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Neuropsychological Impairment in Patients with Chronic Hepatitis C
  ABSTRACT: Hepatitis C is the most common cause of chronic liver disease in the United States and it significantly reduces quality of life. The role of cognitive deficits contributing to the morbidity of this disease has not been well characterized. The purpose of this study was to examine cognitive functioning in patients with chronic hepatitis C and to investigate relationships among parameters of disease severity and performance on neuropsychological tests. Sixty-six patients with chronic hepatitis C and 14 patients with other chronic liver diseases were administered a brief battery of neuropsychological tests assessing attention, visuoconstructional ability, learning, memory, and psychomotor speed. Cognitive impairment in patients with chronic hepatitis C ranged from 0% on a visuoconstructional task to 82% on a measure of sustained attention and concentration. Test scores of patients with chronic hepatitis C did not differ from those of patients with other chronic liver diseases. Hence, patients with and without chronic hepatitis C experience cognitive deficits, especially in tasks requiring attention and psychomotor speed. In addition, there was a significant relationship between fibrosis stage and test performance, with greater fibrosis associated with poorer performance. However, both patients with and without cirrhosis exhibited cognitive dysfunction. In conclusion, these findings suggest that progressive hepatic injury may result in cognitive problems even before the development of cirrhosis. Future studies need to determine the effect of this decrease in cognitive function on quality of life. (HEPATOLOGY 2002;35:440-446; Hilsabeck, Perry, and Hassanein)
These study findings suggest that attention and concentration may be the cognitive skill most affected early in the course of chronic liver disease. Thus, early identification and treatment of chronic HCV irrespective of histologic stage may improve cognitive functioning. Improvements in cognitive impairment have been reported after treatment with antiviral therapy for HCV.
In all cases, greater levels of fibrosis were associated with greater cognitive dysfunction. These associations suggest that the longer one experiences chronic hepatic injury, the more likely one is to develop neurocognitive problems.
Neurocognitive problems such as these can greatly impact performance on daily activities. Problems paying attention and concentrating can interfere with one's ability to learn new information, focus on a single task for a long period of time, and/or perform multiple tasks simultaneously without error. Psychomotor slowing, especially in combination with impaired attention and concentration, can result in prolonged periods of time needed to complete even routine tasks. Patients with these types of neurocognitive problems may fail to remember (or remember incorrectly) details about their liver disease, treatment regimen, and/or physicians' recommendations. They may experience difficulty performing their household and job duties as efficiently and/or as accurately as they are accustomed to, which may lead to claims of disability. As a result of these difficulties, many patients experience frustration and mood problems, such as depression and anxiety, which often exacerbate the underlying problem.
The current findings must be interpreted within the context of the study sample. Consecutive patients were recruited from a specialty liver clinic at a large university medical center. Thus, this patient population may not be representative of all patients with chronic liver disease. It is likely that our patient sample had more significant liver disease and/or comorbid medical problems than patients managed solely by their primary care physicians or persons in the general population with chronic liver disease. An additional limitation is the low number of initially recruited subjects that actually completed neuropsychological testing (i.e., 86 out of 254); however, there were no significant group differences in age, gender, ethnicity, etiology of liver disease, and fibrosis between patients who did and did not complete neuropsychological measures.
The authors do nor speculate on the causes for cognitive impairment in HCV or other diseases they looked at in this study. However, English researchers speculate in a separate report in the same issue of Hepatology for which a summary is also available on the NATAP website. They suggest that perhaps HCV enters the brain similarly to HIV.

The hepatitis C virus (HCV) is the most common cause of chronic liver disease in the United States and the leading indication for liver transplantation.1 According to a population-based study conducted from 1988 to 1994, an estimated 2.7 million individuals are currently infected with HCV.2 The proportion of HCV-infected patients with cirrhosis is expected to increase from the 15.6% noted in 1988 to an estimated 28.9% by 2018.3 Increases of 84% and 63% are expected in the rates of hepatic decompensation and hepatocellular carcinoma, respectively, and deaths related to HCV are expected to triple over the next 2 decades.3
Multiple studies have revealed that infection with HCV significantly reduces quality of life (QOL), even in the absence of cirrhosis.4,5 Currently, there is no clear explanation for this reduction. Koff6 suggested that pathophysiological events resulting from infection may be contributing to decreased QOL in HCV-infected patients. This decrease may be related to the impact of HCV infection on cognitive abilities, such as attention and memory functioning. In patients with cirrhosis and end-stage liver disease, neuropsychological impairment has been well documented.7,8 These deficits have been attributed to molecules and toxins accumulating in the blood that are not effectively cleared by the cirrhotic liver. In patients with HCV infection, it often takes more than 20 years of chronic hepatic injury before the liver develops cirrhosis and its complications. During this time, liver function is impaired, albeit slightly. The possibility that cognitive dysfunction may result from slight impairment of liver function, even before the development of cirrhosis, has not been well examined, nor has the possibility that infection with HCV itself may result in cognitive impairment.
There were 2 primary purposes of this study. First, we investigated the prevalence of cognitive impairment of patients with HCV. We then compared test performances of HCV-infected patients to those of patients with other types of chronic liver diseases to explore whether infection with HCV was associated with greater cognitive dysfunction. We hypothesized that patients with HCV would perform significantly worse on tests of cognitive functioning than patients with other types of chronic liver disease because of reports of decreased QOL in patients with HCV compared with patients with other types of chronic liver disease.4,9 Second, we examined the relationship between fibrosis stage and test performance to ascertain the association between disease severity and cognitive dysfunction. Our hypothesis was that greater fibrosis would be associated with poorer test performance. We also explored the prevalence of impaired neuropsychological performances of noncirrhotic patients to determine if cognitive deficits exist in the absence of advanced liver injury (i.e., cirrhosis) and then compared performances of noncirrhotic patients with those of cirrhotic patients. We hypothesized that noncirrhotic patients would perform better than cirrhotic patients on all neuropsychological measures.
Average age of the final sample was 45.98 years (SD = 8.55), and average education was 13.31 years (SD = 2.33). The majority of patients were male (64%), and most were White (68%). Average estimated IQ as measured by the Shipley Institute of Living Scale10 was 102.68 (SD = 13.53), which is in the average range. QOL was measured with the SF-36,11 and level of fatigue was assessed using the Fatigue Severity Scale.12 The average SF-36 Physical and Mental Composite Scores (PCS and MCS) for this sample were 37.86 (SD = 11.92) and 42.95 (SD = 11.05), respectively. Average level of fatigue was 4.44 (SD = 1.7) on a scale from "1" (i.e., least severe) to "7" (i.e., most severe). Twenty-seven percent of patients were taking psychiatric medication at the time of the study, and 48% reported they had taken psychiatric medication in the past. These percentages are very similar to those reported by Dwight et al.,13 who found that 28% of their sample were currently depressed and 44% had lifetime histories of major depression or dysthymia. Most of the current sample (67%) admitted to a history of illicit drug abuse, with 3 patients reporting drug abuse in the past month. The majority of patients, 69%, denied current alcohol use, with another 27% reporting alcohol use less than once a month. Thus, only 4% of the sample reported alcohol use more than 2 to 4 times a month.
Sixty-six of the 80 patients were diagnosed with chronic HCV, and 14 were diagnosed with other etiologies of liver disease. Forty-four of the 66 HCV-infected patients had no medical problems other than HCV. The remaining 22 were diagnosed with the following comorbid chronic conditions: alcoholic hepatitis (N = 10), human immunodeficiency virus (HIV; N = 8), hepatitis B (N = 2), alcoholic hepatitis and hepatitis B (N = 1), and a small liver tumor (N = 1). Diagnoses of the 14 patients with chronic liver diseases other than HCV included hepatitis B (N = 5), cryptogenic (N = 4), alcoholic hepatitis (N = 2), autoimmune hepatitis (N = 2), and nonalcoholic fatty liver (N = 1). Of the 66 HCV-infected patients, 24% had been previously treated with interferon therapy and 23% were undergoing interferon therapy at the time of the study.
Fibrosis stage was determined by liver biopsy according to the METAVIR scoring system.14 Level of fibrosis was graded as none in 9 patients, stage 1 (mild) in 15 patients, stage 2 (moderate) in 4 patients, and stage 3 (severe) in 13 patients. Stage 4 (cirrhosis) was identified in 34 patients. Liver biopsy was not performed on 5 patients for the following reasons: severe psychiatric problems (N = 1), hemophilia (N = 1), biopsy at another institution within the past 3 years (N = 1), refusal (N = 1), and failure to return for biopsy (N = 1). Diagnoses of the 5 patients who were not biopsied were HCV (N = 3), HCV and alcoholic hepatitis (N = 1), and HCV and HIV (N = 1). No patient was suffering from delirium or clinically evident hepatic encephalopathy at the time of the study.
Significant differences were found between patients with HCV only and patients with HCV plus another chronic medical condition on 4 of the 8 neuropsychological measures. On all 4 measures, HCV patients with comorbid medical conditions performed significantly worse than patients with HCV only. Additionally, these 2 HCV patient groups differed significantly in level of fibrosis [2 (4) = 12.30; P = .02]; patients with HCV plus another chronic condition had significantly worse fibrosis. HCV-infected patients with comorbid alcoholic hepatitis (N = 10) did not differ significantly from HCV-infected patients with other comorbidities (N = 12) on any of the neuropsychological measures [t (20) ranged from -0.15 to 1.63]. Likewise, patients co-infected with HCV and HIV (N = 8) did not differ significantly from patients with HCV plus other comorbidities (N = 14) on any of the neuropsychological measures [t (20) ranged from 0.47 to -1.90]. However, HCV-infected patients with alcoholic hepatitis were significantly more likely to have cirrhosis than HCV-infected patients with other types of chronic medical conditions [2 (1) = 5.46; P = .02], and HCV/HIV patients were significantly less likely to have cirrhosis than HCV-infected patients with other comorbidities [2 (1) = 12.38; P < .001].
Relationships between disease severity and neuropsychological performance
There were significant associations in the hypothesized direction between stage of fibrosis and cognitive performance on 4 of the 8 neuropsychological Measures. In all cases, greater fibrosis was associated with poorer neuropsychological performance.
This study examined neuropsychological dysfunction in patients with chronic HCV. Results of this study revealed that a significant percentage of patients with chronic HCV experience cognitive deficits, especially in the domains of attention, learning, psychomotor speed, and mental flexibility. In contrast, visuoconstructional skills and the ability to remember previously learned information following a delay were relatively intact. This pattern of cognitive dysfunction is similar to that reported in patients with mild neurocognitive disorder associated with other chronic illness, such as HIV and AIDS-related dementia, and is most consistent with a subcortical pattern of deficits. The neuropsychological manifestation of subcortical deficits usually includes slowed information processing speed, reduced word fluency, psychomotor slowing, and impaired learning in the presence of good recall of previously learned information and intact recognition memory. Verbal skills, such as vocabulary and naming, and basic visuospatial and visuoconstructional abilities are relatively unaffected.
Findings suggest that chronic HCV in combination with comorbid chronic illness may result in increased levels of cognitive dysfunction, especially in the presence of alcoholic hepatitis. This result cannot be attributed to age, education, estimated IQ, overall QOL, fatigue, psychiatric medication usage, substance use, or treatment with interferon.
Replication of this finding using larger, more homogenous samples stratified by level of fibrosis is needed before definitively concluding that there are no HCV-specific pathophysiological effects on cognitive functioning.
This study also reports neuropsychological impairment in patients who have not yet developed cirrhosis. Impaired performances were found in up to 50% of noncirrhotic patients, depending on the neuropsychological function tested. Of the cognitive functions measured, only visuoconstructional ability was within normal limits for all noncirrhotic patients. Maintaining attention and concentration for more than a couple of minutes while performing accurately (i.e., Digit Cancellation) was the most difficult task for noncirrhotic patients, with 50% taking an abnormally long time to complete the task and 28.9% making a significant number of omission errors. In addition, about 20% of noncirrhotic patients performed in the impaired range on 3 other measures involving attention/concentration, visual scanning and tracking, psychomotor speed, and mental flexibility (i.e., Parts A and B of the TMT and SDMT). These results suggest that attention and concentration may be the cognitive skill most affected early in the course of chronic liver disease.
In summary, there were no significant differences in neuropsychological test scores between HCV-infected patients and patients with other chronic liver diseases. However, a greater proportion of patients with HCV plus a comorbid illness performed in the impaired range than patients with HCV only or another type of chronic liver disease. Greater fibrosis was significantly associated with poorer cognitive functioning. Although patients with cirrhosis generally performed more poorly on neuropsychological measures than precirrhotic patients, a significant percentage of patients without cirrhosis were found to exhibit cognitive deficits. In conclusion, results of this study suggest that HCV and other chronic liver diseases adversely affect cognitive functioning, even in the absence of cirrhosis. Attention and concentration abilities appear to be affected earliest in the disease process, although problems with learning, psychomotor speed, and mental flexibility are also present to a lesser extent. These deficits, regardless of their cause, may affect QOL and performance in the work and home environments. Hence, early identification and treatment of chronic liver disease could be critical in diminishing detrimental effects on brain function. The degree of cognitive dysfunction of patients with chronic liver disease should be considered when evaluating the functional capacity of these patients.
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