13. Physical Frailty and Sarcopenia in End-Stage Liver Disease: Do They Improve After Liver Transplantation?

Rahima A. Bhanji¹ and Elizabeth J. Carey²

(1)

Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta, Edmonton, AB, Canada

(2)

Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA

Rahima A. Bhanji (Corresponding author)

Email: rbhanji@ualberta.ca

Elizabeth J. Carey

Email: carey.elizabeth@mayo.edu

Keywords

SarcopeniaFrailtyNatural historyPost-liver transplant

Introduction

Malnutrition is a common but devastating complication of end-stage liver disease (ESLD). Sarcopenia, defined as a generalized and progressive loss of muscle mass, strength, and function, is a major consequence of malnutrition [1]. Sarcopenia is seen in up to 60% of patients awaiting liver transplantation (LT) [2] and is associated with increased risk of decompensation, risk of infections, risk of hospitalization, and risk of wait list mortality [3]. Following LT, sarcopenia is associated with increased ICU stay, prolonged ventilation, and increased hospital length of stay (LOS) [4].

Sarcopenia is a key component of frailty, another common complication of cirrhosis. Although initially described in the geriatric literature, there have been an increasing number of studies evaluating frailty in patients with cirrhosis, particularly over their pretransplant course [5]. It has been defined as an increased susceptibility to stressors resulting in adverse outcomes in individuals with a cumulative decline in physiologic reserve [5]. Frailty is present in up to 25% of patients with cirrhosis [5]. Like sarcopenia, it is a poor prognostic indicator associated with increased risk of hospitalization, increased hospital LOS, and increased wait list mortality [5]. There is a paucity of literature on the course and impact of both frailty and sarcopenia following LT.

Pathophysiology

The pathophysiology of both entities is complex and includes reduced oral intake, malabsorption, need for alternative energy source and breakdown of protein, systemic inflammation, decreased clearance of ammonia, and hypogonadism [2].

The presence of ascites contributes to early satiety, nausea, and abdominal pain, all of which lead to reduced oral intake. Medications prescribed for control of ascites and prescription of a low salt diet may lead to altered taste and further reduce oral intake.

Systemic inflammation likely contributes to the catabolic state seen in cirrhosis leading to further muscle breakdown with prolonged fasting. Increased ammonia promotes protein breakdown by stimulating myostatin [6] an inhibitor of protein synthesis and regeneration. Myostatin acts by activating the major skeletal muscle proteolytic pathways [6]. Finally, low levels of testosterone lead to reduced inhibition of myostatin [6]. Of note, sarcopenia leads to further physical disability and thus functional decline or frailty [1].

Treatment

Lifestyle changes including exercise and nutritional supplementation have been shown to improve both sarcopenia [7, 8] and frailty [7]. Studies are ongoing with regard to use of myostatin antagonists, hormonal replacement (testosterone or growth hormone), or ammonia-lowering agents for treatment of sarcopenia [9].

As LT leads to cure of ascites, improved ammonia clearance, improvement in hypogonadism, and reduced systemic inflammation, it was naturally thought to reverse both sarcopenia and frailty akin to reversal of symptoms secondary to portal hypertension. However, the few studies that have looked at the course of these entities following transplantation do not demonstrate universal improvement.

Sarcopenia Following Liver Transplantation

There is heterogeneity in the literature with regard to both methods and cutoff values for diagnosing sarcopenia, which makes comparison between studies difficult. The L3 skeletal muscle index (L3SMI) assessed by CT has shown to predict survival in patients with ESLD and is considered by many to be the gold standard for diagnosing sarcopenia [10]. However, studies evaluating changes in muscle mass after LT are limited by the fact that not all patients had subsequent CTs following LT, and for those who had the CTs, these were done at varying times and not as protocol.

Muscle Mass

Previous studies assessing body composition following LT using dual-energy X-ray absorptiometry (DEXA) have generally shown no improvement in body composition following LT. In one study, significant reduction in lean body mass was seen up to 9 months after LT, with nonsignificant increase seen up to 24 months following LT [11]. Another study showed an increase in lean body mass from 2 to 24 months post-LT but only in males [12]. Further, no improvement in body composition was seen in patients who were not in an exercise/nutritional counselling group [13].

A Cleveland Clinic study analyzing 53 patients showed 62% (n = 33) had pre-LT sarcopenia [14]. Sarcopenia was diagnosed using CT of the L4 region. CT scans of a control group were used to establish normal muscle mass, and sarcopenia was defined as 5th percentile of age- and sex-specific normalized muscle area. Of these, only 6% (n = 2) had resolution of sarcopenia seen on an indication-based post-LT CT done at a mean of 13.1 ± 8.0 months. Of note, 75% (15/22) had de novo sarcopenia. Patients with ascites were more likely to have sarcopenia both pre- and post-LT (p < 0.05). Patients with hepatocellular carcinoma (HCC) were more likely to have an increase in psoas muscle area following LT (46% vs. 15%), but tumor volume did not predict post-LT sarcopenia.

In another study, subanalysis of 47 patients with sarcopenia pre-LT and a second CT following transplant was done. Sarcopenia was diagnosed using CT of the L3 region. Follow-up CT was done at a mean of 50 ± 6 months showing resolution of sarcopenia in 13 of the 47 patients (28%) [3].

A Korean study (n = 145), using psoas muscle area to diagnose sarcopenia (cutoff 5th percentile of age- and sex-specific normalized muscle area for controls), found 36% of patients had pre-LT sarcopenia. None of these patients had resolution seen on second, indication-based CT done at a mean of 12.3 ± 5.7 months following LT. De novo sarcopenia was diagnosed in 15% (14/93) of patients [15]. Patients with pre-LT sarcopenia were more likely to be males (41% vs. 14%; p = 0.008). Patients with post-LT sarcopenia were more likely to be male (91%; p = 0.003), had a significantly lower BMI (23 Kg/m²; p = 0.015), and most had pre-LT sarcopenia (79%; p < 0.001).

Finally, a study out of University of Pittsburgh including a select group of patients (n = 40) without post-LT risk factors for sarcopenia (i.e., ICU readmission, admission for infection, persistent renal failure, hepatic artery thrombosis, ischemic cholangiopathy, alcohol relapse, and recurrent disease (PSC, NAFLD), or HCC) found 55% (22/40) of the patients to have pre-LT sarcopenia [16]. CT SMI was used to diagnose sarcopenia (cutoffs: females < 38.5 cm²/m²; males <52.4 cm²/m²). Sarcopenia persisted in 45% (10/22) of the patients and resolved in another 55% (12/22) on an indication-based, post-LT CT done at a mean of 20.3 ± 7.4 months. Though these results are not applicable to all patients undergoing LT, it shows, in the absence of risk factors, sarcopenia may improve following LT.

Risk Factors

Not surprisingly, there is some overlap between pre-LT and post-LT risk factors for sarcopenia. Pre-LT risk factors include malnutrition, hypercatabolic state, hyperammonemia, systemic inflammation, hypogonadism, and sedentary lifestyle. Cirrhotic patients have an abnormal fuel metabolism and have an increased energy expenditure (120% of the expected value). Elevated pro-inflammatory and anti-inflammatory cytokine levels in these patients likely contribute to this hypercatabolic state [17]. Thus, an overnight fast in a cirrhotic is comparable to a 72 h fast in a healthy individual [17]. It is likely this hypercatabolic state persists following transplantation and contributes to either persistent or de novo sarcopenia.

The main risk factors for post-LT sarcopenia in addition to persistent hypercatabolic state include immunosuppression, renal failure, hospitalizations, metabolic syndrome, disease recurrence, and lifestyle (Table 13.1).

Table 13.1

Risk factors for post-liver transplant sarcopenia

Risk factor	Mechanism
Sedentary lifestyle	Reduced energy expenditure Increased risk of MS
Metabolic syndrome	IR leading to promotion of proteolysis Inhibition of GH/IGF-1 axis Inactivation mTOR
Hypercatabolic state	Increased energy expenditure Increased inflammation (cytokines)
Immunosuppression Corticosteroids Calcineurin inhibitors mTOR inhibitors	Increase proteolysis, muscle fiber atrophy, MS, infections Impairs gene regulation muscle growth, upregulates myostatin, renal failure, MS, infections Anabolic resistance, uninhibited autophagy, protein degradation, MS, infections
Renal failure	Increased inflammation
Disease recurrence	Hypercatabolic state, increased inflammation, upregulation myostatin
Hospitalization	Immobility