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PURPOSE OF REVIEW: The burden of malnutrition is high in patients with cirrhosis, especially in those with hepatic encephalopathy (HE). This has a bearing on increased morbidity and mortality. Heightened attention needs to be paid to screen the patients at high nutritional risk both in the outpatient and hospitalized settings. This review summarizes the current evidence for nutritional support in HE patients and compares the recommendations about nutritional requirement as laid out by various organizations. RECENT FINDINGS: On survey of the literature, there is a consensus on avoiding protein restriction of the diets in HE patients along with uniform recommendations on caloric requirements. An exciting field of manipulating the gut microbiome in nutritional sciences may hold promise as well as there may be a future role for branched chain amino acids in nutritional management of HE patients. SUMMARY: Even though the data suggest that nutritional improvement lead to better outcomes including lower readmission rates in cirrhosis, operationalizing these into practice remains a challenge. To achieve this, a multi-disciplinary approach with nutritional education of the frontline care providers, earlier nutritional risk screening of patients, involvement of the nutrition professionals as part of the team and repeated dietary counseling for the patient and caregiver/s is required. Ultimately, this may need more focus, resource allocation and uniform guidelines across all countries to make this a success.

Background & Aims Inpatients with cirrhosis have high rates of acute-on-chronic failure (ACLF) development and high mortality within 30 days of admission to the hospital. Better biomarkers are needed to predict these outcomes. We performed metabolomic analyses of serum samples from patients with cirrhosis at multiple centers to determine whether metabolite profiles might identify patients at high risk for ACLF and death. Methods We performed metabolomic analyses, using liquid chromatography, of serum samples collected at time of admission to 12 North American tertiary hepatology centers from 602 patients in the North American Consortium for the Study of End-Stage Liver Disease sites from 2015 through 2017 (mean age, 56 years; 61% men; mean model for end-stage liver disease score, 19.5). We performed analysis of covariance, adjusted for model for end-stage liver disease at time of hospital admission, serum levels of albumin and sodium, and white blood cell count, to identify metabolites that differed between patients who did vs did not develop ACLF and patients who did vs did not die during hospitalization and within 30 days. We performed random forest analysis to identify specific metabolite(s) that were associated with outcomes and area under the curve (AUC) analyses to analyze them in context of clinical parameters. We analyzed microbiomes of stool samples collected from 133 patients collected at the same time and examined associations with serum metabolites. Results Of the 602 patients analyzed, 88 developed ACLF (15%), 43 died in the hospital (7%), and 72 died within 30 days (12%). Increased levels of compounds of microbial origin (aromatic compounds, secondary or sulfated bile acids, and benzoate) and estrogen metabolites, as well as decreased levels of phospholipids, were associated with development of ACLF, inpatient, and 30-day mortality and were also associated with fecal microbiomes. Random forest analysis and logistic regression showed that levels of specific microbially produced metabolites identified patients who developed ACLF with an AUC of 0.84 (95% confidence interval [CI] 0.78–0.88; P = .001), patients who died while in the hospital with an AUC of 0.81 (95% CI 0.74–0.85; P = .002), and patients who died within 30 days with an AUC of 0.77 (95% CI 0.73–0.81; P = .02). The metabolites were significantly additive to clinical parameters for predicting these outcomes. Metabolites associated with outcomes were also correlated with microbiomes of stool samples. Conclusions In an analysis of serum metabolites and fecal microbiomes of patients hospitalized with cirrhosis at multiple centers, we associated metabolites of microbial origin and lipid moieties with development of ACLF and death as an inpatient or within 30 days, after controlling for clinical features.

Background Admissions in cirrhosis are expensive and often unpredictable based on purely clinical variables. Admissions could be related to complications associated with gut microbial changes, which can improve prognostication. However, the cost-effectiveness is unclear. Aims Determine cost-effectiveness of adding gut microbiota analysis to clinical parameters in prediction and subsequent reduction of admissions in cirrhosis. Methods Using a Markov model of 1000 cirrhosis patients over 90 days, we modeled microbiota testing using 16srRNA ($250/sample), low-depth ($350/sample) and high-depth ($650/sample) metagenomics added to standard-of-care (SOC) for prevention of admissions using standard outcome costs and rates of development. We generated quality of life years (QALY) and Incremental cost-effectiveness ratios (ICER) for the base scenarios and performed sensitivity analyses by varying costs for outcomes (transplant, death, admission) and admission rates (40%, range 25%-60%). Results Using fixed costs of outcomes and outcome rates, microbiota analysis was cost-saving ($47K-$97K) at $250 and $350/sample if admissions were reduced by 5%over SOC and >10% with $650/sample. When costs of LT, death and admissions were varied, these cost-savings remained robust provided there was >2.1% reduction (range 1.3%-3.2%) for $250/sample, >2.9% (range 1.8%-4.4%) for $350/sample and >5.4% (range 3.3%-8.2%) for $650/sample. These cost-savings remained robust even when the assumed admission rate was varied for all sample cost values. Conclusions Gut microbiota analysis is cost-effective for predicting and potentially preventing 90-day admissions in cirrhosis over current standard of care. This cost-saving remained robust even after sensitivity analyses that varied the background admission rates.

Cirrhosis is a leading cause of mortality worldwide, affecting people of various incomes and diets. It has been discovered in various studies by Bajaj et al. that a person’s diet can affect cirrhosis indirectly by altering their gut microbiota. In fact, an increase in pathogenic bacteria present in the gut is often associated with disease progression. One of the factors affecting gut microbiota composition is diet, which varies among countries and cultures. In this study, we compared the effect of various diets on the severity of cirrhosis in patients from the United States, Mexico, and Turkey. The study includes patients with decompensated cirrhosis, compensated cirrhosis, and controls with no liver disease within each country. The Turkish diet consists of more probiotics and tea while the US participants with western diet consumed less fermented foods and had more coffee and soda; the Mexican diet, when compared to the American, consisted of lower protein and vegetable intake. Stool samples were collected from all three cohorts, sequenced using Ion Torrent technology, and analyzed using LEfSe, QIIME2, and MaAsLin pipelines. These results show that there is a difference in the gut microbiota among the participants in the various countries, and that diet does affect the microbiome. Understanding how diet affects cirrhosis can impact how the condition is treated, and prevented., Journal of Student-Scientists' Research, Vol. 1 (2019)

International audience; Background & Aims: Dietary changes can modulate gut microbiota and interact with cirrhosis. Our prior study demonstrated that microbial diversity was higher in Turkish versus USA cirrhotics, which was associated with lower risk of 90-day hospitalizations. We aimed to define gut microbial functional and metabolomic changes to increase insight into benefits of the Mediterranean compared to Western diets.Methods: In all, 139 Turkish (46 controls/50 compensated/43 decompensated) and 157 American subjects (48 controls/59 compensated/50 decompensated) were studied. Turkish subjects consumed a modified Mediterranean diet with daily fermented milk intake, whereas Americans consumed a Western diet. Predicted gut microbial functionalities and plasma metabolomics were compared between/within countries. Correlation network differences between microbiota and metabolites in cirrhotics from Turkey vs the USA were evaluated.Results: Predicted microbial function showed lower amino acid, bioenergetics and lipid pathways, with functions related to vitamin B, glycan, xenobiotic metabolism, DNA/RNA synthesis, in cirrhotics from Turkey compared to the USA. Plasma metabolomics demonstrated higher relative lactate levels in Turkey vs the USA. The metabolite changes in decompensated cirrhosis, compared to controls, showed similar trends in Turkey and the USA, with reduced lipids and phosphocholines. Phosphocholines were significantly lower in patients hospitalized in 90 days (P = .03). Correlation networks in cirrhotics demonstrated linkage differences between beneficial taxa, Blautia and Oscillispira, and lactate and unsaturated lipids, in Turkey compared to American patients.Conclusions: A modified Mediterranean diet was associated with altered plasma metabolomics and beneficially alters microbiota functionality and correlations compared to Western diet in cirrhosis. These altered diet-microbial interactions could potentially affect the 90-day hospitalization risk.

Patients with cirrhosis are growing older, which could have an impact on brain dysfunction beyond hepatic encephalopathy. Our aim was to study the effect of concomitant aging and cirrhosis on brain inflammation and degeneration using human and animal experiments. For the human study, age‐matched patients with cirrhosis and controls between 65 and 85 years underwent cognitive testing, quality of life (QOL) assessment, and brain magnetic resonance (MR) spectroscopy and resting state functional MR imaging (rs‐fMRI) analysis. Data were compared between groups. For the animal study, young (10‐12 weeks) and old (1.5 years) C57BL/6 mice were given either CCl4 gavage to develop cirrhosis or a vehicle control and were followed for 12 weeks. Cortical messenger RNA (mRNA) expression of inflammatory mediators (interleukin [IL]‐6, IL‐1β, transforming growth factor β [TGF‐β], and monocyte chemoattractant protein 1), sirtuin‐1, and gamma‐aminobutyric acid (GABA)‐ergic synaptic plasticity (neuroligin‐2 [NLG2], discs large homolog 4 [DLG4], GABA receptor, subunit gamma 1/subunit B1 [GABRG1/B1]) were analyzed and compared between younger/older control and cirrhotic mice. The human study included 46 subjects (23/group). Patients with cirrhosis had worse QOL and cognition. On MR spectroscopy, patients with cirrhosis had worse changes related to ammonia and lower N‐acetyl aspartate, whereas rs‐fMRI analysis revealed that these patients demonstrated functional connectivity changes in the frontoparietal cortical region compared to controls. Results of the animal study showed that older mice required lower CCl4 to reach cirrhosis. Older mice, especially with cirrhosis, demonstrated higher cortical inflammatory mRNA expression of IL‐6, IL‐1β, and TGF‐β; higher glial and microglial activation; and lower sirtuin‐1 expression compared to younger mice. Older mice also had lower expression of DLG4, an excitatory synaptic organizer, and higher NLG2 and GABRG1/B1 receptor expression, indicating a predominantly inhibitory synaptic organization. Conclusion: Aging modulates brain changes in cirrhosis; this can affect QOL, cognition, and brain connectivity. Cortical inflammation, microglial activation, and altered GABA‐ergic synaptic plasticity could be contributory.

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).

Background & Aims Insurance, race, and ethnicity can affect outcomes of patients with cirrhosis, but findings from prospective studies are unclear. We investigated the role of insurance status and race and ethnicity (race/ethnicity) on inpatient and 90-day post-discharge outcomes in a large inpatient cohort of patients with cirrhosis. Methods We used data from the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) database, from 13 tertiary-care centers. Insurance status (uninsured, Medicare, Medicaid, private, and Canadian), race, and ethnicity, were analyzed independent of clinical co-variates for their association with transfer to the intensive care unit, acute on chronic liver failure (ACLF), length of hospital stay, inpatient and 90-day death or liver transplantation, and readmission to the hospital within 90 days. Multi-variable analyses and interaction terms were created for insurance, race/ethnicity, and for each outcome, with or without Canadian patients. Results We analyzed data from 2640 patients in the NACSELD database (971 with private insurance, 770 with Medicare, 456 Canadians, 265 with Medicaid, 178 uninsured, 540 non-Caucasian and 220 Hispanic); 23% required admittance to the intensive care unit, 12% developed NACSELD-defined ACLF, 7% died, 5% underwent liver transplantation. Of the 2288 patients discharged from hospital, 13% underwent liver transplantation, 19% died, and 42% were readmitted within 90 days. In the univariate model, uninsured patients accounted for the highest percentage of alcohol- or bleeding-related admissions and the lowest proportion of outpatient cirrhosis-related medication users. Canadians had the lowest rifaximin use and but higher proportions had hepatic encephalopathy, compared with other groups. Lack of insurance was higher among non-Caucasians, regardless of Hispanic ethnicity. In multi-variable analysis, lack of insurance was associated with ACLF (P=.02) and inversely associated with inpatient liver transplant (P=.05) and 90-day liver transplant (P=.02), regardless of whether Canadians were included or specific insurance type. Race or ethnicity were not significantly associated with outcomes. Conclusions In analyzing the NACSELD database, we found that insurance status, but not race or ethnicity, were independently associated with ACLF and inpatient or 90-day liver transplantation, regardless of inclusion of Canadian patients.

Little is known about patients discharged to hospice following hospitalization for complications of cirrhosis.We sought to understand the current pattern of hospice utilization in patients with cirrhosis by evaluating the North American Consortium for the Study of End-stage Liver Disease (NACSELD) cohort.Patients with cirrhosis from 14 tertiary-care hepatology centers across North America non-electively hospitalized and prospectively enrolled were evaluated. Exclusion criteria included HIV infection, transplantation or non-hepatic malignancy. Random computer-based propensity score matching was undertaken in a 1:2 ratio based on admission MELD score ± 3 points.Totally, 2718 patients were enrolled, 5% (N = 132) were discharged to hospice, 6% (N = 171) died, and the rest were discharged alive. Patients discharged to hospice were older (60 vs. 57 years, p = 0.04), less likely to have had SBP (13% vs. 28%, p = 0.002) and be listed for liver transplantation (11% vs. 26%, p = 0.0007). Features, on multivariable modeling, associated with increased probability of discharge to hospice as opposed to being discharged alive: grade-3-4 hepatic encephalopathy, a higher Child-Turcotte-Pugh (CTP) score, and a higher discharge serum creatinine; however, a higher serum sodium, being listed for transplant and being prescribed rifaximin or a statin were protective from hospice discharge.Patients with more advanced liver disease, hepatic encephalopathy, renal dysfunction, and those not candidates for liver transplantation were more likely to be discharged to hospice. However, in this sick multinational cohort of cirrhotic inpatients, it seems that hospice is markedly underutilized (5%) since 25% of patients not discharged to hospice died within 6 months.

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).

Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells including cholangiocytes. Exosome-mediated cell-cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long non-coding RNA H19 is mainly expressed in cholangiocytes and its aberrant expression is associated with significant down-regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2(−/−)) mice. However, how cholangiocyte-derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte-derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. The hepatic H19 level is correlated with the severity of cholestatic injury in both fibrotic mouse models, including Mdr2(−/−) mice, a well-characterized model of primary sclerosing cholangitis (PSC), or carbon-tetrachloride (CCl(4))-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually upregulated during disease progression in Mdr2(−/−) mice and cirrhotic patients. The H19-carrying exosomes from the primary cholangiocytes of wild type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19(−/−) mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and post-transcriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2(−/−) mice significantly promoted liver fibrosis in young Mdr2(−/−) mice. CONCLUSION: Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal-H19 represents a novel non-invasive biomarker and potential therapeutic target for cholestatic diseases.

Hepatic encephalopathy (HE) is a major cause of morbidity in cirrhosis. However, its severity assessment is often subjective, which needs to be studied systematically. The aim was to determine how accurately trainee and nontrainee practitioners grade and manage HE patients throughout its severity. We performed a survey study using standardized simulated patient videos at 4 US and 3 Canadian centers. Participants were trainees (gastroenterology/hepatology fellows) and nontrainees (faculty, nurse practitioners, physician assistants). We determined the accuracy of HE severity identification and management options between grades 2. Serum ammonia levels were ordered in almost a third of grade ≥2 patients. For trainees and nontrainees, HE grades were identified similarly between groups. Trainees were less likely to order serum ammonia and low-protein diets, more likely to order rifaximin, and more likely to perform a more thorough workup for precipitating factors compared with nontrainee respondents. There was excellent concordance in the classification of grade ≥2 HE between nontrainees versus trainees, but lower grades showed discordance. Important differences were seen regarding blood ammonia, specialized testing, and nutritional management between trainees and nontrainees. These results have important implications at the patient level, interpreting multicenter clinical trials, and in the education of practitioners. Liver Transplantation 24 587-594 2018 AASLD.

The North American Consortium for the Study of End-Stage Liver Disease's definition of acute-on-chronic liver failure (NACSELD-ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD-ACLF's ability to predict 30-day survival (defined as in-hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol-induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End-Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD-ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End-Stage Liver Disease score, and presence of infection. The c-statistics were 0.8073 for the training set and 0.8532 for the validation set. Conclusion Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30-day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (Hepatology 2018;67:2367-2374).

Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut-liver axis. It has been reported that bile duct ligation (BDL)-induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP-/-) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days. No significant hepatocyte apoptosis is detected 7 to 14 days following BDL. However, the inflammatory response is significantly increased after 7 days, which is similar to what we found in human PSC liver samples. BDL-induced loss of stemness in intestinal stem cells (ISCs), disruption of intestinal barrier function, bacterial translocation, activation of hepatic inflammation and M2 macrophage polarization and liver fibrosis are significantly reduced in CHOP-/- mice. In addition, intestinal organoids derived from CHOP-/- mice contain more and longer crypt structures than those from WT mice, which is consistent with the upregulation of stem cell markers (Lgr5, Olfm4 and Sox9) and in vivo findings that CHOP-/- mice have longer villi and crypts as compared to WT mice. Similarly, the mRNA levels of CD14, IL-1β, TNF-α and MCP-1 are increased and stem cell proliferation is suppressed in the duodenum of cirrhotic patients. Conclusion: Activation of ER stress and subsequent loss of stemness of ISCs plays a critical role in BDL-induced systemic inflammation and cholestatic liver injury. Modulation of the ER stress response represents a potential therapeutic strategy for cholestatic liver diseases as well as other inflammatory diseases This article is protected by copyright. All rights reserved.

Gut dysbiosis plays a role in hepatic encephalopathy (HE), while its relationship at the acute episode of overt HE (AHE), the disease progression and clinical outcomes remains unclear. We aimed to identify AHE-specific microbiome and its association to patients' outcomes.We profiled fecal microbiome changes for a cohort of 62 patients with cirrhosis and AHE i) before treatment, ii) 2-3 days after medication and iii) 2-3 months after recovery, and three control cohorts i) healthy individuals, patients with ii) compensated or iii) decompensated cirrhosis.Comparison of the microbiome shift from compensated, decompensated cirrhosis, AHE to recovery revealed the AHE-specific gut-dysbiosis. The gut microbiome diversity was decreased during AHE, further reduced after medication, and only partially reversed during the recovery. The relative abundance of Bacteroidetes phylum in the microbiome decreased, whereas that of Firmicute, Proteobacteria and Actinobacteria increased in patients during AHE compared with those with compensated cirrhosis. A total of 70 operational taxonomic units (OTUs) were significantly different between AHE and decompensated cirrhosis abundances. Of them, the abundance of Veillonella parvula increased the most during AHE via a metagenomics recovery of the genomes. Moreover, the relative abundances of three (Alistipes, Bacteroides, Phascolarctobacterium) and five OTUs (Clostridium-XI, Bacteroides, Bacteroides, Lactobacillus, Clostridium-sedis) at AHE were respectively associated with HE recurrence and overall survival during the subsequent one-year follow-up.AHE-specific gut OTUs were identified that may be involved in HE development and able to predict clinical outcomes, providing new strategies for the prevention and treatment of HE recurrence in patients with cirrhosis.

Alteration of the normal gut-liver axis is important in primary sclerosing cholangitis (PSC). Lack of effective medical therapy for PSC makes microbiome restoration an alluring therapeutic target. Allegretti et al. performed an open-label safety trial of fecal microbiota transplant (FMT) in noncirrhotic PSC patients with inflammatory bowel disease in remission on minimal therapy. FMT was safe in this population, and after FMT, there was a stable, early increase in microbial diversity and donor engraftment with mixed effects on alkaline phosphatase but no significant change in fecal bile acid profile. Further trials are needed to find whether FMT has a role to play in PSC therapy.

Background & Aims Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and health care resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE. Methods We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were assigned randomly to groups that received placebo or OP (10, 15, or 20 g/d, based on the severity of liver disease), plus each institution’s standard of care (eg, lactulose to achieve 2–3 bowel movements with or without rifaximin, in accordance with guidelines). The primary end point was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stages 3/4 or improvement to HEST stages 0/1 from baseline stage 2, in the intent-to-treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory). Results Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P = .129). Analyses of central laboratory–confirmed increases in levels of ammonia at baseline (n = 201) showed clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and in 29% in the placebo group (P = .552). Conclusions In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE. ClinicalTrials.gov no: NCT01966419 .

Progression of stages 2 and 3 acute kidney injury (AKI) in cirrhosis has not been characterized adequately. Patients with higher stages of AKI are believed to have worse outcomes. We assessed outcomes and factors associated with stages 2 and 3 AKI in patients with cirrhosis in the North American Consortium for the Study of End-stage Liver Disease cohort.We collected data from 2297 hospitalized patients with cirrhosis and ascites from December 2011 through February 2017. Our final analysis included 760 patients who developed AKI per the International Ascites Club 2015 definition (419 with maximum stage 1 and 341 with maximum stage 2 or 3; 63% male; mean age, 58 y). We compared demographic features, laboratory values, AKI treatment response, and survival between patients with maximum stage 1 vs patients with stage 2 or 3 AKI.Patients with stage 2 or 3 AKI had higher Model for End-Stage Liver Disease scores (25.9 ± 7.3) than patients with stage 1 AKI (21.9 ± 7.5) (P.0001). More patients fulfilled systemic inflammatory response syndrome criteria on admission, and more developed a second nosocomial infection (P.05 for both comparisons). More patients with stage 2 or 3 AKI also had progression of AKI and required dialysis and admission into intensive care units when compared to stage 1 AKI patients (P.0001 for both). A lower proportion of patients with stage 2 or 3 AKI survived their hospital stay (80% vs 99% with stage 1 AKI; P.0001), or survived for 30 days without a liver transplant (56% vs 81%; P.0001). The development of stage 2 or 3 AKI was associated with a higher Model for End-Stage Liver Disease score at the time of admission (P.0001), presence of systemic inflammatory response on admission (P = .039), and second infection (P.0001).Based on an analysis of data from the North American Consortium for the Study of End-stage Liver Disease cohort, we found that patients with cirrhosis and more advanced liver disease, as well as a second infection, are more likely to develop stages 2 or 3 AKI, with a progressive course associated with decreased 30-day transplant-free survival. Prevention of AKI progression in patients with cirrhosis and stage 2 or 3 AKI might improve their outcomes.

Background/aimsIntestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.Methods/designWe analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.ResultsIn ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.ConclusionsIn ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.

After an initial exposure, patients can develop test-taking/learning strategies called the "test sophistication effect." Patients with cirrhosis with prior overt hepatic encephalopathy (OHE) could have persistent learning impairments. The aim was to define learning/test sophistication on EncephalApp (downloadable application) in OHE patients compared with patients without prior overt hepatic encephalopathy (no-OHE) patients and controls cross-sectionally and longitudinally. The EncephalApp Stroop App consists of 2 sections: the easier "Off" run assesses psychomotor speed while the difficult "On" run assesses cognitive flexibility. For the cross-sectional analysis, outpatients with cirrhosis with/without controlled OHE and healthy controls underwent EncephalApp testing, which requires 5 Off and 5 On runs. We studied the difference in time required between completing trial 1 compared with trial 5 (delta 1-5) in both the On and Off runs in controls, all patients with cirrhosis, and between prior OHE/no-OHE patients with cirrhosis. For the longitudinal analyses, 2 groups of patients with cirrhosis were studied; 1 was administered the EncephalApp ≥ 2 weeks apart, and the second was administered before and 6 months after liver transplantation. The study included 89 controls and 230 patients with cirrhosis (85 prior OHE; Model for End-Stage Liver Disease, 11) with similar age (64 versus 61 years; P = 0.92). Patients with cirrhosis had impaired EncephalApp total times and impaired learning on the On runs compared with controls. OHE patients had worse EncephalApp times and learning with the On runs compared with no-OHE patients, which persisted in the longitudinal cohort. No differences in learning were seen in the Off runs. After transplant, there was restoration of learning capability with the On runs in the OHE patients. In conclusion, cognitive flexibility tested by the EncephalApp On runs improves over time in healthy controls and no-OHE but not prior OHE. Psychomotor speed remains similar over time. The learning impairment manifested by patients with cirrhosis with OHE is restored after transplant. Liver Transplantation 23 1396-1403 2017 AASLD.

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.

Background and Aim Readmissions are a major burden in cirrhosis. A proportion of readmissions in cirrhosis, especially due to hepatic encephalopathy (HE) could be avoided through patient and caregiver engagement. We aimed to define the feasibility of using the Patient Buddy App and its impact on 30-day readmissions by engaging and educating cirrhotic inpatients and caregivers in a pilot study. Methods Cirrhotic inpatients with caregivers were enrolled and followed for 30 days post-discharge. On separately assigned devices loaded with Patient-Buddy, they were trained on entering medication adherence, daily sodium intake and weights, and weekly cognitive (EncephalApp_Stroop) and fall-risk assessment and were educated regarding cirrhosis-related symptoms. These were monitored daily through a Patient-Buddy loaded iPad by the clinical team. The App sent automatic alerts between patient/caregivers and clinical team regarding adherence and critical values. At 30 days, total, and HE-related admissions were analyzed as well as the feasibility and feedback regarding educational values. Results 40 patients and 40 caregivers were enrolled. Seventeen patients were readmitted within 30-days but none for HE. Eight potential HE-related readmissions were prevented through App-generated alerts that encouraged early outpatient interventions. Caregivers and patients were concordant in data entry but six did not complete data entries. Most respondents rated the App favorably for its educational value. Conclusions In this proof-of-concept trial, the use of Patient-Buddy is feasible in recently discharged patients with cirrhosis and their caregivers. Eight HE-related readmissions were potentially avoided after the use of the App. This article is protected by copyright. All rights reserved.

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.

Recent advances in culture-independent laboratory techniques and bioinformatics have contributed to enriched characterizations of the gut microbiota and microbiome in chronic liver diseases such as alcoholic liver disease, nonalcoholic fatty liver disease, primary sclerosing cholangitis, primary biliary cholangitis, and cirrhosis. In this review, the authors focus on studies characterizing and modulating the gut microbiota and microbiome in humans. The majority of studies that characterized microbiota involved a small number of patients using 16S ribosomal RNA genetic sequencing. Few studies applied whole-genome shotgun sequencing and metagenomics analyses. The majority of clinical trials on modulating the microbiome have focused on probiotics or antibiotics in small groups of patients with cirrhosis versus healthy controls. Several trials are underway using fecal microbial transplantation in alcoholic liver disease, nonalcoholic fatty liver disease, primary sclerosing cholangitis, and cirrhosis. Future research is needed on understanding the viral and fungal microbiome and developing user-friendly microbiome tools.

Liver cirrhosis is a public health problem and hepatic encephalopathy is one of its main complications, which can be either overt meaning thereby evident and readily diagnosed, or covert/minimal (covert hepatic encephalopathy-CHE) needing psychometric testing for diagnosis. Patients with CHE hepatic encephalopathy have deficits in multiple domains including visuospatial assessment, attention, response inhibition, working memory, along with psychomotor speed to name a few areas. These patients have poor navigational skills, get fatigued easily, and demonstrate poor insight into their driving deficits. The combination of all these leads them to have poor driving skills leading to traffic violations and crashes as demonstrated not only on the simulation testing but also in real-life driving events. There are multiple psychometric tests for CHE testing but these are not easily available and there is no uniform consensus on the gold standard testing as of yet. It does not automatically connote that all patients who test positive on driving simulation testing are unfit to drive. The physicians are encouraged to take driving history from the patient and the caregivers on every encounter and focus their counseling efforts more on patients with recent history of traffic crashes, with abnormal simulation studies and history of alcohol cessation within last year. As physicians are not trained to determine fitness to drive, their approach toward CHE patients in regards to driving restrictions should be driven by ethical principles while as respecting the local laws.

Gut microbiota changes are important in determining the occurrence and progression of chronic liver disease related to alcohol, nonalcoholic fatty liver disease, and cirrhosis. Specifically, the systemic inflammation, endotoxemia, and the vasodilation that leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy could be related to the gut milieu. Given the poor prognosis of these events, their prevention and early management are essential. Microbiota may be an essential component of the gut milieu that can impact these clinical events, and the study of their composition and function in a culture-independent manner could help understand the prognosis. Recent human and animal studies have shown that the relative abundance and the functional changes of microbiota in the stool, colonic mucosa, and saliva have varying consequences on the presence and prognosis of chronic liver disease and cirrhosis. The impact of therapies on the microbiota is slowly being understood and will likely lead to a more targeted approach to gut microbiota modification in chronic liver disease and cirrhosis.

Chronic liver disease with progression to decompensated cirrhosis and its associated complications, including hepatic encephalopathy, spontaneous bacterial peritonitis, and sepsis, is a leading cause of mortality and morbidity. The pathophysiology of decompensated cirrhosis, which is being intensively studied, leads to the development of gut microbiome changes causing dysbiosis. This is likely related to altered bile acid composition, with a subsequent increase in the relative abundance of potentially pathogenic bacteria that contributes to hepatic encephalopathy and leads to their translocation and the development of spontaneous bacterial peritonitis and bacteremia. Treatments for these conditions have been found to target the gut microbiome, which has become a vital area of study in the treatment of cirrhosis.

The prevalence of coronary artery disease (CAD) is high among patients with cirrhosis; however, the impact of it on cardiovascular disease (CVD) is not known. The aim of the current study was to evaluate CVD events in patients with cirrhosis and impact of cirrhosis on biomarkers of atherogenesis. The study included 682 patients with decompensated cirrhosis referred for liver transplantation (LT) evaluation between 2010 and 2017. All patients were followed until they experienced a CVD event, non-cardiac death, liver transplantation or last follow-up. To evaluate mechanistic link, patients with NASH cirrhosis were propensity matched 1:2 to non-cirrhosis NASH patients and biomarkers of atherogenic risk were compared. The composite CVD outcome occurred in 23(3.4%) patients after a median follow-up period of 585 days (IQR 139, 747). A strong association between presence of any CAD and CVD event was noted (HR = 6.8, 95% CI 2.9, 15.9) that was independent of age, gender, BMI, and MELD score. In competing risk model, the combined rate of LT and non-cardiac was significantly higher when compared to the rate of CVD events. Marker of insulin resistance and inflammation-related markers were similar in patients with and without cirrhosis. Patients with cirrhosis were more likely to have reduced VLDL, sdLDL-C, LDL-C, and triglycerides. Interestingly, patients with cirrhosis had an increase in serum HDL-2, the anti-atherogenic lipoprotein, and adiponectin, a protective serum adipokine. The risk of CVD events in patients with cirrhosis is low and may potentially be due to improvement in markers of atherogenic risk.

The gut microbiome is the natural intestinal inhabitant that has been recognized recently as a major player in the maintenance of human health and the pathophysiology of many diseases. Those commensals produce metabolites that have various effects on host biological functions. Therefore, alterations in the normal composition or diversity of microbiome have been implicated in various diseases, including liver cirrhosis and nonalcoholic fatty liver disease. Moreover, accumulating evidence suggests that progression of dysbiosis can be associated with worsening of liver disease. Here, we review the possible roles for gut microbiota in the development, progression, and complication of liver disease.

Gender differences in the natural history of chronic liver disease have been well-described. Women have lower rates of chronic liver disease and slower fibrosis progression, yet higher rates of waitlist mortality.1,2 Although previous studies have identified several clinical factors including height and creatinine that explain some of this transplant disparity, most have used data from administrative records, which are limited in their ability to identify clinically relevant differences and opportunities for intervention to reduce disparities.3-5 Additionally, most studies have focused on the period between waitlist and transplant, failing to capture gender differences in access to transplant.3,6 In the present study, we took advantage of a multicenter inpatient cohort with granular clinical data to characterize how women and men with cirrhosis differ, to stimulate future research aimed at reducing the well-established gender disparity in liver transplantation.

Hospitalized patients with decompensated liver cirrhosis, infected by either bacterial or fungal organisms, are prone to get severely sick and may require ICU management. These infections are hard to treat given the emergence of multiple drug-resistant organisms (MDROs) and lead to overutilizaton of already stressed hospital resources. Further on, despite optimal hospital management, these patients have higher morbidity and mortality. More focus needs to be put on the nosocomial infections, as these independently predict mortality and readmissions and seem to be target for prevention. The prevalence of MDROs in a liver cirrhosis patient in the United States is between 16% and 37%, and this trend holds true for Europe (23%–29.2%) as well. Fungal infections, which mainly develop in the nosocomial setting, portend poor short-term prognosis. The emerging role of disturbance in the microbiome to the pathogenesis of infections, both fungal and bacterial, is being recognized. Infections in acute-on-chronic liver failure (ACLF)-decompensated cirrhosis patients predict poor 30- day survival depending on the number of organ failures. There is currently lack of good prognostic tools to predict outcomes in these sick and septic patients. The key to successful management of these patients lies in proper initial triage to the intensive care unit or the floor level, appropriate and timely empiric antibiotic administration using local resistance patterns as a guide along with optimal fluid management and ancillary support. Multidisciplinary team approach is highly recommended for improving the outcomes in these patients. Preventive strategies to decrease the initial infection episode and to minimize the second infections are highly desirable.

INTRODUCTION Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. METHODS We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). RESULTS Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). DISCUSSION Sample handling, processing, and protein intake impact ammonia levels across sites.

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

BackgroundHepatic encephalopathy (HE) can adversely affect outcomes in both in-patients and out-patients with cirrhosis.AimTo define targets for improving quality of care in HE management in the multi-centre North American Consortium for End-Stage Liver Disease (NACSELD) cohort.MethodNACSELD in-patient cohort was analysed for (a) medication-associated precipitants, (b) aspiration pneumonia development, (c) HE medication changes, and (d) 90-day HE recurrence/readmissions. Comparisons were made between patients on no-therapy, lactulose only, rifaximin only or both. Ninety-day HE-readmission analysis was adjusted for MELD score.ResultsTwo thousand eight hundred and ten patients (1102 no-therapy, 659 lactulose, 154 rifaximin, 859 both) were included. HE on admission, and HE rates during hospitalisation were highest in those on lactulose only or dual therapy compared to no-therapy or rifaximin only (P&nbsp