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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 & 14.7% had falls. Abnormal and normal TG patients had similar ages, BMI, sex, education level & 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.

Posttraumatic stress disorder (PTSD) is associated with cirrhosis in veterans, and therapeutic results are suboptimal. An altered gut-liver-brain axis exists in cirrhosis due to hepatic encephalopathy (HE), but the added impact of PTSD is unclear. The aim of this study was to define linkages between gut microbiota and cognition in cirrhosis with/without PTSD. Cirrhotic veterans (with/without prior HE) underwent cognitive testing [PHES, inhibitory control test (ICT), and block design test (BDT)], serum lipopolysaccharide-binding protein (LBP) and stool collection for 16S rRNA microbiota composition, and predicted function analysis (PiCRUST). PTSD was diagnosed using DSM-V criteria. Correlation networks between microbiota and cognition were created. Patients with/without PTSD and with/without HE were compared. Ninety-three combat-exposed male veterans [ (58 yr, MELD 11, 34% HE, 31% combat-PTSD (42 no-HE/PTSD, 19 PTSD-only, 22 HE-only, 10 PTSD+HE)] were included. PTSD patients had similar demographics, alcohol history, MELD, but worse ICT/BDT, and higher antidepressant use and LBP levels. Microbial diversity was lower in PTSD (2.1 ± 0.5 vs. 2.5 ± 0.5, P = 0.03) but unaffected by alcohol/antidepressant use. PTSD ( P = 0.02) and MELD ( P < 0.001) predicted diversity on regression. PTSD patients showed higher pathobionts ( Enterococcus and Escherichia/Shigella) and lower autochthonous genera belonging to Lachnospiraceaeae and Ruminococcaceae regardless of HE. Enterococcus was correlated with poor cognition, while the opposite was true for autochthonous taxa regardless of PTSD/HE. Escherichia/Shigella was only linked with poor cognition in PTSD patients. Gut-brain axis-associated microbiota functionality was altered in PTSD. In male cirrhotic veterans, combat-related PTSD is associated with cognitive impairment, lower microbial diversity, higher pathobionts, and lower autochthonous taxa composition and altered gut-brain axis functionality compared with non-PTSD combat-exposed patients. Cognition was differentially linked to gut microbiota, which could represent a new therapeutic target. NEW & NOTEWORTHY Posttraumatic stress disorder (PTSD) in veterans with cirrhosis was associated with poor cognitive performance. This was associated with lower gut microbial diversity in PTSD with higher pathobionts belonging to Enterococcus and Escherichia/Shigella and lower beneficial taxa belonging to Lachnospiraceaeae and Ruminococcaceae, with functional alterations despite accounting for prior hepatic encephalopathy, psychoactive drug use, or model for end-stage liver disease score. Given the suboptimal response to current therapies for PTSD, targeting the gut microbiota could benefit the altered gut-brain axis in these patients.

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.

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) affects cognition in a multidimensional fashion. Current guidelines recommend performing Psychometric Hepatic Encephalopathy Score (PHES) and a second test to diagnose CHE for multi-center trials. We aimed to determine if a two-test combination strategy improved CHE diagnosis agreement, and accuracy to predict overt hepatic encephalopathy (OHE), compared to single testing. METHODS: Cirrhotic outpatients without baseline OHE performed PHES, Inhibitory Control Test (ICT), and Stroop EncephAlapp (StE) at three centers. Patients were followed for OHE development. Areas under the receiver operation characteristic curve (AUROC) were calculated. RESULTS: We included 437 patients (399 with follow-up data). CHE prevalence varied with testing strategy: PHES+ICT 18%, ICT+StE 25%, PHES+StE 29%, ICT 35%, PHES 37%, and StE 54%. Combination with best test agreement was PHES+StE (k=0.34). Sixty patients (15%) developed OHE. Although CHE by StE showed the highest sensitivity to predict OHE, PHES and PHES+StE were more accurate at the expense of a lower sensitivity (55%, AUROC: 0.587; 36%, AUROC: 0.629; and 29%, AUROC: 0.623; respectively). PHES+ICT was the most specific (85%) but all strategies including ICT showed sensitivities in the 33–45% range. CHE diagnosis by PHES (HR=1.79, p=0.04), StE (HR=1.69, p=0.04), and PHES+StE (HR=1.72, p=0.04), were significant OHE predictors even when adjusted for prior OHE and MELD. CONCLUSIONS: Our results demonstrate that combined testing decreases CHE prevalence without improving the accuracy of OHE prediction. Testing with PHES or StE alone, or a PHES+StE combination, is equivalent to diagnose CHE and predict OHE development in a multi-center setting.

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).

The relative ranking of cirrhosis-related deaths differs between high-/middle-income countries. Gut microbiome is affected in cirrhosis and is related to diet. Our aim was to determine the effect of differing dietary habits on gut microbiota and clinical outcomes. Outpatient compensated/decompensated patients with cirrhosis and controls from Turkey and the United States underwent dietary and stool microbiota analysis. Patients with cirrhosis were followed till 90-day hospitalizations. Shannon diversity and multivariable determinants (Cox and binary logistic) of microbial diversity and hospitalizations were studied within/between groups. Two hundred ninety-six subjects (157 U.S.: 48 controls, 59 compensated, 50 decompensated; 139 Turkey: 46 controls, 50 compensated, 43 decompensated) were included. Patients with cirrhosis between cohorts had similar Model for End-Stage Liver Disease (MELD) scores. American patients with cirrhosis had more men, greater rifaximin/lactulose use, and higher hepatitis C/alcohol etiologies. Coffee intake was higher in Americans whereas tea, fermented milk, and chocolate intake were higher in Turkey. The entire Turkish cohort had a significantly higher microbial diversity than Americans, which did not change between their controls and patients with cirrhosis. In contrast, microbial diversity changed in the U.S.-based cohort and was the lowest in decompensated patients. Coffee, tea, vegetable, chocolate, and fermented milk intake predicted a higher diversity whereas MELD score, lactulose use, and carbonated beverage use predicted a lower microbial diversity. The Turkish cohort had a lower risk of 90-day hospitalizations. On Cox and binary logistic regression, microbial diversity was protective against 90-day hospitalizations, along with coffee/tea, vegetable, and cereal intake. Conclusion In this study of patients with cirrhosis and healthy controls from the United States and Turkey, a diet rich in fermented milk, vegetables, cereals, coffee, and tea is associated with a higher microbial diversity. Microbial diversity was associated with an independently lower risk of 90-day hospitalizations. (Hepatology 2018;68:234-247).

Background Cirrhosis and alcohol can independently affect the gut–liver axis with systemic inflammation. However, their concurrent impact in humans is unclear. Methods Our aim was to determine the effect of continued alcohol misuse on the gut-liver axis in cirrhotic patients. Age- and MELD-balanced cirrhotic patients who were currently drinking (Alc) or abstinent (NAlc) and healthy controls underwent serum and stool collection. A subset underwent upper endoscopy and colonoscopy for biopsies and duodenal fluid collection. The groups were compared regarding (i) inflammation/intestinal barrier: systemic tumor necrosis factor levels, intestinal inflammatory cytokine (duodenum, ileum, sigmoid), and ileal antimicrobial peptide expression; (ii) microbiota composition: 16SrRNA sequencing of duodenal, ileal, and colonic mucosal and fecal microbiota; and (iii) microbial functionality: duodenal fluid and fecal bile acid (BA) profile (conjugation and dehydroxylation status), intestinal BA transporter (ASBT, FXR, FGF-19, SHP) expression, and stool metabolomics using gas chromatography/mass spectrometry. Results Alc patients demonstrated a significant duodenal, ileal, and colonic mucosal and fecal dysbiosis, compared to NAlc and controls with lower autochthonous bacterial taxa. BA profile skewed toward a potentially toxic profile (higher secondary and glycine-conjugated BAs) in duodenal fluid and stool in Alc patients. Duodenal fluid demonstrated conjugated secondary BAs only in the Alc group. There was a greater expression of all ileal BA transporters in Alc patients. This group also showed higher endotoxemia, systemic and ileal inflammatory expression, and lower amino acid and bioenergetic-associated metabolites, without change in antimicrobial peptide expression. Conclusions Despite cirrhosis, continued alcohol misuse predisposes patients to widespread dysbiosis with alterations in microbial functionality such as a toxic BA profile, which can lead to intestinal and systemic inflammation.

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.

BACKGROUND & AIMS: Liver transplantation is the only treatment that increases survival times of patients with decompensated cirrhosis. Patients who live further away from a transplant center are disadvantaged. Health care delivery via telehealth is an effective way to remotely manage patients with decompensated cirrhosis. We investigated the effects of telehealth on the liver transplant evaluation process. METHODS: We performed a retrospective study of 465 patients who underwent evaluation for liver transplantation at the Richmond Veterans Affairs Medical Center from 2005 through 2017. Of these, 232 patients were evaluated via telehealth, and 233 via in-person evaluation. Using regression models, we evaluated the differential effects of telehealth vs. usual care on placement on the liver transplant waitlist. We also investigated the effects of telehealth on time from referral to initial evaluation by a transplant hepatologist, liver transplantation, and mortality. RESULTS: Patients in the telehealth group were evaluated significantly faster than patients evaluated in person, without or with adjustment for potential confounders (21.7 days vs. 79.5 days; P

Minimal hepatic encephalopathy (MHE) is epidemic in cirrhosis, but testing strategies often have poor concordance. Altered gut/salivary microbiota occur in cirrhosis and could be related to MHE. Our aim was to determine microbial signatures of individual cognitive tests and define the role of microbiota in the diagnosis of MHE.Outpatients with cirrhosis underwent stool collection and MHE testing with psychometric hepatic encephalopathy score (PHES), inhibitory control test, and EncephalApp Stroop. A subset provided saliva samples. Minimal hepatic encephalopathy diagnosis/concordance between tests was compared. Stool/salivary microbiota were analyzed using 16srRNA sequencing. Microbial profiles were compared between patients with/without MHE on individual tests. Logistic regression was used to evaluate clinical and microbial predictors of MHE diagnosis.Two hundred forty-seven patients with cirrhosis (123 prior overt HE, MELD 13) underwent stool collection and PHES testing; 175 underwent inhibitory control test and 125 underwent Stroop testing. One hundred twelve patients also provided saliva samples. Depending on the modality, 59%-82% of patients had MHE. Intertest Kappa for MHE was 0.15-0.35. Stool and salivary microbiota profiles with MHE were different from those without MHE. Individual microbiota signatures were associated with MHE in specific modalities. However, the relative abundance of Lactobacillaceae in the stool and saliva samples was higher in MHE, regardless of the modality used, whereas autochthonous Lachnospiraceae were higher in those without MHE, especially on PHES. On logistic regression, stool and salivary Lachnospiraceae genera (Ruminococcus and Clostridium XIVb) were associated with good cognition independent of clinical variables.Specific stool and salivary microbial signatures exist for individual cognitive testing strategies in MHE. The presence of specific taxa associated with good cognitive function regardless of modality could potentially be used to circumvent MHE testing.

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.

SummaryBackground Eradication of hepatitis C virus (HCV) is increasing but its residual impact on the pro-inflammatory milieu in cirrhosis, which is associated with gut dysbiosis, is unclear. Aim To define the impact of sustained virological response (SVR) on gut dysbiosis and systemic inflammation in HCV cirrhosis patients. Methods Cirrhotic out-patients with HCV with/without SVR (achieved >1 year prior) and age-matched healthy controls underwent serum and stool collection. Serum was analysed for IL-6, TNF-α and endotoxin while stool microbiota analysis was performed using multitagged pyrosequencing. Microbial comparisons were made using UNIFRAC and cirrhosis dysbiosis ratio (lower score indicates dysbiosis). Comparisons were performed between cirrhotics with/without SVR and controls vs. cirrhotic patients. Results A total of 105 HCV cirrhotics and 45 age-matched healthy controls were enrolled. Twenty-one patients had achieved SVR using pegylated interferon + ribavrin a median of 15 months prior. No significant differences on demographics, cirrhosis severity, concomitant medications or diabetes were seen between cirrhotics with/without SVR. There was no significant difference in overall microbiota composition (UNIFRAC P = 0.3) overall or within specific microbial families (cirrhosis dysbiosis ratio median 1.3 vs. 1.0, P = 0.45) between groups with/without SVR. This also extended towards IL-6, TNF-α and endotoxin levels. Both cirrhosis groups, however, had significant dysbiosis compared to healthy controls [UNIFRAC P = 0.01, cirrhosis dysbiosis ratio (1.1 vs. 2.9, P < 0.001)] along with higher levels of endotoxin, IL-6 and TNF-α. Conclusions Gut dysbiosis and a pro-inflammatory systemic milieu, are found in HCV cirrhosis regardless of SVR. This persistent dysbiosis could contribute towards varying rates of improvement after HCV eradication in cirrhosis.

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.

Diagnosing minimal hepatic encephalopathy (MHE) is challenging, and point-of-care tests are needed. Stroop EncephalApp has been validated for MHE diagnosis in single-center studies. The objective of the study was to validate EncephalApp for MHE diagnosis in a multicenter study.Outpatient cirrhotics (with/without prior overt hepatic encephalopathy (OHE)) and controls from three sites (Virginia (VA), Ohio (OH), and Arkansas (AR)) underwent EncephalApp and two gold standards, psychometric hepatic encephalopathy score (PHES) and inhibitory control test (ICT). Age-/gender-/education-adjusted values for EncephalApp based on direct norms, and based on ICT and PHES, were defined. Patients were followed, and EncephalApp cutoff points were used to determine OHE prediction. These cutoff points were then used in a separate VA-based validation cohort.A total of 437 cirrhotics (230 VA, 107 OH, 100 AR, 36% OHE, model for end-stage liver disease (MELD) score 11) and 308 controls (103 VA, 100 OH, 105 AR) were included. Using adjusted variables, MHE was present using EncephalApp based on norms in 51%, EncephalApp based on PHES in 37% (sensitivity 80%), and EncephalApp based on ICT in 54% of patients (sensitivity 70%). There was modest/good agreement between sites on EncephalApp MHE diagnosis using the three methods. OHE developed in 13% of patients, which was predicted by EncephalApp independent of the MELD score. In the validation cohort of 121 VA cirrhotics, EncephalApp directly and based on gold standards remained consistent for MHE diagnosis with70% sensitivity.In this multicenter study, EncephalApp, using adjusted population norms or in the context of existing gold standard tests, had good sensitivity for MHE diagnosis and predictive capability for OHE development.

The burden of chronic liver disease has increased exponentially, driving more patients toward orthotopic liver transplant (OLT) evaluation.1 Because of limited access to transplant centers, patients often travel long distances to be evaluated for OLT.2 Liver transplantation in the VA system is offered at 6 Veterans Affairs transplant centers (VATCs) across the United States, including Richmond. To increase access to specialty care, the VA introduced the Specialty Care Access Network-Extension of Community Healthcare Outcomes (SCAN-ECHO) program,3,4 which was designed to transfer subspecialty knowledge to primary care physicians. In 2011, the Richmond VA introduced SCAN-ECHO for gastroenterology/hepatology providers to facilitate case-based distance learning combined with real-time consultation in hepatology, and the opportunity for an initial triage without completing a formal transplant evaluation. We studied the role of SCAN-ECHO in triaging OLT evaluations and the utility of this health care delivery in the field of transplantation.

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. 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-a-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. 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. 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.

Liver transplantation (LT) improves daily function and ameliorates gut microbial composition. However, the effect of LT on microbial functionality, which can be related to overall patient benefit, is unclear and could affect the post-LT course. The aims were to determine the effect of LT on gut microbial functionality focusing on endotoxemia, bile acid (BA), ammonia metabolism, and lipidomics. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Microbiota composition (Shannon diversity and individual taxa) and function analysis (serum endotoxin, urinary metabolomics and serum lipidomics, and stool BA profile) and cognitive tests were performed at both visits. We enrolled 40 patients (age, 56 ± 7 years; mean Model for End-Stage Liver Disease score, 22.6). They received LT 6 ± 3 months after enrollment and were re-evaluated 7 ± 3 months after LT with a stable course. A significant improvement in cognition with increase in microbial diversity, increase in autochthonous and decrease in potentially pathogenic taxa, and reduced endotoxemia were seen after LT compared with baseline. Stool BAs increased significantly after LT, and there was evidence of greater bacterial action (higher secondary, oxo and iso-BAs) after LT although the levels of conjugated BAs remained similar. There was a reduced serum ammonia and corresponding rise in urinary phenylacetylglutamine after LT. There was an increase in urinary trimethylamine-N-oxide, which was correlated with specific changes in serum lipids related to cell membrane products. The ultimate post-LT lipidomic profile appeared beneficial compared with the profile before LT. In conclusion, LT improves gut microbiota diversity and dysbiosis, which is accompanied by favorable changes in gut microbial functionality corresponding to BAs, ammonia, endotoxemia, lipidomic, and metabolomic profiles. Liver Transplantation 24 752-761 2018 AASLD.

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.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 or109), 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.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.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.

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.

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. 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. 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. 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.

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.

BackgroundCirrhosis can alter several metabolic pathways. Metabolomics could prognosticate outcomes like hepatic encephalopathy (HE), transplant, hospitalization and death.AimDetermine changes in serum and urine metabolomics in cirrhotics who develop outcomes.MethodsCirrhotic 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.Results211 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).ConclusionsIn this exploratory study, serum and metabolites focused on lipid, bioenergetics and amino acid metabolism are altered in cirrhotics who develop negative outcomes.

N 1,N 11-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC. Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible. DENSPM was given as a short intravenous infusion on days 1, 3, 5, 8, 10, and 12 of each 28-day cycle. The starting dose of 30 mg/m2 was escalated at a fixed increment of 15 mg/m2 until the MTD was identified. The plasma pharmacokinetics of DENSPM for the first and last doses given in cycle 1 was characterized. Thirty-eight patients (male 79 %; median age 61 years; Child-Pugh A 84 %; ≥1 prior systemic therapy 45 %) were enrolled and treated. The most common adverse events (AEs) ≥grade 1 were fatigue (53 %), nausea (34 %), diarrhea (32 %), vomiting (32 %), anemia (29 %), and elevated AST (29 %). The most common grade 3–4 AEs were fatigue/asthenia (13 %), elevated AST (13 %), hyperbilirubinemia (11 %), renal failure (8 %), and hyperglycemia (8 %). The MTD was 75 mg/m2. There were no objective responses, although 7/38 (18 %) patients achieved stable disease for ≥16 weeks. The overall mean (±SD) total body clearance for the initial dose, 66.3 ± 35.9 L/h/m2 (n = 16), was comparable to the clearance in patients with normal to near normal hepatic function. Drug levels in plasma decayed rapidly immediately after the infusion but remained above 10 nM for several days after dosing at the MTD. N 1,N 11-diethylnorspermine treatment at the MTD of 75 mg/m2, given intravenously every other weekday for two consecutive weeks of each 28-day cycle, was relatively well tolerated in patients with advanced HCC including those with mild-to-moderate liver dysfunction. This administration schedule provided prolonged systemic exposure to potentially effective concentrations of the drug. Stable disease was seen in 18 % of patients receiving DENSPM treatment. Further evaluation of DENSPM monotherapy for advanced HCC does not appear to be justified because of insufficient evidence of clinical benefit in the patients evaluated in this study.

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.Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium130 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.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 (p0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups (p0.02). 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.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.

We previously reported that alcohol drinkers with and without cirrhosis showed a significant increase in fecal bile acid secretion compared to nondrinkers. We hypothesized this may be due to activation by alcohol of hepatic cyclic adenosine monophosphate responsive element-binding protein 3-like protein 3 (CREBH), which induces cholesterol 7α-hydroxylase (Cyp7a1). Alternatively, the gut microbiota composition in the absence of alcohol might increase bile acid synthesis by up-regulating Cyp7a1. To test this hypothesis, we humanized germ-free (GF) mice with stool from healthy human subjects (Ctrl-Hum), human subjects with cirrhosis (Cirr-Hum), and human subjects with cirrhosis and active alcoholism (Alc-Hum). All animals were fed a normal chow diet, and none demonstrated cirrhosis. Both hepatic Cyp7a1 and sterol 12α-hydroxylase (Cyp8b1) messenger RNA (mRNA) levels were significantly induced in the Alc-Hum and Ctrl-Hum mice but not in the Cirr-Hum mice or GF mice. Liver bile acid concentration was correspondingly increased in the Alc-Hum mice despite fibroblast growth factor 15, fibroblast growth receptor 4, and small heterodimer partner mRNA levels being significantly induced in the large bowel and liver of the Ctrl-Hum mice and Alc-Hum mice but not in the Cirr-Hum mice or GF mice. This suggests that the normal pathways of Cyp7a1 repression were activated in the Alc-Hum mice and Ctrl-Hum mice. CREBH mRNA was significantly induced only in the Ctrl-Hum mice and Alc-Hum mice, possibly indicating that the gut microbiota up-regulate CREBH and induce bile acid synthesis genes. Analysis of stool bile acids showed that the microbiota of the Cirr-Hum and Alc-Hum mice had a greater ability to deconjugate and 7α-dehydroxylate primary bile acids compared to the microbiota of the Cirr-Hum mice. 16S ribosomal RNA gene sequencing of the gut microbiota showed that the relative abundance of taxa that 7-α dehydroxylate primary bile acids was higher in the Ctrl-Hum and Alc-Hum groups. Conclusion: The composition of gut microbiota influences the regulation of the rate-limiting enzymes in bile acid synthesis in the liver. (Hepatology Communications 2017;1:61-70).

ObjectiveCirrhotics have a high rate of infections, which are increasingly fungal or culture-negative in nature. While infected cirrhotics have bacterial dysbiosis, the role of fungi is unclear. We aimed to evaluate gut bacterial and fungal dysbiosis in cross-sectional and longitudinal analyses of outpatient and inpatient cirrhotics and prediction of hospitalisations.MethodsCross-sectional: Age-matched controls, outpatients (with/without antibiotics) and hospitalised uninfected, culture-negative and culture-positive cirrhotics were included and followed for 90 days. Longitudinal: Three studies were conducted: (1) cirrhotics followed over 6 months, (2) outpatient cirrhotics administered antibiotics per standard of care for 5 days and (3) cirrhotics and controls administered omeprazole over 14 days. In all studies, stool bacterial/fungal profiles were analysed.ResultsCross-sectional: In 143 cirrhotics and 26 controls, bacterial and fungal diversities were significantly linked. Outpatients on antibiotics and patients with culture-positive infections had the lowest diversities. Bacterial and fungal correlations were complex in uninfected, outpatient and control groups but were markedly skewed in infected patients. 21% were admitted on 90-day follow-up. A lower Bacteroidetes/Ascomycota ratio was associated with lower hospitalisations. Longitudinal: Fungal and bacterial profiles were stable on follow-up (5 days and 6 months). After antibiotics, a significantly reduced bacterial and fungal diversity, higher Candida and lower autochthonous bacterial relative abundance were seen. After omeprazole, changes in bacterial diversity and composition were seen but fungal metrics remained stable.ConclusionThere is a significant fungal dysbiosis in cirrhosis, which changes differentially with antibiotics and proton pump inhibitor use, but is otherwise stable over time. A combined bacterial–fungal dysbiosis metric, Bacteroidetes/Ascomycota ratio, can independently predict 90-day hospitalisations in patients with cirrhosis.Clinical trial numberNCT01458990.

Despite the associated adverse outcomes, pharmacologic intervention for covert hepatic encephalopathy (CHE) is not the standard of care. We hypothesized that a video game-based rehabilitation program would improve white matter integrity and brain connectivity in the visuospatial network on brain magnetic resonance imaging (MRI), resulting in improved cognitive function in CHE subjects on measures consistent with the cognitive skill set emphasized by the two video games (e.g., IQ Boost-visual working memory, and Aim and Fire Challenge-psychomotor speed), but also generalize to thinking skills beyond the focus of the cognitive training (Hopkins verbal learning test (HVLT)-verbal learning/memory) and improve their health-related quality of life (HRQOL). The trial included three phases over 8 weeks; during the learning phase (cognitive tests administered twice over 2 weeks without intervening intervention), training phase (daily video game training for 4 weeks), and post-training phase (testing 2 weeks after the video game training ended). Thirty CHE patients completed all visits with significant daily achievement on the video games. In a subset of 13 subjects that underwent brain MRI, there was a significant decrease in fractional anisotropy, and increased radial diffusivity (suggesting axonal sprouting or increased cross-fiber formation) involving similar brain regions (i.e., corpus callosum, internal capsule, and sections of the corticospinal tract) and improvement in the visuospatial resting-state connectivity corresponding to the video game training domains. No significant corresponding improvement in HRQOL or HVLT performance was noted, but cognitive performance did transiently improve on cognitive tests similar to the video games during training. Although multimodal brain imaging changes suggest reductions in tract edema and improved neural network connectivity, this trial of video game brain training did not improve the HRQOL or produce lasting improvement in cognitive function in patients with CHE.

Patients with advanced liver disease have a high prevalence of cardiovascular risk factors, but many of them are asymptomatic. Cardiovascular risk stratification prior to liver transplant can be done by dobutamine stress echocardiography, stress myocardial perfusion imaging, cardiac computer tomography, and coronary angiography, but there are no clear recommendations regarding what method should be used and who should be screened. Because of this and because of inherent risk profile in this population, the variations in practice are significant. Careful screening and rigorous management of cardiovascular risk factors are important to ensure optimal cardiovascular outcomes in the immediate post-transplantation period and in the long term as well.

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

Cholelithiasis (gallstones) is common, with an estimated prevalence of *12 % of adult population in the USA. The prevalence, increasing with age, approaches 33 % in elderly women [1]. Approximately 15 % of patients with cholelithiasis have concurrent choledocholithiasis (bile duct stones), and conversely, 95 % of patients with choledocholithiasis have cholelithiasis [2, 3]. Although the natural history of asymptomatic common bile duct (CBD) stones is not well defined, they are thought to be less benign than asymptomatic gallbladder gallstones. Although CBD stones may pass uneventfully through the ampulla of Vater into the duodenum, their passage can induce acute pancreatitis and stone impaction at the distal bile duct, causing biliary colic and cholangitis. Because adverse events may be serious and life-threatening, it is generally recommended that CBD stones be removed.

Although hepatic encephalopathy (HE) is linked to the gut microbiota, stool microbiome analysis has not found differences between HE and no-HE patients. This study aimed to compare sigmoid mucosal microbiome of cirrhotic patients to controls, between HE vs. no-HE patients, and to study their linkage with cognition and inflammation. Sixty cirrhotic patients (36 HE and 24 no-HE) underwent cognitive testing, stool collection, cytokine (Th1, Th2, Th17, and innate immunity), and endotoxin analysis. Thirty-six patients (19 HE and 17 no-HE) and 17 age-matched controls underwent sigmoid biopsies. Multitag pyrosequencing (including autochthonous genera, i.e., Blautia, Roseburia, Fecalibacterium, Dorea) was performed on stool and mucosa. Stool and mucosal microbiome differences within/between groups and correlation network analyses were performed. Controls had significantly higher autochthonous and lower pathogenic genera compared with cirrhotic patients, especially HE patients. HE patients had worse MELD (model for end-stage liver disease) score and cognition and higher IL-6 and endotoxin than no-HE. Mucosal microbiota was different from stool within both HE/no-HE groups. Between HE/no-HE patients, there was no difference in stool microbiota but mucosal microbiome was different with lower Roseburia and higher Enterococcus, Veillonella, Megasphaera, and Burkholderia abundance in HE. On network analysis, autochthonous genera ( Blautia, Fecalibacterium, Roseburia, and Dorea) were associated with good cognition and decreased inflammation in both HE/no-HE, whereas genera overrepresented in HE ( Enterococcus, Megasphaera, and Burkholderia) were linked to poor cognition and inflammation. Sigmoid mucosal microbiome differs significantly from stool microbiome in cirrhosis. Cirrhotic, especially HE, patients' mucosal microbiota is significantly different from controls with a lack of potentially beneficial autochthonous and overgrowth of potentially pathogenic genera, which are associated with poor cognition and inflammation.

Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 µg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 µg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 µg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.

"INTRODUCTION: Hyponatremia complicates cirrhosis and predicts short term mortality, including adverse outcomes before and after liver transplantation. MATERIAL AND METHODS: From April 1, 2008, through April 2, 2010, all adult candidates for primary liver transplantation with cirrhosis, listed in Region 11 with hyponatremia, were eligible for sodium (Na) exception. RESULTS: Patients with serum sodium (SNa) less than 130 mg/dL, measured two weeks apart and within 30 days of Model for End Stage Liver Disease (MELD) exception request, were given preapproved Na exception. MELD Na was calculated [MELD + 1.59 (135-SNa/30 days)]. MELD Na was capped at 22, and subject to standard adult recertification schedule. On data end of follow-up, December 28, 2010, 15,285 potential U.S. liver recipients met the inclusion criteria of true MELD between 6 and 22. In Region 11, 1,198 of total eligible liver recipients were listed. Sixty-two (5.2%) patients were eligible for Na exception (MELD Na); 823 patients (68.7%) were listed with standard MELD (SMELD); and 313 patients (26.1%) received HCC MELD exception. Ninety percent of MELD Na patients and 97% of HCC MELD patients were transplanted at end of follow up, compared to 49% of Region 11 standard MELD and 40% of U.S.A. standard MELD (USA MELD) patients (p < 0.001); with comparable dropout rates (6.5, 1.6, 6.9, 9% respectively; p = 0.2). MELD Na, HCC MELD, Region 11 SMELD, and USA MELD post-transplant six-month actual patient survivals were similar (92.9, 92.8, 92.2, and 93.9 %, respectively). CONCLUSION: The Region 11 MELD Na exception prospective trial improved hyponatremic cirrhotic patient access to transplant equitably, and without compromising transplant efficacy."

Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We aimed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach. Multitag pyrosequencing (MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. Patients with HE were compared with those without HE using a correlation-network analysis. A select group of patients with HE ( n = 7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days. Twenty-five patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 without HE, age 56 ± 6 yr, model for end-stage liver disease score 16 ± 6] and ten controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae , Alcaligeneceae , and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae ) compared with controls. We found altered flora (higher Veillonellaceae ), poor cognition, endotoxemia, and inflammation (IL-6, TNF-α, IL-2, and IL-13) in HE compared with cirrhotics without HE. In the cirrhosis group, Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment. Fusobacteriaceae , Veillonellaceae , and Enterobacteriaceae were positively and Ruminococcaceae negatively related to inflammation. Network-analysis comparison showed robust correlations (all P < 1E-5) only in the HE group between the microbiome, cognition, and IL-23, IL-2, and IL-13. Lactulose withdrawal did not change the microbiome significantly beyond Fecalibacterium reduction. We concluded that cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared with healthy individuals. Specific bacterial families ( Alcaligeneceae , Porphyromonadaceae , Enterobacteriaceae ) are strongly associated with cognition and inflammation in HE.

Diabetes (DM) is prevalent in cirrhosis and may modulate the risk of hospitalization through gut dysbiosis. We aimed to define the role of gut microbiota on 90-day hospitalizations and of concomitant DM on microbiota. Cirrhotic outpatients with/without DM underwent stool and sigmoid mucosal microbial analysis and were followed for 90 days. Microbial composition was compared between those with/without DM and those who were hospitalized/not. Regression/ROC analyses for hospitalizations were performed using clinical and microbial features. 278 cirrhotics [39% hepatic encephalopathy (HE), 31%DM] underwent stool while 72 underwent mucosal analyses. Ultimately, 94 were hospitalized and they had higher MELD, proton pump inhibitor (PPI) use and HE without difference in DM. Stool/mucosal microbiota were significantly altered in those who were hospitalized (UNIFRAC pBacteroidaceae, Clostridiales XIV, Lachnospiraceae, Ruminococcacae and higher Enterococcaceae and Enterobacteriaceae were seen in hospitalized patients. Concomitant DM impacted microbiota UNIFRAC (stool, p = 0.003, mucosa,p = 0.04) with higher stool Bacteroidaceae and lower Ruminococcaeae. Stool Bacteroidaceaeae and Clostridiales XIV predicted 90-day hospitalizations independent of clinical predictors (MELD, HE, PPI). Stool and colonic mucosal microbiome are altered in cirrhotics who get hospitalized with independent prediction using stool Bacteroidaceae and Clostridiales XIV. Concomitant DM distinctly impacts gut microbiota without affecting hospitalizations.

SUMMARY Background Cirrhotic patients have an impaired health-related quality of life (HRQOL), which is usually analysed using static paper-pencil questionnaires. The Patient Reported Outcomes Measurement Information System (PROMIS) computerised adaptive testing (CAT) are flexible, freely available, noncopyrighted, HRQOL instruments with US-based norms across 11 domains. CAT presents five to seven questions ⁄ domain depending on the patient’s response, from large validated question banks. This provides brevity and precision equivalent to the entire question bank.