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In patients with decompensated cirrhosis, sarcopenia and frailty are prevalent. Although several definitions exist for these terms, in the field of hepatology, sarcopenia has commonly been defined as loss of muscle mass, and frailty has been broadly defined as the phenotypic manifestation of the loss of muscle function. Prompt recognition and accurate assessment of these conditions are critical as they are both strongly associated with morbidity, mortality, poor quality of life and worse post-liver transplant outcomes in patients with cirrhosis. In this review, we describe the complex pathophysiology that underlies the clinical phenotypes of sarcopenia and frailty, their association with decompensation, and provide an overview of tools to assess these conditions in patients with cirrhosis. When available, we highlight data focusing on patients with acutely decompensated cirrhosis, such as inpatients, as this is an area of unmet clinical need. Finally, we discuss management strategies to reverse and/or prevent the development of sarcopenia and frailty, which include adequate nutritional intake of calories and protein, as well as regular exercise of at least moderate intensity, with a mix of aerobic and resistance training. Key knowledge gaps in our understanding of sarcopenia and frailty in decompensated cirrhosis remain, including best methods to measure muscle mass and function in the inpatient setting, racial/ethnic variation in the development and presentation of sarcopenia and frailty, and optimal clinical metrics to assess response to therapeutic interventions that translate into a reduction in adverse outcomes associated with these conditions.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease with no approved treatments. C-C chemokine receptor types 2 and 5 (CCR2/CCR5) play an important role in inflammation and fibrosis and are potential therapeutic targets for PSC. We evaluated the efficacy and safety of cenicriviroc (CVC), a dual antagonist of CCR2 and CCR5, for the treatment of PSC. This was a single-arm, open-label, exploratory study of CVC in adults with a clinical diagnosis of PSC, serum alkaline phosphatase (ALP) ≥1.5 times the upper limit of normal (ULN), with or without inflammatory bowel disease, across eight sites in the United States and Canada. The primary endpoint was percent change in ALP over 24 weeks; key secondary efficacy endpoints were proportion of participants who achieved ALP normalization and overall response (decrease to

Background & aimsGut-homing lymphocytes that express the integrin α4β7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4β7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD.MethodsWe collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes.ResultsIn the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation.ConclusionsIn an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.

Loss of muscle mass and function, or sarcopenia, is a common feature of cirrhosis and contributes significantly to morbidity and mortality in this population. Sarcopenia is a main indicator of adverse outcomes in this population, including poor quality of life, hepatic decompensation, mortality in patients with cirrhosis evaluated for liver transplantation (LT), longer hospital and intensive care unit stay, higher incidence of infection following LT, and higher overall health care cost. Although it is clear that muscle mass is an important predictor of LT outcomes, many questions remain, including the best modality for assessing muscle mass, the optimal cut-off values for sarcopenia, the ideal timing and frequency of muscle mass assessment, and how to best incorporate the concept of sarcopenia into clinical decision making. For these reasons, we assembled a group of experts to form the North American Working Group on Sarcopenia in Liver Transplantation to use evidence from the medical literature to address these outstanding questions regarding sarcopenia in LT. We believe sarcopenia assessment should be considered in all patients with cirrhosis evaluated for liver transplantation. Skeletal muscle index (SMI) assessed by computed tomography constitutes the best-studied technique for assessing sarcopenia in patients with cirrhosis. Cut-off values for sarcopenia, defined as SMI < 50 cm2 /m2 in male and < 39 cm2 /m2 in female patients, constitute the validated definition for sarcopenia in patients with cirrhosis. Conclusion: The management of sarcopenia requires a multipronged approach including nutrition, exercise, and additional pharmacological therapy as deemed necessary. Future studies should evaluate whether recovery of sarcopenia with nutritional management in combination with an exercise program is sustainable as well as how improvement in muscle mass might be associated with improvement in clinical outcomes.

BackgroundWe examined the association between sarcopenia and post-transplant mortality in acutely ill inpatients with cirrhosis who underwent urgent liver transplantation.MethodsIncluded were inpatients at 4 centers who were urgently listed as nonstatus 1 and transplanted from 2005 to 2017 with an abdominal computed tomography scan 48 cm/m experienced higher rates of death at 1 year (86% versus 95%) and 3 years (73% versus 95%) (Log-rank P = 0.01). In MELD-adjusted analysis, sarcopenia was strongly associated with post-transplant mortality (HR = 4.39, 95% CI 1.49-12.97). Among women, 35% died. Median SMI was similar in women who died versus survived (45 versus 44 cm/m). SMI was not associated with post-transplant mortality (HR = 1.02, 95% CI 0.96-1.09). Optimal search did not identify any SMI cutoff that predicted post-transplant mortality.ConclusionsAmong patients who underwent urgent inpatient evaluation and liver transplantation, we identified an SMI cutoff value of 48 cm/m to predict post-transplant mortality in men. Our data support the use of SMI as a tool to capture the impact of muscle depletion on post-transplant mortality in acutely ill men with cirrhosis undergoing urgent liver transplantation.

Frailty has emerged as a powerful predictor of outcomes in patients with cirrhosis and has inevitably made its way into decision making within liver transplantation. In an effort to harmonize integration of the concept of frailty among transplant centers, the AST and ASTS supported the efforts of our working group to develop this statement from experts in the field. Frailty is a multidimensional construct that represents the end-manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. In hepatology/liver transplantation, investigation of frailty has largely focused on physical frailty, which subsumes the concepts of functional performance, functional capacity, and disability. There was consensus that every liver transplant candidate should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. The working group agreed that frailty should not be used as the sole criterion for delisting a patient for liver transplantation, but rather should be considered one of many criteria when evaluating transplant candidacy and suitability. A road map to advance frailty in the clinical and research settings of liver transplantation is presented here.

BackgroundImpaired physical capacity increases peri-liver transplant complications. Patient perceptions regarding exercise prior to transplantation are not known.AimsThis study aimed to assess patient and caregiver activity levels, perceptions of willingness to exercise, and of provider advice.MethodsConsecutive patients listed for liver transplant and caregivers presenting for routine outpatient visits were evaluated over a 3-month interval. Anonymous surveys adapted to patients and caregivers addressed the importance and safety of exercise, type and duration of exercise performed, barriers, willingness to wear a monitoring device, and perceived provider recommendations. Responses were logged on a Likert scale from 1 to 5.ResultsThree hundred and sixty-eight responses were received. Most participants perceived exercise as important. Patients exercised three times per week for 30 min. Eighty percent endorsed walking (median response: 2-agree; IQR 1-2). Most did not jog, swim, cycle, or strength train. Fatigue, reported by 70%, was the major barrier (2, IQR 1-3). Over 90% of caregivers endorsed exercise as important (1-strongly agree, IQR 1-2) and encouraged exercise (median response 2, IQR 1-2). Over 60% of patients (median response 2, IQR 1-3) and caregivers (median response 2, IQR 2-3) felt providers encouraged exercise.ConclusionsPatients and caregivers are willing to exercise to optimize physical fitness prior to liver transplantation.

BackgroundSarcopenia, characterized by low muscle mass, associates with mortality in patients with cirrhosis. Skeletal muscle area in a single computed tomography image at the level of the third lumbar vertebrate (L3) is a valid representative of whole body muscle mass. Controversy remains regarding applicability of psoas muscle to identify patients at greater risk of mortality. We aimed to determine psoas muscle index (PMI) association with skeletal muscle index (SMI) and to evaluate the capacity of PMI to predict liver transplant waitlist mortality.MethodsWe evaluated listed adult patients with cirrhosis from 2012 to 2013 at four North American liver transplant centres. From L3 computed tomography images within 3 months of listing, we determined SMI and PMI expressed by cm2 /m2 . Low SMI was defined as SMI  0.7, P

Sarcopenia is associated with increased wait-list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end-stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross-sectional area (cm2 ) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait-list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex-specific potential cutoff values to define sarcopenia were determined with a grid search guided by log-rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm2 /m2 : 50.0 in men and 42.0 in women. At a median of 8.8 months follow-up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm2 /m2 ; P

Author(s): Maryam Ebadi [sup.1], Aldo J. Montano-Loza [sup.1] Author Affiliations: (1) Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, Canada Introduction A novel coronavirus disease 2019 (COVID-19) [...]