Background and Aims:Cirrhosis is associated with dysbiosis, but its functional consequences are still largely unknown. Short-chain fatty acids (SCFAs) account for physiological interactions between the gut microbiota and host. Our aim was to assess the impact of cirrhotic dysbiosis on the production of SCFAs. Methods: Seventeen patients with cirrhosis and 17 controls were selected. Microbiota composition in faecal samples was assessed by next-generation 16S rRNA gene sequencing. SCFAs were measured with GC-MS in faecal samples and after in vitro batch fermentations using arabinoxylan, resistant starch, pectin, and lactulose as substrates.Results: Among the 17 cirrhotic patients (mean age 58, eight males), six, nine and two were, respectively, Child-Pugh class A, B and C. Eleven patients were on oral antibiotics, 11 on lactulose and 13 on proton pump inhibitors. Cirrhotic patients showed marked differences in the composition and diversity of gut microbiome when compared to controls, that were more pronounced with increased severity. Stool samples from cirrhotic patients showed lower SCFAs content and reduced capacity to produce SCFAs in batch fermentations, with butyrate production being the most abnormal. These functional aberrancies were more pronounced with greater liver disease severity. Abundance of Ruminococcus faecis (in family Ruminococcaceae), Faecalicatena fissicatena and Fusicatenibacter saccharivorans (in family Lachnospiraceae) was positively correlated with the SCFAs production. Conclusion:Cirrhotic dysbiosis is associated with a decreased capacity to ferment non-digestible carbohydrates into SCFAs, especially into butyrate. These functional abnormalities are more pronounced as disease progresses. These results might inform the design of gut-targeted therapies for cirrhosis. K E Y W O R D Scirrhosis, microbiota, short-chain fatty acids

Background/Aims There is increased interest in the therapeutic use of statins in cirrhosis, but preferred statin and safety outcomes are still not well known. In this systematic review we aimed to address pharmacokinetics (PK), safety, and effects on cardiovascular (CV) outcomes of statins in cirrhosis. Methods Our systematic search in several electronic databases and repositories of two regulatory bodies up to 2020-06-11 yielded 22 articles and 2 drug monographs with relevant data. Results Rosuvastatin and pitavastatin showed minimal PK changes in Child–Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study. Atorvastatin showed pronounced PK changes in cirrhosis. No PK data was found for simvastatin, the most commonly used statin in cirrhosis trials. There was insufficient data to assess CV effects of statins in cirrhosis. Clinical trials in cirrhosis were limited to simvastatin, atorvastatin, and pravastatin. In patients taking simvastatin 40 mg, pooled frequency of rhabdomyolysis was 2%, an incidence 40-fold higher than that reported in non-cirrhosis patients, while this was no rhabdomyolysis observed in patients on simvastatin 20 mg, atorvastatin 20 mg, or pravastatin 40 mg. Drug-induced liver injury was of difficult interpretation due to co-existence of muscle damage. No overt liver failure was reported. Conclusions Simvastatin 40 mg should be avoided in decompensated cirrhosis. Safety data on simvastatin 20 mg or other statins are based on small study sample size. This rarity of evidence combined with lack of data in dose adjustment methods in cirrhosis is a barrier for using statins for CV indications or for investigational use for liver indications.

Nonselective beta-blockers (NSBBs) have been the backbone for the treatment of portal hypertension in cirrhosis for the last 3 decades. A publication in 2010 of a prospective observational study suggested that NSBBs could increase mortality in patients with refractory ascites. This opened a controversy about the safety and efficacy of NSBBs in patients with advanced liver disease and led to the publication of a large corpus of observational data assessing the safety of NSBBs in patients with advanced cirrhosis. In this article, we briefly review the clinical pharmacology of NSBBs, the pathophysiological basis for the underlying benefits and harms of NSBBs in advanced cirrhosis, and the evidence in favor and against the use of NSBBs in specific scenarios. Finally, we summarize the current recommendations and propose areas of opportunity for future research. Liver Transplantation 23 1058-1069 2017 AASLD.

Acute‐on‐chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short‐term mortality. Both the European Association for the Study of the Liver‐Chronic Liver Failure (EASL‐CLIF) and North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL‐CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in‐hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL‐CLIF and NACSELD‐ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL‐CLIF definitions of ACLF above baseline parameters on in‐hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child‐Pugh‐Turcotte score, 10 ± 2; Model for End‐Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL‐CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in‐hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in‐hospital mortality, but the presence of NACSELD‐ACLF did. However, neither system was better than baseline parameters in the prediction of 30‐ or 90‐day outcomes. The presence of NACSELD‐ACLF is equally effective as the EASL‐CLIF ACLF grade, and better than baseline parameters in the prediction of in‐hospital mortality in patients with cirrhosis, but not superior in the prediction of longer‐term 30‐ or 90‐day outcomes.

BackgroundAchievement of normal volume status is crucial in hemodialysis (HD), since both volume expansion and volume contraction have been associated with adverse outcome and events.ObjectivesThe objectives of this study are to assess the prevalence of fluid volume expansion and depletion and to identify the best clinical parameter or set of parameters that can predict fluid volume expansion in HD patients.DesignThis study is cross-sectional.SettingThis study was conducted in three hemodialysis units.PatientsIn this study, there are 194 HD patients. MethodsVolume status was assessed by multifrequency bio-impedance spectroscopy (The Body Composition Monitor, Fresenius) prior to the mid-week HD session.ResultsOf all patients, 48 % (n = 94) were volume-expanded and 9 % of patients were volume-depleted (n = 17). Interdialytic weight gain was not different between hypovolemic, normovolemic, and hypervolemic patients. Fifty percent of the volume-expanded patients were hypertensive. Paradoxical hypertension was very common (31 % of all patients); its incidence was not different between patient groups. Intradialytic hypotension was relatively common and was more frequent among hypovolemic patients. Multivariate regression analysis identified only four predictors for volume expansion (edema, lower BMI, higher SBP, and smoking). None of these parameters displayed both a good sensitivity and specificity.LimitationsThe volume assessment was performed once.ConclusionsThe study indicates that volume expansion is highly prevalent in HD population and could not be identified using clinical parameters alone. No clinical parameters were identified that could reliably predict volume status. This study shows that bio-impedance can assist to determine volume status. Volume status, in turn, is not related to intradialytic weight gain and is unable to explain the high incidence of paradoxical hypertension.