Rifaximin has the potential to prevent complications of cirrhosis.
ABSTRACT: Background:Cirrhosis-related complications are associated with poor prognosis. With our analyses, we examined the potential benefit of rifaximin in reducing the risk of developing cirrhosis-related complications. Methods:Adults with cirrhosis and hepatic encephalopathy (HE) in remission were randomly assigned to receive rifaximin 550?mg twice daily or placebo for 6?months with concomitant lactulose permitted. Post hoc analyses examined time to cirrhosis-related complications (HE, spontaneous bacterial peritonitis (SBP), variceal bleeding, acute kidney injury/hepatorenal syndrome). Subgroup analyses evaluated efficacy for select baseline disease characteristics. Results:Of patients receiving rifaximin (n = 140) and placebo (n = 159), 53.6% and 49.1%, respectively, had baseline Model for End-Stage Liver Disease (MELD) score ? 12 and international normalized ratio (INR) ? 1.2. Baseline ascites was observed in 36.4% (rifaximin) and 34.6% (placebo) of patients. In patients with MELD score ? 12 and INR ? 1.2, rifaximin reduced the relative risk (RR) of any first complication experienced during trial by 59% [hazard ratio (HR) = 0.41, 95% confidence interval (CI): 0.25-0.67; p < 0.001] versus placebo. For patients with baseline ascites, rifaximin reduced the RR of any first complication experienced during trial by 42% versus placebo (HR = 0.58, 95% CI: 0.34-1.0; p = 0.045). For some subgroups, there was a decrease in RR of complications of SBP, variceal bleeding, and acute kidney injury/hepatorenal syndrome with rifaximin versus placebo, although there were few events reported in the study. Conclusion:Rifaximin may reduce the incidence of cirrhosis-related complications and the recurrence of overt HE.[ClinicalTrials.gov identifier: NCT00298038.].
Project description:Scoring systems such as Model for End-stage Liver Disease (MELD) and Child-Pugh are often used by clinicians to determine prognosis in patients with cirrhosis. Since clinical complications are important in determining cirrhosis outcomes, our goal was to use these to develop a novel prognostic staging model. Data from the Nationwide Inpatient Sample (NIS), years 2003-2011, were queried for records of patients over the age of 18 with cirrhosis excluding patients with prior or inpatient liver transplantation. The primary outcome was inpatient mortality with focus on cirrhosis-related complications: non-bleeding esophageal varices, variceal hemorrhage, ascites, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS). Of 59 862 903 hospitalizations, 824?783 (1.4%) with cirrhosis were identified. Overall mortality was 7% with two-thirds (66%) of deaths occurring in patients with a decompensating event, defined as variceal hemorrhage, ascites, HE, SBP, and/or HRS. Overall mortality rates decreased from 2003 to 2011 (9.0-6.0%), in both compensated and decompensated groups. Mortality was higher in patients with variceal haemorrhage (OR 1.56; p<0.05), HE (OR 1.75; p<0.05), SBP (OR 2.64; p<0.05) and HRS (OR 9.10; p<0.05) compared with patients with no complications. HRS had the highest mortality, whether alone or in combination with another event such as HE (OR 12.40; p<0.05) or SBP (OR 12.64; p<0.05). Cirrhosis inpatient outcomes are related to the severity of liver disease, with more severe complications such as HE, SBP, and HRS having the most significant effect on inpatient mortality, and are utilised in this novel four-stage clinical model.
Project description:BACKGROUND AND AIMS:Macrophages play a significant role in chronic liver disease as reflected by elevated soluble (s)CD163 and mannose receptor (sMR) levels and associated with liver disease severity and prognosis. Extracellular matrix remodelling associated with fibrogenesis may be affected by systemic inflammation induced by bacterial translocation. Therefore, we aimed to investigate the effect of rifaximin-?, an antibiotic with effect on gut bacteria, on sCD163, sMR, and collagen metabolites. METHODS:Fifty-four clinically stable patients with decompensated cirrhosis were randomized to 4 weeks treatment with rifaximin-? (n = 36) or placebo (n = 18). Macrophage markers sCD163, sMR and markers of collagen fibrogenesis (C3M and C4M) and formation (PRO-C3 and P4NPS7) were analysed in plasma before and after treatment. RESULTS:sCD163 and sMR levels were associated with liver disease severity (MELD score, sCD163 rho = 0.47, p<0.001 and sMR rho = 0.37, p = 0.005). There was no effect of Rifaximin-? on sCD163 levels (median (range) sCD163 5.64(2.02 to 10.8) at baseline versus 4.42(1.98 to 8.92) at follow-up in the rifaximin-? group and 4.85 (2.29 to 12.1) at baseline versus 4.32 (1.98 to 12.4) at follow-up in the placebo-group), p = 0.34); nor sMR levels, p = 0.34. Also in patients with elevated lipopolysaccharide binding protein (> 5.9 ?g/ml, 38 patients) there was no effect of rifaximin-? on sCD163 (p = 0.49) or sMR levels (p = 0.32). CONCLUSION:We confirmed that macrophage activation markers sCD163 and sMR are directly associated to liver disease severity (MELD score). However, rifaximin-? has no effect on sCD163, sMR or collagen markers in decompensated cirrhosis and does therefore not seem to interfere with macrophage activation or fibrogenesis.
Project description:Hepatic encephalopathy (HE) can cause major morbidity despite standard of care (SOC; rifaximin/lactulose). Fecal microbial transplant (FMT) enemas postantibiotics are safe, but the effect of FMT without antibiotics using the capsular route requires investigation. The aim of this work was to determine the safety, tolerability, and impact on mucosal/stool microbiota and brain function in HE after capsular FMT in a randomized, single-blind, placebo-controlled clinical trial in Virginia. Patients with cirrhosis with recurrent HE with MELD (Model for End-Stage Liver Disease) <17 on SOC were randomized 1:1 into receiving 15 FMT capsules versus placebo from a single donor enriched in Lachnospiraceae and Ruminococcaceae. Endoscopies with duodenal and sigmoid biopsies, stool analysis, cognition, serum lipopolysaccharide-binding protein (LBP), and duodenal antimicrobial peptide (AMP) expression at baseline were used. Clinical follow-up with SOC maintenance was performed until 5 months. FMT-assigned patients underwent repeat endoscopies 4 weeks postenrollment. Twenty subjects on lactulose/rifaximin were randomized 1:1. MELD score was similar at baseline (9.6 vs. 10.2) and study end (10.2 vs. 10.5). Six patients in the placebo group required hospitalizations compared to 1 in FMT, which was deemed unrelated to FMT. Infection/HE episodes were similar between groups. Baseline microbial diversity was similar in all tissues between groups. Post-FMT, duodenal mucosal diversity (P = 0.01) increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post-FMT in sigmoid (P = 0.04) and stool (P = 0.05). Duodenal E-cadherin (P = 0.03) and defensin alpha 5 (P = 0.03) increased whereas interleukin-6 (P = 0.02) and serum LBP (P = 0.009) reduced post-FMT. EncephalApp performance improved post-FMT only (P = 0.02). Conclusion: In this phase 1 study, oral FMT capsules are safe and well tolerated in patients with cirrhosis and recurrent HE. FMT was associated with improved duodenal mucosal diversity, dysbiosis, and AMP expression, reduced LBP, and improved EncephalApp performance. Further studies are needed to prove efficacy.
Project description:BACKGROUND:Statins may improve outcomes in patients with cirrhosis. We performed a systematic review and meta-analysis to evaluate the effect of statins on patients with cirrhosis and related complications, especially portal hypertension and variceal haemorrhage. METHODS:Studies were searched in the PubMed, Embase and Cochrane library databases up to February 2019. The outcomes of interest were associations between statin use and improvement in portal hypertension (reduction >20% of baseline or <12 mm Hg) and the risk of variceal haemorrhage. The relative risk (RR) with a 95% CI was pooled and calculated using a random effects model. Subgroup analyses were performed based on the characteristics of the studies. RESULTS:Eight studies (seven randomised controlled trials (RCTs) and one observational study) with 3195 patients were included. The pooled RR for reduction in portal hypertension was 1.91 (95% CI, 1.04 to 3.52; I2=63%) in six RCTs. On subgroup analysis of studies that used statin for 1 month, the RR was 2.01 (95% CI, 1.31 to 3.10; I2=0%); the pooled RR for studies that used statins for 3 months was 3.76 (95% CI, 0.36 to 39.77; I2=75%); the pooled RR for studies that used non-selective beta-blockers in the control group was 1.42 (95% CI, 0.82 to 2.45; I2=64%); the pooled RR for studies that used a drug that was not reported in the control group was 4.21 (95% CI, 1.52 to 11.70; I2=0%); the pooled RR for studies that used simvastatin was 2.20 (95% CI, 0.92 to 5.29; I2=69%); RR for study using atorvastatin was 1.82 (95% CI, 1.00 to 3.30). For the risk of a variceal haemorrhage, the RR based on an observational study was 0.47 (95% CI, 0.23 to 0.94); in two RCTs, the pooled RR was 0.88 (95% CI, 0.52 to 1.50; I2=0%). Overall, the summed RR was 0.64 (95% CI, 0.42 to 0.99; I2=6%). CONCLUSION:Statins may improve hypertension and decrease the risk of variceal haemorrhage according to our assessment. However, further and larger RCTs are needed to confirm this conclusion.
Project description:Although the Model for End-Stage Liver Disease sodium (MELD Na) score is now used for liver transplant allocation in the United States, mortality prediction may be underestimated by the score. Using aggregated electronic health record data from 7834 adult patients with cirrhosis, we determined whether the cause of cirrhosis or cirrhosis complications was associated with an increased risk of death among patients with a MELD Na score ?15 and whether patients with the greatest risk of death could benefit from liver transplantation (LT). Over median follow-up of 2.3 years, 3715 patients had a maximum MELD Na score ?15. Overall, 3.4% were waitlisted for LT. Severe hypoalbuminemia, hepatorenal syndrome, and hepatic hydrothorax conferred the greatest risk of death independent of MELD Na score with 1-year predicted mortality >14%. Approximately 10% possessed these risk factors. Of these high-risk patients, only 4% were waitlisted for LT, despite no difference in nonliver comorbidities between waitlisted patients and those not listed. In addition, risk factors for death among waitlisted patients were the same as those for patients not waitlisted, although the effect of malnutrition was significantly greater for waitlisted patients (hazard ratio 8.65 [95% CI 2.57-29.11] vs. 1.47 [95% CI 1.08-1.98]). Using the MELD Na score for allocation may continue to limit access to LT.
Project description:Background and Aim:Variceal bleeding is the second most important precipitating factor related to the development of episodic hepatic encephalopathy; but to date there are no recommendations to prevent this complication. The aim of this study was to compare if primary prophylaxis with lactulose or L-ornithine L-aspartate or rifaximin, in cirrhotic patients with variceal bleeding, is better than placebo for avoiding the development of hepatic encephalopathy. Methods:A randomized, double-blind, placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT02158182) which included cirrhotic patients with variceal bleeding, without minimal or clinical hepatic encephalopathy at admission. Findings:87 patients were randomized to one of four groups. The basal characteristics were similar between groups. Comparatively with placebo, the frequency with regard to the development of hepatic encephalopathy was as follows: lactulose (54.5% versus 27.3%; OR = 0.3, 95% CI 0.09-1.0; P = 0.06); L-ornithine L-aspartate (54.5% versus 22.7%, OR = 0.2, 95% CI 0.06-0.88; P = 0.03); rifaximin (54.5% versus 23.8%; OR = 0.3, 95% CI 0.07-0.9; P = 0.04). There was no significant difference between the three groups receiving any antiammonium drug (P = 0.94). In the group receiving lactulose, 59.1% had diarrhea, and 45.5% had abdominal discomfort, bloating, and flatulence. Two patients (10%) treated with lactulose and a patient (4.5%) in the placebo group developed spontaneous bacterial peritonitis due to E. coli; one of them died due to recurrent variceal bleeding. There were no other adverse effects. Conclusions:Antiammonium drugs, particularly L-ornithine L-aspartate and rifaximin, proved to be effective in preventing the development of hepatic encephalopathy in those cirrhotic patients with variceal bleeding.
Project description:Cirrhosis is a leading cause of morbidity and mortality throughout the world. Significant complications include variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and infection. When these complications are severe, admission to the intensive care unit (ICU) is often required for organ support and management. Intensive care therapy can also serve as a bridge to liver transplantation. Along with decompensation of cirrhosis, the concept of acute-on-chronic liver failure (ACLF) has emerged. This involves an acute precipitating event, such as the development of infection in a patient with cirrhosis, which leads to acute deterioration of hepatic function and extrahepatic organ failure. Extrahepatic complications often include renal, cardiovascular, and respiratory failures. Patients with significant extrahepatic and hepatic failures need ICU admission for organ support. Again, in patients who are deemed suitable liver transplant candidates, intensive care management may allow bridging to liver transplantation. However, patients with a Chronic Liver Failure Consortium ACLF score greater than 70 at 48 to 72 hours post-ICU admission do not seem to benefit from ongoing intensive support and a palliative approach may be more appropriate.
Project description:BACKGROUND/AIMS:The MELD score was developed to predict survival after transjugular intrahepatic portosystemic shunt (TIPS) placement. Given changes in practice patterns and development of new prognostic tools in cirrhosis, we aimed to evaluate common models to predict mortality after TIPS placement. METHODS:Analysis of consecutive patients who underwent TIPS placement for ascites or bleeding. Performance to predict 90-day mortality was assessed by C statistic for six models (MELD, MELD-Na, CLIF-C ACLF, Child-Pugh, Platelet-Albumin-Bilirubin, and Emory score). Added predictive value to MELD score was assessed for univariate predictors of 90-day mortality. Stratified analysis by TIPS indication, emergent placement status, and TIPS stent type was performed. RESULTS:413 patients were analyzed (248 with variceal bleeding, 165 with refractory ascites). 90-day mortality was 27% (113/413). Mean MELD score was 15 ± 7.9. MELD score best predicted mortality for all patients (c = 0.779), for variceal bleeding (c = 0.844), and for emergent TIPS (c = 0.817). CLIF-C ACLF score best predicted mortality for refractory ascites (c = 0.707). Addition of sodium to the MELD score did not improve predictive value across multiple strata. Addition of hemoglobin improved MELD score's predictive value in variceal bleeding. Addition of age improved MELD score's predictive value in refractory ascites. CONCLUSIONS:MELD score best predicted 90-day mortality. Addition of sodium to the MELD score did not improve its performance, though mortality prediction was improved using Age-MELD for ascites and Hemoglobin-MELD for bleeding. An individualized risk stratification approach may be best when considering candidates for TIPS placement.
Project description:Hospitalizations for advanced liver disease are costly and associated with significant mortality. This population-based study aimed to evaluate factors associated with in-hospital mortality and resource use for the management of hospitalized patients with cirrhosis.Mortality records and resource utilization for 52,027 patients hospitalized with cirrhosis and/or complications of portal hypertension (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, or hepatorenal syndrome) were extracted from a nationally representative sample of Thai inpatients covered by Universal Coverage Scheme during 2009 to 2013.The rate of dying in the hospital increased steadily by 12% from 9.6% in 2009 to 10.8% in 2013 (P < .001). Complications of portal hypertension were independently associated with increased in-hospital mortality except for ascites. The highest independent risk for hospital death was seen with hepatorenal syndrome (odds ratio [OR], 5.04; 95% confidence interval [CI], 4.38-5.79). Mortality rate remained high in patients with infection, particularly septicemia (OR, 4.26; 95% CI, 4.0-4.54) and pneumonia (OR, 2.44; 95% CI, 2.18-2.73). Receiving upper endoscopy (OR, 0.29; 95% CI, 0.27-0.32) and paracentesis (OR, 0.93; 95% CI, 0.87-1.00) were associated with improved patient survival. The inflation-adjusted national annual costs (P = .06) and total hospital days (P = .07) for cirrhosis showed a trend toward increasing during the 5-year period. Renal dysfunction, infection, and sequelae of portal hypertension except for ascites were independently associated with increased resource utilization.Renal dysfunction, infection, and portal hypertension-related complications are the main factors affecting in-hospital mortality and resource utilization for hospitalized patients with cirrhosis. The early intervention for modifiable factors is an important step toward improving hospital outcomes.
Project description:To determine the predictive performance of cholinesterase compared to existing prognostic models in evaluating liver function in patients with chronic hepatitis D.In an observational, cross-sectional and retrospective study, consecutive patients with hepatitis D cirrhosis were evaluated. Demographic, clinical and laboratory parameters were recorded. Serum cholinesterase levels were correlated with existing scoring models for chronic liver disease and Liver function tests. Receiver operating characteristic (ROC) curves were constructed to find an optimal cholinesterase level predicting ascites, Child Turcotte Pugh (CTP) score ≥ 10, model for end stage liver disease (MELD) score ≥ 15, baseline-event-anticipation (BEA) score for hepatitis D ≥ 5 and the aspartate transaminase to Platelet Ratio Index (APRI) ≥ 1.5.This study investigated 233 patients with chronic liver disease due to hepatitis D; 192 were male, median age 42 (16-69 years). Fifty patients had ascites and 15 had encephalopathy. One hundred and sixty-seven (71.7%) were in Child class A, 52 (22.3%) in Child class B and 14 (5.0%) in class C. A MELD score of 15 or more was seen in 24 patients. Cholinesterase levels correlated well with the INR, albumin, CTP score, MELD, MELD sodium, BEA and APRI scores (P < 0.001 each). Area under the ROC curve for ascites, CTP ≥ 10, MELD ≥ 15, BEA ≥ 5, APRI ≥ 1.5 was 0.836, 0.966, 0.913, 0.871 and 0.825 respectively (P < 0.001 each). Cut off values of cholinesterase (IU/L) for predicting ascites, CTP ≥ 10, MELD ≥ 15, BEA ≥ 5 and APRI ≥ 1.5 were < 3812, < 2853, < 2829, < 4719 and < 3954 with a sensitivity of 80%, 100%, 91.67%, 82.50%, 58.0% and specificity of 81.97%, 84.79%, 87.56%, 77.06% and 55.64% respectively.Serum cholinesterase demonstrates promising correlations with serum albumin, INR and CTP, MELD, BEA and APRI scores and is predictive of liver reserves in hepatitis D cirrhosis.