NATAP - DDW Liver Conference, San Diego, May 21-24 - Report 11
and Brain Dysfunction
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.
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
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.
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%).
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.
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.
there direct infection by HCV of the CNS?
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.
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.
BRAIN FUNCTION IS SUBCLINICALLY IMPAIRED IN PATIENTS WITH CHRONIC HEPATITIS C -
DOES HEPATITIS C AFFECT THE BRAIN?
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.
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.