Robert P. Myers was supported by a Clinical Investigator Award from the Alberta Heritage Foundation for Medical Research (now Alberta Innovates–Health Solutions) and by a New Investigator Award from the Canadian Institutes for Health Research. Puneeta Tandon was supported by a University of Alberta Hospital Foundation Award.
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The adoption of the Model for End-Stage Liver Disease (MELD) score for the allocation of deceased donor hepatic grafts has resulted in reductions in waiting-list mortality and the time to liver transplantation (LT).1, 2 Despite these advantages, the MELD score has recognized limitations,3, 4 including inferior performance in predicting mortality in a subgroup of patients with lower MELD scores.5-7 In order to optimize the utility of the MELD score for the prediction of waiting-list mortality in a broader range of patients and to identify those patients at the greatest risk of deterioration, continued attempts at modifying this score are important. Muscle mass loss, a major feature of malnutrition,8 has long been recognized as an independent predictor of mortality in patients with cirrhosis9-12 and particularly in patients with less severe hepatic dysfunction.9, 13 The addition of an objective marker of muscle mass depletion to the MELD score is a promising target that has yet to be evaluated.
In patients with cirrhosis, the utility of bedside tools [eg, the body mass index (BMI), subjective global assessment (SGA), and anthropometric measures] for the estimation of muscle mass loss is limited by the subjective nature of the tools and by the impact of hepatic synthetic dysfunction and salt and water retention. The severe depletion of muscle mass, which is termed sarcopenia, is an objective marker that can be determined with cross-sectional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), which are performed routinely for hepatocellular carcinoma surveillance. In patients without cirrhosis, sarcopenia has been associated with an increased risk of infections, prolonged hospital stays, and decreased survival.14-16 In a study by Montano-Loza et al.,17 sarcopenia was an independent predictor of mortality in 112 patients with cirrhosis. The impact of sarcopenia on the outcomes of patients with cirrhosis awaiting LT has yet to be determined. We hypothesized that sarcopenia would have a greater impact on mortality among patients with lower MELD scores, as observed with hyponatremia and hypoalbuminemia.18, 19 We also hypothesized that sarcopenia might have a greater impact on mortality in female patients. In the setting of disease-related loss of energy stores, evidence suggests that unlike males, females with cirrhosis use their fat stores preferentially over their muscle stores. We hypothesized, therefore, that those female patients who came to the point of losing muscle mass would be more severely affected and would have worse outcomes.12, 20-23
Therefore, our objectives were to (1) describe the prevalence and predictors of sarcopenia in patients with cirrhosis awaiting LT and (2) determine whether sarcopenia has independent prognostic significance beyond the MELD score for predicting transplant waiting-list mortality.
BMI, body mass index; CI, confidence interval; CP, Child-Pugh; CPA, Child-Pugh class A; CPB, Child-Pugh class B; CPC, Child-Pugh class C; CT, computed tomography; HR, hazard ratio, IQR, interquartile range; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; N/A, not available; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio; SGA, subjective global assessment.
PATIENTS AND METHODS
In this retrospective study, the University of Alberta liver transplant database was used to identify adult patients (≥18 years) activated on the LT waiting list between February 2005 and November 2009. Local ethics approval was obtained before the initiation of the study. For patients to meet the study criteria, cross-sectional abdominal imaging with CT or MRI was required within 6 weeks of activation on the transplant waiting list. At our center, cross-sectional imaging is commonly performed for patients undergoing transplant evaluations. The exclusion criteria were hepatocellular carcinoma, acute liver failure, prior LT, and listing for multivisceral transplantation or living related transplantation. The LT database and transplant dietary records were searched for each patient's demographic details, etiology and severity of liver disease, height and weight, laboratory data, and outcome on the waiting list.
The estimated dry weight is the subjective estimation of a patient's weight without ascites or pedal edema. At our center, this is estimated by dieticians who use the postparacentesis body weight or (if this is unavailable) estimate the dry weight by subtracting 5% of the patient's weight in the presence of mild ascites, 10% in the presence of moderate ascites, and 15% in the presence of severe ascites. An additional 5% is subtracted if bilateral pedal edema is present. The dry-weight BMI (kg/m2) is calculated by the division of the patient's estimated dry weight (kg) by the square of the patient's height (m2). SGA is a nutritional assessment tool developed by Detsky et al.24; it divides patients into 3 categories based on the bedside history and physical examination parameters: (A) well nourished, (B) moderately malnourished, and (C) severely malnourished. This tool is a more structured means of eyeballing the patient to get a subjective estimation of the nutritional status and, as part of this, the muscle mass.
Identification of Sarcopenia: Muscle Mass Image Analysis
With available CT and MRI images, the L3 vertebral level was identified, and SliceOmatic 4.3 (Tomovision, Montreal, Canada) was used to measure the cross-sectional area of surrounding muscles (ie, the psoas, paraspinals, transversus abdominis, rectus abdominis, and internal and external obliques). The muscle cross-sectional area at this level is used because it best corresponds to the whole body muscle mass in cancer and noncancer patients and has been validated against dual X-ray absorptiometry.25-27 Muscle areas were analyzed by an operator trained in musculoskeletal anatomy with tissue-specific Hounsfield unit thresholds. The L3 skeletal muscle area was normalized to stature by the division of the muscle area by the height squared. Sarcopenia is a reduction in the quantity of muscle mass to >2 standard deviations below normal.28 Sarcopenia cutoffs for the lumbar skeletal muscle index were based on a CT-based sarcopenia study of cancer patients29; the same cutoffs were used by Montano-Loza et al.17 for patients with cirrhosis. Sarcopenia was considered present when the L3 muscle area was ≤52.4 cm2/m2 in males and ≤38.5 cm2/m2 in females.
Statistical analyses were performed with SPSS 18 statistical software (SPSS, Inc., Chicago, IL) and Stata 11.0 statistical software (StataCorp, College Station, TX). Patient characteristics were described with absolute frequencies, percentages, medians, and interquartile ranges (IQR). Comparisons between groups were made with Fisher's exact test and the Mann-Whitney test as appropriate. Potential predictors of sarcopenia, including age, sex, liver disease etiology [classified as hepatitis C, alcohol, autoimmune, nonalcoholic fatty liver disease (NAFLD)/cryptogenic, or other], dry-weight BMI, SGA, MELD score (and its laboratory components), Child-Pugh (CP) class, and serum sodium and albumin concentrations, were evaluated with a logistic regression analysis. A multivariate logistic model for predictors of sarcopenia included age, sex, and variables significant in the univariate analysis (P < 0.05). Survival was estimated with the Kaplan-Meier survival method, and comparisons between groups were made with the log-rank test. The influence of sarcopenia on mortality was determined with a Cox proportional hazards regression. Patients were followed until death, LT, removal from the waiting list, or the end of the study period (January 27, 2011), whichever came first. Patients removed from the waiting list because they were considered too sick to undergo transplantation were counted as deaths. Patients removed because they were deemed too well to undergo transplantation and patients who underwent transplantation were censored. A multivariate Cox model was adjusted for a limited number of variables (age, MELD score, and sarcopenia) because of the small number of events (33 deaths). To determine whether the effect of sarcopenia was influenced by the severity of liver disease or sex, interaction terms for sarcopenia and MELD scores and for sarcopenia and sex were also examined. Two-sided P values less than 0.05 were considered statistically significant.
One hundred sixteen of 258 potentially eligible patients were excluded because of the unavailability of a CT or MRI scan of the abdomen taken within 6 weeks of activation on the transplant waiting list. The baseline characteristics of these patients and the remaining 142 patients are provided in Table 1. The median age of the included patients was 53 years (IQR = 47-57 years), and 60% were male. For the included patients, hepatitis C with or without alcohol abuse was the most common etiology of cirrhosis (38%), and the median MELD score at activation was 15 (IQR = 12-22). As shown in Table 1, the included and excluded patients did not differ significantly in their baseline characteristics, including the MELD score (P = 0.76). Because cross-sectional imaging was performed quite routinely for patients undergoing transplant evaluations and was not reserved for the sickest patients, the potential for selection bias was minimized.
Table 1. Characteristics of Patients at the Time of Waiting-List Registration
Included Patients (n = 142)
Excluded Patients (n = 116)
NOTE: All data are presented as medians and IQRs unless otherwise indicated.
Because of rounding, the etiology percentages for included patients do not add up to 100.
Included primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis.
In all, 41% of the patients listed for LT (58/142) were sarcopenic. Although the median skeletal lumbar muscle mass index was higher in males [50.8 cm2/m2 (IQR = 44.2-57.7 cm2/m2)] than females [44.9 cm2/m2 (IQR = 40.2-50.0 cm2/m2), P < 0.001], sarcopenia was more prevalent in males (54% versus 21%, P < 0.001). Overall, the prevalence of sarcopenia increased with the CP class [10% for Child-Pugh class A (CPA), 34% for Child-Pugh class B (CPB), and 54% for Child-Pugh class C (CPC), P = 0.007]; however, in sex-stratified analyses, this association was observed only in males (Fig. 1). Sarcopenia was not associated with age, liver disease etiology, serum sodium, the MELD score, or its laboratory components (Table 2). Similarly, SGA was not associated with sarcopenia. Of the 140 patients with available SGA information, sarcopenia was identified in 40% of the patients (17/42) in the well-nourished SGA category (A), in 38% of the patients (33/87) in the moderately malnourished category (B), and in 64% of the patients (7/11) in the severely malnourished category (C; P = 0.28). On the contrary, a lower dry-weight BMI was associated with an increased prevalence of sarcopenia [100% (8/8) with a BMI ≤ 18.5 kg/m2 (underweight), 46% (29/63) with a BMI of 18.6-25 kg/m2 (normal weight), and 30% (21/71) with a BMI > 25 kg/m2 (overweight), P < 0.001]. These associations were consistent across the sexes (Fig. 2A). Although the median dry-weight BMI differed significantly between sarcopenic patients [24.2 kg/m2 (IQR = 20.4-26.2 kg/m2] and nonsarcopenic patients [26.4 kg/m2 (23.5-30.1 kg/m2), P < 0.001], there was a significant overlap between the groups, and this limited the utility of the dry-weight BMI as a predictor of sarcopenia (Fig. 2B).
Table 2. Predictors of Sarcopenia Among Patients on the LT Waiting List (n = 142)
OR (95% CI)
OR (95% CI)
NOTE: The multivariate model included age, sex, CP class, serum albumin, and estimated dry-weight BMI.
Included primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis.
In a multivariate logistic regression analysis including age, sex, CP class, and serum albumin, male sex [odds ratio (OR) = 5.91, 95% confidence interval (CI) = 2.38-14.6], CPC cirrhosis (versus CPA: OR = 15.4, 95% CI = 1.44-165.7), and a lower dry-weight BMI (OR = 0.82, 95% CI = 0.74-0.90) were independent predictors of sarcopenia (Table 2). The inclusion of the MELD score instead of the CP class in this model yielded similar results (data not shown), although the MELD score was not statistically significant (OR = 1.03, 95% CI = 0.99-1.07, P = 0.18).
Outcomes on the LT Waiting List
During a median follow-up of 6.5 months (IQR = 1.6-20.4 months), 23% of the patients (33/142) died, and 58% (83/142) underwent LT. There were 17 deaths among the 58 patients (29%) with sarcopenia: 8 (47%) due to sepsis, 4 (24%) due to multisystem organ failure, 2 (12%) due to intracerebral hemorrhage, 1 (6%) due to gastrointestinal hemorrhage, 1 (6%) due to delisting for deterioration, and 1 (6%) due to an unknown cause. There were 16 deaths among the 84 patients (19%) without sarcopenia: 6 (38%) due to multisystem organ failure, 5 (31%) due to sepsis, 2 (13%) due to delisting for deterioration, 2 (12%) due to gastrointestinal hemorrhage, and 1 (6%) due to intracerebral hemorrhage.
Predictors of Wait-List Mortality
Waiting-list mortality was significantly greater among sarcopenic patients than nonsarcopenic patients (log-rank P = 0.04; Fig. 3A). The estimated survival rates at 1, 2, and 3 years were 79%, 74%, and 70%, respectively, for nonsarcopenic patients and 63%, 51%, and 51%, respectively, for sarcopenic patients. In a subgroup analysis using the MELD score at listing, the presence of sarcopenia was associated with increased mortality in patients with low MELD scores (<15; log-rank P = 0.02) but not in patients with higher MELD scores (≥15; P = 0.59). As shown in Fig. 3B, waiting-list mortality was similar for patients with low MELD scores and sarcopenia and patients with high MELD scores (with or without sarcopenia).
Table 3 includes univariate and multivariate Cox proportional hazards regression models for overall waiting-list mortality. After adjustments for age and MELD scores, sarcopenia was found to be an independent predictor of mortality [hazard ratio (HR) = 2.36, 95% CI = 1.23-4.53, P = 0.009]. As expected, older age (HR per year = 1.06, 95% CI = 1.01-1.10, P = 0.02) and higher MELD scores (HR = 1.13, 95% CI = 1.09-1.19, P < 0.001) were also associated with increased mortality (Table 3). Interaction terms for sarcopenia and MELD scores (P = 0.71) and for sarcopenia and sex (P = 0.75) were not statistically significant.
Table 3. Predictors of Overall Mortality Among Patients on the LT Waiting List (n = 142)
HR (95% CI)
HR (95% CI)
NOTE: The multivariate model included age, MELD score, and sarcopenia.
Included primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis.
This retrospective review of 142 patients is the first to evaluate the contribution of muscle mass loss to the prediction of transplant waiting-list mortality. The results confirm data from previous studies showing that muscle mass loss is common among patients awaiting LT and that it increases in prevalence with the severity of liver dysfunction. The novel finding of the study is that sarcopenia is an independent predictor of mortality on the LT waiting list.
The assessment of sarcopenia by cross-sectional imaging has several advantages over traditional means for diagnosing muscle mass loss and, therefore, is a good starting point for evaluating the impact of muscle mass loss on transplant waiting-list mortality. Importantly, it is objective and effort-independent and is not influenced by hepatic synthetic dysfunction or salt and water retention.30-32 Cross-sectional imaging has been identified as an independent predictor of mortality in the setting of cirrhosis.17 BMI and SGA are subjective tools for detecting malnutrition, a large component of which is muscle mass loss. Neither of these tools was useful for the prediction of transplant waiting-list mortality in our patients. The lack of significance of SGA as a predictive marker for transplant waiting-list mortality points to the inadequacy of eyeballing the patient and the importance of an objective assessment tool. We recognize that a cross-sectional imaging–based muscularity assessment is time-consuming and, therefore, is unlikely to be a practical tool for incorporation into daily practice. For the purposes of this study, as a starting point for assessing the importance of muscle mass depletion to transplant waiting-list mortality, we felt that it would be best to use an accepted objective tool. We are in the process of comparing cross-sectional imaging–based muscle mass assessment to alternative, more practical bedside assessment tools.
In agreement with the literature,9, 12, 33 liver dysfunction and muscle mass loss were highly correlated in our series of patients awaiting LT. The prevalence of sarcopenia increased significantly with advancing liver disease according to the CP classification (10% for CPA, 34% for CPB, and 54% for CPC). Despite this association, after adjustments for age and MELD scores, sarcopenia was associated with an approximately 2.4-fold risk of transplant waiting-list mortality. Notably, sarcopenia appeared to have the greatest influence on mortality among patients with MELD scores less than 15. In fact, the outcomes of patients with low MELD scores and sarcopenia were similar to the outcomes of patients with high MELD scores with or without sarcopenia (Fig. 3B). This finding is in keeping with data from Merli et al.,9 who demonstrated that muscle loss (as measured by the midarm muscle circumference) was predictive of mortality in CPA and CPB patients but not in patients with CPC cirrhosis.9 Therefore, pending prospective validation, sarcopenia may be useful as an objective and potentially modifiable tool for risk-stratifying patients with low MELD scores. A diagnosis of sarcopenia can identify those patients who may benefit from more intensive nutritional supplementation and exercise therapy, both of which have been shown to improve outcomes for patients with cirrhosis.34, 35 Additional study will be required to determine whether MELD exception points should be granted to sarcopenic patients with low MELD scores, particularly in the setting of nonresponses to conservative measures.
Sarcopenia was found in 54% of the men and in 21% of the women in our cohort. These sex-based differences have also been identified with the midarm muscle circumference,9, 12 dual-energy X-ray absorptiometry,20 and in vivo neutron activation analysis33 and, therefore, are unlikely to be related to incorrect sex-specific cutoffs for the cross-sectional imaging–based diagnosis of sarcopenia. It has been hypothesized that women are more likely to lose fat mass than muscle mass because of the presence of greater baseline fat stores in women.33, 36 These sex differences in the patterns of muscle mass loss play an important role in the use of muscle mass for the diagnosis of malnutrition and in the utility of a MELD and sarcopenia-based prognostic score. We hypothesized that women with sarcopenia may be at a more advanced stage of malnutrition because they have reached the point of requiring their muscle mass as an energy store. However, we did not observe a significant interaction between sarcopenia and sex with respect to transplant waiting-list mortality. These negative findings are at odds with a study by Morgan et al.,37 who observed a significant relationship between nutritional status and mortality among men but not among women. Nevertheless, additional study of the sex-specific prognostic implications of sarcopenia is required because of the small number of sarcopenic females in each of these studies and because of the use of more subjective markers (eg, BMI and dietary intake) in the study by Morgan et al. It remains unclear to us whether the difference in the sex-specific rates of sarcopenia means that female patients are less likely to have muscle mass depletion or that alternate assessment methods are required for females. Interestingly, the prevalence of sarcopenia increased with advancing stages of liver disease in males (P = 0.002) but not in females (P > 0.99; Fig. 1). This lack of a correlation of liver function with muscle mass loss in females also supports the potential for a sex-specific difference in the prevalence and pathophysiological basis of sarcopenia in cirrhosis.
Our study has several limitations, including its retrospective design, its modest sample size, and the inclusion of nonconsecutive patients according to the availability of cross-sectional abdominal imaging. Reassuringly, the characteristics of the included patients and the patients who were excluded because of the unavailability of scans within 6 weeks of activation were similar (Table 1), and this reduced the chance of selection bias. We used both CT and MRI scans to define sarcopenia. Ideally, a single method will be employed in future studies. The optimal cutoffs for the lumbar skeletal muscle area that define sarcopenia, particularly among patients with cirrhosis, require further study. Due to the retrospective nature of our study, we could not compare sarcopenia to other anthropometric measures (eg, midarm muscle circumference and hand grip). Finally, the limited number of deaths in our study precluded a formal assessment of the utility of incorporating sarcopenia into the MELD score [akin to the addition of sodium to the MELD score (MELD-sodium)]. Future prospective studies will determine whether the addition of sarcopenia to MELD (and MELD-sodium) will improve the prediction of mortality among patients on the LT waiting list.
In conclusion, this is the first study to evaluate the independent prognostic contribution of muscle mass loss to transplant waiting-list mortality. It appears that a MELD-based score including sarcopenia may improve prognostication in comparison with existing methods. Further prospective studies are needed to confirm our findings, to evaluate the sex-specific differences in the prevalence of sarcopenia, to compare the prognostic utility of sarcopenia to other anthropometric measures, and to determine which patients can be declared sarcopenic on the basis of simple bedside testing.