It has been suggested that patient-reported outcomes indicate an umbrella term to measure any facet of a patient’s health status directly resulting from the patient without interpretation by anyone else(Reference McSweeney, Breckons and Fattakhova1). Patient-reported outcomes may encompass symptom duration, frequency, severity pertinent to daily living activities or more complex issues surrounding health-related quality of life (HRQoL). More recently, HRQoL has attracted increasing interest as a major patient-reported outcome measure that is referred to the patient’s subjective perception of the impact of diseases and along with its treatment on individual daily life, including physical, emotional, social function and well-being(Reference Gutteling, de Man and Busschbach2,Reference Afendy, Kallman and Stepanova3) . In this regard, authorised bodies such as the European Medicines Agency and US Food and Drug Administration have provided standards to guide clinical trials or researches in relation to potential therapeutic avenue, securing supportive information of intervention impact on the patient’s perspective(Reference McKenna4). Accordingly, a generic-based construct designated as the EuroQol-5D (EQ-5D) has routinely been carried out in our department to decipher any HRQoL perturbation among hospitalised patients with cirrhosis(Reference Hui, Li and Yu5). The EQ-5D questionnaire includes a wide spectrum of health profiles, including mobility, self-care, usual activities, pain and anxiety/depression; its validity and reproducibility have also been verified in the realm of hepatology(Reference Zhang, Ren and Liu6–Reference Chugh, Katoch and Sharma8). On the other hand, the practitioners can obtain a utility index on the basis of EQ-5D scale to perform comparisons between the respondents and population norms if available(Reference Zoe, Jane and Rebecca9).
Malnutrition occurs in ∼70 % of adult patients with chronic liver diseases due to multifactorial aetiologies on account of poor intake, increased resting energy expenditure and impaired nutrient absorption/utilisation(Reference Ooi, Gilmour and Yap10). The presence of malnutrition has been linked to varying dismal outcomes such as morbidity/mortality, development of complications and other related health deficits(Reference Maharshi, Sharma and Srivastava11,Reference Hui, Wang and Yu12) . Several international societies highlight the importance and necessity to screen for malnutrition risk and consider the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) as a sensitive, consistent and simplified tool(13–Reference Lai, Tandon and Bernal15). After reviewing the existing literature, one concern is that previous studies looking into the nutritional stats of cirrhotic patients have, to some extent, applied inappropriate measure not specific to advanced chronic liver diseases (e.g. subjective global assessment)(Reference Rojas-Loureiro, Servin-Caamano and Perez-Reyes16,Reference Chiu, Marr and Taylor17) . Furthermore, there remains a lack of clarity around the relationship between HRQoL and risk of malnutrition, and to which degree varying health dimensions are affected. Taken together, in a well-built cohort of inpatients with decompensated cirrhosis we aimed to (i) investigate whether risk of malnutrition assessed by the RFH-NPT score is an independent predictor of low HRQoL in terms of EQ-5D utility index and (ii) identify the variation across categories of malnutrition risk and which health domains within EQ-5D instrument are substantially affected.
Subjects and methods
Study population
The current study belonged to a prospective observational cohort study; all assessments were carried out within 48 h of the hospitalisation. The study population comprised inpatients with cirrhosis referred to Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital (TJMUGH). To meet the inclusion criteria, participants had to be aged ≥ 18 years, able to give informed consent and had a cirrhosis diagnosis conforming to liver biopsy, radiological data, medical history and/or laboratory evaluation. All patients were present with signs of decompensation. Patients were excluded if they had concurrent hepatocellular carcinoma or other extrahepatic malignancy, acute-on-chronic liver failure, severe hepatic encephalopathy (HE) interrupting completeness of the questionnaire and refused to scheduled follow-up. The study period was from 2019 to 2021. The study was employed in accordance with the Declaration of Helsinki and approved by Ethnic Committee of TJMUGH.
Sample size
The calculation of sample size was carried out by using http://powerandsamplesize.com/ for testing OR between two groups with an α error = 0·01, a power (1 – β error) = 0·99, group ‘A’ proportion = 0·70, group ‘B’ proportion = 0·30 and sampling ratio = 1, obtaining that a total of eighty individuals is required. Given there is no reference to both proportions in relation to high/low malnutrition risk, the data extracted from the current study were used. In particular, group ‘A’ was indicative of malnourished subjects (253/364) in relative to group ‘B’ as nourished subjects (111/364).
Expose and outcome
Data on patient’s demographic feature, cirrhosis aetiology, laboratory values, clinical manifestations and conventional scores (i.e., Child–Turcotte–Pugh categorisation and model for end-stage liver disease (MELD) score) were collected in order to decipher the cohort.
The EQ-5D indicates a well-built quality-of-life instrument that is preference and generic based(18). The questionnaire comprises a descriptive construct with five different dimensions (mobility, self-care, usual activities, pain and anxiety/depression). By using the three levels of each domain (EQ-5D-3L), the practitioner can obtain a total number of 35 (243) possibly disparate health conditions. The questionnaire is on a scale from 1 to 3: 1 is no problems, 2 some problems and 3 extreme problems. By modelling HRQoL as the primary outcome, it is pivotal to calculate a single value for each of these disparate health conditions. Accordingly, the EQ-5D utility index arises from a country-specific value setting, exhibiting the preference of a particular country in terms of trade-off method. Since a validated Chinese value setting is unavailable, the calculated utility index from the Japanese population is of choice, taking consideration of the comparability between these two East Asia countries(Reference Tsuchiya, Ikeda and Ikegami19). Of note, a negative utility index value implicates the condition that respondents might judge their health status worse than death. Moreover, a higher utility index value reflects a better HRQoL wherein the ‘1’ value is equal to the best health status.
On the other hand, the RFH-NPT score is implemented in our previous work along with detailed processes(Reference Wang, Feng and Hui20). Briefly, the risk of malnutrition is categorised into low (0 points), moderate (1 point) and high (2–7 points) according to the RFH-NPT score. First, the acute alcoholic hepatitis or tube feeding is inquired, as these medical issues may identify respondents as high risk. Next, we discriminate between the categories of patients with and without oedema/ascites. At last, the respondents are assigned to the corresponding risk groups on the basis of score summed.
Statistical analysis
Baseline characteristics were compared by using the Pearson χ 2 test or Fisher’s exact test for categorical variables and Mann–Whitney test for continuous data. The cohort was illustrated by their complaints in any EQ-5D domain. Multiple linear regression analysis was used to determine the independent association between risk of malnutrition assessed by the RFH-NPT score and HRQoL, with the EQ-5D utility index as the dependent variable. The variables age, BMI, ascites, HE, platelet-to-lymphocyte ratio and Na along with the RFH-NPT score entered into final model on account of their clinical/statistical significance. Entry criteria were P < 0·05 in the simple regression analysis. The spearman’s rank correlation analysis (r s) was calculated between the EQ-5D utility index/single dimension of the EQ-5D and the RFH-NPT score. The threshold for statistical significance was referred to P < 0·05. All statistical analyses were performed by using SPSS 21.0 (IBM) and GraphPad Prism 8.0.1.
Results
Patients and depictive data
As shown in Table 1, 364 inpatients with decompensated cirrhosis were consecutively included during the study period. The median age was 64 years (interquartile range: 57, 69) and 50·5 % (184) were female. The main aetiologies for cirrhosis were chronic viral infection and cholestatic/autoimmune liver disease, experienced in 24·7 % (90) and 29·4 % (107), respectively. The median MELD score for the cohort was 8·5 (interquartile range: 4·9, 11·4), and 66·2 % (241) had Child–Turcotte–Pugh B/C categorisation. The distribution of holistic EQ-5D-3L profile is shown in Fig. 1. Notably, 44·5 % (162) of the respondents reported no complaint in any health domain, 20·1 % (73) had no complaints in four domains, 15·4 % (56) had no complaints in three domains, 14·0 % (51) had no complaints in two domains and in single domain, while 6·0 % (22) reported complaints across all health domains. Furthermore, patients without any HRQoL deficit were prone to be younger, male sex, had lower BMI and RFH-NPT score.
Patients’ baseline characteristics (n 364)
(Numbers and percentages)
IQR, interquartile range; AILD, autoimmune liver disease; NAFLD, non-alcoholic fatty liver disease; HE, hepatic encephalopathy; CTP, Child–Turcotte–Pugh; RFH-NPT, Royal Free Hospital-Nutritional Prioritizing Tool; MELD, model for end-stage liver disease.
Distribution of holistic EQ-5D profile among patients with decompensated cirrhosis (n 364). The EQ-5D questionnaire comprises five health dimensions: mobility, self-care, usual activities, pain and anxiety/depression. Each of these dimensions consists of three levels: no, some or extreme problems. The distribution of the profiles of patients with decompensated cirrhosis in terms of each health domain is shown. EQ-5D, EuroQol-5D.
Risk of malnutrition assessed by the Royal Free Hospital-Nutritional Prioritizing Tool score was an independent predictor of low health-related quality of life
Table 2 shows the results of a linear regression analysis for the risk of malnutrition in relation to HRQoL by using EQ-5D utility index. Our simple regression analysis found that age (β-coefficient = –0·139, P = 0·008), BMI (β-coefficient = 0·220, P < 0·001), ascites (β-coefficient = –0·134, P = 0·012), HE (β-coefficient = –0·176, P = 0·001), platelet-to-lymphocyte ratio (β-coefficient = –0·158, P = 0·003) and Na (β-coefficient = 0·202, P < 0·001) along with RFH-NPT score (β-coefficient = –0·180, P = 0·001) are predictors in relation to EQ-5D utility index with P < 0·05. Further multiple linear regression indicated that age (β-coefficient = –0·150, P = 0·004), HE (β-coefficient = –0·127, P = 0·016), platelet-to-lymphocyte ratio (β-coefficient = –0·151, P = 0·004) along with the RFH-NPT score (β-coefficient = –0·114, P = 0·038) are independently related to low EQ-5D utility index (low HRQoL), while BMI (β-coefficient = 0·201, P < 0·001) and Na (β-coefficient = 0·105, P = 0·049) to high EQ-5D utility index.
A multiple linear regression analysis to assess associations between the following variables and the EQ-5D utility index as dependent variable*
(β-coefficients and 95 % confidence intervals)
RFH-NPT, Royal Free Hospital-Nutritional Prioritizing Tool; CTP, Child–Turcotte–Pugh; PLR, platelet-to-lymphocyte ratio; ALT, alanine aminotransferase; TBIL, total bilirubin; MELD, model for end-stage liver disease.
* Results describe the standardised correlation parameter (β), its 95% CI and the associated P value.
Correlation analysis between the EuroQol-5D and risk of malnutrition
The correlation analysis between the global EQ-5D utility index and the RFH-NPT score led to a significantly inverse correlation (r s = –0·171, P = 0·001). The correlations were also observed for mobility (r s = 0·218, P < 0·001), self-care (r s = 0·205, P < 0·001), usual activities (r s = 0·232, P < 0·001) and pain (r s = 0·118, P = 0·024) in contrast to anxiety/depression (r s = –0·018, P = 0·732) by looking into each dimension within EQ-5D instrument (Fig. 2).
Correlation analyses between each domain of the EQ-5D and RFH-NPT score. Correlation analyses between the following domains: mobility (a), self-care (b), usual activities (c), pain (d) and anxiety/depression (e). EQ-5D, EuroQol-5D; RFH-NPT, Royal Free Hospital-Nutritional Prioritizing Tool.
Comparison of EuroQol-5D profiles in accordance with the categories of malnutrition risk
Next, we aimed to identify which HRQoL domains are substantially affected in terms of the categories of malnutrition risk. When stratified by the RFH-NPT, the most substantially impaired dimensions in the cohort were mobility, self-care and usual activities (all P < 0·001). Notably, 32·6 % (62) of the respondents with high risk of malnutrition reported some or extreme problems in mobility, followed by moderate risk of malnutrition in 17·5 % (11) and low risk of malnutrition in 13·5 % (15). Although the proportions of respondents with some or extreme problems were comparable between low and moderate risk of malnutrition groups, patients with cirrhosis and concomitant high risk of malnutrition still experienced a considerable health burden on pain (22·5 % v. 22·2 % v. 35·8 %, P = 0·020). The EQ-5D utility index was also significantly higher in low risk of malnutrition group in comparison with high risk of malnutrition group (P = 0·002) (Fig. 3 and online Supplementary Table S1).
EQ-5D domains stratified by risk of malnutrition according to the RFH-NPT (low risk: 0 points; moderate risk: 1 points; high risk: 2–7 points). EQ-5D, EuroQol-5D; RFH-NPT, Royal Free Hospital-Nutritional Prioritizing Tool.
Discussion
In this observational investigation of 364 patients, impairment in any or several EQ-5D dimensions was observed in 55·5 % (202) of the cohort, suggesting low HRQoL as a common dismal event among the patients with decompensated cirrhosis. After adjustment for significant variables like age, BMI and markers of decompensation, multiple analysis still denoted that risk of malnutrition is independently associated with low HRQoL. Notably, we found that health dimensions representing physical function (i.e., mobility, self-care and usual activities) are substantially affected, whereas malnourished patients reported less frequencies of complaints in other domain such as anxiety/depression. It is operational to improve HRQoL by identifying patients at high malnutrition risk and providing timely nutrition treatment.
Cirrhosis is broadly prevalent around the world and associated with high morbidity and mortality(Reference Gines, Krag and Abraldes21). Decompensated cirrhosis occurs irreversibly and accompanies with various complications leading to frequent and recurrent hospitalisation, patient decease in the absence of liver transplantation and impaired HRQoL among patient as well as caregivers(Reference Allen, Kim and Moriarty22,Reference Fabrellas, Moreira and Carol23) . Therefore, it is pivotal to identify modifiable factors with the purpose of improving HRQoL and directing patient-centred care in the context of cirrhosis(Reference Labenz, Toenges and Schattenberg24). For instance, Wu et al. showed that the proportions of compensated HBV cirrhosis reporting no problems in all EQ-5D dimensions significantly increase from 57·8 to 72·0 % along with increased utility index after 5 years of entecavir treatment(Reference Wu, Hong and Zhou7). Notably, malnutrition is present in more than half patients with decompensated cirrhosis and renders subjects susceptible to sarcopenia and physical frailty. Taking consideration of its high prevalence, weight on prognosis and management following prompt recognisation, we believe it is of utmost importance to investigate the relationship between malnutrition and HRQoL.
Although the literature surrounding the relationship between the risk of malnutrition and low HRQoL is scattered, findings from our study corroborate with previous works. Rojas et al. assessed the nutritional status and HRQoL in separation by using a general tool subjective global assessment and disease-specific measure as the Chronic Liver Disease Questionnaire(Reference Rojas-Loureiro, Servin-Caamano and Perez-Reyes16). In that study, malnutrition was in relation to decreased HRQoL independent of disease severity or complications, while malnourished subjects exhibited mostly impaired aspects pertinent to body pain, daily activities, physical activities and weakness. Another study among a pre-transplant cirrhotic population of eighty-one participants revealed that general health, vitality and social functioning (constituents of Short-Form 36) are significantly lower in subjective global assessment-defined malnourished patients after fully adjustment for age, sex or disease severity, but no association was observed between worsen subjective global assessment and bodily pain(Reference Chiu, Marr and Taylor17). In the current study, our findings are somewhat a confluence of aforesaid reports: as risk of malnutrition advanced, patients with some or extreme problems in mobility, self-care, usual activities and pain were proportionately increased. Additionally, the RFH-NPT score remained an independent predictor of EQ-5D utility index controlling for baseline characteristics, cirrhosis-related complications and major laboratory indices.
Furthermore, our findings uncovered that health dimensions pertinent to physical function are substantially affected. One explanation might be that malnutrition servers as a contributor to sarcopenia and frailty. Moreover, frailty and sarcopenia can interconnect with each other; muscle contractile function impairment can promote loss of muscle mass and vice versa. The interdependence of malnutrition, frailty and sarcopenia in patients with cirrhosis accounts for dys-regulated physical activities(Reference Lai, Tandon and Bernal15). On the other hand, the proportion of cirrhosis with high risk of malnutrition alongside a health burden on pain was 35·8 %. Actually, pain represents a common and debilitating symptom among cirrhosis. The pain symptom can occur outside of underpinning liver disease or be disease-specific such as ascites-associated abdominal pain(Reference Waterman, Ramsey and Whitsett25). Given the altered bioavailability and metabolism of pain medications in the context of cirrhosis, it is often difficult to treat(Reference Kaplan and Rosenblatt26). Our results adding the knowledge that it may be practical to mitigate pain problem as a HRQoL deficit via nutritional support. Conversely, our findings showed that malnourished patients report less frequencies of anxiety/depression. In fact, the presence of anxiety or depression exhibits neuropsychological indicators of HE in the context of decompensated cirrhosis; thus, these symptoms may be masked by HE of varying severity grades(Reference Dellatore, Cheung and Mahpour27). Moreover, several studies demonstrated that the impairment pertinent to anxiety/depression is in alignment with deteriorated liver function among cirrhosis. Xiao et al. showed that the anxiety score and depression score are significantly elevated in patients with minimal HE along with highest levels among Child–Turcotte–Pugh C subsettings(Reference Xiao, Ye and Han28). Another report implicated that patients with MELD-Na score 20–29 exhibit significantly higher levels of anxiety and depression in comparison to those with MELD-Na < 10(Reference Stine, Stukenborg and Wang29). Accordingly, the exclusion of patients with severe HE having difficulties to complete the EQ-5D questionnaire of the current study may give rise to selection bias. Taken together, further prospective clinical trials are warranted to validate our preliminary findings.
Another issue surrounding the clinical implementation of this study is to arouse prompt and intensive care of patients with cirrhosis. Actually, the improvement in nursing care in the field of liver diseases has not been accompanied with the management of patients with other chronic conditions, such as lung diseases, heart failure, arterial hypertension and diabetes(Reference Fabrellas, Carol and Torrabadella30). From clinical perspective of view, nurses are able to facilitate patient education, in consequence of obtaining self-care to prevent complications and improving their well-being and responsibility for their own care(Reference Williams, Ashton and Aspinall31,Reference Fabrellas, Carol and Palacio32) . In the case of decompensated disease, regular assessment of HRQoL and frailty are proposed procedures. Accordingly, the RFH-NPT and EQ-5D questionnaire are measures of choice to evaluate malnutrition risk and impairment in HRQoL in our department as daily practice settings (taken 3–5 min). These are deliberate options in terms of their easy-to-measure, effective point-of-care and cirrhosis-specific characteristics. This is particularly relevant in the clinic with a dramatical work load on patients with decompensated cirrhosis. As a matter of fact, it has been demonstrated that 91 % of cirrhosis providers note competing demands for time as an obvious barrier to engaging in palliative care(Reference Ufere, Donlan and Waldman33). Taken together, we believe that specific education of these tools, for the ease of use, can engage more nurses in the care of patients with cirrhosis with the purpose of bridging the gap between clinicians and families.
The results of current study should be interpreted in light of its limitations. First, the RFH-NPT score and EQ-5D were only assessed at baseline in our cohort. Actually, it might be of interest to consider a dynamic evaluation of malnutrition risk and HRQoL and to investigate whether alteration in the RFH-NPT score over a period might correspond to ever-changing HRQoL. Second, although the study population was sizeable, there were no conventional scores (i.e. Child–Turcotte–Pugh categorisation or MELD score) that emerge as independent contributors of HRQoL. Notably, the predictive ability of disease severity indices appears to be heterogeneous, since the disparities are partially attributed to different methods and measurements used for evaluating HRQoL(Reference Rabiee, Ximenes and Nikayin34). Last, this was a population derived from a single centre among Chinese, and hence, results might not be readily generalisable to all populations with cirrhosis.
In conclusion, worse HRQoL is generally prevalent among patients with decompensated cirrhosis. In addition, risk of malnutrition assessed by the RFH-NPT score is independently associated with low HRQoL. It is operational to improve HRQoL by identifying patients at high malnutrition risk and providing timely nutrition treatment.
Acknowledgements
We thank all nurses who took part in this study.
Y.-Y. H., B.-X. C., X.-Y. W. and C. S. designed the study, analysed the data and prepared the original draft, L.-H. M., Y.-F. L. and M.-Y. S. conducted the study and edited the manuscript. X.-F. F. analysed the data and reviewed the manuscript. G.-Y. G. and W.-T. Y. collected the data and conducted statistical analysis. C. S. designed and monitored the study and made critical revisions of the manuscript. All authors have approved the final draft submitted.
There are no conflicts of interest.
Supplementary material
For supplementary material referred to in this article, please visit https://doi.org/10.1017/S0007114522003841
