LIVER, PANCREAS, AND BILIARY TRACT

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: LIVER, PANCREAS, AND BILIARY TRACT Factors That Reduce Health-Related Quality of Life in Patients With Primary Sclerosing Cholangitis MARIA BENITO DE VALLE,* MONIRA RAHMAN, BJÖRN LINDKVIST,* EINAR BJÖRNSSON,* ROGER CHAPMAN, and EVANGELOS KALAITZAKIS*, *Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and Department of Gastroenterology, John Radcliffe Hospital, Oxford, United Kingdom BACKGROUND & AIMS: Health-related quality of life (HRQL) is frequently reduced in patients with chronic liver disease, but there are limited data from patients with primary sclerosing cholangitis (PSC). We aimed to evaluate HRQL and its potential determinants in 2 population-based cohorts of patients with PSC and to study the prevalence of fatigue among these patients. METHODS: Validated questionnaires were used to measure quality of life (the Short- Form 36 [SF-36] and the chronic liver disease questionnaire), fatigue (the fatigue impact scale), and psychological distress (the hospital anxiety and depression scale) in 182 PSC patients residing in Sweden or England. Results were compared with those from the general population (controls). Regression analysis was performed to identify factors independently associated with HRQL. RESULTS: Patients with PSC had significantly lower scores from several areas of the SF-36, compared with controls (P.05). Age ( 0.62 to 0.21, P.05) and systemic symptoms ( , P.05) such as pruritus were associated with lower scores from specific areas of the SF-36; serum level of alkaline phosphatase ( 1.12 to 0.75, P.05), and large-duct PSC ( to 10.05, P.05) were associated with lower scores on mental health questionnaires. The proportion of patients with significant fatigue, depression, or anxiety did not differ between patients and controls (P.05). CONCLUSIONS: Quality of life is impaired in unselected patients with PSC. Fatigue does not seem to be a specific symptom of PSC. Older age, large-duct disease, and systemic symptoms seem to reduce HRQL in patients with PSC. Keywords: CLDQ; FIS; HAD; Cholestatic Liver Disease. Health-related quality of life (HRQL) is impaired in patients with chronic liver disease. 1 3 Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease affecting predominantly young men during a productive part of their lives and with a major impact on morbidity and mortality. However, previous studies assessing HRQL in patients with chronic liver disease included only few patients with PSC who were recruited mostly from tertiary referral centers. 1,4 Several factors, such as liver disease severity, psychological distress, and liver disease related symptoms, have been reported to affect HRQL in patients with chronic liver disease. 5 7 PSC is also associated with symptoms, such as pruritus, that could potentially impair HRQL. To date, no study has specifically explored HRQL in unselected patients with PSC, and knowledge of the factors that influence HRQL in these patients is limited. Fatigue is considered a common symptom in cholestatic liver disease Previous studies have extensively explored the impact of fatigue on HRQL in primary biliary cirrhosis (PBC), 8 10 but data on the prevalence and severity of fatigue in PSC are scarce. Although a previous study evaluating fatigue in PSC patients from 2 Northern European referral centers reported that fatigue is not a specific symptom of PSC, 7 to our knowledge, no study has evaluated fatigue and its impact on HRQL in unselected patients with PSC. The aims of the current study were to evaluate HRQL and its potential determinants in 2 well-defined European cohorts of patients with PSC. Furthermore, we aimed to study the prevalence of fatigue and its potential relation to HRQL in these patients. Methods Patients All patients with PSC residing in Västra Götaland, Sweden (population 1.8 million) and in Oxfordshire, England (population 600,000) in October 2008 were invited to participate in the study. In Sweden, patients were identified through a search of the computerized discharge diagnosis register of all the hospitals in the region. Private patient treatment for chronic liver disease is very rare in Sweden, and patients with liver disease might not be followed up in a hospital outside their region of residence. Thus, Swedish hospital-provided medical services for liver disease are, in effect, population-based. In Oxford, England, all patients with a diagnosis of PSC followed at the outpatient clinic of the John Radcliffe Hospital were identified. The John Radcliffe Hospital is a tertiary hepatology center in England that is renowned for PSC patient care. Although PSC patients in Oxfordshire might have Abbreviations used in this paper: CLDQ, chronic liver disease questionnaire; FIS, fatigue impact scale; HAD, hospital anxiety and depression scale; HRQL, health-related quality of life; IBD, inflammatory bowel disease; MCS, mental component summary; PBC, primary biliary cirrhosis; PCS, physical component summary; PSC, primary sclerosing cholangitis; SD, standard deviation; SF-36, Short-Form by the AGA Institute /$

2 770 BENITO DE VALLE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 chosen to be under the care of a private health care provider or public hospitals outside the region, we are confident that the vast majority of PSC patients residing in Oxfordshire are included in the present study. Patients whose permanent address was not within the Västra Götaland region in Sweden or Oxfordshire in England in October 2008 were excluded. Patients unable to understand Swedish (in Sweden) or English (in England) were also excluded. Medical records of all patients were scrutinized to confirm PSC diagnosis and to collect relevant clinical and biochemical data. Comorbid illness was assessed by means of the Charlson comorbidity index. 11 The study protocol was approved by the ethics committee of Västra Götaland in Sweden and Milton Keynes in England. Written informed consent was obtained from all patients. Questionnaires All patients were sent a letter asking them to participate in the study. Those who accepted were sent the study questionnaires. A reminder letter was sent 2 6 weeks later to those who had not responded. The questionnaire booklet contained questions on work, marital status, and education as well as the following questionnaires. Short-Form 36. This 36-item instrument was used to assess HRQL (physical, emotional, and social functioning). 12,13 The Short-Form 36 (SF-36) is scored from 0 to 100, with higher scores indicating better HRQL. The SF-36 has previously been used for the assessment of HRQL in patients with chronic liver disease. 3,5,14 An age-matched (2-year age interval) and gendermatched reference sample (n 364), randomly drawn from the Swedish SF-36 normative database (n 8930), was used as a control group. 13 Chronic liver disease questionnaire. The chronic liver disease questionnaire (CLDQ) is a liver disease specific HRQL questionnaire that consists of 29 items divided into 6 domains: abdominal symptoms, activity, emotional function, fatigue, systemic symptoms, and worry. Summary scores for each domain range from 1 (most impairment) to 7 (least impairment). The questionnaire has good test-retest reliability and cross-sectional validity. 6,15,16 By means of the CLDQ, separate systemic symptoms were prospectively assessed in all patients (question numbers 3, 6, 21, 23, and 27, ie, bodily pain, shortness of breath, muscle cramps, dry mouth, pruritus). Patients with a CLDQ domain score 4 (ie, symptoms more frequent than some of the time ) were considered to have significant symptoms. Fatigue impact scale. The fatigue impact scale (FIS) was initially developed and validated for use in patients with chronic fatigue syndrome 17 and PBC. 18 This 40-item questionnaire was constructed to evaluate the impact of perceived fatigue during the last month on 3 subscales: physical (10 items), cognitive (10 items), and psychosocial functioning (20 items). Each item uses a 5-grade scale (0 4), yielding a maximum of 160. Higher scores indicate increased fatigue. To provide a control group from the general population for comparison, a random sample of 2000 subjects (20 75 years of age) from the population in Gothenburg, Sweden were sent the FIS by mail. A total of 858 subjects from the general population returned the questionnaire. 7,19 From this group of subjects from the general population, 2 sex-matched and age-matched controls were randomly assigned for each PSC patient. Patients were classified as fatigued if they had an FIS score 2 standard deviations (SDs) compared with the sex- and age-matched controls. Hospital anxiety and depression scale. The hospital anxiety and depression (HAD) scale was used to assess psychological distress. Each item uses a 4-grade scale (0 3) with subscales for anxiety (7 items) and depression (7 items). Higher scores indicate higher levels of anxiety and depression. 20 Normal values from the Swedish population are available. 21 Statistics Data are reported as means and SD or n (%) as appropriate. Analysis of variance or the Mann Whitney test was performed to compare continuous variables. The Pearson coefficient was calculated for correlation analysis. The 2 or Fisher exact test was used for comparisons between categorical variables as appropriate. To identify factors independently associated with HRQL as assessed by the SF-36 domain and summary scores, variables univariately related with each SF-36 domain with a P value.1 were entered in multivariate linear regression models. We modeled the relationship between HRQL and patient features by using a staged approach. The first stage included demographic and clinical variables, whereas the second stage added domain scores from the (liver-specific) CLDQ questionnaire. In case the systemic symptoms CLDQ domain score was found to be independently related to SF-36 domains in the second stage, each specific CLDQ symptom status (significant vs nonsignificant; CLDQ question numbers 3, 6, 21, 23, and 27) 15 was tested in a third stage. All tests were two-tailed and conducted at 5% significance level. Results Two hundred eighteen PSC patients in Västra Götaland, Sweden and 60 in Oxfordshire, England were identified and asked to fill in the questionnaires. Completed questionnaires were returned by a total of 182 patients, giving a response rate of 65% (69% in Sweden and 55% in England). Twenty-two patients (12%) had received a liver transplant because of PSC. Patients opting to participate in the study, compared with nonparticipants, had more advanced liver disease, a higher mean Mayo score (0.33, SD, 1.10 vs 0.16, SD, 0.79; P.006), as well as a higher proportion of overt liver cirrhosis (7% vs 0%, P.01) and decompensated liver disease (6% vs 0%, P.001). However, there was no significant difference regarding age, gender, extension of biliary tree involvement, presence of hepatobiliary malignancy, or the proportion of transplant recipients between the 2 groups (P.05 for all). General characteristics of patients with PSC who had not received a liver transplant and were participating in the study (n 160) are summarized in Table 1. No patient was known to have active cholangitis at the time of questionnaire completion. Patients from England were older (56 [17] vs 48 [15] years, P.02) and had been followed up for a longer period of time (11 [6] vs 7 [6] years, P.01) compared with those from Sweden. Although there was no significant difference in the number of comorbidities diagnosed in each group, the proportion of patients with more severe comorbid illness in the English cohort was higher compared with the Swedish cohort (P.01). Patients from England had lower SF-36 physical function-

3 July 2012 QUALITY OF LIFE IN PSC 771 Table 1. General Characteristics of PSC Patients Who Had Not Received a Transplant and Were Participating in the Study (n 160) Age (y) 50 (16) Gender (M/F) 112/48 (70%/30%) Small-duct disease 17 (11%) Liver cirrhosis 12 (8%) Decompensated liver disease 9 (6%) Mayo Risk Score 0.34 (1.10) Cholangiocarcinoma 2 (1%) Follow-up (y) 10 (6) Comorbid illness a 146 (91%) Charlson comorbidity index b 1 18 (11%) 2 9 (6%) 3 2 (1%) IBD c 126 (79%) Medications d 116 (73%) Ursodeoxycholic acid treatment 62 (39%) Living with a spouse or partner 132 (83%) 10 Years of school education 23 (14%) Working or studying 106 (66%) NOTE. Data are presented as mean (SD) or n (%) as appropriate. a Patients who had other types of disease apart from PSC (arterial hypertension 62%, cardiovascular 3%, endocrinological other than diabetes 4%, diabetes mellitus 5%, celiac disease 3%, autoimmune hepatitis 8%, depression 2%, pulmonary disease 4%, other 21%). b Higher Charlson index indicates more severe comorbid illness. c Ulcerative colitis 67%, Crohn colitis 10%, indeterminate colitis 2%. d Other than ursodeoxycholic acid. ing scores compared with those from Sweden, but no other significant differences were found in demographic and clinical characteristics or SF-36 HRQL data between the 2 cohorts (Supplementary Table 1 and Supplementary Figure 1). Health-Related Quality of Life Patients with PSC had significantly lower scores in all SF-36 domains compared with the general population, with the exception of the physical functioning and bodily pain domains (Figure 1). Patients who had undergone liver transplantation did not report significantly different HRQL compared with controls (P.05), with the exception of the general health SF-36 domain (59 [21] vs 72 [24], respectively, P.03) (Supplementary Figure 2). The prevalence of significant subjective symptoms, as assessed by the CLDQ, is shown in Figure 2. Age was found to be negatively related to all SF-36 physical domain scores and to physical component summary (PCS) score (r 0.09 to 0.49, P.05) and positively to SF-36 mental health, role emotional, and mental component summary (MCS) scores (r , P.05). Serum alkaline phosphatase levels were found to be negatively related to all SF-36 domain scores (r 0.12 to 0.29, P.05). Patients with large-duct PSC, compared with those with small-duct PSC, had lower SF-36 vitality, social functioning, mental health, and MCS (P.05 for all). Comorbid illness, expressed as the Charlson comorbidity index, was related only to SF-36 physical functioning and PCS (P.05). Severity of liver disease was related to HRQL, because patients with cirrhosis had lower SF-36 physical functioning, role functional, general health, mental health, and PCS scores compared with noncirrhotic patients (P.05 for all). All CLDQ domain scores were related to SF-36 PCS and MCS (r , P.01). Exclusion of patients with cholangiocarcinoma (n 2) did not change the results of the analyses presented above (data not shown). Figure 1. HRQL in patients with PSC who had not received a transplant (n 160) compared with controls (n 364) as assessed by SF-36 (mean, 95% confidence intervals). *P.05.

4 772 BENITO DE VALLE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 Figure 2. Proportions of PSC patients who had not received a transplant (n 160) with significant symptoms as assessed by CLDQ. Patients with CLDQ domain score 4 (ie, occurring at least some of the time) were considered to have significant symptoms. Two percent of patients had significant systemic symptoms as assessed by CLDQ. However, analysis of specific symptoms CLDQ questions showed that 24% had significant bodily pain, 8% had shortness of breath, 11% had muscle cramps, 18% had mouth dryness, and 24% had pruritus. Fatigue Fatigue, as assessed by the FIS, did not differ significantly between PSC patients and controls (Figure 3). Patients who had undergone liver transplantation did not report significantly different fatigue levels compared with the rest of the cohort or controls (significant fatigue according to the total FIS score in 5.3% PSC patients without prior transplantation, 5.3% in PSC patients who had received a transplant, and 4.7% in controls, P.05). Psychological Distress The proportion of subjects with significant or borderline depression, as assessed by the HAD, did not differ between patients and controls (9% vs 15%, P.06). The same was true for anxiety (9% vs 6%, P.4). Regression Analyses In an attempt to identify independent predictors of HRQL, linear regression analyses were performed in 3 stages with the SF-36 domain and summary scores as dependent variables. In the first stage, demographic and clinical variables were included (Table 2). Age was found to have a negative impact on 2 of 4 physical SF-36 domains (physical functioning, bodily pain), whereas serum alkaline phosphatase concentration was negatively associated with 3 mental SF-36 domains (vitality, general health, and mental health). Large-duct disease, as opposed to small-duct PSC, was related to lower vitality and mental health scores. However, liver disease severity (Mayo Risk Score, presence of cirrhosis), comorbid illness, including inflammatory bowel disease (IBD), ursodeoxycholic acid treatment, or duration of follow-up were not found to be major predictors of HRQL in these patients (Table 2). In the second stage, subjective symptoms as assessed by the CLDQ were included in the linear regression analysis (Table 2). Serum alkaline phosphatase levels were excluded from this (and the next) stage to avoid potential confounding with pruritus and other symptoms. Significant fatigue according to CLDQ was found to be an independent predictor of all physical SF-36 domains, PCS, and 2 mental domains (social functioning, vitality). Not unexpectedly, emotional function, as assessed by the CLDQ, was associated with lower scores in all mental SF-36 domains. Systemic symptoms were independently related to all physical SF-36 domains, with the exception of general health (Table 2). In the third stage of the analysis, each specific symptom status (significant vs nonsignificant; question numbers 3, 6, 21, 23, and 27 on the CLDQ) 15 was included in the regression analysis for SF-36 domains that in the second stage were found to be independently related to the CLDQ systemic symptom domain (ie, physical functioning, role functional, bodily pain, and PCS). Pruritus was identified as an independent predictor of the SF-36 bodily pain ( 9.3, P.01) and role functioning ( 15.1, P.01) domains and the SF-36 PCS ( 3.38, P.02), whereas, not unexpectedly, the CLDQ bodily pain domain was related to SF-36 bodily pain domain ( 31.7, P 0.01) as well as the SF-36 PCS ( 6.76, P.01). Discussion The current study shows that patients with PSC have impaired HRQL compared with the general population. Older age and systemic symptoms seem to have a negative impact on physical HRQL, whereas large-duct disease and serum alkaline phosphatase levels were found to be independent predictors of mental HRQL. Neither fatigue nor psychological distress was found to be more common in PSC patients compared with the general population, in accordance with previously published data. 7 To our knowledge, ours is the largest study of HRQL in PSC; it is performed in 2 well-defined cohorts of patients from 2 Northern European countries by using validated questionnaires assessing HRQL, fatigue, and psychological distress. Although previous studies have shown reduced HRQL in chronic liver diseases, 2,5 published data on HRQL in PSC, originating from tertiary centers and liver transplant programs, are Figure 3. Proportions of patients with PSC who had not received a transplant (n 160), and controls (n 320) with significant fatigue as assessed by FIS (%, 95% confidence intervals). P.05 for all. Patients were classified as fatigued if they had an FIS score 2 SDs compared with the sex- and age-matched controls from the general population.

5 July 2012 QUALITY OF LIFE IN PSC 773 Table 2. Factors Independently Related to SF-36 Domains Scores and PCS and MCS After Linear Regression Analyses in Patients With PSC Not Having Received a Liver Transplant (n 160) Stage 1 Stage 2 Unstandardized coefficient P value Unstandardized coefficient P value Physical functioning Age Fatigue a Systemic symptoms a Role functional Decompensated liver disease Fatigue a Systemic symptoms a Vitality Serum alkaline phosphatase Large-duct disease Medications Fatigue a Emotional function a Bodily pain Age Fatigue a Systemic symptoms a Role emotional Emotional function a Social functioning Ursodeoxycholic treatment Fatigue a Emotional function a General health Serum alkaline phosphatase Fatigue a Worry a Activity a Mental health Serum alkaline phosphatase Large-duct disease Emotional function a PCS Age Systemic symptoms a Emotional function a Fatigue a MCS Emotional function a a As assessed by CLDQ. Lower scores in CLDQ domains indicate worse symptoms. somewhat discordant. 1,4,6,7 Data presented in the current report are in line with those of previous studies that used the same HRQL instrument (SF-36) and showed impaired HRQL in patients with cholestatic liver disease. 1,4,6 Furthermore, we found a score difference of more than 5 points between patients and controls in most of the SF-36 domains and higher than 2 points for the SF-36 MCS, which suggests clinically relevant differences. 22,23 Also, our findings indicate that liver disease severity is not a major determinant of HRQL in unselected patients with PSC, which is in contrast to previous reports in patients with cholestatic liver disease. 1,6 A possible explanation for this could be the fact that previous studies included both patients with PBC and with PSC and that they were conducted in tertiary centers with 39% 61% of enrolled PSC patients having cirrhosis, 1,6 compared with 7% in our cohort. Thus, although it appears that end-stage liver disease does affect HRQL in PSC patients, 5 our findings suggest that factors other than liver disease severity (such as subjective systemic symptoms) are more closely related to HRQL in unselected noncirrhotic PSC patients. Systemic symptoms in general and pruritus in particular were found to be related to reduced HRQL in the current study. This is in accordance with previous reports identifying pruritus as an independent predictor of impaired HRQL in patients with cholestatic liver disease 6 and showing that subjective, non life-threatening symptoms are more important determinants of HRQL than liver disease severity in patients with cirrhosis. 5 HRQL was found to be reduced in patients with large-duct disease compared with those with small-duct disease. Similarly, worse prognosis in terms of survival and development of cho-

6 774 BENITO DE VALLE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 langiocarcinoma has been previously reported among patients with large-duct disease compared with those with small-duct PSC. 24 Thus, more extensive disease among PSC patients with large-duct involvement seems to have an impact not only on patient outcome but also on HRQL. Also, elevated serum alkaline phosphatase levels were associated with lower SF-36 domain scores. Raised serum alkaline phosphatase levels might be a surrogate for more extensive biliary disease. However, cholestasis per se, resulting in higher serum concentrations of bile acids, could be related to impaired HRQL through inhibition of glucocorticoid clearance, leading to inhibition of the hypothalamus-pituitary-adrenal axis. 25 Inhibition of the hypothalamuspituitary-adrenal axis has been previously reported to contribute to impaired HRQL in several chronic diseases. 26 However, further studies are needed to test this hypothesis, because bile acid levels were not analyzed in our study and because liver function tests are known to vary in the course of PSC. Patients with PSC showed impairment in SF-36 mental domains. However, the significance of this finding is unclear because neither depression nor anxiety, as assessed by the HAD, was more common in patients with PSC compared with the general population. Because the scale scores of HAD are not affected by bodily illness, 3 our findings imply that poorer HRQL in our PSC patients could be related to increased psychological distress, possibly in part because of awareness of the PSC diagnosis, and not clinically significant depression or anxiety. In our cohort, 2% of PSC patients had been diagnosed with clinical depression, which is similar to the proportion of patients with PSC diagnosed with depression in a previous study by means of a structured psychiatric interview (1 of 37 patients, 2.7%). 27 In the latter report, the prevalence of depression in the liver disease cohort was not significantly different from that in the general population. Nevertheless, no prospective psychiatric evaluation was performed within the protocol of our study, and thus, we cannot fully exclude the potential influence of undiagnosed psychiatric disease on HRQL in our patients. Fatigue was not found to be more common in patients with PSC compared with the general population. Although fatigue is generally considered to be a troublesome symptom in cholestatic liver disease, previous studies have focused mainly on PBC. 8 10,18 Our findings are in agreement with those of a previous study performed on PSC patients recruited from 2 tertiary centers, which showed that fatigue is not a specific symptom of PSC. 7 It is noteworthy to mention, however, that 11% of patients had significant fatigue, as assessed by the CLDQ, and that this symptom was found to be an independent predictor of reduced HRQL in our cohort. Thus, it is conceivable that fatigue could be an important symptom only in a certain subgroup of patients with PSC. Further studies are clearly warranted to fully elucidate the potential role of fatigue in these patients. The strength of the current study is its design, ie, that it comprises a large, well-defined patient sample from 2 different countries, and that HRQL was assessed systematically with validated instruments. However, certain potential limitations should also be considered when interpreting our findings. Although the study design was prospective regarding HRQL data collection, clinical data were obtained retrospectively after scrutinizing medical records. Previous studies have reported impaired quality of life among patients with IBD. 28,29 In the present cohort, 79% of PSC patients had concomitant IBD, and no statistically significant differences on SF-36 scores were observed between patients with and those without associated IBD. This is in line with a previous report in which no significant differences were found in general well-being or fatigue between patients with PSC and controls with IBD alone. 7 However, because no control group of patients with IBD but not PSC was included in our study, we cannot fully exclude the possibility that IBD might have confounded our results. In conclusion, HRQL is impaired in PSC patients compared with the general population. Fatigue does not seem to be a specific symptom of PSC. Physical HRQL was associated with older age and systemic symptoms, whereas mental HRQL was associated mainly with large-duct disease and serum alkaline phosphatase. Neither liver disease severity nor coexisting IBD seems to be of major importance for HRQL in unselected predominantly noncirrhotic PSC patients. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at /j.cgh References 1. 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: Afendy A, Kallman JB, Stepanova M, et al. Predictors of healthrelated quality of life in patients with chronic liver disease. Aliment Pharmacol Ther 2009;30: Häuser W, Holtmann G, Grandt D. Determinants of health-related quality of life in patients with chronic liver diseases. Clin Gastroenterol Hepatol 2004;2: Gross CR, Malinchoc M, Kim WR, et al. Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology 1999;29: Marchesini G, Bianchi G, Amodio P, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120: Younossi ZM, Kiwi ML, Boparai N, et al. Cholestatic liver diseases and health-related quality of life. Am J Gastroenterol 2000; 95: Björnsson E, Simren M, Olsson R, et al. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol 2004;39: Goldblatt J, Taylor PJ, Lipman T, et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 2002;122: Huet PM, Deslauriers J, Tran A, et al. Impact of fatigue on the quality of life of patients with primary biliary cirrhosis. Am J Gastroenterol 2000;95: Cauch-Dudek K, Abbey S, Stewart DE, et al. Fatigue in primary biliary cirrhosis. Gut 1998;43: Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I conceptual framework and item selection. Med Care 1992;30: Sullivan MKJ, Taft C, Ware JE, et al. Health survey: Swedish manual and interpretation guide. 2nd ed. Gothenburg, Sweden: Sahlgrenska University Hospital, Kanwal F, Hays RD, Kilbourne AM, et al. 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7 July 2012 QUALITY OF LIFE IN PSC 775 life in patients with end-stage liver disease? Am J Gastroenterol 2004;99: 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: Younossi ZM, Boparai N, McCormick M, et al. Assessment of utilities and health-related quality of life in patients with chronic liver disease. Am J Gastroenterol 2001;96: Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis 1994;18(Suppl 1):S79 S Prince MI, James OF, Holland NP, et al. Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use. J Hepatol 2000;32: Björnsson E, Simren M, Olsson R, et al. Fatigue is not a specific symptom in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2005;17: Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67: Lisspers J, Nygren A, Söderman E. Hospital anxiety and depression scale (HAD): some psychometric data for a Swedish sample. Acta Psychiatr Scand 1997;96: Wyrwich KW, Nienaber NA, Tierney WM, et al. Linking clinical relevance and statistical significance in evaluating intra-individual changes in health-related quality of life. Med Care 1999;37: Ferguson RJ, Robinson AB, Splaine M. Use of the reliable change index to evaluate clinical significance in SF-36 outcomes. Qual Life Res 2002;11: Björnsson E, Boberg KM, Cullen S, et al. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut 2002;51: Swain MG, Maric M. Defective corticotropin-releasing hormone mediated neuroendocrine and behavioral responses in cholestatic rats: implications for cholestatic liver disease-related sickness behaviors. Hepatology 1995;22: Zietz B, Lock G, Plach B, et al. Dysfunction of the hypothalamicpituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatol 2003;15: van Os E, van den Broek WW, Mulder PG, et al. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2007;46: Bryant RV, van Langenberg DR, Holtmann GJ, et al. Functional gastrointestinal disorders in inflammatory bowel disease: impact on quality of life and psychological status. J Gastroenterol Hepatol 2011;26: Simrén M, Axelsson J, Gillberg R, et al. Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors. Am J Gastroenterol 2002;97: Reprint requests Address requests for reprints to: Evangelos Kalaitzakis, MD, PhD, Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Magtarmlab, Vita stråket 12, Sahlgrenska University Hospital, Gothenburg, Sweden. kalvag@hotmail.com; fax: Conflicts of interest The authors disclose no conflicts. Funding Supported by a grant from the medical research council of Västra Götaland in Sweden (ALF-22101).

8 July 2012 QUALITY OF LIFE IN PSC 775.e1 Supplementary Table 1. General Characteristics of English and Swedish PSC Patients Who Had Not Received a Transplant English cohort (n 33) Swedish cohort (n 127) P value Age (y) 56 (17) 48 (15).02 Gender (M/F) 20/13 (60%/39%) 92/34 (73%/27%).17 Small-duct disease 5 (15%) 12 (10%).44 Liver cirrhosis 1 (3%) 11 (9%).25 Decompensated liver disease 2 (6%) 7 (6%).62 Mayo Risk Score 0.43 (0.7) 0.35 (1).62 Follow-up (y) 11 (6) 7 (6).01 Comorbid illness a 32 (97%) 114 (93%).30 Charlson index b 1 6 (18%) 12 (9%) (15%) 4 (3%) 3 1 (3%) 1 (1%) IBD c 28 (87%) 99 (80%).36 Medications d 22 (67%) 94 (74%).39 Ursodeoxycholic acid 15 (45%) 47 (37%).42 treatment Living with a spouse or partner 28 (85%) 91 (79%) Years of school 7 (21%) 19 (16%).34 education Working or studying 25 (76%) 83 (71%).63 NOTE. Data are presented as mean (SD) or n (%) as appropriate. a Patients who had other types of disease apart from PSC (arterial hypertension 45% vs 24%, cardiovascular 6% vs 1%, endocrinological other than diabetes mellitus 6% vs 4%, diabetes mellitus 3% vs 7%, celiac disease 1% vs 11%, autoimmune hepatitis 0 vs 11%, depression 3% vs 2%, pulmonary disease 12% vs 10%, others 18% vs 26% for the English and Swedish cohorts, respectively). b Higher Charlson index indicates more severe comorbid illness. c Ulcerative colitis 54% vs 74%, Crohn colitis 30% vs 10%, indeterminate colitis 0 vs 2.5% for the English and Swedish cohorts, respectively. d Other than ursodeoxycholic acid. Supplementary Figure 1. HRQL in English vs Swedish patients with PSC who had not received a transplant, as assessed by SF-36 (mean, 95% confidence intervals). *P.05.

9 775.e2 BENITO DE VALLE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 7 Supplementary Figure 2. HRQL in transplanted PSC patients vs controls, as assessed by SF-36 (mean, 95% confidence intervals). *P.05.