower plasma low density lipoprotein levels and improve glycemic control . Colestimide , a BAS , has been cl aim ed by computed tomography to reduce liver fat . Therefore , we examined the efficacy of colesevelam , a potent BAS , to decrease liver fat in patients with biopsy‐proven nonalcoholic steatohepatitis ( NASH ) . Liver fat was measured by a novel magnetic resonance imaging ( MRI ) technique , the proton‐density‐fat‐fraction ( PDFF ) , as well as by conventional MR spectroscopy ( MRS ) . Fifty patients with biopsy‐proven NASH were r and omly assigned to either colesevelam 3.75 g/day orally or placebo for 24 weeks . The primary outcome was change in liver fat as measured by MRI‐PDFF in colocalized regions of interest within each of the nine liver segments . Compared with placebo , colesevelam  increased liver fat by MRI‐PDFF in all nine segments of the liver with a mean difference of 5.6 % ( P = 0.002 ) . We cross‐vali date d the MRI‐PDFF‐determined fat content with that assessed by colocalized MRS ; the latter showed a mean difference of 4.9 % ( P = 0.014 ) in liver fat between the colesevelam and the placebo arms . MRI‐PDFF correlated strongly with MRS‐determined hepatic fat content ( r2 = 0.96 , P < 0.0001 ) . Liver biopsy assessment of steatosis , cellular injury , and lobular inflammation did not detect any effect of treatment . Conclusion : Colesevelam  increases liver fat in patients with NASH as assessed by MRI as well as MRS without significant changes seen on histology . Thus , MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH . Underlying mechanisms and whether the small MR‐detected increase in liver fat has clinical consequences is not known . ( HEPATOLOGY 2012;56:922–932 Both rosiglitazone and metformin increase hepatic insulin sensitivity , but their mechanism of action has not been compared in humans . The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content , hepatic insulin sensitivity , insulin clearance , and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes . A total of 20 drug-naive patients with type 2 diabetes ( age 48 + /- 3 years , fasting plasma glucose 152 + /- 9 mg/dl , BMI 30.6 + /- 0.8 kg/m2 ) were treated in a double-blind r and omized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks . Both drugs similarly decreased HbA1c , insulin , and free fatty acid concentrations . Body weight decreased in the metformin ( 84 + /- 4 vs. 82 + /- 4 kg , P < 0.05 ) but not the rosiglitazone group . Liver fat ( proton spectroscopy ) was decreased with rosiglitazone by 51 % ( 15 + /- 3 vs. 7 + /- 1 % , 0 vs. 16 weeks , P = 0.003 ) but not by metformin ( 13 + /- 3 to 14 + /- 3 % , NS ) . Rosiglitazone ( 16 + /- 2 vs. 20 + /- 1 ml.kg(-1).min(-1 ) , P = 0.02 ) but not metformin increased insulin clearance by 20 % . Hepatic insulin sensitivity in the basal state increased similarly in both groups . Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin .  Serum adiponectin concentrations increased by 123 % with rosiglitazone but remained unchanged during metformin treatment . The decrease of serum adiponectin concentrations correlated with the decrease in liver fat ( r = -0.74 , P < 0.001 ) . Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma , adiponectin , and lipoprotein lipase in adipose tissue . In conclusion , rosiglitazone but not metformin decreases liver fat and increases insulin clearance . The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations . Both agents increase hepatic insulin sensitivity , but only rosiglitazone increases peripheral glucose uptake BACKGROUND Probiotics have profound effect on nonalcoholic steatohepatitis ( NASH ) in animal models . We aim ed to test the hypothesis that probiotics treatment was superior to usual care in reducing liver fat in NASH patients . MATERIAL AND METHODS Patients with histology-proven NASH were r and omized to receive probiotics ( n = 10 ) or usual care ( n = 10 ) for 6 months . The Lepicol probiotic formula contained Lactobacillus plantarum , Lactobacillus deslbrueckii , Lactobacillus acidophilus , Lactobacillus rhamnosus and Bifidobacterium bifidum . The primary endpoint was change in intrahepatic triglyceride content ( IHTG ) , as measured by proton-magnetic resonance spectroscopy , from baseline to month 6 . Secondary endpoints included changes in liver biochemistry and metabolic profile . RESULTS IHTG decreased from 22.6 ± 8.2 % to 14.9 ± 7.0 % in the probiotic group ( P = 0.034 ) but remained static in the usual care group ( 16.9 ± 6.1 % to 16.0 ± 6.6 % ; P = 0.55 ) . Six subjects in the probiotic group had IHTG reduced by more than 30 % from baseline , compared to 2 subjects in the usual care group ( P = 0.17 ) . The probiotic group also had greater reduction in serum aspartate aminotransferase level ( P = 0.008 ) . On the other h and , the use of probiotics was not associated with changes in body mass index , waist circumference , glucose and lipid levels . CONCLUSIONS Probiotics treatment may reduce liver fat and AST level in NASH patients . The therapeutic potential of probiotics in NASH should be tested in larger studies Abstract Background Non-alcoholic fatty liver disease is a common health problem associated with increased liver and vascular specific complications . Aim The purpose of this study was to assess and compare the effect of fenofibrate alone or in combination with pentoxifylline on the measured biochemical parameters , inflammatory pathway and liver stiffness in patients with non-alcoholic fatty liver disease . Methods The study design was r and omized controlled trial . From July 2013 to June 2014 , we recruited 90 non-alcoholic fatty liver patients from the Internal Medicine Department at Tanta University Hospital , Egypt . They were classified r and omly into two groups to receive fenofibrate 300 mg daily or fenofibrate 300 mg daily plus pentoxifylline 1200 mg/day in three divided doses for 24 weeks . Fasting blood sample was obtained before and 24 weeks after treatment for biochemical analysis of liver and lipid panels , tumor necrosis factor-alpha , hyaluronic acid , transforming growth factor beta 1 , fasting plasma insulin and fasting glucose . Liver stiffness measurement was carried out using fibro-scan . Data were statistically analyzed by paired and unpaired Student ’s t test . Results The data obtained suggests that adding pentoxifylline to fenofibrate does not provide a beneficial effect on lipid panel , but has a beneficial effect on indirect biochemical markers of hepatic fibrosis , a direct marker linked to matrix deposition ( hyaluronic acid ) , a cytokine/growth factor linked to liver fibrosis ( transforming growth factor beta 1 ) , the inflammatory pathway , insulin resistance and liver stiffness as compared to fenofibrate alone . Conclusion The combination pentoxifylline plus fenofibrate may represent a new therapeutic strategy for non-alcoholic fatty liver disease as it result ed in more beneficial effects on direct and indirect markers of liver fibrosis , liver stiffness , insulin resistance and inflammatory pathway implicated in NAFLD Objective . The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease ( NAFLD ) , which is characterized by insulin resistance . However , the evidence for its beneficial effects is limited , and conflicting reports have been published . The purpose of this study was to conduct a r and omized , double-blind , placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease . Material and methods . Forty-eight patients with biopsy-proven NAFLD were r and omized to treatment with metformin ( n=24 ) or placebo ( n=24 ) for 6 months . A second liver biopsy was obtained in all subjects who completed the trial ( n=44 ) . Data analyses are restricted to this group ( per- protocol analyses ) . The primary outcome was changes in histologically assessed liver steatosis . Secondary outcomes were changes in NAFLD activity (NAS)-score , liver steatosis assessed by computed tomography ( CT ) , liver transaminases , body-weight , metabolic variables and inflammatory markers . Results . No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis , assessed either histologically or by CT , NAS-score , liver transaminases or on markers of insulin resistance or inflammation . In contrast , beneficial effects of metformin were observed on changes in body-weight ( p<0.001 ) , serum levels of cholesterol ( p=0.004 ) , LDL-cholesterol ( p<0.001 ) , glucose ( p=0.032 ) and on HbA1c ( p=0.020 ) . Conclusions . Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD . Nevertheless , the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose . ( Clinical Trials.gov number , NCT00303537 The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non-alcoholic fatty liver disease ( NAFLD ) . The aim of the present 52-week r and omized controlled trial was to compare the effects of low-dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance , non-invasive indices of hepatic steatosis and fibrosis , liver function tests , circulating adipokines and hormones in patients with histologically confirmed NAFLD . Homeostasis model of assessment of insulin resistance ( HOMA-IR ) and non-invasive indices of steatosis and fibrosis were calculated . Analysis was intention-to-treat . NAFLD liver fat score , an index of steatosis , decreased significantly in the combination treatment group ( P = .028 ) , but not in the vitamin E group , and the difference for group*time interaction was significant ( P = .047 ) . Alanine aminotransferase-to-platelet ratio index , an index of fibrosis , did not change . Insulin levels and HOMA-IR decreased significantly only within the combination group ( P = .011 and P = .011 , respectively ) . In conclusion , the combined low-dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score . Larger-scale trials are needed to clarify the effect of low-dose spironolactone on hepatic histology OBJECTIVES : Nonalcoholic steatohepatitis ( NASH ) is a known metabolic disorder of the liver . No treatment has been conclusively shown to improve NASH or prevent disease progression . The function of L-carnitine to modulate lipid profile , glucose metabolism , oxidative stress , and inflammatory responses has been shown . The aim of this study was to evaluate the effects of L-carnitine 's supplementation on regression of NASH . METHODS : In patients with NASH and control subjects , we r and omly dispensed one 1-g L-carnitine tablet after breakfast plus diet and one 1 g tablet after dinner plus diet for 24 weeks or diet alone at the same dosage and regimen . We evaluated liver enzymes , lipid profile , fasting plasma glucose , C-reactive protein ( CRP ) , tumor necrosis factor (TNF)-α , homeostasis model assessment (HOMA)-IR , body mass index , and histological scores . RESULTS : At the end of the study , L-carnitine-treated patients showed significant improvements in the following parameters : aspartate aminotransferase ( P=0.000 ) , alanine aminotransferase ( ALT ) ( P=0.000 ) , γ-glutamyl-transpeptidase ( γ-GT ) ( P=0.000 ) , total cholesterol ( P=0.000 ) , low-density lipoprotein ( LDL ) ( P=0.000 ) , high-density lipoprotein ( HDL ) ( P=0.000 ) , triglycerides ( P=0.000 ) , glucose ( P=0.000 ) , HOMA-IR ( P=0.000 ) , CRP ( P=0.000 ) , TNF-α ( P=0.000 ) , and histological scores ( P=0.000 ) . CONCLUSIONS : L-carnitine supplementation to diet is useful for reducing TNF-α and CRP , and for improving liver function , glucose plasma level , lipid profile , HOMA-IR , and histological manifestations of NASH BACKGROUND & AIMS Nonalcoholic steatohepatitis ( NASH ) is a liver disease that complicates insulin-resistant states . This trial tested the efficacy and safety of rosiglitazone , an insulin-sensitizing agent , in patients with NASH . METHODS Sixty-three patients with histologically proven NASH were r and omly assigned to receive rosiglitazone ( 4 mg/day for the first month and 8 mg/day thereafter ; n = 32 ) or placebo ( n = 31 ) for 1 year . Liver biopsy was performed at the end of treatment . End points were improvement in the histologic score of steatosis , normalization of serum transaminase levels , and improvement in necroinflammation and fibrosis . RESULTS More patients treated with rosiglitazone than receiving placebo had improved steatosis ( 47 % vs 16 % ; P = .014 ) and normalized transaminase levels ( 38 % vs 7 % ; P = .005 ) , although only half of patients responded . There was no improvement in other histologic lesions , including fibrosis , and a composite score of activity , the nonalcoholic fatty liver disease activity score . Improvement of steatosis correlated with reduction of transaminase levels ( r = 0.36 ; P < .005 ) , improvement in insulin sensitivity ( r = 0.34 ; P = .008 ) , and increase in adiponectin levels ( r = -0.54 ; P < .01 ) but not with weight variations . Independent predictors of response were rosiglitazone treatment , the absence of diabetes , and massive steatosis . Weight gain was the main adverse effect ( mean gain of 1.5 kg in the rosiglitazone group vs -1 kg in the placebo group ; P < .01 ) , and painful swollen legs was the main reason for dose reduction/discontinuation . Serum hemoglobin level was slightly but significantly reduced . There was no hepatic toxicity . CONCLUSIONS In patients with NASH , rosiglitazone improves steatosis and transaminase levels despite weight gain , an effect related to an improvement in insulin sensitivity . However , there is no improvement in other parameters of liver injury Goals This study was design ed to assess the utility of statin therapy in patients with biopsy proven nonalcoholic steatohepatitis ( NASH ) and hyperlipidemia . Background Nonalcoholic fatty liver disease , as the hepatic manifestation of the metabolic syndrome , has become a growing public health concern . Nonalcoholic steatohepatitis ( NASH ) represents a subset of nonalcoholic fatty liver disease manifested by hepatic fatty infiltration and inflammation which may progress to cirrhosis and its subsequent complications , to include hepatocellular carcinoma . As the metabolic syndrome is thought to be central in the pathogenesis of NASH , it has been speculated that medications that improve metabolic profiles may be beneficial in treatment . In fact , recent studies have demonstrated potential benefit of 3-hydroxy-3-methyglutaryl-coenzyme A ( HMG-CoA ) reductase inhibitors ( statins ) , which are used in clinical practice to improve lipid panels . Study This double-blinded r and omized placebo-controlled trial compared the HMG-CoA reductase inhibitor , simvastatin , with placebo in the treatment of NASH over a 12-month period using serum aminotransferases and repeat liver biopsy to assess for improvement . Results Sixteen patients with biopsy proven NASH were enrolled : 14 completed the study and 10 underwent 1-year repeat liver biopsy . Mean age : 53 years ( ±10.1 ) , mean body mass index : 32.4 ( ±6.1 ) with 11 male and 5 female patients . Although a 26 % reduction in low-density lipoprotein was seen in the simvastatin group compared with placebo , there was no statistically significant improvement in serum aminotransferases , hepatic steatosis , necroinflammatory activity or stage of fibrosis within or between groups . Conclusions In this pilot trial , monotherapy with simvastatin does not seem to be an effective treatment for NASH UNLABELLED No proven treatment exists for nonalcoholic fatty liver disease ( NAFLD ) in children and adolescents . We sought to determine the efficacy of lifestyle intervention with or without antioxidant therapy in pediatric NAFLD . A total of 53 patients ( age 5.7 - 18.8 years , 37 boys ) were included .  Lifestyle intervention consisting of a diet tailored to the patient 's calorie needs , and increased physical activity was prescribed in all . Patients were concomitantly r and omized to alpha-tocopherol 600 IU/day plus ascorbic acid 500 mg/day ( n = 25 ) or placebo ( n = 28 ) , and treated for 24 months . The study was an extension of a previous study aim ed at evaluating the effect of 12-month lifestyle intervention and antioxidant therapy on serum levels of aminotransferases . The primary end point of the present study was change in liver histology on repeated biopsy at 24 months . Secondary end points were changes in body weight , liver enzymes , and insulin sensitivity indices on 2-hour oral glucose tolerance test . The amount of weight lost at 24 months was similar in the placebo and antioxidant groups ( -4.75 [ range , -16 - 4.0 ] versus -5.5 [ range , -12.2 - 0.4 ] kg , respectively , P = 0.9 ) . A significant improvement occurred in the grade of steatosis , lobular inflammation , and hepatocyte ballooning , and in the NAFLD activity score in both groups . Levels of aminotransferases , triglycerides , cholesterol , fasting glucose , and insulin , and insulin sensitivity indices improved significantly as well . The improvement in all these parameters was not significantly different between the two groups . CONCLUSION Lifestyle intervention with diet and increased physical activity induces weight loss and is associated with a significant improvement in liver histology and laboratory abnormalities in pediatric NAFLD . Alpha-tocopherol plus ascorbic acid does not seem to increase the efficacy of lifestyle intervention alone BACKGROUND & AIMS Insulin resistance and oxidative stress contribute to the pathogenesis of nonalcoholic steatohepatitis ( NASH ) . We conducted a pilot study for the following reasons : ( 1 ) to test the hypothesis that a combination of an antioxidant ( vitamin E ) and an insulin sensitizer ( pioglitazone ) would be superior to vitamin E alone for the treatment of NASH , and ( 2 ) to define the effects of these interventions on insulin-sensitive metabolic functions and correlate the effects with changes in liver histology . METHODS A r and omized prospect i ve trial was performed to compare the efficacy and safety of vitamin E alone ( 400 IU/day ) vs. vitamin E ( 400 IU/day ) and pioglitazone ( 30 mg/day ) in nondiabetic , noncirrhotic subjects with NASH . Metabolic functions were assessed by a 2-step , hyperinsulinemic ( 10 and 40 mU/m2/min ) euglycemic clamp . RESULTS A total of 10 patients were r and omized to each arm . Two patients on combination therapy discontinued treatment ; one because of pregnancy and the other because of hepatotoxicity . Treatment with vitamin E only produced a significant decrease in steatosis ( mean grade , 2.2 vs. 1.4 ; P < .02 ) . Compared with baseline , combination therapy produced a significant decrease in steatosis ( mean , 2.3 vs. 1 ; P < .002 ) , cytologic ballooning ( 1.3 vs. 0.2 ; P < .01 ) , Mallory 's hyaline ( 0.7 vs. 0.2 ; P < .04 ) , and pericellular fibrosis ( 1.2 vs. 0.6 ; P < .03 ) . Although vitamin E had no significant effects , combination therapy produced a significant increase in metabolic clearance of glucose and a decrease in fasting free fatty acid ( FFA ) and insulin . The decrease in fasting FFA and insulin independently predicted improvement in hepatic steatosis and cytologic ballooning . CONCLUSIONS A combination of vitamin E and pioglitazone produces a greater improvement in NASH histology . The improvement in steatosis and cytologic ballooning are related to treatment-associated decreases in fasting FFA and insulin levels In order to determine the effect of ursodeoxycholic acid on nonalcoholic fatty liver disease , 30 patients with body mass indices higher than 25 , serum levels of alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) or gamma-glutamyltransferase ( gamma-GT ) at least more than 1.5 times the upper limit of normality , and hepatic steatosis demonstrated by ultrasonography were r and omized into two groups of 15 patients to receive placebo or 10 mg kg-1 day-1 ursodeoxycholic acid for three months . Abdominal computed tomography was performed to quantify hepatic fat content , which was significantly correlated with histological grading of steatosis ( r s = -0.83 , P < 0.01 ) . Patient body mass index remained stable for both groups throughout the study , but a significant reduction in mean ( + /- SEM ) serum levels of ALT , AST and gamma-GT was observed only in the treated group ( ALT = 81.2 + /- 9.7 , 44.8 + /- 7.7 , 48.1 + /- 7.7 and 52.2 + /- 6.3 IU/l at the beginning and after the first , second and third months , respectively , N = 14 , P < 0.05 ) . For the placebo group ALT values were 66.4 + /- 9.8 , 54.5 + /- 7 , 60 + /- 7.6 and 43.7 5 IU/l , respectively . No alterations in hepatic lipid content were observed in these patients by computed tomography examination ( 50.2 + /- 4.2 Hounsfield units ( HU ) at the beginning versus 51.1 + /- 4.1 HU at the third month ) . These results show that ursodeoxycholic acid is able to reduce serum levels of hepatic enzymes in patients with nonalcoholic fatty liver disease , but this effect is not related to modifications in liver fat content There is no licensed treatment for non-alcoholic fatty liver disease ( NAFLD ) , a condition that increases risk of chronic liver disease , type 2 diabetes and cardiovascular disease . We tested whether 15 - 18 months treatment with docosahexaenoic acid ( DHA ) plus eicosapentaenoic acid ( EPA ) ( Omacor/Lovaza ) ( 4 g/day ) decreased liver fat and improved two histologically-vali date d liver fibrosis biomarker scores ( primary outcomes ) . Patients with NAFLD were r and omised in a double blind placebo-controlled trial [ DHA+EPA(n=51 ) , placebo(n=52 ) ] . We quantified liver fat percentage ( % ) by magnetic resonance spectroscopy in three liver zones . We measured liver fibrosis using two vali date d scores . We tested adherence to the intervention ( Omacor group ) and contamination ( with DHA and EPA ) ( placebo group ) by measuring erythrocyte percentage DHA and EPA enrichment ( gas chromatography ) . We undertook multivariable linear regression to test effects of : a ) DHA+EPA treatment ( ITT analyses ) and b ) erythrocyte DHA and EPA enrichment ( secondary analysis ) . Median ( IQR ) baseline and end of study liver fat% were 21.7 ( 19.3 ) and 19.7 ( 18.0 ) ( placebo ) , and 23.0 ( 36.2 ) and 16.3 ( 22.0 ) , ( DHA+EPA ) . In the fully adjusted regression model there was a trend towards improvement in liver fat%  with DHA+EPA treatment ( β=-3.64 ( 95%CI -8.0,0.8 ) ; p=0.1 ) but there was evidence of contamination in the placebo group and variable adherence to the intervention in the Omacor group . Further regression analysis showed that DHA enrichment was independently associated with a decrease in liver fat% ( for each 1 % enrichment , β=-1.70 ( 95%CI -2.9,-0.5 ) ; p=0.007 ) . No improvement in the fibrosis scores occurred . Conclusion . Erythrocyte DHA enrichment with DHA+EPA treatment is linearly associated with decreased liver fat% . Substantial decreases in liver fat% can be achieved with high percentage erythrocyte DHA enrichment in NAFLD . ( Hepatology 2014 ; ) The only currently recommended treatment for nonalcoholic fatty liver disease ( NAFLD ) is lifestyle modification . Preliminary studies of silybin showed beneficial effects on liver function .  Realsil ( RA ) comprises the silybin phytosome complex ( silybin plus phosphatidylcholine ) coformulated with vitamin E. We report on a multicenter , phase III , double-blind clinical trial to assess RA in patients with histologically documented NAFLD . Patients were r and omized 1:1 to RA or placebo ( P ) orally twice daily for 12 months . Prespecified primary outcomes were improvement over time in clinical condition , normalization of liver enzyme plasma levels , and improvement of ultrasonographic liver steatosis , homeostatic model assessment ( HOMA ) , and quality of life . Secondary outcomes were improvement in liver histologic score and /or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines , ferritin , and liver fibrosis markers .  We treated 179 patients with NAFLD ; 36 were also HCV positive . Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol ( 69 per group ) . Baseline patient characteristics were generally well balanced between groups , except for steatosis , portal infiltration , and fibrosis . Adverse events ( AEs ) were generally transient and included diarrhea , dysgeusia , and pruritus ; no serious AEs were recorded . Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels , HOMA , and liver histology . Body mass index normalized in 15 % of RA patients ( 2.1 % with P ) . HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers . This is the first study to systematic ally assess silybin in NAFLD patients . Treatment with RA but not P for 12 months was associated with improvement in liver enzymes , insulin resistance , and liver histology , without increases in body weight . These findings warrant further investigation Insulin resistance is a major feature of type 2 diabetes mellitus , obesity and nonalcoholic fatty liver disease ( NAFLD ) . Several studies pointed out the possible role of increased leptin in NAFLD in humans . The aim of this study is to determine the effect of metformin on plasma leptin levels in obese patients with type 2 diabetes mellitus and NAFLD compared with lifestyle interventions .  Thirty-four obese patients with newly diagnosed type 2 diabetes mellitus were prospect ively followed for 6 months . All patients had ultrasonographic evidence of NAFLD at baseline . The patients were r and omized into two groups : group 1 ( n = 15 ) followed lifestyle changes only and group 2 ( n = 19 ) received metformin ( 1,700 mg/day ) . At the end of treatment , BMI , WHR , HbA1c , fasting glucose , leptin , HOMA-IR , alanine aminotransferase values decreased in both groups . No significant difference in the end-points was observed between two groups . Only in group 2 , LDL decreased and HDL increased significantly . Liver echogenity decreased significantly at the end of study in both groups . The percentage of patients who no longer had evidence of NAFLD was not significantly different between the groups ( 20 % of patients on lifestyle intervention vs. 16 % of patients on metformin ) . The data demonstrate that , metformin and lifestyle interventions equally affected the plasma leptin levels , BMI and degree of NAFLD in obese patients with type 2 diabetes mellitus . In addition , the effects of metformin on the variables were not found to be mediated by leptin The presence of fatty liver per ultrasound and liver-associated enzymes were measured in a select cohort of youth with both obesity and insulin resistance , and the effect of metformin on these parameters evaluated . Fifty obese , multiethnic , insulin-resistant adolescents ( mean age 15.1 yr , mean body mass index 39.8 kg/m2 ) were r and omized to receive lifestyle recommendations plus either twice per day doses of 850 mg of metformin or placebo .  Fasting and post-glucose challenge biochemistries and liver ultrasounds were compared at baseline and 6 months . The prevalence of fatty liver was 74 % , elevated alanine aminotransferase ( ALT ) 14 % , aspartate aminotransferase ( AST ) 14 % , and gamma-glutamyl transferase ( GGT ) 17 % . Fatty liver was mild in 23 % , moderate in 31 % , and severe in 46 % . Fatty liver was more common in male and Hispanic subjects and elevated ALT more common in Hispanic subjects . Subjects with fatty liver appeared more insulin resistant ( higher fasting insulin and triglycerides , lower high-density lipoprotein cholesterol ) and had higher ALT and AST . At 6 months , mean ALT , GGT , and fasting insulin improved significantly in all subjects . Fatty liver prevalence ( p < 0.04 ) , severity ( p < 0.04 ) , and fasting insulin ( p < 0.025 ) improved significantly with metformin compared to placebo . Non-alcoholic fatty liver disease ( NAFLD ) occurs with a high prevalence and severity in obese , insulin-resistant adolescents . While metformin plus lifestyle intervention appears promising , defining NAFLD therapies capable of preventing fibrosis and cirrhosis requires further study OBJECTIVE : Nonalcoholic steatohepatitis ( NASH ) is a common cause of liver disease . Although usually indolent , this disease can progress to cirrhosis in some patients . There is currently no proven medical therapy for the treatment of NASH . The aim of our study was to evaluate the efficacy of combination α-tocopherol ( vitamin E ) and vitamin C in reducing histologic inflammation and fibrosis . METHODS : This was a prospect i ve , double-blind , r and omized , placebo-controlled trial with a total enrollment of 49 patients ; 45 patients completed the study . All patients were r and omized to receive either vitamins E and C ( 1000 IU and 1000 mg , respectively ) or placebo daily for 6 months , based on their initial histologic diagnosis of NASH . Additionally , all patients were given st and ard weight-loss counseling and encouraged to follow a low fat diet ( < 30 fat g/day ) . The pre- and posttreatment liver biopsies were review ed by a single pathologist , who was blinded to the patient 's medication . Biopsies were scored based on a modification of the scoring system published by Brunt et al. ( Am J Gastroenterol 1999;94:2467–74 ) . A score of 0–4 was possible for fibrosis , and a score of 0–6 was possible for inflammation and hepatocyte degeneration and necrosis . In addition , body mass index , glycohemoglobin , lipids , and liver enzymes were followed throughout the study . RESULTS : Forty-five patients completed 6 months of therapy without significant side effects  . Vitamin treatment result ed in a statistically significant improvement in fibrosis score ( p = 0.002 ) . No changes were noted in inflammation with treatment . CONCLUSIONS : Vitamin E and vitamin C , in the doses used in this study , were well tolerated and were effective in improving fibrosis scores in NASH patients . No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy . A larger , multicenter , longer-term trial with vitamin E and vitamin C seems to be warranted UNLABELLED The primary aim of this study was to compare the effects of pentoxifylline ( PTX ) versus placebo on the histological features of nonalcoholic steatohepatitis ( NASH ) . In all , 55 adults with biopsy-confirmed NASH were r and omized to receive PTX at a dose of 400 mg three times a day ( n = 26 ) or placebo ( n = 29 ) over 1 year . The primary efficacy endpoint was defined as improvement in histological features of NASH through reduction in steatosis , lobular inflammation , and /or hepatocellular ballooning as reflected by a decrease of ≥ 2 points in the nonalcoholic fatty liver disease ( NAFLD ) activity score ( NAS ) . After 1 year , intention-to-treat analysis showed a decrease of ≥ 2 points in the NAS in 38.5 % of patients on PTX versus 13.8 % of those on placebo ( P = 0.036 ) . Per protocol analysis , a decrease of ≥ 2 points in the NAS from baseline was observed in 50 % of the patients on PTX versus 15.4 % of those on placebo ( P = 0.01 ) . The mean change in NAS score from baseline was -1.6 in the PTX group , versus -0.1 in the placebo group ( P < 0.001 ) . PTX  significantly improved steatosis ( mean change in score -0.9 versus -0.04 with placebo , P < 0.001 ) and lobular inflammation ( median change -1 versus 0 with placebo , P = 0.02 ) . No significant effects in hepatocellular ballooning were observed . PTX  also improved liver fibrosis ( mean change in fibrosis score was -0.2 among those on PTX versus + 0.4 among those on placebo , P = 0.038 ) . Although not statistically significant ( P = 0.17 ) , improvement in fibrosis was observed in a greater proportion ( 35 % ) of patients in the PTX group compared to placebo ( 15 % ) . Adverse effects were similar in both groups . CONCLUSION PTX  improved histological features of NASH compared to placebo . PTX was well tolerated in patients with NASH OBJECTIVES : Metformin proved useful in the treatment of nonalcoholic fatty liver disease ( NAFLD ) , but its superiority over nutritional treatment and antioxidants has never been demonstrated . We aim ed to compare the usefulness of metformin versus prescriptive diet or vitamin E. METHODS : In an open label , r and omized trial , nondiabetic NAFLD patients were given metformin ( 2 g/day ; n = 55 ) for 12 months . The control cases were given either vitamin E ( 800 IU/day ; n = 28 ) or were treated by a prescriptive , weight-reducing diet ( n = 27 ) . Outcome measures were liver enzymes , insulin resistance ( homeostasis model assessment ) , parameters of the metabolic syndrome , and histology . RESULTS : Aminotransferase levels improved in all groups , in association with weight loss . The effects in the metformin arm were larger ( p < 0.0001 ) , and alanine aminotransferase normalized in 56 % of cases ( odds ratio ( OR ) versus . controls , 3.11 ; 95 % confidence interval ( CI ) , 1.56–6.20 ; p = 0.0013 ) . In multivariate analysis , metformin treatment was associated with higher rates of aminotransferase normalization , after correction for age , gender , basal aminotransferases , and change in body mass index ( OR , 5.98 ; 95 % CI , 2.05–17.45 ) . Differences were maintained when the two control groups were separately analyzed . The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm ( p = 0.001 , signed rank test ) . A control biopsy in 17  metformin-treated cases ( 14 nonresponders ) showed a significant decrease in liver fat ( p = 0.0004 ) , necroinflammation , and fibrosis ( p = 0.012 for both ) . No side effects were observed during metformin treatment . CONCLUSIONS : Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling . Limited histological data support an association between improved aminotransferases and biopsy findings , which require confirmation in a double-blind trial with appropriate statistical power based on liver histology BACKGROUND AND AIMS Very little information is available on whether docosahexaenoic acid ( DHA ) supplementation has a beneficial effect on liver fat and cardiovascular disease ( CVD ) risk factors in children with nonalcoholic fatty liver disease ( NAFLD ) . In a double-blind , placebo-controlled  r and omized trial we investigated whether 6-month treatment with DHA improves hepatic fat and other fat depots , and their associated CVD risk factors in children with biopsy-proven NAFLD . METHODS AND RESULTS Of 58 r and omized children , 51 ( 25 DHA , 26 placebo ) completed the study . The main outcome was the change in hepatic fat fraction as estimated by magnetic resonance imaging . Secondary outcomes were changes in visceral adipose tissue ( VAT ) , epicardial adipose tissue ( EAT ) , and left ventricular ( LV ) function , as well as alanine aminotransferase ( ALT ) , triglycerides , body mass index-st and ard deviation score ( BMI -SDS ) , and insulin sensitivity . At 6 months , the liver fat was reduced by 53.4 % ( 95 % CI , 33.4 - 73.4 ) in the DHA group , as compared with 22.6 % ( 6.2 - 39.0 ) in the placebo group ( P = 0.040 for the comparison between the two groups ) . Likewise , in the DHA group VAT and EAT were reduced by 7.8 % ( 0 - 18.3 ) and 14.2 % ( 0 - 28.2 % ) , as compared with 2.2 % ( 0 - 8.1 ) and 1.7 % ( 0 - 6.8 % ) in the placebo group , respectively ( P = 0.01 for both comparisons ) . There were no significant between-group changes for LV function as well as BMI -SDS and ALT , while fasting insulin and triglycerides significantly decreased in the DHA-treated children ( P = 0.028 and P = 0.041 , respectively ) . CONCLUSIONS DHA supplementation decreases liver and visceral fat , and ameliorates metabolic abnormalities in children with NAFLD UNLABELLED Medication combinations that improve the efficacy of thiazolidinediones or ameliorate weight-gain side effects of therapy represent an attractive potential treatment for ( NASH ) . The aim of this r and omized , open-label trial was to assess the efficacy of rosiglitazone and metformin in combination versus rosiglitazone and losartan , compared to rosiglitazone alone , after 48 weeks of therapy . A total of 137 subjects with biopsy-proven NASH were enrolled and r and omly assigned to receive either 4 mg twice-daily of rosiglitazone , 4 mg of rosiglitazone and 500 mg of metformin twice-daily , or 4 mg of rosiglitazone twice-daily and 50 mg of losartan once-daily for 48 weeks . Patients were screened for other etiologies of chronic liver disease , including daily alcohol intake in excess of 20 g. Repeat liver biopsy was performed after 48 weeks of therapy and review ed in a blinded fashion by a single expert hepatopathologist . The primary aim of the study was to assess for differences between treatment groups in the improvement of steatosis , hepatocellular inflammation , and fibrosis . In total , 108 subjects completed the trial . Primary outcome revealed no significant difference between treatment groups in all histologic parameters ( steatosis , P = 0.137 ; hepatocellular inflammation , P = 0.320 ; fibrosis , P = 0.229 ) . Overall improvement in steatosis , hepatocellular inflammation , ballooning degeneration , and fibrosis was observed ( P ≤ 0.001 ) . Serum aminotransferases were reduced in all three groups ( P < 0.001 within treatment , P > 0.05 between groups ) . Metformin did not significantly mitigate weight gain ( P = 0.051 ) . CONCLUSIONS Forty-eight weeks of combination therapy with rosiglitazone and metformin or rosiglitazone and losartan confers no greater benefit than rosiglitazone alone with respect to histopathology Objective To investigate whether dietary supplementation with docosahexaenoic acid ( DHA ) decreases liver fat content in children with non-alcoholic fatty liver disease ( NAFLD ) . Design , setting and patients We performed a r and omised controlled trial of DHA supplementation ( 250 and 500 mg/day ) versus placebo in 60 children with biopsy-proven NAFLD ( 20 children per group ) . Main outcome measures The main outcome was the change in liver fat content as detected by ultrasonography after 6 months of treatment . Secondary outcomes were the changes in insulin sensitivity index , alanine transaminase , triglycerides and body mass index after 6 months of treatment . Results Blood DHA increased in children supplemented with DHA ( 0.65 % , 95 % CI 0.30 % to 1.10 % for the DHA 250 mg group and 1.15 % , 0.87 % to 1.43 % for the DHA 500 mg group ) . The odds of more severe versus less severe liver steatosis after treatment was lower in children treated with DHA 250 mg/day ( OR = 0.01 , 0.002 to 0.11 , p < 0.001 ) and DHA 500 mg/day ( OR = 0.04 , 0.002 to 0.46 , p = 0.01 ) as compared to placebo but there was no difference between the DHA groups ( p = 0.4 ) . Insulin sensitivity index increased and triglycerides decreased to a similar degree in both DHA groups as compared to placebo but there was no effect on alanine transaminase and body mass index . Conclusion DHA supplementation improves liver steatosis and insulin sensitivity in children with NAFLD AIM To investigate the efficacy and safety of n-3 polyunsaturated fatty acids ( PUFA ) from seal oils for patients with nonalcoholic fatty liver disease ( NAFLD ) associated with hyperlipidemia . METHODS One hundred and forty-four patients with NAFLD associated with hyperlipidemia were included in the 24-wk , r and omized , controlled trial . The patients were r and omized into two groups . Group A ( n=72 ) received recommended diet and 2 g n-3 PUFA from seal oils , three times a day . Group B ( n=72 ) received recommended diet and 2 g placebo , three times a day . Primary endpoints were fatty liver assessed by symptom scores , liver alanine aminotransferase ( ALT ) and serum lipid levels after 8 , 12 , 16 , and 24 wk . Hepatic fat infiltration was detected by ultrasonography at weeks 12 and 24 after treatment . RESULTS A total of 134 patients ( 66 in group A , 68 in group B ) were included in the study except for 10 patients who were excluded from the study . After 24 wk of treatment , no change was observed in body weight , fasting blood glucose ( FBG ) , renal function and blood cells of these patients . Total symptom scores , ALT and triglyceride ( TG ) levels decreased more significantly in group A than in group B ( P<0.05 ) . As expected , there was a tendency toward improvement in aspartate aminotransferase ( AST ) , gamma-glutamyltranspeptidase ( GGT ) , and total cholesterol ( TCHO ) and high-density lipoprotein ( HDL ) cholesterol levels ( P<0.05 ) after administration in the two groups . However , no significant differences were found between the two groups . The values of low-density lipoprotein ( LDL ) were significantly improved in group A ( P<0.05 ) , but no significant change was found in group B at different time points and after a 24-wk treatment . After treatment , complete fatty liver regression was observed in 19.70 % ( 13/66 ) of the patients , and an overall reduction was found in 53.03 % ( 35/66 ) of the patients in group A. In contrast , in group B , only five patients ( 7.35 % , 5/68 ) achieved complete fatty liver regression ( P=0.04 ) , whereas 24 patients ( 35.29 % , 24/68 ) had a certain improvement in fatty liver ( P=0.04 ) . No serious adverse events occurred in all the patients who completed the treatment . CONCLUSION Our results indicate that n-3 PUFA from seal oils is safe and efficacious for patients with NAFLD associated with hyperlipidemia and can improve their total symptom scores , ALT , serum lipid levels and normalization of ultrasonographic evidence . Further study is needed to confirm these results Objective A beneficial role of antioxidants in hepatopathic obese individuals has hitherto been inferred only from uncontrolled pilot studies . The authors compared the effect of vitamin E and weight loss on transaminase values and on ultrasonographic bright liver in a controlled group of children with obesity-related liver dysfunction . Methods Twenty-eight children with obesity-related hypertransaminasemia and bright liver were r and omly allocated to two single-blind groups : group 1 ( n = 14 ) treated with a low-calorie diet associated with oral placebo for 5 months , and group 2 ( n = 14 ) treated with a low-calorie diet associated with oral vitamin E ( 400 mg/d × 2 months , 100 mg/d × 3 months ) . Transaminase values and ultrasonographic liver brightness along with weight loss and vitamin E levels were monitored . Results Variations in transaminase levels and percentage of patients with normalized transaminase values were comparable in the two groups . The disappearance of bright liver was observed only in patients who lost weight and was twice as common in patients from group 1 . Two subgroups of patients with complete normalization of transaminase values emerged as a consequence of controlled adherence to diet alone ( n = 6 ; significant decrease of percent overweight : P = 0.0019 ) and to vitamin E alone ( n = 7 ; unmodified percent overweight and significant increase of vitamin E/cholesterol ratio : P < 0.0001 ) . Changes in treatment-induced alanine aminotransferase levels in these two subgroups were comparable at month 2 , whereas values at month 5 were significantly lower in the subgroup adherent to diet alone ( P = 0.04 ) . In the subgroup adherent to vitamin E alone , after 2 months washout , transaminase remained stable in 5 patients and increased in 2 ; bright liver persisted in all . Conclusions Oral vitamin E warrants consideration in obesity-related liver dysfunction for children unable to adhere to low-calorie diets Background Non-alcoholic fatty liver disease ( NAFLD ) is associated with a high morbidity in patients with impaired fasting glucose ( IFG ) .  Bicyclol is a synthetic compound known to protect the liver against oxidation and lipid injuries . Objective The objective of this study was to evaluate the efficacy and safety of metformin and bicyclol in the treatment of NAFLD patients with IFG . Methods After lifestyle changes and metformin treatment ( 500 mg orally three times daily ) , the 248 patients enrolled with NAFLD and IFG were equally r and omized to two 24-week treatment groups : bicyclol 25 mg three times daily or vitamin E ( α-tocopherol ) 100 mg three times daily ( control )  . Anthropometric measurements , serum biochemistry , liver/spleen computed tomography ratio , and changes in liver histological parameters were compared before and after treatments . Results A total of 223 patients completed the treatment , and there were significant improvements in body mass index , waist-to-hip ratio , and biochemical parameters in both groups ( P < 0.01 ) . Compared with the control group , the improvement in serum alanine aminotransferase levels in the bicyclol group was statistically significant ( P < 0.01 ) . Liver histological assessment s revealed that steatosis , inflammation , hepatocellular ballooning , and NAFLD activity scores ( NAS ) were all decreased in both groups after treatment ( P < 0.01 ) . However , decreases in inflammation and NAS in the bicyclol group were statistically significant compared with the vitamin E group ( P < 0.01 ) . Adverse events in the bicyclol and control groups occurred in 1.79 and 1.80 % , respectively . Conclusion Metformin combined with bicyclol is effective and safe in the treatment of patients with NAFLD and IFG . However , further studies with a larger sample size are needed to confirm the efficacy and safety of the combination BACKGROUND The bile acid derivative 6-ethylchenodeoxycholic acid ( obeticholic acid ) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease . We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis . METHODS We did a multicentre , double-blind , placebo-controlled , parallel group , r and omised clinical trial at medical centres in the USA in patients with non-cirrhotic , non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally ( 25 mg daily ) or placebo for 72 weeks . Patients were r and omly assigned 1:1 using a computer-generated , central ly administered procedure , stratified by clinical centre and diabetes status . The primary outcome measure was improvement in central ly scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment . A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment ( 72 weeks ) biopsies supported the decision to continue the trial ( relative change in alanine aminotransferase -24 % , 95 % CI -45 to -3 ) . A planned interim analysis of the primary outcome showed improved efficacy  of obeticholic acid ( p=0·0024 ) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients , but to continue the trial to obtain the 24-week post-treatment measures . Analyses were done by intention-to-treat . This trial was registered with Clinical Trials.gov , number NCT01265498 . FINDINGS Between March 16 , 2011 , and Dec 3 , 2012 , 141 patients were r and omly assigned to receive obeticholic acid and 142 to placebo . 50 ( 45 % ) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 ( 21 % ) of 109 such patients in the placebo group ( relative risk 1·9 , 95 % CI 1·3 to 2·8 ; p=0·0002 ) . 33 ( 23 % ) of 141 patients in the obeticholic acid developed pruritus compared with nine ( 6 % ) of 142 in the placebo group . INTERPRETATION Obeticholic acid improved the histological features of non-alcoholic steatohepatitis , but its long-term benefits and safety need further clarification . FUNDING National Institute of Diabetes and Digestive and Kidney Diseases , Intercept Pharmaceuticals Background : Increased insulin resistance is the major pathogenic mechanism in the development of non‐alcoholic steatohepatitis OBJECTIVE The present pilot trial was carried out to evaluate the effects of an acute treatment with a mixture containing 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus per day in patients with non alcoholic fatty liver disease ( NAFLD ) . RESEARCH METHODS A sample of 30 patients with NAFLD ( diagnosed by liver biopsy ) was enrolled and 28 patients were analyzed in a double blind r and omized clinical trial . Patients were r and omized to one of the following treatments during 3 months : group I , treated with one tablet per day with 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus and group II , treated with one placebo tablet ( 120 mg of starch ) . RESULTS In group I , alanine amino transferase ( ALT : 67.7 + /- 25.1 vs. 60.4 + /- 30.4 UI/L ; p < 0.05 ) , aspartate aminotransferase activity ( AST : 41.3 + /- 15.5 vs. 35.6 + /- 10.4 UI/L ; p < 0.05 ) and gammaglutamine transferase levels ( gammaGT : 118.2 + /- 63.1 vs. 107.7 + /- 60.8 UI/L ; p < 0.05 ) decreased . In group II , all liver function parameters remained unchanged ( ALT : 60.7 + /- 32.1 vs. 64.8 + /- 35.5 UI/L ; p < 0.05 ) , aspartate aminotransferase activity ( AST : 31.7 + /- 13.1 vs. 36.4 + /- 13.8 UI/L ; ns ) and gammaglutamine transferase levels ( gammaGT : 82.1 + /- 55.1 vs. 83.6 + /- 65.3 UI/L ; ns ) . Anthropometric parameters and cardiovascular risk factors remained unchanged after treatment in both groups . CONCLUSION A tablet of 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus , with a r and omized clinical design , improved liver aminotransferases levels in patients with NAFLD AIM To evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis ( NASH ) . METHODS Twelve patients with biopsy-proven NASH were r and omized to sitagliptin ( 100 mg daily ) ( n = 6 ) or placebo ( n = 6 ) for 24 wk . The primary outcome was improvement in liver fibrosis after 24 wk . Secondary outcomes included evaluation of changes in NAFLD activity score ( NAS ) , individual components of NAS ( hepatocyte ballooning , lobular inflammation , and steatosis ) , glycemic control and insulin resistance [ including measurements of glycated hemoglobin ( HbA1C ) and adipocytokines ] , lipid profile including free fatty acids , adipose distribution measured using magnetic resonance imaging ( MRI ) , and thrombosis markers ( platelet aggregation and plasminogen activator inhibitor 1 levels ) . We also sought to determine the correlation between changes in hepatic fat fraction ( % ) [ as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation ( IDEAL ) MRI technique ] and changes in hepatic steatosis on liver biopsy .  RESULTS Sitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy ( mean difference between sitagliptin and placebo arms , 0.40 , P = 0.82 ) . There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS . Compared to baseline , those patients who received sitagliptin demonstrated improved HbA1C ( 6.7 % ± 0.4 % vs 7.9 % ± 1.0 % , P = 0.02 ) , and trended towards improved adiponectin levels ( 4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL , P = 0.06 ) and triglyceride levels ( 1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L , P = 0.08 ) . However , when compared with placebo , sitagliptin did not cause a statistically significant improvement in HbA1C ( mean difference , -0.7 % , P = 0.19 ) nor triglyceride levels ( mean difference -1.10 mmol/L , P = 0.19 ) but did trend towards improved adiponectin levels only ( mean difference , 0.60 μg/mL , P = 0.095 ) . No significant changes in anthropometrics , liver enzymes , other adipocytokines , lipid profile , thrombosis parameters , or adipose distribution were demonstrated . The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment , and the Spearman correlation coefficients ranged from r = 0.819 ( baseline ) to r = 0.878 ( post-treatment ) , P = 0.002 . CONCLUSION Sitagliptin does not improve fibrosis score or NAS after 24 wk of therapy . The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis Background : Nonalcoholic steatohepatitis ( NASH ) is common and severe in patients with diabetes mellitus . Although , there are no effective treatments for NASH in diabetic patients , preliminary reports suggest that polyunsaturated fatty acids ( PUFA ) may be beneficial in these patients . Aim : A prospect i ve , r and omized , double-blind placebo-controlled study ( NCT 00323414 ) was performed in NASH patients with diabetes . Clinical trials.gov ( NCT 00323414 ) . Subjects and Methods : A total of 37 patients ( 50.6±9.8 y ) with well-controlled diabetes ( HbA1C<8.5 % ) were r and omized to receive either PUFA containing eicosapentaenoic acid ( 2160 mg ) and docosahexaenoic acid ( 1440 mg ) daily or an isocaloric , identical placebo containing corn oil for 48 weeks under CONSORT guidelines . Clinical , demographics , biochemical laboratory tests , body composition using DEXA , and liver biopsy were performed at r and omization and at the end of treatment . Liver biopsy was scored by the NASH CRN criteria . An intention-to-treat analysis was performed . Results : At inclusion , sex , age , body weight , biochemical tests , glucose control , and liver histology were similar in the 2 treatment groups . There was no change in liver enzymes , body weight , or body composition during the study in either group . At the end of the treatment , hepatic steatosis and the activity score improved ( P<0.05 ) and lobular inflammation worsened ( P<0.001 ) with placebo but was unchanged with PUFA . At the end of the treatment , insulin resistance ( serum glucose and HOMA ) worsened with PUFA but not placebo . Conclusions : PUFA provided no benefit over placebo in NASH patients with diabetes . The effects of PUFA on histology and insulin resistance were inferior to placebo . These data provide no support for PUFA supplements in NASH Fish oil has been used effectively in the treatment of cardiovascular disease via triglyceride reduction and inflammation modulation . This study aim ed to assess the effects of fish oil on patients with nonalcoholic fatty liver disease ( NAFLD ) associated with hyperlipidemia . Eighty participants with NAFLD associated with hyperlipidemia were r and omly assigned to consume fish oil ( n=40 , 4 g/d ) or corn oil capsules ( n=40 , 4 g/d ) for 3 months in a double-blind , r and omized clinical trial . Blood levels of lipids , glucose and insulin , liver enzymes , kidney parameters and cytokines at baseline and the end of the study were measured . Seventy people finished the trial .  Plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid significantly increased in the fish oil group after intervention . After adjustment for age , gender and BMI , fish oil significantly decreased fasting serum concentrations of total cholesterol , triglyceride , apolipoprotein B and glucose ( by ( mean±SD ) 0.49±0.43 mmol/L , 0.58±0.89 mmol/L , 0.28±0.33 g/L and 0.76±0.56 mmol/L , respectively , P<0.05 ) , as well as alanine aminotransferase and γ-glutamyl transpeptidase levels ( by ( median ( interquartile ) ) 9.0(0.5 , 21.5 ) and 7.0(2.2 , 20.0 ) IU/L , respectively , P<0.05 ) , significantly increased serum adiponectin levels ( by 1.29±0.62 μg/mL , P<0.001 ) , and reduced serum levels of tumor necrosis factor α , leukotrienes B4 , fibroblast growth factor 21 ( FGF21 ) , cytokeratin 18 fragment M30 and prostagl and in E2 ( by 1.70±1.18 pg/mL , 0.59±0.28 ng/mL , 121±31 pg/mL , 83±60 IU/L and 10.9±2.3 pg/mL , respectively , P<0.001 ) . Corn oil had no effect except for increasing serum creatinine concentrations by 7.7±8.9 μmol/L ( P=0.008 ) . The effects of fish oil on lipids , glucose and γ-glutamyl transpeptidase were positively correlated with the reductions of serum FGF21 and prostagl and in E2 concentrations after adjustment for age , gender and BMI ( r = 0.275 to 0.360 and 0.261 to 0.375 , respectively , P<0.05 ) . In conclusion , our findings suggest that fish oil can benefit metabolic abnormalities associated with NAFLD treatment . Trial Registration Objectives : This study aims to evaluate the effects of some probiotics on sonographic and biochemical nonalcoholic fatty liver disease ( NAFLD ) . Methods : This r and omized triple-blind trial was conducted among 64 obese children with sonographic NAFLD . They were r and omly allocated to receive probiotic capsule ( containing Lactobacillus acidophilus ATCC B3208 , 3 × 109 colony forming units [ CFU ] ; Bifidobacterium lactis DSMZ 32269 , 6 × 109 CFU ; Bifidobacterium bifidum ATCC SD6576 , 2 × 109 CFU ; Lactobacillus rhamnosus DSMZ 21690 , 2 × 109 CFU ) or placebo for 12 weeks . Results : After intervention , in the probiotic group the mean levels of alanine aminotransferase decreased from 32.8 ( 19.6 ) to 23.1 ( 9.9 ) U/L ( P = 0.02 ) and mean aspartate aminotransferase decreased from 32.2 ( 15.7 ) to 24.3 ( 7.7 ) U/L ( P = 0.02 ) . Likewise the mean cholesterol , low-density lipoprotein-C , and triglycerides as well as waist circumference decreased in the intervention group , without significant change in weight , body mass index , and body mass index z score . After the trial , normal liver sonography was reported in 17 ( 53.1 % ) and 5 ( 16.5 % ) of patients in the intervention and placebo groups , respectively . Conclusions : The present findings suggest that a course of the abovementioned probiotic compound can be effective in improving pediatric NAFLD Background / Aim : Telmisartan can attenuate two hit pathogenesis of non-alcoholic steatohepatitis ( NASH ) . This study aim ed to observe the effect of Telmisartan on  non-alcoholic fatty liver disease ( NAFLD ) activity score ( NAS ) and fibrosis score in NASH patients . Patients and Methods : A total of 50 NASH patients were r and omized ; 35 of group 1 were treated with Telmisartan 40/80 mg once daily with life style modification ( TL ) and 15 of group 2 underwent only life style modification ( L ) for 1 year . At the end , 20 of TL group and 10 of L group were analyzed . Those who showed NAS improvement ≥ 2 or NAS improvement ≥ 1 with fibrosis improvement ≥ 1 were considered as responders . Results : Baseline alanine aminotransferase ( ALT ) , aspartate aminotransferase ( AST ) , insulin resistance index , components of metabolic syndrome , age , and sex were similar in both groups . At the end of study , NAS improvement in TL and L groups was 2.15 ± 1.66 and 1.10 ± 0.57 ( P = 0.017 ) and fibrosis improvement was 0.65 ± 0.93 and –0.30 ± 0.48 ( P = 0.001 ) , respectively . NAS improved by ≥ 2 in 13 ( 65 % ) and 2 ( 20 % ) patients and fibrosis score improved by ≥ 1 in 8 ( 40 % ) patients and none of the patients in TL group and L group , respectively  . Telmisartan and life style modification could improve steatosis , ballooning , lobular inflammation , and fibrosis . Life style modification could improve ballooning only , but fibrosis deteriorated . TL group showed improvement in NAS and fibrosis score [ P value : 0.035 ; odds ratio ( OR ) = 92.07 , confidence interval ( CI ) = 1.39–6106 ] to the level of response by regression analysis . Weight reduction and improvement of metabolic syndrome did not influence the response . There were similar minor adverse events in both groups . Conclusion : Telmisartan  improved NAS and fibrosis score in NASH with insignificant adverse events BACKGROUND & AIMS Nonalcoholic fatty liver disease ( NAFLD ) , characterized by accumulation of hepatic triglycerides ( steatosis ) , is associated with abdominal obesity , insulin resistance , and inflammation . Although weight loss via calorie restriction reduces features of NAFLD , there is no pharmacologic therapy . Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism . We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD . METHODS Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane , Australia from 2011 through 2012 . They were r and omly assigned to groups given 3000 mg resveratrol ( n = 10 ) or placebo ( n = 10 ) daily for 8 weeks . Outcomes included insulin resistance ( assessed by the euglycemic-hyperinsulinemic clamp ) , hepatic steatosis , and abdominal fat distribution ( assessed by magnetic resonance spectroscopy and imaging ) . Plasma markers of inflammation , as well as metabolic , hepatic , and antioxidant function , were measured ; transcription of target genes was measured in peripheral blood mononuclear cells .  Resveratrol pharmacokinetics and safety were assessed . RESULTS Eight-week administration of resveratrol did not reduce insulin resistance , steatosis , or abdominal fat distribution when compared with baseline . No change was observed in plasma lipids or antioxidant activity . Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group . Resveratrol did not significantly alter transcription of NQO1 , PTP1B , IL6 , or HO1 in peripheral blood mononuclear cells . Resveratrol was well-tolerated . CONCLUSIONS Eight weeks administration of resveratrol did not significantly improve any features of NAFLD , compared with placebo , but it increased hepatic stress , based on observed increases in levels of liver enzymes . Further studies are needed to determine whether agents that are purported to mimic calorie restriction , such as resveratrol , are safe and effective for complications of obesity . Clinical trials registration no : ACTRN12612001135808 Purpose Tumor necrosis factor-α ( TNF-α ) is implicated in non-alcoholic steatohepatitis ( NASH ) . Pentoxifylline inhibits TNF-α . We wanted to evaluate the efficacy of Pentoxifylline on NASH patients . Methods Patients with biopsy proven NASH and persistently elevated alanine aminotransferase ( ALT ) greater than 1.5 times the upper limit of normal were r and omized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo . Liver function tests , serum lipids and TNF-α , Interleukin 6 ( IL-6 ) , and plasma hyaluronic acid were measured at baseline , at weeks 6 and 12 . Categorical data were analyzed by Fisher ’s exact test while independent sample t-test and Mann – Whitney test were used for continuous data . Results Eleven patients were r and omized into the Pentoxifylline and nine to the placebo group . After 3 months of treatment body mass index ( BMI ) , ALT and aspartate aminotransferase ( AST ) decreased significantly in both groups . There was no difference between the two groups in reduction of BMI ( P = 0.897 ) . There was significantly greater reduction in AST in the Pentoxifylline group ( P = 0.038 ) . There was a trend toward lower ALT level ( P = 0.065 ) in the Pentoxifylline  group . TNF-α and IL-6 decreased significantly in both groups after treatment , but there was no significant difference between the two groups . Conclusion Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls Objective : We aim ed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease ( NAFLD ) . Methods : We carried out a 6-month prospect i ve study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis . In total , 50 patients were enrolled and r and omized into two groups : the first group ( n=25 ) was given metformin ( 1 g per day ) plus dietary treatment and the second group ( n=25 ) was given dietary treatment alone . Results : At the end of the study , the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin ( P<0.0001 ) and the diet group ( P=0.029 ) . Moreover , patient body mass index and waist circumference significantly decreased in both groups ( P<0.001 ) . Fasting glucose , insulin resistance ( evaluated as homeostasis model assessment of insulin resistance ( HOMA-IR ) ) and serum adiponectin decreased in both groups , although these changes reached statistical significance only in the metformin group . In this group , HOMA-IR decreased from 3.3±1.6 to 2.4±1.2 ( P=0.003 ) , whereas it decreased from 3.2±1.6 to 2.8±1.1 ( not significant , NS ) in the diet group . Similarly , the proportion of patients with impaired fasting glucose declined from 35 to 5 % ( P=0.04 ) in the metformin and from 32 to 12 % ( NS ) in the diet group . At baseline , ∼40 % of patients in both groups met the diagnostic criteria of metabolic syndrome . This proportion decreased to 20 % in the metformin group ( P=0.008 ) and to 32 % in the diet group ( NS ) . Conclusions : In our 6-month prospect i ve study , both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD . However , metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients AIM Apart from its angiotensin receptor blocker ( ARB ) activity , telmisartan is also a partial agonist of peroxisome proliferator-activated receptor gamma ( PPAR-γ ) . Therefore , we assessed whether telmisartan treatment attenuates myocardial ischaemia/reperfusion ( I/R ) injury in diabetic rats through PPAR-γ pathway . METHODS Diabetic rats were r and omized to receive vehicle ( sham and I/R ) , telmisartan ( 10 mg/kg/day , orally ) , PPAR-γ antagonist GW9662 ( 1 mg/kg/day , intraperitoneally ) or both for 14 days . On 15th day , excluding sham group , left anterior descending coronary artery occlusion was performed for 45 min followed by 1 h of reperfusion . Haemodynamic , biochemical , histopathological , ultrastructural , immunohistochemical ( Bax and Bcl-2 protein ) , TUNEL positivity , infa rct size and western blot studies were performed . RESULTS Telmisartan treatment significantly improved cardiac function by normalizing mean arterial pressure , left ventricular pressure ( ±LVdP/dt(max ) , a marker of myocardial contraction and relaxation ) , by decreasing left ventricular end-diastolic pressure ( a marker of preload , 3.7 ± 0.41 vs. 7.3 ± 0.89 , p < 0.001 ) and percent infa rct area ( 37.52 ± 5.83 vs. 46.27 ± 3.20 , p < 0.01 ) as compared to diabetic I/R group . Interestingly , GW9662 worsens the I/R injury ( percent infa rct area , 54.38 ± 6.48 vs. 46.27 ± 3.20 , p < 0.01 ) , whereas telmisartan with GW9662 ( percent infa rct area , 41.16 ± 8.23 vs. 46.27 ± 3.20 , p < 0.05 ) showed lesser significant results as compared to telmisartan alone . Additionally , telmisartan significantly ameliorates activities of endogenous antioxidants , creatine kinase-MB isoenzyme , lactate dehydrogenase and prevented the increase of tumour necrosis factor-alpha and malondialdehyde in myocardium . Furthermore , telmisartan also decreased Bax expression ( 4.45 ± 1.24 % vs. 10.25 ± 0.96 % , p < 0.01 ) , number of TUNEL-positive cells ( 6.2 ± 0.98 % vs. 13.0 ± 1.6 , p < 0.01 ) , inflammation , myonecrosis and increased Bcl-2 expression ( 5.45 ± 0.15 % vs. 1.24 ± 0.3 % , p < 0.01 ) . On the other h and , GW9662 treatment alone increased the Bax expression , TUNEL positivity and decreased Bcl-2 expression . Telmisartan protective effects were partially attenuated by a co-administration with GW9662 . Western blot analysis showed that telmisartan treatment enhanced PPAR-γ expression , whereas GW9662 decreased it in myocardium . CONCLUSIONS In addition to the class effect of ARBs , telmisartan has a beneficial effect in I/R injury in diabetic rats in part because of activation of PPAR-γ No effective medical therapy is available for all patients with nonalcoholic steatohepatitis ( NASH ) .  Ursodeoxycholic acid ( UDCA ) has been suggested to be of benefit based on open label clinical studies . We r and omized 166 patients with liver biopsy-proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years . End points included changes in liver test results and liver histology at 2 years of therapy . The treatment groups were comparable at entry with regard to age , gender , risk factors for NASH , serum liver biochemistries , and baseline liver histology . A total of 126 patients completed 2 years of therapy . Pre- and posttreatment liver biopsies were available in 107 patients for review at the end of the study . UDCA was well tolerated and body weight was stable during the study duration . Serum liver biochemistries were stable or improved in both the UDCA and placebo-treated groups . Changes in the degree of steatosis , necroinflammation , or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups . In conclusion , 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d , although safe and well tolerated , is not better than placebo for patients with NASH BACKGROUND & AIMS Nonalcoholic steatohepatitis ( NASH ) is a frequent liver disease that can progress to cirrhosis and for which there is no recognized therapy . UDCA and vitamin E have been considered separately as therapeutic options and have not been shown to be effective . This study tested their combination . METHODS Patients with elevated aminotransferase levels and drinking less than 40 g alcohol/week with biopsy-proven NASH were r and omly assigned to receive UDCA 12 - 15 mg.kg-1.day-1 with vitamin E 400 IU twice a day ( UDCA/Vit E ) , UDCA with placebo ( UDCA/P ) , or placebo/placebo ( P/P ) . After 2 years , they underwent a second liver biopsy . Biopsy specimens were collected , blinded , and scored by a single liver pathologist . RESULTS Forty eight patients were included , 15 in the UDCA/Vit E group , 18 in the UDCA/P group , and 15 in the P/P group ; 8 patients dropped out , none because of side effects .  Baseline parameters were not significantly different between the 3 groups . Body mass index remained unchanged during the study . Serum aspartate aminotransferase ( AST ) and alanine aminotransferase ( ALT ) levels diminished significantly in the UDCA/Vit E group . Neither the AST nor the ALT levels improved in the P/P group and only the ALT levels in the UDCA/P group . Histologically , the activity index was unchanged at the end of the study in the P/P and UDCA/P groups , but it was significantly better in the UDCA/Vit E group , mostly as a result of regression of steatosis . CONCLUSIONS Two years of treatment with UDCA in combination with vitamin E improved laboratory values and hepatic steatosis of patients with NASH . Larger trials are warranted OBJECTIVE To evaluate the efficacy and safety of omega-3 fatty acid supplementation in children with nonalcoholic fatty liver disease ( NAFLD ) . STUDY DESIGN Overweight/obese children with NAFLD ( n = 76 ; median age , 13 years ; IQR , 11.1 - 15.2 years ) were eligible to participate in the study . The diagnosis of NAFLD was based on elevated alanine aminotransferase ( ALT ) to ≥ 30 % of the upper limit of normal ( ULN ) and liver hyperechogenicity on ultrasound . Patients were r and omized to receive omega-3 fatty acids ( docosahexaenoic acid and eicosapentaenoic acid , 450 - 1300 mg/day ) or placebo ( omega-6 sunflower oil ) . The primary outcome was the number of patients who demonstrated decreased ALT activity by ≥ 0.3 times the ULN . Secondary outcomes included alterations in liver function tests , liver hyperechogenicity , insulin resistance , and other metabolic markers after 6 months of intervention . RESULTS Out of 76 enrolled patients , 64 completed the trial and were analyzed . After 6 months , we found no significant differences between the omega-3 and placebo groups in the number of patients with decreased ALT by ≥ 0.3 times the ULN ( 24 vs 23 ) or in median ( IQR ) ALT activity ( 48.5 [ 31 - 62 ] U/L vs 39 [ 27 - 55 ] U/L ) , liver hyperechogenicity , insulin resistance , or serum lipid levels . However , patients in the omega-3 group had lower levels of aspartate aminotransferase ( 28 [ 25 - 36 ] U/L vs 39 [ 27 - 55 ] U/L ; P = .04 ) and gamma-glutamyl transpeptidase ( 26 [ 17.5 - 36.5 ] U/L vs 35 [ 22 - 52 ] U/L ; P = .04 ) , and significantly higher levels of adiponectin . CONCLUSION Omega-3 fatty acid supplementation did not increase the number of patients with decreased ALT levels and it did not affect liver steatosis on ultrasound , but it improved aspartate aminotransferase and gamma-glutamyl transpeptidase levels in children with NAFLD compared with placebo . TRIAL REGISTRATION Registered with Clinical Trials.gov : NCT01547910 BACKGROUND / AIMS Adipokines and hepatocellular apoptosis participate in the pathogenesis of nonalcoholic steatohepatitis ( NASH ) . In a r and omized trial ursodeoxycholic acid ( UDCA ) with vitamin E ( VitE ) improved serum aminotransferases and hepatic histology . The present work evaluates the effect of this combination on adipokines and hepatocellular apoptosis . METHODS Circulating levels of adiponectin , resistin , leptin , interleukin (IL)-6 , IL-8 , retinol binding protein-4 , monocyte chemoattractant protein-1 and tumour necrosis factor-alpha were measured by enzyme-linked immunoassays at the beginning and after 2 years of treatment with either UDCA+VitE , UDCA+placebo ( P ) or P+P.  Apoptosis was assessed by immunohistochemistry for activated caspase-3 and circulating levels of apoptosis-associated cytokeratin 18 fragments ( M30 ) . RESULTS Levels of adiponectin increased in patients treated with UDCA+VitE , whereas they decreased in the two other groups ( P<0.04 ) and correlated with the improvement of liver steatosis ( P<0.04 ) . M30 levels worsened in the P/P group and improved in the other two groups . They correlated with hepatocellular apoptosis ( P<0.02 ) and steatosis ( P<0.02 ) as well as negatively with adiponectin levels ( P<0.04 ) . CONCLUSIONS UDCA+VitE improves not only aminotransferase levels and liver histology of patients with NASH , but also decreases hepatocellular apoptosis and restores circulating levels of adiponectin . These results suggest that the UDCA+VitE combination has metabolic effects in addition to its beneficial cytoprotective properties BACKGROUND / AIMS A final step in the pathology of non-alcoholic steatohepatitis ( NASH ) is oxidative damage to hepatocytes . Probucol is a lipid-lowering agent with strong antioxidant properties . We design ed a double-blind r and omized controlled study to evaluate the effects of probucol in NASH . METHODS Thirty cases of biopsy-proven NASH were included . Subjects were r and omly allocated to either the treatment group or to the control group by a 2:1 ratio . The treatment group was given 500 mg of probucol daily for 6 months , and the control group , an identically appearing placebo . RESULTS Twenty-seven cases completed the study . The mean aspartate transaminase ( AST ) and alanine transaminase ( ALT ) levels changed from 81.9 to 36.2 and 102.2 to 44.7 in the treatment group and from 57.6 to 49.6 and 96.8 to 96.2 in the control group , respectively . The decrease in ALT level in the treatment group as compared to the control group was significant at the P<0.005 level ( 95 % confidence interval : 20.2 - 93.7 IU ) . Both AST and ALT levels dropped to normal in nine cases of the treatment group ( 50 % ) but none of the control group ( P=0.01 ) . CONCLUSIONS Probucol appears to be significantly effective in decreasing the ALT levels in patients with NASH There are few data evaluating plasma and /or peripheral blood monocyte cytokine concentrations/production or attempts to manipulate proinflammatory cytokines in nonalcoholic steatohepatitis ( NASH ) . A pilot project in a general clinical research center evaluated the effects of a step 1 American Heart Association diet plus aerobic exercise with or without 800 IU of vitamin E daily on cytokine profiles and liver enzyme levels in 16 patients with biopsy-proven NASH .  Biochemical assessment of liver function , lipid profiles , and body mass index significantly improved during the first 6 weeks of therapy and remained stable during the following 6 weeks . Plasma hyaluronic acid ( HA ) concentrations decreased in parallel with weight loss . Plasma tumor necrosis factor ( TNF ) concentrations were significantly elevated in patients with NASH and similar to patients with stable alcoholic cirrhosis but not as elevated as in patients with acute alcoholic steatohepatitis ( AH ) . Although plasma TNF , interleukin 8 ( IL-8 ) , and IL-6 concentrations were all significantly elevated compared with control values , only plasma IL-6 levels significantly decreased with therapy . Peripheral blood monocyte TNF , IL-8 , and IL-6 production was significantly elevated in patients with NASH but did not significantly decrease . Independent effects of vitamin E were not observed in this small sample . In conclusion , patients with NASH have dysregulated cytokine metabolism similar to , but less pronounced than abnormalities documented in AH . Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study . Lifestyle modifications ( low-fat diet and exercise ) were associated with improvement in liver enzymes , cholesterol , and plasma HA levels in patients with NASH , whereas the level of vitamin E supplementation used in this short-term pilot study provided no apparent added benefit Gut microbiota modifiers may have beneficial effects of non‐alcoholic fatty liver disease ( NAFLD ) but r and omised controlled trials ( RCT ) are lacking in children BACKGROUND & AIMS : Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum ; it has shown antioxidant , anti‐inflammatory and antifibrotic effects , and may be useful in patients with nonalcoholic fatty liver disease ( NAFLD ) . We aim ed to study the efficacy of silymarin in patients with nonalcoholic steatohepatitis (NASH)—the more severe form of NAFLD . METHODS : We performed a r and omized , double‐blind , placebo‐controlled trial of consecutive adults with biopsy‐proven NASH and a NAFLD activity score ( NAS ) of 4 or more at a tertiary care hospital in Kuala Lumpur , Malaysia , from November 2012 through August 2014 . Patients were r and omly assigned to groups given silymarin ( 700 mg ; n = 49 patients ) or placebo ( n = 50 patients ) 3 times daily for 48 weeks . After this 48‐week period , liver biopsies were repeated . The primary efficacy outcome was a decrease of 30 % or more in NAS ; findings from 48‐week liver biopsies were compared with those from the baseline biopsy . Secondary outcomes included changes in steatosis , lobular inflammation , hepatocyte ballooning , NAS and fibrosis score , and anthropometric measurements , as well as glycemic , lipid , and liver profiles and liver stiffness measurements . RESULTS : The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups ( 32.7 % in the silymarin group vs 26.0 % in the placebo group ; P = .467 ) . A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology ( reductions of 1 point or more ; 22.4 % ) than did the placebo group ( 6.0 % ; P = .023 ) , and based on liver stiffness measurements ( decrease of 30 % or more ; 24.2 % ) than did the placebo group ( 2.3 % ; P = .002 ) . The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index ( reduction of 0.14 , P = .011 compared with baseline ) , fibrosis‐4 score ( reduction of 0.20 , P = .041 compared with baseline ) , and NAFLD fibrosis score ( reduction of 0.30 , P < .001 compared with baseline ) ; these changes were not observed in the placebo group ( reduction of 0.07 , P = .154 ; increase of 0.18 , P = .389 ; and reduction of 0.05 , P = .845 , respectively ) . There was no significant difference between groups in number of adverse events ; adverse events that occurred were not attributed to silymarin . CONCLUSIONS : In a r and omized trial of 99 patients , we found that silymarin ( 700 mg , given 3 times daily for 48 weeks ) did not reduce NAS scores by 30 % or more in a significantly larger proportion of patients with NASH than placebo . Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial . It appears to be safe and well tolerated . Clinical Trials.gov : NCT02006498 We compared the effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease ( NAFLD ) . Obese ( body mass index ≥30 kg/m2 , mean weight 96.0 ± 16.3 kg ) non-diabetic Asian adults , with NAFLD diagnosed by liver fat fraction ( LFF ) ≥ 5.5 % on magnetic resonance imaging without other causes of hepatic steatosis , were r and omized to a supervised program of dieting ( restriction by 400 kilocalories/d ) plus moderate-intensity aerobic exercise ( ~200 min/wk ; DE group , n = 12 ) , or liraglutide at the 3 mg daily dose approved for weight loss ( LI group , n = 12 ) , for 26 weeks . Both DE and LI groups had significant ( P < .01 ) and similar reductions in weight ( -3.5 ± 3.3 vs -3.5 ± 2.1 kg , respectively , P = .72 ) , LFF ( -8.9 ± 13.4 vs -7.2 % ± 7.1 % , P = .70 ) , serum alanine aminotransferase ( -42 ± 46 vs -34 ± 27 U/L , P = .52 ) and aspartate aminotransferase ( -23 ± 24 vs -18 ± 15 U/L , P = .53 ) . In this first r and omized study comparing the 2 weight-loss modalities for improving NAFLD , liraglutide was as effective as structured lifestyle modification PURPOSE Oral antidiabetic drugs ( OADs ) such as pioglitazone and metformin have beneficial effects in patients with nonalcoholic steatohepatitis . We prospect ively assessed the effects of OADs on nonalcoholic fatty liver disease ( NAFLD ) in 886 men with type 2 diabetes mellitus and in a murine model of NAFLD . METHODS Patients were r and omized to receive pioglitazone , metformin , sitagliptin , or a non-OAD ( control ) for 6 months . All the patients received dietary and exercise guidance once a month during this study . Changes in the liver-to-spleen ratio on computed tomography ( CT ) and NAFLD-related parameters were measured from baseline to the end of treatment . FINDINGS The liver/spleen ratio improved significantly in the pioglitazone and metformin groups compared with the control group ( both P < 0.01 ) , but not in the sitagliptin group ( P = 0.73 ) . The mean changes from baseline were -3.464 ± 10.156 % , 19.236 ± 9.896 % , 4.783 ± 1.467 % , and 1.328 ± 0.802 % in the control , pioglitazone , metformin , and sitagliptin groups , respectively . Multivariable analysis showed that the liver/spleen ratio was strongly correlated with high-sensitivity C-reactive protein concentration in the pioglitazone group ( F = 9.973 ; P < 0.01 ) and abdominal visceral fat volume in the metformin group ( F = 6.049 ; P < 0.05 ) . CONCLUSIONS Pioglitazone elicited the greatest improvements in features of NAFLD in type 2 diabetes mellitus . ( Trial Registration : www.is rct n.org/ , IS RCT N33414972 , http://www.is rct n.org/ ) Based on animal studies and pilot studies in humans , betaine , a methyl donor for the remethylation of homocysteine , may be a therapeutic agent for nonalcoholic steatohepatitis ( NASH ) . We evaluated the safety and efficacy of betaine for patients with NASH and whether betaine positively modified factors postulated to be “ second hits ” and underlying mechanisms of NASH . We conducted a r and omized placebo‐control study of 55 patients with biopsy‐proven NASH who received either oral betaine ( 20 g daily ) or placebo for 12 months . Pre‐ and posttreatment variables were analyzed using the paired t test or Wilcoxon rank test . Treatment groups were comparable at baseline . Of the 35 patients ( 17 betaine , 18 placebo ) who completed the study , 34 patients ( 16 betaine , 18 placebo ) underwent posttreatment liver biopsy . Patients r and omized to betaine had a decrease in steatosis grade . No intra‐ or intergroup differences or changes in nonalcoholic fatty liver disease activity score or fibrosis stage were noted . Elevations of insulin , glucose , and proinflammatory cytokines and the reduced antioxidant status noted in NASH patients did not improve with betaine therapy . The antiinflammatory agent adiponectin was significantly reduced in both groups and did not change with therapy . Lastly , S‐adenosylhomocysteine was approximately twice normal and was not reduced by betaine therapy . Conclusion : Compared to placebo , betaine improved hepatic steatosis and may protect against worsening steatosis . High‐dose betaine supplementation failed to reduce S‐adenosylhomocysteine and did not positively affect any of the second hit mechanisms postulated to contribute to NASH that we studied . Although betaine has been proven effective in treating hepatic steatosis in several animal models , translating novel therapeutic options noted in animal studies to humans with NASH will prove challenging . ( HEPATOLOGY 2009 . Although non-alcoholic fatty liver disease ( NAFLD ) is the leading aetiology of liver disorders in the world , there is no proven treatment for NAFLD patients with normal or low BMI . The aim of this study was to evaluate the efficacy of synbiotics supplementation in NAFLD patients with normal or low BMI . In this r and omised , double-blind , placebo-controlled , clinical trial , fifty patients with NAFLD were assigned to take either a synbiotic supplement or a placebo capsule for 28 weeks . Both groups were advised to follow a healthy lifestyle . At the end of the study , hepatic steatosis and fibrosis reduced in both groups ; however , the mean reduction was significantly greater in the synbiotic group rather than in the placebo group ( P<0·001 ) . Furthermore , serum levels of fasting blood sugar , TAG and most of the inflammatory mediators reduced in the synbiotic group significantly compared with the placebo group ( P<0·05 ) . Our results provide evidence that synbiotic supplementation improves the main features of NAFLD in patients with normal and low BMI , at least partially through reduction in inflammatory indices . Further studies are needed to address the exact mechanism of action of these effects AIM To examine whether poly-unsaturated fatty acid ( PUFA ) therapy is beneficial for improving  nonalcoholic steatohepatitis ( NASH ) . METHODS In total , 78 patients pathologically diagnosed with NASH were enrolled and were r and omly assigned into the control group and the PUFA therapy group ( added 50 mL PUFA with 1:1 ratio of EHA and DHA into daily diet ) . At the initial analysis and after 6 mo of PUFA therapy , parameters of interest including liver enzymes , lipid profiles , markers of inflammation and oxidation , and histological changes were evaluated and compared between these two groups . RESULTS At the initial analysis , in patients with NASH , serum levels of alanine aminotransferase ( ALT ) and aspartase aminotransferase ( AST ) were slightly elevated . Triglyceride ( TG ) , total cholesterol ( TC ) and low-density lipoprotein cholesterol levels , markers of systemic inflammation [ C-reactive protein ( CRP ) ] and oxidation [ malondialdehyde ( MDA ) ] , as well as fibrosis parameters of type IV collagen and pro-collagen type III pro-peptide were also increased beyond the normal range . Six months later , ALT and AST levels were significantly reduced in the PUFA group compared with the control group . In addition , serum levels of TG and TC , CRP and MDA , and type IV collagen and pro-collagen type III pro-peptide were also simultaneously and significantly reduced . Of note , histological evaluation showed that steatosis grade , necro-inflammatory grade , fibrosis stage , and ballooning score were all profoundly improved in comparison to the control group , strongly suggesting that increased PUFA consumption was a potential way to offset NASH progression . CONCLUSION Increased PUFA consumption is a potential promising approach for NASH prevention and reversal This study aim ed to assess the effect of luseogliflozin on liver fat deposition and compare luseogliflozin to metformin in type 2 diabetes ( T2D ) patients with non-alcoholic fatty liver disease ( NAFLD ) . Thirty-two T2D patients with NAFLD diagnosed by computed tomography or abdominal sonography were recruited . Participants were r and omly assigned to receive either luseogliflozin ( 2.5 mg , newly administered ) or metformin ( 1500 mg , newly or additionally administrated ) . Data on the liver-to-spleen attenuation ratio ( L/S ) , visceral fat area , body mass index , glycated hemoglobin ( HbA1c ) , alanine aminotransferase ( ALT ) , fasting plasma glucose , C-peptide immunoreactivity ( CPR ) , and CPR index were collected at baseline and after 6 months . The change in L/S was significantly greater in the luseogliflozin group than in the metformin group . Similarly , the changes in the visceral fat area , HbA1c , and body mass index were significantly greater in the luseogliflozin group than in the metformin group . The changes in ALT , fasting glucose , CPR , and CPR index were not significant in both groups . In conclusion , luseogliflozin significantly reduced liver fat deposition as compared to metformin , which may indicate clinical relevant benefits for NAFLD BACKGROUND Glucagon-like peptide-1 ( GLP-1 ) analogues reduce hepatic steatosis , concentrations of liver enzymes , and insulin resistance in murine models of fatty liver disease . These analogues are licensed for type 2 diabetes , but their efficacy in patients with non-alcoholic steatohepatitis is unknown . We assessed the safety and efficacy of the long-acting GLP-1 analogue , liraglutide , in patients with non-alcoholic steatohepatitis . METHODS This multicentre , double-blinded , r and omised , placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide ( 1·8 mg daily ) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis . Patients were r and omly assigned ( 1:1 ) using a computer-generated , central ly administered procedure , stratified by trial centre and diabetes status . The trial was design ed using A'Hern 's single-group method , which required eight ( 38 % ) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinical ly significant . Patients , investigators , clinical trial site staff , and pathologists were masked to treatment assignment throughout the study . The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment ( 48 weeks ) , as assessed central ly by two independent pathologists . Analysis was done by intention-to-treat analysis , which included all patients who underwent end-of-treatment biopsy . The trial was registered with Clinical Trials.gov , number NCT01237119 . FINDINGS Between Aug 1 , 2010 , and May 31 , 2013 , 26 patients were r and omly assigned to receive liraglutide and 26 to placebo . Nine ( 39 % ) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two ( 9 % ) of 22 such patients in the placebo group ( relative risk 4·3 [ 95 % CI 1·0 - 17·7 ] ; p=0·019 ) . Two ( 9 % ) of 23 patients in the liraglutide group versus eight ( 36 % ) of 22 patients in the placebo group had progression of fibrosis ( 0·2 [ 0·1 - 1·0 ] ; p=0·04 ) . Most adverse events were grade 1 ( mild ) to grade 2 ( moderate ) in severity , transient , and similar in the two treatment groups for all organ classes and symptoms , with the exception of gastrointestinal disorders in 21 ( 81 % ) of 23 patients in the liraglutide group and 17 ( 65 % ) of 22 patients in the placebo group , which included diarrhoea ( ten [ 38 % ] patients in the liraglutide group vs five [ 19 % ] in the placebo group ) , constipation ( seven [ 27 % ] vs none ) , and loss of appetite ( eight [ 31 % ] vs two [ 8 % ] ) . INTERPRETATION Liraglutide was safe , well tolerated , and led to histological resolution of non-alcoholic steatohepatitis , warranting extensive , longer-term studies . FUNDING Wellcome Trust , National Institute of Health Research , and Novo Nordisk BACKGROUND & AIMS n-3 polyunsaturated fatty acids reduce insulin resistance , lipogenesis , and inflammation , which are features of nonalcoholic steatohepatitis ( NASH ) . Ethyl-eicosapentanoic acid ( EPA-E ) is a synthetic polyunsaturated fatty acid that reduces hypertriglyceridemia . We report the final results of a phase 2b multicenter , prospect i ve , double-blind , r and omized , placebo-controlled trial of EPA-E for NASH . METHODS Our study , performed at 37 sites in North America , included subjects with NASH and nonalcoholic fatty liver disease ( NAFLD ) activity scores ≥ 4 , with minimum scores of 1 for steatosis and inflammation , along with either ballooning or at least stage 1a fibrosis . A total of 243 subjects were r and omly assigned to groups given placebo ( n = 75 ) , low-dosage EPA-E ( 1800 mg/d ; n = 82 ) , or high-dosage EPA-E ( 2700 mg/d ; n = 86 ) for 12 months . Subjects were examined at 4-week intervals for 3 months , 6-week intervals for the next 3 months , and every 3 months thereafter , until 1 month after the last dose was taken . Liver biopsies were collected 2 weeks after the last dose of EPA-E or placebo . The primary efficacy end point was NAFLD activity score ≤ 3 , without worsening of fibrosis ; or a decrease in NAFLD activity score by ≥ 2 with contribution from > 1 parameter , without worsening of fibrosis , 1 year after the last dose of EPA-E or placebo was given . RESULTS Similar proportions of subjects in each group met the primary end point ( 40 % , 37 % , and 35.9 % for placebo , low-dosage , and high-dosage EPA-E , respectively ) . EPA-E had no significant effects on steatosis , inflammation , ballooning , or fibrosis scores . There were no significant effects on levels of liver enzymes , insulin resistance , adiponectin , keratin 18 , high-sensitivity C-reactive protein , or hyaluronic acid . High-dosage EPA-E  reduced levels of triglyceride ( -6.5 mg/dL vs an increase of 12 mg/dL in the placebo group ; P = .03 ) . There were no treatment-related serious adverse events . CONCLUSIONS In a phase 2 trial , EPA-E had no significant effect on the histologic features of NASH  . EPA-E reduced subjects ' levels of triglyceride compared with placebo , without any increase in serious adverse events . Clinical trials.gov Number : 01154985 BACKGROUND & AIMS Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ . Elafibranor improves insulin sensitivity , glucose homeostasis , and lipid metabolism and reduces inflammation . We assessed the safety and efficacy of elafibranor in an international , r and omized , double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis ( NASH ) . METHODS Patients with NASH without cirrhosis were r and omly assigned to groups given elafibranor 80 mg ( n = 93 ) , elafibranor 120 mg ( n = 91 ) , or placebo ( n = 92 ) each day for 52 weeks at sites in Europe and the United States . Clinical and laboratory evaluations were performed every 2 months during this 1-year period . Liver biopsies were then collected and patients were assessed 3 months later . The primary outcome was resolution of NASH without fibrosis worsening , using protocol -defined and modified definitions . Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression , adjusting for baseline nonalcoholic fatty liver disease activity score . RESULTS In intention-to-treat analysis , there was no significant difference between the elafibranor and placebo groups in the protocol -defined primary outcome . However , NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group ( 19 % vs 12 % ; odds ratio = 2.31 ; 95 % confidence interval : 1.02 - 5.24 ; P = .045 ) , based on a post-hoc analysis for the modified definition . In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 ( n = 234 ) , elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition ( 20 % vs 11 % ; odds ratio = 3.16 ; 95 % confidence interval : 1.22 - 8.13 ; P = .018 ) and the modified definitions ( 19 % vs 9 % ; odds ratio = 3.52 ; 95 % confidence interval : 1.32 - 9.40 ; P = .013 ) . Patients with NASH resolution  after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution ( mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders ; P < .001 ) . Liver enzymes , lipids , glucose profiles , and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group . Elafibranor was well tolerated and did not cause weight gain or cardiac events , but did produce a mild , reversible increase in serum creatinine ( effect size vs placebo : increase of 4.31 ± 1.19 μmol/L ; P < .001 ) . CONCLUSIONS A post-hoc analysis of data from trial of patients with NASH showed that elafibranor ( 120 mg/d for 1 year ) resolved NASH without fibrosis worsening , based on a modified definition , in the intention-to-treat analysis and in patients with moderate or severe NASH . However , the predefined end point was not met in the intention to treat population . Elafibranor was well tolerated and improved patients ' cardiometabolic risk profile . Clinical Trials.gov number : NCT01694849 Liraglutide , an analogue of human glucagon-like peptide 1 , reduces cardiovascular events in patients with type 2 diabetes ; however , it has still been unknown by which mechanisms liraglutide could reduce cardiovascular events . Type 2 diabetic patients with insulin treatment were enrolled in this r and omized , open-label , comparative study . Participants were r and omly assigned to liraglutide plus insulin ( liraglutide group ) and insulin treatment ( control group ) at 1:1 allocation . Primary endpoint was the change in viscera fat are ( VFA , cm2 ) at 24 weeks . Liver attenuation index ( LAI ) measured by abdominal computed tomography , urinary albumin-to-creatinine ratio ( ACR , mg/g ) , and C-reactive protein ( CRP ) levels , skeletal muscle index ( SMI ) , and quality of life ( QOL ) related to diabetes treatment were also determined . Seventeen patients ( 8 ; liraglutide group , 9 ; control group , mean age 59 ± 13 years ; 53 % female ) completed this study . Liraglutide treatment significantly reduced VFA at 24 weeks ; whereas , SFA was unchanged . ACR , LAI , and CRP levels were significantly reduced by liraglutide at 24 weeks and there was no difference in SMI between the two groups . Changes in VFA from baseline to 24 weeks were significantly associated with those in LAI , albuminuria , and HbA1c . Liraglutide treatment significantly improved QOL scores associated with anxiety and dissatisfaction with treatment and satisfaction with treatment . No severe adverse events were observed in both groups . Our data suggest that liraglutide could reduce visceral adiposity in parallel with attenuation of hepatic fat accumulation , albuminuria and micro-inflammation and improve QOL related to diabetes care in insulin-treated patients with type 2 diabetes
Aim Several drugs have been used for treating non-alcoholic fatty liver disease ( NAFLD ) .
The present study is a network meta- analysis of such drugs .