Health-Related Quality of Life and Frailty in Chronic Liver Diseases

We sought to examine the relationship between frailty and health-related quality of life as evaluated using the 36-item Short-Form Health Survey (SF-36) questionnaire in Japanese chronic liver disease (CLD) patients (n = 341, 122 liver cirrhosis cases, median age = 66 years). Frailty was defined as a clinical syndrome in which three or more of the following criteria were met (frailty score 3, 4, or 5): unintentional body weight loss, self-reported exhaustion, muscle weakness (grip strength: <26 kg in men and <18 kg in women), slow walking speed (<1.0 m/s), and low physical activity. Robust (frailty score 0), prefrail (frailty score 1 or 2), and frailty were found in 108 (31.7%), 187 (54.8%), and 46 (13.5%) patients, respectively. In all eight scales of the SF-36 (physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, role emotion, and mental health), and the physical component summary score and mental component summary score, each score was well stratified according to the frailty status (all p < 0.0001). In the multivariate analysis, age (p = 0.0126), physical functioning (p = 0.0005), and vitality (p = 0.0246) were independent predictors linked to the presence of frailty. In conclusion, Japanese CLD patients with frailty displayed poorer conditions, both physically and mentally.

A total of 341 CLD patients who visited our hospital between July 2015 and October 2019 were analyzed. All of these patients had data for frailty and SF-36. A case with CLD was a case confirmed to be accompanied by inflammation of the liver that had continued for 6 months or more at the time of the visit or in the past. LC was determined via histological findings, imaging studies, and/or laboratory data. Frailty was defined as a clinical syndrome in which three or more of the following criteria were met (i.e., frailty score 3, 4, or 5): unintentional body weight (BW) loss (2 kg, 3 kg, or more BW loss within the past 6 months), self-reported exhaustion, muscle weakness (grip strength (GS): < 26 kg in men and < 18 kg in women), slow walking speed (WS, < 1.0 m/s), and low physical activity (doing light exercise or not), while prefrail was defined as patients with one or two above-mentioned phenotypes (i.e., frailty score 1 or 2). Patients with none of five phenotypes were regarded as having a robust status (frailty score 0) [30,31]. These criteria are reported by Satake and Arai as the Japanese version of Cardiovascular Health Study (CHS) criteria [30]. GS was measured according to the current guidelines [32]. In all analyzed subjects, a six-meter walking test was done. The six-meter walking test was done twice in all subjects and the WS (m/s) was defined as the mean value of them. The assessment of frailty and the questionnaire using SF-36 in each patient were done on the same day. Patients with large ascites or overt hepatic encephalopathy who are potentially involved in frailty were excluded due to unreliable self-reporting.

Questionnaire
Our patients were requested to fill out the Japanese version of the SF-36 (self-reported questionnaire). The SF-36 consists of 36 items that are classified into multiple scales (a total of eight scales): physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, role emotion, and mental health [33][34][35][36]. Each scale is scored from 0 to 100 points, and a higher score on the scale indicates a better health status [33][34][35][36]. The physical component summary score (PCS) and the mental component summary score (MCS) were additionally calculated and examined.

Our Study
We retrospectively examined the relationship between the frailty status and the values of the eight scales of SF-36, the PCS, and the MCS. Ethical approval was obtained from the ethics committee of our hospital. The protocol in the study rigorously observed all regulations of the Declaration of Helsinki.

Statistical Considerations
JMP 14 software (SAS Institute Inc., Cary, NC, USA) was used to perform the statistical analysis. For the numerical variables, Student's t-test, the Mann-Whitney U-test, analysis of variance, or the Kruskal-Wallis test was used to assess group characteristics when appropriate. Numerical data were expressed as the median value (interquartile range (IQR)). Baseline significant items in our univariate analysis were subject to the multivariate logistic regression analysis to select candidate parameters. The statistical significance level was set at p < 0.05.

Subgroup Analysis 1: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in LC Patients
In LC patients (n = 122), robust, prefrail, and frailty statuses were identified in 22 (

Subgroup Analysis 1: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in LC Patients
In LC patients (n = 122), robust, prefrail, and frailty statuses were identified in 22 (

Subgroup Analysis 3: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in Male Patients
In male patients (n = 164), robust, prefrail, and frail statuses were identified in 54 (32.9%), 90 (54.9%), and 20 (12.2%) patients, respectively. For all eight scales, the overall p-values of the robust, prefrail, and frail groups reached significance (overall p-values: p < 0.0001 in all scales) (Figure 7).

Subgroup Analysis 3: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in Male Patients
In male patients (n = 164), robust, prefrail, and frail statuses were identified in 54 (32.9%), 90 (54.9%), and 20 (12.2%) patients, respectively. For all eight scales, the overall p-values of the robust, prefrail, and frail groups reached significance (overall p-values: p < 0.0001 in all scales) (Figure 7).

Subgroup Analysis 3: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in Male Patients
In male patients (n = 164), robust, prefrail, and frail statuses were identified in 54 (32.9%), 90 (54.9%), and 20 (12.2%) patients, respectively. For all eight scales, the overall p-values of the robust, prefrail, and frail groups reached significance (overall p-values: p < 0.0001 in all scales) (Figure 7).

Subgroup Analysis 4: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in Female Patients
In female patients (n = 177), robust, prefrail, and frail statuses were identified in 54 (30.5%), 97 (54.8%), and 26 (14.7%) patients, respectively. For all eight scales, the overall p-values of the robust, prefrail, and frail groups reached significance (overall p-values: p = 0.0010 for social functioning and p < 0.0001 for the remaining seven scales) (Figure 8).

Subgroup Analysis 4: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in Female Patients
In female patients (n = 177), robust, prefrail, and frail statuses were identified in 54 (30.5%), 97 (54.8%), and 26 (14.7%) patients, respectively. For all eight scales, the overall p-values of the robust, prefrail, and frail groups reached significance (overall p-values: p = 0.0010 for social functioning and p < 0.0001 for the remaining seven scales) (Figure 8).

Subgroup Analysis 4: Scores of the Eight Scales of the SF-36 Relative to the Frailty Status in Female Patients
In female patients (n = 177), robust, prefrail, and frail statuses were identified in 54 (30.5%), 97 (54.8%), and 26 (14.7%) patients, respectively. For all eight scales, the overall p-values of the robust, prefrail, and frail groups reached significance (overall p-values: p = 0.0010 for social functioning and p < 0.0001 for the remaining seven scales) (Figure 8).

Discussion
Frailty is a multi-dimensional disease concept that represents the end-stage manifestation of disorders in numerous physiological systems, resulting in physiological reserve decline and an increase in vulnerability to health stressors [15]. The SF-36 can measure the Hr-QoL for various diseases and can compare the Hr-QoL between patients with different diseases [33][34][35][36]. To the best of our knowledge, this is the first study elucidating the relationship between frailty and Hr-QoL as assessed using the SF-36 in Japanese patients with CLDs. In our data, the lowest median score of general health (median value = 55) among the eight scales may be due to the long-standing disease burden of CLDs. Meanwhile, scores of role physical (median value = 100), social functioning (median value = 100), and role emotion (median value = 100) were well maintained.
Physical functioning at the top of the eight scales in the SF-36 is most strongly associated with physical health. Mental health at the bottom of the eight scales in the SF-36 is most strongly associated with mental health [33][34][35][36]. For the six scales between physical functioning and mental health, the higher the scale, the stronger the relationship with physical health, and the lower the scale, the stronger the relationship with mental health [33][34][35][36]. This structure helped us interpret our results. In our results, the scores of the eight scales of the SF-36, the PCS, and the MCS were all well stratified according to the frailty condition. In our multivariate analysis for frailty, physical functioning and vitality were independent predictors linked to frailty. Physical functioning, role physical, bodily pain, and general health perception are categorized as physical health, while vitality, social functioning, role emotion, and mental health are categorized as mental health [33][34][35][36]. Taken together, frailty in CLDs could be associated with both physical aspects and mental aspects. Before the current analysis, we hypothesized that frailty in CLDs as assessed by the Japanese version of the CHS criteria was linked to only physical health because five phenotypes for the assessment of frailty (unintentional BW loss, self-reported exhaustion, muscle weakness, slow WS, and low physical activity) are phenotypes mainly about physical health. The CHS criteria are a representative assessment tool for physical frailty [30,31]. For that reason, the current results were surprising to us. Role emotion was significantly stratified with a strong p-value (all, p < 0.0001) relative to the frailty status for all analyses. Role emotion indicates the effect of social activities on the psychological state [33][34][35][36]. Social frailty is clearly defined as poor participation in social networks and the awareness of lacking in contacts and surrounding support [38]. The CHS criteria may be somewhat linked to social frailty.
In our 46 frail patients, 34 patients (73.9%) had a GS decline. GS decline, rather than muscle mass decline, seems to be closely associated with poor QOL in CLDs [39]. Sarcopenia as assessed in terms of muscle mass decline and muscle strength decline or low physical activity is a key component in physical frailty, which is in line with our current data [15]. The prevalence of frailty may be difficult to report precisely because several assessment tools and cut-off values are currently available [15]. Lai et al. demonstrated that out of 983 LC patients, 151 (15%) displayed frailty and the median age of frail LC patients was 59 years [26]. In our data, 46 (13.5%) were identified as frail, and in patients less than 65 years (n = 155), 80 patients (51.6%) were prefrail and 8 patients (5.2%) were frail. We believe that frailty in CLDs should not be restricted to elderly patients and a disease-specific frailty condition should be fully assessed, even in younger CLD patients. Muscle protein synthesis may decrease in younger advanced CLD patients due to protein energy malnutrition or other metabolic disorders [15,40]. Out of our eight frail patients less than 65 years old, 7 (87.5%) had LC. In this sense, disease-specific frailty should be emphasized. In our multivariate analysis for frailty, age was also an independent factor, along with physical functioning and vitality, while the presence of LC tended to be significant. In LC patients, age did not significantly influence the frailty status (p = 0.6884). Inversely, in non-LC patients, age significantly influenced the frailty status (p < 0.0001). Considering these results, frailty in CLDs may be involved in both aging-related factors and liver-function-related factors.
Several limitations of this study need to be acknowledged. First, this study was a single-center observational study with a retrospective nature. Second, the study data was derived from Japanese CLD population data; additional exams on other ethnic backgrounds are needed to further verify and extend the application to these ethnic backgrounds. Third, GS or WS (i.e., one of phenotypes for frailty assessment) can vary depending on measurement conditions. Fourth, patients with large ascites or overt hepatic encephalopathy who are potentially frail were excluded due to unreliable self-reporting, creating bias. Our data should be therefore interpreted with caution. Nevertheless, our study results denoted that frailty in Japanese CLD patients had decreased Hr-QOL, as evaluated by the SF-36 in terms of both physical and mental components. In conclusion, Japanese CLD patients with frailty display poorer conditions, both physically and mentally. Appropriate interventions will be required for such patients.

Acknowledgments:
The authors gratefully thank Yasuko Higuchi in our nutritional guidance room for her significant help with data collection. This work was partly granted by the Hyogo Innovative Challenge, Hyogo College of Medicine, Japan.

Conflicts of Interest:
The authors declare no conflict of interest.