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DR. ANAHITA RABIEE (Orcid ID : 0000-0002-8833-3592) DR. SINA NIKAYIN (Orcid ID : 0000-0001-9024-038X) DR. GUADALUPE GARCIA TSAO (Orcid ID : 0000-0002-6175-8216)
Article type
: Reviews
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Title: Factors Associated with Health-Related Quality of Life in Patients with Cirrhosis: A Systematic Review Short Title: Factors Associated with HRQoL in Cirrhosis Authors: Dr. Anahita Rabiee, Section of Digestive Diseases, Yale School of Medicine; Dr. Rafael Oliveira Ximenes, Division of Gastroenterology, University of Sao Paulo School of Medicine; Dr. Sina Nikayin, Department of Psychiatry, Westchester Medical Center; Andy Hickner, Interprofessional Health Sciences Library, Seton Hall University; Prerak Juthani, Yale School of Medicine; Dr. Robert H. Rosen, Yale School of Medicine; Dr. Guadalupe Garcia-Tsao, Section of Digestive Diseases, Yale School of Medicine and VA-CT Healthcare System. Grant Support: NIH P30 DK34989 Correspondence: Guadalupe Garcia-Tsao, MD Yale University School of Medicine
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/LIV.14680 This article is protected by copyright. All rights reserved
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Digestive Diseases Section 333 Cedar St – 1080 LMP New Haven, CT 06510 Email: [email protected] Phone: 203-737-6063 Fax: 203-785-7273
Disclosures: Authors have no conflicts of interest to disclose. Ethics approval: Not applicable Patient consent: Not applicable Permission to reproduce material from other sources: Not applicable Number of tables and figures: Three tables, one figure.
Key Points: Among decompensating events in cirrhosis, hepatic encephalopathy is the only factor showing consistent association with declining HRQoL. Child-Pugh classification was more commonly associated with impairment in HRQoL compared to MELD. Multiple modifiable factors such as psychiatric comorbidities (depression and anxiety), frailty, falls, malnutrition, physical symptoms (muscle cramps, sleep), and anemia are associated with poor HRQoL.
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Factors Associated with Health-Related Quality of Life in Patients with Cirrhosis: A Systematic Review Abstract Background: Patients with cirrhosis have a poor health related quality of life (HRQoL). Recognizing factors that affect HRQoL is key in delivering patient-centered care. Aim: To identify factors most commonly associated with a poor HRQoL in adults with cirrhosis in a systematic review of the literature. Methods: Four databases (MEDLINE, EMBASE, CENTRAL and PsycINFO) were searched from inception to March 2020, using terms related to patient-reported outcomes plus cirrhosis. Studies that analyzed an association between at least one factor and HRQoL in adult patients with cirrhosis were included. Abstract and full-text screening was performed by two reviewers. Data were collected on factors evaluated in each study and the significance of their association with HRQoL. Results: A total of 10,647 citations were reviewed, of which 109 met eligibility criteria. 76% of the studies used a generic instrument while only 45% used liver-specific instruments. Among identified factors, demographic factors and cirrhosis etiology were not generally associated with poor HRQoL except for poor social support. Depression, poor sleep and muscle cramps affected HRQoL in all the studies that evaluated them. Among comorbidities, frailty, falls, malnutrition and cognitive impairment were also associated with poor HRQoL in the majority of studies. Among cirrhosis-specific decompensating events, only hepatic encephalopathy (HE) was consistently associated with impairment in HRQoL (75% of studies).
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Conclusion: Many factors impact poor HRQoL in patients with cirrhosis such as depression,
muscle cramps, poor sleep, falls, frailty and malnutrition. Among cirrhosis decompensating events, HE was the complication most commonly associated with a poor HRQoL. Keywords: Quality of life; Cirrhosis; Patient-reported outcomes
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Body of Paper Introduction: Cirrhosis is a major cause of global health burden, accounting for one million deaths, or 2% of all deaths worldwide and 1.2% of global Disability Adjusted Life Years (DALY) 1,2. Although liver transplantation offers a significant survival advantage and improvement in quality of life in patients with decompensated cirrhosis 3,4, it is only attainable for a minority of patients. A large proportion of patients die on the waiting list or are not even eligible for transplant 5. Traditionally most research and health care interventions in cirrhosis have focused on improving clinical outcomes such as delaying progression of the disease and improving survival. However, the relation between these clinical measures and patient reported outcomes (PRO) is not always present 6,7. PROs are measures of patient’s health perception and experiences that are directly reported by the patient 9,10. One of the most commonly used PROs is Health-Related
Quality of Life (HRQoL), which includes multiple domains such as physical function, symptom burden, mental health and social interaction 11. PROs such as HRQoL are more meaningful to patients and are increasingly recognized as important outcomes in clinical trials of patients with cirrhosis. Patients with cirrhosis have significant symptom and emotional burdens. At the compensated stage, patients can have symptoms that have been associated with minimal hepatic encephalopathy (MHE) 12 such as impairment in working or driving performance and subjective cognitive complaints 13 as well as sleep disturbance and fatigue 14–16. As the disease progresses and patients become decompensated, they can develop ascites, variceal bleeding or overt hepatic encephalopathy (HE) which cause physical and emotional discomfort. Therefore, HRQoL can be negatively impacted in patients with both compensated and decompensated cirrhosis 17,18.
There has been recent emphasis on incorporating PROs into research and clinical practice in order to evaluate the effect of management strategies and deliver quality care that is meaningful for patients19. A comprehensive understanding of the factors that drive impairment in HRQoL
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in patients with cirrhosis is equally important as it can help clinicians prioritize targets of therapy (both in clinical practice and research) and thereby improve patient-centered care. The aim of this study was to identify factors (including decompensating events) that have the most impact on the HRQoL of patients with cirrhosis via a systematic review of the literature. Methods: For the conduct and reporting of this systematic review the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 20 was used: Search Strategy
In collaboration with a librarian (A.H.), a search strategy was developed to identify studies evaluating HRQoL in adult patients with cirrhosis. Four major electronic databases, including MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid), and the Cochrane Library (Wiley) were searched from inception until March 2020 (Figure 1). The Yale MeSH Analyzer was used to identify pertinent Medical Subject Headings for use in the MEDLINE search21. Controlled
vocabulary was combined with synonymous free text keywords using Boolean operators to capture patients with “cirrhosis” or “end-stage liver disease” and outcomes such as “patientreported outcomes”, “quality of life” that were reported by patients (e.g. “questionnaire”, “interview”, “self-report”, “survey”) (Appendix 1). Additionally, a hand search of the reference list of all included studies was performed to ensure all eligible studies were captured. Study selection
The following inclusion criteria were used: 1) English language original research published in a peer-reviewed journal, 2) study focused on adult patients with cirrhosis, 3) study used a HRQoL instrument defined as self-reported multidimensional questionnaire, encompassing multiple domains such as physical function, psychological state, social interaction and somatic sensation 11,
and 4) study analyzed an association between at least one factor (defined as any independent
variable) and HRQoL. Studies were excluded if they 1) evaluated the results of a specific intervention, 2) included 50 and one third had sample sizes above 150. The studies were from 28 different countries, with the majority from European (34%) and North American (31%) countries. Most studies (76%) used a generic instrument to measure HRQoL, with SF-36 being the most common (73%). Less than half (45%) of the studies used a disease-specific instrument, with Chronic Liver Disease Questionnaire (CLDQ) 24 being the most common (73%) (ESM Appendix 3, Supplementary Table 1). Description of included patients:
The majority of studies (76%) included patients with mean or median age of 50 to 60 years old and 74% of studies had a predominantly male population (male patients > 60%) (Table 1). Of the 109 studies, 41 (38%) included patients awaiting liver transplant, 40 (37%) included mostly patients with decompensated cirrhosis (Child B & C ≥ 50% or a decompensating event (HE, VB,
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Ascites) ≥ 50%), 16 (15%) included predominantly compensated patients (Child A>50%), and 12 (11%) of the studies did not provide information regarding the stage of cirrhosis. Among the studies that reported on specific decompensating events, the median percentage of patients with HE was 23% (in 51 studies) and the median percentage of patients with ascites was 49% (in 51 studies). Among the studies that reported on current or prior diagnosis of HCC (42 studies), the median prevalence of HCC was 9%. Critical appraisal
The most common source of bias (59% of studies) was confounding measurement, that is, the relationship between the factor and HRQoL was likely to be distorted by a confounding factor (e.g. severity of cirrhosis) affecting the HRQoL, that was not properly adjusted for in the analyses. Overall, 34% of studies were categorized as good quality, 54% as moderate quality, and 12% as poor quality (ESM Appendix 3, Supplementary Table 2). Factors associated with HRQOL
Of 165 factors, 54 factors were evaluated in more than two studies. These 54 factors were organized into 9 major categories as outlined in table 2. Demographic factors and cirrhosis etiology were not associated with poor HRQoL in the majority of studies, with the exception of lack of social support. From disease severity indices, Child-Pugh Classification was more closely associated with impairment in HRQoL when compared with MELD (69% vs 49%). Among cirrhosis-specific decompensating events including ascites, HE, and VB, only HE was consistently associated with impairment in HRQoL (75% of studies). When looking at the lab abnormalities commonly seen in patients with cirrhosis, anemia and Creactive protein were associated with impairment in HRQoL in 63% and 67% of the studies, respectively. Psychiatric symptoms such as depression and anxiety were associated with impairment in HRQoL in 100% and 83% of the studies, respectively. Lastly, physical symptoms such as muscle cramps and poor sleep were associated with impairment in HRQoL in all studies that looked at these factors. Among comorbidities, frailty, falls and malnutrition were associated with poor HRQoL in 80%, 80% and 67% of studies, respectively.
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Overall, 21 factors were associated with impairment in HRQoL in more than 50% of the studies. For these factors we specifically looked at good-quality studies, the results of which are available in table 3.
Discussion: This systematic review of 109 studies provides a comprehensive summary of the factors associated with poor HRQoL in patients with cirrhosis. It differs from a recent scoping review that analyzed 11 studies of patient reported outcomes which had an entirely different goal.25 Its goal was to identify and summarize PRO domains that could serve as candidate outcomes in quality improvement efforts in cirrhosis. In contrast, the present systematic review had the objective of identifying factors in cirrhosis that have the most impact in HRQoL. Among top factors that were identified, many are potentially modifiable factors such as psychiatric comorbidities (depression and anxiety), frailty, falls, malnutrition, physical symptoms (muscle cramps and sleep) and anemia. Among disease severity indices, Child-Pugh classification was more commonly associated with impairment in HRQoL compared to MELD. This could potentially be explained by the inclusion of variables such as HE and ascites in Child-Pugh score that are not captured in the MELD score. Currently, the MELD has replaced the Child–Pugh in the prioritization of liver transplant candidates 26,27; thus it is important to note that MELD might fail to capture candidates’ impairment in quality of life. Among the decompensating events, HE was the only factor that showed consistent results across studies in terms of decline in HRQoL. HE was related to poor HRQoL even when controlling for severity of liver disease with Child-Pugh or MELD. This is even more significant considering that many studies excluded patients with overt HE at the time of enrollment. Notably, most studies reporting on HE did not adjust for lactulose use as a confounder. Only 12 (43%) of 28 studies evaluating ascites showed it to be associated with a poor HRQoL but most of these studies did not grade the severity of ascites. Conversely, ascites was associated with a
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poor HRQoL in 7/9 (78%) of studies that evaluated the severity of ascites or included only patients with at least moderate ascites. MHE and poor performance on psychometric tests (per each study’s definition) were also significantly associated with poor HRQoL in most studies. This association could be partly due to inclusion of patients with history of overt HE and other decompensations in these studies, which makes the comparison more difficult. Previous episodes of overt HE are associated with a cumulative decline in cognitive function and these patients are more likely to perform poorly on psychometric tests 28; also, as shown in our study, history of HE is associated with poor HRQoL (in 18 of 24 studies, Table 2). Only one study evaluated the factors, including MHE, separately in patients with compensated vs decompensated cirrhosis. This study was able to show that MHE affects HRQoL in patients with compensated cirrhosis while overt HE, but not MHE, is associated with poor HRQoL in decompensated patients. Although some studies attempted to adjust for history of previous HE, future studies focusing on purely compensated patients with MHE are recommended before a conclusion regarding this association can be drawn. Psychiatric factors such as depression and anxiety were associated with poor HRQoL in almost all studies that evaluated these factors. This uniform association has been shown across multiple disease entities and is not unique to cirrhosis 29,30. Regardless, it emphasizes the importance of monitoring patients with cirrhosis for psychiatric comorbidities. And lastly among comorbidities, frailty, falls, and malnutrition are significantly associated with poor HRQoL in the majority of studies. They have been shown to correlate with mortality as well 31,32, thus it is important to consider evaluating these factors in patients with cirrhosis, and consider treatments such as exercise programs, physical therapy and nutritional supplementation which could improve HRQoL based on previous studies. 33–35 The heterogeneity in study results for some factors could have many different explanations. First, the statistical method, sample size and study quality were very heterogenous in this review. This can potentially explain why some studies did not have enough power to identify an association between a factor and HRQoL, or might have overestimated an association by not adjusting for important confounders. Second, the type of HRQoL instruments used varied
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between included studies, with studies using different generic or disease specific instruments with varying performance characteristics. Third, HRQoL is a subjective and dynamic target. Changes in an individual's health status may prompt behavioral, cognitive and coping strategies necessary for accommodating illness 36. As an example, while developing cancer in a healthy
individual can significantly impair that person’s HRQoL, new detection of HCC in a patient with decompensated cirrhosis might not have the same effect as the patient’s expectations and standards are different since they are already dealing with multiple decompensating events such as HE and ascites resulting in disability. Our study has some important limitations dependent on the quality of the studies analyzed. First, the majority of the studies included in the systematic review evaluated a wide range of factors for association with HRQoL without an a-priori hypothesis. Therefore, findings could be incidental, and a number of statistically significant associations with HRQoL may have been prone to type I error. Given the extensive nature of this review, this type of error would be minimized by repeated results in multiple studies, increasing the confidence for the external validity of the observed association. Second, most studies were cross-sectional in design, so causal inferences cannot be drawn from the results. Third, there was a vast heterogeneity between studies in terms of design, statistical methods, HRQoL instruments, and reporting of results, so a meta-analysis to quantify the effect size of the factors could not be performed. Fourth, most of the included studies combined patients with compensated and decompensated cirrhosis. These populations have potentially different HRQoL impairments, as a majority of patients with compensated cirrhosis are asymptomatic. Thus, inclusion of compensated patients in the population could have caused significant confounding. And lastly, the factors that were examined in relation to HRQoL were limited to those that were investigated in more than 2 studies, as we did not focus on factors that were only evaluated in 1 or 2 studies to ensure reproducibility of the results.
In conclusion, this is the first study to systematically summarize the factors associated with HRQoL in cirrhosis across a growing body of literature. We find that specific decompensations
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such as HE are associated with significant impairment in HRQoL. Additionally, our study found a multitude of modifiable factors such as psychiatric comorbidities (depression and anxiety), frailty, falls, malnutrition, physical symptoms (muscle cramps, sleep), and anemia that contribute to poor HRQoL in patients with cirrhosis, factors that could be targets of future studies for tailoring treatments focused on improving HRQoL in patients with cirrhosis.
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References 1.
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(Updated March 2011). The Cochrane Collaboration, 2011. Available from Www.Handbook.Cochrane.Org.
10. Willke RJ, Burke LB, Erickson P. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels. Control Clin Trials 2004;25:535-552.
11. H Schipper, JJ Clinch, CLM Olweny. Quality of Life Studies: Definitions and Conceptual Issues. In Spilker B, Ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Philadelphia: Lippincott-Raven Publishers, 1996.
12. Nabi E, Thacker LR, Wade JB, et al. Diagnosis of covert hepatic encephalopathy without specialized tests. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2014;12:1384-1389.e2.
13. Ortiz M, Jacas C, Córdoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 2005;42:S45-S53.
14. Kim S-H, Oh E-G, Lee W-H, et al. Symptom experience in Korean patients with liver cirrhosis. J Pain Symptom Manage 2006;31:326-334.
15. Swain MG. Fatigue in liver disease: pathophysiology and clinical management. Can J Gastroenterol J Can Gastroenterol 2006;20:181-188.
16. Balakrishnan M, Falker C, Conley S, et al. Sleep Abnormalities are More Prominent Among Patients with Compensated Cirrhosis with Portosystemic Collaterals. Hepatology 2016:1430.
17. Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170-178.
18. Younossi ZM, Boparai N, Price LL, et al. Health-related quality of life in chronic liver disease: the impact of type and severity of disease. Am J Gastroenterol 2001;96:2199-2205.
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19. Kanwal F, Tapper EB, Ho C, et al. Development of Quality Measures in Cirrhosis by the Practice Metrics Committee of the American Association for the Study of Liver Diseases. Hepatol Baltim Md 2019;69:1787-1797.
20. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. PLoS Med 2009;6:e1000097.
21. Grossetta Nardini H, Wang L. The Yale MeSH Analyzer., 2019. http://mesh.med.yale.edu. Accessed October 20, 2019.
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23. Hayden JA, van der Windt DA, Cartwright JL, et al. Assessing bias in studies of prognostic factors. Ann Intern Med 2013;158:280-286.
24. Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut 1999;45:295300.
25. Tapper EB, Kanwal F, Asrani SK, et al. Patient-reported outcomes in cirrhosis: A scoping review of the literature. Hepatol Baltim Md 2018;67:2375-2383.
26. Freeman R. The new liver allocation system: Moving toward evidence-based transplantation policy. Liver Transpl 2002;8:851-858.
27. Wiesner R. MELD and PELD: Application of survival models to liver allocation. Liver Transpl 2001;7:567-580.
28. Bajaj JS, Schubert CM, Heuman DM, et al. Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology 2010;138:2332-2340.
29. Goldney RD, Phillips PJ, Fisher LJ, et al. Diabetes, Depression, and Quality of Life: A population study. Diabetes Care 2004;27:1066-1070.
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30. Brenes GA. Anxiety, depression, and quality of life in primary care patients. Prim Care Companion J Clin Psychiatry 2007;9:437-443.
31. Tandon P, Tangri N, Thomas L, et al. A Rapid Bedside Screen to Predict Unplanned Hospitalization and Death in Outpatients With Cirrhosis: A Prospective Evaluation of the Clinical Frailty Scale: Am J Gastroenterol 2016;111:1759-1767.
32. Sam J, Nguyen GC. Protein-calorie malnutrition as a prognostic indicator of mortality among patients hospitalized with cirrhosis and portal hypertension. Liver Int 2009;29:1396-1402.
33. Román E, Torrades MT, Nadal MJ, et al. Randomized Pilot Study: Effects of an Exercise Programme and Leucine Supplementation in Patients with Cirrhosis. Dig Dis Sci 2014;59:19661975.
34. Maharshi S, Sharma BC, Sachdeva S, et al. Efficacy of Nutritional Therapy for Patients With Cirrhosis and Minimal Hepatic Encephalopathy in a Randomized Trial. Clin Gastroenterol Hepatol 2016;14:454-460.e3.
35. Plank LD, Gane EJ, Peng S, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: A randomized 12-month trial. Hepatology 2008;48:557-566.
36. Sprangers MA, Schwartz CE. Integrating response shift into health-related quality of life research: a theoretical model. Soc Sci Med 1982 1999;48:1507-1515.
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Tables and Figures Table 1 - Study Participant Characteristics
Age
Sex
Etiology
Child-Pugh class
Child-Pugh score
MELD score
No. of studies reporting data 107
108
104
62
31
69
No. of studies
%
60 yrs.
12
11%
75%
19
18%
Alcohol
15
12%
Hepatitis C
11
8%
Hepatitis B
6
5%
NASH
1
1%
Mixed etiologies*
71
55%
Child A >50%
19
31%
Child B/C ≥50%
43
69%
Score 9
1
3%
MELD score
DR. ANAHITA RABIEE (Orcid ID : 0000-0002-8833-3592) DR. SINA NIKAYIN (Orcid ID : 0000-0001-9024-038X) DR. GUADALUPE GARCIA TSAO (Orcid ID : 0000-0002-6175-8216)
Article type
: Reviews
Title Page
Title: Factors Associated with Health-Related Quality of Life in Patients with Cirrhosis: A Systematic Review Short Title: Factors Associated with HRQoL in Cirrhosis Authors: Dr. Anahita Rabiee, Section of Digestive Diseases, Yale School of Medicine; Dr. Rafael Oliveira Ximenes, Division of Gastroenterology, University of Sao Paulo School of Medicine; Dr. Sina Nikayin, Department of Psychiatry, Westchester Medical Center; Andy Hickner, Interprofessional Health Sciences Library, Seton Hall University; Prerak Juthani, Yale School of Medicine; Dr. Robert H. Rosen, Yale School of Medicine; Dr. Guadalupe Garcia-Tsao, Section of Digestive Diseases, Yale School of Medicine and VA-CT Healthcare System. Grant Support: NIH P30 DK34989 Correspondence: Guadalupe Garcia-Tsao, MD Yale University School of Medicine
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/LIV.14680 This article is protected by copyright. All rights reserved
Accepted Article
Digestive Diseases Section 333 Cedar St – 1080 LMP New Haven, CT 06510 Email: [email protected] Phone: 203-737-6063 Fax: 203-785-7273
Disclosures: Authors have no conflicts of interest to disclose. Ethics approval: Not applicable Patient consent: Not applicable Permission to reproduce material from other sources: Not applicable Number of tables and figures: Three tables, one figure.
Key Points: Among decompensating events in cirrhosis, hepatic encephalopathy is the only factor showing consistent association with declining HRQoL. Child-Pugh classification was more commonly associated with impairment in HRQoL compared to MELD. Multiple modifiable factors such as psychiatric comorbidities (depression and anxiety), frailty, falls, malnutrition, physical symptoms (muscle cramps, sleep), and anemia are associated with poor HRQoL.
This article is protected by copyright. All rights reserved
Accepted Article
Factors Associated with Health-Related Quality of Life in Patients with Cirrhosis: A Systematic Review Abstract Background: Patients with cirrhosis have a poor health related quality of life (HRQoL). Recognizing factors that affect HRQoL is key in delivering patient-centered care. Aim: To identify factors most commonly associated with a poor HRQoL in adults with cirrhosis in a systematic review of the literature. Methods: Four databases (MEDLINE, EMBASE, CENTRAL and PsycINFO) were searched from inception to March 2020, using terms related to patient-reported outcomes plus cirrhosis. Studies that analyzed an association between at least one factor and HRQoL in adult patients with cirrhosis were included. Abstract and full-text screening was performed by two reviewers. Data were collected on factors evaluated in each study and the significance of their association with HRQoL. Results: A total of 10,647 citations were reviewed, of which 109 met eligibility criteria. 76% of the studies used a generic instrument while only 45% used liver-specific instruments. Among identified factors, demographic factors and cirrhosis etiology were not generally associated with poor HRQoL except for poor social support. Depression, poor sleep and muscle cramps affected HRQoL in all the studies that evaluated them. Among comorbidities, frailty, falls, malnutrition and cognitive impairment were also associated with poor HRQoL in the majority of studies. Among cirrhosis-specific decompensating events, only hepatic encephalopathy (HE) was consistently associated with impairment in HRQoL (75% of studies).
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Conclusion: Many factors impact poor HRQoL in patients with cirrhosis such as depression,
muscle cramps, poor sleep, falls, frailty and malnutrition. Among cirrhosis decompensating events, HE was the complication most commonly associated with a poor HRQoL. Keywords: Quality of life; Cirrhosis; Patient-reported outcomes
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Body of Paper Introduction: Cirrhosis is a major cause of global health burden, accounting for one million deaths, or 2% of all deaths worldwide and 1.2% of global Disability Adjusted Life Years (DALY) 1,2. Although liver transplantation offers a significant survival advantage and improvement in quality of life in patients with decompensated cirrhosis 3,4, it is only attainable for a minority of patients. A large proportion of patients die on the waiting list or are not even eligible for transplant 5. Traditionally most research and health care interventions in cirrhosis have focused on improving clinical outcomes such as delaying progression of the disease and improving survival. However, the relation between these clinical measures and patient reported outcomes (PRO) is not always present 6,7. PROs are measures of patient’s health perception and experiences that are directly reported by the patient 9,10. One of the most commonly used PROs is Health-Related
Quality of Life (HRQoL), which includes multiple domains such as physical function, symptom burden, mental health and social interaction 11. PROs such as HRQoL are more meaningful to patients and are increasingly recognized as important outcomes in clinical trials of patients with cirrhosis. Patients with cirrhosis have significant symptom and emotional burdens. At the compensated stage, patients can have symptoms that have been associated with minimal hepatic encephalopathy (MHE) 12 such as impairment in working or driving performance and subjective cognitive complaints 13 as well as sleep disturbance and fatigue 14–16. As the disease progresses and patients become decompensated, they can develop ascites, variceal bleeding or overt hepatic encephalopathy (HE) which cause physical and emotional discomfort. Therefore, HRQoL can be negatively impacted in patients with both compensated and decompensated cirrhosis 17,18.
There has been recent emphasis on incorporating PROs into research and clinical practice in order to evaluate the effect of management strategies and deliver quality care that is meaningful for patients19. A comprehensive understanding of the factors that drive impairment in HRQoL
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Accepted Article
in patients with cirrhosis is equally important as it can help clinicians prioritize targets of therapy (both in clinical practice and research) and thereby improve patient-centered care. The aim of this study was to identify factors (including decompensating events) that have the most impact on the HRQoL of patients with cirrhosis via a systematic review of the literature. Methods: For the conduct and reporting of this systematic review the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 20 was used: Search Strategy
In collaboration with a librarian (A.H.), a search strategy was developed to identify studies evaluating HRQoL in adult patients with cirrhosis. Four major electronic databases, including MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid), and the Cochrane Library (Wiley) were searched from inception until March 2020 (Figure 1). The Yale MeSH Analyzer was used to identify pertinent Medical Subject Headings for use in the MEDLINE search21. Controlled
vocabulary was combined with synonymous free text keywords using Boolean operators to capture patients with “cirrhosis” or “end-stage liver disease” and outcomes such as “patientreported outcomes”, “quality of life” that were reported by patients (e.g. “questionnaire”, “interview”, “self-report”, “survey”) (Appendix 1). Additionally, a hand search of the reference list of all included studies was performed to ensure all eligible studies were captured. Study selection
The following inclusion criteria were used: 1) English language original research published in a peer-reviewed journal, 2) study focused on adult patients with cirrhosis, 3) study used a HRQoL instrument defined as self-reported multidimensional questionnaire, encompassing multiple domains such as physical function, psychological state, social interaction and somatic sensation 11,
and 4) study analyzed an association between at least one factor (defined as any independent
variable) and HRQoL. Studies were excluded if they 1) evaluated the results of a specific intervention, 2) included 50 and one third had sample sizes above 150. The studies were from 28 different countries, with the majority from European (34%) and North American (31%) countries. Most studies (76%) used a generic instrument to measure HRQoL, with SF-36 being the most common (73%). Less than half (45%) of the studies used a disease-specific instrument, with Chronic Liver Disease Questionnaire (CLDQ) 24 being the most common (73%) (ESM Appendix 3, Supplementary Table 1). Description of included patients:
The majority of studies (76%) included patients with mean or median age of 50 to 60 years old and 74% of studies had a predominantly male population (male patients > 60%) (Table 1). Of the 109 studies, 41 (38%) included patients awaiting liver transplant, 40 (37%) included mostly patients with decompensated cirrhosis (Child B & C ≥ 50% or a decompensating event (HE, VB,
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Ascites) ≥ 50%), 16 (15%) included predominantly compensated patients (Child A>50%), and 12 (11%) of the studies did not provide information regarding the stage of cirrhosis. Among the studies that reported on specific decompensating events, the median percentage of patients with HE was 23% (in 51 studies) and the median percentage of patients with ascites was 49% (in 51 studies). Among the studies that reported on current or prior diagnosis of HCC (42 studies), the median prevalence of HCC was 9%. Critical appraisal
The most common source of bias (59% of studies) was confounding measurement, that is, the relationship between the factor and HRQoL was likely to be distorted by a confounding factor (e.g. severity of cirrhosis) affecting the HRQoL, that was not properly adjusted for in the analyses. Overall, 34% of studies were categorized as good quality, 54% as moderate quality, and 12% as poor quality (ESM Appendix 3, Supplementary Table 2). Factors associated with HRQOL
Of 165 factors, 54 factors were evaluated in more than two studies. These 54 factors were organized into 9 major categories as outlined in table 2. Demographic factors and cirrhosis etiology were not associated with poor HRQoL in the majority of studies, with the exception of lack of social support. From disease severity indices, Child-Pugh Classification was more closely associated with impairment in HRQoL when compared with MELD (69% vs 49%). Among cirrhosis-specific decompensating events including ascites, HE, and VB, only HE was consistently associated with impairment in HRQoL (75% of studies). When looking at the lab abnormalities commonly seen in patients with cirrhosis, anemia and Creactive protein were associated with impairment in HRQoL in 63% and 67% of the studies, respectively. Psychiatric symptoms such as depression and anxiety were associated with impairment in HRQoL in 100% and 83% of the studies, respectively. Lastly, physical symptoms such as muscle cramps and poor sleep were associated with impairment in HRQoL in all studies that looked at these factors. Among comorbidities, frailty, falls and malnutrition were associated with poor HRQoL in 80%, 80% and 67% of studies, respectively.
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Overall, 21 factors were associated with impairment in HRQoL in more than 50% of the studies. For these factors we specifically looked at good-quality studies, the results of which are available in table 3.
Discussion: This systematic review of 109 studies provides a comprehensive summary of the factors associated with poor HRQoL in patients with cirrhosis. It differs from a recent scoping review that analyzed 11 studies of patient reported outcomes which had an entirely different goal.25 Its goal was to identify and summarize PRO domains that could serve as candidate outcomes in quality improvement efforts in cirrhosis. In contrast, the present systematic review had the objective of identifying factors in cirrhosis that have the most impact in HRQoL. Among top factors that were identified, many are potentially modifiable factors such as psychiatric comorbidities (depression and anxiety), frailty, falls, malnutrition, physical symptoms (muscle cramps and sleep) and anemia. Among disease severity indices, Child-Pugh classification was more commonly associated with impairment in HRQoL compared to MELD. This could potentially be explained by the inclusion of variables such as HE and ascites in Child-Pugh score that are not captured in the MELD score. Currently, the MELD has replaced the Child–Pugh in the prioritization of liver transplant candidates 26,27; thus it is important to note that MELD might fail to capture candidates’ impairment in quality of life. Among the decompensating events, HE was the only factor that showed consistent results across studies in terms of decline in HRQoL. HE was related to poor HRQoL even when controlling for severity of liver disease with Child-Pugh or MELD. This is even more significant considering that many studies excluded patients with overt HE at the time of enrollment. Notably, most studies reporting on HE did not adjust for lactulose use as a confounder. Only 12 (43%) of 28 studies evaluating ascites showed it to be associated with a poor HRQoL but most of these studies did not grade the severity of ascites. Conversely, ascites was associated with a
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poor HRQoL in 7/9 (78%) of studies that evaluated the severity of ascites or included only patients with at least moderate ascites. MHE and poor performance on psychometric tests (per each study’s definition) were also significantly associated with poor HRQoL in most studies. This association could be partly due to inclusion of patients with history of overt HE and other decompensations in these studies, which makes the comparison more difficult. Previous episodes of overt HE are associated with a cumulative decline in cognitive function and these patients are more likely to perform poorly on psychometric tests 28; also, as shown in our study, history of HE is associated with poor HRQoL (in 18 of 24 studies, Table 2). Only one study evaluated the factors, including MHE, separately in patients with compensated vs decompensated cirrhosis. This study was able to show that MHE affects HRQoL in patients with compensated cirrhosis while overt HE, but not MHE, is associated with poor HRQoL in decompensated patients. Although some studies attempted to adjust for history of previous HE, future studies focusing on purely compensated patients with MHE are recommended before a conclusion regarding this association can be drawn. Psychiatric factors such as depression and anxiety were associated with poor HRQoL in almost all studies that evaluated these factors. This uniform association has been shown across multiple disease entities and is not unique to cirrhosis 29,30. Regardless, it emphasizes the importance of monitoring patients with cirrhosis for psychiatric comorbidities. And lastly among comorbidities, frailty, falls, and malnutrition are significantly associated with poor HRQoL in the majority of studies. They have been shown to correlate with mortality as well 31,32, thus it is important to consider evaluating these factors in patients with cirrhosis, and consider treatments such as exercise programs, physical therapy and nutritional supplementation which could improve HRQoL based on previous studies. 33–35 The heterogeneity in study results for some factors could have many different explanations. First, the statistical method, sample size and study quality were very heterogenous in this review. This can potentially explain why some studies did not have enough power to identify an association between a factor and HRQoL, or might have overestimated an association by not adjusting for important confounders. Second, the type of HRQoL instruments used varied
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between included studies, with studies using different generic or disease specific instruments with varying performance characteristics. Third, HRQoL is a subjective and dynamic target. Changes in an individual's health status may prompt behavioral, cognitive and coping strategies necessary for accommodating illness 36. As an example, while developing cancer in a healthy
individual can significantly impair that person’s HRQoL, new detection of HCC in a patient with decompensated cirrhosis might not have the same effect as the patient’s expectations and standards are different since they are already dealing with multiple decompensating events such as HE and ascites resulting in disability. Our study has some important limitations dependent on the quality of the studies analyzed. First, the majority of the studies included in the systematic review evaluated a wide range of factors for association with HRQoL without an a-priori hypothesis. Therefore, findings could be incidental, and a number of statistically significant associations with HRQoL may have been prone to type I error. Given the extensive nature of this review, this type of error would be minimized by repeated results in multiple studies, increasing the confidence for the external validity of the observed association. Second, most studies were cross-sectional in design, so causal inferences cannot be drawn from the results. Third, there was a vast heterogeneity between studies in terms of design, statistical methods, HRQoL instruments, and reporting of results, so a meta-analysis to quantify the effect size of the factors could not be performed. Fourth, most of the included studies combined patients with compensated and decompensated cirrhosis. These populations have potentially different HRQoL impairments, as a majority of patients with compensated cirrhosis are asymptomatic. Thus, inclusion of compensated patients in the population could have caused significant confounding. And lastly, the factors that were examined in relation to HRQoL were limited to those that were investigated in more than 2 studies, as we did not focus on factors that were only evaluated in 1 or 2 studies to ensure reproducibility of the results.
In conclusion, this is the first study to systematically summarize the factors associated with HRQoL in cirrhosis across a growing body of literature. We find that specific decompensations
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such as HE are associated with significant impairment in HRQoL. Additionally, our study found a multitude of modifiable factors such as psychiatric comorbidities (depression and anxiety), frailty, falls, malnutrition, physical symptoms (muscle cramps, sleep), and anemia that contribute to poor HRQoL in patients with cirrhosis, factors that could be targets of future studies for tailoring treatments focused on improving HRQoL in patients with cirrhosis.
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Tables and Figures Table 1 - Study Participant Characteristics
Age
Sex
Etiology
Child-Pugh class
Child-Pugh score
MELD score
No. of studies reporting data 107
108
104
62
31
69
No. of studies
%
60 yrs.
12
11%
75%
19
18%
Alcohol
15
12%
Hepatitis C
11
8%
Hepatitis B
6
5%
NASH
1
1%
Mixed etiologies*
71
55%
Child A >50%
19
31%
Child B/C ≥50%
43
69%
Score 9
1
3%
MELD score
![[No title available]](/assets/img/hold.png)
