Impaired lower limb muscle mass, quality and function in end stage liver disease: A cross-sectional study.

NEW FINDINGS: What is the central question of this study? To what extent does musculoskeletal impairment occur (i.e., muscle mass, quality and function) in patients with end stage liver disease (ESLD) by comparison to a healthy age/sex-matched control group? What is the main finding and its importance? Muscle mass, quality and function are impaired in patients with ESLD (compared to age/sex matched controls). Importantly, greater impairments were seen in lower limb compared to arm and trunk muscle groups. These findings may suggest that there should be greater consideration of muscle health in functionally relevant lower limb muscle groups. ABSTRACT: Sarcopenia is associated with reduced quality of life and increased mortality in patients with end stage liver disease (ESLD). Historically, sarcopenia identification in ESLD utilised L3 skeletal muscle index (SMI). There are few data on muscle quality and function within lower limb muscle groups with high functional relevance. The aim of this prospective case-control study was to evaluate the quadriceps muscle in patients with ESLD. Muscle mass and quality were evaluated using MRI (quadriceps anatomical cross sectional area (ACSA), quadriceps volume index, L3 SMI, quadriceps intermuscular adipose tissue (IMAT)), mid-arm muscle circumference (MAMC) and ultrasonography (vastus lateralis (VL) thickness and quadriceps ACSA). Muscle strength/function was assessed by handgrip strength, peak quadriceps isokinetic torque and chair rise time. Thirty-nine patients with ESLD (55 years, 61% male, 48% alcoholic related liver disease (ArLD), 71% Child-Pugh B/C) and 18 age/sex-matched healthy control participants (HC) were studied. Quadriceps mass was significantly reduced in ESLD versus HC (-17%), but L3 SMI and MAMC were unchanged. Quadriceps IMAT percentage was increased in ESLD (+103%). Handgrip strength (-15%), peak isokinetic torque (-29%), and chair rise time (+56%) were impaired in ESLD. Ultrasound measures of VL thickness (r = 0.56, r = 0.57, r = 0.42) and quadriceps ACSA (r = 0.98, r = 0.86, r = 0.67) correlated to MRI quadriceps ACSA, quadriceps volume and L3 SMI, respectively. Quadriceps muscle mass, quality, and function were impaired in patients with ESLD, whereas conventional assessments of muscle (L3 SMI and MAMC) highlighted no differences between ESLD and HC. Full evaluation of lower limb muscle health is essential in ESLD in order to accurately assess sarcopenia and target future interventions.

Duke Activity Status Index and Liver Frailty Index predict mortality in ambulatory patients with advanced chronic liver disease: A prospective, observational study.

BACKGROUND: There remains a lack of consensus on how to assess functional exercise capacity and physical frailty in patients with advanced chronic liver disease (CLD) being assessed for liver transplantation (LT). Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. AIM: To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. METHODS: We recruited patients from outpatient clinics at University Hospitals Birmingham, UK (2018-2019). We prospectively collated the DASI and LFI to identify the prevalence of, respectively, functional capacity and physical frailty, and to evaluate their accuracy in predicting overall and pre-LT mortality. RESULTS: We studied 307 patients (57% male; median age 54 years; UKELD 52). Median DASI score was 28.7 (IQR 16.2-50.2), mean LFI was 3.82 (SD = 0.72), and 81% were defined either 'pre-frail' or 'frail'. Female sex and hyponatraemia were significant independent predictors of both DASI and LFI. Age and encephalopathy were significant independent predictors of LFI, while BMI significantly predicted DASI. DASI and LFI were significantly related to overall (HR 0.97, p = 0.001 [DASI], HR 2.04, p = 0.001 [LFI]) and pre-LT mortality (HR 0.96, p = 0.02 [DASI], HR 1.94, p = 0.04 [LFI]). CONCLUSIONS: Poor functional exercise capacity and physical frailty are highly prevalent among ambulatory patients with CLD who are being assessed for LT. The DASI and LFI are simple, low-cost tools that predict overall and pre-LT mortality. Implementation of both should be considered in all outpatients with CLD to highlight those who may benefit from targeted nutritional and exercise interventions.

Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease.

Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes.

An overview of the challenges and key initiatives in hepatology practice in the UK in 2022: a cautionary tale, but reasons for optimism - British Association for the Study of the Liver (BASL) Annual Meeting 2022 Conference Report.

The mortality and working years lost from liver cirrhosis present a significant challenge both in the UK and globally. The recent British Association for the Study of the Liver (BASL) annual meeting highlighted the inequities present across the UK in terms of the burden of liver disease and access to specialist services. Innovative new ways of working and novel technologies are needed to address the growing demands of the specialty, while bearing in mind the need for sustainable and patient-focused interventions.

The Effect of Ex Vivo Human Serum from Liver Disease Patients on Cellular Protein Synthesis and Growth.

Sarcopenia is a common complication affecting liver disease patients, yet the underlying mechanisms remain unclear. We aimed to elucidate the cellular mechanisms that drive sarcopenia progression using an in vitro model of liver disease. C2C12 myotubes were serum and amino acid starved for 1-h and subsequently conditioned with fasted ex vivo serum from four non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD), four decompensated end-stage liver disease patients (ESLD) and four age-matched healthy controls (CON) for 4- or 24-h. After 4-h C2C12 myotubes were treated with an anabolic stimulus (5 mM leucine) for 30-min. Myotube diameter was reduced following treatment with serum from ESLD compared with CON (−45%) and NAFLD (−35%; p < 0.001 for both). A reduction in maximal mitochondrial respiration (24% and 29%, respectively), coupling efficiency (~12%) and mitophagy (~13%) was identified in myotubes conditioned with NAFLD and ESLD serum compared with CON (p < 0.05 for both). Myostatin (43%, p = 0.04) and MuRF-1 (41%, p = 0.03) protein content was elevated in myotubes treated with ESLD serum compared with CON. Here we highlight a novel, experimental platform to further probe changes in circulating markers associated with liver disease that may drive sarcopenia and develop targeted therapeutic interventions.

Assessment of the Frail Patient With End-Stage Liver Disease: A Practical Overview of Sarcopenia, Physical Function, and Disability.

Frailty has emerged as a powerful predictor of clinical outcomes (e.g., decompensation, hospitalization, mortality) in patients with end-stage liver disease (ESLD). It is therefore of paramount importance that all patients with ESLD undergo an assessment of frailty, to support life and death decision making (i.e., candidacy for critical care, transplantation) and aid with prioritization of evolving prehabilitation services (i.e., nutrition, physiotherapy, psychotherapy). This article aims to provide a practical overview of the recent advances in the clinical, radiological, and remote assessment tools of the frail patient with ESLD. Historically, clinicians have incorporated an assessment of frailty using the "end-of-the-bed test" or "eyeball test" into their clinical decision making. However, over the last decade, numerous nonspecific and specific tools have emerged. The current evidence supports the use of a combination of simple, user-friendly, objective measures to first identify frailty in ESLD (notably Clinical Frailty Scale, Liver Frailty Index), followed by a combination of serial tools to assess specifically sarcopenia (i.e., muscle ultrasound), physical function (i.e., chair stands, hand grip strength), functional capacity (i.e., 6-minute walk test), and physical disability (i.e., activities of daily living).

Sleep and liver disease: a bidirectional relationship.

Sleep is a complex, highly regulated process essential for human health and wellbeing. Increasingly, sleep-wake disturbance has been implicated in the pathogenesis of chronic liver disease, particularly the development and progression of non-alcoholic fatty liver disease and alcohol-related liver disease. Patients with cirrhosis also have a high burden of sleep abnormalities with substantial implications for their quality of life and physical health. This Review summarises the epidemiology and pathophysiology of sleep-wake disturbance in liver disease and discusses the multiple converging pathways leading to abnormal sleeping patterns in patients with cirrhosis. This includes contributions from altered melatonin metabolism, neuromuscular complications, and aberrant thermoregulation. In turn, a vicious cycle is established whereby disrupted sleep can further contribute to liver disease progression. We also begin to unravel the complex, interlinking relationship between sleep-wake disturbance and hepatic encephalopathy, discussing both overlapping and distinct mechanisms and clinical features. Finally, we summarise the current and future therapeutic approaches aiming to improve sleep quality in patients with cirrhosis.

Evaluation of the mechanisms of sarcopenia in chronic inflammatory disease: protocol for a prospective cohort study.

BACKGROUND: Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. METHODS: This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. DISCUSSION: This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. ETHICS AND DISSEMINATION: The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734496.

Review article: impact of exercise on physical frailty in patients with chronic liver disease.

BACKGROUND: Physical frailty is common in chronic liver disease and the setting of liver transplantation. It is associated with poor quality of life, increased hospitalisation and mortality. Despite this, the impact of exercise in these patients remains poorly understood. AIM: To summarise the impact of physical exercise on physical frailty in patients with chronic liver disease until after liver transplantation. METHODS: A MEDLINE and PubMed search was undertaken using the terms; "physical activity", "functional capacity", "exercise", "prehabilitation", "frailty", "liver cirrhosis", "liver failure", "liver transplantation" "chronic liver disease" and "end-stage liver disease" from January 1990 to June 2019. RESULTS: Eleven studies (five randomised controlled, five observational, one case study) demonstrated that exercise improves VO2 peak, anaerobic threshold, 6-minute walk distance, muscle mass/function and quality of life in patients with compensated and decompensated cirrhosis. Improvements were most significant with a combination of aerobic and resistance exercises at moderate-high intensity. The studies were small (n = 1-50) and mainly focused on supervised, hospital-based exercises, excluding patients with significant liver failure (MELD > 12). Seven studies (four randomised controlled and three observational) demonstrated that predominantly supervised (only one home-based) aerobic exercise after liver transplantation improves aerobic capacity, muscle mass/strength and quality of life. There was marked heterogeneity in timing, intensity and type of exercises. CONCLUSION: Exercise improves key components of physical frailty (functional/aerobic capacity, sarcopenia) and quality of life in chronic liver disease and after liver transplantation. Understanding the type, compliance, intensity and duration of exercise and its impact on hard clinical outcomes should be the focus of future large controlled clinical trials.