doi: /hepr.12524

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1 bs_bs_banner Hepatology Research 2016; 46: E45 E50 doi: /hepr Original Article Validation of the Japanese version of the Chronic Liver Disease Questionnaire for the assessment of health-related quality of life in patients with chronic viral hepatitis Atsushi Tanaka, 1 Kentaro Kikuchi, 2 Ryo Miura, 1 Kotaro Miura, 1 Masaki Mikami, 1 Mitsuhiko Aiso, 1 Yoriyuki Takamori 1 and Hajime Takikawa 1 1 Department of Medicine, Teikyo University School of Medicine, Tokyo and 2 The 4th Department of Internal Medicine, Teikyo University, School of Medicine, Kanagawa, Japan Aim: Patients with chronic liver diseases (CLD) suffer from a variety of subjective symptoms, and the assessment of healthrelated quality of life (HRQOL) is crucial. The Chronic Liver Disease Questionnaire (CLDQ) is the first liver disease-specific instrument for this purpose. In this study we aimed to develop the Japanese version of CLDQ and to assess its validity and reliability in Japanese patients with chronic viral hepatitis. Methods: The participants included 135 Japanese patients chronically infected with hepatitis B or C virus. The Japanese version of the CLDQ was developed according to the standard back-translation method. In addition to the Japanese version of the CLDQ, we asked the patients to fill out two other selfreport questionnaires: the Japanese versions of the 36-Item Short Form Survey (SF-36) and Hospital Anxiety and Depression Scale (HADS). Then, the internal consistency, convergent and discriminant validity of the Japanese version of CLDQ were statistically examined. Results: Cronbach s alpha of the Japanese version of the CLDQ was acceptable. The mean score was lower in emotional domains of the CLDQ, compared with those in somatic domains. Pearson correlations between Japanese CLDQ and SF-36 and HADS were significant. The mean of the CLDQ scores decreased in all domains in patients with liver cirrhosis compared with those in patients with chronic hepatitis. Conclusion: The Japanese version of the CLDQ is a reliable and valid instrument for assessment of the HRQOL of Japanese patients with chronic viral hepatitis. The results also suggest that the HRQOL of Japanese patients is mainly impaired by emotional factors rather than somatic symptoms, and significantly worsened by progression of the disease. Key words: chronic liver disease, health-related quality of life, Hospital Anxiety and Depression Scale, 36-Item Short Form Survey INTRODUCTION PATIENTS WITH CHRONIC liver diseases (CLD), especially in the advanced stage, usually experience a variety of subjective symptoms, including general malaise, fatigue, pruritus and muscle cramp. 1 Moreover, it is not uncommon that patients with CLD suffer from anxiety and/or depression due to worries of deteriorating from their in the future. As a result, the health-related quality of life (HRQOL) of patients with CLD could be greatly impaired by various somatic and psychological factors which are directly and indirectly associated with CLD, and the Correspondence: Prof Atsushi Tanaka, Department of Medicine, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo , Japan. a-tanaka@med.teikyo-u.ac.jp Received 12 September 2014; revision 3 April 2015; accepted 6 April objective and reproducible assessment of HRQOL, namely, the assessment of physical, mental and social dimensions of well-being and social functioning, is crucial in the management of patients with CLD. Indeed, the maintenance of good HRQOL has been regarded as one of the significant outcomes of treatment in the clinical setting. 2 Various questionnaires have been developed to measure the HRQOL in patients with CLD. Generic questionnaires for the assessment of HRQOL are already available. The most popular one for this purpose is the 36-Item Short Form Survey (SF-36), 3 5 and the Japanese version of the SF-36 has been already validated and is available. 6 The SF- 36 has been used in the setting of clinical hepatology for the assessment of HRQOL of patients with CLD. 7,8 However, generic questionnaires such as the SF-36 are not well capable of assessing liver disease-specific aspects of E45

2 E46 Atsushi Tanaka et al. Hepatology Research 2016 HRQOL, and thus instruments that are specialized to liver diseasesarealsorequiredtoadequatelyassesshrqolof patients with CLD. In this regard, the Chronic Liver Disease Questionnaire (CLDQ) is the first one for that purpose, designed as a liver-disease specific instrument for evaluation of HRQOL. 9 The original version in English consists of 29 items, and is a short, easy-to-answer questionnaire for patients within the whole range of severity. The validity and reliability of the CLDQ have been demonstrated in various liver diseases Also, the translated versions of CLDQ into various languages have been validated in each population, including Asian countries, Thailand, southern China and eastern India In this study, we aimed to develop the Japanese version of the CLDQ and to assess its validity and reliability in Japanese patients with chronic viral hepatitis, a representative CLD in Japan. METHODS Study population WE ASKED PATIENTS with chronic viral hepatitis, chronically infected with hepatitis B or C virus regularly visiting outpatient clinics of two liver units in Japan to participate this study. The severity of liver disease, chronic hepatitis (CH) and liver cirrhosis (LC) was determined using histological, biochemical and/or imaging studies. Child Pugh classification was also determined in patients with LC. Exclusion criteria for this study included: (i) patients who had been treated with interferon within 6 months prior to the entry of this study; and (ii) patients with presence or past history of hepatocellular carcinoma (HCC). We excluded patients with HCC, because the HRQOL of these patients is greatly altered both qualitatively and quantitatively and therefore the HRQOL of these patients should be measured with devices other than the CLDQ. This project received ethical approval from the ethics committee of each hospital involved in the study. All subjects entering the protocol provided written informed consent after receiving a complete description of the study from attending physicians and having the opportunity to ask questions. Development of the Japanese version of the CLDQ The original version of the CLDQ consists of 29 items, divided into six subdomains: (i) abdominal symptoms (three items); (ii) fatigue (five items); (iii) systemic symptoms (five items); (iv) activity (three items); (v) emotional function (eight items); and (vi) worry (five items). 9 The Japanese version of the CLDQ was developed according to the standard back-translation method, namely, by translating the original CLDQ into Japanese and then back-translating the instrument to determine possible discrepancies with the English-language original version. The resulting instruments were reviewed and modified by a team of physicians who usually provide care to patients with CLD, and the final Japanese version was determined. Other questionnaires In addition to the Japanese version of the CLDQ, we asked the participants to fill out two other self-report questionnaires, the Japanese versions of the SF-36 and the Hospital Anxiety and Depression Scale (HADS). The SF-36 includes 36 items divided into eight scales or indices, which can be aggregated into two summary scores: a mental component summary and a physical component summary. These indices include physical functioning, role physical (role limitations as a result of physical health), bodily pain, general health perception, vitality, social functioning, role-emotional (role limitations as a result of mental problems) and mental health. 6 On the other hand, the HADS was developed for the assessment of anxiety and depression, and consist of 14 items divided into these two subdomains. 19 The Japanese versions of the SF- 36 and HADS were already published, and statistically validated. 6,20 The participants were requested to fill these three questionnaires and return them to the physicians as soon as possible. Statistical analyses First, Cronbach s alpha was calculated to examine the internal consistency and reliability of the Japanese version of the CLDQ. Next, the convergent validity of the constructs measured by this instrument was assessed by comparison between the Japanese version of the CLDQ and SF-36 scores, with Pearson correlation coefficients. Also, we observed the statistical association of CLDQ with HADS scores, to investigate how HRQOL was associated with anxiety and depression dimensions. Finally, to test the discriminant validity we compared CLDQ scores according to the etiologies as well as the severity of liver diseases, CH and LC. All statistical analyses were performed using SPSS software version 14.0 J (SPSS Japan, Tokyo, Japan). RESULTS Patients THE DEMOGRAPHIC AND clinical characteristics of the enrolled patients are shown in Table 1. Onehundred and thirty-five patients with chronic viral hepatitis, 63 male and 72 female, were enrolled in this study. The

3 Hepatology Research 2016 HRQOL in chronic liver diseases E47 Table 1 Demographic and clinical characteristics of the enrolled patients n Age (years) (mean ± SD) All ± /72 Etiology Hepatitis C* ± /63 Hepatitis B* ± /9 Severity Chronic hepatitis** ± /47 Liver cirrhosis** ± /25 Child A ± /16 Child B ± 9.2 6/4 Child C ± 2.4 3/2 Sex (male/female) *The mean age of patients with hepatitis C and B was comparable. **There was no significant difference in age and sex between chronic hepatitis and liver cirrhosis. SD, standard deviation. Table 2 Cronbach s alpha coefficients and mean score in each subdomain of the Japanese version of the CLDQ CLDQ domains Cronbach s alpha Mean score (SD) Overall (1.34) Abdominal symptoms (1.25) Fatigue (1.35) Systemic symptoms (1.48) Activity (1.45) Emotional function (1.10) Worry (1.25) CLDQ, Chronic Liver Disease Questionnaire; SD, standard deviation. mean age overall was 66.2 years. The etiologies included 113 patients chronically infected with hepatitis C and 22 with hepatitis B. The mean age of patients with hepatitis C and B was comparable. The number of patients with CH and LC were 90 and 45, respectively. We failed to notice any statistical difference in age and sex distribution between CH and LC. Thirty, 10 and five patients out of 45 with LC were classified as Child Pugh A, B and C, respectively. Internal consistency To confirm the internal consistency of each domain of the Japanese version of the CLDQ, we calculated Cronbach s alpha in each domain (Table 2). Cronbach s alpha was overall, and ranged from (activity domain) to (emotional function domain), which were above the acceptable threshold, The mean score of each domain was the lowest in worry (4.74) and fatigue (4.80), and the highest in activity (5.45) and abdominal symptoms (5.40). Although floor effect was not observed in any item, ceiling effect was found in item 7 (not eating enough), 14 (bothered by diet limitation) and 29 (worried about transplantation). Convergent validity To test the convergent validity of the Japanese CLDQ, we compared scores between the Japanese version of the CLDQ and SF-36 scores, with Pearson correlation coefficients (Table 3). We found that each domain of the Japanese CLDQ was significantly associated with relevant domains of the SF-36. For instance, there were strong and significant associations between fatigue of the Japanese CLDQ and role physical (r = 0.555), vitality (r = 0.636) and role emotion (r = 0.545), activity and physical function (r = 0.510), role physical (r = 0.582) and vitality (r = 0.542), emotional function and role emotion (r = 0.565) and worry and general health perception (r = 0.513) and role emotion (r = 0.572). These results suggested the acceptable convergent validity of the Japanese version of the CLDQ. Table 3 Pearson correlation between Japanese CLDQ and SF-36 SF-36 domains CLDQ domains Abdominal symptoms Fatigue Systemic symptoms Activity Emotional function Worry Physical function 0.290* 0.490** 0.411** 0.510** 0.432** 0.345** Role physical 0.442** 0.555** 0.465** 0.582** 0.512** 0.487** Bodily pain 0.301* 0.394** 0.368** 0.276* 0.327** General health perception 0.416** 0.482** 0.396** 0.380** 0.482** 0.513** Vitality 0.452** 0.636** 0.425** 0.542** 0.613** 0.502** Social function * Role emotion 0.452** 0.545** 0.372** 0.482** 0.565** 0.572** Mental health *P < **P < CLDQ, Chronic Liver Disease Questionnaire; SF-36, 36-Item Short Form Survey.

4 E48 Atsushi Tanaka et al. Hepatology Research 2016 Table 4 Pearson correlation between Japanese CLDQ and HADS HADS domains CLDQ domains Abdominal symptoms Fatigue Systemic symptoms Activity Emotional function Worry Anxiety 0.482*** 0.452*** 0.392*** 0.440*** 0.672*** 0.570*** Depression * 0.232* 0.293** 0.276** 0.197* Please note that higher scores indicate more anxiety and depression in HADS score, and thus Pearson correlations between CLDQ and HADS were all negative. *P < 0.05, **P < 0.01, ***P < CLDQ, Chronic Liver Disease Questionnaire; HADS, Hospital Anxiety and Depression Scale. Then, we examined whether the Japanese CLDQ scores were correlated with the HADS score, indicating anxiety or depression status of the individuals (Table 4). As seen, the scores of all CLDQ domains except for systemic symptoms were strongly correlated with anxiety domain of the HADS score; correlation coefficients between the anxiety domain of the HADS and CLDQ domains were less than in emotional function and worry domains of the CLDQ. On the other hand, associations of CLDQ scores with depression domain of the HADS were relatively weak; the most remarkable correlation was observed between depression of the HADS and activity of the CLDQ, yet the correlation coefficient was Discriminant validity Finally, we investigated how the etiologies and the severity of liver diseases affected the Japanese CLDQ scores. We failed to detect any difference in each domain of the Japanese CLDQ between HBV and hepatitis C virus (Table 5). Meanwhile, in 135 patients with CLD, 90 and 45 were Table 5 Comparison of CLDQ scores according to the etiologies of liver diseases CLDQ domains HCV (n =113) HBV (n =22) Overall 4.92 (1.12) 5.10 (0.72) Abdominal 5.38 (1.28) 5.50 (1.20) symptoms Fatigue 4.73 (1.18) 5.10 (0.80) Systemic 5.05 (1.12) 5.48 (0.65) symptoms Activity 5.37 (1.30) 5.60 (0.82) Emotional 4.83 (1.25) 4.83 (0.95) function Worry 4.78 (1.30) 4.62 (0.95) *P-value was calculated using unpaired Student s t-test. CLDQ, Chronic Liver Disease Questionnaire; HBV, hepatitis B virus; HCV, hepatitis C virus; SD, standard deviation. P* clinically and/or histologically diagnosed as having CH and LC, respectively, and the LC individuals classified as Child Pugh A, B and C were 30, 10 and five, respectively (Table 1). Overall, the mean of the CLDQ scores were 5.05 in CH, 4.82 in LC Child A, and 4.25 in LC Child B/C; thus, gradually decreasing along with progression of liver diseases, although not statistically significant with one-way ANOVA (P = 0.074) (Table 6). The mean score of each domain except for the abdominal symptoms domain was also decreased with deterioration of liver function, and the decline was statistically significant among three groups in systemic symptoms (P = 0.011) and worry (P = 0.019) (Table 6). DISCUSSION BECAUSE MOST PATIENTS with CLD suffer from physical symptoms and/or worries which could greatly diminish their HRQOL and well-being, 21 it is crucial for physicians to appropriately evaluate and manage HRQOL problems of patients with CLD. For this purpose, the original CLDQ has been developed and validated, and its translated versions into other languages have been proved to be also reliable ,17,18,22 In this report, we performed a validation study of the Japanese version of the CLDQ in Japanese patients with chronic viral hepatitis. We provided evidences of the validity of the instrument for survey of the HRQOL in Japanese patients with chronic viral hepatitis, with acceptable internal consistency, convergent and discriminate validity. We need to address several issues which should be noted. First, although floor effect was not observed in any item, ceiling effect was found in items 7 (not eating enough), 14 (bothered by diet limitation) and 29 (worried about transplantation). Among these three items, 7 and 14 belonged to the activity domain, and indeed the internal consistencyoftheactivitydomain was 0.809, which was acceptable but lower compared with those of other domains. Therefore, it should be kept in mind that the activity

5 Hepatology Research 2016 HRQOL in chronic liver diseases E49 Table 6 Comparison of CLDQ scores according to the severity of liver diseases CLDQ domains CH (n = 90) LC, Child A (n =30) LC, Child B/C (n =15) P* Overall 5.05 (1.10) 4.82 (0.88) 4.25 (1.05) Abdominal symptoms 5.45 (1.22) 5.38 (1.12) 4.70 (0.98) Fatigue 4.95 (1.10) 4.68 (1.13) 4.50 (0.92) Systemic symptoms 5.35 (0.88) 4.75 (0.85) 4.35 (1.02) Activity 5.50 (1.22) 5.38 (0.95) 4.60 (1.32) Emotional function 4.88 (1.12) 4.65 (1.05) 4.05 (1.12) Worry 4.95 (1.15) 4.46 (1.17) 3.96 (1.35) *P-value was calculated using one-way ANOVA. CH chronic hepatitis; CLDQ, Chronic Liver Disease Questionnaire; LC, liver cirrhosis; SD, standard deviation. domain may not reflect the HRQOL of Japanese CLD patients very well. Also, another ceiling effect seen in item 29 (worried about transplantation) may be interpreted as that liver transplantation is not generally recognized as a routine therapeutic option by CLD patients yet. Convergent validity of the Japanese CLDQ, examined by comparison with the SF-36 and HADS, is also satisfactory. We found that each domain of the Japanese CLDQ was significantly associated with relevant domains of the SF-36. These ample correlations were also demonstrated in the original publication 9 and other validation studies. 13,14,17,18 Interestingly, the correlations of the CLDQ domains were more remarkable in the anxiety domain of HADS, compared with the depression domain. We found only one validation study examining convergent validity of the translated CLDQ using the HADS, performed in German-speaking countries, 14 which showed that there seemed to be no difference in correlation scores between depression and anxiety domain. So far, we have had no clear explanation why the higher correlations were seen in the anxiety domains of the HADS but it may be reasonable to assume that Japanese patients of CLD tend to experience anxiety, rather than depression, during the clinical course of CLD. This observation was also confirmed by the correlations between the SF-36 and CLDQ; very little correlation was found between the mental health domain of the SF-36 and each CLDQ domain (Table 3). Because the mental health domain in the SF-36 consist of nine items and mainly focuses on depressive state, not on anxiety, we failed to note a good correlation between the CLDQ and mental health domain. We found that CLDQ scores were reduced in patients with LC compared with CH in Japanese patients with chronic viral hepatitis. This deterioration of HRQOL along with progression of liver diseases is frequently observed in other studies performed not only in North America and Europe, 9,13,14,23 but also in recent studies in Asia. 18,22,24,25 The current study confirmed this observation, even though the number of the subjects was relatively small compared with other studies. The subjects in this study were enrolled at outpatient clinics, and thus had relatively mild disease; only 10 and five patients were graded as Child Pugh B and C, respectively. Therefore, we were not able to investigate whether CLDQ scores were more declined in Child Pugh B o C. Future study with a larger scale including patients with severer liver diseases during admission will be warranted. In addition, we noticed in this study that the HRQOL of Japanese CLD patients seems to be mainly impaired by emotional factors rather than somatic symptoms, because the mean score of CLDQ was lower in fatigue (4.80), emotional factor (4.83) and worry (4.74) domains, compared with those in abdominal symptoms (5.40), systemic symptoms (5.12) and activity (5.45) (Table 2). Therefore, physicians must be aware that considerate and individualized care for mental and emotional status of the CLD patients, in addition to appropriate treatment plans for CLD itself, is extremely important to improve the HRQOL of the patients. We exclude patients with presence or a history of HCC from this study. Because HCC is not uncommon in patients with chronic viral hepatitis in Japan, there may be a reason that patients with HCC should be included in the study population. However, the presence of HCC, even in the past, may greatly alter the HRQOL both qualitatively and quantitatively, and therefore we believe that the HRQOL of patients with HCC should be measured with different questionnaires, not with the CLDQ. Indeed, the patients with HCC were not included in the study that originally developed the CLDQ. 9 In conclusion, we confirmed in the current study that the Japanese version of the CLDQ is a valid and reliable

6 E50 Atsushi Tanaka et al. Hepatology Research 2016 instrument for assessment of the HRQOL of patients with chronic viral hepatitis, as shown in other populations worldwide. The improvement of HRQOL is indeed one of the significant outcomes of treatment for patients with CLD, and is it strongly advisable for physicians to adequately measure and improve HRQOL of patients with CLD using this globally-spread instrument. 26 ACKNOWLEDGMENTS WE ARE SINCERELY grateful to Dr Lorenzo Montali and Ms Yuka Takahashi for providing excellent statistical analyses and advices, and also Ms Wakana Furuya for secretarial assistance. REFERENCES 1 Martin LM, Sheridan MJ, Younossi ZM. The impact of liver disease on health-related quality of life: a review of the literature. Curr Gastroenterol Rep : Gutteling JJ, de Man RA, Busschbach JJ, Darlington AS. Overview of research on health-related quality of life in patients with chronic liver disease. 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