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Background & Aims: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers' opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patient's HCC risk on the choice of surveillance modality., Methods: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states., Results: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patient's HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001)., Conclusions: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients' estimated HCC risk, instead of our current "one-size-fits all" strategy., (Copyright © 2022 AGA Institute. All rights reserved.)

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., (Copyright © 2021 by The American College of Gastroenterology.)

Background and Aims: Cirrhosis is associated with changes in intestinal microbiota that can lead to hepatic encephalopathy (HE) and infections, especially with antibiotic-resistant organisms. However, the impact of gut microbial antibiotic resistance gene (ARG) burden on clinical outcomes is unclear. The aims of the study were to determine the impact of ARGs in cirrhosis-related gut metagenome on outcomes and disease progression, study the effect of rifaximin on ARG burden, and compare ARGs in cirrhosis with chronic kidney disease (CKD) and diabetes., Methods: In outpatients with cirrhosis who underwent metagenomics, we evaluated change in ARG abundances with progression and their multivariable impact on 90-day hospitalizations and deaths over 1 year. We also studied ARGs pre- and 8 weeks post-rifaximin in patients with compensated cirrhosis in an open-label trial. Finally, ARGs from CKD and diabetes studies were compared with cirrhosis on machine learning., Results: A total of 163 patients with cirrhosis (43 compensated, 20 ascites-only, 30 HE-only, 70 both) and 40 controls were included. ARG abundances were higher in cirrhosis versus controls and worsened with advancing cirrhosis severity; 44 patients were hospitalized and 14 died. ARG abundances were associated with hospitalizations and mortality while controlling for cirrhosis complications, medications, and demographics. Rifaximin trial: ARG abundance patterns were minimally affected in 19 patients post-rifaximin. CKD/diabetes comparison: ARG abundance patterns in cirrhosis are distinguishable on machine learning and include more gram-positive ARGs., Conclusions: Cirrhosis is associated with high gut microbial ARG gene burden compared with controls, which worsens with disease progression and may be different from CKD and diabetes. ARGs are not affected by rifaximin and are associated with hospitalizations and death., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Altered bacterial composition is associated with disease progression in cirrhosis but the role of virome, especially phages, is unclear., Design: Cross-sectional and pre/post rifaximin cohorts were enrolled. Cross-sectional: controls and cirrhotic outpatients (compensated, on lactulose (Cirr-L), on rifaximin (Cirr-LR)) were included and followed for 90-day hospitalisations. Pre/post: compensated cirrhotics underwent stool collection pre/post 8 weeks of rifaximin. Stool metagenomics for bacteria and phages and their correlation networks were analysed in controls versus cirrhosis, within cirrhotics, hospitalised/not and pre/post rifaximin., Results: Cross-sectional: 40 controls and 163 cirrhotics (63 compensated, 43 Cirr-L, 57 Cirr-LR) were enrolled. Cirr-L/LR groups were similar on model for end-stage liver disease (MELD) score but Cirr-L developed greater hospitalisations versus Cirr-LR (56% vs 30%, p=0.008). Bacterial alpha/beta diversity worsened from controls through Cirr-LR. While phage alpha diversity was similar, beta diversity was different between groups. Autochthonous bacteria linked negatively, pathobionts linked positively with MELD but only modest phage-MELD correlations were seen. Phage-bacterial correlation network complexity was highest in controls, lowest in Cirr-L and increased in Cirr-LR. Microviridae and Faecalibacterium phages were linked with autochthonous bacteria in Cirr-LR, but not Cirr-L hospitalised patients had greater pathobionts, lower commensal bacteria and phages focused on Streptococcus, Lactococcus and Myoviridae. Pre/post: No changes in alpha/beta diversity of phages or bacteria were seen postrifaximin. Phage-bacterial linkages centred around urease-producing Streptococcus species collapsed postrifaximin., Conclusion: Unlike bacteria, faecal phages are sparsely linked with cirrhosis characteristics and 90-day outcomes. Phage and bacterial linkages centred on urease-producing, ammonia-generating Streptococcus species were affected by disease progression and rifaximin therapy and were altered in patients who experienced 90-day hospitalisations., Competing Interests: Competing interests: DK, EH, TSR and TW are employees of Diversigen, where the metagnomic and virome analysis was performed., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Background & Aims: Altered gut microbiota is associated with poor outcomes in cirrhosis, including infections and hepatic encephalopathy (HE). However, the role of bacterial virulence factors (VFs) is unclear. Aim: Define association of VFs with cirrhosis severity and infections, their linkage with outcomes, and impact of fecal microbiota transplant (FMT)., Methods: VF abundances were determined using metagenomic analysis in stools from controls and cirrhosis patients (compensated, HE-only, ascites-only, both and infected). Patients were followed for 90-day hospitalizations and 1-year death. Stool samples collected before/after a placebo-controlled FMT trial were also analyzed. Bacterial species and VFs for all species and selected pathogens ( Escherichia, Klebsiella, Pseudomonas, Staphylococcus, Streptococcus , and Enterococcus spp) were compared between groups. Multi-variable analyses were performed for clinical biomarkers and VFs for outcome prediction. Changes in VFs pre/post-FMT and post-FMT/placebo were analyzed. Results : We included 233 subjects (40 controls, 43 compensated, 30 HE-only, 20 ascites-only, 70 both, and 30 infected). Decompensated patients, especially those with infections, had higher VFs coding for siderophores, biofilms, and adhesion factors versus the rest. Biofilm and adhesion VFs from Enterobacteriaceae and Enterococcus spp associated with death and hospitalizations independent of clinical factors regardless of when all VFs or selected pathogens were analyzed. FMT was associated with reduced VF post-FMT versus pre-FMT and post-placebo groups., Conclusions: Virulence factors from multiple species focused on adhesion and biofilms increased with decompensation and infections, associated with death and hospitalizations independent of clinical factors, and were attenuated with FMT. Strategies focused on targeting multiple virulence factors could potentially impact outcomes in cirrhosis., Presentations: Portions of this manuscript were an oral presentation in the virtual International Liver Congress 2021., Abbreviations: VF: virulence factors, HE: hepatic encephalopathy, FMT: Fecal microbiota transplant, PPI: proton pump inhibitors, LPS: lipopolysaccharides, VFDB: Virulence factor database, OTU: operational taxonomic units, SBP: spontaneous bacterial peritonitis, UTI: urinary tract infections, MRSA: methicillin resistant Staphylococcus aureus, VRE: vancomycin-resistant Enterococcus, MAAsLin2: Microbiome Multivariable Associations with Linear Models, LPS: lipopolysaccharides, AKI: acute kidney injury.

Background & Aims: Altered microbiota can affect the gut-liver-brain axis in cirrhosis and hepatic encephalopathy (HE), but the impact of sex on these changes is unclear. We aimed to determine differences in fecal microbiota composition/functionality between men and women with cirrhosis and HE on differing treatments., Methods: Cross-sectional stool microbiome composition (16s rRNA sequencing) and microbial functional analyses were performed in men and women with cirrhosis, and controls. Patients with HE on rifaximin+lactulose (HE-Rif), patients with HE on lactulose only (HE-Lac) and those with cirrhosis without HE (No-HE) were compared to controls using random forest classifier. Men and women were also compared., Results: A total of 761 individuals were included, 619 with cirrhosis (466 men, 153 women) and 142 controls (92 men, 50 women). Men were older and more frequently used proton pump inhibitors (PPIs), but model for end-stage liver disease score, No-HE (n = 319), HE-lac (n = 130) and HE-Rif (n = 170) proportions were similar. PPI/age-adjusted AUC of differentiation between controls vs. all cirrhosis, and controls vs. No-HE were higher within women than men, but the adjusted AUC for No-HE vs. HE-Rif was higher in men. Control vs. HE-Rif differentiation was similar across sexes. Men vs. women were different in all cirrhosis, No-HE and HE-Lac but not HE-Rif on PERMANOVA and AUC analyses. Autochthonous taxa decreased and pathobionts increased with disease progression regardless of sex. In men, Lactobacillaceae were higher in HE-Lac but decreased in HE-Rif, along with Veillonellaceae. Pathways related to glutamate and aromatic compound degradation were higher in men at all stages. Degradation of androstenedione, an estrogenic precursor, was lower in men vs. women in HE-Rif, likely enhancing feminization., Conclusions: There are differences in gut microbial function and composition between men and women with cirrhosis, which could be implicated in differential responses to HE therapies. Further studies linking these differences to sex-specific outcomes are needed., Lay Summary: Patients with cirrhosis develop changes in their brain function, and men often develop feminization with disease progression. However, the interaction between sex, microbiota and disease severity is unclear. We found that as disease progressed in men, their microbial composition began to approach that observed in women, with changes in specific microbes that are associated with male hormone metabolism., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Antibiotic resistance leads to poor outcomes in cirrhosis. Fecal microbiota transplant (FMT) is associated with reduction in antibiotic resistance gene (ARG) burden in patients without cirrhosis; however, the impact in cirrhosis is unclear. We aimed to study the effect of capsule and enema FMT on ARG abundance in fecal samples, which were collected during two published FMT trials in patients with cirrhosis on rifaximin, lactulose, and proton pump inhibitors. ARGs were identified using metagenomics and mapped against the Comprehensive Antibiotic Resistance Database. Changes in ARG abundance were studied within/between groups. The capsule FMT trial involved a one-time FMT or placebo capsule administration with stool collection at baseline and week 4 postintervention. Antibiotics+enema FMT included preprocedure antibiotics followed by FMT enema versus standard-of-care (SOC). Stool was collected at baseline, postantibiotics, and day 7/15 postintervention. Both trials included 20 patients each. There was no safety/infection signal linked to FMT. In the capsule trial, beta-lactamase (OXY/LEN) expression decreased post-FMT versus baseline. Compared to placebo, patients who were post-FMT had lower abundance of vancomycin (VanH), beta-lactamase (ACT), and rifamycin ARGs; the latter was associated with cognitive improvement. No changes were seen within patients treated with placebo. In the antibiotics+enema trial for postantibiotics at day 7 versus baseline, there was an increase in vancomycin and beta-lactamase ARGs, which decreased at day 15. However, quinolone resistance increased at day 15 versus baseline. Between SOC and FMT, day 7 had largely lower ARG (CfxA beta-lactamase, VanW, and VanX) that continued at day 15 (cepA beta-lactamase, VanW). No changes were seen within the SOC group. Conclusion: Despite differences in routes of administration and preintervention antibiotics, we found that ARG abundance is largely reduced after FMT compared to pre-FMT baseline and non-FMT groups in decompensated cirrhosis., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

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.

Background & Aims: Patients with cirrhosis have intestinal dysbiosis and are prone to itching and skin or soft-tissue infections. The skin microbiome, and its relationship with intestinal microbiome, have not been characterized. We investigated alterations in skin microbiota of patients with cirrhosis and their association with intestinal microbiota and modulators of itch., Methods: We collected skin swabs at 7 sites and blood and stool samples from 20 healthy individuals (control subjects; mean age, 59 years) and 50 patients with cirrhosis (mean age, 61 years; mean model for end-stage disease score, 12; 20 with decompensation). Skin and stool samples were analyzed by 16s rRNA sequencing and serum samples were analyzed by liquid chromatography and mass spectrometry for levels of bile acids (BAs) and by an ELISA for autotaxin (an itch modulator). Participants were analyzed by the visual analog itch scale (VAS, 0-10,10 = maximum intensity). Data were compared between groups (cirrhosis vs control subjects, with vs without decompensation, VAS 5 or higher vs less than 5). Correlation networks between serum levels of BAs and skin microbiomes were compared between patients with cirrhosis with vs without itching., Results: The composition of microbiomes at all skin sites differed between control subjects and patients with cirrhosis and between patients with compensated vs decompensated cirrhosis. Skin microbiomes of patients with cirrhosis (especially those with decompensation) contained a higher relative abundance of Gammaproteobacteria, Streptococaceae, and Staphylococcaceae, and fecal microbiomes contained a higher relative abundance of Gammaproteobacteria, than control subjects. These bacterial taxa were associated with serum levels of autotaxin and BAs, which were higher in patients with VAS scores ≥5. Based on network statistics, microbial and BA interactions at all sites were more complex in patients with greater levels of itching in the shin, the most common site of itch., Conclusions: We identified alterations in skin microbiome of patients with cirrhosis (in Gammaproteobacteria, Streptococcaceae, and Staphylococcaceae)-especially in patients with decompensation; fecal microbiomes of patients with cirrhosis had a higher relative abundance of Gammaproteobacteria than control subjects. These specific microbial taxa are associated with itching intensity and itch modulators, such as serum levels of BAs and autotaxin., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Cirrhosis can alter several metabolic pathways. Metabolomics could prognosticate outcomes like hepatic encephalopathy (HE), transplant, hospitalization and death., Aim: Determine changes in serum and urine metabolomics in cirrhotics who develop outcomes., Methods: Cirrhotic outpatients underwent data, serum/urine collection and were followed for 90 days. Demographics, cirrhosis details and medications were collected. Metabolomics was performed on urine/serum using GC/MS with subsequent bioinformatics analyses (ChemRICH, MetaMAPP and PLS-DA). Logistic regression adjusting for covariates (demographics, alcohol etiology, prior HE, PPI, SBP prophylaxis, rifaximin/lactulose) were performed and ROC curves comparing MELD to adjusted serum & urine metabolites were created., Results: 211 patients gave serum, of which 64 were hospitalized, 19 developed HE, 13 were transplanted and 11 died. 164 patients gave urine of which 56 were hospitalized, 18 developed HE, 12 were transplanted and 11 died. Metabolomics: Saturated fatty acids, amino acids and bioenergetics-related metabolites differentiated patients with/without outcomes. After regression, 232, 228, 284 and 229 serum metabolites were significant for hospitalization, HE, death and transplant. In urine 290, 284, 227 & 285 metabolites were significant for hospitalization, HE, death and transplant respectively. AUC was higher for serum metabolites vs MELD for HE (0.85 vs.0.76), death (0.99 vs.0.88), transplant (0.975 vs.0.94) and hospitalizations (0.84 vs.0.83). Similarly, urinary metabolite AUC was also higher than MELD for HE (0.87 vs.0.72), death (0.92 vs 0.86), transplant (0.99 vs.0.90) and hospitalizations (0.89 vs.0.84)., Conclusions: In this exploratory study, serum and metabolites focused on lipid, bioenergetics and amino acid metabolism are altered in cirrhotics who develop negative outcomes., Competing Interests: The authors have declared that no competing interests exist.

Patients with cirrhosis are often exposed to antibiotics that can lead to resistance and fungal overgrowth. The role of fecal microbial transplant (FMT) in restoring gut microbial function is unclear in cirrhosis. In a Food and Drug Administration-monitored phase 1 clinical safety trial, patients with decompensated cirrhosis on standard therapies (lactulose and rifaximin) were randomized to standard-of-care (SOC, no antibiotics/FMT) or 5 days of broad-spectrum antibiotics followed by FMT from a donor enriched in Lachnospiraceae and Ruminococcaceae. Microbial composition (diversity, family-level relative abundances), function (fecal bile acid [BA] deconjugation, 7α-dehydroxylation, short-chain fatty acids [SCFAs]), and correlations between Lachnospiraceae, Ruminococcaceae, and clinical variables were analyzed at baseline, postantibiotics, and 15 days post-FMT. FMT was well tolerated. Postantibiotics, there was a reduced microbial diversity and autochthonous taxa relative abundance. This was associated with an altered fecal SCFA and BA profile. Correlation linkage changes from beneficial at baseline to negative after antibiotics. All of these parameters became statistically similar post-FMT to baseline levels. No changes were seen in the SOC group., Conclusion: In patients with advanced cirrhosis on lactulose and rifaximin, FMT restored antibiotic-associated disruption in microbial diversity and function. (Hepatology 2018; 00:000-000)., (© 2018 by the American Association for the Study of Liver Diseases.)

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.

Background: Cirrhosis is associated with gut microbial changes, but current 16S rDNA techniques sequence both dead and live bacteria. We aimed to determine the rRNA content compared with DNA from the same stool sample to evaluate cirrhosis progression and predict hospitalizations., Methods: Cirrhotics and controls provided stool for RNA and DNA analysis. Comparisons were made between cirrhotics/controls and within cirrhosis (compensated/decompensated, infected/uninfected, renal dysfunction/not, rifaximin use/not) with respect to DNA and RNA bacterial content using linear discriminant analysis. A separate group was treated with omeprazole for 14 days with longitudinal microbiota evaluation. Patients were followed for 90 days for hospitalizations. Multivariable models for hospitalizations with clinical data with and without DNA and RNA microbial data were created., Results: Twenty-six controls and 154 cirrhotics (54 infected, 62 decompensated, 20 renal dysfunction, 18 rifaximin) were included. RNA and DNA analysis showed differing potentially pathogenic taxa but similar autochthonous taxa composition. Thirty subjects underwent the omeprazole study, which demonstrated differences between RNA and DNA changes. Thirty-six patients were hospitalized within 90 days. In the RNA model, MELD score and Enterococcus were independently predictive of hospitalizations, while in the DNA model MELD was predictive and Roseburia protective. In both models, adding microbiota significantly added to the MELD score in predicting hospitalizations., Conclusion: DNA and RNA analysis of the same stool sample demonstrated differing microbiota composition, which independently predicts the hospitalization risk in cirrhosis. RNA and DNA content of gut microbiota in cirrhosis are modulated differentially with disease severity, infections, and omeprazole use., Trial Registration: NCT01458990., Funding: VA Merit I0CX001076.

Background: In veterans, post-traumatic stress disorder (PTSD) is often associated with substance abuse, which in turn can lead to cirrhosis. Cirrhotic patients are prone to cognitive impairment, which is typically due to covert hepatic encephalopathy (CHE), but can also be affected by PTSD. The aim was to define the impact of PTSD on cognitive performance and the diagnosis of CHE in cirrhotic patients., Methods: Outpatient veterans with cirrhosis underwent two separate modalities for CHE cognitive testing [Psychometric Hepatic Encephalopathy Scale (PHES) and Inhibitory Control Test (ICT)]. ICT tests for inhibitory control and response inhibition, while PHES tests for attention and psychomotor speed. Comparisons were made between patients with/without PTSD. Multivariable logistic regression with CHE on PHES and CHE on ICT as dependent variables including prior OHE, demographics, PTSD and psychotropic medications was performed., Results: Of 402 patients with cirrhosis, 88 had evidence of PTSD. Fifty-five of these were on psychoactive medications, 15 were undergoing psychotherapy, while no specific PTSD-related therapy was found in 28 patients. Cirrhotic patients with/without PTSD were statistically similar on demographics and cirrhosis severity, but cirrhotic subjects with PTSD had a higher frequency of alcoholic cirrhosis etiology and psychotropic drug use. PTSD cirrhosis had higher ICT lure and switching errors (NCT-B response), but on regression, there was no significant impact of PTSD on CHE diagnosis using either the ICT or PHES., Conclusions: Veterans with cirrhosis and PTSD have a higher frequency of psychotropic drug use and alcoholic cirrhosis etiology. CHE diagnosis using PHES or ICT is not affected by concomitant PTSD.

Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients with cirrhosis, but the effect of LT on microbial composition, especially with poor post-LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score [PHES]), health-related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre-/post-LT data were compared with age-matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End-Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre-LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907-914 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: Patient-Reported Outcomes Measurement Information System (PROMIS) tools can identify health-related quality of life (HRQOL) domains that could differentially affect disease progression. Cirrhotics are highly prone to hospitalizations and re-hospitalizations, but the current clinical prognostic models may be insufficient, and thus studying the contribution of individual HRQOL domains could improve prognostication., Aim: Analyze the impact of individual HRQOL PROMIS domains in predicting time to all non-elective hospitalizations and re-hospitalizations in cirrhosis., Methods: Outpatient cirrhotics were administered PROMIS computerized tools. The first non-elective hospitalization and subsequent re-hospitalizations after enrollment were recorded. Individual PROMIS domains significantly contributing toward these outcomes were generated using principal component analysis. Factor analysis revealed three major PROMIS domain groups: daily function (fatigue, physical function, social roles/activities and sleep issues), mood (anxiety, anger, and depression), and pain (pain behavior/impact) accounted for 77% of the variability. Cox proportional hazards regression modeling was used for these groups to evaluate time to first hospitalization and re-hospitalization., Results: A total of 286 patients [57 years, MELD 13, 67% men, 40% hepatic encephalopathy (HE)] were enrolled. Patients were followed at 6-month (mth) intervals for a median of 38 mths (IQR 22-47), during which 31% were hospitalized [median IQR mths 12.5 (3-27)] and 12% were re-hospitalized [10.5 mths (3-28)]. Time to first hospitalization was predicted by HE, HR 1.5 (CI 1.01-2.5, p = 0.04) and daily function PROMIS group HR 1.4 (CI 1.1-1.8, p = 0.01), independently. In contrast, the pain PROMIS group were predictive of the time to re-hospitalization HR 1.6 (CI 1.1-2.3, p = 0.03) as was HE, HR 2.1 (CI 1.1-4.3, p = 0.03)., Conclusions: Daily function and pain HRQOL domain groups using PROMIS tools independently predict hospitalizations and re-hospitalizations in cirrhotic patients.

The functional basis of cognitive and quality of life changes after liver transplant is unclear. We aimed to evaluate the neurometabolic and functional brain changes as modulators of cognition and quality of life after transplant in patients with cirrhosis who were with/without pretransplant cognitive impairment and hepatic encephalopathy (HE). Patients with cirrhosis underwent detailed cognitive and quality of life assessment at enrollment and 6 months after transplant. A subset underwent brain magnetic resonance imaging (functional magnetic resonance imaging [fMRI], diffusion tensor imaging [DTI], and magnetic resonance spectroscopy [MRS]) before and after transplant. Changes before and after transplant were analyzed in all patients and by dividing groups in those with/without pretransplant cognitive impairment or with/without pretransplant HE. MRS evaluated ammonia-related metabolites; fMRI studied brain activation for correct lure inhibition on the inhibitory control test; and DTI studied white matter integrity. Sixty-six patients (mean Model for End-Stage Liver Disease score, 21.8; 38 HE patients and 24 cognitively impaired [CI] patients) were enrolled. Quality of life was significantly worse in CI and HE groups before transplant, which improved to a lesser extent in those with prior cognitive impairment. In the entire group after transplant, there was (1) significantly lower brain activation needed for lure inhibition (shown on fMRI); (2) reversal of pretransplant ammonia-associated changes (shown on MRS); and (3) improved white matter integrity (shown on DTI). Importantly, study findings suggest that pretransplant cognitive impairment serves as a marker for clinical outcomes. Regardless of pretransplant history of HE, it was the pretransplant cognitive impairment that was predictive of both posttransplant cognitive and psychosocial outcomes. Therefore, when working with patients and their families, a clinician may rely on the pretransplant cognitive profile to develop expectations regarding posttransplant neurobehavioral recovery. We conclude that functional brain changes after liver transplant depend on pretransplant cognitive impairment and are ultimately linked with posttransplant cognition and quality of life in cirrhosis. Liver Transplantation 22 1379-1390 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Health-related quality of life (HRQOL) is an important determinant of prognosis in cirrhosis and hepatic encephalopathy (HE). However due to inherent cognitive dysfunction, insight into HRQOL severity in patients with liver disease may be impaired. To assess insight into HRQOL using PROMIS tools compared to norms in cirrhotic patients. PROMIS tools are validated HRQOL instruments that test the domains of anger, anxiety, depression, physical function, pain behavior/impact, sleep disturbances/impairment, and social activities/roles, compared to US-norms. Patients were administered the PROMIS tools, the results of which were reviewed using a visual comparison with thed norms. Then two Likert scales from 0 to 10 per domain were administered that inquired about (1) Surprise Intensity: 0-4: not surprised, 5-10: surprised; and (2) Expectancies: 0-4: results better than expected, 5:10: as/worse than expected. Comparisons between HE/no-HE were also performed. 203 cirrhotic patients (57 yrs., 62 % men, MELD 12, 83 HE) were included. All HE patients were controlled on therapy. Prior HE patients were significantly impaired on all PROMIS domains (p < 0.01) except anger, compared to the re st. The majority (76-85 %) were not surprised with their placement vis-à-vis the norms. Similarly, a majority (59-61 %) thought their results were worse or as expected. However, a third of patients found that their PROMIS results were better than expected. Prior HE status did not significantly impact expectations or surprise based on placement with the norms. The majority of cirrhotic patients, regardless of prior HE, have good insight regarding their HRQOL issues.

Background & Aims: Minimal hepatic encephalopathy (MHE) has been linked to higher real-life rates of automobile crashes and poor performance in driving simulation studies, but the link between driving simulator performance and real-life automobile crashes has not been clearly established. Furthermore, not all patients with MHE are unsafe drivers, but it is unclear how to distinguish them from unsafe drivers. We investigated the link between performance on driving simulators and real-life automobile accidents and traffic violations. We also aimed to identify features of unsafe drivers with cirrhosis and evaluated changes in simulated driving skills and MHE status after 1 year., Methods: We performed a study of outpatients with cirrhosis (n = 205; median 55 years old; median model for end-stage liver disease score, 9.5; none with overt hepatic encephalopathy or alcohol or illicit drug use within previous 6 months) seen at the Virginia Commonwealth University and McGuire Veterans Administration Medical Center, from November 2008 through April 2014. All participants were given paper-pencil tests to diagnose MHE (98 had MHE; 48%), and 163 patients completed a standardized driving simulation. Data were collected on traffic violations and automobile accidents from the Virginia Department of Motor Vehicles and from participants' self-assessments when they entered the study, and from 73 participants 1 year later. Participants also completed a questionnaire about alcohol use and cessation patterns. The driving simulator measured crashes, run-time, road center and edge excursions, and illegal turns during navigation; before and after each driving simulation session, patients were asked to rate their overall driving skills. Drivers were classified as safe or unsafe based on crashes and violations reported on official driving records; simulation results were compared with real-life driving records. Multivariable regression analyses of real-life crashes and violations was performed using data on demographics, cirrhosis details, MHE status, and alcohol cessation patterns, at baseline and at 1 year., Results: Drivers categorized as unsafe had more crashes and made more illegal turns on the driving simulator than drivers categorized as safe; a higher proportion of subjects with MHE were categorized as unsafe drivers at baseline (16%) than subjects without MHE (7%; P = .02), and at 1-year follow-up (18% vs 0%; P = .02). Alcohol cessation within <1 year and illegal turns during simulator navigation tasks were associated with real-life automobile crashes and MHE in regression analysis; road edge excursions in the simulator were associated with real-life traffic violations. Personal assessment of driving skills improved after each simulation episode., Conclusions: In a study of 205 patients with cirrhosis, we associated results from driving simulation tests with real-life driving records and MHE. Traffic safety counseling should focus on patients with cirrhosis who recently quit consuming alcohol and perform poorly on driving simulation., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Detection of covert hepatic encephalopathy (CHE) is difficult, but point-of-care testing could increase rates of diagnosis. We aimed to validate the ability of the smartphone app EncephalApp, a streamlined version of Stroop App, to detect CHE. We evaluated face validity, test-retest reliability, and external validity., Methods: Patients with cirrhosis (n = 167; 38% with overt HE [OHE]; mean age, 55 years; mean Model for End-Stage Liver Disease score, 12) and controls (n = 114) were each given a paper and pencil cognitive battery (standard) along with EncephalApp. EncephalApp has Off and On states; results measured were OffTime, OnTime, OffTime+OnTime, and number of runs required to complete 5 off and on runs. Thirty-six patients with cirrhosis underwent driving simulation tests, and EncephalApp results were correlated with results. Test-retest reliability was analyzed in a subgroup of patients. The test was performed before and after transjugular intrahepatic portosystemic shunt placement, and before and after correction for hyponatremia, to determine external validity., Results: All patients with cirrhosis performed worse on paper and pencil and EncephalApp tests than controls. Patients with cirrhosis and OHE performed worse than those without OHE. Age-dependent EncephalApp cutoffs (younger or older than 45 years) were set. An OffTime+OnTime value of >190 seconds identified all patients with CHE with an area under the receiver operator characteristic value of 0.91; the area under the receiver operator characteristic value was 0.88 for diagnosis of CHE in those without OHE. EncephalApp times correlated with crashes and illegal turns in driving simulation tests. Test-retest reliability was high (intraclass coefficient, 0.83) among 30 patients retested 1-3 months apart. OffTime+OnTime increased significantly (206 vs 255 seconds, P = .007) among 10 patients retested 33 ± 7 days after transjugular intrahepatic portosystemic shunt placement. OffTime+OnTime decreased significantly (242 vs 225 seconds, P = .03) in 7 patients tested before and after correction for hyponatremia (126 ± 3 to 132 ± 4 meq/L, P = .01) 10 ± 5 days apart., Conclusions: A smartphone app called EncephalApp has good face validity, test-retest reliability, and external validity for the diagnosis of CHE., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Poor brain reserve in alcoholic cirrhosis could worsen insight regarding disease severity and increase the patients' vulnerability toward further deterioration. The aim of this study was to analyze brain reserve in abstinent alcoholic cirrhotic (Alc) patients compared to nonalcoholic cirrhotic (Nalc) patients in the context of hepatic encephalopathy (HE) and to evaluate relative change in brain reserve between groups over time and before and after elective transjugular intrahepatic portosystemic shunt (TIPS) placement. The cross-sectional study included 46 Alc and 102 Nalc outpatients with or without HE. Cognitive tests were followed by magnetic resonance imaging (MRI), including proton magnetic resonance spectroscopy (1 H-MRS), diffusion tensor imaging, and T1-weighted imaging. The prospective study included 1H-MRS on a subset of 10 patients before and after TIPS placement. Another subset of 26 patients underwent (1) H-MRS at least 1 year apart. For the cross-sectional study, Alc patients were worse on cognitive tests than Nalc patients. MRI results suggest a greater effect of hyperammonemia, brain edema, and significantly higher cortical damage in Alc as compared to Nalc patients. The effect of HE status on cognitive tests and brain reserve was more marked in the Nalc than in the Alc group. For the TIPS study, Nalc patients showed a greater adverse relative change after TIPS compared to the Alc group. At 1-year follow-up, both groups remained stable between the 2 visits. However, Alc patients continued to show poor brain reserve compared to Nalc patients over time. In conclusion, Alc patients, despite abstinence, have a poor brain reserve, whereas Nalc patients have a greater potential for brain reserve deterioration after HE and TIPS. Information regarding the brain reserve in cirrhosis could assist medical teams to refine their communication and monitoring strategies for different etiologies., (© 2015 American Association for the Study of Liver Diseases.)

Background & Aims: Covert hepatic encephalopathy (CHE) is associated with cognitive dysfunction, which affects daily function and health-related quality of life (HRQOL) in patients with cirrhosis. The effects of CHE and liver disease are determined by cognitive reserve—the ability of the brain to cope with increasing damage while continuing to function—and are assessed by composite intelligence quotient (IQ) scores. We examined cognitive reserve as a determinant of HRQOL in patients with cirrhosis., Methods: We performed a prospective study of 118 outpatients with cirrhosis without overt HE (age, 56 y). We studied cognition using the standard paper-pencil battery; patients with below-normal results for more than 2 tests were considered to have CHE. We also assessed HRQOL (using the sickness impact profile [SIP]), psychosocial and physical scores (a high score indicates reduced HRQOL), model for end-stage liver disease (MELD) scores, and cognitive reserve (using the Barona Index, a validated IQ analysis, based on age, race, education, residence area, and occupation). Cognitive reserve was divided into average and high groups (<109 or >109), and MELD and SIP scores were compared. We performed regression analyses, using total SIP score and psychosocial and physical dimensions as outcomes, with cognitive reserve, CHE, and MELD score as predictors., Results: Study participants had average MELD scores of 9, and 14 years of education; 81% were white, 63% were urban residents, their mean IQ was 108 ± 8, and 54% had average cognitive reserve (the remaining 46% had high reserves). CHE was diagnosed in 49% of patients. Cognitive reserve was lower in patients with CHE (109) than without (105; P = .02). Cognitive reserve correlated with total SIP and psychosocial score (both r = -0.4; P < .001) and physical score (r = -0.3; P = .01), but not MELD score (P = .8). Patients with high cognitive reserve had a better HRQOL, despite similar MELD scores. In regression analyses, cognitive reserve was a significant predictor of total SIP (P < .001), psychosocial (P < .001), and physical scores (P < .03), independent of CHE, MELD, or psychiatric disorders., Conclusions: A higher cognitive reserve is associated with a better HRQOL in patients with cirrhosis, despite similar disease severity and prevalence. This indicates that patients with good cognitive reserve are better able to withstand the demands of cirrhosis progression and CHE, leading to a better HRQOL. Patients with lower cognitive reserve may need more dedicated and earlier measures to improve HRQOL. Cognitive reserve should be considered when interpreting HRQOL and cognitive tests to evaluate patients with cirrhosis., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: In patients with cirrhosis, sleep disturbances are assumed to result from hepatic encephalopathy (HE). The effects of obstructive sleep apnea (OSA) on cognition, sleep parameters, or driving in patients with cirrhosis are unclear., Methods: We performed a cross-sectional and prospective study of 118 subjects. Subjects were assigned to 1 of 4 groups: those with OSA and cirrhosis (without hepatic encephalopathy or ascites, n = 34), those with cirrhosis only (n = 30), those with OSA only (n = 29), and those without OSA or cirrhosis (controls, n = 25). None of the OSA patients were receiving continuous positive airway pressure (CPAP) therapy. Subjects underwent cognitive testing (paper-pencil tests for psychomotor speed and attention, as well as executive function tests), sleep assessment (daytime sleepiness and night-time sleep quality), and a monotonous driving simulation (worsening lane deviations over time indicated poor performance). We also tested patients with OSA, with cirrhosis (n = 10) and without cirrhosis (n = 7), before and after CPAP therapy., Results: Daytime sleepiness and sleep quality were worse in subjects in the OSA groups (with or without cirrhosis) than subjects with cirrhosis alone or controls. Of subjects with only OSA, 36% had impaired psychomotor speed and attention, compared with more than 60% of subjects in both cirrhosis groups. In contrast, executive function was uniformly worse in subjects with OSA, with or without cirrhosis, than groups without OSA. Simulator performance (lane deviations) worsened over time in both OSA groups. CPAP therapy significantly increased executive function and sleep quality, and reduced simulator lane deviations and sleepiness, in OSA subjects with and without cirrhosis. After CPAP therapy, performance on the paper-pencil test improved significantly only in subjects with OSA without cirrhosis., Conclusions: OSA should be considered in evaluating sleep impairment in patients with cirrhosis. In patients with cirrhosis and OSA, psychomotor speed and attention issues likely are related to cirrhosis, whereas executive function and simulator performance are affected by OSA. CPAP therapy improves executive function and simulator performance in patients with OSA, regardless of cirrhosis., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Minimal hepatic encephalopathy (MHE) impairs daily functioning in cirrhosis, but its functional brain impact is not completely understood. To evaluate the effect of rifaximin, a gut-specific antibiotic, on the gut-liver-brain axis in MHE., Hypothesis: Rifaximin will reduce endotoxemia, enhance cognition, increase activation during working memory(N-back) and reduce activation needed for inhibitory control tasks., Methods: Cirrhotics with MHE underwent baseline endotoxin and cognitive testing, then underwent fMRI, diffusion tensor imaging and MR spectroscopy(MRS). On fMRI, two tasks; N-back (outcome: correct responses) and inhibitory control tests(outcomes: lure inhibition) were performed. All procedures were repeated after 8 weeks of rifaximin. RESULTS were compared before/after rifaximin., Results: 20 MHE patients (59.7 years) were included; sixteen completed pre/post-rifaximin scanning with 92% medication compliance. Pre-rifaximin patients had cognitive impairment. At trial-end, there was a significantly higher correct 2-back responses, ICT lure inhibitions and reduced endotoxemia(p = 0.002). This was accompanied by significantly higher activation from baseline in subcortical structures (thalamus, caudate, insula and hippocampus) and left parietal operculum (LPO) during N-back, decrease in fronto-parietal activation required for inhibiting lures, including LPO during ICT compared to baseline values. Connectivity studies in N-back showed significant shifts in linkages after therapy in fronto-parietal regions with a reduction in fractional anisotropy (FA) but not mean diffusivity (MD), and no change in MRS metabolites at the end of the trial. A significant improvement in cognition including working memory and inhibitory control, and fractional anisotropy without effect on MD or MRS, through modulation of fronto-parietal and subcortical activation and connectivity was seen after open-label rifaximin therapy in MHE.

Objectives: Despite the high prevalence of covert hepatic encephalopathy (CHE) in cirrhotics without previous overt HE (OHE), its independent impact on predicting clinically relevant outcomes is unclear. The aim of this study was to define the impact of CHE on time to OHE, hospitalization, and death/transplant in prospectively followed up patients without previous OHE., Methods: Outpatient cirrhotics without OHE were enrolled and were administered a standard paper-pencil cognitive battery for CHE diagnosis. They were systematically followed up and time to first OHE development, hospitalization (liver-related/unrelated), and transplant/death were compared between CHE and no-CHE patients at baseline using Cox regression., Results: A total of 170 cirrhotic patients (55 years, 58% men, 14 years of education, Model for End-Stage Liver Disease (MELD 9), 53% hepatitis C virus (HCV), 20% nonalcoholic etiology) were included, of whom 56% had CHE. The entire population was followed up for 13.0 ± 14.6 months, during which time 30% developed their first OHE episode, 42% were hospitalized, and 19% had a composite death/transplant outcome. Age, gender, etiology, the MELD score, and CHE status were included in Cox regression models for time to first OHE episode, hospitalization, death, and composite death/transplant outcomes. On Cox regression, despite controlling for MELD, those with CHE had a higher risk of developing OHE (hazard ratio: 2.1, 95% confidence interval 1.01-4.5), hospitalization (hazard ratio: 2.5, 95% confidence interval 1.4-4.5), and death/transplant (hazard ratio: 3.4, 95% confidence interval 1.2-9.7) in the follow-up period., Conclusions: Covert HE is associated with worsened survival and increased risk of hospitalization and OHE development, despite controlling for the MELD score. Strategies to detect and treat CHE may improve these risks.

Background & Aims: Covert hepatic encephalopathy (CHE) impairs quality of life (QOL) and can be difficult to diagnose. Patient-administered methods that do not require specialized tests or equipment might increase rates of detection. We performed a longitudinal study to determine whether demographic data and responses to a validated QOL questionnaire, the Sickness Impact Profile (SIP), can identify patients with CHE., Methods: Patients with cirrhosis without prior overt HE were recruited from outpatient liver clinics at the Virginia Commonwealth University Medical Center, from August 2008 through February 2012. We performed cognitive tests on 170 patients (mean age, 55 y; mean model for end-stage liver disease score, 9; 50% with hepatitis C-associated and 11% with alcohol-associated cirrhosis). Patients also were given the SIP questionnaire (136 questions on 12 QOL topics, requiring a yes or no answer) at enrollment, at 6 months, and at 12 months. The proportion of patients that responded "yes" to each question was compared between those with and without CHE. Patient variables (noncognitive), demographics (age, education, sex, alcoholic etiology), and SIP questions that produced different responses between groups were analyzed by logistic regression and receiver operating characteristic analyses., Results: Based on cognitive test results, 93 patients (55%) had CHE when the study began. They had a higher proportion of "yes" responses to 54 questions on the SIP questionnaire, across all categories. We developed a formula to identify patients with CHE based on age, sex, and responses to 4 SIP questions (a SIP CHE score). Baseline SIP CHE scores greater than 0 identified patients with CHE with 80% sensitivity and 79% specificity. Of the 98 patients who returned for the 6-month evaluation, 50% had CHE (the SIP CHE identified these patients with 88% sensitivity). Of the 50 patients who returned for the 12-month evaluation, 32% had CHE (the SIP CHE score identified these patients with 81% sensitivity)., Conclusions: We developed a system to identify patients with CHE based on age, sex, and responses to 4 SIP questions; this formula identified patients with CHE with more than 80% sensitivity over a 12-month period after the initial enrollment. Patient-administered CHE screening strategies that do not include specialized tests could increase the detection of CHE and improve therapy., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The histologic hallmarks of chronic HCV include inflammation and fibrosis. The impact of interferon therapy on liver histology was evaluated., Material and Methods: The study population consisted of 348 patients with chronic HCV who underwent a baseline liver biopsy, received either no treatment or a single course of interferon based therapy, were followed for 5 years without any treatment or additional treatment and then underwent a repeat liver biopsy. The patients were divided into 3 groups; deferred treatment (NoTx = 47), received interferon based therapy but failed to achieve SVR (NoSVR = 189) and achieved SVR (SVR = 112)., Results: Patients with NoTx and NoSVR had significant increases in mean inflammation scores (from 4.3 to 6.3 and 5.4 to 6.7 respectively; p < 0.001 for both) and fibrosis scores (from 0.9 to 1.8 and 1.9 to 2.5; p < 0.001 for both). The amounts by which inflammation, fibrosis and rate of fibrosis progression increased were not significantly different between the two groups. Increases in total inflammation and the piecemeal necrosis sub-score over time were strongly associated with fibrosis progression. Patients with SVR had a significant decline in mean inflammation and fibrosis scores (from 6.7 to 2.2 and 3.3 to 1.8; p < 0.001 for both); 40% of patients resolved all fibrosis and 50% of patients resolved cirrhosis., Conclusion: Increases in inflammation are associated with fibrosis progression and in the absence of SVR interferon treatment does not appear to affect the long term natural history of this process. Patients with SVR have resolution of inflammation and fibrosis and many resolve cirrhosis.

Alcohol abuse with/without cirrhosis is associated with an impaired gut barrier and inflammation. Gut microbiota can transform primary bile acids (BA) to secondary BAs, which can adversely impact the gut barrier. The purpose of this study was to define the effect of active alcohol intake on fecal BA levels and ileal and colonic inflammation in cirrhosis. Five age-matched groups {two noncirrhotic (control and drinkers) and three cirrhotic [nondrinkers/nonalcoholics (NAlc), abstinent alcoholic for >3 mo (AbsAlc), currently drinking (CurrAlc)]} were included. Fecal and serum BA analysis, serum endotoxin, and stool microbiota using pyrosequencing were performed. A subgroup of controls, NAlc, and CurrAlc underwent ileal and sigmoid colonic biopsies on which mRNA expression of TNF-α, IL-1β, IL-6, and cyclooxygenase-2 (Cox-2) were performed. One hundred three patients (19 healthy, 6 noncirrhotic drinkers, 10 CurrAlc, 38 AbsAlc, and 30 NAlc, age 56 yr, median MELD: 10.5) were included. Five each of healthy, CurrAlc, and NAlc underwent ileal/colonic biopsies. Endotoxin, serum-conjugated DCA and stool total BAs, and secondary-to-primary BA ratios were highest in current drinkers. On biopsies, a significantly higher mRNA expression of TNF-α, IL-1β, IL-6, and Cox-2 in colon but not ileum was seen in CurrAlc compared with NAlc and controls. Active alcohol use in cirrhosis is associated with a significant increase in the secondary BA formation compared with abstinent alcoholic cirrhotics and nonalcoholic cirrhotics. This increase in secondary BAs is associated with a significant increase in expression of inflammatory cytokines in colonic mucosa but not ileal mucosa, which may contribute to alcohol-induced gut barrier injury., (Copyright © 2014 the American Physiological Society.)

Background & Aims: Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality of life (HRQOL) and cognition in cirrhosis. We aimed at studying the effect of hyponatremia on cognition, HRQOL, and brain MR spectroscopy (MRS) independent of HE., Methods: Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium <130 mEq/L), HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psychosocial and physical sub-scores) and brain MRS (myoinositol (mI) and glutamate+glutamine (Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal., Results: 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN, and 10 HN, MELD 12, 63% hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN: 3, HN: 3.5, HE: 6.5, HE+HN: 7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP (p<0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE, HE+HN, and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psychosocial SIP scores., Conclusions: Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression., Methods: Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC-MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin., Results: Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p<0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r=0.57, p<0.008) while Ruminococcaceae were positively correlated with DCA (r=0.4, p<0.05). A positive correlation between Ruminococcaceae and DCA/CA (r=0.82, p<0.012) and Blautia with LCA/CDCA (r=0.61, p<0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios., Conclusions: Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE., Methods: Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin., Results: There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar., Conclusions: Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance., Trial Registration: ClinicalTrials.gov NCT01069133.

Background & Aims: Asymmetric dimethylarginine (ADMA) is an inhibitor of nitric oxide synthase that accumulates in liver disease and may contribute to hepatic encephalopathy (HE). We aimed at evaluating the association of ADMA with cognition and brain MR spectroscopy (MRS) in cirrhosis., Methods: Cirrhotic patients with/without prior HE and non-cirrhotic controls underwent cognitive testing and ADMA determination. A subgroup underwent brain MRS [glutamine/glutamate (Glx), myoinositol (mI), N-acetyl-aspartate (NAA) in parietal white, occipital gray, and anterior cingulated (ACC)]. Cognition and ADMA in a cirrhotic subgroup before and one month after transjugular intrahepatic portosystemic shunting (TIPS) were also tested. Cognition and MRS values were correlated with ADMA and compared between groups using multivariable regression. ADMA levels were compared between those who did/did not develop post-TIPS HE., Results: Ninety cirrhotics (MELD 13, 54 prior HE) and 16 controls were included. Controls had better cognition and lower ADMA, Glx, and higher mI compared to cirrhotics. Prior HE patients had worse cognition, higher ADMA and Glx and lower mI compared to non-HE cirrhotics. ADMA was positively correlated with MELD (r=0.58, p<0.0001), abnormal cognitive test number (r=0.66, p<0.0001), and Glx and NAAA (white matter, ACC) and negatively with mI. On regression, ADMA predicted number of abnormal tests and mean Z-score independent of prior HE and MELD. Twelve patients underwent TIPS; 7 developed HE post-TIPS. ADMA increased post-TIPS in patients who developed HE (p=0.019) but not in others (p=0.89)., Conclusions: A strong association of ADMA with cognition and prior HE was found independent of the MELD score in cirrhosis., (Published by Elsevier B.V.)

Psychiatric disorders and medications may affect the cognitive performance of patients with cirrhosis and complicate the diagnosis and prediction of hepatic encephalopathy (HE). The aim of this study was to study the association of psychoactive medications with cognitive performance and their effects on the ability of tests to predict HE development in patients with cirrhosis referred for transplant evaluation. Cirrhosis details, psychiatric disorders, psychoactive medications, and any history of prior HE were recorded for patients with cirrhosis at 2 transplant centers. Patients were followed until the development of HE. Five cognitive tests--number connection test A (NCT-A), number connection test B, the digit symbol test (DST), the block design test, and the inhibitory control test (ICT)--were administered. A high lure score and a low ICT target score indicated poor performance. The cognitive performances of patients with psychiatric disorders/medications and patients without them were compared. A proportional hazards model was created with the time to HE as the outcome, and it was based on demographics, psychoactive medications, cirrhosis details, and individual cognitive scores. Patients with prior HE and patients without prior HE were then studied separately. One hundred fifty-five patients with a mean age of 57.5 ± 6.2 years and a mean Model for End-Stage Liver Disease (MELD) score of 15.1 ± 6.2 were included [prior HE, 48%; diabetes, 34%; selective serotonin reuptake inhibitors (SSRIs), 32%; opioids, 19%; and antipsychotics, 10%]. Prior HE and antipsychotics (but not opioids or diabetes) were associated with worse cognition. SSRI users had better NCT-A and DST performance. One hundred forty-eight patients were followed for a median of 182.5 days; 58 developed HE at a median of 99 days after inclusion. In the entire group, the model showed that prior HE (hazard ratio = 4.13), the MELD score (hazard ratio = 1.07), and a high lure score (hazard ratio = 1.04) decreased the time to HE, whereas the use of SSRIs (hazard ratio = 0.42), a high target score (hazard ratio = 0.95), and a high sodium level (hazard ratio = 0.89) increased the time to HE. For patients without prior HE, the MELD score (hazard ratio = 1.25) and lures (hazard ratio = 1.09) predicted the time to HE. Lures (hazard ratio = 1.03), targets (hazard ratio = 0.96), and sodium (hazard ratio = 0.87) were associated with the time to HE in patients with prior HE. In conclusion, cognitive tests (particularly the ICT) remain valid predictors of HE in the face of psychiatric diseases and medications. SSRI use is associated with better cognitive performance and a reduced likelihood of developing HE., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Minimal hepatic encephalopathy (MHE) is associated with poor driving skills and insight. Increasing insight may improve receptiveness for therapy or driving restrictions., Aim: To evaluate the change in the self-assessment of driving skills (SADS) using a driving simulator., Methods: Cirrhotic patients and age/education-matched controls underwent MHE testing with inhibitory control (ICT) and the psychometric hepatic encephalopathy score (PHES). SADS, a Likert scale from 0 to 10, was administered just before and after a standardized driving simulation comprising testing and navigation tasks. The percentage SADS change from baseline was compared within/between groups., Results: A total of 84 patients (60% men, age 55 years) and 12 controls were included. Controls were significantly better than cirrhotics on cognitive/simulator testing. The baseline SADS was similar between the groups. The baseline patient SADS was only correlated with ICT lures (r = -0.4, P = 0.001). Post-simulation, 60% of patients improved their insight, i.e., reduced SADS (from 8 to 6.5, P = 0.0001) compared to 25% of controls (P = 0.02). The mean percentage SADS reduction was also higher in cirrhotics (18% vs. 8%, P = 0.03). MHE on ICT patients had a significantly higher SADS improvement (P = 0.004) compared to the other patients; no difference was seen in those with/without MHE due to the PHES. The percentage SADS reduction in patients was correlated with getting lost (r = 0.468, P < 0.0001), crashes (P = 0.002), and centerline/road-edge excursions (P = 0.01). There was a significantly higher percentage SADS reduction in cirrhotics who got lost (25%) compared to those who did not get lost (12%) and controls (8%, P = 0.014)., Conclusions: Insight into driving skills in cirrhosis improves after driving simulation and is highest in those with navigation errors and MHE on ICT. Driving simulator-associated insight improvement may be the first step towards the cognitive rehabilitation of driving skills in cirrhosis.

Objectives: Cirrhosis and hepatic encephalopathy (HE) can adversely affect survival, but their effect on socioeconomic and emotional burden on the family is not clear. The aim was to study the emotional and socioeconomic burden of cirrhosis and HE on patients and informal caregivers., Methods: A cross-sectional study in two transplant centers (Veterans and University) of cirrhotic patients and their informal caregivers was performed. Demographics for patient/caregivers, model-for-end-stage liver disease (MELD) score, and cirrhosis complications were recorded. Patients underwent a cognitive battery, sociodemographic, and financial questionnaires. Caregivers were given the perceived caregiver burden (PCB; maximum=155) and Zarit Burden Interview (ZBI)-Short Form (maximum=48) and questionnaires for depression, anxiety, and social support., Results: A total of 104 cirrhotics (70% men, 44% previous HE, median MELD 12, 49% veterans) and their caregivers (66% women, 77% married, relationship duration 32±14 years) were included. Cirrhosis severely impacted the family unit with respect to work (only 56% employed), finances, and adherence. Those with previous HE had worse unemployment (87.5 vs. 19%, P=0.0001) and financial status (85 vs. 61%, P=0.019) and posed a higher caregiver burden; PCB (75 vs. 65, P=0.019) and ZBI (16 vs. 11, P=0.015) compared with others. Cognitive performance and MELD score were significantly correlated with employment and caregiver burden. Veterans and non-veterans were equally affected. On regression, depression score, MELD, and cognitive tests predicted both PCB and ZBI score., Conclusions: Previous HE and cognitive dysfunction are associated with worse employment, financial status, and caregiver burden. Cirrhosis-related expenses impact the family unit's daily functioning and medical adherence. A multidisciplinary approach to address this burden is required.

Background & Aims: Fibrosis progression might be accelerated in patients who are coinfected with human immunodeficiency virus (HIV) and HCV (HIV/HCV). However, no studies have directly compared fibrosis progression by paired liver biopsy between patients infected with HIV and HCV versus those infected with only HCV., Methods: Liver biopsy samples were collected from patients with HIV/HCV (n = 306) and those with HCV; biopsies from 59 without a sustained virologic response (SVR) or cirrhosis were matched with those from patients with only HCV (controls) for initial fibrosis stage, demographics, and HCV treatment. For HIV/HCV patients, categorical variables at baseline and the area under the curve of continuous variables per unit time were analyzed for associations with fibrosis progression., Results: Liver biopsies from HIV/HCV patients had more piecemeal necrosis than controls (P = .001) and increased lobular inflammation (P = .002); HIV/HCV patients also had shorter intervals between liver biopsies (4.7 vs 5.9 years, P < .0001). Between the first and second biopsies, fibrosis remained unchanged or progressed 1 or 2 units in 55%, 18%, and 18% of HIV/HCV patients, respectively, compared with 45%, 30%, and 9% of controls. The fibrosis progression rate was similar between HIV/HCV and control patients (0.12 ± 0.40 vs 0.091 ± 0.29 units/y; P = .72). In paired biopsies from 66 patients, including those with SVR, there were no associations between fibrosis progression and demographics; numbers of CD4+ T cells; levels of aspartate aminotransferase or alanine aminotransferase; use of highly active antiretroviral therapy; response to HCV therapy (no treatment, SVR, or non-response); baseline levels of FIB-4; or histologic features including inflammation, fibrosis, or steatosis., Conclusions: On the basis of analysis of liver biopsy samples, fibrosis progression was similar between HIV/HCV-infected and HCV-infected patients; no clinical or laboratory parameters predicted disease progression., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)