Sarcopenia is a frequent complication in cirrhosis. It is the major component of malnutrition and is not reversed after liver transplantation; in fact, it may worsen.
ReviewSarcopenia from mechanism to diagnosis and treatment in liver disease
Introduction
Malnutrition in liver disease has been used for decades to describe the phenotype of skeletal muscle loss with or without loss of fat mass [1]. The majority of “malnourished” patients with cirrhosis experience skeletal muscle wasting or sarcopenia, a major predictor of adverse clinical outcomes [2], [3], [4]. Although alterations in body composition in cirrhosis have been reported using a number of methods, radiographic image analysis is believed to be the most precise technique to quantify muscle mass and define sarcopenia [5], [6]. Over the past few years, a number of investigators have reported that sarcopenia occurs in 30–70% of cirrhotic patients [2], [7], [8], [9], [10]. The clinical significance of sarcopenia in liver disease, primarily cirrhosis, is due to the high prevalence and adverse impact on clinical outcome measures including survival, quality of life, development of other complications of cirrhosis, and post liver transplant outcomes [1], [4], [10], [11], [12], [13], [14]. Etiology and severity of the underlying liver disease, duration of illness, age and co-morbidities contribute to the severity of sarcopenia [1], [4], [9], [15], [16]. Despite being widely recognized as a major complication of cirrhosis, most therapies to date are based on the principle of “deficiency replacement” rather than targeted treatments, and have generally been ineffective [17]. Nutritional supplementation has been a particular therapeutic focus because reduced dietary intake was believed to be the major cause of malnutrition and sarcopenia. However, these approaches have been frequently inadequate in improving survival [18], [19], [20]. An integrated metabolic-molecular approach in a comprehensive array of models has shown that hyperammonemia is a mediator of the liver-muscle axis [21], [22]. Physical activity has been suggested to improve functional capacity but the effect on skeletal muscle mass is still unclear [23]. In recent years, a combination of sarcopenia with obesity has been increasingly recognized, especially in patients with non-alcoholic fatty liver disease (NAFLD) and post liver transplantation. Whether sarcopenia is mechanistically related to obesity and NAFLD, however, is still under debate [24], [25]. The major deficiency in the field of sarcopenia in cirrhosis is the lack of understanding of the mechanisms involved. A number of excellent recent reviews have described the clinical relevance of sarcopenia in cirrhosis but have not focused on the possible mechanisms and on the relevance of novel therapeutic targets that have the potential for clinical translation [1], [17], [26], [27], [28], [29].
In the present review we will provide an overview of the clinical relevance of sarcopenia in liver cirrhosis, but the emphasis will be on the possible molecular and metabolic perturbations involved and the promising novel therapeutic approaches that could be made possible by these discoveries.
Section snippets
Diagnosis of sarcopenia in cirrhosis
Most studies to date have used the term “malnutrition” to identify primarily skeletal muscle loss determined by one or more criteria that are not always uniform or precise and an alteration in energy metabolism and potentially fat mass depletion. The diagnosis of skeletal muscle loss requires analysis of the body composition using one or more of a number of available techniques (Table 1) as well as the normal values to define the appropriate cut-off values for sarcopenia [3], [6], [29]. Even
Clinical impact of sarcopenia in cirrhosis
A number of cross sectional and longitudinal studies using different methods to quantify muscle mass have reported that median survival and probability of survival are lower in patients who have cirrhosis with sarcopenia than those without sarcopenia (Table 2) [7], [9], [10], [33], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52]. Some of these reports suggest that sarcopenia adds to the prognostic value of the model for end-stage liver disease (MELD) scoring
Alterations in protein turnover, energy disposal and metabolic changes induce muscle depletion in cirrhotic patients
As seen above, a number of studies and reviews have provided descriptive data on the high prevalence and adverse clinical impact of sarcopenia in cirrhosis [1], [4], [7], [10], [26], [60]. Skeletal muscle is the major protein store in the human body [61]. Skeletal muscle mass is maintained by a balance between protein synthesis, protein breakdown and regenerative capacity regulated by muscle satellite cell function [1]. Broadly, two types of studies have contributed to the current understanding
Management strategies
There is compelling evidence that sarcopenia is associated with adverse consequences while there are limited data showing that increasing muscle mass improves survival in the non-transplanted and post liver transplant population of cirrhotics [31], [32]. Therefore, reversing muscle mass is a priority area for therapeutic interventions in cirrhotic patients (Fig. 3). Interventions that focus only on deficiency replacement have generally been ineffective while targeted therapies have the
Conclusion
In summary, there is compelling evidence to show that sarcopenia is the major complication of cirrhosis and adversely affects outcomes during the entire course of a cirrhotic patient’s life. Evidence to show that sarcopenia can be reversed is much more limited and it is not clear if reversing sarcopenia will indeed improve outcomes as expected. Nutritional supplementation is not consistently effective in improving outcomes but long-term BCAA with leucine are promising therapies to prevent and
Financial support
Funded in part by NIH RO1 DK83414, R21 AA 022742, UO1 DK 061732, UO1 AA021893 and P50 AA024333-01 8236 to SD.
Conflict of interest
Dr. Dasarathy reports grants from National Institutes of Health, during the conduct of the study. These include grants RO1 DK83414, R21 AA 022742, UO1 DK 061732, UO1 AA021893 and P50 AA024333-01 8236. Dr. Merli declared that she does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Authors’ contributions
Dr. Dasarathy generated the initial draft, edited the manuscript, generated the figures and tables and approved the final draft. Dr Merli assisted with the initial draft, edited the draft, edited the figures and approved the final manuscript.
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