Fatigue is increasingly recognized as one of the most disabling complaints of patients with hepatitis C virus (HCV) infection, at any stage of disease . The pathophysiology of fatigue is poorly understood, as it involves physical, emotional and psychological domains . Although it is tempting to assume a causal link between fatigue and chronic inflammation, no correlation between serum cytokine concentrations and fatigue severity exists . Although fatigue is frequently considered the result of advancing liver disease, its severity is poorly related to the biochemical and histological activity of hepatitis . Only recent work has identified associations between fatigue and female sex, age over 50 years, extrahepatic symptoms of HCV infection, and cirrhosis .
After the recent detection of neurocognitive dysfunction and cerebral metabolic abnormalities on 1H magnetic resonance spectroscopy in patients with mild HCV infection , potential neurocognitive aspects of HCV-related fatigue are receiving increased attention. In a previous study , we identified subclinical brain dysfunction by abnormal event-related potentials in a proportion of patients with chronic HCV infection. Impairment of the health-related quality of life (HRQL), however, occurred largely independently from cognitive dysfunction, as confirmed by a subsequent study for all but the most severe forms of HCV-related liver disease .
The present study was performed to investigate the hypothesis that severity of fatigue rather than subclinical cognitive dysfunction had an independent effect on HCV-associated impairment of HRQL. As one of the main clinical problems with fatigue assessment is the absence of an objective measurement, we used both the fatigue impact scale (FIS)  and the more recently developed brief fatigue inventory (BFI, see Fig. 1) , and compared their respective association with HRQL measures and clinical data. The FIS has been validated in patients with chronic hepatitis C and was found to be an internally consistent, reproducible measurement of fatigue severity . The BFI, which has been developed as a tool for assessing fatigue in cancer, has not been thoroughly validated in HCV infection so far.
Materials and methods
We investigated 120 consecutive untreated patients referred to our liver clinic with chronic hepatitis C (aged 45 ± 12 years, range 21–74). Inclusion criteria were age between 18 and 80 years and presence of anti-HCV antibodies and HCV RNA in serum. Patients with decompensated cirrhosis, alcoholic liver disease, cryoglobulinaemia, liver transplantation, other bacterial or viral infections, renal failure, insulin-treated diabetes, cerebrovascular disease and a current or past history of neurological or psychiatric illness including attention and learning deficits, medication with tranquillizers or antidepressants, or a history of alcohol or injection drug abuse within 6 months before the study were excluded. All patients gave written informed consent before participation. The study protocol was approved by the Ethics Committee of the Vienna Medical University.
The control group consisted of 100 age-matched healthy individuals (44 ± 13 years, range 21–74, 68% men) who were recruited from hospital employees and their personal contacts, visitors of a public health information stand, and individuals interviewed at a shopping mall. We interviewed the controls to exclude alcoholism, drug abuse or a history of neuropsychiatric disease. No biochemical, drug screening, HCV or HIV tests were performed in the control population. Sex distribution was similar between controls (68% men) and patients (64% men, P = 0.63).
Diagnosis of chronic hepatitis C
Diagnosis was established by repeated elevations of alanine aminotransferase over 6 months, the detection of HCV antibodies by enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, IL, USA) and HCV-RNA (Cobas Amplicor HCV test; Roche Diagnostic Systems, Branchburg, NY, USA).
The mini-mental state examination, a bedside test of neurocognitive function, was used for the exclusion of global impairment of cognitive and psychomotor function .
Assessment of health-related quality of life
The SF-36 (QualityMetric, Inc., Lincoln, RI, USA) is a self-report, generic HRQL measure including eight multi-item scales (36 items) that evaluate the extent to which an individual's health limits his or her physical, emotional, and social functioning . The SF-36 measures eight domains of HRQL: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health, and is scored from 0 to 100, with higher scores indicating a better HRQL. Summary scores for physical health (physical component score) and mental health can be gained (mental component score). The reliability and validity of the SF-36 for comparing the disease burden of different chronic diseases and the sensitivity for measuring the potential benefits of treatment are well-established . A German version of the SF-36 has been validated, and population-based normative data are available.
Assessment of fatigue
The FIS is a self-reported questionnaire that has been developed to assess the functional limitations caused by chronic fatigue . Forty statements within three subscales (physical, cognitive and psychosocial) are presented in random order and scored from 0 (indicating ‘no problem’) to 4 (‘extreme problem’). The BFI questionnaire comprises 10 different items regarding current and past aspects of fatigue, and has been shown to be an internally stable measure, tapping a single dimension, interpreted as severity of fatigue. German versions of the FIS and BFI have been validated in cancer and non-cancer patients [15,16].
P300 event-related cognitive evoked potentials
Evoked potentials were recorded on a Nicolet Spirit (Nicolet, Madison, WI, USA) with Ag/AgCl-sinter electrodes (Picker Int., Munich, Germany) and adhesive electrolyte gel (Grass, Quincy, MA, USA). Active electrodes placed at Cz (vertex, international 10/20 system) and Fz (frontal) were referenced to linked earlobes. The common electrode was C3. Impedance was < 3 kOhms; filter bandpass was 0.01–30 Hz. Randomly intermixed background (80%, 1000 Hz) and target (20%, 2000 Hz) tones were delivered by shielded headphones at 55 dB normal hearing level. Subjects were seated comfortably and kept a running mental count of target tones. At least 25 electroencephalograph episodes following the target tones were averaged and the task was repeated to confirm reproducibility. Attention was verified by comparing actual target tone count with the number counted by the subjects. In the case of more than a 10% discrepancy, the task was repeated. Peak latencies were obtained by extrapolation of adjacent slopes and were reviewed by a second investigator. The P300 was defined as a large positive deflection later than 280 ms; amplitudes were calculated between P300 and N400 peaks.
Blood chemistry was analysed on a BM-Hitachi 917 (Roche Diagnostics, Mannheim, Germany). Full blood counts were analysed using a Sysmex hematology analyser (TAO Medical Electronics Company, Kobe, Japan).
Liver biopsy was performed in 105 patients using a modified 1.6 mm Menghini needle (Hepafix B, Braun-Melsungen AG, Germany). Histology was graded for inflammatory activity and fibrosis according to Ludwig .
Data are expressed as means ± SD unless otherwise indicated. Statistical analysis was performed using SigmaStat software, version 2.0 (Jandel Scientific Corp., San Rafael, CA, USA). P values less than 0.05 were considered statistically significant; all tests were two-tailed. Data were tested for normality using the Kolmogornow–Smirnov test. Group comparison was performed with Student's t-test for normally distributed data and with the Mann–Whitney U test for non-parametric data. As log-transformed scores did not appreciably change the results, we present untransformed scores in all the tables. The performance of FIS and BFI scores was investigated using: (i) discriminant validity to explore the ability to discriminate between patients and controls according to the characteristics of fatigue; and (ii) concurrent validity by correlating the scores for the specific fatigue scales with those for the SF-36 scales. The concurrent validity was fulfilled when the scale scores for fatigue showed close correlation (Spearman > 0.4) .
The influence of fatigue severity, clinical and P300 characteristics on HRQL was explored using Pearson and Spearman (non-parametric) correlation coefficient tests. Significant correlations were further investigated using best subset and backward linear regression analysis. Similarly, we investigated the relationship between fatigue severity, mode of infection, duration and severity of liver disease, and serum biochemical parameters reflecting hepatic function. Multicollinearity between variables was excluded according to Belsley et al. .
Patient characteristics are presented in Table 1. Most of the patients had mild chronic hepatitis. All patients with cirrhosis (n = 25) were in Child A stage and none had ascites. Previous injection drug users were younger than other patient groups (38 versus 48 years, P = 0.002).
None of the patients had overt cognitive dysfunction or dementia as indicated by normal scores in the mini mental state examination (median score, 30; range 26–30).
Sixty-one patients with HCV infection (51%) claimed to be affected by severe fatigue. A detailed assessment of fatigue severity is presented in Table 2. FIS scores ranged between 0 and 125, median 41.5 points. BFI scores ranged between 0.8 and 11, median 2.9. BFI and FIS scores were significantly higher in patients than in controls. The scores were significantly correlated with each other (r = 0.77, P < 0.001, Fig. 2), supporting concurrent validity. Both scores showed similar correlations with all generic SF-36 domains and compound scores (Table 3). Female patients had more pronounced fatigue compared with men (FIS 58 ± 35 versus 44 ± 34, P = 0.05; BFI 3.5 ± 2.4 versus 2.4 ± 2.1, P = 0.04). A similar albeit not statistically significant trend was observed in the control group (FIS 31 ± 21 in women versus 24 ± 18 in men, P = 0.09; BFI 1.9 ± 1.7 versus 1.4 ± 1.3, P = 0.10, respectively).
Compared with healthy control subjects, the group of patients with chronic hepatitis C infection exhibited significantly delayed P300 peak latencies (358 ± 37 versus 344 ± 27 ms, P = 0.002) and reduced amplitudes (13 ± 8 versus 18 ± 7 ms, P < 0.001). Twenty-one of the 120 HCV-infected patients (18%) exhibited P300 latencies outside the age-adjusted normal range, suggesting subclinical cognitive dysfunction. These patients scored worse for current fatigue and general impairment of activity (P = 0.02, respectively) but not for total FIS and BFI (Table 4). They also displayed a trend towards a prolonged duration of HCV infection (7 versus 4 years, P = 0.08), more severe liver disease (bilirubin 1.0 versus 0.7 mg/dl, means, P = 0.05; serum albumin 43 versus 45 mg/dl, P = 0.04; platelets 155 versus 197 G/l, P = 0.01).
Health-related quality of life
Eleven patients left parts of the questionnaires uncompleted, thus 109 patients were analysed. Patients scored significantly below population-derived normative values for all of the SF-36 domains. Role physical, role emotional and social function were most significantly impaired (Table 4). The component scores of the SF-36, which summarize the eight domains of the SF-36 and are adjusted for values of the general population, demonstrated slightly less severe physical (physical component score 48 ± 10) than mental health impairment (mental component score 40 ± 9, P = 0.03) in patients with HCV infection.
The influence of fatigue, cognitive function, clinical parameters and age on HRQL was investigated by multivariate analysis. The multiple linear regression model revealed independent effects for the BFI score, age, and P300 amplitude on the physical component score (Table 5a). A similar relationship existed between FIS, BFI, age and the mental health component score (Table 5b). In contrast, no independent effects of cognitive dysfunction, sex, previous drug abuse and histological or biochemical features of hepatitis C activity could be demonstrated (data not shown).
This study demonstrates that fatigue severity and age are independently associated with impairment of HRQL in chronic HCV infection. Seen apart from a small effect of P300 amplitude, subclinical neurocognitive dysfunction was not independently related to HRQL impairment. Therefore, although patients with prolonged P300 latencies differed in some clinical aspects on univariate analysis, subclinical neurocognitive dysfunction, as the activity of hepatitis, had no apparent role in the pathogenesis of HRQL impairment.
Potential associations between HCV-induced fatigue and impaired HRQL have not been evaluated until recently. However, the studies assessing HCV-related fatigue have generated conflicting results . As a complex multidimensional symptom involving both somatic and psychological domains, fatigue is influenced by multiple factors, including awareness of disease . Asymptomatic HCV-infected blood donors show little difference from healthy controls , whereas fatigue becomes a frequent symptom in patients with an established diagnosis . In the well-documented cohort of 376 Irish women infected by HCV-contaminated anti-D globulin, the incidence of fatigue was as high as 66%, despite a very low incidence of cirrhosis (2%) . The importance of psychological factors is also reflected by the frequent persistence of fatigue despite a virological response to therapy . Mechanisms related to increased oxidative stress , fibromyalgia , cryoglobulinemia, interferon treatment or decompensated liver disease may also add to the subjective burden of disease.
The present study is the first to demonstrate that fatigue, rather than the severity of liver disease, sex or neurocognitive dysfunction, is a significant factor in the pathogenesis of HCV-associated HRQL reduction. Although assessment of fatigue and HRQL may overlap to some extent, no collinearity between the SF-36 and fatigue scores was detected, indicating that different dimensions were assessed. The FIS and the BFI performed similarly over a wide range of fatigue severity, demonstrating concurrent validity. Although the BFI tracks only a single dimension, best described as fatigue severity , multivariate analysis showed the independent relationship of the BFI with both physical and mental health. In contrast, the more complex FIS score was related to mental health impairment only. The BFI might therefore be at least as suitable as the FIS for the rapid assessment of fatigue in the clinical setting.
We employed the P300 method as an objective and independent measure of cerebral information processing to gain insight into the mechanism of cognitive impairment and to avoid the potential bias of fatigue, latent depression, or impaired self-rating in psychometric assessment. P300 latency, which correlates with reaction time and age, yielded abnormal findings in 18% of patients. Such P300 abnormalities occur early in HIV encephalopathy, even in virally suppressed HIV patients on antiretroviral therapy . A reduction of P300 amplitudes, reflecting cortical activation associated with conscious attention, was even more pronounced. Conversely, higher P300 amplitudes were related to better mental health compound scores on multivariate analysis (Table 5). Overall, subclinical dysfunction played a comparatively limited role in the pathogenesis of subjective health impairment, and was weakly related to reductions in general health and the physical component score.
As the severity of HCV-associated liver disease is only weakly associated with fatigue and effects on HRQL persisted even after liver transplantation , psychological factors leading to fatigue clearly need to be identified. Considering the negative media coverage of most HCV-related issues, the purported HRQL improvement in treatment responders is best explained by the relief of disease-related concerns, as patients are usually not blinded to their virological status . In line with this, former injection drug users aware of their HCV seropositivity scored worse for some SF-36 domains than otherwise comparable patients unaware of their HCV status .
Based on the increased prevalence of fatigue and neurocognitive abnormalities in HCV-infected compared with hepatitis B-infected patients, Foster and colleagues  raised the hypothesis of a HCV-induced cerebral dysfunction. Subsequently, neuropsychological, neurophysiological and cerebral 1H magnetic resonance abnormalities have all been attributed to the effects of HCV infection [6,7,31]. A direct infection with brain-specific quasispecies HCV variants has recently been discussed as a potential reason for neurocognitive symptoms , but causality is extremely difficult to prove.
Confirming other studies , we found no difference between previous injection drug users and other patients with respect to HRQL. This could relate to the younger age of drug users compared with patients infected by transfusion or contaminated equipment during plasmapheresis . In contrast, drug abuse was one of the main factors associated with HRQL impairment in patients co-infected with HIV and HCV . As in the French multicentre study , women appeared to be particularly affected by fatigue. As a similar, albeit statistically insignificant, difference existed in the control population, sociocultural or biological sex differences seem also to influence the perception of fatigue. Given a known correlation between fatigue and depression, sex differences in the incidence of latent depression might explain some of that difference .
Patient-based assessments of HRQL are increasingly used as endpoints in therapeutic trials of chronic hepatitis C . Given that most patients with HCV infection, and particularly those with additional risk factors such as HIV infection, will exhibit some degree of fatigue , our findings have potential implications: The treatment of fatigue will probably become a therapeutic requirement for healthcare providers dealing with hepatitis C. The side-effects of current antiviral treatment, including anaemia, depression, pain and weakness, have detrimental effects on subjective health perception . Because of the multidimensional nature of hepatitis C-related symptoms, a multimodal intervention that could be individually tailored including pharmacological and non-pharmacological components may be the best approach. Unfortunately, the available psychostimulants have a high potential for dependency, and new drugs such as modafinil still need to be investigated in patients with HCV infection . In contrast, structured exercise effectively improved HRQL in patients with the chronic fatigue syndrome, cancer, and AIDS, and may be the best treatment option currently available [39,40]. Consequently, we have initiated a randomized trial to investigate a structured exercise programme in patients with HCV infection.
The results of this study do not necessarily apply to all groups of HCV-infected patients. Our patients did not receive antiviral therapy, and the absence of associated negative HRQL effects may explain a comparatively moderate impairment in fatigue scores . As we excluded decompensated liver disease, complications of cirrhosis were unlikely to cause HRQL impairment, possibly rendering a more prominent role for fatigue. Even if patients with treated depression were excluded, we cannot waive the possibility that undisclosed depressive symptoms contributed to fatigue. Correlations between depression and fatigue, anxiety, somatization, interpersonal sensitivity and hostility have been documented in HCV-infected individuals . In contrast to other cohorts , patients exhibited no overt cognitive dysfunction compared with controls. The use of age and education-based population norms for the mini mental state could have slightly modified patient and control selection. Unfortunately, such data are not available for Austria. As patients were not blinded to their virological status, an awareness of disease may have impaired HRQL findings by a labeling effect . Finally, the absence of HCV and HIV tests in controls is a further potential weakness of this study.
In summary, fatigue severity and age but not neurocognitive dysfunction or hepatic function are associated with impaired HRQL in patients with untreated chronic HCV infection. Female patients were particularly affected by fatigue. These findings stress the need for effective therapeutic interventions to ameliorate the burden of fatigue in patients with HCV infection.
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