Use of a Mobile-Assisted Telehealth Regimen to Increase Exercise in Transplant Candidates: A Home-Based Prehabilitation Pilot and Feasibility Trial.

INTRODUCTION: Physical fitness assessed by the Liver Frailty Index (LFI) and 6-minute walk test (6MWT) informs the prognosis of liver transplant candidates, although there are limited data on its reversibility after prehabilitation. On a home-based exercise trial, we aimed to improve LFI and 6MWT and to investigate trial feasibility and intervention adherence. METHODS: Liver transplant candidates with cirrhosis wore a personal activity tracker and used Exercise and Liver FITness app for 14 weeks, including a 2-week technology acclimation run-in. The 12-week intervention consisted of Exercise and Liver FITness app plus personal activity tracker and 15-/30-minute weekly calls with a physical activity coach aiming to complete ≥2 video-training sessions/week, or ≥500 step/d baseline increase for ≥8 weeks. We defined feasibility as ≥66% of subjects engaging in the intervention phase and adherence as ≥50% subjects meeting training end point. RESULTS: Thirty-one patients (61 ± 7 years, 71% female, model for end-stage liver disease 17 ± 5, ∼33% frail) consented and 21 (68%) started the intervention. In the 15 subjects who completed the study, LFI improved from 3.84 ± 0.71 to 3.47 ± 0.90 ( P = 0.03) and 6MWT from 318 ± 73 to 358 ± 64 m ( P = 0.005). Attrition reasons included death (n = 4) and surgery (n = 2). There was 57% adherence, better for videos than for walking, although daily steps significantly increased (3,508 vs baseline: 1,260) during best performance week. One adverse event was attributed to the intervention. DISCUSSION: Our clinical trial meaningfully improved LFI by 0.4 and 6MWT by 41 m and met feasibility/adherence goals. In-training daily step increase supported physical self-efficacy and intervention uptake, but maintenance remained a challenge despite counseling.

Elevated serum globulin fraction as a biomarker of multiyear disease severity in inflammatory bowel disease.

Background: Serum protein reflects albumin and globulin levels, both of which can be altered in inflammatory bowel disease (IBD). The implications of a high globulin fraction in IBD are unknown. We hypothesized that a high globulin fraction may function independently of albumin as a biomarker of disease severity in IBD patients over a multiyear period. Methods: This was an observational study from a prospective IBD registry of a tertiary care center. High globulin fraction was defined as an elevated globulin level >4 g/dL. Data collected included patient demographics, medication exposures, quality-of-life scores, disease activity, emergency department visits, telephone calls, hospitalizations, and IBD-related surgeries over a 4-year period. Comparisons between patients with a high globulin fraction and those without were performed using Pearson's chi-squared, Student's and Mann-Whitney tests. Multivariate analyses were used to assess the relationship between high globulin fraction and healthcare utilization. Results: A total of 1767 IBD patients with a 4-year follow up were included: 53.5% female, mean age 48.4±15.1 years, and 65.4% with Crohn's disease. Of these patients, 446 (25.2%) presented with elevated globulin fraction. Patients with a high globulin fraction were more likely to be hospitalized during the study period. This result remained significant after multivariate analysis for both Crohn's disease patients and those with ulcerative colitis. Conclusion: A high globulin fraction is independently associated with greater disease severity and healthcare utilization in IBD patients, and may function as a routinely available biomarker of a more severe future disease trajectory.

Sarcopenic visceral obesity is associated with increased post-liver transplant mortality in acutely ill patients with cirrhosis.

"Sarcopenic obesity" refers to a condition of low muscle mass in the context of obesity, though may be difficult to assess in patients with cirrhosis who are acutely ill. We aimed to define sarcopenic visceral obesity (SVO) using CT-based skeletal muscle index (SMI) and visceral-to-subcutaneous adipose tissue ratio (VSR) to examine its association with post-transplant mortality. We analyzed 116 adult inpatients with cirrhosis who were urgently listed and transplanted between 1/2005 and 12/2017 at 4 North American transplant centers. SVO was defined as patients with sarcopenia (SMI <50 cm2 /m2 in men and <39 cm2 /m2 in women) and visceral obesity (VSR ≥ 1.54 in men and ≥1.37 in women). The percentage who met criteria for sarcopenia, visceral obesity, and SVO were 45%, 42%, and 20%, respectively. Cumulative rates of post-transplant mortality were higher in patients with SVO compared to patients with sarcopenia or visceral obesity alone at 36 months (39% vs. 14% vs. 8%) [logrank p = .01]. In univariable regression, SVO was associated with post-transplant mortality (HR 2.92, 95%CI 1.04-8.23) and remained significant after adjusting for age, sex, diabetes, encephalopathy, hepatocellular carcinoma, and MELD-Na (HR 3.50, 95%CI 1.10-11.15). In conclusion, SVO is associated with increased post-transplant mortality in acutely ill patients with cirrhosis.

Low Daily Step Count Is Associated With a High Risk of Hospital Admission and Death in Community-Dwelling Patients With Cirrhosis.

BACKGROUND & AIMS: Daily step count measures cardiorespiratory fitness and has been associated with clinical outcomes. However, its utility in patients with cirrhosis remains largely unexplored. We aimed to investigate the association between step count, frailty metrics, and clinical outcomes in cirrhosis. METHODS: All participants underwent frailty evaluation with the liver frailty index, 6-minute walk test, and gait speed test. To monitor step count, participants were given a personal activity tracker (PAT). A subset also was invited to use Exercise and Liver FITness (EL-FIT). Daily step counts from the first week of PAT use and frailty metrics were investigated as predictors of hospital admission and mortality. RESULTS: There were 116 patients included (age, 56 ± 11 y; male, 55%; body mass index, 31 ± 7; model for end-stage liver disease-sodium, 15 ± 7). The main etiologies of cirrhosis were alcohol-related (33%) and nonalcoholic steatohepatitis (30%). Monitoring for the week was accomplished in 80% of participants given both PAT+EL-FIT vs 62% in those with PAT only (P = .04). During follow-up evaluation, hospital admission was observed in 55% and death in 15%. Kaplan-Meir curves showed increased readmission and deaths among patients performing in the lowest quartile (ie, <1200 steps/d). When adjusted by model for end-stage liver disease-sodium and EL-FIT use, the lowest quartile was associated with hospital admission and death (hazard ratio, HR [95% confidence interval], 1.90 [1.09-3.30] and 3.46 [1.23-9.68], respectively), along with the 6-minute walk test (HR, 0.63 [0.47-0.83] and 0.66 [0.44-0.99] per 100 m, respectively) and gait speed test (HR, 0.29 [0.11-0.72] and 0.21 [0.05-0.84], respectively). CONCLUSIONS: Daily step count predicted hospital admission and mortality rates in patients with cirrhosis, similar to the current standard frailty metrics. Incorporation of a physical training-dedicated smartphone application was associated with increased PAT use and step reporting.

Cognitive Impairment and Physical Frailty in Patients With Cirrhosis.

Physical frailty and impaired cognition are common in patients with cirrhosis. Physical frailty can be assessed using performance-based tests, but the extent to which impaired cognition may impact performance is not well characterized. We assessed the relationship between impaired cognition and physical frailty in patients with cirrhosis. We enrolled 1,623 ambulatory adult patients with cirrhosis waiting for liver transplantation at 10 sites. Frailty was assessed with the liver frailty index (LFI; "frail," LFI ≥ 4.4). Cognition was assessed at the same visit with the number connection test (NCT); continuous "impaired cognition" was examined in primary analysis, with longer NCT (more seconds) indicating worse impaired cognition. For descriptive statistics, "impaired cognition" was NCT ≥ 45 seconds. Linear regression associated frailty and impaired cognition; competing risk regression estimated subhazard ratios (sHRs) of wait-list mortality (i.e., death/delisting for sickness). Median NCT was 41 seconds, and 42% had impaired cognition. Median LFI (4.2 vs. 3.8) and rates of frailty (38% vs. 20%) differed between those with and without impaired cognition. In adjusted analysis, every 10-second NCT increase associated with a 0.08-LFI increase (95% confidence interval [CI], 0.07-0.10). In univariable analysis, both frailty (sHR, 1.63; 95% CI, 1.43-1.87) and impaired cognition (sHR, 1.07; 95% CI, 1.04-1.10) associated with wait-list mortality. After adjustment, frailty but not impaired cognition remained significantly associated with wait-list mortality (sHR, 1.55; 95% CI, 1.33-1.79). Impaired cognition mediated 7.4% (95% CI, 2.0%-16.4%) of the total effect of frailty on 1-year wait-list mortality. Conclusion: Patients with cirrhosis with higher impaired cognition displayed higher rates of physical frailty, yet frailty independently associated with wait-list mortality while impaired cognition did not. Our data provide evidence for using the LFI to understand mortality risk in patients with cirrhosis, even when concurrent impaired cognition varies.

Frailty, mortality, and health care utilization after liver transplantation: From the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study.

BACKGROUND AND AIMS: Frailty is a well-established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have undergone LT is unknown. APPROACH AND RESULTS: Adult LT recipients from 8 US centers (2012-2019) were included. Pre-LT frailty was assessed in the ambulatory setting using the Liver Frailty Index (LFI). "Frail" was defined by an optimal cut point of LFI ≥ 4.5. We used the 75th percentile to define "prolonged" post-LT length of stay (LOS; ≥12 days), intensive care unit (ICU) days (≥4 days), and inpatient days within 90 post-LT days (≥17 days). Of 1166 LT recipients, 21% were frail pre-LT. Cumulative incidence of death at 1 and 5 years was 6% and 16% for frail and 4% and 10% for nonfrail patients (overall log-rank p = 0.02). Pre-LT frailty was associated with an unadjusted 62% increased risk of post-LT mortality (95% CI, 1.08-2.44); after adjustment for body mass index, HCC, donor age, and donation after cardiac death status, the HR was 2.13 (95% CI, 1.39-3.26). Patients who were frail versus nonfrail experienced a higher adjusted odds of prolonged LT LOS (OR, 2.00; 95% CI, 1.47-2.73), ICU stay (OR, 1.56; 95% CI, 1.12-2.14), inpatient days within 90 post-LT days (OR, 1.72; 95% CI, 1.25-2.37), and nonhome discharge (OR, 2.50; 95% CI, 1.58-3.97). CONCLUSIONS: Compared with nonfrail patients, frail LT recipients had a higher risk of post-LT death and greater post-LT health care utilization, although overall post-LT survival was acceptable. These data lay the foundation to investigate whether targeting pre-LT frailty will improve post-LT outcomes and reduce resource utilization.

Prehabilitation-Driven Changes in Frailty Metrics Predict Mortality in Patients With Advanced Liver Disease.

INTRODUCTION: Frailty is a predictor of morbidity and mortality in cirrhosis. Although evidence for prehabilitation is promising, the data for liver transplant (LT) candidates are limited. The primary aim of this study was to evaluate the effect of a novel prehabilitation strategy on changes in frailty metrics and survival in LT candidates. The secondary aim was to determine liver-related and extrahepatic conditions associated with frailty. METHODS: In this ambispective cohort study, all patients underwent frailty assessment using the liver frailty index (LFI), 6-minute walk test, and gait speed test performed by a dedicated physical therapist. Home-based exercise prescription was individualized to each patient's baseline physical fitness. RESULTS: We included 517 patients (59% men, median age 61 years, and a model for end-stage liver disease score of 12) evaluated during 936 PT visits. Frailty metrics were affected by age, sex, and liver-related parameters, but not by model for end-stage liver disease. Patients with nonalcoholic fatty liver disease and alcohol-related cirrhosis had worse frailty metrics by all tools. We demonstrated the feasibility of prehabilitation in improving both LFI and 6-minute walk test, particularly in adherent patients. A median LFI improvement of 0.3 in frail patients was associated with improved survival in univariate analysis. Compliance with physical therapist visits (hazards ratio = 0.35 [0.18-0.67] for 2 visits and hazards ratio = 0.54 [0.31-0.94] for ≥3 visits) was independently associated with increased survival. DISCUSSION: Prehabilitation improves frailty metrics in LT candidates and is associated with a survival advantage. Our findings provide a framework for the standardized prehabilitation program in LT candidates while prioritizing compliance, adherence, and on-training LFI goal accomplishment.

The relationship between frailty and cirrhosis etiology: From the Functional Assessment in Liver Transplantation (FrAILT) Study.

BACKGROUND & AIMS: Cirrhosis leads to malnutrition and muscle wasting that manifests as frailty, which may be influenced by cirrhosis aetiology. We aimed to characterize the relationship between frailty and cirrhosis aetiology. METHODS: Included were adults with cirrhosis listed for liver transplantation (LT) at 10 US centrer who underwent ambulatory testing with the Liver Frailty Index (LFI; 'frail' = LFI ≥ 4.4). We used logistic regression to associate aetiologies and frailty, and competing risk regression (LT as the competing risk) to determine associations with waitlist mortality (death/delisting for sickness). RESULTS: Of 1,623 patients, rates of frailty differed by aetiology: 22% in chronic hepatitis C, 31% in alcohol-associated liver disease (ALD), 32% in non-alcoholic fatty liver disease (NAFLD), 21% in autoimmune/cholestatic and 31% in 'other' (P < .001). In univariable logistic regression, ALD (OR 1.53, 95% CI 1.12-2.09), NAFLD (OR 1.64, 95% CI 1.18-2.29) and 'other' (OR 1.58, 95% CI 1.06-2.36) were associated with frailty. In multivariable logistic regression, only ALD (OR 1.40; 95% 1.01-1.94) and 'other' (OR 1.59; 95% 1.05-2.40) remained associated with frailty. A total of 281 (17%) patients died/were delisted for sickness. In multivariable competing risk regression, LFI was associated with waitlist mortality (sHR 1.05, 95% CI 1.03-1.06), but aetiology was not (P > .05 for each). No interaction between frailty and aetiology on the association with waitlist mortality was found (P > .05 for each interaction term). CONCLUSIONS: Frailty is more common in patients with ALD, NAFLD and 'other' aetiologies. However, frailty was associated with waitlist mortality independent of cirrhosis aetiology, supporting the applicability of frailty across all cirrhosis aetiologies.

Inpatient Frailty Assessment Is Feasible and Predicts Nonhome Discharge and Mortality in Decompensated Cirrhosis.

Objective inpatient frailty assessments in decompensated cirrhosis are understudied. We examined the feasibility of inpatient frailty measurements and associations with nonhome discharge, readmission, and all-cause mortality among patients admitted for cirrhosis complications. We conducted a prospective study at 3 liver transplantation (LT) centers. Frailty was assessed using the liver frailty index (LFI). Multivariable logistic and competing risk models evaluated associations between frailty and clinical outcomes. We included 211 patients with median MELD-Na score 21 (interquartile range [IQR],15-27); 96 (45%) were women, and 102 (48%) were on the LT waiting list. At a median follow-up of 8.3 months, 29 patients (14%) were nonhome discharged, 144 (68%) were readmitted, 70 (33%) underwent LT, and 44 (21%) died. A total of 124 patients (59%) were frail, with a median LFI of 4.71 (IQR, 4.07-5.54). Frail patients were older (mean, 59 versus 54 years) and more likely to have chronic kidney disease (40% versus 20%; P = 0.002) and coronary artery disease (17% versus 7%; P = 0.03). Frailty was associated with hospital-acquired infections (8% versus 1%; P = 0.02). In multivariable models, LFI was associated with nonhome discharge (odds ratio, 1.81 per 1-point increase; 95% confidence interval [CI], 1.14-2.86). Frailty (LFI≥4.5) was associated with all-cause mortality in models accounting for LT as competing risk (subhazard ratio [sHR], 2.4; 95% CI, 1.13-5.11); results were similar with LFI as a continuous variable (sHR, 1.62 per 1-point increase; 95% CI, 1.15-2.28). A brief, objective inpatient frailty assessment was feasible and predicted nonhome discharge and mortality in decompensated cirrhosis. Inpatient point-of-care frailty assessment prior to hospital discharge can be useful for risk stratification and targeted interventions to improve physical fitness and reduce adverse outcomes.

Wearables, Physical Activity, and Exercise Testing in Liver Disease.

Physical inactivity is a major cause of deterioration in all forms of advanced liver disease. It is especially important as a driver of the components of the metabolic syndrome, with nonalcoholic fatty liver disease rapidly becoming the dominant cause of liver-related death worldwide. Growing realization of the health benefits of moderate-to-vigorous physical activity has captured the interest of persons who desire to improve their health, including those at risk for chronic liver injury. They are increasingly adopting wearable activity trackers to measure the activity that they seek to improve. Improved physical activity is the key lifestyle behavior that can improve cardiorespiratory fitness, which is most accurately measured with cardiopulmonary exercise testing (CPET). CPET is showing promise to identify risk and predict outcomes in transplant hepatology. Team effort among engaged patients, social support networks, and clinicians supported by web-based connectivity is needed to fully exploit the benefits of physical activity tracking.

Clinical Characteristics of Inflammatory Bowel Disease Patients Requiring Long-Term Parenteral Support in the Present Era of Highly Effective Biologic Therapy.

BACKGROUND: Despite advances in the medical management of inflammatory bowel disease (IBD), a subset of patients may require extensive surgery, leading to short-bowel syndrome/intestinal failure requiring long-term home parenteral nutrition (PN) or customized intravenous fluid (IVF) support. Our aim was to further define the characteristics of IBD patients requiring home PN/IVF. METHODS: This is an observational study from a prospective IBD research registry. Patients receiving long-term home PN/IVF support during 2009-2015 were identified and compared with remaining IBD patients. Demographics, surgical history, smoking, narcotic use, IBD treatment, healthcare charges, and presence of biomarkers were reviewed. The IBD-PN group was stratified into 3 groups based on median healthcare charges. RESULTS: Of 2359 IBD patients, there were 25 (1%, 24 with Crohn's disease) who required home PN/IVF, and 250 randomly selected IBD patients matched for disease type formed the control population. Median duration of PN use was 27 months (interquartile range, 11-66). PN use was significantly associated with smoking, narcotic use, IBD-related operations, and lower quality-of-life scores. Among IBD-PN patients, 7 of 25 (28%, 3 after use of teduglutide) were able to successfully discontinue this modality. Median healthcare charges in the IBD-PN group were $51,456 annually. Median charges in the controls were $3427. Period prevalence mortality was 11.5% in IBD-PN and 3.8% in controls. CONCLUSIONS: IBD patients requiring long-term home PN/IVF support are a small minority in the present era of immunomodulator/biologic therapy. These refractory patients have a 15-fold increase in annual median healthcare charges compared with control IBD patients.

Serum IgG4 Subclass Deficiency Defines a Distinct, Commonly Encountered, Severe Inflammatory Bowel Disease Subtype.

BACKGROUND: Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity. METHODS: We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels. RESULTS: We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals. CONCLUSIONS: An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup.

Identifying an Optimal Liver Frailty Index Cutoff to Predict Waitlist Mortality in Liver Transplant Candidates.

BACKGROUND AND AIMS: Frailty, as measured by the Liver Frailty Index (LFI), is associated with liver transplant (LT) waitlist mortality. We sought to identify an optimal LFI cutoff that predicts waitlist mortality. APPROACH AND RESULTS: Adults with cirrhosis awaiting LT without hepatocellular carcinoma at nine LT centers in the United States with LFI assessments were included. Multivariable competing risk analysis assessed the relationship between LFI and waitlist mortality. We identified a single LFI cutoff by evaluating the fit of the competing risk models, searching for the cutoff that gave the best model fit (as judged by the pseudo-log-likelihood). We ascertained the area under the curve (AUC) in an analysis of waitlist mortality to find optimal cutoffs at 3, 6, or 12 months. We used the AUC to compare the discriminative ability of LFI+Model for End Stage Liver Disease-sodium (MELDNa) versus MELDNa alone in 3-month waitlist mortality prediction. Of 1,405 patients, 37 (3%), 82 (6%), and 135 (10%) experienced waitlist mortality at 3, 6, and 12 months, respectively. LFI was predictive of waitlist mortality across a broad LFI range: 3.7-5.2. We identified an optimal LFI cutoff of 4.4 (95% confidence interval [CI], 4.0-4.8) for 3-month mortality, 4.2 (95% CI, 4.1-4.4) for 6-month mortality, and 4.2 (95% CI, 4.1-4.4) for 12-month mortality. The AUC for prediction of 3-month mortality for MELDNa was 0.73; the addition of LFI to MELDNa improved the AUC to 0.79. CONCLUSIONS: LFI is predictive of waitlist mortality across a wide spectrum of LFI values. The optimal LFI cutoff for waitlist mortality was 4.4 at 3 months and 4.2 at 6 and 12 months. The discriminative performance of LFI+MELDNa was greater than MELDNa alone. Our data suggest that incorporating LFI with MELDNa can more accurately represent waitlist mortality in LT candidates.

Association of Frailty and Sex With Wait List Mortality in Liver Transplant Candidates in the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study.

Importance: Female liver transplant candidates experience higher rates of wait list mortality than male candidates. Frailty is a critical determinant of mortality in patients with cirrhosis, but how frailty differs between women and men is unknown. Objective: To determine whether frailty is associated with the gap between women and men in mortality among patients with cirrhosis awaiting liver transplantation. Design, Setting, and Participants: This prospective cohort study enrolled 1405 adults with cirrhosis awaiting liver transplant without hepatocellular carcinoma seen during 3436 ambulatory clinic visits at 9 US liver transplant centers. Data were collected from January 1, 2012, to October 1, 2019, and analyzed from August 30, 2019, to October 30, 2020. Exposures: At outpatient evaluation, the Liver Frailty Index (LFI) score was calculated (grip strength, chair stands, and balance). Main Outcomes and Measures: The risk of wait list mortality was quantified using Cox proportional hazards regression by frailty. Mediation analysis was used to quantify the contribution of frailty to the gap in wait list mortality between women and men. Results: Of 1405 participants, 578 (41%) were women and 827 (59%) were men (median age, 58 [interquartile range (IQR), 50-63] years). Women and men had similar median scores on the laboratory-based Model for End-stage Liver Disease incorporating sodium levels (MELDNa) (women, 18 [IQR, 14-23]; men, 18 [IQR, 15-22]), but baseline LFI was higher in women (mean [SD], 4.12 [0.85] vs 4.00 [0.82]; P = .005). Women displayed worse balance of less than 30 seconds (145 [25%] vs 149 [18%]; P = .003), worse sex-adjusted grip (mean [SD], -0.31 [1.08] vs -0.16 [1.08] kg; P = .01), and fewer chair stands per second (median, 0.35 [IQR, 0.23-0.46] vs 0.37 [IQR, 0.25-0.49]; P = .04). In unadjusted mixed-effects models, LFI was 0.15 (95% CI, 0.06-0.23) units higher in women than men (P = .001). After adjustment for other variables associated with frailty, LFI was 0.16 (95% CI, 0.08-0.23) units higher in women than men (P < .001). In unadjusted regression, women experienced a 34% (95% CI, 3%-74%) increased risk of wait list mortality than men (P = .03). Sequential covariable adjustment did not alter the association between sex and wait list mortality; however, adjustment for LFI attenuated the mortality gap between women and men. In mediation analysis, an estimated 13.0% (IQR, 0.5%-132.0%) of the gender gap in wait list mortality was mediated by frailty. Conclusions and Relevance: These findings demonstrate that women with cirrhosis display worse frailty scores than men despite similar MELDNa scores. The higher risk of wait list mortality that women experienced appeared to be explained in part by frailty.

Introducing EL-FIT (Exercise and Liver FITness): A Smartphone App to Prehabilitate and Monitor Liver Transplant Candidates.

Preserved physical function is key for successful liver transplantation (LT); however, prehabilitation strategies are underdeveloped. We created a smartphone application (app), EL-FIT (Exercise and Liver FITness), to facilitate exercise training in end-stage liver disease (ESLD). In this feasibility study, we tested EL-FIT app usage and the accuracy of physical activity data transfer and obtained feedback from initial users. A total of 28 participants used the EL-FIT app and wore a physical activity tracker for 38 ± 12 days (age, 60 ± 8 years; 57% males; Model for End-Stage Liver Disease-sodium, 19 ± 5). There was fidelity in data transfer from the tracker to the EL-FIT app. Participants were sedentary (1957 [interquartile range, 873-4643] steps/day) at baseline. Level of training assigned by the EL-FIT app agreed with that from a physical therapist in 89% of cases. Participants interacted with all app features (videos, perceived exertion, and gamification/motivational features). We rearranged training data to generate heart rate-validated steps as a marker of performance and showed that 35% of the participants had significant increases in their physical performance. Participants emphasized their interest in having choices to better engage in exercise, and they appreciated the sense of community the EL-FIT app generated. We showed that patients with ESLD are able to use and interact with the EL-FIT app. This novel smartphone app has the potential of becoming an invaluable tool for home-based prehabilitation in LT candidates.

Changes in frailty are associated with waitlist mortality in patients with cirrhosis.

BACKGROUND & AIMS: To date, studies evaluating the association between frailty and mortality in patients with cirrhosis have been limited to assessments of frailty at a single time point. We aimed to evaluate changes in frailty over time and their association with death/delisting in patients too sick for liver transplantation. METHODS: Adults with cirrhosis, listed for liver transplantation at 8 US centers, underwent ambulatory longitudinal frailty testing using the liver frailty index (LFI). We used multilevel linear mixed-effects regression to model and predict changes in LFI (ΔLFI) per 3 months, based on age, gender, model for end-stage liver disease (MELD)-Na, ascites, and hepatic encephalopathy, categorizing patients by frailty trajectories. Competing risk regression evaluated the subhazard ratio (sHR) of baseline LFI and predicted ΔLFI on death/delisting, with transplantation as the competing risk. RESULTS: We analyzed 2,851 visits from 1,093 outpatients with cirrhosis. Patients with severe worsening of frailty had worse baseline LFI and were more likely to have non-alcoholic fatty liver disease, diabetes, or dialysis-dependence. After a median follow-up of 11 months, 223 (20%) of the overall cohort died/were delisted because of sickness. The cumulative incidence of death/delisting increased by worsening ΔLFI group. In competing risk regression adjusted for baseline LFI, age, height, MELD-Na, and albumin, a 0.1 unit change in ΔLFI per 3 months was associated with a 2.04-fold increased risk of death/delisting (95% CI 1.35-3.09). CONCLUSION: Worsening frailty was significantly associated with death/delisting independent of baseline frailty and MELD-Na. Notably, patients who experienced improvements in frailty had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty, using the LFI, in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty. LAY SUMMARY: Frailty, as measured at a single time point, is predictive of death in patients with cirrhosis, but whether changes in frailty over time are associated with death is unknown. In a study of over 1,000 patients with cirrhosis who underwent frailty testing, we demonstrate that worsening frailty is strongly linked with mortality, regardless of baseline frailty and liver disease severity. Notably, patients who experienced improvements in frailty over time had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty.

Frailty as Tested by Gait Speed Is a Risk Factor for Liver Transplant Respiratory Complications.

OBJECTIVES: Frailty and sarcopenia are known risk factors for adverse liver transplant outcomes and mortality. We hypothesized that frailty or sarcopenia could identify the risk for common serious transplant-related adverse respiratory events. METHODS: For 107 patients (74 men, 33 women) transplanted over 1 year, we measured frailty with gait speed, chair stands, and Karnofsky Performance Scale (KPS) and sarcopenia with Skeletal Muscle Index on computed tomography at L3. We recorded the stress-tested cardiac double product as an index of cardiac work capacity. Outcomes included days of intubation, aspiration, clinical pneumonia, reintubation/tracheostomy, days to discharge, and survival. We modeled the outcomes using unadjusted regression and multivariable analyses controlled for (i) age, sex, and either Model for End-Stage Liver Disease-Na (MELDNa) or Child-Turcotte-Pugh scores, (ii) hepatocellular carcinoma status, and (iii) chronic obstructive pulmonary disease and smoking history. Subgroup analysis was performed for living donor liver transplant and deceased donor liver transplant recipients. RESULTS: Gait speed was negatively associated with aspiration and pulmonary infection, both in unadjusted and MELDNa-adjusted models (adjusted odds ratio for aspiration 0.10 [95% confidence interval [CI] 0.02-0.67] and adjusted odds ratio for pulmonary infection 0.12 [95% CI 0.02-0.75]). Unadjusted and MELDNa-adjusted models for gait speed (coefficient -1.47, 95% CI -2.39 to -0.56) and KPS (coefficient -3.17, 95% CI -5.02 to -1.32) were significantly associated with shorter intubation times. No test was associated with length of stay or need for either reintubation or tracheostomy. DISCUSSION: Slow gait speed, an index of general frailty, indicates significant risk for post-transplant respiratory complications. Intervention to arrest or reverse frailty merits exploration as a potentially modifiable risk factor for improving transplant respiratory outcomes.