Sarcopenia evaluated by EASL/AASLD computed tomography-based criteria predicts mortality in patients with cirrhosis: A systematic review and meta-analysis

Background & Aims Sarcopenia is associated with increased morbidity and mortality in patients with cirrhosis, but its definition in current literature is very heterogeneous. We performed a systematic review and meta-analysis to assess the association between mortality and sarcopenia evaluated by computed tomography (CT) in patients with cirrhosis, both overall and stratified for the criteria used to define sarcopenia. Methods Medline, Embase, Scopus, and Cochrane Library were searched up to January 2023. We included studies assessing sarcopenia presence with CT scans and providing data on the risk of mortality. Adjusted hazard ratios (HRs) and 95% CIs were pooled using a random-effects model. Results Thirty-nine studies comprising 12,827 patients were included in the meta-analysis. The summary prevalence of sarcopenia was 44% (95% CI 38-50%). The presence of sarcopenia (any definition) was an independent predictor of mortality with an adjusted HR of 2.07 (95% CI 1.81-2.36), and the result was consistent in all subgroup analyses. The prognostic role of the EASL/AASLD criteria was confirmed for the first time with an HR of 1.86 (95% CI 1.53-2.26) (n = 14 studies). The cut-offs used to define sarcopenia based on psoas muscle parameters varied among studies, thus, a subgroup analysis was not feasible. There was no substantial heterogeneity for the main estimates and no significant risk of publication bias. Conclusions Sarcopenia on CT is associated with a 2-fold higher risk of mortality in patients with cirrhosis. The cut-offs proposed by EASL/AASLD are prognostically relevant and should be the recommended criteria used to define sarcopenia in clinical practice. Impact and implications: Sarcopenia assessed by the reference standard (computed tomography scan) is an independent predictor of mortality in patients with cirrhosis, with a 2-fold increase in the risk of death in all sensitivity analyses. This finding is particularly valid in patients from Europe and North America, and in transplant candidates. Stratifying for the parameters and cut-offs used, we confirmed for the first time the prognostic impact of the definition proposed by EASL/AASLD, supporting their use in clinical practice. Psoas muscle assessment is promising, but data are still limited and too heterogeneous to recommend its routine use at present.


c) Embase (n=2686)
'sarcopeni$' AND ('liver cirrhosis'/exp OR 'liver disease'/exp) d) Cochrane Library (n=144) ('liver disease' OR 'cirrhosis*') AND ('sarcopenia' OR 'sarcopenic')      Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

7-8
10b List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information. 7 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.8

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

8-9
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.8-9 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

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13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).8-9 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.

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Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).9 Certainty 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.

# Checklist item
Location where item is reported assessment

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.9 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.9

Study characteristics
17 Cite each included study and present its characteristics.9-10

Risk of bias in studies
18 Present assessments of risk of bias for each included study.9

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.

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Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.12 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

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20c Present results of all investigations of possible causes of heterogeneity among study results.10-12 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.12 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.12 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.12 DISCUSSION Discussion 23a Provide a general interpretation of the results in the context of other evidence.13-14 23b Discuss any limitations of the evidence included in the review.13-14 23c Discuss any limitations of the review processes used.13 23d Discuss implications of the results for practice, policy, and future research.15-16

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered.6 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared.6 24c Describe and explain any amendments to information provided at registration or in the protocol.6 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.

Fig. S2 -
Fig. S2 -Risk of mortality in the presence of sarcopenia in cirrhotic patients.

Fig. S3 -
Fig.S3-Risk of mortality with each unit increase of skeletal muscle index.

Table S1 -
Variables included in the multivariate model in the evaluated studies.
Abbreviations APACHE: Acute Physiology and Chronic Health Evaluation MELD: Model for End-stage Liver Disease; Na: Natrium; N/A: not applicable; SMI: skeletal muscle index.

Table S2 -
Prevalence of sarcopenia in subgroup analysis.Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.Present the full search strategies for all databases, registers and websites, including any filters and limits used.6

analyses Of Observational Studies in Epidemiology) Checklist
reporting checklist for Authors, Editors, and Reviewers of Meta-analyses of Observational Studies.You must report the page number in your manuscript where you consider each of the items listed in this checklist.If you have not included this information, either revise your manuscript accordingly before submitting or note N/A.