Nonalcoholic steatohepatitis (NASH) is a well-recognized cause of cirrhosis and has been increasingly associated with the development of hepatocellular carcinoma (HCC). The aims of this study were to (1) estimate the incidence of HCC in patients with NASHrelated cirrhosis, (2) compare incidence in NASH-related cirrhosis with hepatitis C virus (HCV)-related cirrhosis, and (3) identify risk factors of HCC in patients with NASHrelated cirrhosis compared with HCV-related cirrhosis. Adult patients with cirrhosis secondary to chronic HCV (n 5 315) or NASH (n 5 195) were evaluated at our hepatobiliary clinic between 2003 and 2007. To assess for HCC development, all patients were monitored using serial abdominal computed tomography and serum alpha-fetoprotein every 6 months. Kaplan-Meier analysis was performed to estimate the cumulative incidence of HCC. Descriptive statistics were computed for all factors. Univariate and multivariate Cox regression analysis were used to assess associations between HCC and factors of interest. The median follow-up was 3.2 years (25th percentile [P25], 75th percentile [P75]: 1.7, 5.7) during which 25/195 (12.8%) of NASH-cirrhotic and 64/315 (20.3 %) of HCV-cirrhotic patients developed HCC (P 5 0.03). Yearly cumulative incidence of HCC was found to be 2.6% in patients with NASH-cirrhosis, compared with 4.0% in patients with HCV cirrhosis (P 5 0.09). Multivariate regression analysis revealed that older age (P 5 0.006) and alcohol consumption (P 5 0.002) were independent variables associated with development of HCC in patients with NASH-cirrhosis. Compared with nondrinkers, patients who reported any regular alcohol consumption were at greater risk for HCC development (hazard ratio: 3.6; P25, P75: 1.5, 8.3). Conclusion: Patients with NASH cirrhosis have a greatly increased risk of liver cancer. Alcohol consumption, a modifiable risk factor, appears to be the most significant factor associated with risk of HCC development in our study population. (HEPATOLOGY 2010;51:1972-1978

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In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3-generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly in-

Background/Aims: Ultrasound is used to screen for hepatic steatosis, the most common liver disease in the United States. However, few studies have prospectively evaluated the accuracy of ultrasound to diagnose hepatic steatosis. Therefore, a double blinded prospective 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 reviewed 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 ≥ 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 less than ≥ 20% fat.

Background Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist), in patients with IBS with diarrhea. Methods We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26. Results For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P=0.01 and P=0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P=0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P=0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%). Conclusions Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747 , respectively.).

Collectively, these data suggest that increased hepatic IL-6 production may play an important role in NASH development, as well as in systemic insulin resistance and diabetes.

Background The primary aim of this study was to compare the effects of pentoxifylline (PTX) versus placebo on the histological features of NASH. Methods 55 adults with biopsy-confirmed NASH were randomized to receive PTX at a dose of 400mg three times a day (n=26) or placebo (n=29) over 1 year. The primary efficacy endpoint was defined as improvement on histological features of NASH through reduction in steatosis, lobular inflammation, and/or hepatocellular ballooning as reflected by a decrease of ≥ 2 points in the NAFLD activity score (NAS). Results After 1 year, intention-to-treat analysis showed a decrease of >=2 points in the NAS in 38.5% of patients on PTX vs 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, vs −0.1 in the placebo group (p<0.001). PTX significantly improved steatosis (mean change in score −0.9 vs −0.04 with placebo, p<0.001) and lobular inflammation (median change −1 vs 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 (ClinicalTrials.gov number NCT00590161).

This article is available online at http://www.jlr.org S. L. Hazen. Mass spectrometric profi ling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J. Lipid Res. 2010. 51: 3046-3054.Supplementary key words oxidized fatty acids • mass spectrometry • chiral mass spectrometry Nonalcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease affecting both adults and children, and it is strongly associated with obesity and insulin resistance ( 1, 2 ). One in three adults and one in ten children or adolescents in the United States have hepatic steatosis, a stage within the spectrum of NAFLD that is characterized by triglyceride accumulation in liver cells and follows a benign, nonprogressive clinical course ( 3, 4 ). Nonalcoholic steatohepatitis (NASH) is defi ned as lipid accumulation with evidence of cellular damage, infl ammation, and different degrees of scarring or fi brosis ( 5 ). NASH is a serious condition as approximately 25% of these patients progress to cirrhosis and its feared complications of portal hypertension, liver failure, and hepatocellular carcinoma ( 6-8 ).At present, the available noninvasive markers for NAFLD include a set of clinical signs and symptoms, nonspecifi c laboratory and radiological imaging tests, and combinations of clinical and blood test results ( 9 ). Although several of these markers are generally useful for the diagnostic evaluation of a patient with suspected Abstract Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to defi ne the circulating profi le of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels refl ect histological changes in the liver. The levels of multiple structurally specifi c oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9-and 13-HODEs and 9-and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were signifi cantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (infl ammation, fi brosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold ( P < 0.0001) more likely to have NASH than those with low levels (b...