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Biopsychosocial Predictors of Health-Related Quality of Life in Patients With Chronic Hepatitis C Winfried Häuser, MD, Christoph Zimmer, Peter Schiedermaier, MD and Daniel Grandt, MD http://www.psychosomaticmedicine.org/cgi/content/full/66/6/954 From the Department of Internal Medicine I, Klinikum Saarbrücken gGmbH, Saarbrücken, Germany. Address correspondence and reprint requests to Winfried Häuser, MD, Department of Internal Medicine I, Klinikum Saarbrücken gGmbH, Winterberg 1,D-66119 Saarbruecken, Germany. E-mail: whaeuser@klinikum-saarbruecken.de ABSTRACT   OBJECTIVES: To assess biopsychosocial predictors of health-related quality of life (HRQOL) in patients with chronic hepatitis C. METHODS: In 94 consecutive patients with chronic hepatitis C attending a liver center, HRQOL was assessed by the Medical Outcome Study Short Form Health Survey 36 (SF-36) and by the German version of the Chronic Liver Disease Questionnaire. The predictive effect on HRQOL of disease-related worries measured by the worry subscale of the Chronic Liver Disease Questionnaire, psychiatric comorbidity (defined by at least one Hospital Anxiety and Depression Scale German Version Score 11), the Child-Pugh score in case of cirrhosis, interferon therapy, and active medical comorbidities was assessed by a multiple regression analysis. RESULTS: From 88 patients (age, 48.6 ± 14.6 years; 50% female), 62 (70%) had no cirrhosis, 15 (17%) Child A, 5 (6%) Child B, and 6 patients (7%) Child C cirrhosis. The mental summary score of SF-36 was predicted by the amount of disease-related worries (corrected R2 = 0.33; ß = 3.2; p < .001) and psychiatric comorbidity (corrected R2 = 0.42; ß = –9.0; p < .001), by the physical summary score of SF-36 by the amount of disease related worries (corrected R2 = 0.33; ß = 4.0; p < .001), and by the number of active medical comorbidities (corrected R2 = 0.39; ß = –2.0; p = .006). CONCLUSIONS: The HRQOL in chronic hepatitis C is not determined by the severity of the liver disease but by psychiatric and medical comorbidities and disease-related worries. Key Words: chronic hepatitis C, • health-related quality of life, • active medical comorbidity, • disease-related worries, • psychiatric comorbidity. Abbreviations: HRQOL = health-related quality of life;; IFN = interferon;; HCV = hepatitis C virus;; SF-36 = Medical Outcome Study Short Form Health Survey 36;; CLDQ-D = German version of the Chronic Liver Disease Questionnaire;; HADS-D = German version of the Hospital Anxiety and Depression. INTRODUCTION   With increasing emphasis on the patient as the focal point of health care, preservation of patient functioning and well-being is viewed as the principal goal of medical care and is best evaluated by the patient. As a consequence, measurement of patient-based assessment of health-related quality of life (HRQOL) has become an important focus of outcome research in somatic medicine. HRQOL measurement includes the assessment of somatic symptoms; psychological status; social interactions; physical, cognitive, and psychosocial functioning; and sense of well-being as influenced by the health status (1). HRQOL should be measured by generic and disease-specific instruments validated for a given disease (2). Quality-adjusted life years are applied for measures in cost-effectiveness analyses (3). Not only physicians and psychologists but also pharmaceutical companies are engaged in the development of HRQOL questionnaires, because the American Food and Drug Administration requires proof of HRQOL benefits for the license of a drug (4). In particular, diseases that are common in the general population and that have a potential effect on life expectancy and HRQOL are of interest for health care providers. Chronic hepatitis C, with an estimated prevalence of 1.6% in the United States and 1% in other countries of the Western world (5), has undergone extensive analysis regarding HRQOL and the cost-effectiveness of interferon (IFN)/ribavirin therapy (3,6). The clinical course of hepatitis C virus (HCV) is extremely variable, with 13% to 46% of infected men and 1% to 29% of infected women—depending on hepatitis C virus genotype and lifestyle variables such as alcohol and tobacco consumption—developing cirrhosis of the liver over a 30-year period. The incremental cost-effectiveness of a combination therapy with pegylated IFN/ribavirin for men (women) ranged from US$26,000 (US$32,000) to US$64,000 (US$90,000) per quality-adjusted life year for HCV genotype 1. To date, the benefits of chronic HCV infection treatment have been realized largely in the form of improvements of HRQOL rather than prolonged survival (3,5). Although recent treatment options for chronic HCV infection on average appear to be reasonably cost-effective, the results vary widely across different patient subgroups and depend critically on HRQOL assumptions and the methods of its measurement. Thus, the German Hepatitis C Model Group and the International Hepatitis Interventional Group based their cost-effectiveness analysis of peginterferon -2b plus ribavirin versus IFN -2b plus ribavirin for initial treatment of chronic hepatitis C (6) on HRQOL data of a German single center, which, up to now, had been published only in abstract form (7). HRQOL was measured by a transformed visual analogue scale, the EuroQol (8), and physician-based estimates. The basic assumption was that HRQOL decreases with the severity of the liver disease (mild and moderate chronic hepatitis C, compensated and decompensated liver cirrhosis; 6). The studies of the German Hepatitis C Model Group and International Hepatitis Interventional Group were sponsored by pharmaceutical companies that produce and sell IFN. However, other fully published studies on HRQOL found no correlations between HRQOL, especially fatigue, and the degree of hepatitis (9–11). Rather, HRQOL was influenced by psychiatric comorbidities (9,11–14), active medical comorbidities (13,14), and illness understanding (12) or disease-related worries (15), such as stigmatization (15,16). Moreover, in some studies, HRQOL in chronic hepatitis C was negatively influenced by higher age, female sex (9), and IFN therapy (17). Therefore, the aim of our study was to assess the relative predictive effect on HRQOL of the severity of the liver disease, IFN treatment, comorbid somatic and psychiatric diseases, disease-related worries, and sociodemographic variables (age and sex) in patients with chronic hepatitis C. We hypothesized that within a biopsychosocial model of HRQOL in chronic gastrointestinal diseases (18), the somatic domains of HRQOL in chronic hepatitis C are determined by somatic variables such as the severity of the disease, active medical comorbidities, IFN therapy, and age, and that the psychosocial domains of HRQOL are determined by psychiatric comorbidity, disease-related worries, and female gender. METHODS   Patients Consecutive adult patients with the diagnosis of a chronic HCV hepatitis, confirmed by laboratory tests and by liver histology, attending a referral center for patients with liver diseases were enrolled in the study. Enrollment started in August 2002 and ended in August 2003. Non–German-speaking patients, patients after liver transplantation, patients with dementia or psychosis, and patients with refractory encephalopathy (grade II and more) preventing the correct filling in of the questionnaires were excluded. Patients with active gastrointestinal bleeding, bacterial infection, or other acute complications of the liver disease were included after successful treatment of the intervening complication. Data were recorded from medical records, including current therapy and complications, routine biochemistry testing such as the Child-Pugh score (19), and current medication for comorbid medical and psychiatric illness. Active somatic comorbidity was defined as current disease requiring pharmacological therapy based on physicians’ notes and medication lists (14). Ascites was diagnosed by ultrasound. Encephalopathy was assessed clinically and graded on a scale from 1 to 4 (where 1 indicates hypersomnia; 2, somnolence; 3, severe somnolence or stupor; and 4, severe stupor or coma; 20). All patients gave their informed written consent after receiving a detailed explanation of the purposes of the study (assessment of the HRQOL in patients with chronic hepatitis C and its determinants). The study was performed within routine medical care and outside a therapy study. The study was approved by the ethics committee of the board of physicians of the Saarland. Questionnaires The Sociodemographic Questionnaire of the German Competence Network Bowel Diseases (21) includes standard demographic questions to assess gender, marital status, age, religion, lifestyle variables (regular cigarette smoking, regular intake of alcohol, regular sports), and present working status. The Medical Outcome Study Short-Form 36 (SF-36; 22) is a reliable and valid instrument to measure all domains of the health status. It measures four domains in the area of physical health (physical functioning, role limitation—physical, bodily pain, and general health) and four domains in the area of mental health (role limitation—emotional, vitality, mental health, and social functioning). Two comprehensive indexes of HRQOL can also be computed (physical component summary and mental component summary). Data from representative population samples of different countries and from different groups of physical diseases and psychic disorders are available (22,23). The SF-36 is regarded as the most appropriate generic instrument for HRQOL measurement in chronic liver diseases (24). The Chronic Liver Disease Questionnaire (CLDQ; 25) is designed to assess all relevant domains of HRQOL in patients with chronic liver disease and has recently been validated for German-speaking patients CLDQ-D (26). With 29 items on a 7-point Likert scale ranging from 1 (all of the time) to 7 (none of the time), six subscale scores (abdominal symptoms, fatigue, systemic symptoms, activity, emotional functioning, worry) and a CLDQ overall score can be calculated. CLDQ data from US-American and German samples with mixed liver diseases proving a good reliability and validity are available (25,26). The CLDQ is the only disease-specific HRQOL instrument that has been validated for all etiologies and degrees of severity of liver diseases (2). The Hospital Anxiety and Depression Scale (HADS) was specifically designed for the assessment of anxiety and depression in patients with physical illness (27). The HADS is a reliable and valid psychological measure for the screening of anxiety and depression in physically ill people and is validated for German-speaking patients (28). With seven items each on a 4-point Likert scale ranging from 0 (not present) to 3 (always present), a subscale score for the two subscales, anxiety and depression, can be calculated. Because the HADS does not include somatic items of depression such as loss of appetite or fatigue, which may also be caused by the somatic disease, it is regarded as the most appropriate screening instrument for mental disorders in somatic medicine (28). Those scoring 11 on either subscale have a symptom severity of depression or anxiety indicative of a probable psychological disorder (27). Normative data of the German version HADS-D from a general German population and from large international medically ill populations are available (27–29). Methods Patients were asked to complete the questionnaires on regular outpatient visits or during a hospital stay after admission for any acute complications of the liver disease or for liver biopsy. The treating physicians were trained to give instructions when needed, to collect the questionnaires, and to record clinical data using standardized forms. Statistical Analysis All data were analyzed using Winstat for Excel (Version 2001.1; R. Fitch Software, Staufen, Germany). All but one missing item of the CLDQ-D, HADS-D, and SF-36 were replaced by the median of the items of the respective subscale. If more than one item of a subscale was unanswered, the respective questionnaire was excluded from further analyses. Data derived from descriptive statistical analysis are presented in the form of percentages for category variables and of the mean and 1 SD for continuous data. HRQOL was measured by the physical and mental summary score of the SF-36 and the subscale scores of the CLDQ-D with the exception of the worries subscale. Stepwise multiple regression analyses were performed to identify independent variables that predict on HRQOL, measured by the summary scales of the SF-36 and the subscale scores of the CLDQ-D, with the exception of the worries subscale. The following seven variables were entered into regression analysis to test the hypothesis based on the literature: Medical variables of the liver disease: severity of liver disease (no cirrhosis, cirrhosis Child-Pugh A, B, and C), specific therapy of liver disease by IFN Number of active current medical comorbidities Psychiatric comorbidity: a probable psychiatric disorder was assumed if the patient scored 11 in at least one subscale of the HADS-D (27). Because hepatologists tend to underestimate psychiatric symptoms (30), we renounced the definition of active psychiatric comorbidity by corroborating HADS-D scores and actual psychotropic therapy Sociodemographic and lifestyle variables: age and sex The significance limit to enter and leave the multiple regression steps was set at p = .007 (the significance level of p = .05 was divided by the number of independent variables entered into multiple regression) to avoid inflated type 1 error caused by multiple testing. RESULTS   One hundred twenty consecutive patients were recorded. Ten patients were unable to participate because of their inability to understand German or because of end-stage complications of the liver disease. Sixteen patients refused to take part in the study. Ninety-four patients agreed to participate in the study and completed questionnaires. Eighty-eight complete data sets were available for analysis (response rate, 80%). There was no difference in terms of gender, age, and severity of the liver disease in patients who agreed and did not agree to participate in the study. Fifty-four (61%) of the patients were investigated within the inpatient setting. Forty-four (50%) of the patients were female. Mean age was 48.6 ± 14.6 years. Twenty-six (29.5%) of the patients were single, and 62 (70.5%) were living with a family or partner. The current working status was as follows: 35 (39.8%) in work, 18 (20.7%) unemployed, 16 (18.4%) house wife or house man, and 19 (21.8%) in retirement. Forty-six (52.3%) of the patients were regular smokers, and 22 (25.0%) had 2 alcoholic drinks/day. The medical data of the study group are listed in Table 1. TABLE 1. Medical Data of the Study Population Variable     Severity of the liver disease (%)       No cirrhosis 62 (70.4)     Child-Pugh A 15 (17.0)     Child-Pugh B 5 (5.7)     Child-Pugh C 6 (6.8) Current complications (%)       Gastrointestinal bleeding 5 (5.7)     Hepatic encephalopathy >2 6 (6.8)     Hepatocellular carcinoma 4 (4.5) Specific pharmacological therapy of liver disease (%)       Diuretics 12 (13.6)     ß-Blocker 10 (11.4)     Interferon 21 (23.9) Active medical comorbidity (%)       None 27 (30.7)     One 10 (11.4)     Two 25 (28.4)     More than two 26 (29.5) Psychiatric comorbidity (%)       Hospital Anxiety and Depression 11, either depression or anxiety 35 (39.8)     Current psychotropic therapy 19 (21.6)   TABLE 1. Medical Data of the Study Population     Patients with chronic hepatitis C reported a poor HRQOL, with a mean physical summary score of 40.94 ± 12.06 and a mean mental summary score of 43.21 ± 11.98 compared with data of representative samples of the German populations generated by the German version of the SF-36 (11). Thirty-five of 88 patients (39.8%) scored 11 on either the depression or the anxiety subscale, indicating a possible psychiatric disorder. The percentage of patients with chronic hepatitis C with a probable psychiatric disorder because of a score 11 in at least one HADS-D subscale was significantly higher than in the German general population (17.4%). Table 2 shows the results of the stepwise multiple regression analyses when each of the summary scores of the SF-36 were used as the dependent variable. Each row indicates the variables selected that best predict the SF-36 summary score. TABLE 2. Multiple Regression of Biopsychosocial Predictors on Health-Related Quality of Life (Measured by the Summary Scores of the Medical Outcome Study Short Form Health Survey 36 [SF-36]) Criterion   Step   Predictor   ß   Adjusted R2   F Step   df   F Total   p   Physical 1 Worry 4.0 33.2 5.2 80 25.4 <.0001 summary score,   CLDQ-D             SF- 36 2 Number active medical comorbidities –2.0 38.8 –0.7 5   .006   / Severity liver disease 0.2     3   .9   / Age –0.1     81   .2   / Psychiatric comorbidity –6.8     1   .01   / Sex 4.0     1   .06   / IFN –1.3     1   .7 Mental 1 Worry 3.2 33.2 3.8 80 29.2 .0004 summary score,   CLDQ-D             SF-36 2 Psychiatric –9.0 42.3 –3.6 1   .0005     Comorbidity               / Number active medical comor-bidities –0.2     5   .8   / Severity liver disease 0.8     3   .6   / Age 0.2     81   .05   / Sex 0.9     1   .6   / IFN –2.6     1   .3   CLDQ-D = German version of the Chronic Liver Disease Questionnaire; IFN = interferon.         Thirty-nine percent of the variance of the physical summary score of the SF-36 could be explained by disease-related worries and number of active comorbid medical diseases. The severity of the liver disease and its therapy by IFN did not contribute significantly to the physical summary score. Forty-two percent of the mental summary score of the SF-36 could be predicted by psychiatric comorbidity and disease-related worries. The severity of the liver disease, IFN therapy, and the number of active medical comorbidities did not contribute significantly to the mental summary score of the SF-36. Age and sex did not contribute to either summary score of the SF-36. Table 3 shows the results of the stepwise multiple regression analyses when each of the subscale scores of the CLDQ-D (with the exception of the worry subscale worry) were used as the dependent variable. Each row indicates the variables selected that best predict the CLDQ subscale scores. TABLE 3. Multiple Regression of Biopsychosocial Predictors on Health-Related Quality of Life (Measured by the Subscale Scores of the German Version of the Chronic Liver Disease Questionnaire With the Exception of the Worries Subscale) Criterion   Step   Predictor   ß   Adjusted R2   F Step   df   F Total   p   Abdominal 1 Psychiatric comorbidity –1.2 30.6 –3.9 1 27.9 .0002 symptoms 2 Worries 0.3 38.2 3.4 80   .001 Systemic symptoms 1 Worries 0.5 26.8 5.7 80 32.8 <.0001 Fatigue 1 Worries 0.5 30.4 4.1 80 23.6 <.0001   2 Psychiatric comorbidity –1.3 39.1 –3.6 1   .0005   3 Interferon –1.0 43.8 –2.9 1   .005 Activity 1 Worries 0.3 31.6 3.2 80 25.1 .002   2 Psychiatric comorbidity –1.1 38.4 –3.6 1   .0006   3 Number active medical comorbidities 0.3 45.3 –3.4 5   .0001 Emotional function 1 Worries 0.5 49.3 6.2 80   <.0001   2 Psychiatric comorbidity –1.3 61.9 –5.4 1   <.0001       All subscale scores, even the somatic ones (abdominal symptoms, systemic symptoms) were significantly predicted by disease-related worries. With the exception of the subscale systemic symptoms, psychiatric comorbidity had an additional independent predictive value. The number of active medical comorbidities and IFN therapy, respectively, had a small significant additional predictive impact on one subscale of the CLDQ-D (fatigue and activity, respectively). The severity of the liver disease, age, and sex did not contribute significantly to the CLDQ-D subscale scores. DISCUSSION   This is the first study with simultaneous assessment of biopsychosocial predictors of HRQOL in patients with chronic hepatitis C measured by a generic and a disease-specific instrument. The reduced overall HRQOL in patients with chronic hepatitis C could be best predicted by disease-related worries and psychiatric and active medical comorbidities, and not by the severity of the liver disease or sociodemographic factors such as age, both in generic and in disease-specific HRQOL measures. Our results are in accordance with other studies. In patients with chronic hepatitis C, other authors also found no influence of the (histological) severity of the liver disease on HRQOL measured by the SF-36 augmented by a hepatitis C-specific module (9–11). Another study failed to demonstrate any significant differences in HRQOL and the frequency of the clinical diagnosis of anxiety or depression between women with an iatrogenic HCV infection and women with a self-limiting HCV infection (31). A meta-analysis of HRQOL studies recently showed that mental health has a much greater effect on HRQOL than physical functioning. The mental health scores of generic HRQOL measures in particular are influenced by depression (32). The outstanding influence of psychiatric comorbidity as an independent factor on the psychosocial and even somatic domains of HRQOL in chronic hepatitis C (14) is highlighted in our study. The psychosocial domains of HRQOL, measured by the SF-36 and CLDQ-D, were determined only by psychiatric comorbidity and disease-related worries. Even the variance of the somatic domains of both questionnaires could be explained more by psychiatric comorbidity and disease-related worries than by active medical comorbidities or IFN therapy. The high prevalence of a probable psychiatric disorder in 39.8% of our patients indicated by a score 11 in either subscale of the HADS-D agrees with the prevalence of previous studies using psychiatric interviews (33). The high prevalence of psychiatric comorbidity in patients with chronic hepatitis C can be explained by (former) substance disorders and associated psychiatric disorders (13,14,33). Partially independent from psychiatric comorbidity disease-related worries regarding potential lethal complications of the viral infection, the potential of sexual transmission of HCV virus to a patient’s partner and (the fear of) social stigmatization appear to have a negative effect on mental health (12,15). The importance of the mental coping with the diagnosis and the information provided by the medical system is highlighted by a study of Cordoba (34), who could demonstrate a decrease of HRQOL in asymptomatic blood donors after the diagnosis of a chronic hepatitis C. Comorbid somatic diseases and their medical treatment are other possible factors influencing HRQOL in chronic diseases. In an US-American sample of patients with chronic HCV infection, significant correlations were found between reduced HRQOL scores in the hepatitis C modified SF-36 and active medical comorbidities, defined as chronic medical conditions requiring treatment and monitoring, especially for painful medical comorbidities (14). Similar to the findings of Hussain et al. (14), we could demonstrate a negative impact of the number of medical comorbidities on some domains of the physical health. In accordance with Fontana et al. (13), we found no significant influence of sex and age on HRQOL. Some limitations of the present study must be considered. The patients were recruited from a tertiary referral center and may therefore not be representative of all patients with chronic HCV infection. In population-based studies, chronic liver patients report a better HRQOL than patients from a referral center (10). On the other hand, the study was conducted outside the context of a treatment trial. Therefore, the HRQOL data may be more representative for patients presenting for medical evaluation and therapy than data of patients in treatment trials with medical and psychiatric exclusion criteria. In noncirrhotic patients, we did not stratify according to the degree of inflammation or fibrosis because previous studies found no correlations between HRQOL measures and histological scores (9–11). Because the study took place in the context of routine medical care, we were unable to use standardized psychiatric interviews for the confirmation of a psychiatric diagnosis when the critical cutoff scores of the HADS-S were reached. However, a sensitivity and a specificity of the HADS-D of 75% (with a cutoff value >8) for the diagnosis of a mental disorder made by a structured interview according to the criteria of the DSM-III-R could be demonstrated in patients with chronic inflammatory bowel disease (35). We conclude that the assumptions of HRQOL measurement in cost-benefit analyses of pharmacological therapies of chronic hepatitis C (6) should be reconsidered with evidence from several studies that the reduced HRQOL of patients with chronic HCV is not determined by the severity of the disease itself but by psychiatric comorbidities and disease-related worries. We speculate that the positive effect on HRQOL after virus elimination by IFN/ribavirin (36) is also caused by psychological effects, eg, the elimination of worries of dying from an infectious disease or transmitting it to partners. Especially for patients with no or slight fibrosis or inflammation in liver histology, who have a low risk of developing cirrhosis (5), nonpharmacological therapies—probably with lower costs and lesser side effects than IFN therapy—should be evaluated to improve the reduced HRQOL in patients with chronic hepatitis C. 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