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Health-related quality of life in chronic liver disease: the impact of type and severity of disease
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 96, No. 7, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02519-9
Health-Related Quality of Life in Chronic Liver Disease: The Impact of Type and Severity of Disease Zobair M. Younossi, M.D., M.P.H., Navdeep Boparai, M.S., Lori Lyn Price, B.S., Michelle L. Kiwi, M.P.H., Marilyn McCormick, R.N., and Gordon Guyatt, M.D. The Cleveland Clinic Foundation, Cleveland, Ohio; Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia; and McMaster University, Hamilton, Ontario, Canada
OBJECTIVE: The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment. METHODS: In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patient’s HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study. RESULTS: In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Child’s class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36’s physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL. CONCLUSIONS: We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL. (Am J Gastroenterol 2001;96:2199 –2205. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION In the past 2 decades, an integrated approach to health care that combines traditional biomedical outcomes with psycho-
social outcomes has become increasingly important. The traditional biomedical model of health emphasizes the basic sciences (molecular biology, genetics, physiology, and biochemistry). In contrast, the “social science” model of health focuses on patients’ psychosocial health, overall well-being, and quality of life. Proponents of an integrated approach advocate assessing both biomedical and psychosocial outcomes of disease, an approach that requires measuring additional outcomes, such as those related to patients’ healthrelated quality of life (HRQL) (1– 4). In the United States, ⬎5 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV), and millions more suffer from a variety of other chronic hepatocellular and cholestatic liver diseases. Liver disease is the ninth leading cause of death in the United States and is responsible for billions of dollars in direct and indirect medical costs (5). Patients with chronic liver disease suffer from fatigue, loss of self-esteem, inability to function at work, anxiety, depression, and other emotional problems that profoundly decrease their quality of life and well-being (6). Furthermore, HCV infection, alcoholic liver disease, and other liver disorders have their highest prevalence in the third and fourth decades of life, a period considered to be the most productive for a large number of people (5–7). Despite the importance of HRQL for patients with chronic liver disease, few investigators have assessed quality of life and its determinants in these patients. We evaluated the impact of chronic liver disease on HRQL, looked for differences in HRQL by type and severity of disease, and tried to identify clinical or pathological variables with disproportionate effects on HRQL.
METHODS Patient Selection Between August, 1997, and February, 1999, all patients presented to the Cleveland Clinic Foundation with the diagnosis of chronic liver disease were approached for participation in the study. Patients with another chronic active
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medical (such as congestive heart failure, etc) or psychiatric condition, malignancy, a transplanted liver, and those unable to communicate in English or who declined to participate were excluded. Patients were also classified into three categories of chronic liver disease: viral disease, cholestatic liver disease, or hepatocellular disease. In addition to convenience and simplifying data analysis, patients included in these categories may have similar clinical issues. Each patient had an established diagnosis by a hepatologist. The category “viral hepatitis” included chronic HBV and HCV. The diagnosis of chronic HCV was based on a positive hepatitis C antibody (ELISA II analysis), elevated serum alanine aminotransferase levels, with or without HCV RNA as detected by polymerase chain reaction. The diagnosis of chronic HBV was based on the presence of hepatitis B surface antigen, elevated serum alanine aminotransferase levels, with or without HBV DNA as detected by the hybridization method. For both HBV and HCV, patients receiving interferon therapy in the previous 3 months were also excluded. The category “cholestatic liver disease” included primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The diagnosis of PBC was based on positive antimitochondrial antibody test results and elevated liver enzymes, with or without liver biopsy. The diagnosis of PSC was based on a typical cholangiogram and elevated liver enzymes, with or without liver biopsy. Patients with hepatocellular diseases included genetic hemochromatosis, alcoholic liver disease, nonalcoholic fatty liver disease, ␣-1-antitrypsin deficiency, Wilson’s disease, and cryptogenic cirrhosis. The Institutional Review Board of the Cleveland Clinic Foundation approved the study protocol, and all participants gave written informed consent. Data Collection During an office visit, each patient gave his or her informed consent and then completed two self-administered HRQL questionnaires: the Medical Outcomes Study Short Form 36 (SF-36) (8, 9), a widely used and validated generic HRQL questionnaire, and the Chronic Liver Disease Questionnaire (CLDQ), a validated liver disease-specific HRQL questionnaire (10 –12). Extensive demographic and clinical data were also collected at this time (see below). The SF-36 consists of 36 items divided into eight scales that can be aggregated into two summary scores, a mental component summary and a physical component summary. The eight scales are: 1) physical function (PF), 2) role physical (RP), 3) bodily pain (BP), 4) general health (GH), 5) vitality (VT), 6) social functioning (SF), 7) role emotion (RE), and 8) mental health (MH). Scores for these eight SF-36 scales range between 0 and 100, whereas the summary scores for the physical component range between 8 and 73 and those for the mental component range between 10 and 74 (8).
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The CLDQ is a liver disease-specific HRQL questionnaire that consists of 29 items divided into six domains: 1) abdominal symptoms (ABM), 2) activity (ACM), 3) emotional function (EMM), 4) fatigue (FAM), 5) systemic symptoms (SYM), and 6) worry (WOM). Summary scores for each domain range from 1 (most impairment) to 7 (least impairment). An overall CLDQ score ranging from 1 to 7 may also be calculated. The questionnaire has good testretest reliability and cross-sectional validity (10 –12). In both the SF-36 and the CLDQ, higher scores suggest less impairment of HRQL. We also collected laboratory data reflective of hepatic functional reserve (total bilirubin, serum albumin, and prothrombin time), as well as a hepatic panel that included aspartate and alanine aminotransferases, alkaline phosphatase, and ␥-glutamyl transferase (GGT). In patients with HCV, the level of viremia was measured as a continuous variable by the amount of HCV RNA, as determined by a polymerase chain reaction with a detection threshold of 1 ⫻ 103 copies/ml (Amplicore HCV Monitor, Roche Molecular Systems, Brachburg, NJ). In patients with HBV, the level of viremia was measured as a continuous variable by the amount of HBV DNA, as determined by the liquid hybridization method with a detection threshold of 5 pg/ml (ARUP Laboratories, Salt Lake City, UT). Measures of Disease Severity As one overall measure of disease severity, patients were classified as noncirrhotic, early cirrhotic (Child’s stage A), or advanced cirrhotic (Child’s stages B and C), using a modified Child’s-Pugh classification (13–15). The diagnosis of cirrhosis was established either histologically or clinically, from the signs of decompensated cirrhosis: ascites, variceal bleeding, and so on. For patients with chronic viral hepatitis, histological severity was determined using the modified histological activity index (16). Widely used in clinical research, this index provides a numerical score for both inflammatory and fibrosis components of liver histology in patients with chronic hepatitis. Each component score can be analyzed separately as a continuous variable. Higher inflammatory or fibrosis score suggests severe histological disease. Similarly, in patients with cholestatic liver diseases (PBC and PSC), we applied the histological criteria suggested by Ludwig et al. (17, 18) in classifying patients into one of four ordinal severity stages: stage 1, portal hepatitis; stage 2, periportal hepatitis; stage 3, bridging necrosis or fibrosis or both; and stage 4, cirrhosis. In addition to histological staging, in patients with PBC, we also defined severity of disease with the Mayo PBC risk scores. These scores come from a disease-specific prognostic model predicting 1–7-yr survival for patients with PBC. This model is based on bilirubin, age, albumin, prothrombin time, and the presence of edema (19). In patients with PBC, Mayo risk score and the total serum bilirubin value are measures of clinical severity and are routinely used to pre-
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Table 1. Clinical and Demographic Characteristics of 353 Patients With Chronic Liver Disease Completing the SF-36 and CLDQ, by Type of Disease Chronic Viral Hepatitis
Chronic Cholestatic
Hepatocellular Disease
Characteristic
(B and C) (n ⫽ 133)
Liver Disease*† (n ⫽ 126)
(n ⫽ 94)
p
Mean age ⫾ SD, yr Men, n (%) Child-Pugh class, n (%) No cirrhosis A B C Ludwig’s criteria, n (%) 1. Portal hepatitis 2. Periportal hepatitis 3. Bridging necrosis/fibrosis 4. Cirrhosis Mayo PBC scores, mean ⫾ SD Diagnosis, n (%) Chronic viral hepatitis HBV HCV Cholestatic liver disease PBC PSC Hepatocellular disease Alcoholic cirrhosis Cryptogenic cirrhosis Autoimmune hepatitis Nonalcoholic steatohepatitis ␣-1-antitrypsin def Genetic hemochromatosis Wilson’s disease
46 ⫾ 9 86 (64.7)
54 ⫾ 11 38 (30.2)
52 ⫾ 13 56 (59.6)
0.0001 0.001
77 (57.9) 24 (18.1) 23 (17.2) 9 (6.8)
47 (38.8) 43 (35.5) 27 (22.3) 4 (3.3)
3 (3.2) 33 (35.0) 33 (35.0) 25 (26.6)
0.001
4 (6.5) 5 (8.1) 30 (48.4) 23 (37.1) 5.6 ⫾ 1.8 9 (6.8) 124 (93.2) 81 (64.3) 45 (35.7) 41 (43.6) 27 (28.7) 12 (23.8) 6 (6.4) 3 (3.2) 2 (2.1) 1 (1.06)
* Primary biliary cirrhosis (n ⫽ 81) and primary sclerosing cholangitis (n ⫽ 45). † Histological data were available only for 62 patients.
dict survival and to make important treatment decisions, including the need for orthotopic liver transplantation (17– 19). Comparison Groups SF-36 scores are available for the U.S. general population and for patients with a variety of chronic conditions (8, 9). Thus, we also compared our SF-36 scores for patients with chronic liver disease with those of patients with two other slowly progressive, chronic conditions: chronic obstructive pulmonary disease and congestive heart failure. These two conditions were chosen because they are similar to chronic liver disease in that they have a major impact on physical and emotional function and can progress to end-stage disease. Patients’ CLDQ scores were compared with the scores of 61 healthy individuals recruited from the practices of two primary care physicians at The Cleveland Clinic Foundation. These individuals presented for their yearly physical examinations and had no specific complaints or illness requiring treatment. They completed the CLDQ questionnaire and provided the same demographic and clinical data (10 – 12).
Statistical Methods Continuous variables were summarized as mean ⫾ SD, and analysis for normal distributed data was done using Student’s t-test or analysis of variance. If a significant difference was noted by analysis of variance, a more restrictive ␣ level was computed with the Bonferroni method, and the p values of pair-wise differences were compared with the new ␣. Non-normal data were compared using Wilcoxon Rank sum test or the Kruskal Wallis test. Spearman’s rank-order correlation coefficient was used as a measure of association between variables. All tests done were two-tailed; p values ⬍0.05 were considered to be statistically significant unless otherwise noted. All analyses were performed with the SAS statistical software package (SAS, Cary, NC).
RESULTS Clinical and Demographic Characteristics of Respondents Of the 390 patients approached for the study, 353 (90%) completed both questionnaires (Table 1). Inability to provide informed consent was the main reason for the exclusion from the study. The viral group was mainly composed of patients with chronic HCV. They were significantly younger
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Table 2. HRQL Scores for Patients With Different Types of Chronic Liver Disease, Other Chronic Diseases, and for Normal Controls
Dimension SF-36* (mean ⫾ SD) PF RP BP GH VT SF RE MH Physical component summary* Mental component summary* CLDQ† (mean ⫾ SD) ABM FAM SYM ACM EMM WOM Overall score
Chronic Viral Hepatitis (B and C)
Cholestatic Liver Disease
Hepatocellular Disease
(n ⫽ 133)
(n ⫽ 126)
(n ⫽ 94)
66 ⫾ 32 52 ⫾ 45 62 ⫾ 27 50 ⫾ 26 44 ⫾ 26 66 ⫾ 30 64 ⫾ 44 68 ⫾ 20 41 ⫾ 13 46 ⫾ 12
65 ⫾ 31 48 ⫾ 46 62 ⫾ 28 46 ⫾ 23 43 ⫾ 28 68 ⫾ 31 62 ⫾ 43 68 ⫾ 21 39 ⫾ 12 46 ⫾ 12
43 ⫾ 30 22 ⫾ 35 52 ⫾ 28 35 ⫾ 25 34 ⫾ 25 52 ⫾ 34 41 ⫾ 45 63 ⫾ 22 31 ⫾ 11 42 ⫾ 12
5.1 ⫾ 1.8 3.9 ⫾ 1.7 4.9 ⫾ 1.5 4.8 ⫾ 1.9 4.7 ⫾ 1.3 4.5 ⫾ 1.7 4.5 ⫾ 1.5
4.9 ⫾ 1.7 4.0 ⫾ 1.8 4.9 ⫾ 1.4 4.9 ⫾ 1.7 4.7 ⫾ 1.3 4.7 ⫾ 1.6 4.6 ⫾ 1.4
4.2 ⫾ 1.9 3.1 ⫾ 1.5 4.4 ⫾ 1.4 3.9 ⫾ 1.6 4.2 ⫾ 1.4 3.9 ⫾ 1.7 3.8 ⫾ 1.4
Normal Controls
Congestive Heart Failure
Chronic Obstructive Pulmonary Disease
“Normal” Population
(n ⫽ 61)
(n ⫽ 216)
(n ⫽ 85)
(n ⫽ 2474)
48 ⫾ 31 34 ⫾ 40 63 ⫾ 31 47 ⫾ 24 44 ⫾ 24 71 ⫾ 33 64 ⫾ 43 75 ⫾ 21 35 ⫾ 12 50 ⫾ 11
57 ⫾ 29 34 ⫾ 39 55 ⫾ 26 45 ⫾ 19 45 ⫾ 20 72 ⫾ 31 60 ⫾ 45 68 ⫾ 20 36 ⫾ 10 48 ⫾ 11
84 ⫾ 23 81 ⫾ 34 75 ⫾ 24 72 ⫾ 20 61 ⫾ 21 83 ⫾ 23 81 ⫾ 33 75 ⫾ 18 50 ⫾ 10 50 ⫾ 10
6.2 ⫾ 1.2 5.4 ⫾ 1.3 6.2 ⫾ 0.9 6.1 ⫾ 1.3 5.7 ⫾ 1.0 6.6 ⫾ 0.8 5.9 ⫾ 1.1
* Scale scores for SF-36 range between 0 and 100; summary scores range between 8 and 73 for PCS and between 10 and 74 for MCS. † CLDQ scores for each domain range from 1 (most impairment) to 7 (least impairment). The overall CLDQ score also ranges from 1 to 7.
with more men and less severe disease than the other groups. The cholestatic group included a larger proportion of older people and a greater proportion of women. In our study, 221 patients had cirrhosis with 101 (46%) having histologically proven cirrhosis and others with clinical cirrhosis (ascites, etc). Of those with biopsy-proven cirrhosis, time of biopsy to questionnaire administration was 2.65 ⫾ 3.92 yr. Almost all the patients in the hepatocellular group had cirrhosis, most either Child’s class B or C. Quality of Life in Patients With Viral Hepatitis Compared with U.S. general population and healthy controls, patients with viral hepatitis had more impairment of HRQL as measured by both SF-36 and CLDQ (Table 2). For all domains of SF-36 and CLDQ, the HRQL declined significantly with worsening of disease severity from noncirrhosis to advanced cirrhosis. In patients with viral hepatitis, level of viremia, route of transmission, level of aminotransferases, and other clinicodemographic data (except for age and gender) were not associated with HRQL impairment. Analyzing HBV and HCV separately, we found that the HAI inflammatory scores of patients with HCV were moderately but significantly correlated with the CLDQ’s emotional function domain (r ⫽ ⫺0.50, p ⫽ 0.01) and systemic function domain (r ⫽ ⫺0.43, p ⫽ 0.02). Additionally, in patients with HCV, advanced fibrosis (stage 3 and 4) had significantly lower HRQL scores than did in those with early fibrosis (stage 1 and 2).
Quality of Life in Patients With Cholestatic Liver Disease Patients with cholestatic liver disease or its individual types (PBC, PSC) had significantly lower HRQL than the general population and healthy controls as measured by both the SF-36 and the CLDQ (Table 2). For all domains of SF-36, the HRQL scores significantly declined from early to advanced to cirrhosis. Similarly, all CLDQ domain scores, as well as the overall CLDQ score, gradually declined with disease severity (CLDQ median overall score: no cirrhosis 5.4, early cirrhosis 5.5, and advanced cirrhosis 3.33, p ⬍ 0.001). In patients with cholestatic liver disease, fatigue measured by the CLDQ worsened with disease severity (CLDQ median fatigue score: no cirrhosis 5.0, early cirrhosis 4.8, advanced cirrhosis 2.3, p ⬍ 0.001). We found no significant difference in the SF-36 domains with worsening of histological stage. However, CLDQ systemic function, activity and overall CLDQ domain scores were significantly lower in more advanced stages (3, 4) as compared with less severe stages (1, 2) (p ⫽ 0.02, 0.01, and 0.01, respectively). Analyzing PBC and PSC separately, we found strong inverse relationships between patients’ PBC Mayo risk scores with their overall CLDQ scores (⫺0.61, p ⬍ 0.001) as well as with their SF-36 physical component summary scores (⫺0.60, p ⬍ 0.001). Additionally, in these patients, total bilirubin was inversely correlated with overall CLDQ scores (⫺0.54, p ⬍ 0.001) and SF-36 physical component (r ⫽ ⫺0.48, p ⬍ 0.001). We found no correlations between
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Table 3. HRQL Scores for Patients With and Without Cirrhosis and by Sex Cirrhosis Test Score SF-36* (mean ⫾ SD) PF RP BP GH VT SF RE MH Physical component summary Mental component summary CLDQ† (mean ⫾ SD) ABM FAM SYM ACM EMM WOM Overall score
Sex
Present
Absent
p
Men
Women
p
50 ⫾ 31 32 ⫾ 41 54 ⫾ 28 37 ⫾ 22 35 ⫾ 25 58 ⫾ 33 51 ⫾ 45 65 ⫾ 21 34 ⫾ 11 44 ⫾ 12
76 ⫾ 27 63 ⫾ 44 68 ⫾ 26 58 ⫾ 24 51 ⫾ 26 72 ⫾ 28 69 ⫾ 42 70 ⫾ 20 45 ⫾ 12 46 ⫾ 12
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.03 ⬍0.001 0.05
62 ⫾ 32 44 ⫾ 45 61 ⫾ 27 46 ⫾ 25 43 ⫾ 27 63 ⫾ 32 62 ⫾ 44 68 ⫾ 20 39 ⫾ 13 45 ⫾ 12
57 ⫾ 32 41 ⫾ 45 57 ⫾ 29 43 ⫾ 24 39 ⫾ 26 62 ⫾ 32 53 ⫾ 45 66 ⫾ 22 37 ⫾ 13 44 ⫾ 12
0.13 0.49 0.17 0.23 0.10 0.67 0.09 0.32 0.42 0.22
4.4 ⫾ 1.8 3.3 ⫾ 1.6 4.4 ⫾ 1.4 4.1 ⫾ 1.7 4.4 ⫾ 1.3 4.11 ⫾ 1.7 4.0 ⫾ 1.4
5.5 ⫾ 1.6 4.4 ⫾ 1.7 5.3 ⫾ 1.3 5.4 ⫾ 1.6 4.9 ⫾ 1.3 5.0 ⫾ 1.6 5.0 ⫾ 1.3
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
4.9 ⫾ 1.8 3.8 ⫾ 1.7 4.9 ⫾ 1.4 4.6 ⫾ 1.8 4.6 ⫾ 1.4 4.4 ⫾ 1.7 4.4 ⫾ 1.5
4.6 ⫾ 1.8 3.7 ⫾ 1.7 4.6 ⫾ 1.4 4.6 ⫾ 1.8 4.5 ⫾ 1.3 4.4 ⫾ 1.7 4.3 ⫾ 1.4
0.13 0.46 0.10 0.99 0.28 0.80 0.70
* Scale scores for SF-36 range between 0 and 100; summary scores range between 8 and 73 for PCS and between 10 and 74 for MCS. † CLDQ scores for each domain range from 1 (most impairment) to 7 (least impairment). The overall CLDQ score also ranges from 1 to 7.
the SF-36 mental component summary scores and Mayo PBC risk scores or total bilirubin. Quality of Life in Patients With Hepatocellular Liver Disease Except for body pain, vitality, role emotion, mental health, and mental health component of SF-36 and systemic function, emotion and worry domains of CLDQ, all the other domains of SF-36 and CLDQ showed a significant decline (p ⬍ 0.05) in HRQL as disease severity advanced from no cirrhosis or early cirrhosis (Child’s A) to advanced cirrhosis (Child’s B and C). The Effect of Cirrhosis Almost all patients without cirrhosis had either viral or cholestatic disease (Table 1). In patients without cirrhosis, both CLDQ and SF-36 scores were generally similar between the different types of liver disease. Patients with cirrhosis had more HRQL impairment than those without cirrhosis (Table 3). In patients with cirrhosis, the cholestatic group had significantly less impairment in several HRQL dimensions (physical function, role function, general health, social function, role emotion, and physical component summary for SF-36 and fatigue in CLDQ), than did cirrhotic patients in the hepatocellular group (p ⬍ 0.01) for these domains. There was no difference in cirrhotic patients between the viral group and the cholestatic or hepatocellular groups. Quality of Life in Chronic Liver Disease Compared With That in Other Populations Regardless of the presence or absence of cirrhosis, quality of life was substantially lower in patients with chronic liver disease than in the healthy population, as measured both by
CLDQ and SF-36 summary scores (p ⬍ 0.001 for both physical and mental summary scores) (Table 2). Compared with patients with congestive heart failure or chronic obstructive pulmonary disease, patients with chronic liver disease had similar impairment in the physical aspects of HRQL but more impairment in mental health (p ⫽ 0.006). Effect of Gender and Age on Quality of Life We found that age was inversely but weakly correlated with physical component of SF-36 (r ⫽ ⫺0.2, p ⫽ 0.002) (Table 4). Patients in age group ⬍50 yr had significantly higher HRQL for the following SF-36 domains PF (p ⫽ 0.001), RP (p ⫽ 0.03), and PCS (p ⫽ 0.002), and CLDQ’s AC (p ⫽ 0.01) and overall CLDQ score (p ⫽ 0.05). Looking at the chronic viral hepatitis group alone, patients with age ⬍50 yr have better HRQL for the AC domain (p ⫽ 0.04). In the hepatocellular group, younger patients did better for the following domains: PF (p ⫽ 0.004), VT (p ⫽ 0.03), and PCS (p ⫽ 0.04). Overall CLDQ was also marginally significant with p ⫽ 0.07. Analyses for gender revealed that more women than men within the cholestatic disease group scored lower on the PF domain of SF-36 (60 ⫾ 31 vs 76 ⫾ 27, p ⫽ 0.01). No differences were found between men and women in the viral or the hepatocellular groups (Table 3).
DISCUSSION This study evaluates the impact of type and severity of liver disease on HRQL. We found that HRQL in patients with chronic liver disease is much lower than that of healthy people and that it is comparable with patients with chronic obstructive pulmonary disease and congestive heart failure. In comparing patients with different types of liver disease,
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Table 4. Correlations Between Demographic Characteristics, Laboratory Measures of Disease Severity, and HRQL Scores for Patients With Chronic Liver Disease SF-36
Variable Age HAI Aspartate aminotransferase Alanine aminotransferase Alkaline phosphatase Total bilirubin (overall) Prothrombin time HCV RNA Serum albumin Mayo (PBC only) Total bilirubin (PBC only)
CLDQ
Mental r p n
Physical r p n
Total Score r p n
0.04 0.51 329 ⫺0.22 0.18 39 ⫺0.13 0.10 165 0.15 0.02 245 ⫺0.05 0.46 204 ⫺0.13 0.03 272 ⫺0.16 0.01 232 0.07 0.69 38 0.20 ⬍0.001 271 0.28 0.11 33 ⫺0.18 0.16 64
⫺0.17 0.002 329 ⫺0.16 0.34 39 ⫺0.20 0.01 165 0.13 0.04 245 ⫺0.17 0.02 204 ⫺0.40 ⬍0.001 272 ⫺0.40 ⬍0.001 232 0.07 0.66 38 0.48 ⬍0.001 271 ⫺0.60 ⬍0.001 33 ⫺0.48 ⬍0.001 64
⫺0.06 0.25 323 ⫺0.33 0.05 36 ⫺0.24 0.002 159 0.12 0.08 238 ⫺0.14 0.06 196 ⫺0.36 ⬍0.001 260 ⫺0.33 ⬍0.001 225 0.13 0.44 39 0.43 ⬍0.001 286 ⫺0.61 ⬍0.001 33 ⫺0.54 ⬍0.001 64
we found that patients with early liver disease have a similar quality of life, regardless of the underlying cause of their liver disease. However, among patients with cirrhosis, those with cholestatic liver disease have less impairment in the physical aspects of HRQL than do patients with hepatocellular disease. As expected, chronic fatigue is prevalent in patients with chronic cholestatic liver disease and has an important impact on their HRQL. When liver disease becomes more severe, as indicated by a higher Child-Pugh class, a higher Mayo risk score, or a rising serum bilirubin level, HRQL also becomes more impaired. This relationship is most prominent in the diseasespecific and physical dimensions of SF-36 but not always for the mental health dimension of the SF-36. As histological severity worsened (reflected by higher histological stages on liver biopsies), some of the diseasespecific aspects of HRQL deteriorated. We observed this relationship in both chronic cholestatic and viral diseases. The only other clinical or demographic variables influ-
encing HRQL in patients with chronic liver disease was age. Although the correlations between age and HRQL scores were weak, these data are consistent with those reported in other studies (9). We found that a recently developed disease-specific HRQL instrument, the CLDQ, consistently and negatively correlated with all dimensions of disease severity (Mayo scores, total bilirubin, Child-Pugh class, and worsening histological features). These results likely reflect CLDQ’s usefulness in targeting disease-specific aspects of dysfunction in patients with chronic liver disease, and they highlight the impact of this progressive illness on patients’ experience. Consistent with previous studies of patients with chronic hepatitis C and those awaiting liver transplantation, our results show that HRQL of patients with chronic liver disease is more impaired than that of healthy population and becomes even worse with cirrhosis (20). Our study is unique in providing comparative data on HRQL of a relatively large number of patients with a variety of types of liver disease using both generic and disease-specific HRQL instruments. Our study has some limitations. All subjects were recruited from one tertiary health care center, potentially introducing problems with applicability of our results to patients seen in primary care centers. The cross-sectional design of our study does not allow us to describe how progression of disease relates to changes in HRQL. However, the fact that HRQL was substantially impaired in those with early liver disease suggests that the possible recruitment bias does not account for these findings. Additionally, progressive worsening of CLDQ scores with disease severity also suggests that the relationship between disease severity and HRQL should remain. We found that chronic liver diseases substantially reduce HRQL. Further, this impairment increases with disease severity. This association between HRQL impairment and cirrhosis was further supported by another recent publication (21, 22). The ability of the CLDQ to detect associations with disease severity and its applicability to all types and stages of liver disease suggest that it can be an additional, important outcome in natural history studies and in clinical trials designed to modify the course of chronic liver disease. Quality-of-life measures, such as the CLDQ and SF-36, can complement clinical outcomes, such as the Mayo risk score, Child-Pugh class, liver enzyme indicators, histological stage, and mortality rates, helping to integrate the biomedical and the psychosocial models of health. This integrated approach to the study of chronic liver disease will capture the total impact of these diseases on patients’ health and well-being.
ACKNOWLEDGMENTS This research was supported in part by a Junior Faculty Award from the American College of Gastroenterology and
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by a grant from The Cleveland Clinic Foundation’s I. H. Page Centre for Clinical Effectiveness. The authors gratefully acknowledge the help of medical writer Tom Lang, who facilitated the writing process of this manuscript. Z.M.Y. is also a senior researcher at the I. H. Page Centre for Clinical Effectiveness, Cleveland Clinic Foundation, Cleveland, Ohio. Reprint requests and correspondence: Zobair M. Younossi, M.D., M.P.H., Director, Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, 330 Gallows Road, Falls Church, VA 22042-3300. Received Nov. 13, 2000; accepted Feb. 7, 2001.
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health summary scales: A user’s manual. Boston, MA: The Health Institute, New England Medical Center, 1994. Younossi Z, Guyatt G, Kiwi M, et al. Development of a disease-specific health-related quality of life index for chronic liver disease. Gut 1999;44:1– 6. Younossi ZM, Kiwi M, Boparai N, Guyatt G. An in depth assessment of quality of life in chronic cholestatic liver disorders. Am J Gastroenterol 2000;95:497–502. 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;96:579 – 83. Child CG III, Turcotte JG. Surgery and portal hypertension. In: Child CG III, ed. The liver and portal hypertension. Philadelphia, PA: Saunders, 1964:49 –50. Turcotte JG, Lambert MJ III. Variceal hemorrhage, hepatic cirrhosis, and portacaval shunts. Surgery 1973;73:810 –7. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Trans oesophagus varices. Br J Surg 1973;60:646 –9. Knodell R, Ishak K, Black W, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–5. Kaplan MM. Primary biliary cirrhosis. N Engl J Med 1996; 335:1570 – 80. Ludwig J, Dickson E, McDonald G. Staging of chronic nonsuppurative cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch (A) 1978;379:103–12. Dickson ER, Grambsch PM, Fleming TR, et al. Prognosis in primary biliary cirrhosis: Model for decision making. Hepatology 1989;10:1–7. Younossi Z. Economic and quality of life outcomes in viral hepatitis. Viral Hepatitis Rev 1999;5:220 –30. Marchesini G. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170 – 8. Younossi Z. Chronic liver disease and health-related quality of life. Gastroenterology 2001;120:305–7.
Vol. 96, No. 7, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02519-9
Health-Related Quality of Life in Chronic Liver Disease: The Impact of Type and Severity of Disease Zobair M. Younossi, M.D., M.P.H., Navdeep Boparai, M.S., Lori Lyn Price, B.S., Michelle L. Kiwi, M.P.H., Marilyn McCormick, R.N., and Gordon Guyatt, M.D. The Cleveland Clinic Foundation, Cleveland, Ohio; Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia; and McMaster University, Hamilton, Ontario, Canada
OBJECTIVE: The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment. METHODS: In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patient’s HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study. RESULTS: In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Child’s class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36’s physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL. CONCLUSIONS: We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL. (Am J Gastroenterol 2001;96:2199 –2205. © 2001 by Am. Coll. of Gastroenterology)
INTRODUCTION In the past 2 decades, an integrated approach to health care that combines traditional biomedical outcomes with psycho-
social outcomes has become increasingly important. The traditional biomedical model of health emphasizes the basic sciences (molecular biology, genetics, physiology, and biochemistry). In contrast, the “social science” model of health focuses on patients’ psychosocial health, overall well-being, and quality of life. Proponents of an integrated approach advocate assessing both biomedical and psychosocial outcomes of disease, an approach that requires measuring additional outcomes, such as those related to patients’ healthrelated quality of life (HRQL) (1– 4). In the United States, ⬎5 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV), and millions more suffer from a variety of other chronic hepatocellular and cholestatic liver diseases. Liver disease is the ninth leading cause of death in the United States and is responsible for billions of dollars in direct and indirect medical costs (5). Patients with chronic liver disease suffer from fatigue, loss of self-esteem, inability to function at work, anxiety, depression, and other emotional problems that profoundly decrease their quality of life and well-being (6). Furthermore, HCV infection, alcoholic liver disease, and other liver disorders have their highest prevalence in the third and fourth decades of life, a period considered to be the most productive for a large number of people (5–7). Despite the importance of HRQL for patients with chronic liver disease, few investigators have assessed quality of life and its determinants in these patients. We evaluated the impact of chronic liver disease on HRQL, looked for differences in HRQL by type and severity of disease, and tried to identify clinical or pathological variables with disproportionate effects on HRQL.
METHODS Patient Selection Between August, 1997, and February, 1999, all patients presented to the Cleveland Clinic Foundation with the diagnosis of chronic liver disease were approached for participation in the study. Patients with another chronic active
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medical (such as congestive heart failure, etc) or psychiatric condition, malignancy, a transplanted liver, and those unable to communicate in English or who declined to participate were excluded. Patients were also classified into three categories of chronic liver disease: viral disease, cholestatic liver disease, or hepatocellular disease. In addition to convenience and simplifying data analysis, patients included in these categories may have similar clinical issues. Each patient had an established diagnosis by a hepatologist. The category “viral hepatitis” included chronic HBV and HCV. The diagnosis of chronic HCV was based on a positive hepatitis C antibody (ELISA II analysis), elevated serum alanine aminotransferase levels, with or without HCV RNA as detected by polymerase chain reaction. The diagnosis of chronic HBV was based on the presence of hepatitis B surface antigen, elevated serum alanine aminotransferase levels, with or without HBV DNA as detected by the hybridization method. For both HBV and HCV, patients receiving interferon therapy in the previous 3 months were also excluded. The category “cholestatic liver disease” included primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The diagnosis of PBC was based on positive antimitochondrial antibody test results and elevated liver enzymes, with or without liver biopsy. The diagnosis of PSC was based on a typical cholangiogram and elevated liver enzymes, with or without liver biopsy. Patients with hepatocellular diseases included genetic hemochromatosis, alcoholic liver disease, nonalcoholic fatty liver disease, ␣-1-antitrypsin deficiency, Wilson’s disease, and cryptogenic cirrhosis. The Institutional Review Board of the Cleveland Clinic Foundation approved the study protocol, and all participants gave written informed consent. Data Collection During an office visit, each patient gave his or her informed consent and then completed two self-administered HRQL questionnaires: the Medical Outcomes Study Short Form 36 (SF-36) (8, 9), a widely used and validated generic HRQL questionnaire, and the Chronic Liver Disease Questionnaire (CLDQ), a validated liver disease-specific HRQL questionnaire (10 –12). Extensive demographic and clinical data were also collected at this time (see below). The SF-36 consists of 36 items divided into eight scales that can be aggregated into two summary scores, a mental component summary and a physical component summary. The eight scales are: 1) physical function (PF), 2) role physical (RP), 3) bodily pain (BP), 4) general health (GH), 5) vitality (VT), 6) social functioning (SF), 7) role emotion (RE), and 8) mental health (MH). Scores for these eight SF-36 scales range between 0 and 100, whereas the summary scores for the physical component range between 8 and 73 and those for the mental component range between 10 and 74 (8).
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The CLDQ is a liver disease-specific HRQL questionnaire that consists of 29 items divided into six domains: 1) abdominal symptoms (ABM), 2) activity (ACM), 3) emotional function (EMM), 4) fatigue (FAM), 5) systemic symptoms (SYM), and 6) worry (WOM). Summary scores for each domain range from 1 (most impairment) to 7 (least impairment). An overall CLDQ score ranging from 1 to 7 may also be calculated. The questionnaire has good testretest reliability and cross-sectional validity (10 –12). In both the SF-36 and the CLDQ, higher scores suggest less impairment of HRQL. We also collected laboratory data reflective of hepatic functional reserve (total bilirubin, serum albumin, and prothrombin time), as well as a hepatic panel that included aspartate and alanine aminotransferases, alkaline phosphatase, and ␥-glutamyl transferase (GGT). In patients with HCV, the level of viremia was measured as a continuous variable by the amount of HCV RNA, as determined by a polymerase chain reaction with a detection threshold of 1 ⫻ 103 copies/ml (Amplicore HCV Monitor, Roche Molecular Systems, Brachburg, NJ). In patients with HBV, the level of viremia was measured as a continuous variable by the amount of HBV DNA, as determined by the liquid hybridization method with a detection threshold of 5 pg/ml (ARUP Laboratories, Salt Lake City, UT). Measures of Disease Severity As one overall measure of disease severity, patients were classified as noncirrhotic, early cirrhotic (Child’s stage A), or advanced cirrhotic (Child’s stages B and C), using a modified Child’s-Pugh classification (13–15). The diagnosis of cirrhosis was established either histologically or clinically, from the signs of decompensated cirrhosis: ascites, variceal bleeding, and so on. For patients with chronic viral hepatitis, histological severity was determined using the modified histological activity index (16). Widely used in clinical research, this index provides a numerical score for both inflammatory and fibrosis components of liver histology in patients with chronic hepatitis. Each component score can be analyzed separately as a continuous variable. Higher inflammatory or fibrosis score suggests severe histological disease. Similarly, in patients with cholestatic liver diseases (PBC and PSC), we applied the histological criteria suggested by Ludwig et al. (17, 18) in classifying patients into one of four ordinal severity stages: stage 1, portal hepatitis; stage 2, periportal hepatitis; stage 3, bridging necrosis or fibrosis or both; and stage 4, cirrhosis. In addition to histological staging, in patients with PBC, we also defined severity of disease with the Mayo PBC risk scores. These scores come from a disease-specific prognostic model predicting 1–7-yr survival for patients with PBC. This model is based on bilirubin, age, albumin, prothrombin time, and the presence of edema (19). In patients with PBC, Mayo risk score and the total serum bilirubin value are measures of clinical severity and are routinely used to pre-
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Table 1. Clinical and Demographic Characteristics of 353 Patients With Chronic Liver Disease Completing the SF-36 and CLDQ, by Type of Disease Chronic Viral Hepatitis
Chronic Cholestatic
Hepatocellular Disease
Characteristic
(B and C) (n ⫽ 133)
Liver Disease*† (n ⫽ 126)
(n ⫽ 94)
p
Mean age ⫾ SD, yr Men, n (%) Child-Pugh class, n (%) No cirrhosis A B C Ludwig’s criteria, n (%) 1. Portal hepatitis 2. Periportal hepatitis 3. Bridging necrosis/fibrosis 4. Cirrhosis Mayo PBC scores, mean ⫾ SD Diagnosis, n (%) Chronic viral hepatitis HBV HCV Cholestatic liver disease PBC PSC Hepatocellular disease Alcoholic cirrhosis Cryptogenic cirrhosis Autoimmune hepatitis Nonalcoholic steatohepatitis ␣-1-antitrypsin def Genetic hemochromatosis Wilson’s disease
46 ⫾ 9 86 (64.7)
54 ⫾ 11 38 (30.2)
52 ⫾ 13 56 (59.6)
0.0001 0.001
77 (57.9) 24 (18.1) 23 (17.2) 9 (6.8)
47 (38.8) 43 (35.5) 27 (22.3) 4 (3.3)
3 (3.2) 33 (35.0) 33 (35.0) 25 (26.6)
0.001
4 (6.5) 5 (8.1) 30 (48.4) 23 (37.1) 5.6 ⫾ 1.8 9 (6.8) 124 (93.2) 81 (64.3) 45 (35.7) 41 (43.6) 27 (28.7) 12 (23.8) 6 (6.4) 3 (3.2) 2 (2.1) 1 (1.06)
* Primary biliary cirrhosis (n ⫽ 81) and primary sclerosing cholangitis (n ⫽ 45). † Histological data were available only for 62 patients.
dict survival and to make important treatment decisions, including the need for orthotopic liver transplantation (17– 19). Comparison Groups SF-36 scores are available for the U.S. general population and for patients with a variety of chronic conditions (8, 9). Thus, we also compared our SF-36 scores for patients with chronic liver disease with those of patients with two other slowly progressive, chronic conditions: chronic obstructive pulmonary disease and congestive heart failure. These two conditions were chosen because they are similar to chronic liver disease in that they have a major impact on physical and emotional function and can progress to end-stage disease. Patients’ CLDQ scores were compared with the scores of 61 healthy individuals recruited from the practices of two primary care physicians at The Cleveland Clinic Foundation. These individuals presented for their yearly physical examinations and had no specific complaints or illness requiring treatment. They completed the CLDQ questionnaire and provided the same demographic and clinical data (10 – 12).
Statistical Methods Continuous variables were summarized as mean ⫾ SD, and analysis for normal distributed data was done using Student’s t-test or analysis of variance. If a significant difference was noted by analysis of variance, a more restrictive ␣ level was computed with the Bonferroni method, and the p values of pair-wise differences were compared with the new ␣. Non-normal data were compared using Wilcoxon Rank sum test or the Kruskal Wallis test. Spearman’s rank-order correlation coefficient was used as a measure of association between variables. All tests done were two-tailed; p values ⬍0.05 were considered to be statistically significant unless otherwise noted. All analyses were performed with the SAS statistical software package (SAS, Cary, NC).
RESULTS Clinical and Demographic Characteristics of Respondents Of the 390 patients approached for the study, 353 (90%) completed both questionnaires (Table 1). Inability to provide informed consent was the main reason for the exclusion from the study. The viral group was mainly composed of patients with chronic HCV. They were significantly younger
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Table 2. HRQL Scores for Patients With Different Types of Chronic Liver Disease, Other Chronic Diseases, and for Normal Controls
Dimension SF-36* (mean ⫾ SD) PF RP BP GH VT SF RE MH Physical component summary* Mental component summary* CLDQ† (mean ⫾ SD) ABM FAM SYM ACM EMM WOM Overall score
Chronic Viral Hepatitis (B and C)
Cholestatic Liver Disease
Hepatocellular Disease
(n ⫽ 133)
(n ⫽ 126)
(n ⫽ 94)
66 ⫾ 32 52 ⫾ 45 62 ⫾ 27 50 ⫾ 26 44 ⫾ 26 66 ⫾ 30 64 ⫾ 44 68 ⫾ 20 41 ⫾ 13 46 ⫾ 12
65 ⫾ 31 48 ⫾ 46 62 ⫾ 28 46 ⫾ 23 43 ⫾ 28 68 ⫾ 31 62 ⫾ 43 68 ⫾ 21 39 ⫾ 12 46 ⫾ 12
43 ⫾ 30 22 ⫾ 35 52 ⫾ 28 35 ⫾ 25 34 ⫾ 25 52 ⫾ 34 41 ⫾ 45 63 ⫾ 22 31 ⫾ 11 42 ⫾ 12
5.1 ⫾ 1.8 3.9 ⫾ 1.7 4.9 ⫾ 1.5 4.8 ⫾ 1.9 4.7 ⫾ 1.3 4.5 ⫾ 1.7 4.5 ⫾ 1.5
4.9 ⫾ 1.7 4.0 ⫾ 1.8 4.9 ⫾ 1.4 4.9 ⫾ 1.7 4.7 ⫾ 1.3 4.7 ⫾ 1.6 4.6 ⫾ 1.4
4.2 ⫾ 1.9 3.1 ⫾ 1.5 4.4 ⫾ 1.4 3.9 ⫾ 1.6 4.2 ⫾ 1.4 3.9 ⫾ 1.7 3.8 ⫾ 1.4
Normal Controls
Congestive Heart Failure
Chronic Obstructive Pulmonary Disease
“Normal” Population
(n ⫽ 61)
(n ⫽ 216)
(n ⫽ 85)
(n ⫽ 2474)
48 ⫾ 31 34 ⫾ 40 63 ⫾ 31 47 ⫾ 24 44 ⫾ 24 71 ⫾ 33 64 ⫾ 43 75 ⫾ 21 35 ⫾ 12 50 ⫾ 11
57 ⫾ 29 34 ⫾ 39 55 ⫾ 26 45 ⫾ 19 45 ⫾ 20 72 ⫾ 31 60 ⫾ 45 68 ⫾ 20 36 ⫾ 10 48 ⫾ 11
84 ⫾ 23 81 ⫾ 34 75 ⫾ 24 72 ⫾ 20 61 ⫾ 21 83 ⫾ 23 81 ⫾ 33 75 ⫾ 18 50 ⫾ 10 50 ⫾ 10
6.2 ⫾ 1.2 5.4 ⫾ 1.3 6.2 ⫾ 0.9 6.1 ⫾ 1.3 5.7 ⫾ 1.0 6.6 ⫾ 0.8 5.9 ⫾ 1.1
* Scale scores for SF-36 range between 0 and 100; summary scores range between 8 and 73 for PCS and between 10 and 74 for MCS. † CLDQ scores for each domain range from 1 (most impairment) to 7 (least impairment). The overall CLDQ score also ranges from 1 to 7.
with more men and less severe disease than the other groups. The cholestatic group included a larger proportion of older people and a greater proportion of women. In our study, 221 patients had cirrhosis with 101 (46%) having histologically proven cirrhosis and others with clinical cirrhosis (ascites, etc). Of those with biopsy-proven cirrhosis, time of biopsy to questionnaire administration was 2.65 ⫾ 3.92 yr. Almost all the patients in the hepatocellular group had cirrhosis, most either Child’s class B or C. Quality of Life in Patients With Viral Hepatitis Compared with U.S. general population and healthy controls, patients with viral hepatitis had more impairment of HRQL as measured by both SF-36 and CLDQ (Table 2). For all domains of SF-36 and CLDQ, the HRQL declined significantly with worsening of disease severity from noncirrhosis to advanced cirrhosis. In patients with viral hepatitis, level of viremia, route of transmission, level of aminotransferases, and other clinicodemographic data (except for age and gender) were not associated with HRQL impairment. Analyzing HBV and HCV separately, we found that the HAI inflammatory scores of patients with HCV were moderately but significantly correlated with the CLDQ’s emotional function domain (r ⫽ ⫺0.50, p ⫽ 0.01) and systemic function domain (r ⫽ ⫺0.43, p ⫽ 0.02). Additionally, in patients with HCV, advanced fibrosis (stage 3 and 4) had significantly lower HRQL scores than did in those with early fibrosis (stage 1 and 2).
Quality of Life in Patients With Cholestatic Liver Disease Patients with cholestatic liver disease or its individual types (PBC, PSC) had significantly lower HRQL than the general population and healthy controls as measured by both the SF-36 and the CLDQ (Table 2). For all domains of SF-36, the HRQL scores significantly declined from early to advanced to cirrhosis. Similarly, all CLDQ domain scores, as well as the overall CLDQ score, gradually declined with disease severity (CLDQ median overall score: no cirrhosis 5.4, early cirrhosis 5.5, and advanced cirrhosis 3.33, p ⬍ 0.001). In patients with cholestatic liver disease, fatigue measured by the CLDQ worsened with disease severity (CLDQ median fatigue score: no cirrhosis 5.0, early cirrhosis 4.8, advanced cirrhosis 2.3, p ⬍ 0.001). We found no significant difference in the SF-36 domains with worsening of histological stage. However, CLDQ systemic function, activity and overall CLDQ domain scores were significantly lower in more advanced stages (3, 4) as compared with less severe stages (1, 2) (p ⫽ 0.02, 0.01, and 0.01, respectively). Analyzing PBC and PSC separately, we found strong inverse relationships between patients’ PBC Mayo risk scores with their overall CLDQ scores (⫺0.61, p ⬍ 0.001) as well as with their SF-36 physical component summary scores (⫺0.60, p ⬍ 0.001). Additionally, in these patients, total bilirubin was inversely correlated with overall CLDQ scores (⫺0.54, p ⬍ 0.001) and SF-36 physical component (r ⫽ ⫺0.48, p ⬍ 0.001). We found no correlations between
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Table 3. HRQL Scores for Patients With and Without Cirrhosis and by Sex Cirrhosis Test Score SF-36* (mean ⫾ SD) PF RP BP GH VT SF RE MH Physical component summary Mental component summary CLDQ† (mean ⫾ SD) ABM FAM SYM ACM EMM WOM Overall score
Sex
Present
Absent
p
Men
Women
p
50 ⫾ 31 32 ⫾ 41 54 ⫾ 28 37 ⫾ 22 35 ⫾ 25 58 ⫾ 33 51 ⫾ 45 65 ⫾ 21 34 ⫾ 11 44 ⫾ 12
76 ⫾ 27 63 ⫾ 44 68 ⫾ 26 58 ⫾ 24 51 ⫾ 26 72 ⫾ 28 69 ⫾ 42 70 ⫾ 20 45 ⫾ 12 46 ⫾ 12
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.03 ⬍0.001 0.05
62 ⫾ 32 44 ⫾ 45 61 ⫾ 27 46 ⫾ 25 43 ⫾ 27 63 ⫾ 32 62 ⫾ 44 68 ⫾ 20 39 ⫾ 13 45 ⫾ 12
57 ⫾ 32 41 ⫾ 45 57 ⫾ 29 43 ⫾ 24 39 ⫾ 26 62 ⫾ 32 53 ⫾ 45 66 ⫾ 22 37 ⫾ 13 44 ⫾ 12
0.13 0.49 0.17 0.23 0.10 0.67 0.09 0.32 0.42 0.22
4.4 ⫾ 1.8 3.3 ⫾ 1.6 4.4 ⫾ 1.4 4.1 ⫾ 1.7 4.4 ⫾ 1.3 4.11 ⫾ 1.7 4.0 ⫾ 1.4
5.5 ⫾ 1.6 4.4 ⫾ 1.7 5.3 ⫾ 1.3 5.4 ⫾ 1.6 4.9 ⫾ 1.3 5.0 ⫾ 1.6 5.0 ⫾ 1.3
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
4.9 ⫾ 1.8 3.8 ⫾ 1.7 4.9 ⫾ 1.4 4.6 ⫾ 1.8 4.6 ⫾ 1.4 4.4 ⫾ 1.7 4.4 ⫾ 1.5
4.6 ⫾ 1.8 3.7 ⫾ 1.7 4.6 ⫾ 1.4 4.6 ⫾ 1.8 4.5 ⫾ 1.3 4.4 ⫾ 1.7 4.3 ⫾ 1.4
0.13 0.46 0.10 0.99 0.28 0.80 0.70
* Scale scores for SF-36 range between 0 and 100; summary scores range between 8 and 73 for PCS and between 10 and 74 for MCS. † CLDQ scores for each domain range from 1 (most impairment) to 7 (least impairment). The overall CLDQ score also ranges from 1 to 7.
the SF-36 mental component summary scores and Mayo PBC risk scores or total bilirubin. Quality of Life in Patients With Hepatocellular Liver Disease Except for body pain, vitality, role emotion, mental health, and mental health component of SF-36 and systemic function, emotion and worry domains of CLDQ, all the other domains of SF-36 and CLDQ showed a significant decline (p ⬍ 0.05) in HRQL as disease severity advanced from no cirrhosis or early cirrhosis (Child’s A) to advanced cirrhosis (Child’s B and C). The Effect of Cirrhosis Almost all patients without cirrhosis had either viral or cholestatic disease (Table 1). In patients without cirrhosis, both CLDQ and SF-36 scores were generally similar between the different types of liver disease. Patients with cirrhosis had more HRQL impairment than those without cirrhosis (Table 3). In patients with cirrhosis, the cholestatic group had significantly less impairment in several HRQL dimensions (physical function, role function, general health, social function, role emotion, and physical component summary for SF-36 and fatigue in CLDQ), than did cirrhotic patients in the hepatocellular group (p ⬍ 0.01) for these domains. There was no difference in cirrhotic patients between the viral group and the cholestatic or hepatocellular groups. Quality of Life in Chronic Liver Disease Compared With That in Other Populations Regardless of the presence or absence of cirrhosis, quality of life was substantially lower in patients with chronic liver disease than in the healthy population, as measured both by
CLDQ and SF-36 summary scores (p ⬍ 0.001 for both physical and mental summary scores) (Table 2). Compared with patients with congestive heart failure or chronic obstructive pulmonary disease, patients with chronic liver disease had similar impairment in the physical aspects of HRQL but more impairment in mental health (p ⫽ 0.006). Effect of Gender and Age on Quality of Life We found that age was inversely but weakly correlated with physical component of SF-36 (r ⫽ ⫺0.2, p ⫽ 0.002) (Table 4). Patients in age group ⬍50 yr had significantly higher HRQL for the following SF-36 domains PF (p ⫽ 0.001), RP (p ⫽ 0.03), and PCS (p ⫽ 0.002), and CLDQ’s AC (p ⫽ 0.01) and overall CLDQ score (p ⫽ 0.05). Looking at the chronic viral hepatitis group alone, patients with age ⬍50 yr have better HRQL for the AC domain (p ⫽ 0.04). In the hepatocellular group, younger patients did better for the following domains: PF (p ⫽ 0.004), VT (p ⫽ 0.03), and PCS (p ⫽ 0.04). Overall CLDQ was also marginally significant with p ⫽ 0.07. Analyses for gender revealed that more women than men within the cholestatic disease group scored lower on the PF domain of SF-36 (60 ⫾ 31 vs 76 ⫾ 27, p ⫽ 0.01). No differences were found between men and women in the viral or the hepatocellular groups (Table 3).
DISCUSSION This study evaluates the impact of type and severity of liver disease on HRQL. We found that HRQL in patients with chronic liver disease is much lower than that of healthy people and that it is comparable with patients with chronic obstructive pulmonary disease and congestive heart failure. In comparing patients with different types of liver disease,
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Table 4. Correlations Between Demographic Characteristics, Laboratory Measures of Disease Severity, and HRQL Scores for Patients With Chronic Liver Disease SF-36
Variable Age HAI Aspartate aminotransferase Alanine aminotransferase Alkaline phosphatase Total bilirubin (overall) Prothrombin time HCV RNA Serum albumin Mayo (PBC only) Total bilirubin (PBC only)
CLDQ
Mental r p n
Physical r p n
Total Score r p n
0.04 0.51 329 ⫺0.22 0.18 39 ⫺0.13 0.10 165 0.15 0.02 245 ⫺0.05 0.46 204 ⫺0.13 0.03 272 ⫺0.16 0.01 232 0.07 0.69 38 0.20 ⬍0.001 271 0.28 0.11 33 ⫺0.18 0.16 64
⫺0.17 0.002 329 ⫺0.16 0.34 39 ⫺0.20 0.01 165 0.13 0.04 245 ⫺0.17 0.02 204 ⫺0.40 ⬍0.001 272 ⫺0.40 ⬍0.001 232 0.07 0.66 38 0.48 ⬍0.001 271 ⫺0.60 ⬍0.001 33 ⫺0.48 ⬍0.001 64
⫺0.06 0.25 323 ⫺0.33 0.05 36 ⫺0.24 0.002 159 0.12 0.08 238 ⫺0.14 0.06 196 ⫺0.36 ⬍0.001 260 ⫺0.33 ⬍0.001 225 0.13 0.44 39 0.43 ⬍0.001 286 ⫺0.61 ⬍0.001 33 ⫺0.54 ⬍0.001 64
we found that patients with early liver disease have a similar quality of life, regardless of the underlying cause of their liver disease. However, among patients with cirrhosis, those with cholestatic liver disease have less impairment in the physical aspects of HRQL than do patients with hepatocellular disease. As expected, chronic fatigue is prevalent in patients with chronic cholestatic liver disease and has an important impact on their HRQL. When liver disease becomes more severe, as indicated by a higher Child-Pugh class, a higher Mayo risk score, or a rising serum bilirubin level, HRQL also becomes more impaired. This relationship is most prominent in the diseasespecific and physical dimensions of SF-36 but not always for the mental health dimension of the SF-36. As histological severity worsened (reflected by higher histological stages on liver biopsies), some of the diseasespecific aspects of HRQL deteriorated. We observed this relationship in both chronic cholestatic and viral diseases. The only other clinical or demographic variables influ-
encing HRQL in patients with chronic liver disease was age. Although the correlations between age and HRQL scores were weak, these data are consistent with those reported in other studies (9). We found that a recently developed disease-specific HRQL instrument, the CLDQ, consistently and negatively correlated with all dimensions of disease severity (Mayo scores, total bilirubin, Child-Pugh class, and worsening histological features). These results likely reflect CLDQ’s usefulness in targeting disease-specific aspects of dysfunction in patients with chronic liver disease, and they highlight the impact of this progressive illness on patients’ experience. Consistent with previous studies of patients with chronic hepatitis C and those awaiting liver transplantation, our results show that HRQL of patients with chronic liver disease is more impaired than that of healthy population and becomes even worse with cirrhosis (20). Our study is unique in providing comparative data on HRQL of a relatively large number of patients with a variety of types of liver disease using both generic and disease-specific HRQL instruments. Our study has some limitations. All subjects were recruited from one tertiary health care center, potentially introducing problems with applicability of our results to patients seen in primary care centers. The cross-sectional design of our study does not allow us to describe how progression of disease relates to changes in HRQL. However, the fact that HRQL was substantially impaired in those with early liver disease suggests that the possible recruitment bias does not account for these findings. Additionally, progressive worsening of CLDQ scores with disease severity also suggests that the relationship between disease severity and HRQL should remain. We found that chronic liver diseases substantially reduce HRQL. Further, this impairment increases with disease severity. This association between HRQL impairment and cirrhosis was further supported by another recent publication (21, 22). The ability of the CLDQ to detect associations with disease severity and its applicability to all types and stages of liver disease suggest that it can be an additional, important outcome in natural history studies and in clinical trials designed to modify the course of chronic liver disease. Quality-of-life measures, such as the CLDQ and SF-36, can complement clinical outcomes, such as the Mayo risk score, Child-Pugh class, liver enzyme indicators, histological stage, and mortality rates, helping to integrate the biomedical and the psychosocial models of health. This integrated approach to the study of chronic liver disease will capture the total impact of these diseases on patients’ health and well-being.
ACKNOWLEDGMENTS This research was supported in part by a Junior Faculty Award from the American College of Gastroenterology and
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by a grant from The Cleveland Clinic Foundation’s I. H. Page Centre for Clinical Effectiveness. The authors gratefully acknowledge the help of medical writer Tom Lang, who facilitated the writing process of this manuscript. Z.M.Y. is also a senior researcher at the I. H. Page Centre for Clinical Effectiveness, Cleveland Clinic Foundation, Cleveland, Ohio. Reprint requests and correspondence: Zobair M. Younossi, M.D., M.P.H., Director, Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, 330 Gallows Road, Falls Church, VA 22042-3300. Received Nov. 13, 2000; accepted Feb. 7, 2001.
Chronic Liver Disease and QoL
10. 11. 12. 13. 14. 15.
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