*Purpose: Frailty is a clinical condition characterized by a loss of physiologic reserve and increased susceptibility to stressors. Molecular frailty biomarkers may reflect the dysregulation of physiological systems leading to this reduced physiological reserve, but as yet such complementary biomarkers have not been identified. The aims of this research were to assess the prevalence of frailty in those referred to the Irish Liver Transplant Program, assess its impact on outcomes and analyse the relationship between clinical frailty and biomarkers of frailty.

*Methods: 70 patients were prospectively evaluated while undergoing liver transplant assessment. Frailty assessments included Liver Frailty Index (LFI), Fried Frailty Index (FFI), and Rockwood Frailty Score (RFS) and standardized sarcopenia measurements. Serum irisin, S100B, leptin and PAI-1 concentrations were assayed (ELISA) in a subset of patients Assessments were repeated at 3-monthly intervals whilst wait-listed. Clinical outcomes included decompensation-related hospitalisations, time on the waiting-list, post-transplant ICU- and overall-length of stay, 30-day mortality and morbidity post-transplant.

*Results: Clinical frailty ranged from 20% to 37%, depending on the frailty score. Increasing FFI and RFS scores were associated with increased S100B (p=0.02). There was also a positive correlation between higher MELD-Na (Model for End-Stage Liver Disease) and PAI-1 (p=0.014) and negative correlation between MELD-Na and Leptin (p=0.059). While waitlisted, frail patients showed a trend towards increased admissions with decompensation compared to non-frail patients (70% vs 29.4%, p=0.057). Increasing MELD-Na, RFS and female sex were associated with an increased likelihood of admission with liver decompensation while on the waiting list. Frailty increased while on the waitlist, but the frailest patients spent a significantly shorter period on the waiting list, due to transplantation or death (Median 22 days (frail) vs 95 days (non-frail), p= 0.026).

*Conclusions: Frail patients portended towards a worse stage of liver disease and were admitted to hospital more frequently with decompensation, but spent less time on the waiting list. This adds objectivity to what was previously a nuanced aspect of patient selection at the time of donor offer. An association between clinical frailty scores and novel molecular biomarkers of frailty was demonstrated for the first time. This has significant diagnostic and prognostic implications going forward and warrants validation in larger cohorts.

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