NATAP - DDW Liver Conference, San Diego, May 21-24 - Report 11

HCV and Brain Dysfunction

We know that HIV enters the brain shortly after a person is infected with HIV. It does appear as though individuals with HIV may experience symptoms related to this such as reduced alertness or a slower thinking capacity due to HIV. At both recent liver conferences--DDW and EASL--two different research groups reported research findings suggesting that HCV in individuals with less advanced disease (non-cirrhotics or mild fibrosis) affects the brain and reduces its functioning capacity. This suggests to me that a person with both HCV and HIV may be affected even more with regards to brain functioning. Over the years people with HIV have complained about experiencing fatigue and/or itching. We now know that many people with HIV also have HCV, and that HCV can cause itching and fatigue. The findings reported at DDW and EASL suggest that HCV related fatigue may be associated with the affect of HCV on the brain.

It's known that individuals with advanced cirrhosis can experience hepatic encephalopothy which can cause brain disorder, but it's important to bear in mind that the participants in the studies discussed below did not have such advanced HCV disease so the brain dysfunctioning found was not due to hepatic encephalopoathy.

At DDW, Ludwig Kramer and a research group from the University of Austria, reported that "cognitive processing was subclinically impaired in patients as compared to healthy subjects". They studied the impact of HCV infection on sensitive markers of cognitive brain function. Fifty-eight noncirrhotic patients with chronic HCV infection (age, 45±13 years, mean±SD) were studied by P300 event-related potentials (an objective measure of cognitive processing) and by the SF-36 questionnaire for assessment of health-related quality of life. Findings were compared to 58 matched healthy subjects. He found that P300 test results were imparied in patients with HCV compared to healthy volunteers, and conluded that patients with chronic HCV infection in the absence of cirrhosis exhibit a subclinical neurophysiological impairment. Cerebral function, however, seems to normalize with antiviral treatment. Although it was not apparent to me if normalization was tied with significant reductions in HCV viral levels, my feeling is that improvements in cerebral function can improve with HCV treatment despite no HCV viral level reductions. More detailed data and discussion are available below at the end of this report.

At EASL, DM Horton presented an oral talk on brain dysfunction in people with HCV for a UK research group from the Imperial College School of Medicine and St Mary's Hospital in London. First he reviewed two studies. He mentioned a UK study (Foster et al 1998) using the SF-36 questionaire, and reported people with HCV compared to normal controls scored worse in physical and social functioning, energy and fatigue, and other measures. These  results were independent of intravenous drug use. In a large US (Johnson et al 1998), 309 IVDUs both with or without HCV were tested for depression and those with HCV (57.2%) were found to have significantly more depressive symptomology than those who were negative to hepatitis (48.2%).

In an attempt to further define this neuropsychological syndrome, they administered a battery of neuropsychometric tests to 15 patients with histologically mild hepatitis C from liver biopsy. They tested for attention (included: simple reaction time, choice reaction time), working memory (numeric & spatial working memory), and secondary memory (delayed word recall). They found that patients with mild or minimal hepatis C from liver biopsy were slower in tests of working memory. He noted that although they were slow their accuracy on these tasks was preserved, and this has been described in chronic fatigue syndrome. There were no attention or secondary memory abnormalities.

In the view of these findings they asked themselves if HCV infects cells in the CNS (central nervous system), does this cause cerebral metabolite abnormalities, and is cerebral HCV infection the cause of the observed neuropsychological symptoms? They carried out a proton cerebral magnetic resonance spectroscopy study to determine if metabolite abnormalities exist in the brain of patients with hitologically mild hepatitis C. They randomly selected 30 patients with biopsy proven mild or minimal hepatitis due to HCV. As well, they studied 29 matched controls, and 12 eAG+ve patients with chronic HBV. No patient in the HBV or HCV groups had significant fibrosis or cirrhosis. The researchers reported seeing metabolic abnormalities in the testing in those with HCV compared to both normals (volunteers) and chronic HBV patients. There were no statistical differences between the normals and those with HBV. These abnormalities were not due to hepatic encephalopathy. They described the abnormalities as being similar to those abnormalities observed in HIV. Again, no patient in this study had significant fibrosis or cirrhosis. None of the study participants had used IV drugs in the 6 months preceding the study.  There was no statistical difference in the study results between those with or without prior drug use. Those with prior drug use had the same abnormalities as those who never used IV drugs. The researchers concluded that prior drug use did not affect the outcome of the study.

Is there direct infection by HCV of the CNS?

He presented a suggested potential model by which this could happen. Microglial cells in the brain turn over slowly and are replenished by circulating monocytes, possibly up to 30% in one year. Circulating monocytes are potentially infectable by HCV, and may carry the virus across the blood brain barrier into the brain and the microglial cells. Once in the cells they become activated and produce chemokines, cytokines, and neurosteroids which may mediate the neuropsychiatric symptoms described in this presentation. The question still remains--does HCV infect the microglial cells in the brain? The only way to answer this question is to conduct direct post mortem viralogic examination of brain tissue which is being currently undertaken at Imperial College School of Medicine in London.

He also sugested that of equal or possibly greater importance is the possibility that the  brain may act as a sancutary site for HCV allowing immune evasion and protection against antiviral therapy. He suggested that cessation of viral production from the liver may occur during phase 1 of viral decline after starting HCV therapy, but the slower viral decline during phase 2 may be due to a continued release of virus from the brain. He suggested that an alternative explanation for possible brain dysfunction seen with HCV could be that systemic cytokines cross the blood-brain barrier and may exert an effect. But he discounted this theory because in this study patients with HBV had normal spectroscopy. HCV antiviral therapy has been administered to the study patients and results are pending. In the study reported at DDW, and discussed above, the study authors reported therapy improved cerebral function, and they suggest their data may indicate a direct action of HCV infection on the brain.

DDW abstract:

COGNITIVE BRAIN FUNCTION IS SUBCLINICALLY IMPAIRED IN PATIENTS WITH CHRONIC HEPATITIS C - DOES HEPATITIS C AFFECT THE BRAIN?

Ludwig Kramer, Edith Bauer, Harald Hofer, Georg Funk, Petra Munda-Steindl, Christian Madl, Peter Ferenci, Dept of Medicine IV, Univ of Vienna, Vienna, Austria; Univ Hosp of Vienna, Vienna, Austria; Dept of Medicine IV, Vienna, Austria.

Fatigue and depression occur more frequently in chronic hepatitis C virus (HCV) infection than in other causes of chronic liver disease. However there is no correlation between severity of hepatitis and cerebral symptoms. It has been hypothesized that HCV exerted a direct effect on the brain. We studied the impact of HCV infection on sensitive markers of cognitive brain function. Fifty-eight noncirrhotic patients with chronic HCV infection (age, 45±13 years, mean±SD) were studied by P300 event-related potentials (an objective measure of cognitive processing) and by the SF-36 questionnaire for assessment of health-related quality of life. P300 latency is related to signal-processing speed; P300 amplitude reflects the amount of conscious attention paid to a stimulus. Findings were compared to 58 matched healthy subjects. We found that cognitive processing was subclinically impaired in patients (P300 latency: 361±38 ms, means±SD) as compared to healthy subjects (344±27 ms, p=0.01). Similarly, P300 amplitude was reduced in patients with HCV infection (12±7 vs. 18±7 µV, p<0.01). Health-related quality of life was significantly reduced in patients with HCV infection but there was no clear correlation between neurophysiological function and health-related quality of life or activity of hepatitis. In 7 out of 9 patients who were followed during antiviral combination treatment, P300 latency was improved after 12 weeks (345±29 ms) as compared to baseline (363±48 ms, p=0.08). In conclusion, patients with chronic HCV infection in the absence of cirrhosis exhibit a subclinical neurophysiological impairment. Cerebral function, however, seems to normalize with antiviral treatment. Our data might indicate a direct action of HCV infection on the brain. A theory that I've heard is that improvement from therapy is due to ribavirin because interferon does not enter the brain. But in HIV it's hypothesized that brain or cognivtive functioning may improve also because of improved immune function and not necessarily due only to direct antiviral drug affect in the brain or CNS.