Cirrhosis is a prevalent illness worldwide and is linked with substantial morbidity and mortality [1,2]. According to a recent report by Smith et al [3], cirrhosis has resulted in the deaths of over 40,000 individuals in America, ranking it as the 12th most prevalent cause of death. Furthermore, it is the third most prevalent cause of mortality among individuals aged 45‐64 years [4]. The global annual mortality from chronic liver disease is estimated to be approximately 2 million. Amongst them, cirrhosis is associated with the advancement of chronic inflammatory diseases and accounts for approximately 45% of all-cause mortality worldwide [5].

Cirrhosis often causes physiological decline, making patients more vulnerable to frailty, which further compromises their overall health [6]. Frailty is a clinical syndrome defined by increased susceptibility and impaired antistress response due to the cumulative functional loss of numerous physiological systems [7]. Furthermore, frailty is characterized by a deterioration across three primary domains: physical health, mental health, and social function [8]. Previously, frailty was considered primarily a geriatric condition linked with aging, although its link to chronic diseases is now extensively understood [9-11].

At present, evidence is increasing that frailty is a risk factor for increased mortality and complications, longer hospital stays, risk of falls, and other issues in patients with cirrhosis [12-14]. However, the assessment tools used in prior research on the unfavorable consequences of patients with cirrhosis vary, and more investigation is required to determine the prognostic significance of frailty in these individuals [12,15]. The prognostic significance of frailty in patients with cirrhosis is inconsistent among different studies and requires immediate clarification [16,17]. For example, several researchers have demonstrated that frailty serves as a prognostic indicator for mortality in individuals with cirrhosis [17,18], but conflicting findings have been reported in another investigation [16]. In addition, one study explored the relationship between frailty and outcome in patients with cirrhosis, but it only demonstrated that frailty can predict liver transplant-free survival; the risk of other complications remains unknown [19]. There are still limited systematic reviews and meta-analyses on the prognostic value of frailty in patients with cirrhosis.

Therefore, to determine the association between frailty and the prognosis of patients with cirrhosis, we did a comprehensive review and meta-analysis on the predictive value of frailty in the prognosis of patients with cirrhosis. This information can help develop targeted management measures for patients with cirrhosis and promote their well-being.

The study protocol was officially registered on the PROSPERO website (No. CRD42024497698).

A comprehensive search was conducted in PubMed, Cochrane Library, Embase, and Web of Science, as well as the China Knowledge Resource Integrated Database, to identify potential articles describing frailty and cirrhosis from inception until 22 December 2023. The search method was conducted with a combination of keywords and Mesh terms: (“frailty” or “frail”) and (“liver cirrhosis,” “hepatic cirrhosis,” “liver fibrosis,” “cirrhosis,” or “cirrhotic”). In addition, we conducted a thorough manual examination of the reference lists of relevant primary and secondary research papers. The search strategy is demonstrated in Table S1 in Multimedia Appendix 1.

The following were the inclusion criteria: (1) cohort studies revealed details about the frailty among patients with cirrhosis; (2) patients (18 years or above) diagnosed with cirrhosis; (3) frailty was assessed using a standardized and reliable instrument, such as the fried frailty score (FFS) and liver frailty index (LFI); (4) at least one clinical outcome between cirrhosis with and without frailty was reported during follow-up; and (5) publications were in English or Chinese.

The following were the exclusion criteria: (1) reviews, non-cohort studies, letters, and conference abstracts; (2) studies that did not provide complete data; (3) duplicated papers; (4) studies not reporting the prevalence of frailty or the predictive value of frailty on the outcomes of patients with cirrhosis; and (5) patients included other diseases rather than cirrhosis

Author and publication year, country, study design, study population, sample size, age, follow-up (months), frailty instruments, and prevalence of frailty were extracted by two researchers working independently. For each study, the relative ratio (RR) and 95% CI were extracted, both with and without adjustment for confounding variables. Furthermore, from the studies that were incorporated, the true positive (TP), false positive (FP), true negative (TN), and false negative (FN) values were extracted.

Two authors independently assessed the cohort studies using the Newcastle–Ottawa Scale (NOS) instrument [20]. It contained three components, including the study group selection, group comparability, and ascertainment of outcomes. The instrument had a maximum score of 9, with a score higher than 5 indicating high-quality literature [21]. If discrepancies existed, the corresponding author assisted in reaching a consensus.

The meta-analysis was conducted using Review Manager (version 5.3) and R software (version 4.2.2; R Foundation for Statistical Computing).

For the purpose of estimating the effect size, the RR and 95% CI were used. The χ² test was used to investigate heterogeneity among the outcomes of each study, and the I² test was utilized to quantify the level of heterogeneity. The funnel plot was used to evaluate the publication bias when the number of publications reached or exceeded 10. When there were less than 10 publications, the Egger test was used to evaluate literature bias. Further investigation was conducted using the trim-and-fill method if the published literature was biased. Statistical significance was considered to be indicated by P values less than .05.

The average sensitivity, specificity, false-positive rate (FPR), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) of the included studies were computed using the random-effect model. Furthermore, the accuracy of the test and the consistency of the outcomes of the included studies were determined using the summary receiver operating characteristic (SROC) curve.

All analyses were conducted using previously published studies, and therefore, ethics approval and patient consent were unnecessary. This review does not include human subject information, primary data collection, or any form of experimentation involving individuals.

Following the identification of 1790 articles during the preliminary search, 780 duplicate articles were eliminated. By reviewing titles and abstracts, an additional 926 sources were eliminated from consideration primarily owing to their lack of relevance to the meta-analysis. The remaining 84 studies were read completely. A total of 58 were deemed ineligible for the reasons outlined in Figure 1. Finally, 26 studies were considered in this analysis. The search flow of this study is presented in Figure 1; the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist has been shown as Checklist 1.

As shown in Table 1, the meta-analysis comprised 26 cohort studies with 9597 patients with cirrhosis [12,13,15,18,22-43]. Among the 26 articles, 3 were retrospective studies [13,18,41] and 23 were prospective studies [12,15,22-40,42,43]. They were published between 2013 and 2023, and performed in the USA [13,15,18,27,30-32,35,40,41], Canada [39,43], Chile [38], China [22-25,33], Egypt [12], Germany [26,28,29], India [34], the Netherlands [42], Slovakia [37], and Thailand [36]. Considering the included patients, 15 were patients with cirrhosis [12,22-26,29,32-34,36-40], 8 were patients with cirrhosis waiting for liver transplants, 3 were patients who received liver transplants [13,35,41], and the remaining 1 patient had cirrhosis after surgery [18]. Moreover, the number of patients included was between 88 and 9597. A variety of tools were used to diagnose frailty, including the short physical performance battery (SPPB) [12,39], Carolina frailty index (CFI) [22,25], fried frailty score (FFS) [15,28,37], liver frailty index (LFI) [23,26,27,30-32,34-37,43], clinical frailty scale (CFS) [29,39], gait speed test (GST) [13,32,40], and others [18,24,33,38,41]. The mean follow-up durations varied between 1 and 60 months. The prevalence of frailty in patients with cirrhosis ranged from 10.50% to 75.40%. The NOS scores of the studies included in the study varied between 6 and 8, indicating a high level of quality in these studies. Table S2 in Multimedia Appendix 1 displays the evaluation criteria for literature quality.

In this meta-analysis, our main findings demonstrated that patients with cirrhosis with frailty had a significantly higher risk of mortality, higher readmission, and lower QoL than those without frailty. According to our evaluation of the literature, the current study provided the most thorough evidence that frailty was a predictor of unfavorable clinical outcomes in patients with cirrhosis.

In this study, the prevalence of frailty in patients with cirrhosis ranged from 10.50% to 75.40%, depending on the specific techniques used to diagnose frailty, the characteristics of the study participants, and the operational definitions used. For example, the study conducted by Lai used the LFI to evaluate frailty in patients with cirrhosis and found that it has a prevalence rate of 94% [31], while another study used the CFI to assess frailty, and results show that the prevalence is only 14.56% [22]. Sensitivity and specificity are influenced by the assessment instrument and the chosen threshold [44]. When selecting frailty-assessment tools for patients with cirrhosis, understanding the content of existing frailty-assessment tools and the suitable population is critical to choosing the most appropriate frailty-screening tool. Furthermore, the instrument most frequently reported in this research was the LFI, a specialized tool designed to evaluate the frailty of liver disease. Other assessment tools included the SPPB, CFI, FFS, CFS, and 6-minute walk test (6MWT). Each of these tool tests is a performance-based measure that necessitates active patient participation, restricting their applicability in patients with severe or acute decompensation [45]. At present, researchers still debate about which evaluation tool for cirrhosis faltering is the standard, and a significant number of relevant studies are required to confirm it in the future.

This meta-analysis demonstrated that frailty was more likely linked to poor survival in patients with cirrhosis, consistent with previous studies [46]. Subgroup analysis further revealed that frailty-assessment tools, sample size, and study subject characteristics may not significantly influence the association between frailty and mortality in patients with cirrhosis. Previous research has shown that patients with cirrhosis with frailty had a considerably worse prognosis than those without frailty, showing that frailty is a poor prognostic factor for chronic liver disease [47,48]. The mechanisms of frailty leading to poor prognosis in patients with cirrhosis include the upregulation of the inflammatory response, impaired immune function, low testosterone levels, intestinal flora disorder, decreased intestinal barrier function, and potential neuromuscular weakness [49-51]. For example, testosterone has been proven to be associated with frailty [52,53]. It is necessary to maintain physiological homeostasis, and its deficiency may decrease muscle strength, increasing the risk of falls, disability, and complications from acute illnesses [54]. In addition, the mechanisms involved in the relationship between frailty and unfavorable outcomes may increase susceptibility to complications, such as inflammatory insults [55], infection [56], and hepatic encephalopathy [13,57] in patients with cirrhosis, thereby affecting the survival of patients. However, the mechanism of action between frailty and cirrhosis prognosis is bidirectional, meaning that liver decompensation reimbursement increases the risk of frailty development [45]. Additionally, this study demonstrated that the probability of compensation in frail patients with cirrhosis was 2.55 times greater than that in non-frail patients. Specifically, only a limited number of studies have assessed the association between frailty and decompensation in patients with cirrhosis, and further investigation is necessary to delve into this association in the future.

This study’s findings suggested that patients with cirrhosis with frailty were more prone to have the risk of readmission than non-frail patients, as confirmed in other populations, including cancer patients [58,59], patients with chronic disease [60,61], and surgical patients [62,63]. A recent study conducted by Witt et al to evaluate the predictive value of frailty in 80 patients with chronic obstructive pulmonary disease has demonstrated that they have a higher risk of readmission than patients without frailty (OR 19.31, 95% CI 1.07‐349.03) [64]. This result may be explained by reduced physiological reserve, malnutrition, and impaired immune function in debilitated patients with cirrhosis [45,65]. For example, frail patients with reduced physiological reserve are more prone to complications and increased risk of infection when encountering stressors, which in turn increases the likelihood of patient readmission [66].

Our study provided some evidence of a correlation between frailty and diminished QoL among patients with cirrhosis. Frailty in patients with chronic liver disease is a multidimensional syndrome [49]. Frailty is characterized by the gradual decline of various physiological systems, such as the cardiovascular and musculoskeletal systems, which affects the patient’s daily activities and self-care ability and may increase the risk of death and hospitalization, thereby decreasing the QoL [34,49]. Two recent systematic reviews have shown a clear relationship between frailty, anxiety, and depression, which showed that frailty may lead to lower QoL levels by causing negative psychological effects [67,68]. Although this study found a significant decline in the QoL of patients with frailty due to the high heterogeneity, future larger and well-designed studies are needed to explore the relationship between frailty and QoL in patients with cirrhosis.

An essential aspect of this study is to make health care professionals aware of the importance of frailty as one of the risk predictors of cirrhosis prognosis. Standardized assessment tools, such as the CFI and LFI, can identify the patients’ frailty status as early as possible to provide timely intervention. In addition, clinical staff can include frailty in the prognosis management plan of patients. In the meantime, personalized management measures can be formulated for patients with cirrhosis with different degrees of frailty, which can significantly improve the prognosis of patients. In addition, health care professionals should strengthen the positive management and follow-up of patients with cirrhosis, especially those with a higher degree of frailty, determine the abnormal situation of patients with cirrhosis in time, adjust the management plan, and ultimately improve the prognosis of patients.

This systematic review has important implications for future studies. If frailty is regarded as an important part of the routine assessment of patients with cirrhosis, researchers need to further compare the prognostic value of different frailty indicators in patients with cirrhosis and reach a consensus on the assessment tools for frailty in patients with cirrhosis. In addition, we suggest that future studies should target the protective factors of frailty to inform preventive strategies for patients with cirrhosis. In addition, researchers and policy makers should develop comprehensive treatment approaches and strengthen interdisciplinary collaboration to provide better management strategies for frailty in patients with cirrhosis.

This was the first systematic review to examine the predictive value of unfavorable outcomes of frailty in patients with cirrhosis. We established that frailty was a good prognostic factor of the clinical outcomes in patients with cirrhosis, including mortality, readmission, and decreased QoL. A systematic review by Bowers et al revealed that several frailty assessments can reliably assess mortality in patients with cirrhosis who are ineligible for transplantation [69]. Future investigations should explore the trajectory of frailty change and its effect on outcomes across time. We aimed to perform a meta-analysis on the longitudinal patterns of frailty and their association with outcome measures.

This study had a few limitations. First, we included only literature reported in Chinese and English, which may have left out some relevant studies in other languages. Second, our study had an inadequate sample size, necessitating higher sample sizes in future research to evaluate the correlation between frailty and outcome in patients with cirrhosis. Furthermore, variations existed across the studies in the tools used to evaluate frailty, which may have influenced the outcomes.

The results of this meta-analysis demonstrate a significant correlation between frailty and an unfavorable clinical outcome in patients with cirrhosis, specifically in terms of mortality and readmission. Future research should be conducted to further explore the most effective screening tools for diagnosing frailty in patients with cirrhosis, as well as whether frailty-related interventions were connected with better clinical outcomes in patients with cirrhosis.