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Fatigue Associated with Degree of Fibrosis: fatigue level may predict severity of fibrosis
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"Our study suggests a significant association of physical aspects of HRQoL and fatigue with the extent of fibrosis. Fibrosis stage should be considered for the identification and management of HCV patients at risk for reduced physical HRQoL.....According to the results of the respective multiple linear regression analysis, only fibrosis (p=0.043) and gender (p=0.017) could be identified as independent significant predictors of impairment of the absolute FIS score (fatigue)..."
"Confirming the results of one study published by Poynard et al. [21], we found a relation between the impairment of the absolute fatigue score with the degree of fibrosis while other authors were not able to demonstrate such a relationship [5], [15]. Our findings support the fact that from a clinical point of view fatigue seems to be more frequent and pronounced in patients with severe fibrosis or liver cirrhosis and also represents a characteristic symptom of hepatic encephalopathy.....In concordance with other studies, females were more strongly affected by fatigue compared with male patients....Age, by contrast, turned out to be of minor importance as a further potential confounding parameter for fatigue in the present study.....Impaired health-related quality of life is generally associated with disability and lower work productivity (reflected in part by the SF-36 physical summary score), both therefore illustrating the social and economic dimension of this chronic disease. Thus, besides clinical factors, i.e. degree of inflammatory activity and fibrosis, impaired health-related quality of life should be increasingly considered and taken into account for the decision towards a specific antiviral treatment in these patients. It has been shown in several studies, that successful antiviral treatment is associated with a significant improvement of health-related quality of life in these patients [4], [22], [23]. In addition, our findings stress the need for considering fibrosis stage for the identification and management of hepatitis C patients at risk for reduced health-related quality of life (e.g. without current antiviral treatment options).....
......To summarize, we were able to demonstrate in our study that mainly physical aspects of both health-related quality of life and fatigue are markedly associated with the degree of fibrosis in chronic hepatitis C patients. However, since many clinical features of health-related quality of life and fatigue in patients with chronic hepatitis C are still discussed controversially, further large clinical trials are necessary to elucidate physical, mental and emotional aspects of the disease and its impact on the social and economic dimensions."
Instruments for the assessment of health-related quality of life and fatigue
Health-related quality of life was assessed by a German-validated version of the Short Form Health survey (SF-36). The subscales physical functioning, physical role, bodily pain, general health, vitality, social functioning, emotional role, and mental health were calculated from the questionnaires as described previously [10], [11]. Physical and mental summary measures were obtained from the sum scores of the according subscales, i.e. physical functioning, physical role, bodily pain and general health for the physical summary score and vitality, social functioning, emotional role and mental-health for the mental summary score. According to the recommendations given in the manual [10], [11], subscale scores were calculated if at least half of the items on the respective scale were answered. Otherwise the case was classified as missing for the respective statistical analysis. Missing item values were replaced by individual-specific estimators (i.e. scale means).
At the same time "fatigue" was evaluated by the German-validated version of the Fatigue Impact Scale (FIS-D), an internationally evaluated questionnaire for the assessment of the impact of fatigue on health-related quality of life [12], [13]. This questionnaire was designed to assess patients' perceptions of functional limitations in the physical, cognitive and psychosocial domains attributed to fatigue comprising a total of 40 statements. The items are presented in random order to the respondent who scores each statement on a Likert scale (0-4) with "0" indicating no problem and "4" reflecting a serious problem. The FIS subscales and summary score have proven to significantly discriminate between different patient groups - these results demonstrate the high external validity of the instrument. In the case of more than 50% missing data per scale the respective subject was excluded from the statistical analyses referring to the FIS-D - otherwise missing values were replaced by respective estimators (scale means).
Articles in Press
Deterioration of health-related quality of life and fatigue in patients with chronic hepatitis C: Association with demographic factors, inflammatory activity, and degree of fibrosis
Gerlinde Teuber1, Arne Schafer2, Jasmin Rimpel1, Kathrin Paul1, Christian Keicher2, Michael Scheurlen2, Stefan Zeuzem1, Michael R. Kraus2
published online 22 September 2008.
Uncorrected Proof
Background/Aims
Health-related quality of life (HRQoL) is impaired in patients with chronic hepatitis C. We investigated HRQoL and fatigue in patients with chronic hepatitis C virus (HCV) infection in relation to the degree of fibrosis and inflammation, and controlled for the influence of relevant demographic and medical variables.
Methods
We conducted a cross-sectional two-center study including 215 outpatients with chronic hepatitis C applying the Short-Form Health Survey (SF-36) and the Fatigue Impact Scale (FIS-D). The contribution to the variability of these psychometric scores was evaluated for the degree of fibrosis as well as viremia, gender, age, mode of transmission, genotype, and ALT.
Results
There was a strong negative association between the degree of liver fibrosis and the physical SF-36 summary score (p=0.016). This was independent of the covariate age, also significantly predicting physical HRQoL (p=0.001). The absolute FIS score was significantly increased in patients with advanced fibrosis (p=0.043). In females, mental SF-36 summary score (p=0.007) and fatigue (p=0.017) were significantly more impaired.
Conclusions
Our study suggests a significant association of physical aspects of HRQoL and fatigue with the extent of fibrosis. Fibrosis stage should be considered for the identification and management of HCV patients at risk for reduced physical HRQoL.
RESULTS
Assessment of health-related quality of life
The univariate analysis of the German-validated version of the Short Form Health survey (SF36) showed a significant stage-dependent reduction of the physical summary score in patients with chronic hepatitis C (Table 2) while there was no such correlation with the mental summary score of SF-36. Thus, the SF-36 physical summary score was significantly impaired in patients with severe fibrosis or cirrhosis as compared with patients showing a lower degree of fibrosis (p<0.001, Table 2). The in-depth analysis (ANOVA) of the 4 above-described fibrosis stages showed that the alterations in the physical domain were in particular significant for the three subscales physical functioning (p<0.001), physical role (p=0.006), and general health (p=0.001). In contrast to the stage of liver disease, our analyses revealed no correlation between the histological activity index and the physical and mental summary scores of SF 36.
Interestingly, the SF-36 mental summary score was significantly decreased in female patients with chronic hepatitis C compared with males (p=0.011) affecting particularly the subscales for mental health (p=0.008) and for emotional role (p=0.051). However, in our analysis gender was not significantly related to the physical summary score of SF 36.
Regarding patients' age, the SF-36 physical summary score (p<0.001, Fig. 2) and particulary the subscales physical functioning (p<0.001), physical role (p<0.001), and bodily pain (p=0.002) were significantly reduced in older patients with chronic hepatitis C compared with younger ones. No significant association was found between the SF-36 scores and other demographic and biochemical parameters, i.e. mode of transmission, ALT, viral load, and HCV-genotype.
In a further step, the degree of fibrosis, HAI, age and gender were included in a linear multiple regression model in order to simultaneously assess the association between HRQL and putatively relevant predictor variables.
The linear multiple regression analysis revealed fibrosis (p=0.016) and age (p=0.001) as significant independent predictors for the physical summary score of SF-36. SF-36 mental summary score was best and significantly predicted by the covariates gender (p=0.007) and age (p=0.014, Table 3.
Assessment of fatigue
Similarly as for health-related quality of life, there was a trend for the absolute FIS score towards an increase in patients with severe fibrosis or cirrhosis (F5/6) compared to patients with a lower degree of fibrosis (F0-4, Table 2). This was in particular true for the physical subscale of FIS (p=0.013, Table 2). This tendency was confirmed by a more detailed analysis of the different fibrosis groups showing significant differences between the four subgroups (p=0.020, Fig. 1).
Furthermore, the impairment of the absolute FIS score, including all three subscales, was more pronounced in females with chronic hepatitis C compared with males (FIS score: p=0.019, Fig. 3; physical subscale: p=0.013; cognitive subscale: p=0.013; psychological subscale: p=0.056).
Concerning the association between age and fatigue, only the cognitive and physical FIS subscales were negatively affected in older patients (p=0.038 and p=0.046) while age and the absolute FIS score were not significantly related.
Similarly to the SF-36 analyses, fibrosis, gender, and age as well as the histologic activity index (HAI) were used to build the multiple regression model. According to the results of the respective multiple linear regression analysis, only fibrosis (p=0.043) and gender (p=0.017) could be identified as independent significant predictors of impairment of the absolute FIS score. Our analysis further demonstrated that mode of transmission, biochemical activity, viral load and genotype did not significantly predict the extent of fatigue (Table 3). Analysis of criterion intercorrelations matrix revealed that fatigue (FIS-D total score) was significantly associated with both physical (r=_0.502; P<.001) and mental (r=_0.615; P<0.001) subdomains of SF-36.
Introduction
Chronic hepatitis C virus (HCV) infection currently represents a major health problem and is estimated to affect 170 million persons worldwide [1]. In its natural course, hepatitis C virus infection leads in a significant proportion of chronically infected patients to liver cirrhosis with its potential complications, such as impaired liver function, portal hypertension, or hepatocellular carcinoma. In addition to the known morbidity and mortality, chronic hepatitis C virus infection has been shown to be associated with a considerable impairment of health-related quality of life as compared with healthy controls, irrespective of the stage of the disease [2]. Significantly reduced health-related quality of life was even demonstrable in asymptomatic patients with chronic hepatitis C and persistently normal aminotransferase levels [3]. However, despite the progressive natural course of the disease, most of the small studies published so far could not demonstrate a correlation between the stage of the disease and the extent of the reduction of health related-quality of life [2]. Only one study published recently in a large cohort of patients gave some evidence for impaired health-related quality of life in patients with advanced fibrosis or cirrhosis [4].
Fatigue is one of the most frequent clinical symptoms in patients with chronic hepatitis C infection contributing significantly to the reduction of health-related quality of life. Compared with healthy controls, fatigue has been found to be significantly increased in patients with chronic hepatitis C. Nevertheless, this symptom has only been evaluated systematically in a small number of studies, not evaluating the relationship between stage of fibrosis and fatigue as a primary study objective [5], [6]. A significant association with the degree of fibrosis was not demonstrable in the majority of these studies. However, there is some evidence that fatigue is more pronounced in cirrhotic patients with chronic hepatitis C treated with a beta-blocker for oesophageal varices or diuretics after previous hepatic decompensation [7]. A relation to the inflammatory activity could not be demonstrated.
Moreover, gender and age were identified as important factors contributing to health-related quality of life and to the presence and extent of symptoms of fatigue [8]. Despite this fact, most studies on health-related quality of life and fatigue in patients with hepatitis C have failed to control for both, gender and age as potentially relevant covariates in the context of evaluating predicting parameters such as the degree of liver fibrosis, the inflammatory activity or other disease related medical factors.
Therefore, the aims of the present cross-sectional two-center study were to prospectively investigate health-related quality of life and fatigue in a group of patients with chronic hepatitis C. By this approach, the influence of disease-associated (inflammatory disease activity, degree of fibrosis, viral co-factors) as well as relevant demographic variables (gender, age, mode of transmission) on these parameters was to be assessed.
Discussion
In the present cross-sectional two-center study, we found a significant association between the impairment of the physical aspects of both, health-related quality of life and fatigue, and the extent of fibrosis in untreated patients with chronic hepatitis C while the degree of inflammatory activity and viral factors were of minor importance. In concordance with our results, several previously published studies failed to demonstrate a relation between health-related quality of life or fatigue and the inflammatory disease activity as well as viral factors such as genotype and viremia [15], [16].
The majority of the up-to-now published studies on chronic hepatitis C failed to show a difference in health-related quality of life in patients with different degrees of fibrosis [2], [17]. Only one of the earlier studies described a significant impairment of health-related quality of life in patients with advanced cirrhosis, especially those receiving treatment with diuretics and beta-blockers, when compared with non-cirrhotic patients [7]. However, two large recently published studies showed - in accordance with our results - a stage-dependent relation between the degree of fibrosis and the impairment of health-related quality of life in patients with severe fibrosis or cirrhosis, compared to those with moderate fibrosis [4], [18]. The discrepancy may be explained in part by the relatively small sample sizes included in the earlier published studies failing to demonstrate a relevant association between health-related quality of life and the stage of liver disease in patients with chronic hepatitis C infection.
According to our results, the impairment of the physical components of health-related quality of life was more pronounced in elderly patients, thus identifying fibrosis and age as independent predicting parameters for the observed diminished health-related quality of life in our patients. However, gender was not related to this observed impairment of the physical aspects of health-related quality of life.
With respect to mental domains of health-related quality of life and fatigue, a significant reduction was observed in female patients with chronic hepatitis C in comparison with male study participants. One might speculate that this observation may be to some extent due to a different, gender-specific disease perception. Furthermore, these results are confirmed by two previously published studies [6], [18]. As the reasons for this phenomenon are yet not identified, it is assumed that social and familiar factors may play an essential role for the affection of the mental aspects of health-related quality of life in female patients with chronic hepatitis C. In particular, disease-related concerns, the stigma of an infectious disease itself including the potential transmission risk to spouses and children as well as concerns about the future ability to take care of the family seem to affect women in a more pronounced manner than males [8], [19], [20].
The impact of previous intravenous drug abuse as one of the major transmission risks for hepatitis C virus infection on health-related quality of life is controversially discussed in previously published studies [2], [8]. However, in concordance with the two more recently published studies, we were not able to demonstrate a relevant association between current health-related quality of life and previous intravenous drug abuse. This may be explained by the fact that most of our patients stopped intravenous drug abuse years ago and were socially well integrated.
Despite the high frequency of "fatigue" as a clinical symptom in patients with chronic hepatitis C [5], [6], the phenomenon fatigue and its contributing physical, psychological, social, and emotional dimensions remain so far only poorly characterized. The relation between fatigue and degree of fibrosis has been discussed controversially. Confirming the results of one study published by Poynard et al. [21], we found a relation between the impairment of the absolute fatigue score with the degree of fibrosis while other authors were not able to demonstrate such a relationship [5], [15]. Our findings support the fact that from a clinical point of view fatigue seems to be more frequent and pronounced in patients with severe fibrosis or liver cirrhosis and also represents a characteristic symptom of hepatic encephalopathy.
In concordance with other studies, females were more strongly affected by fatigue compared with male patients. This fact points towards a different, gender-specific disease perception in female hepatitis C patients with a relevant impact on both quality of life (see above) and fatigue or tiredness. Potentially underlying mechanisms for these findings still need to be identified in future research. Age, by contrast, turned out to be of minor importance as a further potential confounding parameter for fatigue in the present study.
As further relevant contributing factors gender and age could be identified. Impaired health-related quality of life is generally associated with disability and lower work productivity (reflected in part by the SF-36 physical summary score), both therefore illustrating the social and economic dimension of this chronic disease. Thus, besides clinical factors, i.e. degree of inflammatory activity and fibrosis, impaired health-related quality of life should be increasingly considered and taken into account for the decision towards a specific antiviral treatment in these patients. It has been shown in several studies, that successful antiviral treatment is associated with a significant improvement of health-related quality of life in these patients [4], [22], [23]. In addition, our findings stress the need for considering fibrosis stage for the identification and management of hepatitis C patients at risk for reduced health-related quality of life (e.g. without current antiviral treatment options).
To summarize, we were able to demonstrate in our study that mainly physical aspects of both health-related quality of life and fatigue are markedly associated with the degree of fibrosis in chronic hepatitis C patients. However, since many clinical features of health-related quality of life and fatigue in patients with chronic hepatitis C are still discussed controversially, further large clinical trials are necessary to elucidate physical, mental and emotional aspects of the disease and its impact on the social and economic dimensions.
Patients and methods
Patients
In the present cross-sectional two-center study, 215 untreated patients (123 males, 92 females, mean age 46.7+13.4 years) with chronic hepatitis C virus infection were enrolled at the university hospitals of Frankfurt and Wuerzburg, Germany. As part of the routine work-up, biochemical parameters, including ALT, AST, γ-GT, bilirubin, albumin and partial thrombin time, as well as quantitative HCV-RNA (COBAS Amplicor HCV MonitorTM) and HCV-genotype (INNO LIPA HCV II; Innogenetics, Gent, Belgium) were determined in all patients. Patients with HBV and HIV coinfection or liver disease of other etiology as well as the presence of severe concomitant diseases and/or active alcohol (>20g/d for females; >40g for males) or drug abuse within the last 12 months were not eligible for the study. Liver biopsy was performed as part of the routine work-up in 204 of the 215 patients and evaluated according to the modified histological activity index [9]. Patients with clinically obvious liver cirrhosis, e.g. patients with impaired liver function, the presence of ascites and/or previous bleeding from varices were considered as grade 6 fibrosis. Only patients with complete clinical work-up were included in the final analysis.
After giving informed consent, patients were asked to complete the psychometric surveys for health-related quality of life (SF-36) and fatigue (FIS-D), before liver biopsy was performed. The study was approved by the Institutional Review Board [IRB] for the protection of human subjects at both participating institutions and was carried out in accordance with the Declaration of Helsinki.
Instruments for the assessment of health-related quality of life and fatigue
Health-related quality of life was assessed by a German-validated version of the Short Form Health survey (SF-36). The subscales physical functioning, physical role, bodily pain, general health, vitality, social functioning, emotional role, and mental health were calculated from the questionnaires as described previously [10], [11]. Physical and mental summary measures were obtained from the sum scores of the according subscales, i.e. physical functioning, physical role, bodily pain and general health for the physical summary score and vitality, social functioning, emotional role and mental-health for the mental summary score. According to the recommendations given in the manual [10], [11], subscale scores were calculated if at least half of the items on the respective scale were answered. Otherwise the case was classified as missing for the respective statistical analysis. Missing item values were replaced by individual-specific estimators (i.e. scale means).
At the same time "fatigue" was evaluated by the German-validated version of the Fatigue Impact Scale (FIS-D), an internationally evaluated questionnaire for the assessment of the impact of fatigue on health-related quality of life [12], [13]. This questionnaire was designed to assess patients' perceptions of functional limitations in the physical, cognitive and psychosocial domains attributed to fatigue comprising a total of 40 statements. The items are presented in random order to the respondent who scores each statement on a Likert scale (0-4) with "0" indicating no problem and "4" reflecting a serious problem. The FIS subscales and summary score have proven to significantly discriminate between different patient groups - these results demonstrate the high external validity of the instrument. In the case of more than 50% missing data per scale the respective subject was excluded from the statistical analyses referring to the FIS-D - otherwise missing values were replaced by respective estimators (scale means).
Normative data are available from the SF-36 manual [10] and a published original paper investigating the FIS-D questionnaire [13].
Statistical analysis
Data were registered and analyzed using the Statistical Package for Social Sciences (SPSS for Windows, German Version 15.0.1) [14]. If not otherwise stated, for mere descriptive analysis, quantitative data are expressed as mean}standard deviation (SD) and qualitative variables are presented as counts and percentages. For the analysis of bivariate associations, we used Pearson's correlation coefficients when appropriate.
All performed tests were two-tailed and considered to be statistically significant at the level of p<0.05. The exact calculated p-values are usually given together with the inferential statistical analyses in order to ensure maximum transparency.
For univariate between-group comparisons for continuous variables, we used one-factorial ANOVA analyses (e.g. testing for significant mean differences in psychometric variables between patient groups on the basis of the degree of fibrosis). In order to get insight in pairwise factor-level comparisons, we performed Bonferroni post-hoc tests. Correspondent univariate calculations for qualitative measures were done using crosstabs analyses (_2 or Fisher's exact test, respectively).
Multiple linear regression analyses ("enter option") were used in order to quantify the simultaneous and mutually independent contribution of previously identified relevant predictor candidates, e.g. degree of fibrosis and histological activity index, to the variation of psychometric scores (dependent variables: SF-36; FIS-D), while controlling for already known confounders such as gender and age.
Sample size considerations
The following considerations refer to the optimal sample size for performing multiple regression analysis: Given a significance level of 0.05 and a statistical power of 0.80 (type II error 0.20), optimum sample size is 125 - even when only a small effect size (f=0.10) is expected. The exact parameters for a multiple regression analysis with 4 predictor variables are: critical F(4,120)=2.447; actual power=0.803. Therefore, it was intended to include at least 200 study patients.
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