Sarcopenia Does Not Worsen Survival in Patients With Cirrhosis Undergoing Transjugular Intrahepatic Portosystemic Shunt for Refractory Ascites

INTRODUCTION: The impact of sarcopenia in patients undergoing transjugular intrahepatic portosystemic shunt (TIPSS) insertion for refractory ascites is unknown. METHODS: All adult patients who underwent TIPSS insertion for refractory ascites between 2010 and 2018 were included. Skeletal muscle index at L3 was used to determine sarcopenia status. RESULTS: One hundred seven patients were followed for 14.2 months. Sarcopenia was present in 57% of patients. No patient had history of pre-TIPSS hepatic encephalopathy (HE). De novo HE occurred in 30% of patients. On multivariate analysis, only platelet count and L3-SMI predicted de novo HE. On multivariate analysis, age and model for end-stage liver disease with sodium predicted mortality, whereas L3-SMI and sarcopenia did not. In patients with repeat imaging, L3-SMI improved significantly post-TIPSS compared with baseline. DISCUSSION: Sarcopenia should not be considered as a contraindication to TIPSS insertion in refractory ascites because it is not associated with de novo HE or increased mortality

Antibiotic treatment for spontaneous bacterial peritonitis in people with decompensated liver cirrhosis:a network meta-analysis

Background: Approximately 2.5% of all hospitalisations in people with cirrhosis are for spontaneous bacterial peritonitis (SBP). Antibiotics, in addition to supportive treatment (fluid and electrolyte balance, treatment of shock), form the mainstay treatments of SBP. Various antibiotics are available for the treatment of SBP, but there is uncertainty regarding the best antibiotic for SBP. Objectives: To compare the benefits and harms of different antibiotic treatments for spontaneous bacterial peritonitis (SBP) in people with decompensated liver cirrhosis. Search methods: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until November 2018 to identify randomised clinical trials on people with cirrhosis and SBP. Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and SBP. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. Data collection and analysis: Two review authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of SBP, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio with 95% credible intervals (CrIs) based on an available‐case analysis, according to the National Institute of Health and Care Excellence (NICE) Decision Support Unit guidance. Main results: We included a total of 12 trials (1278 participants; 13 antibiotics) in the review. Ten trials (893 participants) were included in one or more outcomes in the review. The trials that provided the information included patients having cirrhosis with or without other features of decompensation of varied aetiologies. The follow‐up in the trials ranged from one week to three months. All the trials were at high risk of bias. Only one trial was included under each comparison for most of the outcomes. Because of these reasons, there is very low certainty in all the results. The majority of the randomised clinical trials used third‐generation cephalosporins, such as intravenous ceftriaxone, cefotaxime, or ciprofloxacin as one of the interventions. Overall, approximately 75% of trial participants recovered from SBP and 25% of people died within three months. There was no evidence of difference in any of the outcomes for which network meta‐analysis was possible: mortality (9 trials; 653 participants), proportion of people with any adverse events (5 trials; 297 participants), resolution of SBP (as per standard definition, 9 trials; 873 participants), or other features of decompensation (6 trials; 535 participants). The effect estimates in the direct comparisons (when available) were very similar to those of network meta‐analysis. For the comparisons where network meta‐analysis was not possible, there was no evidence of difference in any of the outcomes (proportion of participants with serious adverse events, number of adverse events, and proportion of participants requiring liver transplantation). Due to the wide CrIs and the very low‐certainty evidence for all the outcomes, significant benefits or harms of antibiotics are possible. None of the trials reported health‐related quality of life, number of serious adverse events, or symptomatic recovery from SBP. Funding: the source of funding for two trials were industrial organisations who would benefit from the results of the trial; the source of funding for the remaining 10 trials was unclear. Authors' conclusions: Short‐term mortality after SBP is about 25%. There is significant uncertainty about which antibiotic therapy is better in people with SBP. We need adequately powered randomised clinical trials, with adequate blinding, avoiding post‐randomisation dropouts (or performing intention‐to‐treat analysis), and using clinically important outcomes, such as mortality, health‐related quality of life, and adverse events

Primary prevention of variceal bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis

BACKGROUND: Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years. There are several different treatments to prevent bleeding, including: beta-blockers, endoscopic sclerotherapy, and variceal band ligation. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES: To compare the benefits and harms of different treatments for prevention of first variceal bleeding from oesophageal varices in adults with liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for prevention of first variceal bleeding from oesophageal varices according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to December 2019 to identify randomised clinical trials in people with cirrhosis and oesophageal varices with no history of bleeding. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and oesophageal varices with no history of bleeding. We excluded randomised clinical trials in which participants had previous bleeding from oesophageal varices and those who had previously undergone liver transplantation or previously received prophylactic treatment for oesophageal varices. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR), and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute for Health and Care Excellence Decision Support Unit guidance. We performed the direct comparisons from randomised clinical trials using the same codes and the same technical details. MAIN RESULTS: We included 66 randomised clinical trials (6653 participants) in the review. Sixty trials (6212 participants) provided data for one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those at high risk of bleeding from oesophageal varices. The follow-up in the trials that reported outcomes ranged from 6 months to 60 months. All but one of the trials were at high risk of bias. The interventions compared included beta-blockers, no active intervention, variceal band ligation, sclerotherapy, beta-blockers plus variceal band ligation, beta-blockers plus nitrates, nitrates, beta-blockers plus sclerotherapy, and portocaval shunt. Overall, 21.2% of participants who received non-selective beta-blockers ('beta-blockers') - the reference treatment (chosen because this was the most common treatment compared in the trials) - died during 8-month to 60-month follow-up. Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all had lower mortality versus no active intervention (beta-blockers: HR 0.49, 95% CrI 0.36 to 0.67; direct comparison HR: 0.59, 95% CrI 0.42 to 0.83; 10 trials, 1200 participants; variceal band ligation: HR 0.51, 95% CrI 0.35 to 0.74; direct comparison HR 0.49, 95% CrI 0.12 to 2.14; 3 trials, 355 participants; sclerotherapy: HR 0.66, 95% CrI 0.51 to 0.85; direct comparison HR 0.61, 95% CrI 0.41 to 0.90; 18 trials, 1666 participants; beta-blockers plus nitrates: HR 0.41, 95% CrI 0.20 to 0.85; no direct comparison). No trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation had a higher number of serious adverse events (number of events) than beta-blockers (rate ratio 10.49, 95% CrI 2.83 to 60.64; 1 trial, 168 participants). Based on low-certainty evidence, beta-blockers plus nitrates had a higher number of 'any adverse events (number of participants)' than beta-blockers alone (OR 3.41, 95% CrI 1.11 to 11.28; 1 trial, 57 participants). Based on low-certainty evidence, adverse events (number of events) were higher in sclerotherapy than in beta-blockers (rate ratio 2.49, 95% CrI 1.53 to 4.22; direct comparison rate ratio 2.47, 95% CrI 1.27 to 5.06; 2 trials, 90 participants), and in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison rate ratio 1.72, 95% CrI 1.08 to 2.76; 1 trial, 140 participants). Based on low-certainty evidence, any variceal bleed was lower in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison HR 0.21, 95% CrI 0.04 to 0.71; 1 trial, 173 participants). Based on low-certainty evidence, any variceal bleed was higher in nitrates than beta-blockers (direct comparison HR 6.40, 95% CrI 1.58 to 47.42; 1 trial, 52 participants). The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease mortality compared to no intervention in people with high-risk oesophageal varices in people with cirrhosis and no previous history of bleeding. Based on low-certainty evidence, variceal band ligation may result in a higher number of serious adverse events than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons

Secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis: a network meta-analysis

BACKGROUND: Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES: To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons. AUTHORS' CONCLUSIONS: The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone

Sex is a major effect modifier between body composition and mortality in patients with cirrhosis assessed for liver transplantation

Background and Aims: Body composition predicts mortality in patients with cirrhosis. The impact of sex on this association is unknown. We investigated the impact of sex on this association in patients with cirrhosis assessed for liver transplantation. Methods: This single-centre retrospective cohort study included adults assessed for liver transplantation. Nutritional status was assessed using the Royal Free Hospital-Global Assessment (RFH-GA). Body composition at the third lumbar vertebrae was determined. SarcopeniaSMI was defined as Skeletal Muscle Index <50 cm2/m2 in males and <39 cm2/m2 in females. SarcopeniaPMI was defined as the sex-specific 25th percentile of the Psoas Muscle Index. Patients were assessed for the occurrence of liver transplantation and death. Analyses were stratified by sex. Results: The cohort comprised 628 patients, including 199 females and 429 males. Both groups were similar in terms of baseline liver disease severity by Model for End-stage Liver Disease (MELD) (p =.98) and nutritional status (p =.24). SarcopeniaSMI was present in 41% of males compared to 27% of females (p <.001). In the male cohort, when adjusted for age and MELD, sarcopeniaPMI (aHR 1.74, 95% CI 1.08–2.80) and RFH-GA (aHR 1.40, 95% CI 1.03–1.90) remained independent predictors of mortality. Adipose tissue had no impact on outcomes in males. In female patients, adipose tissue (TATI or VATI depending on the multivariable model) was independently associated with mortality, whereas sarcopenia and malnutrition were not. Conclusions: This study demonstrates that male patients were susceptible to low muscle mass, whereas female patients were not. Future research in this patient population should minimize sex-related bias and present data for both groups separately

Liver-related and extrahepatic events in patients with non-alcoholic fatty liver disease: a retrospective competing risks analysis

Background &amp; Aim: Non-alcoholic fatty liver disease (NAFLD), and especially fibrotic non-alcoholic steatohepatitis, is associated with high risks of liver-related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy-proven NAFLD stratified according to baseline severity of fibrosis. Methods: Two thousand one hundred thirty-five patients with biopsy-proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause-specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with liver fibrosis severity estimated by liver stiffness measurement by transient elastography was also enrolled. Results: Observed CIFs indicated that the 60-month probabilities of LRE and EHE were 0.2% and 3% in F0-F1, 2% and 3.8% in F2 and 9.7% and 6.4% in F3-F4 patients, respectively. The cause-specific Cox model indicated that in F0-F1 and F2 patients, age&nbsp;&gt;&nbsp;50&nbsp;years (HR 2.7) was the only predictor of LRE, while age&nbsp;&gt;&nbsp;50&nbsp;years (HR 2.96), previous cardiovascular events (CVE, HR 2.07), and previous extra-hepatic cancer (HR 2.36) were independent risk factors for EHE. In F3-F4 patients, age&nbsp;&gt;&nbsp;55&nbsp;years (HR 1.73), obesity (HR 1.52), PLT&nbsp;&lt;&nbsp;150&nbsp;000/mmc (HR 3.66) and log(GGT) (HR 1.77) were associated with LRE, while age&nbsp;&gt;&nbsp;55&nbsp;years (HR 1.74) and previous CVE (HR 2.51) were independent predictors of EHE. Predicted CIFs for HE and EHE in F0-F1, F2 and F3-F4 patients stratified the risk of events. The results were externally replicated. Conclusion: The likelihood of EHE in NAFLD patients is relevant and increases according to the severity of liver fibrosis, while the risk of LRE is negligible in F0-F1, low but clinically relevant in F2 and high in F3-F4 patients