Impacts of glucagon-like peptide-1 receptor agonists on the risk of adverse liver outcomes in patients with metabolic dysfunction-associated steatotic liver disease cirrhosis and type 2 diabetes.

BACKGROUND/AIMS: We examined the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) initiation on long-term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real-world data from the MarketScan database. METHODS: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP-1RAs initiation, modelled as time-dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP-1RAs and 4837 non-GLP-1RAs patients. RESULTS: The non-GLP-1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP-1RAs patients had 32 (7%) ALO over 586.6 person years - risk rate difference 13.5 (95% CI: 11.4-15.7) per 100 person-years. The OPSW-adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54-0.76) in patients with vs. without GLP-1RAs initiation. GLP-1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61-0.88), portal hypertension (HR: 0.73; 95% CI: 0.60-0.88), HCC (HR: 0.37; 95% CI: 0.20-0.63) and LT (HR: 0.24; 95% CI: 0.12-0.43). CONCLUSION: The use of GLP-1RAs was associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes.

Subjective and objective burden on providers from a multicenter app-based study of patients with cirrhosis and caregivers.

BACKGROUND: App-based technologies could enhance patient and caregiver communication and provide alerts that potentially reducing readmissions. However, the burden of App alerts needs to be optimized to reduce provider burnout. AIM: The purpose of this study was to determine subjective and objective burden of using the Patient Buddy App, a health information technology (HIT) on providers in a randomized multicenter trial, who completed a semi-quantitative Likert scale survey regarding training procedures, data and privacy concerns, follow-up details, and technical support. This randomized multicenter trial recruits cirrhosis inpatients and their caregivers, and randomizes them into standard-of-care, HIT (communication only via App) and HIT+visits (App+phone calls/visits) for 30 days after discharge. The alerts are monitored by providers through a central iPad. The reason(s) and number of alerts were recorded as the objective burden. A total of 1442 messages were sent as alerts from the 103 dyads (patient + caregiver) (n=206) randomized to HIT arms. The most common messages related to Hepatic Encephalopathy (HE) (high or low bowel movement=50% or orientation tests=37%). Twelve providers completed the surveys reflecting the following themes-92% and 100%, felt adequately trained and confident about educating the patients and caregivers before roll out of App and had no concerns related to data and privacy; 70%, felt that appropriate time was spent on pursuing reason for data not being logged; 60% each, had issues with availability of adequate technical support and connectivity. CONCLUSION: The Patient Buddy App randomized multicenter trial till date shows an overall favorable rating regarding training procedures/education, privacy concerns, and ease of message follow-up, from providers. However, it is important to gauge and address subjective and objective burdens of monitoring human resources in current and future HIT studies to avoid burnout and to ensure successful study completion.

QuickStroop, a Shortened Version of EncephalApp, Detects Covert Hepatic Encephalopathy With Similar Accuracy Within One Minute.

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) is associated with poor outcomes but is often not diagnosed because of the time requirement. Psychometric hepatic encephalopathy score (PHES) is the gold standard against which EncephalApp Stroop has been validated. However, EncephalApp (5 runs each in "Off" and "On" state) can take up to 10 minutes. This study sought to define the smallest number of EncephalApp runs needed for comparable accuracy to the total EncephalApp using CHE on PHES as gold standard. METHODS: A derivation and a validation cohort of outpatients with cirrhosis who underwent PHES (gold standard) and total EncephalApp was recruited. Data were analyzed for individual runs versus total EncephalApp time versus PHES-CHE. The derivation cohort (n = 398) was split into training (n = 299) and test (n = 99) sets. From the training data set a regression model was created with age, gender, education, and various sums of the "Off" settings. After this, a K-fold cross-validation on the test dataset was performed for both total EncephalApp time and individual Off runs and for the validation cohort. RESULTS: In both cohorts, Off runs 1 + 2 had statistically similar area under the receiver operating curve and P value to the total EncephalApp for PHES-CHE prediction. The adjusted (age, gender, education) regression formula from the derivation cohort showed an accuracy of 84% to diagnose PHES-CHE in the validation cohort. Time for CHE diagnosis decreased from 203.7 (67.82) to 36.8 (11.25) seconds in the derivation and from 178.2 (46.19) to 32.9 (9.94) seconds in the validation cohort. CONCLUSIONS: QuickStroop, which is completed within 1 minute, gives an equivalent ability to predict CHE on the gold standard compared with the entire EncephalApp time.

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

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

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child-Pugh-Turcotte score, 10 ± 2; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

Bowel Movement Frequency Is Not Linked With Cognitive Function in Cirrhosis.

The spectrum of hepatic encephalopathy (HE) ranges from overt HE (OHE) to cognitive impairment (ie, covert) HE (CHE).1 The first-line therapy is lactulose, which is titrated to achieve ~2-3 soft/loose daily bowel movements (BM). This metric is considered dogma for practitioners despite erratic results, GI adverse events, and poor tolerance in Western countries.1 There are logistic barriers for the widespread uptake of rifaximin, the second-line therapy. Moreover, although BM frequency-directed dose titration of lactulose is the usual practice, its impact on objective cognitive performance is unclear. Our aim is to determine the impact of BM frequency on cognition in patients with/without prior OHE.

Multiple bacterial virulence factors focused on adherence and biofilm formation associate with outcomes in cirrhosis.

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

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

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

Hepatic Encephalopathy and Liver Transplantation: The Past, Present, and Future Toward Equitable Access.

Cirrhosis is a debilitating chronic disease with high morbidity and mortality, with the only real cure being liver transplantation (LT). Currently, we allocate organs for transplantation based on the Model for End-Stage Liver Disease-Sodium (MELD-Na) score that does not account for hepatic encephalopathy (HE). HE affects patients, families, and the health care system because of high rates of recurrence and major readmission burden. Moreover, HE casts a long shadow even after LT. Accounting for HE and incorporating it into the current allocation system has many proponents, but the framework to do this is currently lacking because of differences in consensus or in operationalization parameters. We review the latest evidence of the burden of HE, management of HE before and after LT, and evaluate pros and cons of several methods of diagnosing HE objectively to ensure early and equitable access to LT in this underserved population.

Impact of Antibiotic Resistance Genes in Gut Microbiome of Patients With Cirrhosis.

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

Perspectives of Inpatients With Cirrhosis and Caregivers on Using Health Information Technology: Cross-sectional Multicenter Study.

BACKGROUND: Health information technology (IT) interventions to decrease readmissions for cirrhosis may be limited by patient-associated factors. OBJECTIVE: The aim of this study was to determine perspectives regarding adoption versus refusal of health IT interventions among patient-caregiver dyads. METHODS: Inpatients with cirrhosis and their caregivers were approached to participate in a randomized health IT intervention trial requiring daily contact with research teams via the Patient Buddy app. This app focuses on ascites, medications, and hepatic encephalopathy over 30 days. Regression analyses for characteristics associated with acceptance were performed. For those who declined, a semistructured interview was performed with themes focused on caregivers, protocol, transport/logistics, technology demands, and privacy. RESULTS: A total of 349 patient-caregiver dyads were approached (191 from Virginia Commonwealth University, 56 from Richmond Veterans Affairs Medical Center, and 102 from Mayo Clinic), 87 of which (25%) agreed to participate. On regression, dyads agreeing included a male patient (odds ratio [OR] 2.08, P=.01), gastrointestinal bleeding (OR 2.3, P=.006), or hepatic encephalopathy admission (OR 2.0, P=.01), whereas opioid use (OR 0.46, P=.03) and alcohol-related etiology (OR 0.54, P=.02) were associated with refusal. Race, study site, and other admission reasons did not contribute to refusing participation. Among the 262 dyads who declined randomization, caregiver reluctance (43%), perceived burden (31%), technology-related issues (14%), transportation/logistics (10%), and others (4%), but not privacy, were highlighted as major concerns. CONCLUSIONS: Patients with cirrhosis admitted with hepatic encephalopathy and gastrointestinal bleeding without opioid use or alcohol-related etiologies were more likely to participate in a health IT intervention focused on preventing readmissions. Caregiver and study burden but not privacy were major reasons to decline participation. Reducing perceived patient-caregiver burden and improving communication may improve participation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03564626; https://www.clinicaltrials.gov/ct2/show/NCT03564626.

Gut Microbial Signature of Hepatocellular Cancer in Men With Cirrhosis.

The gut microbiome is altered in cirrhosis. Recent evidence has suggested a key role for the gut microbiota in the progression of cirrhosis and the development of hepatocellular carcinoma (HCC). We studied the differences in the microbial composition in patients with cirrhosis with prior and future HCC in the context of other complications (eg, infections, hepatic encephalopathy). The following 2 cohorts were recruited prospectively: the prior HCC cohort, in which outpatients with HCC within 2 years were age-matched, sex-matched, and Model for End-Stage Liver Disease (MELD) score-matched with those without HCC; and the future HCC cohort, in which patients were followed for 2 years and divided into future HCC versus no HCC after age, sex, and MELD-score matching and other complications were also recorded. Microbiota composition and predicted function were analyzed with ribosomal RNA sequencing and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PiCRUST)and compared between (1) prior HCC versus none and (2) future HCC versus none, and in the future cohort, comparisons were also made between those patients who developed (1) HCC only versus without complications, (2) HCC only versus non-HCC complications only, and (3) HCC + other complications versus non-HCC complications only. A total of 142 men (76 total in the prior cohort [38 with/38 without HCC] and 66 total in the future cohort [33 with/33 without future HCC]) were included. The groups had similar etiology, lactulose/rifaximin/proton pump inhibitor use, diabetes mellitus, and non-HCC complications. Microbial diversity was similar between prior HCC/not or future HCC/not. On DESeq2 higher Clostridium sensu stricto and Anaerotruncus were significantly associated with protection from HCC, whereas the reverse was seen with Raoultella and Haemophilus regardless of prior/future HCC comparisons. Functions focused on urea cycle, bioenergetics, tryptophan, and toluene metabolism were different between the groups. Rothia was specific for other complications. Despite age, sex, and MELD-score matching and accounting for other complications, gut microbiota composition and the predicted function are different in men with cirrhosis with and without prior HCC and can be extended toward future HCC development.

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

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

Interaction of bacterial metagenome and virome in patients with cirrhosis and hepatic encephalopathy.

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

Chronic Liver Diseases and the Microbiome-Translating Our Knowledge of Gut Microbiota to Management of Chronic Liver Disease.

Chronic liver disease is reaching epidemic proportions with the increasing prevalence of obesity, nonalcoholic liver disease, and alcohol overuse worldwide. Most patients are not candidates for liver transplantation even if they have end-stage liver disease. There is growing evidence of a gut microbial basis for many liver diseases, therefore, better diagnostic, prognostic, and therapeutic approaches based on knowledge of gut microbiota are needed. We review the questions that need to be answered to successfully translate our knowledge of the intestinal microbiome and the changes associated with liver disease into practice.

Cost-effectiveness of integrating gut microbiota analysis into hospitalisation prediction in cirrhosis.

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.

Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL. METHODS: We recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites. RESULTS: Controls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort. CONCLUSIONS: In a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.