Serum and plasma protein biomarkers associated with frailty in patients with cirrhosis.

Frailty, a clinical phenotype of decreased physiological reserve, is a strong determinant of adverse health outcomes in patients with cirrhosis. The only cirrhosis-specific frailty metric is the Liver Frailty Index (LFI), which must be administered in person and may not be feasible for every clinical scenario. We sought to discover candidate serum/plasma protein biomarkers that could differentiate frail from robust patients with cirrhosis. A total of 140 adults with cirrhosis awaiting liver transplantation in the ambulatory setting with LFI assessments and available serum/plasma samples were included. We selected 70 pairs of patients on opposite ends of the frailty spectrum (LFI>4.4 for frail and LFI<3.2 for robust) who were matched by age, sex, etiology, HCC, and Model for End-Stage Liver Disease-Sodium. Twenty-five biomarkers with biologically plausible associations with frailty were analyzed using ELISA by a single laboratory. Conditional logistic regression was used to examine their association with frailty. Of the 25 biomarkers analyzed, we identified 7 proteins that were differentially expressed between frail and robust patients. We observed differences in 6 of the 7 proteins in the expected direction: (a) higher median values in frail versus robust with growth differentiation factor-15 (3682 vs. 2249 pg/mL), IL-6 (17.4 vs. 6.4 pg/mL), TNF-alpha receptor 1 (2062 vs. 1627 pg/mL), leucine-rich alpha-2 glycoprotein (44.0 vs. 38.6 µg/mL), and myostatin (4066 vs. 6006 ng/mL) and (b) lower median values in frail versus robust with alpha-2-Heremans-Schmid glycoprotein (0.11 vs. 0.13 mg/mL) and free total testosterone (1.2 vs. 2.4 ng/mL). These biomarkers represent inflammatory, musculoskeletal, and endocrine/metabolic systems, reflecting the multiple physiological derangements observed in frailty. These data lay the foundation for confirmatory work and development of a laboratory frailty index for patients with cirrhosis to improve diagnosis and prognostication.

Psychological contributors to the frail phenotype: The association between resilience and frailty in patients with cirrhosis.

We examined whether a key psychological trait-resilience, defined as one's ability to recover quickly from difficulties-contributes to the frail phenotype in patients with cirrhosis. Included were 300 adult patients with cirrhosis who underwent outpatient physical frailty testing using the Liver Frailty Index and resilience testing using the Connor-Davidson Resilience Scale (CD-RISC). The Liver Frailty Index was categorized as robust, prefrail-robust, prefrail-frail, and frail; CD-RISC was categorized using population norms as: least, less, more, and most resilient. Linear regression was used to assess factors associated with frailty (by the Liver Frailty Index per 0.1 unit change). Among the most resilient, only 10% were frail; among the least resilient, 29% were frail. In univariable analysis, resilience was strongly associated with the Liver Frailty Index (coef = -0.13 per point increase; 95% confidence interval [CI], -0.20 to -0.60; P < .001) and remained significantly associated with frailty in multivariable adjustment (coef = -0.13, 95% CI -0.19 to -0.07; P < .001). Low resilience is strongly associated with the frail phenotype in patients with cirrhosis. Given that resilience is modifiable, our data suggest that effective interventions to mitigate frailty should include strategies to build resilience in patients with low baseline resilience.

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.

Variation in skeletal muscle mass among patients with cirrhosis of different self-identified race/ethnicity.

Skeletal muscle index (SMI) remains a strong predictor of mortality in cirrhosis patients. However, the extent to which SMI varies by race/ethnicity has not been fully evaluated. Among 317 patients, 55% identified themselves as non-Hispanic White (NHW), 26% Hispanic White (HW), 13% Asian, and 6% Black. There was significant variation in SMI by race/ethnicity; median SMI was lowest in Asian and highest in Black patients. There were significant differences of sarcopenia by race/ethnicity using established SMI cutpoints: 48% NHW, 33% HW, 67% Asian, and 37% Black (P = 0.003). Using these cutpoints, SMI was significantly associated with waitlist mortality only in NHW patients but not in other racial/ethnic groups.

Symptom Burden Is Associated with Increased Emergency Department Utilization among Patients with Cirrhosis.

Background: Patients with cirrhosis have significant morbidity and mortality, as well as substantial symptom burden. Objective: We investigated the relationship between symptom burden and inpatient health care utilization among patients with cirrhosis. Methods: Adult patients with cirrhosis being evaluated for or awaiting liver transplantation at an academic institution in the United States completed the Edmonton Symptom Assessment Scale (ESAS), a validated symptom evaluation tool with total scores ranging from 0 to 90. The outcomes of interest were emergency department (ED) visits, nonelective hospitalizations, hospital days, intensive care unit (ICU) admissions, and 30-day readmissions within 6 months. Adjusted incidence rate ratios (IRRs) were used to examine the relationship between ESAS scores and outcomes. Results: Of 233 patients (43% female, median age 61), the median total ESAS score was 16 (interquartile range 6-30). Higher total scores on the ESAS were associated with increased ED visits, hospitalizations, hospital days, and ICU days (all p < 0.04). After adjusting for age, gender, and Model for End-Stage Liver Disease-sodium, ESAS total score remained an independent predictor of ED visits (IRR 1.05, confidence interval [95% CI] 1.00-1.10, p = 0.03). Multivariate ESAS subscale analyses revealed that the physical symptom score was associated with ED visits (IRR 1.09, 95% CI 1.02-1.16, p = 0.01), but the psychological symptom score was not (IRR 1.03, 95% CI 1.00-1.08, p = 0.15). Conclusions: Patient-reported symptoms, particularly physical symptoms, are independently associated with ED visits among patients with cirrhosis being considered for liver transplantation. Further research is needed to examine whether addressing symptoms more aggressively, such as with palliative care co-management, could decrease ED utilization in this population.

Frailty is strongly associated with self-reported symptom burden among patients with cirrhosis.

OBJECTIVES: Although patients with cirrhosis often experience debilitating symptoms, few are referred for palliative care. Frailty is increasingly incorporated in liver transplantation evaluation and has been associated with symptom burden in other populations. We hypothesized that frail patients with cirrhosis are highly symptomatic and thus are likely to benefit from palliative care. METHODS: Patients with cirrhosis undergoing outpatient liver transplantation evaluation completed the Liver Frailty Index (grip strength, chair stands and balance) and a composite of validated measures including the Edmonton Symptom Assessment Scale, distress and quality of life (QOL) measures. RESULTS: Of 233 patients (median age 61 years, 43% women), 22% were robust, 59% prefrail and 19% frail. Overall, 38% of patients reported ≥1 severe symptoms based on preestablished Edmonton Symptom Assessment Scale criteria. Higher frailty categories were associated with increased prevalence of pain, dyspnea, fatigue, nausea, poor appetite, drowsiness, depression and poor well-being (test for trend, all P < 0.05). Frail patients were also more likely to report psychological distress and poor QOL (all P < 0.01). In univariate analysis, each 0.5 increase in liver frailty index was associated with 44% increased odds of experiencing ≥1 severe symptoms [95% confidence interval (CI), 1.2-1.7, P < 0.001], which persisted (odds ratio, 1.3, 95% CI, 1.0-1.6, P = 0.004) even after adjusting for Model for End Stage Liver Disease-Sodium, ascites, hepatic encephalopathy and age. CONCLUSION: In patients with cirrhosis, frailty is strongly associated with physical/psychological symptoms, including pain and depression and poor QOL. Frail patients with cirrhosis may benefit from palliative care co-management to address symptoms and improve QOL.