To investigate the impact of physical frailty on risk of hospitalisation in cirrhotic patients on the liver transplant waitlist.

Cirrhotics listed for liver transplantation at a single centre underwent frailty assessments using the Fried Frailty Index, consisting of grip strength, gait speed, exhaustion, weight loss, and physical activity. Clinical and biochemical data including MELD score as collected at the time of assessment. The primary outcome was number of hospitalised days per year; secondary outcomes included incidence of infection. Univariable and multivariable analysis was performed using negative binomial regression to associate baseline parameters including frailty with clinical outcomes and estimated incidence rate ratios (IRR).

Of 587 cirrhotics, 64% were male, median age (interquartile range) was 60 (53-64) years and MELD score was 15 (12-18). Median Fried Frailty Index was 2 (1-3); 31.6% were classified as frail (fried frailty ≥ 3). During 12 mo of follow-up, 43% required at least 1 hospitalisation; 38% of which involved major infection. 107/184 (58%) frail and 142/399 (36%) non-frail patients were hospitalised at least once (P < 0.001). In univariable analysis, Fried Frailty Index was associated with total hospitalisation days per year (IRR = 1.51, 95%CI: 1.28-1.77; P ≤ 0.001), which remained significant on multivariable analysis after adjustment for MELD, albumin, and gender (IRR for frailty of 1.21, 95%CI: 1.02-1.44; P = 0.03). Incidence of infection was not influenced by frailty.

In cirrhotics on the liver transplant waitlist, physical frailty is a significant predictor of hospitalisation and total hospitalised days per year, independent of liver disease severity.

The most commonly used tool to prioritise patients for liver transplantation is the MELD or MELD-sodium score[1], which fails to capture the decline in systemic health suffered by many liver transplant candidates. This is particularly relevant as liver transplant recipients are ageing and accumulating comorbidities[1]. Muscle wasting and weakness are incredibly common, observed in up to 70% of waitlisted individuals[2]. Both quantitative measures of muscle mass and functional measures of muscle strength have been associated with waitlist mortality, infection and post-transplant complications[3-5].

Frailty is a multi-system disorder that is classically associated with ageing, disability and comorbidity, and is known to increase the risk for falls, hospitalisation and mortality[6]. Quantification of frailty is most commonly performed using the Fried Frailty Index. Initially designed for use in geriatric populations, the Fried Frailty Index encompasses handgrip strength, exhaustion, gait speed, unintentional weight loss and physical activity[7]. Some data suggest that functional measures of muscle strength may better predict outcomes in cirrhotics than CT-based measures of sarcopenia[8]. Furthermore, frailty measures can be performed at the bedside, without the need for ionising radiation, which makes them preferable for repeated measures to assess changes over time. This is important as progression of frailty is itself associated with poorer outcome[9].

Physical frailty as measured the by Fried Frailty Index has previously been identified as a risk factor for mortality in cirrhosis[3,4], yet there are little data investigating the impact of frailty on hospitalisation in cirrhosis. An independent link between low muscle mass and infection risk has been identified pre-liver transplantation[5,10], as well as increased hospitalisation days[11], and thus similar findings may be expected for frailty.

This study aims to evaluate the impact of frailty on total number of hospitalisation days. The ultimate goal is to identify an at-risk subset of the cirrhotic population to assist in the development of preventative strategies to improve outcomes in this vulnerable population.

We report a single-centre prospective observational cohort study of 587 pre-transplant cirrhotics, performed at the University of California, San Francisco, between July 2012 and December 2014.

616 consecutive cirrhotic patients were enrolled into the FrAILT study between July 2012 and February 2015. 587 (95%) of these patients had complete data for analysis in this study. The median (IQR) age was 60 (53-64) years, BMI 28.2 (24.8-33.1) cm/m², and median MELD score was 15 (12-18) and 64.2% were male. Fifty-seven percent were Caucasian, 26% Hispanic, 7% Asian, 4% African American, and 6% were of other ethnicity. Four patients had missing Fried Frailty Index. Thirty-one point six percent of patients were classified as frail, as defined by a Fried Frailty Index of 3 or above. Frail patients had more severe liver failure than non-frail patients as measured by MELD score and features of decompensation, and lower rates of hepatocellular carcinoma. Frail patients were slightly but significantly older than non-frail patients. Baseline demographics by frailty group are described in Table 1.

This prospective study, including nearly 600 patients with cirrhosis awaiting liver transplantation, demonstrates that functional measures of frailty are associated with increased hospitalisation days independent of the MELD score. The increase in hospitalisation observed in this study was due to an increased incidence of hospitalisation, predominantly for complications of end-stage liver disease. These data from the ongoing FrAILT study add critical information to our prior report on the significant association between frailty and waitlist mortality[3] by providing an intermediate outcome of hospitalisation. The clinical implication of this finding is that functional frailty measures performed in the outpatient setting can identify patients who may benefit from tailored interventions to reduce the risk of subsequent hospitalisations and ultimately, death.

Our data have important implications for the management of patients with cirrhosis, who impose a high burden on the health care system with frequent exacerbations of their chronic disease. In particular, implementation of a chronic disease model of care for decompensated cirrhotics has strong potential to improve outcomes in this population[15]. Indeed, in one study in Italy, case management was shown to significantly reduce both the 30 d re-hospitalisation rate as well as overall mortality, while reducing cost[16]. Given the resource requirements of such a program it is not practical or feasible to suggest that every cirrhotic should be enrolled, therefore a simple frailty measure such as the Fried Frailty Index is useful in its ability to select patients who are most in need of such an intensive management strategy. Perhaps even more importantly, frailty represents a potentially modifiable outcome through focused pre-habilitation programs that specifically target the individual components that contribute to the frail phenotype[17]. Demonstrating that frailty is associated with increased hospitalisations provides strong justification to develop and implement such programs early in the disease progression to prevent hospitalisation and subsequent deterioration in this vulnerable population.

In our cohort, frailty was not significantly associated with infection on multivariable analysis, although there was a trend to increased infection. This differs from previous research demonstrating that sarcopenia, a major contributor to the frail phenotype, has previously been shown to increase risk of infection-related hospitalisations[10]. It may be that frailty represents an early phenotype, whereas sarcopenia represents more established systemic disturbance that may be required for infection risk. However in the absence of longitudinal data incorporating frailty measures and body composition measurements, this cannot be confirmed. It may also be that quantification of hepatic encephalopathy in this cohort by the numbers count test, a feature recognised to be closely related to frailty[18], allowed us to better ascertain the relative contributions of different factors to infection risk than previous studies. The lack of an independent association between frailty and infection was somewhat surprising, and further studies are required to clarify this issue.

The majority of hospital admissions in our cohort were indeed for liver-related decompensation including infection, but also acute kidney injury, hepatic encephalopathy and hepatorenal syndrome (81%), and thus could be expected to accelerate the progression of liver disease. This sheds important insight into the potential mechanisms of the impact of frailty on adverse health outcomes in cirrhotics: instead of increasing the likelihood of any single complication, frailty decreases a patient’s reserve to withstand any of the typical complications of cirrhosis, increasing the severity of the complications and the likelihood of inpatient admission.

Limitations of this study include its observational nature, albeit prospective, therefore the impact of reversing frailty cannot be proven. However the consistent associations between frailty and poor outcome suggest that it is indeed itself a contributing factor, and the finding that deterioration in frailty further increases risk of mortality adds further weight to this argument[9]. Furthermore, data from a study of patients undergoing TIPS insertion suggest that reversing muscle wasting can indeed improve survival[19]. An additional limitation is the inability to accurately classify the cause for non-infectious hospital admissions in this study, to determine whether the increase in hospitalisation was due to a specific factor, such as hepatic encephalopathy. Most episodes of decompensation of liver disease are multifactorial in nature, the specific triggering factor may never be identified, and standardised diagnostic criteria are lacking. Finally, this study was single-centre, and thus validation in other cohorts is required.

Strengths of this study include a large study population that is representative of transplant waitlist cohorts with a high study uptake of 97% of patients assessed for transplantation, with near-complete (95%) longitudinal data. We therefore believe that these results are representative of a tertiary centre transplant waitlist. Despite the study limitations, our identification of a relationship between frailty - as measured by a simple tool that can easily and rapidly be performed in the clinic setting - a significantly increased risk of hospitalisation has important implications for the management of patients with cirrhosis. The Fried Frailty Index can help clinicians identify those at greatest risk of hospitalisation and thus in greatest need of chronic liver disease management programs to provide additional support.

In conclusion, physical frailty in subjects on the liver transplant waitlist, as measured by the Fried Frailty Index, is a significant predictor of 12 mo hospitalisation days independent of liver disease severity. This findings adds to the previously established link between frailty and mortality. These data provide us with a strong rationale to develop pre-habilitation and chronic disease management programs for frail patients on the transplant waitlist to reduce hospitalisation, reduce mortality and reduce healthcare costs.