Association of biological aging with frailty and post-transplant outcomes among adults with cirrhosis.

Frailty is classically associated with advanced age but is also an important predictor of clinical outcomes in comparatively young adults with cirrhosis. We examined the association of biological aging with frailty and post-transplant outcomes in a pilot of adults with cirrhosis undergoing liver transplantation (LT). Frailty was measured via the Liver Frailty Index (LFI). The primary epigenetic clock DNA methylation (DNAm) PhenoAge was calculated from banked peripheral blood mononuclear cells; we secondarily explored two first-generation clocks (Hannum; Horvath) and two additional second-generation clocks (GrimAge; GrimAge2). Twelve adults were included: seven frail (LFI ≥ 4.4, mean age 55 years) and five robust (LFI < 3.2, mean age 55 years). Mean PhenoAge age acceleration (AgeAccel) was + 2.5 years (P = 0.23) for frail versus robust subjects. Mean PhenoAge AgeAccel was + 2.7 years (P = 0.19) for subjects who were readmitted or died within 30 days of discharge post-LT versus those without this outcome. When compared with first-generation clocks, the second-generation clocks demonstrated greater average AgeAccel for subjects with frailty or poor post-LT outcomes. Measuring biological age using DNAm-derived epigenetic clocks is feasible in adults undergoing LT. While frail and robust subjects had the same average chronological age, average biological age as measured by second-generation epigenetic clocks tended to be accelerated among those who were frail or experienced a poor post-LT outcome. These results suggest that frailty in these relatively young subjects with cirrhosis may involve similar aging mechanisms as frailty classically observed in chronologically older adults and warrant validation in a larger cohort.

Prevalence of cognitive impairment in liver transplant recipients.

Liver transplant (LT) recipients have a high burden of cognitive impairment risk factors identified in other populations, yet little work has explored cognition in the United States LT population. We characterized prevalence of cognitive impairment (CI) in LT recipients pre-LT and ≥3 months post-LT. Adult LT recipients with cirrhosis but without active pre-LT hepatic encephalopathy (HE) were screened for CI using the Montreal Cognitive Assessment (MoCA) for CI (MoCA <24) both pre-LT and ≥3 months post-LT. The association between cognitive performance and recipient characteristics was assessed using logistic regression. Of 107 LT recipients, 36% had pre-LT CI and 27% had post-LT CI [median (Q1-Q3) MoCA 26 (23-28)]. Each 1-point increase in pre-LT MoCA was associated with 26% lower odds of post-LT cognitive impairment (aOR .74, 95% CI .63-.87, p < .001), after adjusting for recipient age, history of HE, and time since LT. In this study of cirrhosis recipients without active pre-LT HE, cognitive impairment was prevalent before LT and remained prevalent ≥3 months after LT (27%), long after effects of portal hypertension on cognition would be expected to have resolved. Our data expose an urgent need for more comprehensive neurologic examination of LT recipients to better identify, characterize, and address predictors of post-LT cognitive impairment.

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.

The tele-liver frailty index (TeLeFI): development of a novel frailty tool in patients with cirrhosis via telemedicine.

Frailty is a critical determinant of outcomes in cirrhosis patients. The increasing use of telemedicine has created an unmet need for virtual frailty assessment. We aimed to develop a telemedicine-enabled frailty tool (tele-liver frailty index). Adults with cirrhosis in the liver transplant setting underwent ambulatory frailty testing with the liver frailty index (LFI) in-person, then virtual administration of (1) validated surveys (eg, SARC-F and Duke Activity Status Index [DASI]), (2) chair stands, and (3) balance. Two models were selected and internally validated for predicting LFI ≥4.4 using: (1) Bayesian information criterion (BIC), (2) C-statistics, and (3) ease of use. Of 145 patients, the median (interquartile range) LFI was 3.7 (3.3-4.2); 15% were frail. Frail (vs not frail) patients reported significantly greater impairment on all virtually assessed instruments. We selected 2 parsimonious models: (1) DASI + chair/bed transfer (SARC-F) (BIC 255, C-statistics 0.78), and (2) DASI + chair/bed transfer (SARC-F) + virtually assessed chair stands (BIC 244, C-statistics 0.79). Both models had high C-statistics (0.76-0.78) for predicting frailty. In conclusion, the tele-liver frailty index is a novel tool to screen frailty in liver transplant patients via telemedicine pragmatically and may be used to identify patients who require in-person frailty assessment, more frequent follow-up, or frailty intervention.

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.

Hepatic and renal function impact concentrations of plasma biomarkers of neuropathology.

Introduction: The impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis. Methods: Plasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression. Results: p-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (ß = 0.75, P < .01), NfL (ß = 0.32, P < .01), and t-tau (ß = 0.31, P < .01), but not GFAP (ß = -0.01, P = .88) or UCHL1 (ß = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (ß = -0.18, P < .01), NfL (ß = -0.22, P < .01), GFAP (ß = -0.17, P < .05), t-tau (ß = -0.20, P = .02), and UCHL1 (ß = -0.15, P = .09). Conclusions: Elevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.

Loneliness in adults awaiting liver transplantation at 7 U.S. transplant centers.

INTRODUCTION: Loneliness, "a subjective feeling of being isolated", is a strong predictor of adverse health. We characterized loneliness in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT). METHODS: We surveyed loneliness in ambulatory ESLD adults awaiting LT at 7 U.S. sites using the validated UCLA Three-Item Loneliness Scale, May2020-Jan2021; "lonely"=total ≥5. Liver Frailty Index (LFI) assessed frailty; "frail"=LFI≥4.4. Logistic regression associated loneliness and co-variables. RESULTS: Of 454 participants, median MELDNa was 14 (IQR 10-19) and 26% met criteria for "lonely". Compared to those not lonely, those lonely were younger (57 v. 61y), more likely to be female (48% v. 31%) or frail (21 v. 11%), and less likely to be working (15% v. 26%) or in a committed partnership (52% v. 71%). After multivariable adjustment, frailty (OR=2.24, 95%CI=1.23-4.08), younger age (OR=1.19, 95%CI=1.07-1.34), female sex (OR=1.83, 95%CI=1.14-2.92), not working (OR=2.16, 95%CI=1.16-4.03), and not in a committed partnership (OR=2.07, 95%CI=1.29-3.32) remained significantly associated with higher odds of loneliness. CONCLUSION: Loneliness is prevalent in adults awaiting LT, and independently associated with younger age, female sex and physical frailty. These data lay the foundation to investigate the extent to which loneliness impacts health outcomes in LT, as in the general population. Clinical Trial Registry Website: https://clinicaltrials.gov Trial Number: NCT03228290.

Evaluating the Associations Between the Liver Frailty Index and Karnofsky Performance Status With Waitlist Mortality.

Frailty has emerged as a critical determinant of mortality in patients with cirrhosis. Currently, the United Network for Organ Sharing registry only includes the Karnofsky Performance Status (KPS) scale, which captures a single component of frailty. We determined the associations between frailty, as measured by the Liver Frailty Index (LFI), and KPS with waitlist mortality. METHODS: Included were 247 adult patients with cirrhosis listed for liver transplantation without hepatocellular carcinoma from February 2014 to June 2019, who underwent outpatient assessments using the LFI and KPS within 30 days of listing. "Frail" was defined using the established LFI cutoff of ≥4.4. Competing risk models assessed associations between the LFI and KPS with waitlist mortality (death/delisting for sickness). RESULTS: At a median 8 months follow-up, 25 (10%) patients died/were delisted. In this cohort, median Model for End-Stage Liver Disease-Sodium was 17, LFI was 3.9 (interquartile range 3.4-4.5), and KPS was 80 (interquartile range 70-90). In multivariable analysis, LFI (sub-hazard ratio 1.07, per 0.1 unit; 95% confidence interval, 1.01-1.12) was associated with waitlist mortality while KPS was not (sub-hazard ratio 1.00, per 10 units; 95% confidence interval, 0.78-1.29). CONCLUSIONS: Our data suggest that frailty, as measured by the LFI, may be more appropriate at capturing mortality risk than KPS and provide evidence in support of using the LFI more broadly in clinical transplant practice in the outpatient setting.

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.