Abstract
Background & aims
Frailty in patients with cirrhosis is associated with increased morbidity and mortality. In this study, we aimed to determine the prevalence of frailty and its impact on mortality and hospitalization in patients with cirrhosis.
Methods
An elaborate search was undertaken in the databases “PubMed, Scopus, Web of Science, and Cochrane, and preprint servers”, and an assessment of all published articles till 17 February 2023 was done. Studies that provided data on prevalence, mortality and hospitalization among frail patients with cirrhosis were included. The study characteristics and data on the prevalence, mortality, and hospitalization were extracted from included studies. The primary outcome was to estimate the pooled prevalence of frailty and determine its impact on mortality and hospitalization in patients with cirrhosis.
Results
Overall, 12 studies were included. Data on prevalence of frailty and mortality were available in 11 studies, while seven studies reported data on hospitalization. The analysis conducted among 6126 patients with cirrhosis revealed pooled prevalence of frailty to be 32% (95% confidence interval [CI], 24–41). A total of 540 events of death revealed a pooled mortality rate of 29% (95% CI, 19–41). Six-month and twelve-month pooled estimates of mortality were found to be 24% (95% CI, 17–33) and 33% (95% CI, 23–45), respectively. The pooled hospitalization rate among the seven studies was 43% (95% CI, 21–68).
Conclusion
The prevalence of frailty in patients with cirrhosis is high, leading to poor outcomes. Frailty assessment should become an integral part of cirrhosis evaluation.
Registry and registration number of study
PROSPERO 2022 CRD42022377507.
Keywords: frailty, cirrhosis, hospitalization, sarcopenia, malnutrition
Graphical abstract
Cirrhosis is a serious and irreversible condition associated with significant morbidity and mortality.1 Hepatitis C virus (HCV) infection and alcohol are the most common causes of cirrhosis in the United States (US), several countries in Europe, and Japan, while hepatitis B virus (HBV) cirrhosis is frequently seen in Asia–Pacific and African regions. Changing lifestyle has increased the incidence of obesity, diabetes mellitus, and metabolic syndrome, leading to non-alcoholic fatty liver disease, which is emerging as a major cause of cirrhosis worldwide. The prognosis of patients with cirrhosis depends on the stage, with a ten-year survival rate of around 47% for compensated cirrhosis and 16% for the decompensated stage.2 Multiple scoring systems such as Child-Turcotte-Pugh (CTP) scoring and Model for End-Stage Liver Disease (MELD) score have been commonly used to predict the prognosis in patients with cirrhosis.2,3 However, these measures are focused on physiological factors only, missing other attributes that impact the health status of patients with cirrhosis.3
Frailty, a concept originally applied in the geriatric domain, has been introduced as a prognostic indicator in advanced liver diseases, in recent years. It is a biological condition that causes individuals to lose physical ability, endurance, strength, and cognitive function, making them more vulnerable to disease-related morbidity, dependence, and death. It denotes a lack of resilience and a vulnerable state of the human body, with low reserve capacity in the organ systems.4,5 Sarcopenia, a condition where the loss of skeletal muscle volume, strength, and function occurs,6 is a component of frailty assessment. Owing to the multifaceted and multisystem involvement in frailty, the pathophysiology is complex and is under study.3 Several scoring systems are available to quantify the frailty in patients with cirrhosis.7,8 The diversity of frailty measurements is such that a systematic review revealed 262 different phenotypes of frailty assessment from past studies.9 Frailty prevalence rate in advanced liver disease patients ranges between 17% and 43%.3
Frailty has been shown to have a significantly poor prognostic relationship with adverse outcomes, especially in patients with decompensated cirrhosis.3,8 Psychological morbidities and poor quality of life had a strong correlation with adverse frailty scores.10,11 Frailty is a significant independent predictive factor of overall mortality, hospitalization rates, and duration of hospitalization among patients with cirrhosis.4,8 A study from the US reported a 5% increase in mortality rate per 0.1 unit change in the frailty index.12 Another study also from the US reported a 45% increase in mortality with a 1-unit increase in the frailty score.13 Similarly a study from India reported a six-month mortality rate of 42% and a hospitalization rate of 92% among frail patients with cirrhosis.7 It has also been reported that the duration of hospital admission rate was high in patients who had poor gait speed–based frailty assessment.14
The duration of follow-up and the outcome rates (mortality and hospitalization) vary between the studies. Also, the frailty phenotypes assessed and tools used for measuring frailty differ across the studies. In this background, it is essential to identify the overall, as well as duration-wise and tool-wise pooled prevalence of mortality among frail patients with cirrhosis. This will strengthen the evidence base of frailty as a prognostic factor in cirrhosis and assist in identifying the gaps for future research. Hence, the following systematic review and meta-analysis were conducted to estimate the pooled prevalence of frailty and determine its impact on the mortality and hospitalization among frail patients with cirrhosis.
Methods
We adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to report this meta-analysis (Table S1).
Search Strategy
A comprehensive search algorithm was prepared based on the Provider, Enrolment, Chain, and Ownership System framework (Table S2). Seven electronic databases, including “PubMed, EMBASE, and Cochrane Library; preprint servers (medRxiv, arXiv, bioRxiv, BioRN, ChiRxiv, ChiRN, and SSRN)” were assessed to extract all published articles from inception to 17 February 2023 that report the prevalence of mortality and hospitalization among patients with cirrhosis and frailty. The following search terms were used: (“cirrhosis” OR “liver cirrhosis”) AND (“frailty” OR “frail” OR “frailty syndrome”) AND (“prevalence OR mortality” OR “hospitalization” OR “admission rate” OR “length of stay”). The complete search algorithm is provided in Table S3. The specific inclusion and exclusion criteria for the studies are enumerated in Table S2.
Data Extraction
Titles and abstracts of the potential studies were independently reviewed by two authors (AGP & SM). The full texts of the potentially eligible studies were then assessed for eligibility by the same authors, independently. Data were extracted from the eligible studies, including author names, year of publication, study design, sample size, age and sex of participants, the prevalence of frailty, mortality, and hospitalization, and the frailty assessment tool used. Any difference in opinion regarding the eligibility of the study and data extraction between the reviewers was adjudicated by the third author (BKP).
Quality Assessment
The risk of bias in the eligible studies was assessed using the “National Heart, Lung, and Blood Institute” quality assessment tools for the included studies.15
Statistical Analysis
The prevalence of frailty, mortality, and hospitalization among frail patients with cirrhosis was estimated using a random-effect meta-analysis model. Heterogeneity was assessed using the I2, with values greater than 50% indicating significant heterogeneity. A random-effect regression model was undertaken to estimate the pooled estimate, owing to high heterogeneity.16 To explore and address the outliers, Baujat plot influences diagnostics and leave-one-out were undertaken. To investigate the causes of heterogeneity, subgroup analyses were performed. Egger's regression test, Luis-Furuya-Kanamori (LFK) index, Doi plot, and funnel diagrams were used to evaluate publication bias. The study protocol was registered at PROSPERO (CRD42022377507).
Results
The PRISMA flow chart demonstrates the results of the article screening, review, and inclusion process (Figure 1). The systematic search yielded 1080 articles, among which 116 duplicates were detected and removed. Two investigators (AGP & SM) independently screened the title/abstract of the 964 articles, and 566 were removed. A review of the full text was undertaken on 398 articles. Among those articles, 18 were eligible for data extraction. Searching through the reference list of the 18 articles resulted in one new eligible study for data extraction. Finally, 19 studies were found eligible. Eight among them were having potentially overlapping study participants. Hence, 12 studies were included in the systematic review and meta-analysis. This meta-analysis was performed following the updated PRISMA (2020) guidelines. The included studies were carried out between the years 2016 and 2022. The baseline features of the 12 studies included in the meta-analysis are enumerated in Table 1. Among the 12 studies, 11 studies reported prevalence of frailty and data on mortality, while seven studies reported data on hospitalization. Most studies were carried out in the United States of America (USA) (67, 58.53%), while three (25%) studies were conducted in India and one each in China, Chile, and Canada. Various tools were used to assess the frailty across the studies, including more than one tool in certain studies. The most commonly used tool was Liver Frailty Index (LFI) in seven studies,12,17, 18, 19, 20, 21, 22, 23 followed by Fried Frailty Criteria (FFC) in four studies,18,24, 25, 26 Clinical Frailty Scale (CFS) in two studies,18,26 and Carolina Frailty Index (CFI) in one study,27 with studies using more than one scale to determine the frailty. The duration of follow-up ranged from six months to 48 months, with the same study reporting the mortality rates at different time points. The mortality rate among patients with cirrhosis with frailty ranged from 25% to 33%.
Figure 1.
PRISMA flow chart depicting the article selection process of included studies in the systematic review and meta-analysis. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Table 1.
Baseline Characteristics of Included Studies (N = 12).
| Study | Country | Cluster | The tool used to assess frailty | Sample size | Mortality | Time duration | Hospitalization | Key findings |
|---|---|---|---|---|---|---|---|---|
| Deng et al., (2020) | China | Patients with cirrhosis | Carolina Frailty Index | 39 | 10.26% | 90 days | NA | Notably, among 35 frail patients, 10.3%, 30.8%, and 41% mortality were reported at 90 days, 12 months, and 24 months, respectively. |
| 30.77% | 12 months | |||||||
| 38.46% | 24 months | |||||||
| Haughen et al., (2020) | USA | Adults (≥18 years) listed for liver transplant | Liver Frailty Index | 209 | 14.83% | 6 months | NA | Wait-list mortality with frailty status (209) was observed as 14.8% (6 months), 25.2% (1 year), and 46.7% (3 years). |
| 25.36% | 12 months | |||||||
| 46.89% | 36 months | |||||||
| 46.89% | Cumulative (36 months) | |||||||
| Lai et al., (2020) | USA | Adult patients with cirrhosis listed for liver transplantation without hepatocellular carcinoma | Liver Frailty Index | 1093 | 28.09% | 6 months | NA | Wait-list mortality of frailty patients (1093) at different follow-up periods was observed as 28.1% at 6 months, 50.9% at 12 months, and 82.6% at 24 months. |
| 50.87% | 12 months | |||||||
| 82.53% | 24 months | |||||||
| 20.40% | Cumulative (11 months to median) | |||||||
| Meena et al., (2022) | India | Patients with cirrhosis who attended the outpatient liver clinic | Liver Frailty Index | 50 | 22.00% | 6 months | 58.00% | Survival was also significantly better in the intervention arm than in controls (96.8% vs 78%). Fewer patients in the intervention arm (19 [38%]) required hospitalization than in controls (29 [58%]) |
| Roman et al., (2021) | Spain | Outpatients with cirrhosis | Fried Frailty Criteria, Timed Up and Go Test, and gait speed. | 35 | 11.43% | 24 months | 37.14% | Among 135 cirrhosis patients, 35 were frail. Hospitalization was observed at 45.7% (3 months) and 2 years (37.1%). Mortality was reported as 17.1% (3 months) and 2 years 11.4%. |
| 17.14% | Cumulative (33 months-mean) | 45.71% | ||||||
| Serper et al., (2021) | USA | Adult patients hospitalized with complications of cirrhosis | Liver Frailty Index | 124 | 27.42% | 8 months | 5.65% | 124 patients had frailty. Among frail patients, 7 were hospitalized and 34 died. |
| Sinclair et al., (2017) | USA | Adult cirrhotic subjects actively listed for liver transplantation | Fried Frailty Index | 184 | NA | 12 months | 58% | At least one hospitalization was experienced by 107/184 (58%) frail patients |
| Singh et al., (2022) | India | Patients with cirrhosis aged ≥18 years attended the outpatient liver clinic | Fried Frailty Criteria, Clinical Frailty Scale, Short Physical Performance Battery, and Liver Frailty Index | 50 | 42.00% | 6 months | 92.00% | 42% (21) mortality and 92% (46) hospitalization were observed among frail patients (50). |
| Soto et al., (2021) | Chile | Cirrhosis patients with a MELD ≥ 15 | Fried frailty phenotype | 82 | 25.61% | 12 months | NA | Over the different follow-up periods, mortality observed among frail patients was 26% (12 months), 47.6% (24 months), and 68.2% (months). |
| 47.56% | 24 months | |||||||
| 67.07% | 48 months | |||||||
| 67.07% | Cumulative (48 months) | |||||||
| Tandon et al., (2016) | Canada | Outpatients with cirrhosis | Clinical Frailty Scale, Fried Frailty Criteria, Short Physical Performance Battery | 54 | 20.37% | 6 months | 38.89% | Of the total 300 patients included in the study, 18% of patients were frail. Among 54 frail patients, 19% of death and 39% of hospital admission were reported. |
| Wang et al., (2022) | India and USA | Adult patients with cirrhosis from outpatient liver or pretransplant assessment clinics. | Liver Frailty Index | 201 | 25.37% | 8 months | NA | A greater proportion of patients who were frail at baseline died (81 [40.3%]) |
| 40.30% | Cumulative (11 months) | |||||||
| Xu et al., (2021) | USA | Ambulatory adult patients with cirrhosis listed for liver transplantation | Liver Frailty Index | 451 | 5.54% | Cumulative (13 months [median]) | NA | Of the overall patients, 17% died at a median follow-up of 13 months. Notably, in frail patients, 25 deaths were reported. |
MELD, Model for End-Stage Liver Disease; USA, United States of America.
The Pooled Prevalence of Frailty
The prevalence data of frailty were available in all 11 eligible studies. The analysis yielded a pooled prevalence of 32% (95% confidence interval [CI], 24–41) (1679 frail patients among 6126 cirrhosis patients) (Figure 2). The prevalence of frailty was highest with the FFC tool (65%, 95% CI, 56–73) followed by the LFI (59%, 95% CI, 52–65). The impact of CTP status and cirrhosis etiology could not be analyzed due to the very fewer number of studies reporting on this. A maximum number of patients were diagnosed by the LFI tool followed by FFC.
Figure 2.
Forrest plot showing A) pooled prevalence of frailty B) Leave-one-out analysis.
Prevalence of Mortality in Frail Patients With Cirrhosis
The meta-analysis conducted among the 2388 patients, with 580 events of deaths reported among them, revealed a pooled mortality rate of 29% (95% CI, 19–41). Heterogeneity among the studies was high (I2 = 96%; P < 0.01) (Figure 3). Hence, a random-effect model was applied. The layout of the funnel plot showed a slightly asymmetrical funnel (Supplementary Figure S1), indicating potential publication bias. However, Egger's test (P = 0.6) and LFK index (1.04) revealed no small study effects. All studies were found to be of fair or good quality, and hence sensitivity analysis was not required (Table S4).
Figure 3.
Forest plots showing overall effect size and its confidence interval; and heterogeneity statistics of the proportion of mortality among cases of cirrhosis with frailty.
Mortality Rate According to Duration of Follow-up
The mortality rate according to the duration of follow-up of frail patients with cirrhosis is given in Table 2. Five of the studies reported a mortality rate at six months (24% [95% CI, 17–33]), while four studies reported a mortality rate at 12 and 24 months.
Table 2.
Sub-group Analysis of Mortality Estimates of Cirrhosis Patients With Frailty.
| Factors | No. of studies | Estimate (95% CI) | P | P subgroup |
|---|---|---|---|---|
| Duration of follow-up | 0.001 | |||
| 1 month | 2 | 14.61 (7.30–27.11) | <0.01 | |
| 3 months | 1 | 10.26 (3.90–24.33) | – | |
| 6 months | 5 | 24.20 (17.34–32.71) | <0.01 | |
| 8 months | 2 | 26.15 (21.66–31.20) | <0.01 | |
| 12 months | 4 | 33.19 (22.97–45.29) | <0.01 | |
| 13 months | 1 | 55.54 (3.77–8.07) | – | |
| 24 months | 4 | 44.56 (18.49–74.02) | <0.01 | |
| 36 months | 1 | 46.89 (40.22–53.67) | – | |
| 48 months | 1 | 67.07 (56.24–76.35) | – | |
| The tool used in the frailty assessment | 0.247 | |||
| Carolina Frailty Index | 1 | 38.46 (24.69–54.37) | – | |
| Clinical Frailty Scale | 1 | 20.37 (11.65–33.16) | – | |
| Liver Frailty Index | 7 | 25.99 (15.56–40.07) | <0.01 | |
| Fried Frailty Criteria | 2 | 40.27 (11.72–77.40) | <0.01 | |
CI, Confidence interval.
The mixed-effect model was applied to the subgroup meta-analysis.
Sub-group Analysis on Mortality Based on the Tool Used to Measure Frailty
When the studies were classified and analyzed based on the tool used to measure the frailty, studies using CFS reported a mortality rate of 20% (95% CI, 11–33), LFI showed a mortality rate of 26% (95% CI, 16–40), FFC reported a mortality rate of 40% (95% CI, 12–77), and CFI reported a mortality rate of 38% (95% CI, 25–54). Meta-regression showed a significant association between the duration of follow-up and the mortality rate (beta = 0.05, P = 0.001) (Supplementary Figure S2). Although the study tool used and duration of follow-up are potential factors causing the heterogeneity in the present analysis, heterogeneity persisted after grouping the studies according to these variables, indicating other unknown factors are responsible for heterogeneity.
Outliers identified through the Baujat plot and influence diagnostics followed by Leave-one-out analysis did yield a significant variation from the pooled estimate (Supplementary Figures S3-5).
Hospitalization
The meta-analysis of hospitalization among the seven studies yielded a pooled hospitalization rate of 43% (95% CI, 21–68), with high heterogeneity between the studies (I2 = 94%; P < 0.01) (Figure 4). All studies were found to be of fair or good quality, and hence sensitivity analysis was not required.
Figure 4.
Forest plots showing overall effect size and its confidence interval; and heterogeneity statistics of the proportion of hospitalization among cases of cirrhosis with frailty.
Discussion
In this systematic review and meta-analysis of 12 studies involving 6126 patients of cirrhosis, the pooled prevalence of frailty was 32%, implying that every third person with cirrhosis is frail. This high prevalence was irrespective of the tool used for assessment. The LFI was the most widely used tool; reason could be it is more user friendly and objective, leaving less room for interobserver variability.
The mortality rate among frail patients with cirrhosis was 29% during the follow-up period from one month to four years, independent of the type of tool used to assess frailty. Overall, more than one-fourth of frail patients with cirrhosis had a fatal outcome. The different tools used to assess frailty in patients with chronic liver disease have shown reproducibility in reporting patient outcomes, specifically the mortality rates.28 These tools can have an essential role in identifying and managing frail patients at the earliest to mitigate adverse outcomes. The relatively lower mortality reported with the CFS (20%) could be explained by selection bias since only outpatients were included and follow-up was comparatively short in these studies.
Healthcare workers exhibit a daunting task and are challenged by varied presentations of frailty in cirrhosis, having a significant effect on both patient outcomes and health.27 Despite the enormous literature showing the negative implications and poor prognosis of frailty in the context of cirrhosis, data on frailty status and its relationship to liver disease management and the response in frailty scores are sparse. Within the individual studies which reported mortality rates among frail patients with cirrhosis at various time frames of follow-up, there was an increase in mortality. This impact of the duration of follow-up on the mortality rate is also evidenced from the meta-regression in the index study. This should be interpreted with caution since other patient characteristics such as sex, duration of the disease, and tools used to assess the frailty might also have impacted the outcomes, which were not adjusted for in the analysis. Wong et al. reported a strong association between low resilience and frailty.29 Additionally, age and mental health were found to impact the resilience of the frail patients. Older age positively impacted and a history of anxiety or depression negatively impacted the resilience.
The high pooled hospitalization rate in this meta-analysis suggests the poor physiological reserves of frail patients that predispose them to the development of recurrent decompensating events and infections, the major reason for hospitalization in such patients. Increased rates of hospitalization among frail patients have been reported for liver diseases as well as diseases of other organ systems.30, 31, 32
The strengths of this systematic review and meta-analysis include the presence of a large number of studies of fair quality with a relatively bigger pool of patients and the inclusion of prospective data. This is the first meta-analysis studying the impact of frailty on the outcome of patients with cirrhosis and highlights the need to include frailty assessment in various prognostic scores for cirrhosis. This is especially applicable in patients with recurrent hepatic encephalopathy and refractory ascites who have low scores and may not be given priority for early liver transplantation based on current listing criteria. Frailty assessment may assist in mitigating the adverse outcomes associated with these complications by early transplantation, following optimization. Third, this meta-analysis explored the potential sources of heterogeneity among studies, which can be important for understanding the reasons for the observed results; it also allows us to identify the gaps in the literature and areas where more research is needed. Lastly, this meta-analysis provides healthcare professionals and policymakers with a comprehensive overview of the current state of research on this topic, which would further provide the impetus for the development of evidence-based guidelines and interventions for the management and treatment of patients with cirrhosis and frailty.
However, the index meta-analysis is not devoid of limitations. High heterogeneity between the studies, which could not be explained by the explored factors, is a major limitation for interpreting the pooled estimate. Factors other than the tool used and the duration of follow-up, such as sex, comorbidity status, socio-economic status, and personal habits, also need to be explored to understand the heterogeneity among the studies in this line of literature. The data on hospitalization were available in only seven studies, and hence publication bias and sub-group analysis could not be performed. Pooling could be made more meaningful, for the studies applying the same tool and following the patients for a similar period. However, such sub-grouping or meta-regression with multiple factors was not possible due to the smaller number of studies in the sub-groups.
To conclude, every third patient with cirrhosis is frail and this has a significant impact on outcomes. Interventions against mental health issues such as anxiety and depression can also improve the resilience of frailty patients and therefore enable its reversal. Further meta-analysis on assessing the risk of mortality associated with frailty among cirrhosis patients should be conducted. Future studies should report findings and outcomes according to the gender and other patient characteristics such as the duration of the morbidity and etiology of cirrhosis. This will enable us to identify the potential impact of these factors and therapeutic targets to reverse frailty.
Credit authorship contribution statement
Bijaya Kumar Padhi (Data curation; Formal analysis; Methodology: Supporting; Resources: Supporting; Writing – original draft: Supporting), Aravind Gandhi P (Data curation; Formal analysis; Methodology: Supporting; Resources: Supporting; Writing – original draft: Supporting), Mokanpally Sandeep (Data curation; Formal analysis; Writing – original draft: Supporting), Muhammad Aaqib Shamim (Data curation; Formal analysis; Writing – original draft: Supporting), Arka De (Formal analysis: Supporting; Resources: Supporting; Writing – original draft: Supporting), Sahaj Rathi (Formal analysis: Supporting; Resources: Supporting; Writing – original draft: Supporting), Surender Singh (Conceptualization: Supporting; Methodology: Supporting; Resources: Supporting; Writing – original draft: Equal), Ajay Duseja (Conceptualization: Supporting; Methodology: Supporting; Resources: Supporting; Writing – original draft: Supporting), Sunil Taneja (Conceptualization: Lead; Formal analysis: Lead; Methodology: Lead; Project administration: Lead; Resources: Lead; Supervision: Lead; Writing – original draft: Lead).
Conflicts of interest
The authors have none to declare.
Funding
No financial disclosures to make.
Ethical statements
N/A.
Informed consent
N/A.
Animal studies
N/A.
Research involving recombinant DNA
N/A.
Data sharing statement
Documents containing all extracted data have been made available in the manuscript and the accompanying supplementary material.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2024.101373.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
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