Association between hospital acquired disability and post-discharge mortality in patients after living donor liver transplantation

Since the first successful liver transplantation performed by Starzl et al. in 1967 [1], in patients with end-stage liver disease, liver transplantation is a life-saving last treatment measure and proven intervention [2, 3]. One and five years survival rates of the patients following liver transplantation were 85%–86% and 68%–74%, respectively [4].

In Japan, only a few liver donors were found while accessing deceased donors. Therefore, in order to facilitate organ donation, the only option left is to choose living donor liver transplantation (LDLT) [5]. In the registry data by the Japanese Liver Transplantation Society, the number of LDLT performed was approximately 400 cases per year [6].

Patients with chronic cirrhosis often develop sarcopenia as loss of skeletal muscle mass and strength due to protein-energy malnutrition and decreased physical activity [7, 8]. These problems have led to decreased quality of life and increased mortality rate, infection, and postoperative complications in patients with cirrhosis [9]. In addition, the disease progression due to the long waiting period, and inactive patients awaiting liver transplantation further increases the risk of sarcopenia progression [10]. Tandon et al.[11] showed that approximately 40% of patients awaiting liver transplantation have sarcopenia. Therefore, it is important to prevent sarcopenia to potentially improve the overall treatment of patients undergoing LDLT [12]. However, previous studies have reported that sarcopenia is not related to prognosis of LDLT [13, 14]. Therefore, the association between sarcopenia and prognosis in LDLT patients is still controversial and far from being elucidated.

Recently, hospital-acquired disability (HAD), a decrease in physical function associated with hospitalization, has been regarded as a major problem [15]. Cheville et al. [16] showed the staggering magnitude of hospitalization-associated disablement which has been recognized for over a decade. Approximately 30% of hospitalized older adults develop a new disability until discharge, which increases the risk for readmission, institutionalization, and mortality [17]. Generally, in-patients are treated with the acute medical and surgery issues priority, due to which these patients decline loss of skeletal muscle function and, activities of daily living (ADL). At the time of discharge these patients often develop a major new disability that was not present before the onset of acute illness [18] Almost all preoperative LDLT patients have expected comorbid HAD, because of their severe condition.

Physiotherapy plays a major role in perioperative management of LDLT and is the most important prevention strategy for HAD. Peri-operative physiotherapy, including early mobilization in LDLT patients, has been considered essential for the prevention of various complications during the postoperative period [19]. However, mobilization after surgery can be often limited because recovery in several LDLT patients is dependent on the liver graft recovery [20]. Although LDLT patients easily develop HAD, the short-and long-term influences of HAD in these patients remain unknown.

There is a potential to develop new prevention strategies for HAD in LDLT patients which can reduce the long-term effects of physical dysfunction and health care costs. We hypothesized that HAD would deteriorate prognosis compared to a control group in LDLT patients. Therefore, the present study aimed to investigate the prevalence of HAD and the association of prognosis after hospitalization in patients undergoing LDLT.

To the best of our knowledge, this is the first study to assess the influence of HAD in LDLT recipients, furthermore, HAD and mortality assessments in LDLT patients are scant in literature. The main findings of the present study were as follows: (1) HAD was identified in approximately 35% of LDLT patients (2); in the HAD/low SMI group, all-cause mortality was the highest, and (3) HAD was an independent risk factor for all-cause mortality, and the HAD/low SMI group had similar outcomes.

Although a different clinical population, Saitoh et al. [23, 35] showed that HAD accounts for approximately 25% of cardiac disease patients. A previous meta-analysis study also reported that HAD occurs in approximately one-third of all hospitalized patients [15]. In our results, above 35% LDLT patients showed HAD, which is consistent with the results of this study. Interestingly, the non-HAD group was also more severely condition with MELD scores, and ADL was significantly more dependent than those in the HAD group. In other words, in the non-HAD group, many preoperative LDLT patients could not independently perform ADL due to poor general condition. However, the Barthel index at hospital discharge in the non-HAD group was not significantly different between the HAD group, indicating that ADL in the HAD group recovered well. Our results suggest that it is important to improve physical function in hospitalized patients.

Improvement in physical activity in solid organ transplantation recipients have shown improved lean mass, muscle strength, and consequently better aerobic capacity, however, little data exist for liver transplant recipients. Berzigotti et al. [36] mentioned dividing the problems into postoperative early and late phases. In the early post-transplantation phase, immobilization is associated with bed rest, extended hospital and intensive care stay, corticosteroid and immunosuppressant drugs-associated myopathy, and episodes of organ rejection. In later phases, calcineurin inhibitor-induced effects (e.g., reduction in mitochondrial respiration and muscle regeneration/remodeling) and metabolic syndrome-related problems are common with post-liver transplantation and contribute to further worsening of aerobic capacity. In addition, he mentioned that only 50% of patients are able to perform regular physical activity within 2 years of liver transplantation, this is one of the potential reasons of failure to reverse muscle loss post-transplantation.

Physical inactivity is clearly associated with obesity, diabetes mellitus, arterial hypertension, coronary heart disease, and osteoarthritis. Skeletal muscle is now recognized as an endocrine organ that secretes cytokines such as myokines and other peptides, which have attracted attention in recent years [37]. Interestingly, myokines are involved in the inflammatory response, and physical activity plays a key role in the anti-inflammatory phenotype homeostasis, and liver function also increases the availability of glucose for uptake and oxidation by myokines [38]. In this way, physical activity has a high potential for providing long-term beneficial effects. Certainly, in our patients, the ADL score was improved at hospital discharge in the HAD group. However, long-term recovery of ADL was unknown because we did not evaluate long-term follow-up. Evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing.

Although all patients also received perioperative rehabilitation, and ADL scores in the non-HAD group were significantly improved from admission to discharge hospital, in our results, the stair and bathing items of the ADL scale were more dependent than other items. Nishiwaki et al. [39] pointed out that stair and bathing items decreased easily in the Barthel index. In particular, stair and bathing were presumed as difficult activities among the ADL assessment tool. Therefore, we were suggested that enhanced rehabilitation programs including these ADL training was need.

The HAD/low SMI group showed the highest all-cause mortality among the groups. Loss of muscle mass, muscle strength, and physical performance are common in patients with chronic liver disease, and are associated with increased all-cause mortality and poor clinical outcomes [40]. Previous studies have shown that similar to pre-transplantation renal dysfunction, SMI was associated with all-cause mortality in chronic liver disease [41‐44]. In post-operative liver transplantation patients sarcopenia is thought to be responsible for the decrease in lean body mass, infections, renal dysfunction [45]. Since renal function was not significantly different in this study, we presumed that HAD has a greater effect than renal function. In addition, the use of immunosuppressive agents such as mTOR and calcineurin inhibitors may have an additional role in affecting the skeletal muscle [46]. Although, the most common cause of death is graft failure, regarding direct consequence with long-term physical activity was unknown. In our previous study, LDLT patients with bile duct complications had pre-operative lower SMI, it cannot be denied that troubles due to bile duct complications may have affected the graft function [13]. Our results suggested that differences in ADL improvement during hospitalization may affect ADL after hospital discharge, and factor for predicting prognosis. However, in our results, it was difficult to draw firm conclusions from lack of the physiological basis.

Furthermore, we considered sub-analysis that divided into the low or high SMI group. As a result, no one died in the non-HAD/low SMI group. Although, preoperative intensive rehabilitation intervention is ideal for LDLT patients with poor general condition and physical function, realistically, patients who have difficult rehabilitation intervention. Therefore, postoperative rehabilitation is important in LDLT patients. However, there are patients who responder and non-responder in recovery of ADL with similar rehabilitation programs. Since our subjects excluded in-hospital deaths, LDLT patients with liver function and general condition should be improving at the hospital discharge. In this study, since the causes of death including carcinoma were different respectively, it was difficult to identify the causal relationship with the cause of death. Our results suggest that HAD patients were no significant differences due to the difference in SMI, but preoperative low SMI patients complicated HAD may have a worse prognosis. However, since the number of patients who died also was small, and multiple comparisons reduce the statistical power to detect significance, and further consideration was not possible.

Our previous studies reported that sarcopenia was not related to short-term prognosis of LDLT patients [13, 14]. It is possible that HAD with physical activity is more important than sarcopenia in terms of long-term mortality. Although increased physical activity improves of mortality is speculated, the physiological basis has not been proven in this study, and the results have to be interpreted with caution. Postoperative patients of liver transplantation is presumed that muscle hypertrophy takes a long time due to the promotion of proteolysis associated with inflammation, and the decrease in protein synthesis ability caused by graft failure and underfeeding. We have previously confirmed decreased quadricep muscle thickness by ultrasound after 1 month of LDLT, thus, it may be difficult to prevent skeletal muscle atrophy in such cases as it depends on the recovery of the graft [10]. Although rehabilitation makes muscle hypertrophy difficult in short-term, it is possible to recovery of ADL is relatively easy. Therefore, to prevent HAD, and for proper perioperative management of LDLT patients, rehabilitation should be started as quickly. Early rehabilitation is suggested that increases physical activity which plays a crucial role in the prevention of sarcopenia and HAD, and decrease of all-cause mortality. In addition, several previous studies have suggested that perioperative nutritional therapy improves skeletal muscle mass and mortality, and the aid of pre-transplantation nutritional intervention combined rehabilitation such as comprehensive management might be able to improve outcomes after LDLT [45, 47].

The present study had several limitations. First, the sample size was relatively small. Second, this study was conducted at a single institute, that may have caused selection bias. Third, this was a retrospective study. Lastly, preoperative physical function and performance (e.g., handgrip and quadriceps force, and 6-min walk test) were not evaluated, which could not investigate the relation of physical performance and HAD. Additionally, long-term follow-up of ADL was not done. Large-scale studies including comprehensive evaluation of muscle mass, muscle force, and physical function are needed to evaluate the association of HAD with mortality in LDLT patients.

This study indicated that HAD could affect prognosis in follow-up patients after LDLT, suggesting that it could be one of the key components in determining prognosis after LDLT. Consequently, it is necessary to initiate increased activity as quickly as possible after LDLT. In the perioperative comprehensive rehabilitation, future larger-scale studies are needed to consider the overall strategy, such as enhanced recovery after surgery (ERAS), including nutritional therapy.