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HCV & Neurologic Dysfunction
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Altered monoaminergic transporter binding in hepatitis C related cerebral dysfunction: a neuroimmunologial condition?
COMMENTARY
Gut Nov 2006;55:1535-1537
D M Forton
Department of Gastroenterology and Hepatology, St George's Hospital, University of London, Blackshaw Rd, London SW17 0QT,
Fatigue, depression, and complaints of mild cognitive impairment, such as poor concentration and forgetfulness, are the commonest symptoms reported by patients with chronic hepatitis C virus (HCV) infection.1 Yet there remains considerable debate as to whether theses symptoms are caused by the virus itself. Fatigue is a multidimensional symptom with multiple, sometimes coexisting, determinants which may be biological, psychological, or sociological. It is an important cause of impaired health related quality of life (HRQL) in HCV infection.2 Numerous surveys have documented high prevalences of fatigue but consistently show no relationship with the degree of liver fibrosis, markers of inflammation, or viral load.3 This has led to the conclusion that there is no causal relationship between HCV and neuropsychological symptoms.4 Rather, psychological processes associated with diagnostic labelling, social functioning, anxiety about treatment, substance abuse, and depression have been invoked to account for impairments in HRQL.5,6 In contrast, a number of neuroimaging studies, including a single photon emission computerised tomography (SPECT) study published in this issue by Weissenborn and colleagues,7 have suggested that measurable abnormalities exist within the central nervous system (CNS) in a proportion of HCV infected individuals (see page 1624).8,9,10,11
The issue has tended to become polarised between functional and biological arguments, and the likely interaction between physical and psychological factors has been relatively ignored. Attempts have been made to control for relevant confounding factors to determine whether CNS dysfunction relates directly to HCV infection. In a carefully executed study where 300 HCV infected patients were screened for potential risk factors for cognitive impairment such as cirrhosis, psychiatric comorbidity, or previous substance abuse, a highly selected cohort of only 37 patients was identified to have no likely cause for cerebral dysfunction, other than HCV infection itself.11 This small group underwent cognitive testing and patients were found to have significant impairments in learning efficiency, which did not relate to fatigue and depression, which were also reported. These findings followed on from previous studies which had demonstrated deficits in attention, learning ability, and memory in HCV infected individuals without cirrhosis.9,10,12
Cerebral magnetic resonance spectroscopy gives information on cerebral metabolism and has been used to test the hypothesis that a biological mechanism underlies the neuropsychological dysfunction in HCV infection. Four published studies have showed significant alterations in cerebral choline (Cho) and N-acetylaspartate (NAA) in HCV infected patients without cirrhosis.8,9,10,11 The findings of elevated Cho and reduced NAA mirror those reported in human immunodeficiency virus (HIV) infection,13 a virus which is tropic to the CNS. Detection of replicative intermediates of HCV (negative strand RNA) within the CNS14 and different viral variants in the CNS, liver, and serum15 support the concept of low level HCV replication within the brain. Although the mild neurocognitive impairments seen in HCV infection are not progressive as in AIDS dementia, it has been suggested that they may result from cerebral immune activation, possibly as a result of CNS infection by HCV.9
There is some clinical evidence that ondansetron, a serotonin type 3 receptor antagonist, may ameliorate HCV associated fatigue.16 In view of this and the evidence of cognitive and cerebral metabolic abnormalities in HCV infection, Weissenborn and colleagues sought to determine whether altered monoaminergic neurotransmission is associated with cognitive dysfunction in selected patients.7 They studied 20 patients with exposure to HCV, 16 of whom were still viraemic and four who had no detectable virus in serum, as determined by polymerase chain reaction (PCR). Patients had been referred to a tertiary hospital neurology clinic for assessment of fatigue and cognitive decline. In agreement with previous studies, these patients displayed varying degrees of neurocognitive impairment, predominantly in the domain of attention. They also recorded high rates of depression, anxiety, and fatigue. The four PCR negative patients appeared to be equally impaired on all scales. Patients were studied with SPECT to measure serotonin and dopamine transporter binding capacity (SERT and DAT, respectively). Statistically significant reductions in hypothalamus/midbrain SERT and striatal DAT binding were found compared with healthy controls. Pathological SERT and DAT binding were evident in 50-60% of HCV exposed cases, including three of the four PCR negative patients. There were no correlations between the SPECT data and fatigue, mood, or HRQL. However, patients with impaired DAT or DAT and SERT binding did worse as a group on the cognitive tests compared with both healthy controls and HCV infected patients with normal SPECT measurements. These novel findings are interpreted as implicating a role for disturbed monoaminergic neurotransmission in the pathophysiology of HCV-associated cerebral dysfunction.
A number of lines of less direct evidence support this conclusion. The therapeutic use of cytokines such as interleukin 2 (IL-2) and interferon (IFN-a) is associated with the induction of depressive symptoms in patients with cancer or viral hepatitis.17 These symptoms respond to treatment with the selective serotonin reuptake inhibitors, which are active at the presynaptic serotonin transporter.18 This has led to research into the immune basis of depression by investigators within the psychoneuroimmunological community.19
Interactions between the immune system and serotonergic neurotransmission have been demonstrated at a number of levels, both peripherally and within the CNS. Cytokine receptors are expressed on glia and neurones within the brain. Peripherally derived cytokines may signal to the CNS through a number of pathways,20 including induction of proinflammatory cytokines by perivascular macrophage-like cells, saturable transport across the blood brain barrier at high concentrations, and an action on afferent nerves to the CNS such as the vagus nerve.21 This mechanism may be particularly relevant in HCV infection where the cytokine milieu in the liver, innervated by the vagus nerve, is deranged. Although the basal level of cytokine production within the brain is likely to be low, a network exists whereby cells, particularly microglia, may produce cytokines in response to peripheral signals. For example, peripheral administration of lipolpolysaccharide to rats results in intracerebral IL-1β production.22 Cerebral immune activation may alter the metabolism of key monoamines (for example, IL-1β increases expression of the serotonin transporter gene in vitro).23 There is also evidence that IFN-a increases serotonin uptake in vitro through increased expression of the serotonin transporter,24 and that intracerebroventricular injections of IFN- in rats reduce frontal cortex and midbrain serotonin concentrations in a dose dependent manner.25
Studies of IFN-a administration in humans have generated data on serotonin metabolism. IFN-a increases serum kynurenine (KYN) concentrations and reduces serum serotonin and tryptophan (TRP) concentrations and these changes have been shown to correlate with depression ratings.17,26 The mechanism whereby this occurs is thought to be related to induction by IFN- of the enzyme indoleamine 2,3-dioxygenase (IDO), expressed on immune cells, including microglia.27 IDO catalyses the conversion of TRP to KYN, reducing the availability of TRP for serotonin synthesis. There is also evidence that endogenous cytokine production in states of chronic immune activation, such as HIV infection or rheumatoid arthritis, may results in TRP depletion and high KYN levels, expressed as an increased KYN/TRP ratio.28 For example, in HIV infection, elevated KYN/TRP correlates with levels of IFN- and neopterin,29 suggesting that in states of chronic Th-1 type immune activation, IDO is induced. Furthermore, an association between TRP depletion and cognitive impairment has been reported in HIV infection.30 To date, there are no data in chronic HCV infection but a similar interaction seems possible.
There are therefore a number of possible mechanisms through which peripheral and central immune activation could result in alterations in monoaminergic neurotransmission in HCV infection. These mechanisms remain theoretical and untested in HCV infection. Given the complexity of these systems and the possibility of changes in regulation of monoaminergic transporters and receptors over time in chronic disease, the functional significance of the findings of reduced midbrain SERT and striatal DAT binding in this study remains unclear. Although the role of these brain regions in cognitive processing is not resolved, the findings in this study do implicate a role, or at least an association, between disturbed monoamine function and cognitive function in HCV infection. Indeed, the concept of cerebral immune activation as the basis for these changes may allow a model that incorporates both the biological and psychological theories to date. Animal data suggest that psychogenic stressors and proinflammatory cytokines may result in similar outcomes, in terms of neurotransmitter activity.20 This may go some way to explaining why reduced SERT and DAT binding were observed in three of the four patients who had cleared HCV from serum. As Weissenborn and colleagues7 have postulated, there may be a sustained CNS effect even after the virus has been eradicated from serum, which may result in some form of sensitisation, conferring increased vulnerability to psychogenic stressors.
CNS symptoms are only present in a proportion of individual with HCV infection. In others it is a truly asymptomatic condition. It is likely that these symptoms result as a consequence of a complex interplay between viral and host genetic factors and external stressor events. Further investigation of the CNS effects of HCV infection and chronic immune activation may enable, in time, the development of strategies to treat the neuropsychological symptoms in those who do not respond to or tolerate antiviral therapy.
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