Recently we had a nice presentation about the data regarding whether or not there is neuropsychological impairment secondary to hepatitis C virus itself in patients so infected. This was presented by a senior medical student who was rotating on our Medical Psychiatry Unit as a subintern, Timothy Kiong. The title of his talk was “Brain Fog: A brief summary of current studies in HCV-related psychiatric changes”. Tim is interested in pursuing a medical-psychiatry combined residency program.
Tim presented some data regarding whether or not there is evidence to support the hypothesis that the hepatitis C virus itself can cause cognitive impairment, perhaps by an inflammatory mechanism. We already know that the main treatment for hepatitis C, which happens to be alpha interferon, can cause a wide variety of neuropsychiatric adverse effects including depression and cognitive impairment. We have already had one post by one of our family medicine residents about depression hepatitis C and interferon, please see link, Depression, Hepatitis C and Interferon: CPCP by Dr. Erin Schmidt – The Practical Psychosomaticist.
- Hepatitis C virus is transmitted through blood products, exchange of body fluids, and sexual contact.
- Hepatitis C effects about 2% of the world population.
- About 75%–85% of cases go on to chronic infection.
- About one third of injection drug users are infected with hepatitis C (rate is higher in older ages)
- Signs and symptoms of acute hepatitis C include fever, fatigue, dark urine and clay-colored stools, nausea and vomiting, and/or joint pain.
- More commonly it is asymptomatic in chronic cases.
- Hepatic transaminases are generally elevated.
- Tests used to confirm infection include the anti-HCV, recombinant immunoblot assay (RIBA), and the polymerase chain reaction (PCR).
HCV-related neuropsychiatric changes:
- Hepatic encephalopathy can be seen, in most cases a synonym for delirium.
- 50% patient’s complaint of “brain fog”, weakness, fatigue, and general life impairment.
- These changes seem to be irrespective of the genotype of HCV.
Studies supporting such a hypothesis:
- 2001: Forton and colleagues identified cerebral metabolic abnormalities in the frontal white matter and basal ganglia of HCV patients.
- 2002: Forton and colleagues identified significant impairment of concentration and working memory in 27 HCV PCR positive, anti-HCV positive versus HCV PCR negative, anti-HCV positive patients.
- A number of studies demonstrated neuropsychiatric changes, but had confounders.
- 2005: McAndrews and colleagues identified minor attention and verbal learning impairments in 37 HCV patients without confounders (substance abuse, cirrhosis, depression).
- 2010: Lowry and colleagues identified 20 females in a homogenous cohort, 11 HCV RNA positive with poor scores in memory, as well as auditory and sustained attention.
- Two studies were done on healthy blood donors compared against those who were HCV positive by PCR. There were no differences in neuropsychiatric function.
- Another study of subjects who had both hepatitis B and hepatitis C showed no differences in cognitive function.
Theories behind the dysfunction:
- There could be direct neurotoxic effects.
- There could be indirect neurotoxic effects mediated by systemic inflammation.
- There have been varied studies with varying results and different confounding factors.
- The subjects generally had persistently normal ALT for 6 months.
- The case for HCV-related neuropsychological findings still appears to be a matter of debate.
Centers for Disease Control web site, Centers for Disease Control and Prevention
Forton, D. M., J. M. Allsop, et al. (2001). “Evidence for a cerebral effect of the hepatitis C virus.” Lancet 358(9275): 38-39.
Patients with hepatitis C virus (HCV) infection frequently complain of symptoms akin to the chronic fatigue syndrome and score worse on health-related quality of life indices than matched controls. We address the hypothesis that HCV itself affects cerebral function. Using proton magnetic-resonance spectroscopy we have shown elevations in basal ganglia and white matter choline/creatine ratios in patients with histologically-mild hepatitis C, compared with healthy volunteers and patients with hepatitis B. This elevation is unrelated to hepatic encephalopathy or a history of intravenous drug abuse, and suggests that a biological process underlies the extrahepatic symptoms in chronic HCV infection.
Forton, D. M., H. C. Thomas, et al. (2002). “Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease.” Hepatology 35(2): 433-439.
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-life 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 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.
Lowry, D., B. Coughlan, et al. (2010). “Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients.” Journal of viral hepatitis 17(5): 352-359.
Neurocognitive dysfunction has been reported in individuals with chronic hepatitis C (CHC) infection, but HCV populations investigated have often included participants with numerous potential confounding comorbidities. This pilot study sought to investigate functional capacity and neurocognitive function in a homogeneous state-infected HCV population with histologically defined mild liver disease, free from the comorbid factors typically associated with HCV populations. A further aim was to examine cognitive function in a treatment naive population with a similar history of iatrogenic HCV exposure and spontaneous viral clearance. A convenience sample of 29 women, all of whom were carefully screened to exclude relevant comorbidities, was recruited to the study. Twenty women with a history of iatrogenic HCV exposure were recruited from prospective specialist tertiary care liver clinics. A comparison group of healthy controls (n = 9) was also assessed. Study participants underwent mood, health-related quality of life and neuropsychological assessment. CHC patients reported significantly higher levels of cognitive fatigue than healthy controls (F = 3.4, P = 0.04). On cognitive testing, CHC patients showed impairments compared with healthy controls on estimates of general memory [F(2,25) = 4.1, P = 0.03, partial eta squared = 0.25], delayed auditory recognition [F(2,25) = 4.2, P = 0.03, partial eta squared= 0.22] and sustained attention [F(2,25) = 3.6, P = 0.04, partial eta squared = 0.22]. Increased cognitive fatigue only correlated with delayed auditory memory recall ability (r = 0.724, P = 0.006). In conclusion, these findings appear to support the presence of neurocognitive abnormalities in an iatrogenically infected, homogeneous female HCV population who were carefully screened to eliminate other factors affecting neurocognitive test performance and may indicate underlying neurophysiological causative mechanisms.
McAndrews, M. P., K. Farcnik, et al. (2005). “Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors.” Hepatology 41(4): 801-808.
Neurocognitive morbidity has been reported in individuals with chronic hepatitis C virus (HCV) infection, but the magnitude of such dysfunction in the absence of disease-correlated factors known to affect the central nervous system (e.g., substance abuse, cirrhosis, depression, interferon treatment) and the impact of any such change on functioning is unclear. We investigated a cohort of individuals with HCV, all of whom were carefully screened to exclude relevant comorbidities, to elucidate virus-related changes in the brain using neuropsychological tests and magnetic resonance spectroscopy (MRS). A cohort of 37 patients with chronic HCV infection was culled from 300 consecutive patients presenting to a tertiary care liver clinic. A comparison group of healthy controls (n = 46) was also assessed. Of 10 neurocognitive measures evaluated, the HCV group showed marginally poorer learning efficiency compared with controls; only 13% of patients demonstrated a clinical level of impairment on this test (defined as 1.5 SD below the normative standard). Although patients reported greater levels of fatigue and symptoms of depression, these factors did not correlate with the degree of learning inefficiency. With respect to MRS, the HCV group demonstrated increased choline and reduced N-acetyl aspartate relative to controls in the central white matter. Indicators of liver disease severity did not correlate with either memory or MRS abnormalities. In conclusion, while our findings support an association between hepatitis C and indicators of central nervous system involvement in a cohort of patients carefully screened to eliminate other factors influencing neurocognitive integrity, the clinical significance of these effects is limited.
Senzolo, M., S. Schiff, et al. (2011). “Neuropsychological alterations in hepatitis C infection: the role of inflammation.” World journal of gastroenterology : WJG 17(29): 3369-3374.
About 50% of patients with hepatitis C virus (HCV) infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease. Since the first observation of HCV-related cognitive deficits, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis, patients who had acquired the infection through previous intravenous drug misuse, who had a history of relatively recent treatment with interferon, or were on psychoactive medication. In addition, different neuropsychological batteries and tests that explored different cognitive domains were used, which makes the results of the studies difficult to compare. Finally, limited information is available on the pathogenesis of HCV-related cognitive impairment. Cerebral and/or systemic inflammation may be important players but their potential role has not been substantiated by experimental data. The present review outlines the available evidence of the presence of cognitive impairment in patients with HCV infection, with a focus on the potential relationship with cerebral and/or systemic inflammation. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160562/pdf/WJG-17-3369.pdf
Capuron, L. and A. H. Miller (2004). “Cytokines and psychopathology: lessons from interferon-alpha.” Biological Psychiatry 56(11): 819-824.
Interferon-alpha is a potent inducer of the cytokine network and is notorious for causing behavioral alterations. Studies on interferon-alpha-treated patients reveal at least two distinct syndromes: 1) a mood/cognitive syndrome that appears late during interferon-alpha therapy is responsive to antidepressants and is associated with activation of neuroendocrine pathways and altered serotonin metabolism; and 2) a neurovegetative syndrome characterized by psychomotor slowing, and fatigue that appears early during interferon-alpha treatment is antidepressant nonresponsive and may be mediated by alterations in basal ganglia dopamine metabolism. Findings from interferon-alpha may provide important clues regarding the pathophysiology and treatment of cytokine-induced behavioral changes in medically ill patients, while also potentially modeling the development of neuropsychiatric symptoms in patients without medical disorders.
Capuron, L., G. Pagnoni, et al. (2005). “Anterior cingulate activation and error processing during interferon-alpha treatment.” Biological Psychiatry 58(3): 190-196.
BACKGROUND: There has been increasing interest in the role of immunologic processes, notably cytokines, in the development of behavioral alterations, especially in medically ill patients. Interferon (IFN)-alpha is notorious for causing behavioral symptoms, including depression, fatigue, and cognitive dysfunction, and has been used to investigate the effects of cytokines on the brain. METHODS: In the present study we assessed the effects of low-dose IFN-alpha on brain activity, using functional magnetic resonance imaging during a task of visuospatial attention in patients infected with hepatitis C virus (HCV). RESULTS: Despite endorsing symptoms of impaired concentration and fatigue, IFN-alpha-treated patients (n = 10) exhibited task performance and activation of parietal and occipital brain regions similar to that seen in HCV-infected control subjects (n = 11). Interestingly, however, in contrast to control subjects, IFN-alpha-treated patients exhibited significant activation in the dorsal part of the anterior cingulate cortex (ACC), which highly correlated with the number of task-related errors. No such correlation was found in control subjects. CONCLUSIONS: Consistent with the role of the ACC in conflict monitoring, ACC activation during IFN-alpha administration suggests that cytokines might increase processing conflict or reduce the threshold for conflict detection, thereby signaling the need to exert greater mental effort to maintain performance. Such alterations in ACC activity might in turn contribute to cytokine-induced behavioral changes.