Clinical and Radiologic Characteristics of Intra-Abdominal Fistulizing Crohn's Disease.

BACKGROUND: Few studies describe the radiological and laboratory characteristics of patients with Crohn's disease (CD) with intra-abdominal fistulae. OBJECTIVES: We aimed to describe a cohort of CD patients with intra-abdominal fistulae and determine characteristics associated with complex fistulae. METHODS: Data were gathered from medical records and imaging studies of patients. Evaluation included type of fistula, number of fistulae, and radiological characteristics. RESULTS: A total of 205 fistulae in 132 patients were identified with an average patient age of 31 (±12) years. The average time from CD diagnosis to fistula development was 7 years. The most common type of fistula was entero-enteric (53%). Patients with an extra-intestinal fistula presented with an average of 1.96 fistulae, compared with an average of 1.28 fistulae for those with a fistula limited to the bowel (p =0.01). Except for the number of fistula no other significant differences were observed in radiological characteristics of patients who were diagnosed with a fistula at time of CD diagnosis compared to those diagnosed with a fistula later. CONCLUSIONS: The most common CD-associated intra-abdominal fistulae are entero-enteric and entero-colonic fistulae. An extra-intestinal fistula and diagnosis of a fistula subsequent to diagnosis of CD were associated with an increased number of fistulae per patient.

Multi-disciplinary patient-centered model for the expedited provision of costly therapies in community settings: the case of new medication for hepatitis C.

BACKGROUND: In January 2015, the first interferon-free direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection was approved for inclusion in Israel's national basket of health services. During 2015, HCV genotype 1 patients with advanced liver fibrosis (stage F3-F4) were eligible for treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir (OMB/PTV/r + DSV) provided through the four national health plans. As all health plans committed to identifying eligible patients nationwide, risk-sharing agreements created an additional incentive to develop an innovative model for rapid treatment delivery. AIM: This article aims to describe the development and implementation of a multi-disciplinary patient-centered model for the expedited provision of costly therapies in a community setting, based on experience delivering new HCV therapy in 2015. METHODS: We present the case of the Central District in Maccabi Healthcare Services (MHS), one of five districts in a 2-million-member healthcare provider. We describe the dimensions of the model and its implementation, including the composition and responsibilities of the multi-disciplinary team, screening for patient eligibility, provision of care, and barriers and facilitators identified at each stage. RESULTS: The experience of the MHS Central District indicates that good communication between all stakeholders was the key driver of successful implementation of the model. Overall, monthly treatment uptake increased following the intervention and by the end of 2015 a total of 99 patients were treated with OMB/PTV/r + DSV in this district. Early data indicate high effectiveness in this population and evaluation in ongoing. CONCLUSIONS: This multi-disciplinary patient-centered model enabled rapid integration of screening and disease staging to identify and treat eligible HCV patients in the MHS central district. The model forms the basis of the 2017 project to deliver DAAs according to broader health basket criteria and may be adapted for the provision of other innovative health technologies in different healthcare settings.

Factors associated with surgery in patients with intra-abdominal fistulizing Crohn's disease.

AIM: To characterize radiological and clinical factors associated with subsequent surgical intervention in Crohn's disease (CD) patients with intra-abdominal fistulae. METHODS: From a cohort of 1244 CD patients seen over an eight year period (2006 to 2014), 126 patients were identified as having intra-abdominal fistulae, and included in the study. Baseline patient information was collected from the medical records. Imaging studies were assessed for: anatomic type and number of fistulae; diameter of the inflammatory conglomerate; length of diseased bowel; presence of a stricture with pre-stenotic dilatation; presence of an abscess; lymphadenopathy; and the degree of bowel enhancement. Multivariate analysis for the prediction of abdominal surgery was calculated via Generalized Linear Models. RESULTS: In total, there were 193 fistulae in 132 patients, the majority (52%) being entero-enteric. Fifty-nine (47%) patients underwent surgery within one year of the imaging study, of which 36 (29%) underwent surgery within one month. Radiologic features that were associated with subsequent surgery included: multiple fistulae (P = 0.009), presence of stricture (P = 0.02), and an entero-vesical fistula (P = 0.01). Evidence of an abscess, lymphadenopathy, or intense bowel enhancement as well as C-reactive protein levels was not associated with an increased rate of surgery. Patients who were treated after the imaging study with combination immunomodulatory and anti-TNF therapy had significantly lower rates of surgery (P = 0.01). In the multivariate analysis, presence of a stricture [RR 4.5 (1.23-16.3), P = 0.02] was the only factor that increased surgery rate. CONCLUSION: A bowel stricture is the only factor predicting an increased rate of surgery. Radiological parameters may guide in selecting treatment options in patients with fistulizing CD.

Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.

Retrospective studies suggest that coffee consumption may exert beneficial effects in patients with nonalcoholic fatty liver; however, prospective data supporting a protective role on liver steatosis development are lacking. In this study, we aimed to evaluate the association between coffee consumption and fatty liver onset in the general population. The analysis was performed both in a cross-sectional cohort (n = 347) and, prospectively, in a subcohort of patients without fatty liver at baseline and followed-up for 7 years (n = 147). Fatty liver was diagnosed with abdominal ultrasound and liver steatosis was quantified noninvasively by hepatorenal index (HRI) and SteatoTest, whereas FibroTest was used to assess fibrosis degree. A structured questionnaire on coffee consumption was administrated during a face-to-face interview. Neither the incidence nor the prevalence of fatty liver according to ultrasonography, SteatoTest, and the HRI was associated with coffee consumption. In the cross-sectional study, high coffee consumption was associated with a lower proportion of clinically significant fibrosis ≥ F2 (8.8% vs 16.3%; P = 0.038); consistently, in multivariate logistic regression analysis, high coffee consumption was associated with lower odds for significant fibrosis (odds ratio = 0.49, 95% confidence interval, 0.25-0.97; P = 0.041) and was the strongest predictor for significant fibrosis. No association was demonstrated between coffee consumption and the new onset of nonalcoholic fatty liver, but coffee intake may exert beneficial effects on fibrosis progression.

The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: We investigated the effects of the fatty acid-bile acid conjugate 3ß-arachidyl-amido, 7α-12α-dihydroxy, 5ß-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function. RESULTS: No serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose-response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis. CONCLUSIONS: Three months' administration of the fatty acid-bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158.

Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial.

AIM: To evaluate the effect of resistance training (RT) on non alcoholic liver disease (NAFLD) patients. METHODS: A randomized clinical trial enrolling NAFLD patients without secondary liver disease (e.g., without hepatitis B virus, hepatitis C virus or excessive alcohol consumption). Patients were randomly allocated either to RT, three times weekly, for 3 mo or a control arm consisting of home stretching. The RT included leg press, chest press, seated rowing, latissimus pull down etc. with 8-12 repetitions, 3 sets for each exercise, for a total duration of 40 min. Hepatic ultrasound, fasting blood tests, anthropometrics and body composition by dual energy X-ray absorptiometry were assessed. At baseline and follow-up, patients filled out a detailed semi-quantitative food frequency questionnaire reporting their habitual nutritional intake. Steatosis was quantified by the hepatorenal-ultrasound index (HRI) representing the ratio between the brightness level of the liver and the right kidney. The HRI has been previously demonstrated to be highly reproducible and was validated against liver biopsy and proton magnetic resonance spectroscopy. RESULTS: Eighty two patients with primary NAFLD were randomized to receive 3 mo of either RT or stretching. After dropout or exclusion from analysis because of protocol violation (weight change > 3 kg), thirty three patients in the RT arm and 31 in the stretching arm completed the study per protocol. All baseline characteristics were similar for the two treatment groups with respect to demographics, anthropometrics and body composition, blood tests and liver steatosis on imaging. HRI score was reduced significantly in the RT arm as compared to the stretching arm (-0.25 ± 0.37 vs -0.05 ± 0.28, P = 0.017). The RT arm had a significantly higher reduction in total, trunk and android fat with increase in lean body mass. There was no correlation between the reduction in HRI in the RT arm and weight change during the study, but it was positively correlated with the change in trunk fat (r = 0.37, P = 0.048). The RT arm had a significant reduction in serum ferritin and total cholesterol. There was no significant difference between arms in dietary changes and these did not correlate with HRI change. CONCLUSION: Three months RT improves hepatic fat content accompanied by favorable changes in body composition and ferritin. RT may serve as a complement to treatment of NAFLD.

Non-high-density lipoprotein cholesterol independently predicts new onset of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular disease (CVD) risk. Non-high-density lipoprotein cholesterol (non-HDL-C), i.e. total cholesterol minus HDL, is a well-established risk factor for CVD; however, its association with NAFLD development has not been established. Our aim was to test whether non-HDL-C is an independent predictor of new onset of NAFLD. METHODS: A prospective cohort study of 213 subjects from the general population, without liver disease, was studied. Evaluation of medical history, dietary and physical activity habits, fasting blood tests and ultrasonographic evidence of NAFLD was performed at baseline and after a 7-year follow-up by identical protocols. RESULTS: From 147 patients that did not have NAFLD at baseline, 28 (19%) developed NAFLD at the 7-year follow-up. The baseline levels of non-HDL-C were higher among subjects who developed NAFLD (179.5 ± 37.1 vs. 157.3 ± 35.1 mg/dl, P = 0.003). Non-HDL-C independently predicted new onset of NAFLD adjusting for age, gender, BMI or waist circumference, lifestyle and serum insulin (OR = 1.02 for every mg/dl increment, 1.01-1.04 95% CI, P = 0.008). Non-HDL-C was a stronger predictor for NAFLD than total cholesterol, low-density lipoprotein cholesterol, triglycerides and HDL. No patients with non-HDL-C < 130 mg/dl developed NAFLD, whereas 20.8% of those with values between 130 to 160 and 24.6% of those with values >160 mg/dl developed NAFLD (P for trend = 0.015). CONCLUSIONS: Non-HDL-C is an independent predictor for NAFLD and a stronger predictor than other lipoproteins. This association may stem from the combined hepato-toxic effect of non-HDL-C and may explain the association between NAFLD and CVD.

Non-alcoholic fatty liver disease independently predicts prediabetes during a 7-year prospective follow-up.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is suspected to confer an increased risk for developing type 2 diabetes (DM). However, only a few prospective studies evaluated NAFLD as a predictor for DM, most did not adjust for the full range of potential cofounders and none used an objectively quantified degree of steatosis. Our aim was to evaluate the independent role of NAFLD in predicting the development of pre-DM in a 7-year prospective follow-up of healthy volunteers. METHODS: A prospective cohort of a subsample of the Israeli National Health Survey evaluated at baseline and after 7 years by identical protocols. Metabolic parameters and ultrasonographic evidence of NAFLD were evaluated in 213 subjects, without known liver disease or history of alcohol abuse. Exclusion criteria were pre-DM at the baseline survey. Steatosis was quantified by ultrasound with the hepato-renal ultrasound index (HRI). RESULTS: The study included 141 volunteers (mean age 48.78 ± 9.68, 24.82% with NAFLD) without pre-DM/DM at baseline. Both NAFLD on regular US (OR=2.93, 1.02-8.41 95%CI) and HRI (OR=7.87, 1.83-33.82) were independent predictors for the development of pre-DM, adjusting for age, gender, BMI, family history of DM, baseline insulin, adiponectin and glucose. Further adjustment for physical activity and dietary intake did not weaken the association. Furthermore, NAFLD was a stronger predictor for pre-DM than the metabolic syndrome. Subjects with both NAFLD and glucose ≥89 had 93.3% incidence rate of pre-DM. CONCLUSION: Non-alcoholic fatty liver disease is a strong and independent risk factor for pre-DM in the general adult population; thus, NAFLD patients should be classified as a population at risk.

Role of glucose-dependent insulinotropic polypeptide in adipose tissue inflammation of dipeptidylpeptidase 4-deficient rats.

OBJECTIVES: Dipeptidyl peptidase 4 (DPP4) inhibitors, used in obese diabetic patients, reduce inflammation in several models. The role of chronic DPP4-deficiency (DPP4-) in diet-induced obesity with respect to insulin sensitivity and adipose tissue inflammation was investigated. DESIGN AND METHODS: Insulin resistance was induced by 2 months high fat diet (HFD). In vitro effects of glucose-dependent insulinotropic polypeptide (GIP) were assessed in adipose tissue explants and stromal vascular fraction (SVF). RESULTS: HFD-fed DPP4-rats gained significantly more weight and visceral fat mass, yet were more insulin sensitive. Adipose tissue of DPP4- rats demonstrated increased adipocyte maturation and increased expression of enzymes involved in triglyceride uptake and synthesis, yet increased adiponectin mRNA, reduced mRNA of proinflammatory cytokines and reduced vascular adhesion molecules, suggesting reduced inflammation. In vitro and in vivo experiments explored the role of GIP in inducing this phenotype. Indeed, we demonstrated that GIP directly enhanced adiponectin expression in rat and human adipose tissue explants and in SVF. Lastly, GIP administration to normal or HFD-fed rats elevated serum adiponectin and improved their glucose tolerance test. CONCLUSION: In a HFD model, DPP4-rats exhibited reduced adipose tissue inflammation and improved insulin resistance, which may be mediated in part by GIP induction of adiponectin.

Comparison of fatty liver index with noninvasive methods for steatosis detection and quantification.

AIM: To compare noninvasive methods presently used for steatosis detection and quantification in nonalcoholic fatty liver disease (NAFLD). METHODS: Cross-sectional study of subjects from the general population, a subgroup from the First Israeli National Health Survey, without excessive alcohol consumption or viral hepatitis. All subjects underwent anthropometric measurements and fasting blood tests. Evaluation of liver fat was performed using four noninvasive methods: the SteatoTest; the fatty liver index (FLI); regular abdominal ultrasound (AUS); and the hepatorenal ultrasound index (HRI). Two of the noninvasive methods have been validated vs liver biopsy and were considered as the reference methods: the HRI, the ratio between the median brightness level of the liver and right kidney cortex; and the SteatoTest, a biochemical surrogate marker of liver steatosis. The FLI is calculated by an algorithm based on triglycerides, body mass index, γ-glutamyl-transpeptidase and waist circumference, that has been validated only vs AUS. FLI < 30 rules out and FLI ≥ 60 rules in fatty liver. RESULTS: Three hundred and thirty-eight volunteers met the inclusion and exclusion criteria and had valid tests. The prevalence rate of NAFLD was 31.1% according to AUS. The FLI was very strongly correlated with SteatoTest (r = 0.91, P < 0.001) and to a lesser but significant degree with HRI (r = 0.55, P < 0.001). HRI and SteatoTest were significantly correlated (r = 0.52, P < 0.001). The κ between diagnosis of fatty liver by SteatoTest (≥ S2) and by FLI (≥ 60) was 0.74, which represented good agreement. The sensitivity of FLI vs SteatoTest was 85.5%, specificity 92.6%, positive predictive value (PPV) 74.7%, and negative predictive value (NPV) 96.1%. Most subjects (84.2%) with FLI < 60 had S0 and none had S3-S4. The κ between diagnosis of fatty liver by HRI (≥ 1.5) and by FLI (≥ 60) was 0.43, which represented only moderate agreement. The sensitivity of FLI vs HRI was 56.3%, specificity 86.5%, PPV 57.0%, and NPV 86.1%. The diagnostic accuracy of FLI for steatosis > 5%, as predicted by SteatoTest, yielded an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI: 0.95-0.98). The diagnostic accuracy of FLI for steatosis > 5%, as predicted by HRI, yielded an AUROC of 0.82 (95% CI: 0.77-0.87). The κ between diagnosis of fatty liver by AUS and by FLI (≥ 60) was 0.48 for the entire sample. However, after exclusion of all subjects with an intermediate FLI score of 30-60, the κ between diagnosis of fatty liver by AUS and by FLI either ≥ 60 or < 30 was 0.65, representing good agreement. Excluding all the subjects with an intermediate FLI score, the sensitivity of FLI was 80.3% and the specificity 87.3%. Only 8.5% of those with FLI < 30 had fatty liver on AUS, but 27.8% of those with FLI ≥ 60 had normal liver on AUS. CONCLUSION: FLI has striking agreement with SteatoTest and moderate agreements with AUS or HRI. However, if intermediate values are excluded FLI has high diagnostic value vs AUS.

Dipeptidyl peptidase 4-deficient rats have improved bile secretory function in high fat diet-induced steatosis.

BACKGROUND/AIMS: Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury. METHODS: Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2 months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters. RESULTS: DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2 months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures. CONCLUSIONS: Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.

Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up.

BACKGROUND & AIMS: Data on the incidence and remission rates of non-alcoholic fatty liver disease (NAFLD) as well as predictive factors are scant. This study aims at evaluating NAFLD's epidemiology in prospective follow-up of individuals sampled from the general population. METHODS: Evaluation of metabolic parameters and ultrasonographic evidence of NAFLD was performed in 213 subjects, with no known liver disease or history of alcohol abuse. The evaluation was performed at baseline and after a 7-year period by identical protocols. RESULTS: Of the 147 patients who did not have NAFLD at baseline, 28 (19%) were found to have NAFLD at a 7-year follow-up. Baseline BMI, HOMA score, blood cholesterol, triglycerides, leptin levels, and weight gain (5.8±6.1 vs. 1.4±5.5kg, p<0.001) were significantly higher and adiponectin was lower among those who developed NAFLD at 7-year follow-up, compared with those who remained NAFLD-free. However, only weight gain and baseline HOMA were independent predictors for the development of NAFLD. Of the 66 patients who were found to have NAFLD at baseline, as many as 24 patients (36.4%) had no evidence of NAFLD at 7years. Weight loss of 2.7±5.0kg was significantly associated with NAFLD remission. Moreover, there was a 75% remission rate among NAFLD patients who lost 5% or more from their baseline weight. CONCLUSIONS: Among the general population, weight gain, and baseline insulin resistance are predictors for NAFLD incidence. One third of NAFLD patients may have remission of disease within a 7-year follow-up, mostly depending on modest weight reduction.

The association between adipocytokines and biomarkers for nonalcoholic fatty liver disease-induced liver injury: a study in the general population.

BACKGROUND AND AIM: Leptin and adiponectin have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). However, the usefulness of adipocytokines as a screening tool for nonalcoholic steatohepatitis (NASH) and fibrosis could not be evaluated in the general population due to the invasive nature of liver biopsy. The aim was to evaluate the association between adipocytokines and presumed liver injury in the general population using noninvasive biomarkers. METHODS: A cross-sectional study of 375 individuals, sampled from the National Health Survey was conducted. The exclusion criterion was any known secondary etiology for liver disease. Anthropometrics, serum leptin, adiponectin, insulin, lipids, and FibroMax were measured. RESULTS: Three hundred and thirty-eight individuals met the inclusion criteria and had valid FibroMax. Fibrosis diagnosed by the FibroTest was found in 25.7% of the patients, of whom 12.8% had significant fibrosis. Steatohepatitis was diagnosed by the NASH test in 0.9% and borderline NASH in 31.4% of the patients. Adiponectin was an independent negative correlate of borderline NASH [odds ratio (OR): 0.92; 95% confidence interval (CI): 0.86-0.98/1 µg/ml] together with high-density lipoprotein, and leptin was a positive correlate (OR: 1.03; CI: 1.01-1.06/1 ng/ml), together with abdominal obesity, serum triglycerides, and HbA1C. The OR for borderline NASH was 20.7 (CI: 7.5-57.5) when both high leptin (upper quartile) and suboptimal adiponectin were present, adjusting for age and sex. The FibroTest was not associated with leptin and adiponectin. The strongest predictors for fibrosis were age, sex, abdominal obesity, and insulin. CONCLUSION: Low adiponectin and high leptin and the combination of both have a strong independent association with presumed early-stage NASH. However, early-stage fibrosis cannot be predicted by these adipocytokines.

[Israeli guidelines for the treatment of chronic hepatitis C infection--2012 Israeli Association for the Study of the Liver].

The current standard of care for the treatment of hepatitis C virus (HCV) is a combination of pegylated interferon alpha (PeglFN] -2a/2b and ribavirin for 24-48 weeks, according to the viral genotype. This treatment is associated with significant side effects and achieves sustained virologic response (SVR) in only 40%-50% of genotype 1 HCV-infected patients. The recent development of direct-acting antiviral agents (DAAs] targeting critical steps of the virus life-cycle led to a major breakthrough in the management of HCV infection. The DAAs include protease inhibitors and polymerase inhibitors. The recently approved protease inhibitors boceprevir and telaprevir, when given with PeglFN and ribavirin in HCV genotype 1 patients, result in a much higher SVR rate [70%] among treatment-naïve and treatment-experienced patients, compared with Peg-IFN and ribavirin. In specific groups of patients this enables a shorter duration of treatment. The DAA-containing regimens are approved for HCV genotype 1 infection in HCV treatment-naïve and HCV treatment-experienced including cirrhotic patients. The Israeli Ministry of Health has recently approved the use of boceprevir (Victretis) and telaprevir (Incivo) in combination with PeglFN and ribavirin for the current standard of care treatment of HCV genotype 1 patients. The consensus opinion of a panel of national HCV-experts appointed by the Israeli Association for the Study of the Liver is presented in this report. These Israeli consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

Increased fibrosis progression rates in hepatitis C patients carrying the prothrombin G20210A mutation.

AIM: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutations suffer from increased rates of liver fibrosis. METHODS: We analyzed DNA samples of 168 HCV patients for three common hypercoagulable gene mutations: prothrombin 20210 (PT20210), factor V Leiden (FV Leiden) and methylene tetrahydrofolate reductase (MTHFR). The patients were consecutively recruited as part of the prospective "Fibroscore Study" in France. The effect of the various mutations on the rate of fibrosis was analyzed statistically and was correlated with epidemiological, clinical and biochemical data such as grade and stage of liver biopsies, patients' risk factors for liver cirrhosis, and timing of infection. RESULTS: Fifty two of the patients were categorized as "fast fibrosers" and 116 as "slow fibrosers"; 13% of the "fast fibrosers" carried the PT20210 mutation as compared with 5.5% of the "slow fibrosers", with an odds ratio of 4.76 (P = 0.033; 95% CI: 1.13-19.99) for "fast" liver fibrosis. Carriage of MTHFR or FV Leiden mutations was not associated with enhanced liver fibrosis. CONCLUSION: Carriage of the PT20210 mutation is related to an increased rate of liver fibrosis in HCV patients.

Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence.

Nonalcoholic fatty liver disease (NAFLD) has been recognized as a major health burden. The high prevalence of NAFLD is probably due to the contemporary epidemics of obesity, unhealthy dietary pattern, and sedentary lifestyle. The efficacy and safety profile of pharmacotherapy in the treatment of NAFLD remains uncertain and obesity is strongly associated with hepatic steatosis; therefore, the first line of treatment is lifestyle modification. The usual management of NAFLD includes gradual weight reduction and increased physical activity (PA) leading to an improvement in serum liver enzymes, reduced hepatic fatty infiltration, and, in some cases, a reduced degree of hepatic inflammation and fibrosis. Nutrition has been demonstrated to be associated with NAFLD and Non-alcoholic steatohepatitis (NASH) in both animals and humans, and thus serves as a major route of prevention and treatment. However, most human studies are observational and retrospective, allowing limited inference about causal associations. Large prospective studies and clinical trials are now needed to establish a causal relationship. Based on available data, patients should optimally achieve a 5%-10% weight reduction. Setting realistic goals is essential for long-term successful lifestyle modification and more effort must be devoted to informing NAFLD patients of the health benefits of even a modest weight reduction. Furthermore, all NAFLD patients, whether obese or of normal weight, should be informed that a healthy diet has benefits beyond weight reduction. They should be advised to reduce saturated/trans fat and increase polyunsaturated fat, with special emphasize on omega-3 fatty acids. They should reduce added sugar to its minimum, try to avoid soft drinks containing sugar, including fruit juices that contain a lot of fructose, and increase their fiber intake. For the heavy meat eaters, especially those of red and processed meats, less meat and increased fish intake should be recommended. Minimizing fast food intake will also help maintain a healthy diet. PA should be integrated into behavioral therapy in NAFLD, as even small gains in PA and fitness may have significant health benefits. Potentially therapeutic dietary supplements are vitamin E and vitamin D, but both warrant further research. Unbalanced nutrition is not only strongly associated with NAFLD, but is also a risk factor that a large portion of the population is exposed to. Therefore, it is important to identify dietary patterns that will serve as modifiable risk factors for the prevention of NAFLD and its complications.

Sampling variability of transient elastography according to probe location.

BACKGROUND AND AIMS: Heterogeneity of fibrosis throughout the liver has been reported. However, the need for several measurements when using transient elastography was not thoroughly investigated. The aim was to find out whether measurement of liver stiffness varies according to the probe location. METHODS: Six hundred and twenty-five consecutive patients with chronic liver diseases referred for transient elastography were enrolled. All patients underwent successive liver stiffness measurements at three different sites. Representative measurements were acquisitions with a success rate greater than 60% and an interquartile range lower than 30% of the median. RESULTS: The sample included 371 eligible patients with three representative measurements. Comparing the three successive measurements categorized to fibrosis stages F0-F4, 68.2% of patients had agreement between all three sites. Discordance of one stage was noted in 28.3% of the patients, in 7% for two stages, and in 1.4% for three stages.The κ for comparing the maximal versus the minimal results was 0.43. There was no significant difference in the characteristics of patients with discordance and patients without discordance including age, sex, waist circumference, BMI, and etiology of liver disease. The stage of fibrosis was associated with discordance between measurements (P<0.001), demonstrating low discordance rate in patients with stages F0-F1 or F4 and high discordance rate in patients with stages F2 and F3. CONCLUSION: Sampling variability according to probe location is seen in transient elastography in approximately 30% of patients. Therefore, it may be suggested to perform transient elastography from various sites to minimize the sample error.

Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase.

BACKGROUND & AIMS: Glucagon-like peptide-1 (GLP-1), a gut-derived peptide degraded by dipeptidyl peptidase-4 (DPP4), stimulates insulin secretion in response to nutrients, yet its direct effect on the liver is controversial. We investigated the effects of GLP-1 on hepatic fat and glucose metabolism and elucidated its mechanism of action. METHODS: Hepatic fat metabolism, including lipogenic enzymes and signal transduction regulators, was assessed in livers of DPP4-deficient rats (DPP4-) with chronically elevated GLP-1 and in GLP-1-treated primary hepatocytes. The effect of chronic elevated GLP-1 on insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp. RESULTS: Normal and high fat diet fed DPP4-rats displayed reduced hepatic triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid ß-oxidation. In vitro studies demonstrated that these effects were directly induced by GLP-1. Mechanistically, GLP-1 increased cAMP in hepatocytes, resulting in the phosphorylation of cAMP-activated protein kinase (AMPK), a suppressor of lipogenesis. Indeed, hepatocytes expressing a dominant negative Ad-DN-AMPK displayed attenuated GLP-1 effects on AMPK phosphorylation and its downstream lipogenic targets. Importantly, normoglycemic DPP4-rats did not display improved hepatic insulin sensitivity in vivo, suggesting a direct effect of GLP-1 on fat metabolism. Finally, DPP4-rats expressed lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient stimuli. CONCLUSIONS: GLP-1 suppresses hepatic lipogenesis via activation of the AMPK pathway. GLP-1 inhibitory effects on hepatic fat accumulation and nutrient-induced hepatic proinflammatory response suggest GLP-1 analogs as novel therapies for non-alcoholic fatty liver diseases.

Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho.

We have previously shown that hyperthyroidism is detrimental for liver fibrosis and in this study we have investigated the mechanisms regulating triiodothyronine (T3) and L-thyroxine (T4) activation of hepatic stellate cells (HSC). Expression of alpha-smooth muscle actin (alphaSMA) and p75 neurotrophin receptor (p75NTR) was determined by western blot analyses and transient transfection of the promoters. Rho activation was assayed using a pull-down assay and by ELISA. Expression of thyroid hormone receptor alpha1 decreases, whereas T4 receptor integrin alphaVbeta3 increases, with transdifferentiation of HSC to myofibroblasts. T3 and T4 enhance HSC activation, without affecting proliferation or phosphorylation of mitogen-activated protein kinase, signal transducer and activator of transcription 3 or Akt. Addition of 10(-7) M T3 or T4 to thyroid hormone-depleted serum induces a twofold increase in activation marker alphaSMA, as well as upregulation of p75NTR protein levels. Both hormones enhance transcription of alphaSMA and p75NTR. We report a novel signaling pathway for thyroid hormones, activation of Rho. T4 induces activation of Rho acting through alphavbeta3 integrin, and the activation is abolished by the T4 antagonist, tetraiodothyroacetic acid, by peptide RGD and by a function-blocking antibody to integrin beta3. T3 and T4 increase phosphorylation of non-muscle myosin light chain II, a downstream signal to Rho/Rho-kinase activation. T3 also induces expression of tumor necrosis factor-alpha. In vivo, administration of T3 or T4 together with thioacetamide (TAA) enhances fibrosis after 3 weeks, compared with the TAA-treated group, accompanied by increased alphaSMA in T3- and T4-treated groups, and of p75NTR in T4-treated rats. Thyroid hormones enhance activation of HSC through increased p75NTR and alphaSMA expression and activation of Rho, therefore accelerating development of liver fibrosis.