Bile acid receptors and nonalcoholic fatty liver disease

With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.

Enteric bacterial proteases in inflammatory bowel diseasepathophysiology and clinical implications

Numerous reports have identified a dysbiosis in the intestinal microbiota in patients suffering from inflammatory bowel diseases(IBD),yet the mechanism(s)in which this complex microbial community initiates or perpetuates inflammation remains unclear.The purpose of this review is to present evidence for one such mechanism that implicates enteric microbial derived proteases in the pathogenesis of IBD.We highlight and discuss studies demonstrating that proteases and protease receptors are abundant in the digestive system.Additionally,we investigate studies demonstrating an association between increased luminal protease activity and activation of protease receptors,ultimately resulting in increased intestinal permeability and exacerbation of colitis in animal models as well as in human IBD.Proteases are essential for the normal functioning of bacteria and in some cases can serve as virulence factors for pathogenic bacteria.Although not classified as traditional virulence factors,proteases originating from commensal enteric bacteria also have a potential association with intestinal inflammation via increased enteric permeability.Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD.A better understanding of these pathways and characterization of the enteric bacteria involved,their proteases,and protease receptors may pave the way for new therapeutic approaches for these diseases.

Fecal Microbiota Transplantation for Fibromyalgia: A Case Report and Review of the Literature

A 58-year-old patient diagnosed with fibromyalgia, irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS), non-responsive to variety of treatments over the years, suffered from significant social and occupational disabilities. The patient was interested in fecal microbiota transplantation (FMT), but given that FMT is not approved for these indications, he used an online protocol for FMT screening and preparation and self-instilled the filtrate using an enema 6 times. FMT resulted in a gradual improvement of symptoms and 9 months after the last treatment, the patient reported full recovery of symptoms, going back to work at full time employment. Improvement of symptoms was associated with major alterations of the enteric microbiota, according to next generation sequencing analysis performed before the first FMT and after the last FMT. Most prominent alterations at the genus level included a decrease in fecal Streptococcus proportion from 26.39% to 0.15% and an increase in Bifidobacterium from 0% to 5.23%. This case is added to several additional case reports that demonstrated the effectivity of FMT in these functional disorders that are lacking an otherwise good medical therapeutic intervention. We conclude that randomized controlled trials are required to ground FMT as a possible therapy for these difficult-to-treat conditions.

Impact of Proteinuria on Liver Enzyme Levels

Dear Editors,We read with great interest the recently published article“Subnormal Serum Liver Enzyme Levels:A Review of Pathophysiology and Clinical Significance”by Youssef and colleagues.1 While much attention is given to elevations of liver enzymes,the authors highlight clinically important,often unrecognized reasons leading to low liver enzyme levels.For example,chronic kidney disease was cited as a cause of low serum aspartate aminotransferase(AST)proportional to the progression of the disease,but the cause(s)are not well defined.Little is known about the possible influence of nephrotic syndrome(NS)on liver enzymes.

Nutritional issues in patients with obesity and cirrhosis

Obesity and metabolic syndrome are considered as responsible for a condition known as the non-alcoholic fatty liver disease that goes from simple accumulation of triglycerides to hepatic inflammation and may progress to cirrhosis.Patients with obesity also have an increased risk of primary liver malignancies and increased body mass index is a predictor of decompensation of liver cirrhosis.Sarcopenic obesity confers a risk of physical impairment and disability that is significantly higher than the risk induced by each of the two conditions alone as it has been shown to be an independent risk factor for chronicliver disease in patients with obesity and a prognostic negative marker for the evolution of liver cirrhosis and the results of liver transplantation.Cirrhotic patients with obesity are at high risk for depletion of various fat-soluble,water-soluble vitamins and trace elements and should be supplemented appropriately.Diet,physical activity and protein intake should be carefully monitored in these fragile patients according to recent recommendations.Bariatric surgery is sporadically used in patients with morbid obesity and cirrhosis also in the setting of liver transplantation.The risk of sarcopenia,micronutrient status,and the recommended supplementation in patients with obesity and cirrhosis are discussed in this review.Furthermore,the indications and contraindications of bariatric surgery-induced weight loss in the cirrhotic patient with obesity are discussed.

HCV infection, B-cell non-Hodgkin's lymphoma and immunochemotherapy: Evidence and open questions

There is plenty of data confirming that hepatitis C virus (HCV) infection is a predisposing factor for a B-cell non-Hodgkin's lymphoma (B-NHL) outbreak, while relatively few reports have addressed the role of HCV in affecting B-NHL patients' outcome. HCV infection may influence the short-term outcome of B-NHL because of the emergence of severe hepatic toxicity (HT) during immunochemotherapy. Furthermore, the long term outcome of HCV-related liver disease and patients' quality of life will possibly be affected by Rituximab maintenance, multiple-lines of toxicity during chemotherapy and hematopoietic stem cell transplantation. In this review, data dealing with aggressive and low-grade B-NHL were separately analyzed. The few retrospective papers reporting on aggressive B-NHL patients showed that HCV infection is a risk factor for the outbreak of severe HT during treatment. This adverse event not infrequently leads to the reduction of treatment density and intensity. Existing papers report that low-grade B-NHL patients with HCV infection may have a more widespread disease, more frequent relapses or a lower ORR compared to HCV-negative patients. Notwithstanding, there is no statistical evidence that the prognosis of HCV-positive patients is inferior to that of HCV-negative subjects. HCV-positive prospective studies and longer follow-up are necessary to ascertain if HCV-positive B-NHL patients have inferior outcomes and if there are long term sequels of immunochemotherapies on the progression of liver disease.

SpyGlass cholangioscopy for management of choledocholithiasis during pregnancy

To the Editor: We read with great interest the article by Chong and Jalihal [1] regarding endoscopic management of biliary disorders during pregnancy which reaffirms that endoscopic retrograde cholangiopancreatography(ERCP)is safe and effective in managing choledocholithiasis during pregnancy. The authors use ERCP under fluoroscopic guidance with lead apron shielding as well as non-fluoroscopic cannulation using bile flow and bile aspiration as indicators of successful

Diet of patients after pouch surgery may affect pouch inflammation

AIM:To investigate the diet of pouch patients compared to healthy controls,and to correlate pouch patients’diet with disease behavior.METHODS:Pouch patients were recruited and prospectively followed-up at the Comprehensive Pouch Clinic at the Tel Aviv Sourasky Medical Center.Pouch behavior was determined based on clinical,endoscopic and histological criteria.Healthy age-and sex-matched volunteers were selected from the"MABAT"Israeli Nutrition and Public Health Governmental Study and served as the control group.All the participants completed a 106-item food frequency questionnaire categorized into food groups and nutritional values based on those used in the United States Department of Agriculture food pyramid and the Israeli food pyramid.Data on Dietary behavior,food avoidance,the use of nutritional supplements,physical activity,smoking habits,and body-mass index(BMI)were also obtained.Pouch patients who had familial adenomatous polyposis(n=3),irritable pouch syndrome(n=4),or patients whose pouch surgery took place less than one year previously(n=5)were excluded from analysis.RESULTS:The pouch patients(n=80)consumed significantly more from the bakery products food group(1.2±1.4 servings/d vs 0.6±1.1 servings/d,P<0.05)and as twice as many servings from the oils and fats(4.8±3.4 servings/d vs 2.4±2 servings/d,P<0.05),and the nuts and seeds food group(0.3±0.6 servings/d vs 0.1±0.4 servings/d,P<0.05)compared to the controls(n=80).The pouch patients consumed significantly more total fat(97.6±40.5 g/d vs 84.4±39 g/d,P<0.05)and fat components[monounsaturated fatty acids(38.4±16.4 g/d vs 30±14 g/d,P<0.001),and saturated fatty acids(30±15.5 g/d vs 28±14.1 g/d,P<0.00)]than the controls.In contrast,the pouch patients consumed significantly fewer carbohydrates(305.5±141.4 g/d vs 369±215.2 g/d,P=0.03),sugars(124±76.2 g/d vs 157.5±90.4 g/d,P=0.01),theobromine(77.8±100 mg/d vs 236.6±244.5 mg/d,P<0.00),retinol(474.4±337.1μg/d vs 832.4±609.6μg/d,P<0.001)and dietary fibers(26.2±15.4 g/d vs 30.7±14 g/d,P=0.05)than the controls.Comparisons of the food consumption of the patients without(n=23)and with pouchitis(n=45)showed that the former consumed twice as many fruit servings as the latter(3.6±4.1 servings/d vs 1.8±1.7 servings/d,respectively,P<0.05).In addition,the pouchitis patients consumed significantly fewer liposoluble antioxidants,such as cryptoxanthin(399±485μg/d vs 890.1±1296.8μg/d,P<0.05)and lycopene(6533.1±6065.7μg/d vs 10725.7±10065.9μg/d,P<0.05),and less vitamin A(893.3±516μg/d vs1237.5±728μg/d,P<0.05)and vitamin C(153.3±130 mg/d vs 285.3±326.3 mg/d,P<0.05)than the patients without pouchitis.The mean BMI of the pouchitis patients was significantly lower than the BMI of the patients with a normal pouch:22.6±3.2 vs 27±4.9(P<0.001).CONCLUSION:Decreased consumption of antioxidants by patients with pouchitis may expose them to the effects of inflammatory and oxidative stress and contribute to the development of pouchitis.

Five years of fecal microbiota transplantation-an update of the Israeli experience

AIM To evaluate and describe the efficacy of fecal microbiota transplantation(FMT) for Clostridium difficile infection(CDI) in a national Israeli cohort.METHODS All patients who received FMT for recurrent(recurrence within 8 wk of the previous treatment) or refractory CDI from 2013 through 2017 in all the five medical centers in Israel currently performing FMT were included. Stool donors were screened according to the Israeli Ministry of Health guidelines. Clinical and laboratory data of patients were collected from patients' medical files, and they included indications for FMT, risk factors for CDI and disease severity. Primary outcome was FMT success(at least 2 mo free of CDI-related diarrhea post-FMT). Secondary outcomes included initial response to FMT(cessation of diarrhea within 7 d) and recurrence at 6 mo.RESULTS There were 111 FMTs for CDI, with a median age of 70 years [interquartile range(IQR): 53-82], and 42%(47) males. Fifty patients(45%) were treated via the lower gastrointestinal(LGI, represented only by colonoscopy) route, 37(33%) via capsules, and 24(22%) via the upper gastrointestinal(UGI) route. The overall success rate was 87.4%(97 patients), with no significant difference between routes of administration(P = 0.338). In the univariant analysis, FMT success correlated with milder disease(P = 0.01), ambulatory setting(P < 0.05) and lower Charlson comorbidity score(P < 0.05). In the multivariant analysis, only severe CDI [odd ratio(OR) = 0.14, P < 0.05] and inpatient FMT(OR = 0.19, P < 0.05) were each independently inversely related to FMT success. There were 35(32%) patients younger than 60 years of age, and 14(40%) of them had a background of inflammatory bowel disease.CONCLUSION FMT is a safe and effective treatment for CDI, with capsules emerging as a successful and well-tolerated route. Severe CDI is less likely to respond to FMT.

Acute hepatitis C:Prospects and challenges

More than 170 million people worldwide have chronic hepatitis C. Acute hepatitis C is rarely diagnosed because it is commonly asymptomatic. Most infected patients are unaware of their condition until the symptoms of chronic infection manifest. Treatment of acute hepatitis C is something of a paradox because spontaneous resolution is possible and many patients do not have symptoms. However, several factors provide a rationale for treating patients who have acute hepatitis C. Compared with acute hepatitis C, chronic hepatitis C is associated with a worse prognosis, the need for more intensive treatment, longer treatment duration, and a decrease in successful treatment outcomes. Conversely, early intervention is associated with improved viral eradication, using a regimen that is better tolerated, less expensive, more convenient, and of shorter duration than the currently approved combination therapies for chronic hepatitis C.

CD74 is a survival receptor on colon epithelial cells

AIM: To investigate the expression and function of CD74 in normal murine colon epithelial cells (CEC) and colon carcinoma cells. METHODS: Expression of CD74 mRNA and protein were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting and fluorescence-activated cell sorter (FACS). The effect of migration inhibitory factor (MIF) on the survival of normal CEC from C57BL/6, NOD/SCID, and CD74 def icient mice both in vitro and in vivo, and on the CT26 carcinoma cell line was analyzed by (quantitative) qRT-PCR, RTPCR, Western blotting and FACS. RESULTS: CD74 was found to be expressed on normalCEC. Stimulation of CD74 by MIF induced a signaling cascade leading to up-regulation of Bcl-2 expression, resulting in a signif icant increased survival of CEC. CD74 was also expressed on the CT26 colon carcinoma cell line and its stimulation by MIF resulted in enhanced cell survival, up-regulation of Akt phosphorylation and Bcl-2 expression.

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 mutationssuffer from increased rates of liver fi brosis. 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 fi-brosis 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 fi brosers" and 116 as "slow fi brosers"; 13% of the "fast fi brosers" carried the PT20210 mutation as compared with 5.5% of the "slow fi brosers", 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 fi brosis. CONCLUSION: Carriage of the PT20210 mutation is related to an increased rate of liver fi brosis in HCV patients.

聚乙二醇干扰素α-2b和利巴韦林治疗慢性丙型肝炎基因型4:治疗耐受和病毒动力学对持续的病毒学反应的影响

Background: The response rates and duration of peginterferon alpha (PEG-IFN-α) and ribavirin combination therapy in chronic hepatitis C genotype 4, the prevalent genotype in the Middle East and Africa, are poorly documented. Aims: To compare the efficacy and safety of 24, 36, or 48 weeks of PEG-IFN-α-2b and ribavirin therapy in chronic hepatitis C genotype 4. Methods: In this prospective, randomised, double blind study, 287 patients with chronic hepatitis C genotype 4 were randomly assigned to PEG-IFN-α-2b (1.5 μg/kg) once weekly plus daily ribavirin (1000-1200 mg) for 24 weeks (group A, n = 95), 36 weeks (group B, n = 96), or 48 weeks (group C, n = 96) and followed for 48 weeks after completion of treatment. Early viral kinetics and histopathological evaluation of pre-and post treatment liver biopsies were performed. The primary end point was viral clearance 48 weeks after completion of treatment. Results: Sustained virological response was achieved in 29%, 66%, and 69%of patients treated with PEG-IFN-α-2b and ribavirin for 24, 36, and 48 weeks, respectively, by intention to treat analysis. No statistically significant difference in sustained virological response rates was detected between 36 and 48 weeks of therapy (p = 0.3). Subjects with sustained virological response showed greater antiviral ef-ficacy(e) and rapid viral load decline from baseline to treatment week 4 compared with non-responders and improvement in liver histology. The incidence of adverse events was higher in the group treated for 48 weeks. Conclusion: PEG-IFN-α-2b and ribavirin for 36 or 48 weeks was more effective in the treatment of chronic hepatitis C genotype 4 than treatment for 24 weeks. Thirty six week therapy was well tolerated and produced sustained virological and histological response rates similar to the 48 week regimen.

Assessment of the Visual Analogue Score in the Evaluation of the Pruritus of Cholestasis

Background and Aims:A visual analogue score (VAS),based on application of a visual analogue scale,has been widely used to assess pruritus in clinical studies of patients with cholestatic liver disease.A VAS is a numerical score of the severity of the perception of pruritus,and,hence,is inherently subjective.The objective of this study was to assessthe reliability of a VAS as an index of pruritus in cholestatic patients.Methods:In 8 patients with chronic pruritus due to primary biliary cholangitis,values for a VAS of pruritus were compared with corresponding measurements of scratching activity,which were generated by a monitoring system specifically designed to quantitate this activity.The relationship between individual values for the VAS and corresponding values for scratching activity during a specific interval immediately preceding the recording of the VAS was examined by determining the Spearman's rank correlation coefficient.Results:The mean Spearman's rank correlation coefficient between individual values for the VAS and corresponding mean values for scratching activity was 0.072;the range of these coefficients was-0.04 to 0.26.A VAS of pruritus is an unreliable index of scratching activity,and,hence,of the pathophysiological process responsible for the pruritus of cholestasis.Conclusion:It is concluded that the use of a VAS as a primary quantitative endpoint in trials of the efficacy of potential therapies for the pruritus of cholestasis may be inappropriate.