Utility of Lille Score in Predicting 30-Day Survival in Steroid-Treated Alcohol-Associated Hepatitis.

BACKGROUND/AIMS: In alcohol-associated hepatitis (AH), the Lille score is used to assess futility of steroids. However, the ability of the Lille score to predict 30-day survival in AH is not well-defined. Our aim is to compare the utility of the Lille score in predicting 30-day survival in those with AH treated with steroids. METHODS: Retrospective chart review of 882 patients hospitalized with AH from January 1st, 2012 through December 30th, 2019 was performed. Of these, 201 patients with severe AH met the threshold to receive steroids. Those with data to calculate Lille score < 0.45 on day 4 (n = 29) or 7 (n = 89) who continued steroids were compared to 83 patients with Lille scores ≥ 0.45 on day 4 (n = 18) or 7 (n = 65) who stopped steroids. The primary outcome was 30-day survival. For comparison, a contemporaneous matched control group was also analyzed of 110 patients who were hospitalized with severe AH, but did not receive steroids. RESULTS: In patients with Lille score < 0.45, survival was higher at 30-day when compared to those with Lille score ≥ 0.45 (94.9% vs. 80.72%; p = 0.002). The sensitivity, specificity, positive predictive value and negative predictive value of Lille score (< 0.45) to predict 30-day survival was 95%, 19%, 63%, and 73%, respectively. CONCLUSIONS: In severe AH, those with Lille score < 0.45 at day 4 or 7 have improved 30-day survival compared to those with Lille score ≥ 0.45. In those receiving steroids, Lille score has excellent sensitivity to predict 30-day survival but poor specificity.

Derivation and Validation of a Model to Predict Clinically Significant Portal Hypertension Using Transient Elastography and FIB-4.

BACKGROUND: Liver biopsy and hepatic venous pressure gradient (HVPG), the gold standard for assessing advanced fibrosis (AF) and clinically significant portal hypertension (CSPH), are invasive, costly, and time-consuming. GOAL: We investigated if the combination of fibrosis index based on 4 factors (FIB-4) and liver stiffness measure (LSM) can identify AF and more importantly, CSPH. PATIENTS AND METHODS: Patients with chronic liver disease referred for transjugular liver biopsy were analyzed retrospectively. FIB-4 and LSM were compared with liver histology for diagnosing AF. FIB-4, LSM, and platelet count were compared with HVPG for diagnosing CSPH. Optimal cutoffs for predicting CSPH were determined by grid search. A composite log-odds to predict CSPH was derived from logistic regression using LSM, FIB-4, and gender. Internal bootstrap validation and external validation were performed. RESULTS: A total of 142 patients were included in the derivation; 42.3% had AF, and 11.3% had CSPH using the current gold standards. The area under the receiver operating characteristic curve (AUROC) for LSM, FIB-4, and their combination to predict AF were 0.7550, 0.7049, and 0.7768, respectively. LSM, FIB-4, and platelet count predicted CSPH with AUROC 0.6818, 0.7532, and 0.7240, respectively. LSM plus FIB-4 showed the best performance in predicting CSPH with AUROC 0.8155. Based on LSM, FIB-4, and gender, a novel model-the Portal Hypertension Assessment Tool (PHAT)-was developed to predict CSPH. PHAT score ≥-2.76 predicted CSPH with sensitivity 94%, specificity 67%, positive predictive value 27%, negative predictive value 99%, and accuracy 70%. In internal and external validation, AUROCs for the model were 0.8293 and 0.7899, respectively. CONCLUSION: A model consisting of FIB-4, LSM, and gender can identify CSPH among patients with chronic liver disease.

A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study.

BACKGROUND & AIMS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. METHODS: Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). RESULTS: Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1ß and endothelial dysfunction markers was also observed in the albumin group. CONCLUSION: In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. CLINICAL TRIALS REGISTRATION: www. CLINICALTRIALS: gov NCT03585257. IMPACT AND IMPLICATIONS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Substance-use simulation impairs driving capability in patients with cirrhosis regardless of hepatic encephalopathy.

Driving is independently affected by cirrhosis and hepatic encephalopathy (HE) and alcohol/substance use, but their concomitant impact is unclear. We aimed to determine the impact of alcohol and other substances on driving-simulator performance in cirrhosis with and without HE. Outpatients with cirrhosis and controls underwent cognitive testing and driving simulation for the following three conditions: baseline, wearing goggles simulating alcohol intoxication, and wearing goggles simulating opioid/benzodiazepine abuse. Outcomes were number of centerline crossings (CCs) and road-edge excursions (REEs). We compared controls versus patients with cirrhosis then subjects with cirrhosis with and without HE for all conditions, using generalized linear modeling (GLM). Sixty subjects (17 controls, 43 with cirrhosis [Model for End-Stage Liver Disease score, 10; 21 subjects with prior HE]) were included. Simulations showed higher CCs and REEs at baseline in patients with cirrhosis with and without HE versus controls. With alcohol- and substance abuse-impairment goggles, CCs increased but REEs decreased in cirrhosis. In the GLM, a time and group interaction was seen (p < 0.001) for CCs and REEs. Patients with cirrhosis showed higher CCs and REEs at baseline than controls (CCs, p = 0.003; REEs, p = 0.0001) and higher CCs (p = 0.03) and lower REEs (p = 0.001) with alcohol-simulating goggles. All groups were equally impaired with opioid/benzodiazepine-simulating goggles (CCs, p = 0.49; REEs, p = 0.46). Controls with alcohol-simulating goggles had similar CCs as the baseline of patients with cirrhosis (p = 0.98). conclusions: Simulating alcohol intake induces greater driving impairment in patients with cirrhosis versus controls, but similar patterns were seen with opioid/benzodiazepine-simulating goggles. At baseline, patients with cirrhosis have simulator outcomes equivalent to intoxicated controls. Driving simulation with goggles modeling substance abuse could improve insight into driving errors and enhance driving rehabilitation in patients with cirrhosis.

Impact of bacterial infections and spontaneous bacterial peritonitis prophylaxis on phage-bacterial dynamics in cirrhosis.

BACKGROUND AND AIMS: Gut microbiota, including bacteria and phages, are altered in cirrhosis, but their role during infections and spontaneous bacterial peritonitis (SBP) prophylaxis is unclear. Our aim was determine metagenomic changes in gut bacteria; phages and their linkages centered around Gram-negative and Gram-positive pathobionts in patients with cirrhosis with/without infections or SBP prophylaxis. APPROACH AND RESULTS: We included uninfected (n = 231) and infected (n = 30, SBP n = 19 and urinary tract infection n = 11 before antibiotics) patients who gave stool for bacterial and phage metagenomics. We matched uninfected to infected patients 1:1 on a model for end-stage liver disease (MELD). We also analyzed subgroups of patients with ascites matched on an MELD (n = 73) to patients on SBP prophylaxis (n = 7) and then to SBP infection. Phage and bacterial taxa differences (DESeq2) and correlation networks centered around Escherichia coli and Enterococcus faecium were analyzed. Infections were mostly due to Enterobacteriaceae and Enterococcus spp. On metagenomics, higher fold changes of Enterobacteriaceae members, Enterococcus and Streptococcus spp., and Escherichia phages were seen in infected patients. Correlation networks showed more complex bacteria-phage linkages in infected patients compared with uninfected ones overall and centered around E. coli and E. faecium. SBP prophylaxis induced higher Gram-positive bacteria. In SBP, Enterococcus and Escherichia were higher versus ascites. Correlation networks around E. coli were complex in ascites but sparse with SBP prophylaxis, whereas the reverse was seen with E. faecium. Lytic phages and those associated with antibiotic resistance were correlated with E. faecium. CONCLUSION: In cirrhosis, there are significant changes in phage-bacterial linkages in infected patients and those on SBP prophylaxis compared to the remaining patients. SBP prophylaxis enriches complexity of E. faecium-centered but induces a collapse in E. coli-centered phage-bacterial correlations.

Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD.

BACKGROUND AND AIMS: Bile acids are hepatic metabolites and have many properties considered to be relevant to the pathophysiology of NAFLD. Circulating levels of the intestinal microbiome-modified bile acid deoxycholate are increased in cirrhosis. APPROACH AND RESULTS: To further elucidate the role of bile acids and intestinal microbiota linked to bile acids in progressively severe NAFLD, a multiomic study of feces including 16S rRNA sequencing, microbial transcriptomics and metabolomics was performed in a cohort with varying phenotypes of NAFLD. Several bile acids of microbial origin derived from deoxycholic acid (DCA) (glycodeoxycholate, 7-ketodeoxycholic acid, dehydrocholic acid) increased with disease activity and fibrosis stage. These were linked to increased expression of microbial bile salt hydrolase, bile acid operon (BaiCD) and hydroxysteroid dehydrogenases (hdhA) required for DCA and downstream metabolite synthesis providing a mechanistic basis for altered bile acid profiles with disease progression. Bacteroidetes and several genera of Lachnospiraceae family containing DCA generating genes increased with increasing disease severity, whereas several potentially beneficial microbes sensitive to antibacterial effects of DCA e.g., Ruminococcaceae were decreased. The clinical relevance of these data was confirmed in an independent cohort enrolled in a clinical trial for NASH where at entry DCA and its conjugates were associated with advanced fibrosis. In patients treated with placebo, DCA declined in those with fibrosis regression and increased in those with fibrosis progression. DCA rose further in those with compensated cirrhosis when they experienced decompensation. CONCLUSIONS: These findings demonstrate a role for bile acids and the bile acid dependent microbiome in the development and progression of NAFLD and set the stage to leverage these findings for NASH biomarker development and for therapeutics.

Liver-Unrelated Comorbid Conditions Do Not Affect Cognitive Performance or Hepatic Encephalopathy Progression in Cirrhosis.

INTRODUCTION: We aimed to determine the effect of comorbidities on covert hepatic encephalopathy (CHE) diagnosis and overt hepatic encephalopathy (OHE) development. METHODS: Cirrhotic outpatients underwent CHE testing and 2-year follow-up. Cox regression was performed for time to OHE. In total, 700 patients (60 years, 84% men, model for end-stage liver disease 11) and 33% prior OHE underwent testing and follow-up. RESULTS: Major comorbidities were hypertension (54%), diabetes (35%), and depression (29%). Common medications were proton pump inhibitor (49%), beta-blockers (32%), and opioids (21%). Approximately 90 (40%) prior-OHE patients developed recurrence 93 (30,206) days post-testing predicted only by liverrelated variables. DISCUSSION: Demographics, cirrhosis characteristics, and opioid use, but not other comorbid conditions, were associated with CHE diagnosis and OHE progression.

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA.

BACKGROUND & AIMS: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. METHODS: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). RESULTS: At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. CONCLUSION: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. LAY SUMMARY: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. CLINICAL TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT03124108.

Liver Transplant Is Associated with Sustained Improvement in Tandem Gait and Risk of Falls.

BACKGROUND: Cirrhosis is associated with poor health-related quality of life (HRQOL), cognitive dysfunction (CD), and lack of coordination leading to falls. Tandem gait (TG; heel-toe) can be used to assess coordination. The impact and relationship between CD, TG and falls pre-/post-liver transplant (LT) is unclear. We aimed to determine the impact of LT on CD, abnormal TG, and HRQOL in cirrhosis. METHODS: We analyzed patients who underwent complete neurological examination, cognitive testing by psychometric hepatic encephalopathy score (PHES), and HRQOL assessment using sickness impact profile (SIP). All patients were followed for 1 post-LT visit at 6 or 12 months post-LT for clinical course and falls. Change in CD, TD, and falls pre-/post-LT were compared. RESULTS: Off 131 recruited, 61 patients completed all visits. Majority were men (84%), with HCV etiology (34%). Pre-LT: Abnormal TG trended towards increased falls (OR 3.3, P = 0.08). Forty-nine % had abnormal TG, 61% had CD, 32.7% had CD + abnormal TG, 62% had prior OHE, and 14.7% had falls. Abnormal and normal TG patients had similar ages, BMI, sex, education level, and MELD scores. Abnormal TG group had higher prior overt HE (P = 0.03) and worse physical SIP score (P = 0.008). Post-LT: There was sustained improvement in CD, HRQOL, falls, and TG post-LT more at 12 than 6 months in all patients. Patients who had abnormal TG pre-LT continued to have a worse PHES (P = 0.0064) and physical SIP score (P = 0.008) compared to normal pre-LT TG patients. CONCLUSION: After LT, there is a sustained improvement in coordination measured via tandem gait, accompanied by a lower rate of falls.

Association Between Lipoprotein Particles and Atherosclerotic Events in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease,1 is independently associated with increased risk of cardiovascular disease (CVD), which is the leading cause of mortality in patients with NAFLD.2 This is likely caused by the centrality of the liver in lipid homeostasis. Prior cross-sectional studies have shown that NAFLD is associated with perturbations in lipid profile and atherogenic lipoprotein subparticles.3 Although statins improve lipid profile and CVD-associated mortality, residual CVD risk has been demonstrated in major statin trials.4,5 A key contributor to this residual risk is the limited ability of the standard lipid profile to precisely quantify atherogenic lipoprotein subparticles, such as small dense low-density lipoprotein (sdLDL), which might confer higher atherogenic risk. There are currently no studies evaluating the longitudinal impact of sdLDL on atherosclerotic events in NAFLD. Thus, we conducted a prospective study in patients with histologically confirmed NAFLD to better define the relationship among NAFLD, residual CVD risk, and sdLDL.

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis.

BACKGROUNDHepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp.METHODSTwenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT.RESULTSFMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes.CONCLUSIONGut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.TRIAL REGISTRATIONClinicaltrials.gov NCT03152188.FUNDINGNational Center for Advancing Translational Sciences NIH grant R21TR002024, VA Merit Review grant 2I0CX001076, the United Kingdom National Institute for Health Research Biomedical Facility at Imperial College London, the British Heart Foundation, Wellcome Trust, and King's College London.

A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (-26.5; 95% confidence interval [CI], -31.8, -21.2) and placebo (-23.4; 95% CI, -30.3, -16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.

Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease.

Lysyl oxidase like-2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly subcutaneous injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 weeks. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Additional endpoints included change in Ishak fibrosis stage and the frequency of PSC-related clinical events. Overall, 234 patients were randomized and started treatment. At week 96, the mean change from baseline in hepatic collagen content was -0.5% for patients receiving simtuzumab 75 mg (P = 0.73 versus placebo), +0.5% for patients receiving simtuzumab 125 mg (P = 0.33 versus placebo), and 0.0 for patients receiving placebo. Compared with placebo, neither dose of simtuzumab led to significant reductions in Ishak fibrosis stage, progression to cirrhosis, or frequency of clinical events. Overall, 80 (34%) patients had fibrosis progression and 47 (20%) experienced PSC-related clinical events. In a multivariate model of baseline factors, PSC-related clinical events were more frequent in patients with advanced fibrosis (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.02-4.06; P = 0.045), higher alkaline phosphatase (HR per 10 U/L, 1.01; 95% CI, 1.00-1.02; P = 0.015), and higher enhanced liver fibrosis score (HR per unit, 1.26; 95% CI, 0.98-1.61; P = 0.073). Overall, rates of adverse events and laboratory abnormalities were similar between groups. Conclusion: Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC.

Prevalence and Severity of Nonalcoholic Fatty Liver Disease Among Caregivers of Patients With Nonalcoholic Fatty Liver Disease Cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting nearly 1 in 3 Americans.1 Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, has a propensity of fibrosis progression and increased risk of cirrhosis and hepatocellular carcinoma. NASH-related cirrhosis is now the most rapidly growing indication for liver transplantation (LT).2 Disease recurrence and progression to advanced fibrosis after LT are high3; however, the key contributors of these are unknown. We hypothesized that patients with NASH cirrhosis reside in a microenvironment conducive to not only development of NASH but also fibrosis progression, which likely persist after LT and contribute to disease recurrence. The hypothesis was tested by performing vibration-controlled transient elastography (VCTE) in primary caregivers and cohabitants of patients with decompensated cirrhosis awaiting LT.

Proton Pump Inhibitor Initiation and Withdrawal affects Gut Microbiota and Readmission Risk in Cirrhosis.

OBJECTIVES: Cirrhosis is associated with gut microbial dysbiosis, high readmissions and proton pump inhibitor (PPI) overuse, which could be inter-linked. Our aim was to determine the effect of PPI use, initiation and withdrawl on gut microbiota and readmissions in cirrhosis. METHODS: Four cohorts were enrolled. Readmissions study: Cirrhotic inpatients were followed throughout the hospitalization and 30/90-days post-discharge. PPI initiation, withdrawal/continuation patterns were analyzed between those with/without readmissions. Cross-sectional microbiota study: Cirrhotic outpatients and controls underwent stool microbiota analysis. Beneficial autochthonous and oral-origin taxa analysis vis-à-vis PPI use was performed. Longitudinal studies: Two cohorts of decompensated cirrhotic outpatients were enrolled. Patients on chronic unindicated PPI use were withdrawn for 14 days. Patients not on PPI were started on omeprazole for 14 days. Microbial analysis for oral-origin taxa was performed pre/post-intervention. RESULTS: Readmissions study: 343 inpatients (151 on admission PPI) were enrolled. 21 were withdrawn and 45 were initiated on PPI resulting in a PPI use increase of 21%. PPIs were associated with higher 30 (p = 0.002) and 90-day readmissions (p = 0.008) independent of comorbidities, medications, MELD and age. Cross-sectional microbiota: 137 cirrhotics (59 on PPI) and 45 controls (17 on PPI) were included. PPI users regardless of cirrhosis had higher oral-origin microbiota while cirrhotics on PPI had lower autochthonous taxa compared to the rest. Longitudinal studies: Fifteen decompensated cirrhotics tolerated omeprazole initiation with an increase in oral-origin microbial taxa compared to baseline. PPIs were withdrawn from an additional 15 outpatients, which resulted in a significant reduction of oral-origin taxa compared to baseline. CONCLUSIONS: PPIs modulate readmission risk and microbiota composition in cirrhosis, which responds to withdrawal. The systematic withdrawal and judicious use of PPIs is needed from a clinical and microbiological perspective in decompensated cirrhosis.

Elbasvir/grazoprevir in black adults with hepatitis C virus infection: a pooled analysis of phase 2/3 clinical trials.

OBJECTIVES: Although direct-acting antiviral regimens have dramatically improved the treatment of hepatitis C virus (HCV) infection, there is some evidence that black race may be an independent predictor of treatment failure. We report a retrospective analysis of black participants receiving elbasvir/grazoprevir (EBR/GZR) in nine phase 2/3 clinical trials. METHODS: Black participants with chronic HCV genotype 1 or 4 (GT1 or GT4) infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks, or in combination with ribavirin for 16 weeks, were included. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/mL). RESULTS: Compared with nonblack participants (n = 1310), black participants (n = 332) were more likely to have chronic kidney disease stage 4/5 (9.2% vs. 31.0%, respectively), while other comorbidities were similar between the groups. In black and nonblack participants receiving EBR/GZR for 12 weeks, SVR12 rates were 93.7% (282/301) and 94.2% (1072/1138) in those with GT1 infection, and 93.8% (15/16) and 94.6% (88/93) in those with GT4 infection. SVR12 was 100.0% (15/15) in black participants and 97.5% (77/79) in nonblack participants with GT1 infection receiving EBR/GZR plus ribavirin for 16 weeks. Rates of drug-related adverse events (AEs) were 30% vs. 36.6%, and serious AEs were 7.6% vs. 3.4% in black and nonblack participants, respectively. CONCLUSION: EBR/GZR showed high efficacy in black participants with HCV GT1 or GT4 infection and was generally well tolerated, with a safety profile similar to that reported overall in phase 2/3 clinical trials.

Treatment of HCV in the Department of Corrections in the Era of Oral Medications.

Chronic hepatitis C virus (HCV) is widely prevalent in the Virginia Department of Corrections (DOC). However, sustained virologic response (SVR) with all oral direct-acting antiviral (DAA) therapy is unknown. HCV treatment was provided through telemedicine following guidelines of the American Association for the Study of Liver Diseases and Infectious Diseases Society of America. SVR12 in the DOC was compared in two control groups: privately insured and indigent patients receiving care in HCV treatment clinics by the same providers during the same time period. Of 220 DOC patients, 180 were started on therapy (158 genotype [GT] 1, 15 GT2, and 10 GT3). SVR12 data on GT1 patients who received ledipasvir/sofosbuvir with or without ribavirin (RBV) were 96%, similar to our indigent (95%) and private clinic (93%) patients despite differences in age, gender, treatment experience, FIB-4, and use of RBV. Multiple logistic regression of GT1 patients identified lower FIB-4 ( p = .008) and treatment clinic ( p = .01) as independent predictors of SVR12. HCV treatment in the DOC by telemedicine with DAA is not only feasible but has a very high SVR12 similar to published trials.

Coronary artery disease in decompensated patients undergoing liver transplantation evaluation.

Coronary artery disease (CAD) is an important contributor to morbidity and mortality in patients undergoing liver transplantation (LT). However, the current literature is limited by sampling bias and nondefinitive assessment of CAD. The current study examines the prevalence of CAD via per protocol coronary angiography and its relationship to etiology of liver disease in patients undergoing liver transplantation evaluation (LTE). Data on 228 patients were prospectively collected who had coronary angiography as part of LTE between 2011 and 2014. Coronary angiography was done in all patients age ≥50 years or with CAD risk factors. CAD was defined as any coronary artery stenosis, whereas stenosis ≥ 70% in distribution of 1 or 3 major coronary arteries was considered as single- or triple-vessel disease. CAD was detected in 36.8% of patients, with the highest prevalence among nonalcoholic steatohepatitis (NASH) patients with cirrhosis (52.8%). Prevalence of single-vessel disease was higher among patients with NASH compared with hepatitis C virus (HCV) and alcoholic cirrhosis (15.1% versus 4.6% versus 6.6%; P = 0.02). Similarly, patients with NASH were more likely to have triple-vessel disease when compared with HCV and alcoholic cirrhosis (9.4% versus 0.9% versus 0%; P = 0.001). While adjusting for traditional risk factors for CAD, only NASH as etiology of liver disease remained significantly associated with CAD. Complications from diagnostic coronary angiography or percutaneous coronary intervention were low (2.6%). In conclusion, patients undergoing LTE have a high prevalence of CAD, which varies widely depending on etiology of liver cirrhosis. The procedural complications from coronary angiography are low. Liver Transplantation 24 333-342 2018 AASLD.

A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. CONCLUSION: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).