Patient Acceptance of Lactulose Varies Between Indian and American Cohorts: Implications for Comparing and Designing Global Hepatic Encephalopathy Trials.

BACKGROUND: Lactulose is the first-line drug for hepatic encephalopathy (HE), but its acceptance widely differs between Western and Eastern studies. Patient preference for lactulose between different parts of the world has not been examined systematically. AIM: To define the preferences and reasons behind acceptance of lactulose in patients from USA and India. METHODS: A discrete-choice questionnaire with six hypothetical scenarios was constructed. Situations 1-3 studied preference for lactulose vs no-lactulose, while 4-6 studied preference for high-dose vs low-dose lactulose varying the overt HE prevention at 6 months and adverse event rates in each situation. This was administered to outpatient cirrhotics without prior/current experience with lactulose after dedicated education. RESULTS: 100 patients (50 Indian, 50 USA) with similar MELD scores were included. A significantly higher proportion of Indian respondents agreed to lactulose in all situations compared to Americans. While their acceptance of lactulose decreased in the situation with the least difference in overt HE prevention, it was consistently higher than Americans. In the high-dose vs low-dose scenario, the relative proportion of American respondents accepting high-dose increased with the higher presented protection against overt HE. On the other hand, Indian respondents remained largely consistent with low-dose lactulose option. CONCLUSIONS: There are significant variations in the acceptance of lactulose in Indian and American populations. The acceptance increases with a more favorable perceived benefit/risk profile, which is strongly influenced by socio-cultural factors. These results have important implications when designing, comparing and interpreting HE trials from different parts of the world.

Neutrophil-to-Lymphocyte Ratio Associates Independently With Mortality in Hospitalized Patients With Cirrhosis.

BACKGROUND & AIMS: The neutrophil to lymphocyte ratio (NLR) is a biomarker of immune dysregulation in patients with cirrhosis and is inexpensive to measure. We investigated the association between NLR and mortality in hospitalized patients with cirrhosis at 4 liver transplant centers, controlling for severity of acute-on-chronic liver failure (ACLF). METHODS: We performed a retrospective study using data from the North American Consortium for the Study of End-stage Liver Disease on patients with index hospitalizations for cirrhosis from December 2011 through December 2016. We collected data on patient demographics, NLR, model for end-stage liver disease (MELD) scores, serum levels of Na, cirrhosis stages, infections, hepatocellular carcinomas, and ACLF severity (based on number of organ failures). Competing risk regression analysis evaluated mortality within 1 year after hospital discharge, accounting for competing events (liver transplant). RESULTS: At admission, the patients' mean age was 57 years, mean MELD score was 21, and mean serum level of Na was 134 mmol/L. Sixty-eight patients had no organ failure, 21 patients had 1 organ failures, 7 patients had 2 organ failures, 4 patients had 3 organ failures, and 1 patient had 4 organ failures; 36% of the patients had confirmed or suspected infections. In univariate models, risk of death associated with increasing NLR, up to a value of 8 (hazard ratio [HR]= 1.14; 95% CI, 1.07-1.20; P < .001), and NLR quartile (for NLR range of 3-5, HR = 2.17; for NLR range of >5-9, HR=2.46; for NLR quartile >9, HR=2.84 vs the lowest quartile [NLR<3]) (P ≤ .001). The NLR remained statistically significant in multivariable models, adjusting for age, MELD score, hepatocellular carcinoma, and ACLF severity. Additionally, NLR was a statistically significant independent predictor of length of index hospital stay and mortality within 90 days after discharge. CONCLUSION: In a retrospective analysis of patients with cirrhosis, we found NLR to associate with death within 1 year after non-elective hospitalization. In these patients, the risk of death associated with acute immune dysregulation persists long after their initial hospitalization.

Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation.

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.

The patient buddy app can potentially prevent hepatic encephalopathy-related readmissions.

BACKGROUND & AIMS: Readmissions are a major burden in cirrhosis. A proportion of readmissions in cirrhosis, especially because of 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 analysed as well as the feasibility and feedback regarding educational values. RESULTS: Forty 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 favourably 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.

Elderly patients have an altered gut-brain axis regardless of the presence of cirrhosis.

Cognitive difficulties manifested by the growing elderly population with cirrhosis could be amnestic (memory-related) or non-amnestic (memory-unrelated). The underlying neuro-biological and gut-brain changes are unclear in this population. We aimed to define gut-brain axis alterations in elderly cirrhotics compared to non-cirrhotic individuals based on presence of cirrhosis and on neuropsychological performance. Age-matched outpatients with/without cirrhosis underwent cognitive testing (amnestic/non-amnestic domains), quality of life (HRQOL), multi-modal MRI (fMRI go/no-go task, volumetry and MR spectroscopy), blood (inflammatory cytokines) and stool collection (for microbiota). Groups were studied based on cirrhosis/not and also based on neuropsychological performance (amnestic-type, amnestic/non-amnestic-type and unimpaired). Cirrhotics were impaired on non-amnestic and selected amnestic tests, HRQOL and systemic inflammation compared to non-cirrhotics. Cirrhotics demonstrated significant changes on MR spectroscopy but not on fMRI or volumetry. Correlation networks showed that Lactobacillales members were positively while Enterobacteriaceae and Porphyromonadaceae were negatively linked with cognition. Using the neuropsychological classification amnestic/non-amnestic-type individuals were majority cirrhosis and had worse HRQOL, higher inflammation and decreased autochthonous taxa relative abundance compared to the rest. This classification also predicted fMRI, MR spectroscopy and volumetry changes between groups. We conclude that gut-brain axis alterations may be associated with the type of neurobehavioral decline or inflamm-aging in elderly cirrhotic subjects.

Liver transplantation significantly improves global functioning and cerebral processing.

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

Cirrhotic patients have good insight into their daily functional impairment despite prior hepatic encephalopathy: comparison with PROMIS norms.

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