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Study Reports Hepatitis C Impairs Cognitive Functioning: memory, concentration, depression
  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
HCV and Brain Dysfunction (report of this study at liver conference 2 years ago)
HCV and Fatigue
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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