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Study Reports Hepatitis C Impairs Cognitive Functioning: memory,
concentration, depression
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This article is published in the current issue of the journal called
Hepatology. The authors report their findings from a small preliminary
study. They recommend further study is needed to confirm their findings.
These authors report patients in their HCV clinic who have HCV appear to have
cognitive impairment and more fatigue, depression, less concentration
ability, and less memory ability. The authors caution this is a small
preliminary study. They also caution that study bias is possible because
these patients were referred to the HCV clinic and so they may not represent
all patients such as those not referred to the clinic. Clinic referrals may
be sicker. The authors suggest two possible explanations for these symptoms:
(1) HCV may directly infect the brain similarly to the way HIV infects the
brain, (2) HCV may stimulate the immune system in a way that dysregulates
cytokine functioning causing these cytokines to be able to enter the brain
and cause dysregulation; this is discussed further near the end of the
article. These study findings are consistent with reports from some patients
with HCV, that they experience fatigue, anger, hostility, anxiety and
depression, and that they feel its associated with having HCV. But, this
association has not been well studied. This study was first reported at liver
meetings two years ago. In addition other studies have reported similar
findings. Here are a few links to these studies, and related articles:
Assessment of Fatigue and Psychologic Disturbances in Patients with Hepatitis
C Virus Infection
www.natap.org/2001/jul/assessment070901.htm
HCV and Brain Dysfunction (report of this study at liver conference 2 years
ago)
www.natap.org/2000/ddw/rpt_11.htm
HCV and Fatigue
www.natap.org/1999/aug/hcvandfatique82399.html
Abstract: Patients with chronic hepatitis C virus (HCV) infection frequently
report fatigue, lassitude, depression, and a perceived inability to function
effectively. Several studies have shown that patients exhibit low quality-of-l
ife scores that are independent of disease severity. We therefore considered
whether HCV infection has a direct effect on the central nervous system,
resulting in cognitive and cerebral metabolite abnormalities. Twenty-seven
viremic patients (HCV+) with biopsy-proven mild hepatitis due to HCV and 16
patients with cleared HCV were tested with a computer-based cognitive
assessment battery and also completed depression, fatigue, and
quality-of-life questionnaires. The HCV-infected patients were impaired on
more cognitive tasks than the HCV-cleared group (mean [SD]: HCV-infected,
2.15 [1.56]; HCV-cleared, 1.06 [1.24]; P = .02). A factor analysis showed
impairments in power of concentration and speed of working memory,
independent of a history of intravenous drug usage (IVDU), depression,
fatigue, or symptom severity. A subgroup of 17 HCV-infected patients also
underwent cerebral proton magnetic resonance spectroscopy (1H MRS). The
choline/creatine ratio was elevated in the basal ganglia and white matter in
this group. Patients who were impaired on 2 or more tasks in the battery had
a higher mean choline/creatine ratio compared with the unimpaired patients.
In conclusion, these preliminary results demonstrate cognitive impairment
that is unaccounted for by depression, fatigue, or a history of IVDU in
patients with histologically mild HCV infection. The findings on MRS suggest
that a biological cause underlies this abnormality. (HEPATOLOGY
2002;35:433-439.)
The HCV-infected group scored significantly worse on the power of
concentration (P = .001) and on the speed of memory processes (P = .001)
factor scores than the healthy controls.
With respect to the affective scores, the HCV-infected group scored worse on
the Hospital Anxiety and Depression Scales.
There were no statistically significant differences in the subjects'
assessment of fatigue in either the physical or mental domains, although
there was a trend toward increased fatigue in the HCV-infected group.
Similarly, with respect to the SF-36 quality-of-life scale, there were no
differences between the 2 groups in the mental summary score. However, there
was a significant difference in the physical summary score (P = .006), with
lower ratings in the HCV-infected group.
Comments By Study Authors
These preliminary findings are consistent with cognitive and cerebral 1H MRS
metabolite abnormalities in patients with histologically defined mild
hepatitis due to HCV infection. The data support the clinical impression and
assertions of many HCV-infected patients that they are cognitively impaired
("brain fog"). However, the mechanism underlying these findings remains to
be defined.
The HCV-infected patients were found to be more depressed than the
HCV-cleared group, as has been previously reported. There were no
statistically significant correlations between the cognitive factor scores
that were abnormal in the HCV-infected group and the depression
scores, indicating that impairment on these tasks is unlikely to be secondary
to depression. Furthermore, if depression was the sole explanation for
cognitive impairment in the HCV-infected patients, it is unlikely that it
would cause the selective cognitive impairments that we report.
A number of explanations may account for or contribute to the cognitive
dysfunction observed in HCV-infected patients, including (1) a biological
effect of HCV infection on the central nervous system, (2) the effect of
personality or HCV acquisition-associated factors such as a history of IVDU,
(3) the effect of affective disorders such as depression, or (4) the effect
of subjectively experienced symptoms such as fatigue. It should be noted that
these explanations are not necessarily mutually exclusive and might interact.
Patients with significant fibrosis or cirrhosis were excluded from the study,
thereby excluding minimal hepatic encephalopathy as the cause of the
abnormalities.
A history of serious drug usage that had stopped at least 2 years before
participation in the study (and in most cases much earlier) did not have an
impact on cognitive performance, regardless of HCV status.
The factor score analysis suggests that concentration and working memory
processes may be preferentially impaired. These scores are derived from the
summation of the reaction times on various tasks. We considered that the
abnormalities might simply be a reflection of pure motor slowing as a result
of a peripheral neuromuscular abnormality, but there were no differences in
the simple reaction time between the 2 groups indicating impairment of
central cognitive processes. Similar findings of slowed processing speed and
impaired working memory are the most prominent features of cognitive
dysfunction in patients with chronic fatigue syndrome. Such findings have
also been reported in the medically asymptomatic stages of HIV infection and
are consistent with the involvement of subcortical or frontostriatal brain
systems.
Although every attempt was made to prevent selection bias in this study, we
accept that the study populations may not be wholly representative of the
HCV-infected population because they were drawn from a tertiary referral HCV
clinic. In particular, it is possible that patients with worse symptoms, both
physical and psychological, are more likely to attend the clinic. Conversely,
the exclusion of patients who were taking antidepressants, comprising
20% of the initial recruits and possibly those HCV-infected patients who were
most likely to have cognitive dysfunction, may have led to an underestimation
of the level of cognitive impairment. The purpose of this study was to
investigate whether cognitive dysfunction is a feature of HCV infection,
whereas larger studies will be required to estimate the prevalence.
What may be the cause?
Using 1H MRS, the authors reported finding an increase in the basal ganglia
and whitematter choline/creatine ratio in patients with chronic HCV
infection.
Similar metabolite abnormalities in the same spatial distribution as those
reported here have been extensively documented in cerebral HIV infection,
both in neurosymptomatic and neuroasymptomatic individuals. In the case of
HIV, infection of cerebral microglia, possibly via infected monocytes
entering the brain, and subsequent microglial activation are believed to
underlie the MRS changes. This raises the prospect that the metabolite
abnormalities reported in this study are due to direct infection of the brain
by HCV. The concept of extrahepatic replication of HCV is not novel, with
several lines of evidence suggesting that peripheral blood mononuclear cells
are infected. Microglia comprise up to 20% of all glial cells and are
developmentally derived from bone marrow precursors of monocytic lineage. It
is believed that resident microglia turn over slowly and are replaced by
circulating monocytes. It is therefore possible that HCV may be introduced to
the central nervous system via infected monocytes, through a "trojan horse"
mechanism.
An alternative explanation for our findings is a centrally mediated effect of
peripherally derived cytokines that may cross the blood-brain barrier.
Although cytokines are large peptides, animal studies have demonstrated
passage of cytokines including tumor necrosis factor , interferons alfa and
gamma, and interleukins (IL) 1 and 1 across the blood-brain and blood-spinal
cord barriers. Alternatively, peripherally derived cytokines may bind to the
cerebral vascular endothelium, inducing the generation of secondary
messengers. Intracerebral cytokines have been associated with immunologic,
neurochemical, neuroendocrine, and behavioral activities. Indeed, treatment
with interferon alfa is associated with a constellation of symptoms,
including depression and reports of memory impairment and cognitive slowing.
Whether elevated endogenous cytokines in chronic inflammatory and infective
conditions exert a significant cognitive effect is unclear. Several studies
have reported elevated levels of circulating cytokines, including IL-1, IL-2,
IL-4, IL-6, IL-10, and tumor necrosis factor, in chronic HCV
infection; however, a recent study found no correlation between levels of
circulating IL-1, IL-6, tumor necrosis factor, and fatigue in chronic HCV
infection.
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