Metabolic Brain Disease

, Volume 24, Issue 1, pp 197–210 | Cite as

Hepatitis C virus infection and the brain

  • Karin Weissenborn
  • Anita B. Tryc
  • Meike Heeren
  • Hans Worthmann
  • Henning Pflugrad
  • Georg Berding
  • Martin Bokemeyer
  • Hans L. Tillmann
  • Annemarie Goldbecker
Original Paper


There is growing evidence that hepatitis C virus (HCV)-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy fatigue persists in about one third of the patients. Many patients, in addition, report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning ability as characteristic for HCV-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebral serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilisation compatible with alterations of the dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in lymphoid tissue. Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain (probably in microglia) and to infect brain cells, especially astrocytes.


Hepatitis C virus Brain Cognition Health related quality of life Fatigue 


  1. Adair D, Wilkinson J, Scheck A, Radkowski M, Rakela J, Laskus T (2004) Differential display and microarray analysis show differentially expressed genes in central nervous system in HCV infected patients and laser capture microscopy points to brain microglia as cells harboring HCV. Hepatology 40:433AGoogle Scholar
  2. Chaudhuri A, Behan PO (2004) Fatigue in neurological disorders. Lancet 363:978–988PubMedCrossRefGoogle Scholar
  3. Cordoba J, Flavia M, Jacas C, Sauleda S, Esteban JI, Vargas V, Esteban R, Guardia J (2003) Quality of life and cognitive function in hepatitis C at different stages of liver disease. J Hepatol 39:231–238PubMedCrossRefGoogle Scholar
  4. Cozzi A, Zignego AL, Carpendo R, Biagiotti T, Aldinucci A, Monti M, Giannini C, Rosselli M, Laffi G, Moroni F (2006) Low serum tryptophan levels, reduced macrophage IDO activity and high frequency of psychopathology in HCV patients. J Viral Hepatitis 13:402–408CrossRefGoogle Scholar
  5. Fishman SL, Murray JM, Eng FJ, Walewski JL, Morgello S, Branch AD (2008) Molecular and bioinformatic evidence of hepatitis C virus evolution in brain. J Infectious Diseases 197:597–607CrossRefGoogle Scholar
  6. Fontana RJ, Bieliauskas LA, Back-Madruga C, Lindsay KL, Kronfol Z, Lok AS, Padmanabhan L, the HALT C trial group (2005) Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial. J Hepatol 43: 614–623PubMedCrossRefGoogle Scholar
  7. Fontana RJ, Bieliauskas LA, Lindsay KL, Back-Madruga C, Wright EC, Snow KK, Lok ASF, Kronfol Z, Padmanabhan L, the HALT-C Trial Group (2007) Cognitive function does not worsen during pegylated interferon and ribavirin retreatment of chronic hepatitis C. Hepatology 45:1154–1163PubMedCrossRefGoogle Scholar
  8. Forton DM (2006). Altered monoaminergic transporter binding in hepatitis C related cerebral dysfunction: a neuroimmunological condition? GUT 55 (11): 1535–1537CrossRefGoogle Scholar
  9. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD (2001) Evidence for a cerebral effect of the hepatitis C virus. Lancet 358:38-39PubMedCrossRefGoogle Scholar
  10. Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, Wesnes KA, Taylor-Robinson SD (2002) Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 35:433–439PubMedCrossRefGoogle Scholar
  11. Forton DM, Karayianni P, Mahmud N, Taylor-Robinson SD, Thomas HC (2004) 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. J Virology 78(10):5170–5183PubMedCrossRefGoogle Scholar
  12. Forton DM, Taylor-Robinson S, Thoma HC (2006) Central nervous system changes in hepatitis C virus infection. Eur J Gastroenterol Hepatol 18:333–338PubMedCrossRefGoogle Scholar
  13. Foster GR, Goldin RD, Thomas HC (1998) Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 27:209–212PubMedCrossRefGoogle Scholar
  14. Hassoun Z, Willems B, Deslauriers J, Nguyen BN, Huet PM (2002) Assessment of fatigue in patients with chronic hepatitis C using the fatigue impact scale. Dig Dis Sci 47(12):2674–2681PubMedCrossRefGoogle Scholar
  15. Hüppe D, Zehnter E, Mauss S, Böker K, Lutz T, Racky S, Schmidt W, Ullrich J, Sbrijer I, Heyne R, Schober A, John C, Hey KH, Bokemeyer B, Kallinowski B, Miller B, Pape S, Gutmann M, Alshuth U, Niederau C (2008) Epidemiolgie der chronischen Hepatitis C in Deutschland—Eine Analyse von 10326 Hepatitis C-Virus-Infizierten aus Schwerpunktpraxen und—ambulanzen. Z Gastrenterol 46:34–44CrossRefGoogle Scholar
  16. Jones EA (1999) Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. Lancet 354:397PubMedCrossRefGoogle Scholar
  17. Jüngling FD, Ebert D, Gut O, Engelbrecht MA, Rasenack J, Nitzsche EU, Bauer J, Lieb K. (2000) Prefrontal cortical hypometabolism during low-dose interferon alpha treatment. Psychopharmacology (Berl) 152(4): 383–389CrossRefGoogle Scholar
  18. Kallman J, O’Neil MM, Larive B, Boparai N, Calabrese L, Younossi ZM (2007) Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci 52:2531–2539PubMedCrossRefGoogle Scholar
  19. Karaivazoglou K, Assimakopoulos K, Thomopoulos K, Theocharis G, Messinis L, Sakellaropoulos G, Labropoulou-Karatza C (2007) Neuropsychological function in Greek patients with chronic hepatitis C. Liver International 27(6):798–805PubMedCrossRefGoogle Scholar
  20. Kenny-Walsh E (1999) Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 340(16):1228–1233Google Scholar
  21. Laskus T, Radkowski M, Adair DM, Wilkinson J, Scheck AC, Rakela J (2005) Emerging evidence of hepatitis C virus neuroinvasion. AIDS 19(suppl 3):S140–S144PubMedCrossRefGoogle Scholar
  22. Laskus T, Radkowski M, Bednarska A, Wikinson J, Adair D, Nowicki M, Nikolopoulou GB, Vargas H, Rakela J (2002) Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. J Virol. 76:10064–10068PubMedCrossRefGoogle Scholar
  23. McAndrews MP, Farcnik K, Carlen P, Damyanovich A, Mrkonjic M, Jones S, Heathcote EJ (2005) Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 2005; 41(4): 801–808CrossRefGoogle Scholar
  24. Niederau C, Bemba G, Kautz A (2006) Sozioökonomische Charakteristika, Lebensqualität und Wissensstand bei Patienten mit Hepatitis C-Virusinfektion in Deutschland. Z Gastroenterol 44:305–317PubMedCrossRefGoogle Scholar
  25. Niederau C, Fischer C, Kautz A (2007) Sozioökonomische Charakteristika, Lebensqualität und Wissensstand bei Patienten mit Hepatitis B-Virusinfektion in Deutschland. Sozioökonomische Aspekte der Hepatitis B. Z Gastroenterol 45:355–368PubMedCrossRefGoogle Scholar
  26. Niederau C, Bemba G, Kautz A (2008) Entwicklung von sozioökonomischen Charakteristika, Lebensqualität und Wissensstand bei patienten mit Hepatitis C während des Projektes Kompetenznetz Hepatitis. Z Gastroenterologie 46:22–33CrossRefGoogle Scholar
  27. Piche T, Vanbiervliet G, Cherikh F, Antoun Z, Huet PM, Gelsi E, Damarquay J-F, Caroli-Bosc F-X, Benzaken S, Rigault M-C, Renou C, Rampal P, Tran A (2005) Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut 54:1169–1173PubMedCrossRefGoogle Scholar
  28. Poynard T, Cacoub P, Ratziu V, Myers RP, Dezailles MH, Mercadier A, Ghillani P, Charlotte F, Piette JC, Moussalli J (2002) Fatigue in patients with chronic hepatitis C. Journal of Viral Hepatitis 2002; 9: 295–303CrossRefGoogle Scholar
  29. Provencher SW (1995) Automated estimation of metabolite concentrations from localized proton MRS. New prospects in psychiatry. The bio-clinical interface:405–413.Google Scholar
  30. Radkowski M, Wilkinson J, Nowicki M, Adair D, Vargas H, Ingui C, Rakela J, Laskus T (2002) Search for hepatitis c virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 76(2):600–608PubMedCrossRefGoogle Scholar
  31. Rodger AJ, Jolley D, Thompson SC, Lanigan A, Crofts N (1999) The impact of diagnosis of hepatitis C virus on quality of life. Hepatology 30:1299–1301PubMedCrossRefGoogle Scholar
  32. Seeff LB (2002) Natural history of chronic hepatitis C. Hepatology 36:S35–S46PubMedCrossRefGoogle Scholar
  33. Soogoor M, Lynn HS, Donfield SM, Gomperts E, Bell TS, Daar ES, for the Hemophilia Growth and Development Study (2006) Hepatitis C virus infection and neurocognitive function. Neurology 67:1482–1485PubMedCrossRefGoogle Scholar
  34. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H (2001) Neuropsychological characterization of hepatic encephalopathy. J Hepatol 34(5):768–773PubMedCrossRefGoogle Scholar
  35. Weissenborn K, Krause J, Bokemeyer M, Hecker H, Schüler A, Ennen JC, Ahl B, Manns MP, Böker KW (2004) Hepatitis C virus infection affects the brain—evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 41(5):845–851PubMedCrossRefGoogle Scholar
  36. Weissenborn K, Ennen JC, Bokemeyer M, Ahl B, Wurster U, Tillmann H, Trebst C, Hecker H, Berding G (2006) Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. GUT 55(11):1624–1630PubMedCrossRefGoogle Scholar
  37. Wiese M, Berr F, Lafrenz M, Porst H, Oesen U (2000) Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in germany: a 20-year multicenter study. Hepatology 32:91–96PubMedCrossRefGoogle Scholar
  38. Wiese M, Grüngreiff K, Güthoff W, Lafrenz M, Oesen U, Porst H, for the East German Hepatitis C Study Group (2005) Outcome in a hepatitis C (genotype 1b). Single source outbreak in Germany—a 25 year multicenter study. J Hepatology 43(4):590–598CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Karin Weissenborn
    • 1
  • Anita B. Tryc
    • 1
  • Meike Heeren
    • 1
  • Hans Worthmann
    • 1
  • Henning Pflugrad
    • 1
  • Georg Berding
    • 2
  • Martin Bokemeyer
    • 3
  • Hans L. Tillmann
    • 4
  • Annemarie Goldbecker
    • 1
  1. 1.Department of NeurologyHannover Medical SchoolHannoverGermany
  2. 2.Department of Nuclear MedicineHannover Medical SchoolHannoverGermany
  3. 3.Department of Diagnostic and Interventional NeuroradiologyHannover Medical SchoolHannoverGermany
  4. 4.Department of Medicine, Division of Gastroenterology, DCRIDuke UniversityDurhamUSA

Personalised recommendations