Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment

Background: The majority of patients with hepatitis C virus (HCV) infection suffer from disabling fatigue, cognitive dysfunction, and quality of life reduction. Meanwhile, there is increasing evidence that HCV infection can affect brain function. Recent studies have shown that fatigue and psychomotor slowing may resolve in patients with hepatitis C after treatment with ondansetron. This observation indicates alteration of serotonergic neurotransmission in HCV infected patients with chronic fatigue. Methods: Data from 20 HCV infected patients who were referred to our clinic because of disabling fatigue and cognitive decline of unknown cause were analysed retrospectively. Patients had undergone a diagnostic programme, including clinical and psychometric examination, electroencephalogram (EEG), magnetic resonance imaging of the brain, cerebrospinal fluid analysis, and I-123-beta-CIT (2β-carbomethoxy-3-β-(4-[123I]iodophenyl)tropane) single photon emission computerised tomography (SPECT) studies of serotonin and dopamine transporter binding capacity. Results: All patients had pathological results on the fatigue impact scale. Two thirds of patients showed pathological attention test results. EEG, magnetic resonance imaging, and cerebrospinal fluid analysis were normal. Pathological dopamine transporter binding was present in 12/20 (60%) patients and pathological serotonin transporter binding in 8/19 (50%) patients. Patients with normal SPECT results did not significantly differ from controls with regard to psychometric test results. Interestingly, patients with both decreased serotonin and dopamine transporter binding showed significantly impaired performance in most of the tests applied. Comorbidity that could have impaired cerebral function was excluded in all patients. Conclusion: Our findings indicate alteration of serotonergic and dopaminergic neurotransmission in HCV infected patients with chronic fatigue and cognitive impairment.

[1]  J. Rakela,et al.  Emerging evidence of hepatitis C virus neuroinvasion. , 2005, AIDS.

[2]  M. Lafrenz,et al.  Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany--a 25-year multicenter study. , 2005, Journal of hepatology.

[3]  J. Bell,et al.  Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. , 2005, Virus research.

[4]  F. Caroli-Bosc,et al.  Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study , 2005, Gut.

[5]  P. Carlen,et al.  Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors , 2005, Hepatology.

[6]  M. Manns,et al.  Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. , 2004, Journal of hepatology.

[7]  Bryan L. Roth,et al.  Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders , 2004, Psychopharmacology.

[8]  H. Thomas,et al.  Identification of Unique Hepatitis C Virus Quasispecies in the Central Nervous System and Comparative Analysis of Internal Translational Efficiency of Brain, Liver, and Serum Variants , 2004, Journal of Virology.

[9]  J. Hornung,et al.  The human raphe nuclei and the serotonergic system , 2003, Journal of Chemical Neuroanatomy.

[10]  V. Pieribone,et al.  Midbrain serotonergic neurons are central pH chemoreceptors , 2003, Nature Neuroscience.

[11]  J. Kalbfleisch,et al.  A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C , 2003, Hepatology.

[12]  D. Brooks,et al.  [123I]β-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson’s disease and multiple system atrophy , 2003, Nuklearmedizin.

[13]  A Pupi,et al.  European Association of Nuclear Medicine procedure guidelines for brain neurotransmission SPET using (123)I-labelled dopamine D(2) transporter ligands. , 2002, European journal of nuclear medicine and molecular imaging.

[14]  L. Kramer,et al.  Subclinical impairment of brain function in chronic hepatitis C infection. , 2002, Journal of hepatology.

[15]  P. Cacoub,et al.  Fatigue in patients with chronic hepatitis C , 2002, Journal of viral hepatitis.

[16]  J. Piette,et al.  Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C. , 2002, Journal of hepatology.

[17]  J. Allsop,et al.  Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease , 2002, Hepatology.

[18]  J. Rakela,et al.  Search for Hepatitis C Virus Negative-Strand RNA Sequences and Analysis of Viral Sequences in the Central Nervous System: Evidence of Replication , 2002, Journal of Virology.

[19]  P. Celada,et al.  Control of Dorsal Raphe Serotonergic Neurons by the Medial Prefrontal Cortex: Involvement of Serotonin-1A, GABAA, and Glutamate Receptors , 2001, The Journal of Neuroscience.

[20]  J. Crowe,et al.  The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection , 2001, Gut.

[21]  J. Allsop,et al.  Evidence for a cerebral effect of the hepatitis C virus , 2001, The Lancet.

[22]  B. Walker,et al.  Hepatitis C virus infection. , 2001, The New England journal of medicine.

[23]  A. Rodger,et al.  Assessment of Long‐Term Outcomes of Community‐Acquired Hepatitis C Infection in a Cohort With Sera Stored From 1971 to 1975 , 2000, Hepatology.

[24]  F. Berr,et al.  Low frequency of cirrhosis in a hepatitis C (genotype 1b) single‐source outbreak in germany: A 20‐year multicenter study , 2000, Hepatology.

[25]  R. Dixon,et al.  Age-related cognitive deficits mediated by changes in the striatal dopamine system. , 2000, The American journal of psychiatry.

[26]  L. Seeff,et al.  45-Year Follow-up of Hepatitis C Virus Infection in Healthy Young Adults , 2000, Annals of Internal Medicine.

[27]  D. Jolley,et al.  The impact of diagnosis of hepatitis C virus on quality of life , 1999, Hepatology.

[28]  J. Crowe,et al.  Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. , 1999, European journal of gastroenterology & hepatology.

[29]  E. Jones Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy , 1999, The Lancet.

[30]  R. Bennett,et al.  Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients. , 1999, The American journal of gastroenterology.

[31]  E. Kenny‐Walsh Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. , 1999, The New England journal of medicine.

[32]  N. Volkow,et al.  Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. , 1998, The American journal of psychiatry.

[33]  H. Thomas,et al.  Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis , 1998, Hepatology.

[34]  M. Bayliss,et al.  Health assessment for chronic HCV infection , 1996, Digestive Diseases and Sciences.

[35]  C. Bréchot Hepatitis C virus , 1996, Digestive Diseases and Sciences.

[36]  J. Karhu,et al.  Imaging of serotonin and dopamine transporters in the living human brain , 1995, European Journal of Nuclear Medicine.

[37]  Huston Gj,et al.  The Hospital Anxiety and Depression Scale. , 1987, The Journal of rheumatology.

[38]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[39]  J. Kornhuber,et al.  SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain , 2005, Journal of Neural Transmission / General Section JNT.

[40]  N. Volkow,et al.  Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism. , 2000, The American journal of psychiatry.

[41]  T. Marrie,et al.  Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. , 1994, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[42]  E. C. Fenner,et al.  Behaviour , 1980 .

[43]  S. Holm A Simple Sequentially Rejective Multiple Test Procedure , 1979 .