Patients with Nonalcoholic Fatty Liver Disease Have a Low Response Rate to Vitamin D Supplementation. Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non-alcoholic fatty liver disease. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Atorvastatin and Antioxidants for the Treatment of Nonalcoholic Fatty Liver Disease: The St Francis Heart Study Randomized Clinical Trial Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Effects of combined low‐dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance, non‐invasive indices of steatosis and fibrosis, and adipokine levels in non‐alcoholic fatty liver disease: a randomized controlled trial Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease Docosahexanoic Acid Plus Vitamin D Treatment Improves Features of NAFLD in Children with Serum Vitamin D Deficiency: Results from a Single Centre Trial Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease Treatment of non-alcoholic steatohepatitis with Phyllanthus urinaria: a randomized trial. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. The utility of radiological imaging in nonalcoholic fatty liver disease. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Efficacy of docosahexaenoic acid-choline-vitamin E in paediatric NASH: a randomized controlled clinical trial. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis
Background : Hypovitaminosis D is associated with an increased severity of nonalcoholic fatty liver disease ( NAFLD ) , but reports on the response to cholecalciferol ( vitamin D3 ) supplementation are conflicting . Objective : The objective of this study was to determine if st and ard vitamin D3 supplementation is effective in NAFLD with hypovitaminosis D. Methods : Sixty-five well-characterized adults [ age ( mean ± SD ) : 51.6 ± 12.3 y ] with biopsy-proven NAFLD were screened . Forty-two patients ( the ratio of men to women was 13:29 ) had hypovitaminosis D ( plasma 25-hydroxyvitamin D [ 25(OH)D ] < 30 ng/mL ) . An observational study was performed in NAFLD patients with hypovitaminosis D treated with 2000 IU cholecalciferol ( vitamin D3 ) daily for 6 mo per clinical practice . Plasma 25(OH)D , hepatic and metabolic panels , and metabolic syndrome components were assessed before and after cholecalciferol supplementation . Body composition was measured by using bioelectrical impedance analysis . The primary outcome measure was plasma 25(OH)D ≥30 ng/mL at the end of the study . Secondary outcomes included change in serum transaminases , fasting plasma glucose , and insulin and homeostasis model assessment of insulin resistance ( HOMA-IR ) . Chi-square , Student 's t tests , correlation coefficient , and multivariate analysis were performed . Results : Twenty-six ( 61.9 % ) patients had nonalcoholic steatohepatitis ( NASH ) , and 16 ( 38.1 % ) had hepatic steatosis . After 6 mo of cholecalciferol supplementation  , plasma 25(OH)D ≥30 ng/mL was observed in 16 subjects ( 38.1 % ; responders ) whereas the remaining 26 patients ( 61.9 % ) were nonresponders with plasma 25(OH)D < 30 ng/mL. Significantly fewer ( P < 0.01 ) patients with NASH were responders ( 4 of 26 , 15.4 % ) than those with hepatic steatosis ( 12 of 16 , 75 % ) . Baseline fasting serum alanine aminotransferase , plasma glucose , and HOMA-IR were similar in the responders and nonresponders , but the NASH score on the liver biopsy was lower ( 16.5 % ) in the responders ( P < 0.001 ) . Nonresponders had a higher fat mass ( 10.5 % ) and lower fat-free mass ( 10.4 % ) than responders did . End-of-treatment alanine aminotransferase and HOMA-IR improved only in responders . The baseline HOMA-IR and histological NASH score were independent predictors of nonresponse to cholecalciferol supplementation . Conclusions : Daily supplementation with 2000 IU cholecalciferol for 6 mo did not correct hypovitaminosis D in the majority of patients with NASH . Further studies are needed to determine if higher doses are effective . This trial was registered at clinical trials.gov as 13 - 00153 BACKGROUND & AIMS Hypovitaminosis D is common in obesity and insulin-resistant states . Increased fat mass in patients with non-alcoholic fatty liver disease ( NAFLD ) may contribute to hypovitaminosis D. To determine the relation among plasma vitamin D concentration , severity of disease and body composition in NAFLD . METHODS  Plasma vitamin D concentration  was quantified in 148 consecutive biopsy-proven patients with NAFLD ( non-alcoholic steatohepatitis - NASH : n = 81 ; and hepatic steatosis : n = 67 ) and healthy controls ( n = 39 ) . NAFLD was scored using the NASH CRN criteria . Body composition was quantified by bioelectrical impedance analysis and abdominal CT image analysis . RESULTS Plasma vitamin D concentration was significantly lower in NAFLD ( 21.2 ± 10.4 ng/ml ) compared with healthy controls ( 35.7 ± 6.0 ng/ml ) . Higher NAFLD activity scores were associated with lower plasma concentration of vitamin D ( r(2 ) = 0.29 ; P < 0.001 ) . Subgroup analysis among patients with NAFLD showed that patients with NASH had significantly lower ( P < 0.01 ) vitamin D levels than those with steatosis alone ( 18.1 ± 8.4 vs. 25.0 ± 11.3 ng/ml ) . Low concentrations of vitamin D were associated with greater severity of steatosis , hepatocyte ballooning and fibrosis ( P < 0.05).On multivariate regression analysis , only severity of hepatocyte ballooning was independently associated ( P = 0.02 ) with low vitamin D concentrations . Plasma vitamin D ( P = 0.004 ) and insulin concentrations ( P = 0.03 ) were independent predictors of the NAFLD activity score on biopsy . Patients with NAFLD had higher fat mass that correlated with low vitamin D ( r(2 ) = 0.26 ; P = 0.008 ) . CONCLUSIONS Low plasma vitamin D concentration is an independent predictor of the severity of NAFLD . Further prospect i ve studies demonstrating the impact of vitamin D replacement in NAFLD patients are required BACKGROUND & AIMS In nonalcoholic fatty liver disease ( NAFLD ) , the distinction between steatosis and steatohepatitis ( NASH ) and the assessment of the severity of the disease rely on liver histology alone . The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH . METHODS Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 sample s collected . The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the kappa reliability test . RESULTS No features displayed high agreement ; substantial agreement was only seen for steatosis grade ; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis ; fair agreement for Mallory bodies ; acidophilic bodies and lobular inflammation displayed only slight agreement . Overall , the discordance rate for the presence of hepatocyte ballooning was 18 % , and ballooning would have been missed in 24 % of patients had only 1 biopsy been performed . The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74 . Discordance of 1 stage or more was 41 % . Six of 17 patients with bridging fibrosis ( 35 % ) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy . Intraobserver variability was systematic ally lower than sampling variability and therefore could not account for most of the sampling error . CONCLUSIONS Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma ; therefore , sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies 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 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 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 In the absence of surrogate markers , the evaluation of suspected nonalcoholic fatty liver disease ( NAFLD ) is highly dependent on histological examination . The extent of sampling variability affecting the reliability of a single liver biopsy in patients with suspected NAFLD is poorly characterized . This prospect i ve study aim ed to correlate precise histological findings in paired biopsies — right and left lobe — in the diagnosis of NAFLD in morbidly obese subjects undergoing bariatric surgery  employing both Brunt and Matteoni classifications and the NAFLD Activity Score ( NAS ) . We also aim ed to determine whether the composite histopathological findings of the two biopsies would improve diagnostic accuracy . Consecutive subjects had an intraoperative biopsy from both right and left lobes , evaluated and scored in a blinded manner . Intraobserver agreement was also assessed . Kappa coefficients of agreement were calculated . Forty‐one subjects had acceptable biopsies . Agreement for steatosis was excellent and moderate for fibrosis . Concordance was only fair for most features of necroinflammation . Intraobserver agreement was only moderate for lobular inflammation . Excellent agreement was seen for the diagnosis of NASH using Brunt criteria and good agreement when using Matteoni and NAS scoring systems . Composite biopsy data particularly improved identification of hepatocyte ballooning . The diagnostic accuracy also improved substantially when composite features were compared with single‐sided biopsy features , especially for the Matteoni and NAS scoring systems . In conclusion , significant sampling variability occurs in NAFLD , particularly for features of necroinflammation . This should be factored into the design of clinical trials and studies of the natural history of the disease . ( HEPATOLOGY 2006;44:874–880 . 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 CONTEXT Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis ( NASH ) . No treatment has been established . OBJECTIVE To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin . DESIGN , SETTING , AND PATIENTS R and omized , double-blind , double-dummy , placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients ( aged 8 - 17 years ) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010 . Interventions Daily dosing of 800 IU of vitamin E ( 58 patients ) , 1000 mg of metformin ( 57 patients ) , or placebo ( 58 patients ) for 96 weeks . MAIN OUTCOME MEASURES The primary outcome was sustained reduction in alanine aminotransferase ( ALT ) defined as 50 % or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment . Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures . RESULTS Sustained reduction in ALT level was similar to placebo ( 10/58 ; 17 % ; 95 % CI , 9 % to 29 % ) in both the vitamin E ( 15/58 ; 26 % ; 95 % CI , 15 % to 39 % ; P = .26 ) and metformin treatment groups ( 9/57 ; 16 % ; 95 % CI , 7 % to 28 % ; P = .83 ) . The mean change in ALT level from baseline to 96 weeks was -35.2 U/L ( 95 % CI , -56.9 to -13.5 ) with placebo vs -48.3 U/L ( 95 % CI , -66.8 to -29.8 ) with vitamin E ( P = .07 ) and -41.7 U/L ( 95 % CI , -62.9 to -20.5 ) with metformin ( P = .40 ) . The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo ( 95 % CI , -0.2 to 0.3 ) vs -0.5 with vitamin E ( 95 % CI , -0.8 to -0.3 ; P = .006 ) and -0.3 with metformin ( 95 % CI , -0.6 to -0.0 ; P = .04 ) ; and in NAFLD activity score , -0.7 with placebo ( 95 % CI , -1.3 to -0.2 ) vs -1.8 with vitamin E ( 95 % CI , -2.4 to -1.2 ; P = .02 ) and -1.1 with metformin ( 95 % CI , -1.7 to -0.5 ; P = .25 ) . Among children with NASH , the proportion who resolved at 96 weeks was 28 % with placebo ( 95 % CI , 15 % to 45 % ; 11/39 ) vs 58 % with vitamin E ( 95 % CI , 42 % to 73 % ; 25/43 ; P = .006 ) and 41 % with metformin ( 95 % CI , 26 % to 58 % ; 16/39 ; P = .23 ) . Compared with placebo , neither therapy demonstrated significant improvements in other histological features . CONCLUSION Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00063635 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 Non-alcoholic steatohepatitis ( NASH ) is a common liver disease that may progress to cirrhosis and hepatocellular carcinoma . There is currently no approved pharmacological treatment for NASH . Phyllanthus urinaria is a commonly used hepatoprotective herb that ameliorates NASH in animal studies . We aim ed to test the hypothesis that Phyllanthus was superior to placebo in improving histological non-alcoholic fatty liver disease ( NAFLD ) activity score . METHODS This was a placebo-controlled parallel-group double-blind r and omized controlled trial . Patients with histology-proven NASH were r and omized to receive Phyllanthus or placebo for 24 weeks . The primary endpoint was change in NAFLD activity score from baseline to week 24 . Secondary endpoints included changes in individual histological parameters , liver biochemistry and metabolic profile . RESULTS We enrolled 60 patients ( 40 received Phyllanthus and 20 received placebo ) . The change in NAFLD activity score was -0.8 ± 1.4 in the Phyllanthus group and -0.3 ± 1.3 in the placebo group ( P = 0.24 ) . The change in steatosis , lobular inflammation , ballooning and fibrosis was also similar between the two groups . Within the Phyllanthus group , although there was reduction in hepatic steatosis ( -0.2 ± 0.7 ; P = 0.039 ) and ballooning grade s ( -0.4 ± 0.5 ; P < 0.001 ) , the change was small and of limited clinical significance . Furthermore , there was no significant difference in the changes in alanine aminotransferase , aspartate aminotransferase , fasting glucose and lipid profile between the two groups . CONCLUSIONS Phyllanthus is not superior to placebo in improving NAFLD activity score in NASH patients 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 BACKGROUND & AIMS This prospect i ve study evaluates the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis ( NASH ) . METHODS Consecutive patients with biopsy-proven nonalcoholic fatty liver disease ( NAFLD ) were enrolled ( 2000 - 2001 ) . Patients with other liver diseases and significant alcohol consumption ( > 20 g/day ) were excluded . Clinicodemographic data were gathered at the time of liver biopsy . Each biopsy specimen was assessed by a hepatopathologist . Each patient underwent a limited abdominal ultrasonography ( US ) , computerized tomography ( CT ) , and magnetic resonance imaging ( MRI ) . Films were interpreted by a radiologist who used a predetermined radiological protocol . Each radiological study was reread by the same radiologist and a second radiologist . RESULTS Patients with NASH had greater aspartate aminotransferase levels ( P = 0.03 ) , greater ferritin levels ( P = 0.05 ) , more hepatocyte ballooning ( P < 0.0001 ) , and more fibrosis ( P = 0.002 ) . None of the radiological features distinguished between NASH and other types of NAFLD . No radiological modality detected the presence of hepatocyte ballooning , Mallory 's hyaline , or fibrosis , which are important features in the diagnosis of NASH . The presence of > 33 % fat on liver biopsy was optimal for detecting steatosis on radiological imaging . CONCLUSIONS Differences between NASH and nonprogressive NAFLD were not apparent with any radiological modality . Of the pathologic features important for establishing the diagnosis of NASH , only the severity of steatosis was reflected in these radiological modalities . Good intraobserver agreement was evident for each modality ( US , CT , and MRI ) that was superior to interobserver agreement 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 UNLABELLED Nonalcoholic fatty liver disease ( NAFLD ) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis ( NASH ) , fibrosis , and cirrhosis . To date , no pharmacological treatment is approved for NAFLD/NASH . Here , we report on pre clinical and clinical data with GFT505 , a novel dual peroxisome proliferator-activated receptor alpha/delta ( PPAR-α/δ ) agonist . In the rat , GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling . The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis ( Western diet [WD]-fed human apolipoprotein E2 [ hApoE2 ] transgenic mice , methionine- and choline-deficient diet-fed db/db mice , and CCl4 -induced fibrosis in rats ) . GFT505  demonstrated liver-protective effects on steatosis , inflammation , and fibrosis . In addition , GFT505  improved liver dysfunction markers , decreased hepatic lipid accumulation , and inhibited proinflammatory ( interleukin-1 beta , tumor necrosis factor alpha , and F4/80 ) and profibrotic ( transforming growth factor beta , tissue inhibitor of metalloproteinase 2 , collagen type I , alpha 1 , and collagen type I , alpha 2 ) gene expression . To determine the role of PPAR-α-independent mechanisms , the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice . In these mice , GFT505 also prevented WD-induced liver steatosis and inflammation , indicating a contribution of PPAR-α-independent mechanisms . Finally , the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients  . GFT505 treatment decreased plasma concentrations of alanine aminotransferase , gamma-glutamyl transpeptidase , and alkaline phosphatase . CONCLUSION The dual PPAR-α/δ agonist , GFT505 , is a promising liver-targeted drug for treatment of NAFLD/NASH . In animals , its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms 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 ( BACKGROUND Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis . Currently , there is no established treatment for this disease . METHODS We r and omly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily ( 80 subjects ) , vitamin E at a dose of 800 IU daily ( 84 subjects ) , or placebo ( 83 subjects ) , for 96 weeks . The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis , as assessed with the use of a composite of st and ardized scores for steatosis , lobular inflammation , hepatocellular ballooning , and fibrosis . Given the two planned primary comparisons , P values of less than 0.025 were considered to indicate statistical significance . RESULTS Vitamin E therapy , as compared with placebo , was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis ( 43 % vs. 19 % , P=0.001 ) , but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant ( 34 % and 19 % , respectively ; P=0.04 ) . Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone , as compared with placebo ( P<0.001 for both comparisons ) , and both agents were associated with reductions in hepatic steatosis ( P=0.005 for vitamin E and P<0.001 for pioglitazone ) and lobular inflammation ( P=0.02 for vitamin E and P=0.004 for pioglitazone ) but not with improvement in fibrosis scores ( P=0.24 for vitamin E and P=0.12 for pioglitazone ) . Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo ; the rates of other side effects were similar among the three groups . CONCLUSIONS Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes . There was no benefit of pioglitazone over placebo for the primary outcome ; however , significant benefits of pioglitazone were observed for some of the secondary outcomes . ( Clinical Trials.gov number , NCT00063622 . 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 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 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 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
These studies demonstrated improvement in biochemical profiles , with a decline in or normalization of liver enzymes .
However , some concerns have been raised regarding the use of vitamin E in patients with NASH due to its adverse effects profile and lack of significant improvement in hepatic fibrosis .
There has been a growing interest in the role of vitamin E supplementation in the treatment and /or prevention of nonalcoholic fatty liver ( NAFLD ) .
Furthermore , histological assessment showed favorable outcomes in lobular inflammation and hepatic steatosis following treatment with vitamin E. Current guidelines regarding the use of vitamin E in the setting of NAFLD recommend that vitamin E-based treatment be restricted to biopsy-proven nondiabetic patients with NASH only .