Pretransplant Frailty on Postoperative Morbidity and Mortality after Liver Transplantation: Bystander or Upstander?

Frailty is prevalent in patients with decompensated cirrhosis, with a prevalence of 18% to 43%.¹ In geriatrics, frailty pertains to a state where physiological resilience diminishes, rendering an individual more susceptible to health-related challenges.² On the other hand, within hepatology, frailty primarily focuses on physical frailty, chiefly driven by sarcopenia and intensified by liver-specific factors such as ammonia-associated muscle toxicity, physical constraints related with encephalopathy, and impaired protein synthesis. Cirrhosis, particularly once decompensated, makes individuals more susceptible to developing physical frailty.¹ The majority of patients with cirrhosis who are on the waiting list for liver transplantation (LT) experience a worsening of frailty over time, with only less than 20% showing improved or stable frailty scores.³ In reverse, physical frailty amplifies the risk of decompensation in cirrhotic patients.⁴ As a result, cirrhosis and physical frailty interact reciprocally in a vicious cycle, exacerbating each other's state.

An important point to note is that physical frailty significantly affects the prognosis of patients with cirrhosis who are on the waiting list for LT. For example, in a study involving over 1,000 ambulatory patients with cirrhosis awaiting LT at nine centers in the United States, frailty, determined by the Liver Frailty Index (LFI) ≥4.5, was associated with an approximately 2-fold increase in the risk of waitlist mortality.⁵ Furthermore, worsening frailty over time during LT waiting was associated with an over 2-fold increase in the risk of death or delisting when the LFI increased ≥0.1 after 3 months.³ However, the data regarding the association between pre-LT frailty and post-LT outcomes are scarce. In a previous study involving 1,166 LT recipients from eight centers in the United States, frailty assessed using the LFI before LT was linked to a 2-fold increase in post-LT mortality.⁶ Another study demonstrated that a lower pre-LT Karnofsky performance status (10% to 40%) was associated with a 43% increased risk of death after LT.⁷ However, there have been no studies to date investigating post-LT outcomes using the Short Physical Performance Battery (SPPB) in Korean LT patients.

In this issue, Goh et al.⁸ investigated the association of pre-LT frailty with post-LT morbidity and mortality among 242 patients with cirrhosis at a single tertiary care center in Korea. They used the SPPB for assessing frailty and categorized patients into a frail group (SPPB <10, n=60) and a non-frail group (SPPB ≥10, n=182). When compared to the non-frail group, the frail group showed a higher proportion of female and alcohol-related cirrhosis as a cause of liver disease and had poorer liver function with a higher incidence of ascites and hepatic encephalopathy. In addition, frail patients received deceased donor LT more frequently than non-frail patients. The hospitalization (median 24 days vs 22 days) and postoperative intensive care unit stay (median 6 days vs 4 days) was longer in the frail group than those in the non-frail group. The frequency of complications (78% vs 59%), major complications (58% vs 35%), and graft failure (21.7% vs 4.9%) after LT was higher in frail patients compared to non-frail patients. Importantly, they showed that frail patients displayed a post-LT mortality exceeding 2-fold in comparison to non-frail patients (hazard ratio, 2.38; 95% confidence interval, 1.02 to 5.57), following adjustments for other covariates in the multivariable analysis. These results were consistently observed in prespecified subgroups, irrespective of the history of hepatocellular carcinoma or donor type (living donor vs decreased donor).

However, caution is required when interpreting the results on this research topic due to certain limitations. First, given that frail patients typically present a more severe underlying liver disease, there is a potential for various types of bias to intervene in comparisons with non-frail patients. Although multivariable analysis and inverse probability-of-treatment-weighting were performed to mitigate the influence of other covariates in the current study, residual confounding effects might persist. In essence, it remains unclear whether frailty itself acts as an “upstander” with a significant impact on post-LT outcomes or functions as a “bystander,” operating indirectly as an indicator for the severity of liver disease. Furthermore, it is important to note that very ill, hospitalized patients are excluded from this type of study because they are too sick to participate in frailty assessment. Which metrices should be used to assess pre-LT frailty among various tools remains to be explored. Currently, the LFI stands out the most exclusively validated tools, particularly in North American populations.⁹

In summary, irrespective of whether pre-LT frailty operates as a “bystander” or an “upstander” concerning post-LT outcomes, it impacts patient outcomes and should not be disregarded. Pre-LT frailty should be factored in alongside traditional metrics of liver disease severity, such as the Model for End-Stage Liver Disease, or conventional mortality indicators like age and body mass index, when making decisions about LT. Further studies are needed to determine the optimal metric for assessing pre-LT frailty among various tools and whether appropriate prehabilitation before LT can improve post-LT outcomes.