Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. The utility of radiological imaging in nonalcoholic fatty liver disease. Noninvasive Diagnosis of Nonalcoholic Fatty Liver Disease and Quantification of Liver Fat Using a New Quantitative Ultrasound Technique. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Unleashing the untold and misunderstood observations on vitamin E Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Magnetic Resonance Elastography Predicts Advanced Fibrosis in Patients With Nonalcoholic Fatty Liver Disease: A Prospective Study Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Clinical spectrum and natural history of non-alcoholic steatohepatitis with normal alanine aminotransferase values. Updated Definitions of Healthy Ranges for Serum Alanine Aminotransferase Levels Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Noninvasive differentiation of simple steatosis and steatohepatitis by using gadoxetic acid-enhanced MR imaging in patients with nonalcoholic fatty liver disease: a proof-of-concept study. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis Effects of aerobic vs. resistance training on visceral and liver fat stores, liver enzymes, and insulin resistance by HOMA in overweight adults from STRRIDE AT/RT. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis.
BACKGROUND / AIMS A total of 213 patients with compensated cirrhosis , portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices . Predictors of the development of hepatocellular carcinoma ( HCC ) , including hepatic venous pressure gradient ( HVPG ) were analyzed . METHODS Baseline laboratory tests , ultrasound and HVPG measurements were performed . Patients were followed prospect ively every three months until development of varices or variceal bleeding or end of the study in 09/02 . The endpoint was HCC development according to st and ard diagnostic criteria . Univariate and multivariate Cox regression models were developed to identify predictors of HCC . RESULTS In a median follow-up of 58 months 26/213 ( 12.2 % ) patients developed HCC . Eight patients were transplanted and 28 patients died without HCC . Twenty-one ( 84 % ) HCC developed in patients with HCV . On multivariate analysis HVPG ( HR 1.18 ; 95%CI 1.08 - 1.29 ) , albumin ( HR 0.34 ; 95%CI 0.14 - 0.83 ) and viral etiology ( HR 4.59 ; 95%CI 1.51 - 13.92 ) were independent predictors of HCC development . ROC curves identified 10 mmHg of HVPG as the best cut-off ; those who had an HVPG above this value had a 6-fold increase in the HCC incidence . CONCLUSIONS Portal hypertension is an independent predictor of HCC development . An HVPG > 10 mmHg is associated with a 6-fold increase of HCC risk 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 BACKGROUND & AIMS Liver biopsy analysis is the st and ard method used to diagnose nonalcoholic fatty liver disease ( NAFLD ) . Advanced magnetic resonance imaging is a noninvasive procedure that can accurately diagnose and quantify steatosis , but is expensive . Conventional ultrasound is more accessible but identifies steatosis with low levels of sensitivity , specificity , and quantitative accuracy , and results vary among technicians . A new quantitative ultrasound ( QUS ) technique can identify steatosis in animal models . We assessed the accuracy of QUS in the diagnosis and quantification of hepatic steatosis , comparing findings with those from magnetic resonance imaging proton density fat fraction ( MRI-PDFF ) analysis as a reference . METHODS We performed a prospect i ve , cross-sectional analysis of a cohort of adults ( N = 204 ) with NAFLD ( MRI-PDFF , ≥5 % ) and without NAFLD ( controls ) . Subjects underwent MRI-PDFF and QUS analyses of the liver on the same day at the University of California , San Diego , from February 2012 through March 2014 . QUS parameters and backscatter coefficient ( BSC ) values were calculated . Patients were assigned r and omly to training ( n = 102 ; mean age , 51 ± 17 y ; mean body mass index , 31 ± 7 kg/m(2 ) ) and validation ( n = 102 ; mean age , 49 ± 17 y ; body mass index , 30 ± 6 kg/m(2 ) ) groups ; 69 % of patients in each group had NAFLD . RESULTS BSC ( range , 0.00005 - 0.25 1/cm-sr ) correlated with MRI-PDFF ( Spearman ρ = 0.80 ; P < .0001 ) . In the training group , the BSC analysis identified patients with NAFLD with an area under the curve value of 0.98 ( 95 % confidence interval , 0.95 - 1.00 ; P < .0001 ) . The optimal BSC cut-off value identified patients with NAFLD in the training and validation groups with 93 % and 87 % sensitivity , 97 % and 91 % specificity , 86 % and 76 % negative predictive values , and 99 % and 95 % positive predictive values , respectively . CONCLUSIONS QUS measurements of BSC can accurately diagnose and quantify hepatic steatosis , based on a cross-sectional analysis that used MRI-PDFF as the reference . With further validation , QUS could be an inexpensive , widely available method to screen the general or at-risk population for NAFLD 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 ] . ) 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 Paradoxically , meta- analysis of human r and omized controlled trials revealed that natural but not synthetic α-tocopherol supplementation significantly increases all-cause mortality at 95 % confidence interval . The root cause was that natural α-tocopherol supplementation significantly depressed bioavailability of other forms of vitamin E that have better chemo-prevention capability . Meta- analysis outcome demonstrated flaws in the underst and ing of vitamin E. Reinterpretation of reported data provides plausible explanations to several important observations . While α-tocopherol is almost exclusively secreted in chylomicrons , enterocytes secrete tocotrienols in both chylomicrons and small high-density lipoproteins . Vitamin E secreted in chylomicrons is discriminately repacked by α-tocopherol transfer protein into nascent very low-density lipoproteins in the liver . Circulating very low-density lipoproteins undergo delipidation to form intermediate-density lipoproteins and low-density lipoproteins . Uptake of vitamin E in intermediate-density lipoproteins and low-density lipoproteins takes place at various tissues via low-density lipoproteins receptor – mediated endocytosis . Small high-density lipoproteins can deliver tocotrienols upon maturation to peripheral tissues independent of α-tocopherol transfer protein action , and uptake of vitamin E takes place at selective tissues by scavenger receptor – mediated direct vitamin E uptake . Dual absorption pathways for tocotrienols are consistent with human and animal studies . α-Tocopherol  depresses the bioavailability of α-tocotrienol and has antagonistic effect on tocotrienols in chemo-prevention against degenerative diseases . Therefore , it is an undesirable component for chemo-prevention . Future research directions should be focused on tocotrienols , preferably free from α-tocopherol , for optimum chemo-prevention and benefits to mankind 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 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 Retrospective studies have shown that two-dimensional magnetic resonance elastography ( 2D-MRE ) , a novel MR method for assessment of liver stiffness , correlates with advanced fibrosis in patients with nonalcoholic fatty liver disease ( NAFLD ) . Prospect i ve data on diagnostic accuracy of 2D-MRE in the detection of advanced fibrosis in NAFLD are needed . The aim of this study is to prospect ively assess the diagnostic accuracy of 2D-MRE , a noninvasive imaging biomarker , in predicting advanced fibrosis ( stage 3 or 4 ) in well-characterized patients with biopsy-proven NAFLD . This is a cross-sectional analysis of a prospect i ve study including 117 consecutive patients ( 56 % women ) with biopsy-proven NAFLD who underwent a st and ardized research visit : history , exam , liver biopsy assessment ( using the nonalcoholic steatohepatitis Clinical Research Network histological scoring system ) , and 2D-MRE from 2011 to 2013 . The radiologist and pathologist were blinded to clinical and pathology/imaging data , respectively . Receiver operating characteristics ( ROCs ) were examined to assess the diagnostic test performance of 2D-MRE in predicting advanced fibrosis . The mean ( ± st and ard deviation ) of age and body mass index was 50.1 ( ± 13.4 ) years and 32.4 ( ± 5.0 ) kg/m2 , respectively . The median time interval between biopsy and 2D-MRE was 45 days ( interquartile range : 50 days ) . The number of patients with fibrosis stages 0 , 1 , 2 , 3 , and 4 was 43 , 39 , 13 , 12 , and 10 , respectively . The area under the ROC curve for 2D-MRE discriminating advanced fibrosis ( stage 3 - 4 ) from stage 0 - 2 fibrosis was 0.924 ( P < 0.0001 ) . A threshold of > 3.63 kPa had a sensitivity of 0.86 ( 95 % confidence interval [ CI ] : 0.65 - 0.97 ) , specificity of 0.91 ( 95 % CI : 0.83 - 0.96 ) , positive predictive value of 0.68 ( 95 % CI : 0.48 - 0.84 ) , and negative predictive value of 0.97 ( 95 % CI : 0.91 - 0.99 ) . Conclusions : MRE is accurate in predicting advanced fibrosis and may be utilized for noninvasive diagnosis of advanced fibrosis in patients with NAFLD . ( Hepatology 2014;60:1920–1928 BACKGROUND & AIMS Prevalence of nonalcoholic fatty liver disease ( NAFLD ) has not been well established . The purpose of this study was to prospect ively define the prevalence of both NAFLD and nonalcoholic steatohepatitis ( NASH ) . METHODS Out patients 18 to 70 years old were recruited from Brooke Army Medical Center . All patients completed a baseline question naire and ultrasound . If fatty liver was identified , then laboratory data and a liver biopsy were obtained . RESULTS Four hundred patients were enrolled . Three hundred and twenty-eight patients completed the question naire and ultrasound .  Mean age ( range , 28 - 70 years ) was 54.6 years ( 7.35 ) ; 62.5 % Caucasian , 22 % Hispanic , and 11.3 % African American ; 50.9 % female ; mean body mass index ( BMI ) ( calculated as kg/m(2 ) ) was 29.8 ( 5.64 ) ; and diabetes and hypertension prevalence 16.5 % and 49.7 % , respectively . Prevalence of NAFLD was 46 % . NASH was confirmed in 40 patients ( 12.2 % of total cohort , 29.9 % of ultrasound positive patients ) . Hispanics had the highest prevalence of NAFLD ( 58.3 % ) , then Caucasians ( 44.4 % ) and African Americans ( 35.1 % ) . NAFLD patients were more likely to be male ( 58.9 % ) , older ( P = .004 ) , hypertensive ( P < .00005 ) , and diabetic ( P < .00005 ) . They had a higher BMI ( P < .0005 ) , ate fast food more often ( P = .049 ) , and exercised less ( P = 0.02 ) than their non-NAFLD counterparts . Hispanics had a higher prevalence of NASH compared with Caucasians ( 19.4 % vs 9.8 % ; P = .03 ) . Alanine aminotransferase , aspartate aminotransferase , BMI , insulin , Quantitative Insulin-Sensitivity Check Index , and cytokeratin-18 correlated with NASH . Among the 54 diabetic patients , NAFLD was found in 74 % and NASH in 22.2 % . CONCLUSION Prevalence of NAFLD and NASH is higher than estimated previously . Hispanics and patients with diabetes are at greatest risk for both NAFLD and NASH 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 Non-alcoholic fatty liver disease ( NAFLD ) including nonalcoholic steatohepatitis ( NASH ) is a well-established cause for chronic liver disease . In most studies on NASH , elevation in alanine aminotransferase ( ALT ) is taken as one of the diagnostic criteria . However , the clinical and histological spectrum and natural history of NAFLD with normal ALT are not well explored . This study was planned to define the clinical spectrum and natural history of patients with NAFLD with normal ALT , and to compare them with NAFLD with abnormal ALT . A prospect i ve study including 81 consecutive patients with ahistological diagnosis ofNAFLD was planned during the period from 1999 to 2003 . Consecutive ( n=81 ) patients with the histological diagnosis of NAFLD were included in the study . In all the patients , clinical , anthropometric , laboratory , histological and imaging features were noted at the baseline . All these patients were followed up regularly at 6-month intervals . Of the 81 cases , 25 patients ( including 60 % cirrhotics ) had persistently normal enzyme , whereas 56 ( including 23 % cirrhotics ) had abnormal ALT . Both the groups were comparable with respect to distribution of age , gender , ethnicity , clinical features , imaging features , histological severity and laboratory features ; except a higher incidence of diabetes and higher occurrence of advanced liver disease at baseline in NAFLD with normal ALT . Natural history of NAFLD was better in patients without cirrhosis irrespective of baseline ALT levels than in patients with cirrhosis ; except for a higher incidence of decompensation in cirrhotics with normal ALT . The entire clinical and histological spectrum of NAFLD is seen in patients with normal ALT and is not different from patients with abnormal ALT . In patients with diabetes and hepatomegaly in the absence of other obvious liver diseases , even normal ALT may not rule out advanced liver disease , and liver biopsy may be necessary to identify the severity of liver disease Context Current upper limits ( 500 nkat/L [ 30 U/L ] for women , 667 nkat/L [ 40 U/L ] for men ) for serum alanine aminotransferase ( ALT ) level were defined in population s that included persons with nonalcoholic fatty liver disease ( NAFLD ) and persons with hepatitis C virus ( HCV ) infection . Contribution This study redefined ALT limits in blood donors at low risk for NAFLD and without hepatitis B or C ( 317 nkat/L [ 19 U/L ] in women , 500 nkat/L [ 30 U/L ] in men ) . When applied to 209 anti-HCV-positive donors , the new thresholds had 76.3 % sensitivity and 88.5 % specificity in identifying patients with hepatitis C viremia compared with 55 % and 97.4 % for old thresholds . Implication s Laboratories should consider revising the upper limits of normal for ALT to improve the sensitivity of this test in identifying sub clinical liver disease . The Editors Serum alanine aminotransferase ( ALT ) concentration is the most commonly used variable for assessment of liver disease ( 1 , 2 ) . However , particularly in the case of chronic hepatitis C virus ( HCV ) infection , ALT measurement often fails to identify patients with minimal to mild necroinflammatory activity ( 3 - 7 ) . Current upper limits of normal for ALT level were set , on average , at 667 nkat/L ( 40 U/L ) ( range , 500 to 833 nkat/L [ 30 to 50 U/L ] ) in studies conducted over the past 10 years ( 1 , 3 - 5 , 7 , 8) . Such thresholds , however , were mostly computed in the 1980s , when ALT testing was introduced as a surrogate marker for the screening of non-A , non-B hepatitis among blood donors and before anti-HCV testing and restrictive behavioral criteria for donor selection were implemented . Furthermore , so-called reference population s were likely to include many persons with nonalcoholic fatty liver disease , now recognized as the most prevalent cause of chronic liver disease in developed countries ( 8 - 10 ) . Current reference ranges for ALT level probably underestimate the frequency of chronic liver disease . Because dietary and behavioral risks for liver disease are widespread in many countries , a critical revision of ALT limits would require the definition of healthy ranges rather than a generic up date of normal ranges . Thus far , several factors have hampered this task . For example , to obtain solid data , many clinical , biochemical , and behavioral variables potentially related to liver disease must be investigated , requiring screening of large numbers of persons . Furthermore , repeated blood donors , who currently represent the vast majority of blood-donation c and i date s , can not be included in the sampling frame , because they have been selected on the basis of ALT activity during the past two decades . We report the results of a 4-year study of first-time blood-donation c and i date s. To up date the definitions of healthy ranges for serum ALT level , we identified a population at low risk for sub clinical liver disease by exploring factors related to enzyme activity in both healthy persons and those with mild abnormalities on liver tests . Next , we tested the sensitivity and specificity of the ranges obtained from these participants in the clinical evaluation of anti-HCVpositive persons with and without chronic liver damage . Methods Participants Figure 1 summarizes the selection of the study participants . Figure 1 . Procedures for selection of the study participants . * Donor c and i date s were not suitable for the following reasons : previous blood transfusion ( 2 % ) ; use of major illicit drugs ( 1.5 % ) ; at-risk sexual exposures ( 9 % ) ; history of hepatitis or other blood borne infections ( 4 % ) ; recent exposure in a malaria-endemic area ( 5 % ) ; low hemoglobin level ( 15 % ) ; use of medication not compatible with blood donation ( 4 % ) ; seizure or central nervous system disorders ( 12 % ) ; hypertension , arrhythmias , or cardiac disease ( 8 % ) ; hypotension ( 9 % ) ; recent surgery ( 2 % ) or other medical or behavioral risks ( 26 % ) ; serologic reactivity on screening assays ( antiHIV 1 , antiHIV 2 , hepatitis B surface antigen , antihepatitis C virus [ HCV ] , or syphilis ) on the sample collected at blood donation ( 2.5 % ) . St and ard upper limits were 667 nkat/L ( 40 U/L ) in men , and 500 nkat/L ( 30 U/L ) in women . Two trained hepatologists used a recently proposed algorithm ( 2 ) to re-evaluate medical history and physical examination . Participants also underwent additional blood testing , including measurement of the following values : aspartate aminotransferase , alanine aminotransferase ( ALT ) , alkaline phosphatase , -glutamyl transpeptidase , total proteins , bilirubin , iron , total iron-binding capacity , serum ferritin , serum protein electrophoresis , creatine kinase , ceruloplasmin , 1-antitrypsin , antibodies to cytomegalovirus and EpsteinBarr virus , and autoantibodies . Participants also underwent ultrasonography of the liver . Anti-HCVNegative First-Time Blood Donors From 1 September 1995 through 26 October 1999 , 9221 blood-donor c and i date s presenting for first-time donation underwent clinical and laboratory examinations as part of procedures for donor selection at Centro Transfusionale e di Immunologia dei Trapianti in Milan , Italy . A blood-bank physician 1 ) administered a psychosocial question naire [ 11 , 12 ] , which was aim ed at identifying and excluding from donation persons at high risk for blood-borne infections ; 2 ) took a medical history ; and 3 ) examined all potential participants and measured body weight and height . Donors c and i date s had blood drawn for laboratory testing .  Clinical data and laboratory-test results were recorded in a relational data base management system , as described previously ( 11 ) . We included in the study donor c and i date s who had no medical or behavioral contraindication to blood donation ( 12 ) and who had negative results on tests for hepatitis B surface antigen ( HBsAg ) , anti-HCV , antiHIV 1 , antiHIV 2 , and hemagglutination ( to assess for presence of syphilis ) . In addition , we used a recently recommended diagnostic algorithm ( 2 ) to conduct a diagnostic work-up in donors who repeatedly had abnormal ALT measurements ( that is , they had increased values , according to current ALT ranges , in three subsequent measurements taken at 1-month intervals in the absence of HBsAg and anti-HCV reactivity ) ( 2 ) . Anti-HCVPositive Blood Donors We also studied 209 blood-donor c and i date s with confirmed anti-HCV reactivity between 1990 and 1999 who presented to our outpatient liver disease clinic for regular follow-up . Of these patients , 78 were HCV RNA negative at initial screening ( 59 patients ) or after antiviral treatment ( 19 patients ) , and 131 were HCV RNA positive .  Serum ALT activity was determined at presentation and in at least two other serial serum sample s collected at 1- to 3-month intervals over at least 6 months . In patients with viremia who underwent treatment , the pattern of serum ALT levels was defined during the period of presumed viremia ( that is , not during or after therapy ) . Liver biopsy was performed in 133 anti-HCVpositive blood donors ( 103 of whom were HCV RNA positive and 30 of whom were HCV RNA negative ) for diagnostic reasons ( 32 patients ) or within clinical trials . These clinical trials were conducted between 1993 and 1998 to define the optimal management of anti-HCVpositive patients with normal or slightly altered ALT levels ( 101 patients ) ( 3 , 4 , 11 , 13 , 14 ) . Laboratory Methods A fasting blood sample was collected in the morning and was centrifuged within 30 minutes of collection . The Laboratory of Biochemistry and the Laboratory of Virology of the Centro Trasfusionale e di Immunologia dei Trapianti at IRCCS Ospedale MaggioreMilan , Italy , performed all analyses by using consistent methods throughout the study period .  Complete blood counts  were performed by using an NE 8000 automatic cell counter ( Sysmex , Kobe , Japan ) . Analyses of serum biochemistry were performed by using an Olympus AU510 analyzer ( EppendorfNetheler , Hamburg , Germany ) . Upper reference limits for serum biochemistry analyses were computed in 1983 on the basis of findings from 5093 women and 9849 men who were apparently healthy donors with negative results on hepatitis B surface antigen and syphilis tests ( 4 , 15 ) . These limits were as follows : for total cholesterol level , 5.70 mmol/L ( 220 mg/dL ) ; for triglyceride level , 2.26 mmol/L ( 200 mg/dL ) ; for blood glucose level , 5.83 mmol/L ( 105 mg/dL ) in men and 5.44 mmol/L ( 98 mg/dL ) in women ; for ALT level , 667 mmol/L ( 40 U/L ) in men and 500 nkat/L ( 30 U/L ) in women . Virologic tests included an hepatitis B surface antigen test ( Wellcozyme HBsAg , Abbott Laboratories , Chicago , Illinois ) , an anti-HIV test ( Ortho HIV1/HIV2 , Ortho Diagnostic Systems , Raritan , New Jersey ) , and an anti-HCV test ( Ortho HCV 3.0 , Ortho Diagnostic Systems ) . Anti-HCV reactivity was confirmed by third-generation recombinant immunoblot assay ( RIBA-3 , Ortho Diagnostic Systems ) . Qualitative analysis of serum HCV RNA was performed by using the Amplicor HCV kit ( Roche Molecular Systems , Basel , Switzerl and ) . Body mass index ( BMI ) was calculated by dividing the weight ( in kg ) by the squared height ( in m ) . On the basis of a recent recommendation ( 16 ) , we considered a BMI of 24.9 kg/m2 the upper limit for healthy weight . The laboratory and the blood donor center were certified according to International Organization for St and ardization 9002 st and ards . The laboratory intra-assay coefficient of variation ( CV ) for ALT was 1.1 % , and the interassay CV over a 2-week period was 2.4 % . Within-individual and between-individual variability were estimated on the basis of 20 donors who were r and omly chosen among those with two measurements taken at 3-month intervals .  Within-individual variability , expressed as CV , was 21.4 % ( CI , 16.4 % to 31.0 % ) ; between-individual variability was 49.8 % ( CI , 37.9%- to 72.8 % ) . Statistical Analysis Statistical analyses were performed by using the SAS package version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . The 5th , 25th , 50th ( median ) , 75th , and 95th percentiles for ALT level were calculated on the basis of the empirical distribution of the data . BACKGROUND AND AIMS Our aim was to identify predictors of clinical decompensation ( defined as the development of ascites , variceal hemorrhage [ VH ] , or hepatic encephalopathy [ HE ] ) in patients with compensated cirrhosis and with portal hypertension as determined by the hepatic venous pressure gradient ( HVPG ) . METHODS We analyzed 213 patients with compensated cirrhosis and portal hypertension but without varices included in a trial evaluating the use of beta-blockers in preventing varices . All had baseline laboratory tests and HVPG . Patients were followed prospect ively every 3 months until development of varices or VH or end of study . To have complete information , until study termination , about clinical decompensation , medical record review was done . Patients who underwent liver transplantation without decompensation were censored at transplantation . Cox regression models were developed to identify predictors of clinical decompensation . Receiver operating characteristic ( ROC ) curves were constructed to evaluate diagnostic capacity of HVPG . RESULTS Median follow-up time of 51.1 months . Sixty-two ( 29 % ) of 213 patients developed decompensation : 46 ( 21.6 % ) ascites , 6 ( 3 % ) VH , 17 ( 8 % ) HE . Ten patients received a transplant and 12 died without clinical decompensation . Median HVPG at baseline was 11 mm Hg ( range , 6 - 25 mm Hg ) . On multivariate analysis , 3 predictors of decompensation were identified : HVPG ( hazard ratio [ HR ] , 1.11 ; 95 % confidence interval [ CI ] , 1.05 - 1.17 ) , model of end-stage liver disease ( MELD ) ( HR , 1.15 ; 95 % CI , 1.03 - 1.29 ) , and albumin ( HR , 0.37 ; 95 % CI , 0.22 - 0.62 ) . Diagnostic capacity of HVPG was greater than for MELD or Child-Pugh score . CONCLUSIONS HVPG , MELD , and albumin independently predict clinical decompensation in patients with compensated cirrhosis . Patients with an HVPG < 10 mm Hg have a 90 % probability of not developing clinical decompensation in a median follow-up of 4 years 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 BACKGROUND & AIMS Severe obesity is implicated in development of nonalcoholic fatty liver disease ( NAFLD ) . Bariatric surgery induces weight loss and increases survival time of obese patients , but little is known about its effects on liver damage . We performed a 5-year prospect i ve study to evaluate fibrosis and nonalcoholic steatosis ( NASH ) in severely obese patients after bariatric surgery .  METHODS  Bariatric surgery was performed on 381 patients . Clinical and biological data , along with liver biopsies , were collected before and at 1 and 5 years after surgery . RESULTS Five years after surgery , levels of fibrosis increased significantly , but 95.7 % of patients maintained a fibrosis score < or= F1 . The percentage of patients with steatosis decreased from 37.4 % before surgery to 16 % , the NAFLD score from 1.97 to 1 , ballooning from 0.2 to 0.1 . Inflammation remained unchanged . The percentage of patients with probable or definite NASH decreased significantly over 5 years , from 27.4 % to 14.2 % . The kinetics of insulin resistance ( IR ) paralleled that of steatosis and ballooning ; the greatest improvements occurred within the first year and were sustained 5 years later . Steatosis and ballooning occurred more frequently in patients with a refractory IR profile . In multivariate analysis , the refractory IR profile independently predicted the persistence of steatosis and ballooning 5 years later . CONCLUSIONS Five years after bariatric surgery for severe obesity , almost all patients had low levels of NAFLD , whereas fibrosis slightly increased . Steatosis and ballooning were closely linked to IR ; long-term effects could be predicted by early improvement in IR BACKGROUND / AIMS Ultrasound is used to screen for hepatic steatosis , the most common liver disease in the United States . However , few studies have prospect ively evaluated the accuracy of ultrasound to diagnose hepatic steatosis . Therefore , a double blinded prospect i ve study was performed in consecutive patients undergoing liver biopsy to evaluate the accuracy of  ultrasound  to diagnose hepatic steatosis .  METHODS Real time ultrasound was performed just prior to the biopsy by a single investigator masked to the clinical diagnosis . The liver biopsy was review ed by a pathologist masked to the clinical indication or sonographic findings . RESULTS Of 73 consecutive patients studied ,  macrovesicular steatosis of any severity on biopsy  was found in 46 ( 63 % ) and  micro vesicular fat  found in 51 ( 69.9 % ) . The overall impression of the sonographer for the presence of macrovesicular hepatic steatosis of any degree had a sensitivity of 60.9 % and a specificity of 100 % . The sensitivity increased to 100 % and the specificity to 90 % when there was > or = 20 % of fat . The zonular distribution of the fat did not alter the diagnostic accuracy of ultrasound . Ultrasound had a poor yield in the diagnosis of microvesicular fat with an overall sensitivity of 43 % and a specificity of 73 % . The combination of increased echogenicity and portal vein blurring on ultrasound had the greatest sensitivity in the diagnosis of hepatic steatosis . CONCLUSION Real time ultrasound using a combination of sonographic findings has a high specificity but underestimates the prevalence of hepatic steatosis when there is<20 % fat 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 Rosiglitazone is an insulin sensitiser used in combination with metformin , a sulfonylurea , or both , for lowering blood glucose in people with type 2 diabetes . We assessed cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5 - 7 years of follow-up . We also assessed comparative safety . METHODS In a multicentre , open-label trial , 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with mean haemoglobin A(1c ) ( HbA(1c ) ) of 7.9 % were r and omly assigned to addition of rosiglitazone ( n=2220 ) or to a combination of metformin and sulfonylurea ( active control group , n=2227 ) . The primary endpoint was cardiovascular hospitalisation or cardiovascular death , with a hazard ratio ( HR ) non-inferiority margin of 1.20 . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00379769 . FINDINGS 321 people in the rosiglitazone group and 323 in the active control group experienced the primary outcome during a mean 5.5-year follow-up , meeting the criterion of non-inferiority ( HR 0.99 , 95 % CI 0.85 - 1.16 ) . HR was 0.84 ( 0.59 - 1.18 ) for cardiovascular death , 1.14 ( 0.80 - 1.63 ) for myocardial infa rct ion , and 0.72 ( 0.49 - 1.06 ) for stroke . Heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group ( HR 2.10 , 1.35 - 3.27 , risk difference per 1000 person-years 2.6 , 1.1 - 4.1 ) . Upper and distal lower limb fracture rates were increased mainly in women r and omly assigned to rosiglitazone . Mean HbA(1c ) was lower in the rosiglitazone group than in the control group at 5 years . INTERPRETATION Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures , mainly in women . Although the data are inconclusive about any possible effect on myocardial infa rct ion , rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with st and ard glucose-lowering drugs . FUNDING GlaxoSmithKline plc , UK The objective of this study was to prospect ively define outcomes of cirrhosis due to nonalcoholic steatohepatitis ( NASH ) and compare them with those associated with hepatitis C virus ( HCV ) infection . We compared 152 patients with cirrhosis due to NASH with 150 matched patients with cirrhosis due to HCV .  Over 10 years , 29/152 patients with cirrhosis due to NASH died compared with 44/150 patients with HCV ( P < .04 ) . This was mainly due to the lower mortality rate in patients with Child class A cirrhosis due to NASH versus HCV ( 3/74 vs. 15/75 ; P < .004 ) . There were no significant across-group differences in mortality in patients with Child class B or C cirrhosis . Sepsis was the most common cause of death in both groups ; patients with NASH had a higher cardiac mortality ( 8/152 vs. 1/150 ; P < .03 ) . Patients with Child class A cirrhosis due to NASH also had a significantly lower risk of decompensation , defined by a 2-point increase in Child-Turcotte-Pugh score ( P < .007 ) . Cirrhosis due to NASH was associated with a lower rate of development of ascites ( 14/101 vs. 40/97 patients at risk ; P < .006 ) . NASH also had a significantly lower risk of development of hepatocellular carcinoma ( 10/149 vs. 25/147 patients at risk ; P < .01 ) . In conclusion , compensated cirrhosis due to NASH is associated with a lower mortality rate compared with that due to HCV . It is also associated with a lower rate of development of ascites , hyperbilirubinemia , and hepatocellular carcinoma . However , cardiovascular mortality is greater in patients with NASH PURPOSE To determine whether gadoxetic acid-enhanced magnetic resonance ( MR ) imaging can be used to distinguish between simple steatosis and nonalcoholic steatohepatitis ( NASH ) in patients with nonalcoholic fatty liver disease ( NAFLD ) , defined according to the steatosis activity and fibrosis ( SAF ) scoring system , which is based on the semiquantitative scoring of steatosis activity and liver fibrosis . MATERIAL S AND METHODS The local institutional review committee approved this study and waived written informed consent . This was a retrospective study of gadoxetic acid-enhanced 3-T MR imaging performed in 81 patients with NAFLD ( 45 men [ 56 % ] ; mean age , 56 years ; range , 25 - 78 years ) . The MR images were analyzed by using the relative enhancement ( the ratio of signal intensities of the liver parenchyma before and 20 minutes after intravenous administration of gadoxetic acid ) . Univariate and multiple regression analyses were applied to identify variables associated with relative enhancement measurements . The ability of relative enhancement to allow differentiation between simple steatosis and NASH was assessed by using area under the receiver operating characteristic ( ROC ) curve analysis . RESULTS Relative enhancement negatively correlated with the degree of lobular inflammation ( r = -0.59 , P < .0001 ) , ballooning ( r = -0.44 , P < .0001 ) , and fibrosis ( r = -0.59 , P ≤ .0001 ) , but not with steatosis ( r = -0.16 , P = .15 ) . Patients with NASH had a significantly lower relative liver enhancement ( 0.82 ± 0.22 ) than those with simple steatosis ( 1.39 ± 0.52 ) ( P < .001 ) . Relative enhancement measurements performed well in the differentiation between simple steatosis and NASH , with an area under the ROC curve of 0.85 ( 95 % confidence interval : 0.75 , 0.91 ) ( cutoff = 1.24 , sensitivity = 97 % , specificity = 63 % ) . CONCLUSION Gadoxetic acid relative enhancement was significantly lower in patients with NASH than in patients with simple steatosis , but further prospect i ve studies are warranted Aims /hypothesisThe evidence on the association between  pioglitazone use and bladder cancer  is contradictory , with many studies subject to allocation bias . The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts . The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach . Methods Prescription , cancer and mortality data from people with type 2 diabetes were obtained from six population s across the world ( British Columbia , Finl and , Manchester , Rotterdam , Scotl and and the UK Clinical Practice Research Data link ) . A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence , with time-dependent adjustment for ever use of pioglitazone . These were then pooled using fixed and r and om effects meta-regression . Results Data were collated on 1.01 million persons over 5.9 million person-years . There were 3,248 cases of incident bladder cancer , with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years . Overall , there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men ( rate ratio [ RR ] per 100 days of cumulative exposure , 1.01 ; 95 % CI 0.97 , 1.06 ) or women ( RR 1.04 ; 95 % CI 0.97 , 1.11 ) after adjustment for age , calendar year , diabetes duration , smoking and any ever use of pioglitazone . No association was observed between rosiglitazone and bladder cancer in men ( RR 1.01 ; 95 % CI 0.98 , 1.03 ) or women ( RR 1.00 ; 95 % CI 0.94 , 1.07 ) . Conclusions /interpretationThe cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large , pooled multi population analysis While the benefits of exercise are clear , many unresolved issues surround the optimal exercise prescription . Many organizations recommend aerobic training ( AT ) and resistance training ( RT ) , yet few studies have compared their effects alone or in combination . The purpose of this study , part of Studies Targeting Risk Reduction Interventions Through Defined Exercise-Aerobic Training and /or Resistance Training ( STRRIDE/AT/RT ) , was to compare the effects of AT , RT , and the full combination ( AT/RT ) on central ectopic fat , liver enzymes , and fasting insulin resistance [ homeostatic model assessment ( HOMA ) ] . In a r and omized trial , 249 subjects [ 18 - 70 yr old , overweight , sedentary , with moderate dyslipidemia ( LDL cholesterol 130 - 190 mg/dl or HDL cholesterol ≤ 40 mg/dl for men or ≤ 45 mg/dl for women ) ] performed an initial 4-mo run-in period . Of these , 196 finished the run-in and were r and omized into one of the following 8-mo exercise-training groups : 1 ) RT , which comprised 3 days/wk , 8 exercises , 3 sets/exercise , 8 - 12 repetitions/set , 2 ) AT , which was equivalent to ∼19.2 km/wk ( 12 miles/wk ) at 75 % peak O(2 ) uptake , and 3 ) full AT + full RT ( AT/RT ) , with 155 subjects completing the intervention . The primary outcome variables were as follows : visceral and liver fat via CT , plasma liver enzymes , and HOMA . AT led to significant reductions in liver fat , visceral fat , alanine aminotransferase , HOMA , and total and subcutaneous abdominal fat ( all P < 0.05 ) . RT result ed in a decrease in subcutaneous abdominal fat ( P < 0.05 ) but did not significantly improve the other variables . AT was more effective than RT at improving visceral fat , liver-to-spleen ratio , and total abdominal fat ( all P < 0.05 ) and trended toward a greater reduction in liver fat score ( P < 0.10 ) . The effects of AT/RT were statistically indistinguishable from the effects of AT . These data show that , for overweight and obese individuals who want to reduce measures of visceral fat and fatty liver infiltration and improve HOMA and alanine aminotransferase , a moderate amount of aerobic exercise is the most time-efficient and effective exercise mode CONTEXT The initial report of the Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer . OBJECTIVE To determine the long-term effect of vitamin E and selenium on risk of prostate cancer  in relatively healthy men . DESIGN , SETTING , AND PARTICIPANTS A total of 35,533 men from 427 study sites in the United States , Canada , and Puerto Rico were r and omized between August 22 , 2001 , and June 24 , 2004 . Eligibility criteria included a prostate-specific antigen ( PSA ) of 4.0 ng/mL or less , a digital rectal examination not suspicious for prostate cancer , and age 50 years or older for black men and 55 years or older for all others . The primary analysis included 34,887 men who were r and omly assigned to 1 of 4 treatment groups : 8752 to receive selenium ; 8737 , vitamin E ; 8702 , both agents , and 8696 , placebo . Analysis reflect the final data collected by the study sites on their participants through July 5 , 2011 . INTERVENTIONS Oral selenium ( 200 μg/d from L-selenomethionine ) with matched vitamin E placebo , vitamin E ( 400 IU/d of all rac-α-tocopheryl acetate ) with matched selenium placebo , both agents , or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years . MAIN OUTCOME MEASURES Prostate cancer incidence . RESULTS This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report . Compared with the placebo ( referent group ) in which 529 men developed prostate cancer , 620 men in the vitamin E group developed prostate cancer ( hazard ratio [ HR ] , 1.17 ; 99 % CI , 1.004 - 1.36 , P = .008 ) ; as did 575 in the selenium group ( HR , 1.09 ; 99 % CI , 0.93 - 1.27 ; P = .18 ) , and 555 in the selenium plus vitamin E group ( HR , 1.05 ; 99 % CI , 0.89 - 1.22 , P = .46 ) . Compared with placebo , the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E , 0.8 for selenium , and 0.4 for the combination . CONCLUSION Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00006392 BACKGROUND & AIMS Non-alcoholic fatty liver disease ( NAFLD ) affects up to 30 % of the population and signifies increased risk of liver fibrosis and cirrhosis , type 2 diabetes , and cardiovascular disease . Therapies are limited . Weight loss is of benefit but is difficult to maintain . We aim ed at examining the effect of the Mediterranean diet ( MD ) , a diet high in monounsaturated fatty acids , on steatosis and insulin sensitivity , using gold st and ard techniques . METHODS Twelve non-diabetic subjects ( 6 Females/6 Males ) with biopsy-proven NAFLD were recruited for a r and omised , cross-over 6-week dietary intervention study . All subjects undertook both the MD and a control diet , a low fat-high carbohydrate diet ( LF/HCD ) , in r and om order with a 6-week wash-out period in- between . Insulin sensitivity was determined with a 3-h hyperinsulinemic-euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance (1)H spectroscopy ( (1)H-MRS ) . RESULTS At baseline , subjects were abdominally obese with elevated fasting concentrations of glucose , insulin , triglycerides , ALT , and GGT . Insulin sensitivity at baseline was low ( M=2.7 ± 1.0 mg/kg/min(-1 ) ) . Mean weight loss was not different between the two diets ( p=0.22 ) . There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/HCD : 39 ± 4 % versus 7 ± 3 % , as measured by (1)H-MRS ( p=0.012 ) . Insulin sensitivity improved with the MD , whereas after the LF/HCD there was no change ( p=0.03 between diets ) . CONCLUSIONS Even without weight loss , MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD , compared to current dietary advice . This diet should be further investigated in subjects with NAFLD BACKGROUND & AIMS Healthy lifestyle is the most important management of non-alcoholic fatty liver disease ( NAFLD ) . This study aim ed at assessing the efficacy of a community-based lifestyle modification programme in the remission of NAFLD . METHODS This was a parallel group , superiority , r and omized controlled trial . 154 adults with NAFLD identified during population screening were r and omized to participate in a dietitian-led lifestyle modification programme at 2 community centres or receive usual care for 12 months . The primary outcome was remission of NAFLD at month 12 as evidence d by intrahepatic triglyceride content ( IHTG ) of less than 5 % by proton-magnetic resonance spectroscopy . RESULTS 74 patients in the intervention group and 71 patients in the control group completed all study assessment s. In an intention-to-treat analysis of all 154 patients , 64 % of the patients in the intervention group and 20 % in the control group achieved remission of NAFLD ( difference between groups 44 % ; 95 % CI 30 - 58 % ; p<0.001 ) . The mean ( SD ) changes in IHTG from baseline to month 12 were -6.7 % ( 6.1 % ) in the intervention group and -2.1 % ( 6.4 % ) in the control group ( p<0.001 ) . Body weight decreased by 5.6 ( 4.4 ) kg and 0.6 ( 2.5 ) kg in the two groups , respectively ( p<0.001 ) . While 97 % of patients with weight loss of more than 10 % had remission of NAFLD , 41 % of those with weight loss of 3.0 - 4.9 % could also achieve the primary outcome . CONCLUSIONS The community-based lifestyle modification programme is effective in reducing and normalizing liver fat in NAFLD patients BACKGROUND & AIMS It is not clear how weight loss affects histologic features of liver in patients with nonalcoholic steatohepatitis ( NASH ) . We examined the association between the magnitude of weight loss through lifestyle modifications and changes in histologic features of NASH . METHODS We conducted a prospect i ve study of 293 patients with histologically proven NASH who were encouraged to adopt recommended lifestyle changes to reduce their weight over 52 weeks , from June 2009 through May 2013 , at a tertiary medical center in Havana , Cuba . Liver biopsies were collected when the study began and at week 52 of the diet and were analyzed histologically . RESULTS Paired liver biopsies were available from 261 patients . Among 293 patients who underwent lifestyle changes  for 52 weeks , 72 ( 25 % ) achieved resolution of steatohepatitis , 138 ( 47 % ) had reductions in nonalcoholic fatty liver disease activity score ( NAS ) , and 56 ( 19 % ) had regression of fibrosis . At week fifty-two , 88 subjects ( 30 % ) had lost ≥5 % of their weight . Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters ( odds ratios = 1.1 - 2.0 ; P < .01 ) . A higher proportion of subjects with ≥5 % weight loss had NASH resolution ( 51 of 88 [ 58 % ] ) and a 2-point reduction in NAS ( 72 of 88 [ 82 % ] ) than subjects who lost < 5 % of their weight ( P < .001 ) . All patients who lost ≥10 % of their weight had reductions NAS , 90 % had resolution of NASH , and 45 % had regression of fibrosis . All patients who lost 7%-10 % of their weight and had few risk factors also had reduced NAS . In patients with baseline characteristics that included female sex , body mass index ≥35 , fasting glucose > 5.5 mmol/L , and many ballooned cells , NAS scores decreased significantly with weight reductions ≥10 % . CONCLUSIONS A greater extent of weight loss , induced by lifestyle changes , is associated with the level of improvement in histologic features of NASH . The highest rates of NAS reduction , NASH resolution , and fibrosis regression occurred in patients with weight losses ≥10 %
IMPORTANCE Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30 % and 5 % , respectively , of the US population .
In patients with nonalcoholic steatohepatitis , half of deaths are due to cardiovascular disease and malignancy , yet awareness of this remains low .
Cirrhosis , the third leading cause of death in patients with nonalcoholic fatty liver disease , is predicted to become the most common indication for liver transplantation .
OBJECTIVES To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis ; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis ; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease .
The incidence of nonalcoholic fatty liver disease-related hepatocellular carcinoma is increasing and up to 50 % of cases may occur in the absence of cirrhosis .
CONCLUSIONS AND RELEVANCE Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver .