Sarcopenia and Frailty in the Prognosis of Patients on the Liver Transplant Waiting List
Abbreviations
-
- ALD
-
- alcoholic liver disease
-
- BMI
-
- body mass index
-
- CT
-
- computed tomography
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- L3
-
- third lumbar vertebrate
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- LT
-
- liver transplantation
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- NA
-
- no assessment
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- NASH
-
- nonalcoholic steatohepatitis
Sarcopenia and frailty are among the most common features of cirrhosis that contribute significantly to morbidity and mortality. However, sarcopenia is not identical to frailty. Sarcopenia is a critical reduction in skeletal muscle mass, which is associated with poor outcomes. The main components of frailty are sarcopenia and physical impairment, which result in a cumulative decline in physiologic reserve.1, 2
Skeletal muscle loss in normal aging occurs at the rate of 1% per year up to age 70 years, increasing later to 1.5% per year. The annual rate of skeletal muscle loss is 2-fold faster in cirrhosis, and an increase to >3% per year raises the risk of mortality.3 The prevalence of sarcopenia in cirrhosis is far higher than other chronic diseases because of the unique metabolic derangements caused by hepatocellular failure.4 Sarcopenia and frailty prevalence in patients with cirrhosis is estimated to be 40%-70%2, 5 and 18%-43%,6, 7 respectively. To put this into perspective, the prevalence at the time of diagnosis of cirrhosis of other complications, such as overt hepatic encephalopathy, is 10%-14%; the annual incidence of bleeding esophageal varices is 10%-15%; incidence of refractory ascites is 5%-10%; and hepatocellular carcinoma occurs in 3%-5% of the cases.
In the liver transplantation (LT) setting, the presence of sarcopenia and frailty are now well established as predictors of poor clinical outcomes, independent of the severity of liver disease.5 Standardized techniques are required to diagnose and manage sarcopenia and frailty in LT patients at initial and serial assessments.
Cirrhosis due to nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD) are now the most common indications for LT. Despite this, there has been a lack of information about the risk factors and implications in patients with a diagnosis of NASH or ALD (Table 1).
| Study | Number of Patients (Frequency of NASH/ALD) | Sarcopenia (Prevalence/Assessment) | Frailty (Prevalence/Assessment) | Other Complications |
|---|---|---|---|---|
| Montano-Loza et al.2 (2015) |
669 patients with cirrhosis 23% NASH 23% ALD |
45% sarcopenic Total muscle area at L3 on CT/height2 ≤41 cm2/m2 (females) and ≤53 cm2/m2 (males) with BMI ≥25 kg/m2 and ≤43 cm2/m2 in patients with BMI <25 kg/m2 |
NA |
Ascites (72%): 78% of sarcopenic versus 67% of nonsarcopenic patients (P = 0.001) Hepatic encephalopathy (38%): 49% of sarcopenic versus 29% of nonsarcopenic patients (P < 0.001) |
| Tandon et al.6 (2016) |
300 patients with cirrhosis 17% NASH 32% ALD |
NA |
18% frail Clinical Frailty Scale >4 |
Ascites (28%): 52% in frail versus 22% in nonfrail (P < 0.001) |
| Cron et al.7 (2016) | 542 patients with cirrhosis referred for LT | NA |
43% frail 5-component Fried Frailty Index ≥ 3 |
Ascites (52%): 63% in frail versus 55% in nonfrail (P = 0.08) Hepatic encephalopathy (41%): 51% in frail versus 39% in nonfrail (P = 0.003) |
| Aby et al.8 (2018) | 146 patients with NASH or cryptogenic cirrhosis |
62% sarcopenic Psoas area measured at the L3 (CT or MRI of the abdomen and pelvis) |
NA |
Ascites (79%): 80% of sarcopenic versus 77% of nonsarcopenic patients (P = 0.68) Hepatic encephalopathy (56%): 57% of sarcopenic versus 55% of nonsarcopenic patients (P = 1.0) |
| Lai et al.1 (2018) |
529 patients with cirrhosis 23% ALD 14% NASH |
NA |
No prevalence reported (continuous index) Liver Frailty Index (grip, chair stands, balance) |
Ascites (34): Mild/moderate (27%) |
In this issue of Liver Transplantation, Bhanji et al.9 address this issue by evaluating 136 patients with NASH and 129 with ALD-related cirrhosis. The prevalence of sarcopenia, as analyzed by computed tomography (CT) scan, was lower in patients with NASH (22% versus 47%; P < 0.001) but with a considerably higher frequency of frailty, which was defined using the frailty deficit index (49% versus 34%; P = 0.03) when compared with patients with ALD at the time of listing. In patients with NASH, frailty, but not sarcopenia, was associated with an elevated length of pre-LT hospitalization (P = 0.05) and an augmented risk of delisting (P = 0.02). Sarcopenia was associated with an increased risk of delisting in univariate analysis (P = 0.01) in patients with ALD.
Notably, the study included other components of body composition (ie, visceral adiposity and muscle radiodensity in relation to the etiology of cirrhosis), providing further insight into the issue that the visceral adiposity index was meaningfully higher in patients with NASH, whereas muscle radiodensity was lower. Additionally, this study reports the frequency of myosteatosis in sarcopenic patients, which showed the incidence was 79% in NASH and 68% in ALD patients. The choice of cutoff for myosteatosis may be questioned because it has been derived from cancer populations, yet this study demonstrates the necessity to determine whether sarcopenia and myosteatosis are 2 different characteristics of the muscle, or considering the high prevalence of myosteatosis in sarcopenic patients, if it is mainly the manifestation of muscle wasting.
Although the current study summarizes significant contributions to our evolving knowledge of cirrhosis etiologies and outcomes, some notes of caution are in order. Sarcopenia and ALD are more frequent in male patients, and these associations might be related to sex difference rather than the etiology of cirrhosis. Recent studies suggest that diminished subcutaneous adipose tissue, rather than sarcopenia, constitutes a risk factor for mortality in female patients.10 Therefore, lower rates of sarcopenia in NASH patients compared with ALD and its nonsignificant association with outcomes might be related to the higher percentage of female patients with NASH compared with ALD.
The authors investigated the importance of changes in muscle mass and radiodensity while on the waiting list as the mean of absolute or percent change. However, some aspects of this analysis are questionable. Changes between –2% and 2% on CTs might be considered as tissue maintenance, given the precision error of 1.5% for muscle and adipose tissue longitudinal change estimation. This reveals the need to categorize patients into losing, gaining, and stable groups by etiology to see how changes in muscle characteristics over time associates with worse outcomes, rather than just considering the mean percent change.
The importance of high visceral adiposity in predicting outcomes in patients with NASH is not addressed. Higher visceral adiposity associates with higher prevalence of comorbidities, which may lead to higher prevalence of frailty in patients with NASH.
Despite these limitations, the results of this study are intriguing because they suggest that the frequency of sarcopenia and frailty differs by the etiology of the liver disease and emphasize their divergent impact on outcomes in wait-listed patients with NASH and ALD.
In conclusion, the current study by Bhanji et al.9 underscores the importance of muscularity and frailty assessment as part of LT assessment, in order to better predict outcomes in patients with cirrhosis. However, prospective longitudinal studies with a larger number of patients are required to overcome the obstacles in our current understanding of the predictive value of sarcopenia and frailty in patients with various etiologies of cirrhosis. Standardized modalities to measure frailty and sarcopenia are required in every LT center at the baseline assessment and prospectively on the waiting list. Sensitivity and specificity of these modalities to capture longitudinal changes are inevitable criteria for predicting patients’ longterm outcomes. More importantly, these tools would allow evaluating the efficacy of management strategies, such as rehabilitation, nutritional support, and exercise programs, to prevent progression and improve survival before and after LT.
Potential conflict of interest
Nothing to report.
