Introduction

Patients with cirrhosis are susceptible to significant symptoms of decompensation which have a significant impact on both quality of life and survival. These symptoms often lead to frequent hospitalizations which can lead to decreased quality of life and increased morbidity and mortality in this patient population. Liver-specific conditions known to be associated with these increased hospitalizations include encephalopathy, ascites, and variceal bleeding [1]. Additional systemic complications such as reduced muscle mass, physical frailty, malnutrition, metabolic syndrome, and immune dysregulation and functional immunosuppression increase the susceptibility of poor outcomes in cirrhosis [2]. Sarcopenia, defined as low muscle mass, is a lethal complication of cirrhosis. This condition in liver transplantation independently associates with waitlist mortality, as well as posttransplant outcomes such as prolonged hospital and intensive care unit stay, increased infection, and post-LT mortality [3–6]. Frailty is often considered the “functional” component of reduced muscle mass. The concept of frailty has been newly applied to patients with cirrhosis and is generally defined as a decline in physiologic reserve resulting in an increased susceptibility to stressors. It has been notoriously difficult to objectively define, although this has changed with the advent of objective measures such as the Liver Frailty Index (LFI) [7].

As a major component to frailty, sarcopenia is tightly linked to this construct and generally one cannot be addressed without the other. With advancing stages of liver disease, there is an increased rate of frailty and sarcopenia, both of which are independently associated with decompensated cirrhosis and mortality [2]. Frailty currently does not have a gold standard assessment tool given its global nature. The currently accepted measurement tools collectively assess for indices in weight loss, physical stamina, and function. Sarcopenia, on the other hand, involves the quantification of muscle mass, and is characterized by the loss of muscle mass and resultant loss of muscle strength. This has also been challenging to objectively measure over the years. However, more recently, the European Working Group on Sarcopenia in Older People (EWGSOP) proposed a definition of sarcopenia that includes the loss of muscle mass plus the presence of low muscle strength or low physical performance [8]. In this chapter, we aim to outline the objective measures of muscle mass and muscle function and review the strengths and weaknesses of each.

Assessment of Sarcopenia

As defined by the EWGSOP, a working definition of sarcopenia includes the presence of both low muscle mass and low muscle function. The latter is defined as strength or performance [8]. Most studies focus on objective measures of muscle mass alone; for example, in the aging population, sarcopenia is defined as loss of muscle mass two standard deviations below the mean. The gold standard of measuring muscle mass relies on skeletal muscle imaging with computed tomography (CT) or magnetic resonance (MR) imaging techniques, which can precisely separate fat from other soft tissues. The location of measurement has varied by study, with L3 (third lumbar vertebrae) or psoas muscle level being commonly used. Limitations to CT and MR include the high cost of imaging, somewhat limited access to image analysis software and concerns regarding radiation exposure over time with CT. However, this modality is becoming more accepted as patients with cirrhosis are generally receiving cross-sectional imaging at frequent intervals for hepatocellular cancer screening and presurgical planning. Dual energy x-ray absorptiometry (DXA) is an alternative method to distinguish fat from other lean tissues while exposing the patient to minimal radiation. DXA equipment is largely not portable, rendering it useful in specific locations that already have the equipment.

Alternative methods to muscle mass measurement include bioimpedance analysis and total or partial body potassium per fat-free soft tissue. Bioimpedance analysis (BIA) has been in use for a longer period of time and can estimate volumes of fat and lean body mass. It is considered to be easy to use and inexpensive, and one of its hallmarks is its appropriateness for both ambulatory and hospitalized patients [8]. It correlates well with MR-based predictions and is validated in multiethnic adult populations [8]. BIA takes fat mass and subtracts it from total body weight in order to estimate lean mass. It is limited in patients with ascites whose total body weight is affected not by fat or muscle but rather by water volume. Body potassium measurements are considered the classic measurement of skeletal muscle as >50% of the body’s potassium pool is located in skeletal muscle. It is not used routinely. Finally, measurements of arm or calf circumference have been used, but changes in fat content and skin elasticity have made this an unreliable measure in older and obese people and thus vulnerable to error [9]. With the wide availability of imaging techniques in cirrhotic patients, these alternative methods have not been widely studied in patients with cirrhosis.

Assessment of Muscle Strength

Measuring muscle strength has proven to be more difficult as there are less well-validated measurements, and factors unrelated to muscle strength, such as pain or posture, can interfere with the correct measurement of strength. Handgrip strength via dynamometer is an easy-to-use, widely available tool that correlates with lower extremity muscle power, knee extension torque, and calf cross-sectional muscle area, all of which are more relevant for gait and overall physical function [10]. In older adults, low handgrip strength was noted to be a better predictor of clinical outcomes than low muscle mass itself [10]. This measurement of muscle strength is predicated upon the belief that muscle strength across different body compartments is generally well correlated.

An important caveat in the measurement of muscle strength is also that of muscle power, a measurement of work per unit time. There is data that suggests power is a better predictor of certain functional activities [8]. This is centered around leg extensor power that can be measured isometrically or isokinetically, the latter of which is more closely associated with every day muscle function. This measurement tool is limited to research settings due to the need for specialized equipment and expert training. Finally, in patients without lung disease, peak expiratory flow measures the strength of respiratory muscles. However, data on its relationship to sarcopenia is limited, and it is not necessarily a valid measurement tool in patients with cirrhosis, who may have occult pulmonary disease.

Assessment of Muscle Function

With only limited, specialized tools to measure strength, more focus has turned toward measuring muscle function, providing a more global picture of a patient’s physical performance incorporating strength, balance, and coordinated muscle movement. Implicitly, these tests also indirectly assess difficult to measure components of muscle use including neurologic connectivity, coordination, balance, and stamina. A number of tests are available and have been used in patients with end-stage liver disease.

The Short Physical Performance Battery (SPPB) examines a patient’s ability to stand with feet together in three different positions (side-by-side, semi-tandem, and tandem), time to walk 8 feet, and rise from a seated position five times. There has been an established relationship between gait speed and leg strength, which suggests that small changes in physiologic reserve may have tremendous effects on performance in frail patients. As a component of the SPPB, gait speed can also be used on its own and carries predictive value for the onset of disability, mobility limitations, and mortality [8]. Finally, the timed get up and go test (TUG) requires a patient to rise from a seated chair; walk a short, defined distance; turn around; and return to a seated position. This tests for the additional component of balance, with a mid-test 180-degree turn. Importantly, these tests represent a composite measure of physical performance as opposed to static measurements of muscle mass, are easy to perform in clinic, and do not require any specialized equipment or training to administer.

Because a significant number of patients with end-stage liver disease fulfill criteria for frailty, additional tests for this specific population include the Fried Frailty Index (FFI), LFI, activities of daily living (ADL) scale, Braden Scale, and 6-minute walk test (6MWT) [2]. The FFI measures unintentional weight loss, hand grip exhaustion (via dynamometer), and low-activity gait speed to derive a composite score, with a higher score being more frail. The LFI, created specifically for patients with cirrhosis, combines grip strength, chair stands, and balance and places a patient on a scale from robust to frail [7]. These two frailty scales can be performed in the ambulatory setting (as long as a dynamometer is available) in less than 5 minutes. They are slightly more difficult to perform in the inpatient setting due to less availability of a dynamometer, potential physical limitations such as hepatic encephalopathy, and competing care priorities. These tests are limited in the encephalopathic patient, those with limited mobility, although, admittedly, we would not expect this type of patient to score “robust” utilizing any measure. The ADL scale measures the need for assistance with ADLs and assigns a score commensurate to the level of independence for each ADL. Finally, the 6-minute walk test can also be completed in the outpatient setting and increase the accessibility of a diagnosis of frailty in routine clinical care. The challenge in using these measures for both sarcopenia and frailty lies in the implementation and integration into clinical practice.

Muscle Mass and End-Stage Liver Disease

Prioritization for liver transplantation currently relies on the Model for End-Stage Liver Disease (MELD), which is based on a “sickest-first” policy; however, it is thought that the MELD score may not accurately capture the true prognosis of patients with cirrhosis. MELD does not capture certain measures which may affect quality of life and function such as ascites, malnutrition, and severe muscle wasting. However, in order to further optimize this score, modifications to this score have been studied over the years, with one such successful example being the addition of sodium level to generate the MELD-Na score. Muscle mass is one of these areas that can carry promising prognostic value.

In patients with cirrhosis, subjective measures such as BMI and anthropometric measures are limited by salt/water retention and subjectivity in measurement. With routine cross-sectional imaging being performed for HCC surveillance, sarcopenia can objectively be determined and defined using sex-specific cutoffs. Many early studies simply applied definitions used in oncology literature and were limited in scope and influence. It was not clear that these definitions were accurate in the population with cirrhosis and thus were felt to misclassify patients. Recently, Carey et al. performed a multicenter image analysis study that yielded skeletal muscle index (SMI) cutoffs of 50 cm²/m² for men and 39 cm²/m² for women, which best correlated with waitlist mortality [13]. Through a variety of mechanisms, not discussed here, sarcopenia has a clear relationship with the development of hepatic encephalopathy (HE) and large volume ascites. Using anthropometric measurements, two separate studies independently found that sarcopenia predicted the presence of HE, adjusting for age, Child-Turcotte-Pugh (CTP) score and diabetes [14, 15].

While promising, the influence of sarcopenia has been shown to be greater on true waitlist and posttransplant outcomes. In an early study [11], patients with cirrhosis had SMI measured at the level of L3 vertebrae. Sarcopenia was identified as an independent predictor of mortality, with a median decrease in survival time of 15 months when compared to nonsarcopenic patients. Interestingly, there was a low level of correlation between sarcopenia and liver dysfunction scoring systems (CTP & MELD). Furthermore, it was seen that sarcopenia was associated with a higher frequency of sepsis-related death, which is consistent with earlier literature demonstrating that sarcopenia might have increased associations with infections in patients with cirrhosis [16]. This also further suggests that conventional scoring systems may not accurately capture true mortality risk. One can argue that an all-comer population of cirrhosis will have a proportion of patients with exceedingly low muscle mass which could skew results, favoring the impact of sarcopenia. A follow-up study from the same group, using the same methodology, determined that sarcopenia is independently associated with a 2.4-fold increased risk of waitlist mortality after adjusting for age and MELD score [17]. Notably, patients with a MELD <15 with sarcopenia had similar survival curves as patients with MELD >15 with and without sarcopenia. This suggests patients with less severe liver disease suffer the greatest impact from sarcopenia and would be an appropriate patient population to target sarcopenic-reversing interventions – nutrition- and exercise-based therapy [17]. Montano-Loza et al. further determined that a “MELD-sarcopenia” score improved upon the predictive power of the MELD alone score especially in those patients with a low MELD score. The authors estimated that sarcopenia adds 10 points to the MELD score [18]. Additionally, this impact was also felt to be greatest in patients with refractory ascites, which contributes to the development of sarcopenia through abdominal distension and thinning of the parietal muscles.

Some of the biggest theoretical limitations to utilizing imaging-based SMI are the time, software, and expertise required. Even though patients with cirrhosis undergo cross-sectional imaging routinely, a center must have the proper software and time needed in order to fully calculate a patient’s muscle mass. The standard algorithm uses computer software to differentiate skeletal muscle from adipose tissue using Hounsfield units and automatically compute cross-sectional areas by summing tissue pixels and multiplying by pixel surface area and standardizing to patient height [11]. It has been shown that calculating the SMI in this manner at the L3 level with a single cross-sectional image correlates well to total body skeletal muscle [19]. However, this method requires specific software and technical skills in order to accurately make the calculations. In order to evaluate a simpler single-image method, Durand and colleagues measured psoas muscle thickness on a single image at the level of the umbilicus, approximately at the same vertical level of L3 [20]. The benefit of this anatomic level is that the psoas muscle is easily identified and not prone to alterations by the presence of ascites, and psoas muscle thickness can be measured on any picture archiving and communication system (PACS), ubiquitous in today’s era of electronic medical record systems. This study demonstrated that psoas thickness was predictive of wait list mortality, independent of the MELD score and a MELD-psoas score performed better than the MELD-Na in patients with a MELD <25 [20]. This again suggested the impact of sarcopenia is strongest in patients with less advanced liver disease. Regarding waitlist mortality, there have been some studies that have not shown an impact on outcome; in 2016, a systematic review was performed to investigate the influence of skeletal muscle mass who were being evaluated for liver transplant [5], which concluded that sarcopenia was associated with waitlist mortality with a hazard ratio of 2, an effect that was independent of MELD [5].

Sarcopenia has also been shown to be linked with worse outcomes after liver transplantation. An early study demonstrated that pretransplant sarcopenia, as defined by psoas muscle area, correlated poorly with MELD score and was associated with increased posttransplant mortality [3]. This impact has also been shown in the living donor liver transplant recipients, who generally have a lower MELD score at the time of transplant and a lower risk of mortality. In two separate cohorts, skeletal muscle mass [21] and psoas muscle index [22] were predictive of survival after living donor liver transplantation. In a more recent study evaluating the quality of muscle tissue, low SMI and high intramuscular adipose tissue content were independently identified as risk factors for death after living donor liver transplant [23]. Finally, a recent meta-analysis by Vugt et al. demonstrated that sarcopenia carried a hazard ratio of 1.84 for posttransplant survival. This effect increased when removing transplants done primarily for malignancy to a hazard ratio of 2.03 [5]. There are a limited number of studies examining this relationship, but the work by Vugt et al. shows that studies in which cross-sectional muscle area was calculated yielded a higher impact on overall survival. In those studies where SMI was the primary variable calculated, the forest plots favored higher muscle mass but not to the same effect. Furthermore, Lee et al. demonstrated that patients with larger dorsal muscle group cross-sectional area have improved survival at 1 year and 5 years with a lower rate of complications at 1 year. To strengthen this relationship, they also demonstrated that dorsal muscle group area correlates well with psoas muscle area, the measure used in previous studies [24]. Valero et al. also demonstrated that the presence of sarcopenia was an independent predictor of postoperative complications, although this study did not demonstrate a difference in 30-day and 90-day mortality rates [25]. Finally, there is data that links the presence of sarcopenia with infections of all types [26] in the posttransplant setting but no clear association with rejection rates.

Muscle Function and End-Stage Liver Disease

One of the biggest limitations of muscle mass measurement is the difficulty incorporating it into daily clinical practice, especially in the ambulatory setting. Additionally, it provides a singular variable, however valuable, that does not necessarily fully capture the degree of functional decline in patients with cirrhosis [27]. There is a desire in the transplant community to find a more practical, reliable, and economical measure to provide an accurate risk assessment of patients both on the waitlist and after liver transplant.

In patients with cirrhosis, there are multiple factors that contribute to waitlist outcomes that are not captured in the MELD score such as age, muscle mass, nutritional status, and comorbidities [12]. Using the “eyeball test,” a clinician is attempting to assess the patient’s global health status in order to withstand stressors while on the waitlist and recover from a major operation. This approach has long been a subjective component of the evaluation of a patient with cirrhosis, especially in the determination of transplant candidacy. This concept has been objectively operationalized as frailty by the FFI and shown to be a more powerful predictor of functional status in the elderly [28]. In liver patients, this functional reserve has been measured by several tools, which aim to include implicit measurements of coordination, neurologic connection, and stamina.

There is a great human and financial burden associated with repeated hospitalizations for patients with cirrhosis, and muscle function seems to play an important role in this pathology. Simpler single-measure tools have independently predicted outcomes in patients with liver disease. On a continuous spectrum, gait speed was shown to be a strong predictor of hospitalizations and hospital costs. With each decrease of 0.1 m/s, length of stay and costs increased [29]. In the same study, grip strength showed a trend toward similar results, however were not significant. The reasons for hospitalizations extended across the spectrum and included ascites, encephalopathy, infections, and GI bleeding, in order. Furthermore, as determined by the FFI, frail patients were more likely to have ascites, explained by increased resting expenditure in these patients [12]. This carries important prognostic information, as patients with cirrhosis with increased decompensating events and hospitalizations have a higher risk of mortality.

By a variety of measures, both muscle function and frailty have been associated with mortality in liver transplant candidates. The 6MWT, as its name suggests, is a simple test, with the ability to evaluate a host of coordinated body functions and reflect daily physical activities. Carey et al. demonstrated that the 6MWT significantly predicts mortality, with a 52% reduction in mortality with every 100 meter increase from baseline distance [30]. This finding is not terribly surprising as subjectively, patients with cirrhosis suffer from fatigue, deconditioning, and decreased physical ability. However, the ability to define this decline can assist transplant physicians with a tool to identify increased risk of waitlist mortality. Tapper et al. examined the predictive ability of additional frailty metrics and found that an ADL score of <12 (out of 15) and an intermediate Braden score were associated with increased mortality, discharge after transplantation to a rehabilitation hospital, and increased hospital length of stay (Braden score only). When comparing odds ratios, the MELD score had lower OR per unit increase as compared to low ADL score or intermediate Braden score [31]. Additionally, this study demonstrated that patients scoring in the frail range of these measures were associated with HE-related decompensations. These studies underscore the broad applicability of these measures and ease of use in both the ambulatory (Carey) and inpatient (Tapper) settings.

The most recent effort in the assessment of frailty and muscle function has been to develop a composite score to be used in patients with cirrhosis. Initially, as defined by the FFI, frail patients had higher rates of complications of liver disease, including ascites and HE, correlating with previous research [12]. More importantly, frail patients had higher risk of mortality after adjustment for liver disease severity. The key advancement here is that many patients’ comorbid conditions and functional decline could now be objectively measured as their liver disease could be. Specifically, the FFI includes subjective components, which the authors argue improves the association of frailty to mortality. The example used is a patient who subjectively is hindered by their liver disease, such that it leads to meeting “frail” criteria, limiting physical activity, and worsening sarcopenia leading to increased risk on the waitlist, that may not be reflected in the MELD score [12]. As with sarcopenia, it was seen that those with a lower MELD score (in this case MELD <18) were seen to have a greater mortality when considered frail. However, the FFI was initially derived in the elderly population. In a seminal study, Lai and colleagues established a specific frailty index for patients with cirrhosis to improve the risk stratification of patients with cirrhosis on the liver transplant waitlist [7]. In this study, gait speed, grip strength, chair stands, balance, low physical activity, ADLs, and IADLs were all associated with waitlist mortality. The final measure consisted of grip strength, chair stands, and balance testing and results in a score across a continuous spectrum defining a patient as robust or frail. This measure, known as the Liver Frailty Index (LFI), enhanced the mortality risk prediction over the MELD-Na score alone, especially in patients who were older and obese and had HE or medical comorbidities [7]. Further analysis of this index demonstrated that frailty is worth about 9 MELD points. Interestingly, increasing LFI scores (indicating pretransplant frailty) were also associated with reduced recovery to robustness posttransplant [32].

Final Thoughts on Muscle Mass or Muscle Function

The spirit of determining reduced muscle mass, or sarcopenia, and loss of physical function, or frailty, are rooted in well-founded principles that these measures have important clinical implications for patients with liver disease awaiting transplantation. Until now, clinical judgment regarding a patient’s physical resilience is subjective and at worst not equitable. Both the quantification of muscle mass and characterization of physical function aim to provide objective measurements for a devastating complication of cirrhosis. Both tools have their merits and, depending on the clinical scenario, may be appropriately utilized.

The limitations of quantifying muscle mass include the need for advanced imaging and radiation exposure with CT, appropriate software, expertise in making measurements, as well as the additional time required. It is true that CT and MRI imaging are already widely used for hepatocellular cancer surveillance in patients with cirrhosis, but each image only provides a static evaluation of a potentially dynamic process. One critique of sarcopenia is the timing of when a study is obtained. Is it sufficient to make a determination about a patient’s level of sarcopenia if the implication is that this single measure would be used to make a determination about transplant candidacy? Should the determination of muscle mass get reevaluated in patients with a low MELD score the longer they are listed? On the other hand, quantifying muscle mass allows for an objective measure in a patient who for other reasons cannot perform a functional assessment. An instance might be the inpatient transfer patient with acute on chronic liver failure where the question becomes whether that person is physically able to survive liver transplantation. In this instance, the lack of previous ambulatory assessments limits the urgent evaluation. Sarcopenia provides insight on increased morbidity and mortality and provides more objective data to help guide clinical decision making. Sarcopenia also provides an objective endpoint as a research tool. It does not replace clinical judgment but can complement it. Its most useful application may be in the inpatient setting where functional assessments are difficult to obtain or in the initial ambulatory visit to establish a baseline from which progression of decline can be determined for future interventions.

Performance-based testing provides multifaceted information on not only muscle strength or mass but coordinated movements such as balance and cognitive ability. Frailty predicts important outcomes in liver transplantation such as waitlist mortality [33]. There is a level of training involved, but many different providers on a transplant or research team can conduct this type of testing quickly, reliably, and economically. It provides an understanding of a dynamic process as it evolves clinically and can be more readily reassessed than measurements of muscle mass which may or may not parallel a change in the patient’s functional status. Measuring physical function can only be performed in patients physically and cognitively able to participate, which in itself is a limitation. Frailty assessments are associated with both pretransplant mortality and posttransplant recovery, suggesting its long-term application. This would be most appropriately used in the outpatient setting, where it can easily be performed and tracked over time to provide prognostic value.

Whether in the research or clinical settings, sarcopenia and frailty may be useful biomarkers to study reduction in physical function and worsened outcomes in patients awaiting liver transplantation. Each has been shown to be linked to morbidity and mortality and is useful in different clinical scenarios. Each requires a certain resource of personnel, equipment, and time. Depending on a center’s experience or practices, one may be preferred over the other, and both can provide great insight into the plight of reduced physical function in patients with advanced liver disease.