Sarcopenia is defined as pathological muscle loss in patients with chronic diseases, and its role in the outcome of patients with cirrhosis is widely accepted 2. Different methods have been proposed to diagnose sarcopenia using cross-sectional imaging 2—8. Most methods evaluated computed tomography CT and require special software, which may be time consuming and difficult to implement in clinical routine 4,7.
Sex, in particular, seems to influence the muscle structure and its distribution in the body and thus possibly influences the diagnosis and the pattern of sarcopenia in cirrhosis Cumulative data emphasize the role of sex in the sarcopenia pattern suggesting different cutoffs for female and male patients 2,8. Patients with cirrhosis with acute decompensations ADs , in particular, are at a higher risk of death and require more health care resources 11— AD can lead to a systemic inflammatory response and progress to acute-on-chronic liver failure ACLF , a syndrome with high short-term mortality.
Systemic inflammation has been associated with age-related sarcopenia and development of ACLF 17, Although a number of risk factors for the development of ACLF have been discussed, the relationship of sarcopenia with ACLF and systemic inflammation has not been investigated yet 19— For this study, we included patients from the NEPTUN study, which prospectively included patients with decompensated cirrhosis who underwent the TIPS procedure in a structured monocentric follow-up program. Noninvasive methods for risk stratification were evaluated. For inclusion in this analysis, CT had to be available.
Exclusion criteria were lack of available or poor-quality CT. The primary end point was 1-year mortality after TIPS. Biochemical blood analyses were performed using standard laboratory tests. We analyzed the transversal psoas muscle thickness TPMT as previously described in cross-sectional images on the level of the umbilicus 5. We chose the umbilicus because it is easy to identify in CT and it was used as a landmark in the aforementioned description of the method 5.
The assessments were performed by 2 hepatologists M. We performed descriptive statistics for all variables. Nonparametric testing was used to compare different groups when suitable.
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Paired nonparametric testing was used to compare data before and after the TIPS procedure of the same patients. Univariate and multivariate risk factor analyses were performed with Cox regression for 1-year mortality, fatal and nonfatal ACLF, occurrence of ascites, and episodes of HE as end points. Concordance of the sarcopenia definitions was expressed by calculating concordance C-index. Continuous variables are presented as median range.
Categorical variables are presented as absolute cases or percentage.
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The median age at TIPS procedure was 56 18—80 years. The median follow-up period was 2. This resulted in an area under the curve AUC of 0. The reported unisex cutoff of To evaluate whether sex-specific differences and therefore sex-specific cutoff values would improve the method, we performed sex-specific ROC analysis. This revealed an optimal cutoff of With sex-specific classification, misclassification is lower compared with unisex classification.
For 1-year mortality, sex-specific classification has a higher C-index and therefore a higher diagnostic accuracy. A Kaplan-Meier survival curve for 1-year mortality showed a significantly increased mortality in sarcopenic patients Figure 1a. Interestingly, sex-specific classification provided superior discrimination compared with unisex classification of sarcopenia Figure 1a. There was no significant difference regarding the causes of death between the sarcopenia and the nonsarcopenia groups data not shown.
Only sex-specific sarcopenia classification was shown to be an independent predictor alongside CLIF-C AD score, age, serum creatinine, and bilirubin Table 2. Unisex classification did not reach statistical significance. Interestingly, sarcopenic patients receiving TIPS for refractory ascites had a higher risk of 1-year mortality compared with those with variceal bleeding as indication for TIPS hazard ratio 5.
Sarcopenic patients showed significantly higher rates of nonfatal ACLF development compared with nonsarcopenic patients Figure 1b. With sex-specific classification, misclassification is lower compared with unisex classification for development of ACLF at 1-year follow-up C-index 0.
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In multivariate Cox regression analysis, unisex classification failed. Absence of sarcopenia was associated with faster resolution of ascites after TIPS, whereas sarcopenic patients displayed a longer response to ascites despite patent TIPS Figure 2a. Furthermore, sarcopenic patients had a significantly higher rate of episodes of HE compared with nonsarcopenic patients Figure 2b.
For the 2 end points, ascites and HE, the sex-specific cutoff showed an improved discrimination compared with the unisex cutoff. The sarcopenia group showed a higher fraction of alcoholic etiology and ascites as indication for TIPS compared with the nonsarcopenia group. In real life, patients with cirrhosis usually seek medical attention, including CT, at the time of decompensating events.
In these situations, the potential to predict outcome is extremely important to stratify patient care. Using these imaging methods, different measures of muscle mass have been described. Interestingly, in that cohort, the authors elaborated only 1 cutoff for both male and female patients. There is growing evidence of the importance to recognize the sex differences in sarcopenic patients 2,4,23— Females tend to have significantly lower muscle indices, which is in line with our results and supports our data 2,8, These previous data explain, in part, our findings that the sex-specific cutoff is superior to the unisex cutoff used previously 5.
There are several possible explanations for these discrepant findings. These differences in characteristics possibly explain the inferior diagnostic accuracy of unisex cutoff compared with the sex-specific cutoff in our cohort. Therefore, sex-specific cutoff values should be applied to minimize misclassification. This is emphasized even more by our results, which identify sex-specific sarcopenia classification as an independent predictor of mortality, whereas the unisex cutoff failed in the multivariate analysis.
Further multicentric studies with large patient cohorts are needed to determine comparable sex-specific cutoff values 2,4,5,9,27— This is especially important regarding the relatively low negative predictive value of our classification in this cohort. It may well be higher in larger cohorts with lower prevalence of 1-year mortality. This has been supported by another study using skeletal muscle index at L3 vertebra L3-SMI requiring special software in a smaller cohort 30 , underlining the robustness of our study.
Moreover, the association of sarcopenia with survival and HE is important because this facilitates the caregiver to select patients who may benefit from additional therapeutic options, such as dietary strategies in sarcopenic patients 31— The limitations of this study are in line with the nature of all retrospective studies, namely that selection bias cannot be excluded despite the cohort showing fairly representative characteristics for patients with cirrhosis in a TIPS program. However, probably not all decompensating events, including nonfatal ACLF, are recorded because we do not have all the information about admissions to other hospitals.
However, we are confident that we have detected all ACLF developments with fatal outcome, which seems to be the more severe clinical entity in our patients. Although the relationship of sarcopenia with survival has been established on several different occasions, the main novel finding of this study is the association of sarcopenia with development of ACLF. Recently, ACLF has been characterized as a syndrome with very high short-term mortality, which may also develop in outpatients with cirrhosis This stresses the robustness of our data.
ACLF is a dynamic syndrome, which can reverse rapidly, especially in the earlier stages. Through the secretion of soluble peptides, or myokines, skeletal muscle interacts in metabolic processes with other organs such as the liver. In turn, metabolic cues from these organs are received by skeletal muscle, adapting their response accordingly.
Cross-talking between anabolic and catabolic pathways characterizes the signaling. Systemic inflammation evokes a catabolic reaction in skeletal muscle leading to excessive energy expenditure and ultimately sarcopenia Systemic inflammation has also been identified in the pathogenesis of ACLF development 17,18, It is conceivable that sarcopenia is therefore a clinical expression of underlying chronic systemic inflammation, which might facilitate development of ACLF.
Interestingly, in this cohort, leukocyte count, a surrogate of systemic inflammation, is significantly higher in sarcopenic patients, further underlining the tight association of systemic inflammation with sarcopenia and ACLF. The question of whether sarcopenia predisposes for systemic inflammation and ACLF development or systemic inflammation causes sarcopenia and ACLF is beyond the scope of this study.
This needs to be investigated in the future because it could also offer therapeutic or preventive approaches. Nevertheless, these results demonstrate that especially the early identification of sarcopenic patients is of clinical relevance because these patients are at risk of developing ACLF.
In these patients, shorter follow-up periods might help to better monitor their progress. Recently, a plethora of different techniques for estimation of muscle mass and frailty has been published. The umbilicus as a landmark shows some variability and has a limitation in patients with giant umbilical hernia. However, in the current literature, there are conflicting data on the different performance of psoas muscle compared with other muscle parameters, where L3-SMI seems to perform better in cohorts with high fraction of hepatocellular carcinoma 4,5, In our cohort, hepatocellular carcinoma was excluded before treatment with TIPS.
A test battery to perform frailty assessment was not possible in this retrospective study Finally, the requirement of CT for this study represents a selection bias, which led to the exclusion of several patients. As for the clinical routine, we emphasize the simplicity and convenience of the method, as cross-sectional imaging is routinely performed in cirrhotic patients, e.
Hence, no additional cost for evaluation of sarcopenia is needed. The measurement itself is fast and reproducible, which is the main limitation for the clinical use of anthropometric parameters, such as mid-arm muscle circumference 8,9. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. Potential competing interests: None. You may be trying to access this site from a secured browser on the server.
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