Skip to main content

Advertisement

SpringerLink
Log in

Depression, fatigue and neurocognitive deficits in chronic hepatitis C

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood–brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

HCV:

Hepatitis C virus

HRQOL:

Health-related quality of life

PBC:

Primary biliary cholangitis

BBB:

Blood–brain barrier

IL:

Interleukin

HPA:

Hypothalamic–pituitary–adrenal

RNA:

Ribonucleic acid

MRS:

Magnetic resonance spectroscopy

HIV:

Human immunodeficiency virus

References

  1. Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 2014;61(1 Suppl):S45–S57

    Article  PubMed  Google Scholar 

  2. Sood S, Holmes A, Everall I, Saling M, Nicoll A. Depression in a real world population of hepatitis C patients. Gastroenterol Pancreatol Liver Disord 2014;1:1–3

    Google Scholar 

  3. Ashrafi M, Modabbernia A, Dalir M, Taslimi S, Karami M, Ostovaneh MR, et al. Predictors of mental and physical health in non-cirrhotic patients with viral hepatitis: a case control study. J Psychosom Res 2012;73(3):218–224

    Article  PubMed  Google Scholar 

  4. Bonkovsky HL, Woolley JM. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. Hepatology 1999;29(1):264–270

    Article  PubMed  CAS  Google Scholar 

  5. Ware JE, Kosinski M. Interpreting SF-36 summary health measures: a response. Qual Life Res 2001;10(5):405–413 (discussion 15–20)

    Article  PubMed  CAS  Google Scholar 

  6. Dan AA, Kallman JB, Srivastava R, Younoszai Z, Kim A, Younossi ZM. Impact of chronic liver disease and cirrhosis on health utilities using SF-6D and the health utility index. Liver Transpl 2008;14(3):321–326

    Article  PubMed  Google Scholar 

  7. Strauss E, Porto-Ferreira FA, de Almeida-Neto C, Teixeira MC. Altered quality of life in the early stages of chronic hepatitis C is due to the virus itself. Clin Res Hepatol Gastroenterol 2014;38(1):40–45

    Article  PubMed  Google Scholar 

  8. Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 1999;340(16):1228–1233

    Article  PubMed  CAS  Google Scholar 

  9. Younossi ZM, Stepanova M, Henry L, Nader F, Hunt S. An in-depth analysis of patient-reported outcomes in patients with chronic hepatitis C treated with different anti-viral regimens. Am J Gastroenterol 2016;111(6):808–816

    Article  PubMed  CAS  Google Scholar 

  10. Younossi ZM, Stepanova M, Marcellin P, Afdhal N, Kowdley KV, Zeuzem S, et al. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: results from the ION-1, -2, and -3 clinical trials. Hepatology 2015;61(6):1798–1808

    Article  PubMed  CAS  Google Scholar 

  11. Younossi ZM, Stepanova M, Sulkowski M, Foster GR, Reau N, Mangia A, et al. Ribavirin-free regimen with sofosbuvir and velpatasvir is associated with high efficacy and improvement of patient-reported outcomes in patients with genotypes 2 and 3 chronic hepatitis C: results from astral-2 and -3 clinical trials. Clin Infect Dis 2016;63(8):1042–1048

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dirks M, Pflugrad H, Haag K, Tillmann HL, Wedemeyer H, Arvanitis D, et al. Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus? J Viral Hepat 2017;24(7):541–550

    Article  PubMed  CAS  Google Scholar 

  13. Coughlan B, Sheehan J, Hickey A, Crowe J. Psychological well-being and quality of life in women with an iatrogenic hepatitis C virus infection. Br J Health Psychol 2002;7(Pt 1):105–116

    Article  PubMed  Google Scholar 

  14. Goh J, Coughlan B, Quinn J, O’Keane JC, Crowe J. Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. Eur J Gastroenterol Hepatol 1999;11(8):833–838

    Article  PubMed  CAS  Google Scholar 

  15. Pattullo V, McAndrews MP, Damyanovich A, Heathcote EJ. Influence of hepatitis C virus on neurocognitive function in patients free from other risk factors: validation from therapeutic outcomes. Liver Int 2011;31(7):1028–1038

    Article  PubMed  Google Scholar 

  16. Fuller BE, Rodriguez VL, Linke A, Sikirica M, Dirani R, Hauser P. Prevalence of liver disease in veterans with bipolar disorder or schizophrenia. Gen Hosp Psychiatry 2011;33(3):232–237

    Article  PubMed  Google Scholar 

  17. Evon DM, Simpson KM, Esserman D, Verma A, Smith S, Fried MW. Barriers to accessing care in patients with chronic hepatitis C: the impact of depression. Aliment Pharmacol Ther 2010;32(9):1163–1173

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Zickmund S, Hillis SL, Barnett MJ, Ippolito L, LaBrecque DR. Hepatitis C virus-infected patients report communication problems with physicians. Hepatology 2004;39(4):999–1007

    Article  PubMed  Google Scholar 

  19. Helbling B, Overbeck K, Gonvers JJ, Malinverni R, Dufour JF, Borovicka J, et al. Host-rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection. Gut 2008;57(11):1597–1603

    Article  PubMed  CAS  Google Scholar 

  20. Boscarino JA, Lu M, Moorman AC, Gordon SC, Rupp LB, Spradling PR, et al. Predictors of poor mental and physical health status among patients with chronic hepatitis C infection: the Chronic Hepatitis Cohort Study (CHeCS). Hepatology 2015;61(3):802–811

    Article  PubMed  Google Scholar 

  21. Golden J, O’Dwyer AM, Conroy RM. Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors. Gen Hosp Psychiatry 2005;27(6):431–438

    Article  PubMed  Google Scholar 

  22. Kroenke K, Strine TW, Spitzer RL, Williams JB, Berry JT, Mokdad AH. The PHQ-8 as a measure of current depression in the general population. J Affect Disord 2009;114(1–3):163–173

    Article  PubMed  Google Scholar 

  23. Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, et al. Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy. Clin Pract Epidemiol Ment Health 2007;3:22

    Article  PubMed  PubMed Central  Google Scholar 

  24. Carta MG, Angst J, Moro MF, Mura G, Hardoy MC, Balestrieri C, et al. Association of chronic hepatitis C with recurrent brief depression. J Affect Disord 2012;141(2–3):361–366

    Article  PubMed  Google Scholar 

  25. Lee K, Otgonsuren M, Younoszai Z, Mir HM, Younossi ZM. Association of chronic liver disease with depression: a population-based study. Psychosomatics 2013;54(1):52–59

    Article  PubMed  Google Scholar 

  26. Zacks S, Beavers K, Theodore D, Dougherty K, Batey B, Shumaker J, et al. Social stigmatization and hepatitis C virus infection. J Clin Gastroenterol 2006;40(3):220–224

    Article  PubMed  Google Scholar 

  27. Wilson MP, Castillo EM, Batey AM, Sapyta J, Aronson S. Hepatitis C and depressive symptoms: psychological and social factors matter more than liver injury. Int J Psychiatry Med 2010;40(2):199–215

    Article  PubMed  Google Scholar 

  28. Dore GJ, Law M, MacDonald M, Kaldor JM. Epidemiology of hepatitis C virus infection in Australia. J Clin Virol 2003;26(2):171–184

    Article  PubMed  Google Scholar 

  29. Brienza RS, Stein MD, Chen M, Gogineni A, Sobota M, Maksad J, et al. Depression among needle exchange program and methadone maintenance clients. J Subst Abuse Treat 2000;18(4):331–337

    Article  PubMed  CAS  Google Scholar 

  30. Cordoba J, Flavia M, Jacas C, Sauleda S, et al. Quality of life and cognitive function in hepatitis C at different stages of liver disease. J Hepatol 2003;39(2):231–238

    Article  PubMed  Google Scholar 

  31. Morasco BJ, Huckans M, Loftis JM, Woodhouse J, Seelye A, Turk DC, et al. Predictors of pain intensity and pain functioning in patients with the hepatitis C virus. Gen Hosp Psychiatry 2010;32(4):413–418

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tsui JI, Cheng DM, Libman H, Bridden C, Samet J. Hepatitis C virus infection is associated with painful symptoms in HIV-infected adults. AIDS Care 2012;24(7):820–827

    Article  PubMed  PubMed Central  Google Scholar 

  33. Adinolfi LE, Restivo L, Zampino R, Lonardo A, Loria P. Metabolic alterations and chronic hepatitis C: treatment strategies. Expert Opin Pharmacother 2011;12(14):2215–2234

    Article  PubMed  CAS  Google Scholar 

  34. Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC, Saadoun D. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis 2016;3(1):3–14

    PubMed  PubMed Central  CAS  Google Scholar 

  35. McDonald J, Jayasuriya J, Bindley P, Gonsalvez C, Gluseska S. Fatigue and psychological disorders in chronic hepatitis C. J Gastroenterol Hepatol 2002;17(2):171–176

    Article  PubMed  Google Scholar 

  36. Tillmann HL, Wiese M, Braun Y, Wiegand J, Tenckhoff S, Mossner J, et al. Quality of life in patients with various liver diseases: patients with HCV show greater mental impairment, while patients with PBC have greater physical impairment. J Viral Hepat 2011;18(4):252–261

    Article  PubMed  CAS  Google Scholar 

  37. Caradonna L, Mastronardi ML, Magrone T, Cozzolongo R, Cuppone R, Manghisi OG, et al. Biological and clinical significance of endotoxemia in the course of hepatitis C virus infection. Curr Pharm Des 2002;8(11):995–1005

    Article  PubMed  CAS  Google Scholar 

  38. Huckans M, Fuller BE, Olavarria H, Sasaki AW, Chang M, Flora KD, et al. Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection. Brain Behav 2014;4(2):123–142

    Article  PubMed  Google Scholar 

  39. Nadeau S, Rivest S. Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood–brain barrier. Neuroscience 1999;93(4):1449–1464

    Article  PubMed  CAS  Google Scholar 

  40. Wilkinson J, Radkowski M, Eschbacher JM, Laskus T. Activation of brain macrophages/microglia cells in hepatitis C infection. Gut 2010;59(10):1394–1400

    Article  PubMed  CAS  Google Scholar 

  41. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9(1):46–56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Silverman MN, Pearce BD, Biron CA, Miller AH. Immune modulation of the hypothalamic–pituitary–adrenal (HPA) axis during viral infection. Viral Immunol 2005;18(1):41–78

    Article  PubMed  CAS  Google Scholar 

  43. Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 2005;10(6):538–544

    Article  PubMed  CAS  Google Scholar 

  44. Nautiyal KM, Hen R. Serotonin receptors in depression: from A to B. F1000Research 2017;6:123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Kronfol Z, Remick DG. Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000;157(5):683–694

    Article  PubMed  CAS  Google Scholar 

  46. Maes M, Mihaylova I, Kubera M, Leunis JC, Geffard M. IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord 2011;135(1–3):414–418

    Article  PubMed  CAS  Google Scholar 

  47. Hardoy MC, Cadeddu M, Serra A, Moro MF, Mura G, Mellino G, et al. A pattern of cerebral perfusion anomalies between major depressive disorder and Hashimoto thyroiditis. BMC Psychiatry 2011;11:148

    Article  PubMed  PubMed Central  Google Scholar 

  48. Tafet GE, Nemeroff CB. The links between stress and depression: psychoneuroendocrinological, genetic, and environmental interactions. J Neuropsychiatry Clin Neurosci 2016;28(2):77–88

    Article  PubMed  Google Scholar 

  49. Wilkinson PO, Goodyer IM. Childhood adversity and allostatic overload of the hypothalamic–pituitary–adrenal axis: a vulnerability model for depressive disorders. Dev Psychopathol 2011;23(4):1017–1037

    Article  PubMed  Google Scholar 

  50. Kudielka BM, Wust S. Human models in acute and chronic stress: assessing determinants of individual hypothalamus–pituitary–adrenal axis activity and reactivity. Stress 2010;13(1):1–14

    Article  PubMed  Google Scholar 

  51. Birerdinc A, Afendy A, Stepanova M, Younossi I, Baranova A, Younossi ZM. Gene expression profiles associated with depression in patients with chronic hepatitis C (CH-C). Brain Behav 2012;2(5):525–531

    Article  PubMed  PubMed Central  Google Scholar 

  52. Matsunami K, Nishida N, Kaneko N, Ikeo K, Toyo-Oka L, Takeuchi H, et al. Genome-wide association study identifies ZNF354C variants associated with depression from interferon-based therapy for chronic hepatitis C. PLoS One 2016;11(10):e0164418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Forton DM, Karayiannis P, Mahmud N, Taylor-Robinson SD, Thomas HC. 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 Virol 2004;78(10):5170–5183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, et al. Hepatitis C virus infects the endothelial cells of the blood–brain barrier. Gastroenterology 2012;142(3):634–643 (e6)

    Article  PubMed  CAS  Google Scholar 

  55. Adair DM, Radkowski M, Jablonska J, Pawelczyk A, Wilkinson J, Rakela J, et al. Differential display analysis of gene expression in brains from hepatitis C-infected patients. AIDS 2005;19(Suppl 3):S145–S150

    Article  PubMed  CAS  Google Scholar 

  56. Fletcher NF, McKeating JA. Hepatitis C virus and the brain. J Viral Hepat 2012;19(5):301–306

    Article  PubMed  CAS  Google Scholar 

  57. Grover VP, Pavese N, Koh SB, Wylezinska M, Saxby BK, Gerhard A, et al. Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation. J Viral Hepat 2012;19(2):e89–e96

    Article  PubMed  CAS  Google Scholar 

  58. Norenberg MD, Itzhak Y, Bender AS. The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy. Adv Exp Med Biol 1997;420:95–111

    Article  PubMed  CAS  Google Scholar 

  59. Paulino AD, Ubhi K, Rockenstein E, Adame A, Crews L, Letendre S, et al. Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling. J Neurovirol 2011;17(4):327–340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005;66(1):41–48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Machado MO, Oriolo G, Bortolato B, Kohler CA, Maes M, Solmi M, et al. Biological mechanisms of depression following treatment with interferon for chronic hepatitis C: a critical systematic review. J Affect Disord 2017;209:235–245

    Article  PubMed  CAS  Google Scholar 

  62. Younossi Z, Henry L. Systematic review: patient-reported outcomes in chronic hepatitis C—the impact of liver disease and new treatment regimens. Aliment Pharmacol Ther 2015;41(6):497–520

    Article  PubMed  CAS  Google Scholar 

  63. Bell AM, Wagner JL, Barber KE, Stover KR. Elbasvir/grazoprevir: a review of the latest agent in the fight against hepatitis C. Int J Hepatol 2016;2016:3852126

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Bertino G, Ardiri A, Proiti M, Rigano G, Frazzetto E, Demma S, et al. Chronic hepatitis C: this and the new era of treatment. World J Hepatol 2016;8(2):92–106

    Article  PubMed  PubMed Central  Google Scholar 

  65. Greig SL. Sofosbuvir/velpatasvir: a review in chronic hepatitis C. Drugs 2016;76(16):1567–1578

    Article  PubMed  CAS  Google Scholar 

  66. Tang LS, Masur J, Sims Z, Nelson A, Osinusi A, Kohli A, et al. Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment. World J Hepatol 2016;8(31):1318–1326

    Article  PubMed  PubMed Central  Google Scholar 

  67. Younossi ZM, Stepanova M, Gordon S, Zeuzem S, Mann MP, Jacobson I, et al. Patient-reported outcomes following treatment of chronic hepatitis C virus infection with sofosbuvir and velpatasvir, with or without voxilaprevir. Clin Gastroenterol Hepatol 2018;16(4):567–574 (e6)

    Article  PubMed  CAS  Google Scholar 

  68. Younossi ZM, Stepanova M, Feld J, Zeuzem S, Sulkowski M, Foster GR, et al. Sofosbuvir and velpatasvir combination improves patient-reported outcomes for patients with HCV infection, without or with compensated or decompensated cirrhosis. Clin Gastroenterol Hepatol 2017;15(3):421–430 (e6)

    Article  PubMed  CAS  Google Scholar 

  69. Bonkovsky HL, Snow KK, Malet PF, Back-Madruga C, Fontana RJ, Sterling RK, et al. Health-related quality of life in patients with chronic hepatitis C and advanced fibrosis. J Hepatol 2007;46(3):420–431

    Article  PubMed  Google Scholar 

  70. Aaronson LS, Teel CS, Cassmeyer V, Neuberger GB, Pallikkathayil L, Pierce J, et al. Defining and measuring fatigue. Image J Nurs Scholarsh 1999;31(1):45–50

    Article  CAS  Google Scholar 

  71. Younossi ZM, Stepanova M, Henry L, Nader F, Younossi Y, Hunt S. Adherence to treatment of chronic hepatitis C: from interferon containing regimens to interferon and ribavirin free regimens. Medicine (Baltimore) 2016;95(28):e4151

    Article  CAS  Google Scholar 

  72. Ho SB, Brau N, Cheung R, Liu L, Sanchez C, Sklar M, et al. Integrated care increases treatment and improves outcomes of patients with chronic hepatitis C virus infection and psychiatric illness or substance abuse. Clin Gastroenterol Hepatol 2015;13(11):2005–2014 (e1–3)

    Article  PubMed  Google Scholar 

  73. Grebely J, Knight E, Genoway KA, Viljoen M, Khara M, Elliott D, et al. Optimizing assessment and treatment for hepatitis C virus infection in illicit drug users: a novel model incorporating multidisciplinary care and peer support. Eur J Gastroenterol Hepatol 2010;22(3):270–277

    Article  PubMed  Google Scholar 

  74. Bonkovsky HL, Tice AD, Yapp RG, Bodenheimer HC Jr, Monto A, Rossi SJ, et al. Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration. Am J Gastroenterol 2008;103(11):2757–2765

    Article  PubMed  CAS  Google Scholar 

  75. Gilbody S, Bower P, Fletcher J, Richards D, Sutton AJ. Collaborative care for depression: a cumulative meta-analysis and review of longer-term outcomes. Arch Intern Med 2006;166(21):2314–2321

    Article  PubMed  Google Scholar 

  76. Groessl EJ, Ho SB, Asch SM, Stepnowsky CJ, Laurent D, Gifford AL. The hepatitis C self-management program: sustainability of primary outcomes at 1 year. Health Educ Behav 2013;40(6):730–740

    Article  PubMed  Google Scholar 

  77. Kraus MR, Schafer A, Schottker K, Keicher C, Weissbrich B, Hofbauer I, et al. Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut 2008;57(4):531–536

    Article  PubMed  CAS  Google Scholar 

  78. Schaefer M, Sarkar R, Knop V, Effenberger S, Friebe A, Heinze L, et al. Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial. Ann Intern Med 2012;157(2):94–103

    Article  PubMed  Google Scholar 

  79. Baraldi S, Hepgul N, Mondelli V, Pariante CM. Symptomatic treatment of interferon-alpha-induced depression in hepatitis C: a systematic review. J Clin Psychopharmacol 2012;32(4):531–543

    Article  PubMed  CAS  Google Scholar 

  80. Schaefer M, Winterer J, Sarkar R, Uebelhack R, Franke L, Heinz A, et al. Three cases of successful tryptophan add-on or monotherapy of hepatitis C and IFNalpha-associated mood disorders. Psychosomatics 2008;49(5):442–446

    Article  PubMed  CAS  Google Scholar 

  81. Smolders EJ, de Kanter CT, de Knegt RJ, van der Valk M, Drenth JP, Burger DM. Drug–drug interactions between direct-acting antivirals and psychoactive medications. Clin Pharmacokinet 2016;55(12):1471–1494

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Friedberg F, Tintle N, Clark J, Bromet EJ. Prolonged fatigue in Ukraine and the United States: prevalence and risk factors. Fatigue 2015;3(1):33–46

    PubMed  Google Scholar 

  83. Swain MG. Fatigue in liver disease: pathophysiology and clinical management. Can J Gastroenterol 2006;20(3):181–188

    Article  PubMed  PubMed Central  Google Scholar 

  84. Kallman J, O’Neil MM, Larive B, Boparai N, Calabrese L, Younossi ZM. Fatigue and health-related quality of life (HRQL) in chronic hepatitis C virus infection. Dig Dis Sci 2007;52(10):2531–2539

    Article  PubMed  Google Scholar 

  85. Poynard T, Cacoub P, Ratziu V, Myers RP, Dezailles MH, Mercadier A, et al. Multivirc g. Fatigue in patients with chronic hepatitis C. J Viral Hepat 2002;9(4):295–303

    Article  PubMed  CAS  Google Scholar 

  86. Arnold LM. Understanding fatigue in major depressive disorder and other medical disorders. Psychosomatics 2008;49(3):185–190

    Article  PubMed  Google Scholar 

  87. Chaudhuri A, Behan PO. Fatigue in neurological disorders. Lancet 2004;363(9413):978–988

    Article  PubMed  Google Scholar 

  88. Heeren M, Weissenborn K, Arvanitis D, Bokemeyer M, Goldbecker A, Tountopoulou A, et al. Cerebral glucose utilisation in hepatitis C virus infection-associated encephalopathy. J Cereb Blood Flow Metab 2011;31(11):2199–2208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Monaco S, Ferrari S, Gajofatto A, Zanusso G, Mariotto S. HCV-related nervous system disorders. Clin Dev Immunol 2012;2012:236148

    Article  PubMed  PubMed Central  Google Scholar 

  90. Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol 2012;33(3):315–327

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med 2006;36(10):881–909

    Article  PubMed  Google Scholar 

  92. Weissenborn K, Ennen JC, Bokemeyer M, Ahl B, Wurster U, Tillmann H, et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut 2006;55(11):1624–1630

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. NeuroImmunoModulation 1997;4(3):134–153

    Article  PubMed  CAS  Google Scholar 

  94. Sarkar S, Jiang Z, Evon DM, Wahed AS, Hoofnagle JH. Fatigue before, during and after antiviral therapy of chronic hepatitis C: results from the Virahep-C study. J Hepatol 2012;57(5):946–952

    Article  PubMed  PubMed Central  Google Scholar 

  95. Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramirez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA 2001;286(11):1360–1368

    Article  PubMed  CAS  Google Scholar 

  96. Cook NF, Boore JR. Managing patients suffering from acute and chronic fatigue. Br J Nurs 1997;6(14):811–815

    Article  PubMed  CAS  Google Scholar 

  97. Gleason OC, Yates WR, Philipsen MA. Major depressive disorder in hepatitis C: an open-label trial of escitalopram. Prim Care Companion J Clin Psychiatry 2005;7(5):225–230

    Article  PubMed  PubMed Central  Google Scholar 

  98. Weissenborn K, Krause J, Bokemeyer M, Hecker H, Schuler A, Ennen JC, et al. Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 2004;41(5):845–851

    Article  PubMed  Google Scholar 

  99. Morales M, Battenberg E, de Lecea L, Bloom FE. The type 3 serotonin receptor is expressed in a subpopulation of GABAergic neurons in the rat neocortex and hippocampus. Brain Res 1996;731(1–2):199–202

    Article  PubMed  CAS  Google Scholar 

  100. Gerrard P, Malcolm R. Mechanisms of modafinil: a review of current research. Neuropsychiatr Dis Treat 2007;3(3):349–364

    PubMed  PubMed Central  CAS  Google Scholar 

  101. Rabkin JG, McElhiney MC, Rabkin R. Modafinil and armodafinil treatment for fatigue for HIV-positive patients with and without chronic hepatitis C. Int J STD AIDS 2011;22(2):95–101

    Article  PubMed  CAS  Google Scholar 

  102. Martin KA, Krahn LE, Balan V, Rosati MJ. Modafinil’s use in combating interferon-induced fatigue. Dig Dis Sci 2007;52(4):893–896

    Article  PubMed  CAS  Google Scholar 

  103. McAndrews MP, Farcnik K, Carlen P, Damyanovich A, Mrkonjic M, Jones S, et al. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 2005;41(4):801–808

    Article  PubMed  Google Scholar 

  104. Cherner M, Letendre S, Heaton RK, Durelle J, Marquie-Beck J, Gragg B, et al. Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology 2005;64(8):1343–1347

    Article  PubMed  CAS  Google Scholar 

  105. Murray J, Fishman SL, Ryan E, Eng FJ, Walewski JL, Branch AD, et al. Clinicopathologic correlates of hepatitis C virus in brain: a pilot study. J Neurovirol 2008;14(1):17–27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Kramer L, Bauer E, Funk G, Hofer H, Jessner W, Steindl-Munda P, et al. Subclinical impairment of brain function in chronic hepatitis C infection. J Hepatol 2002;37(3):349–354

    Article  PubMed  Google Scholar 

  107. Forton DM, Allsop JM, Main J, Foster GR, Thomas HC, Taylor-Robinson SD. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001;358(9275):38–39

    Article  PubMed  CAS  Google Scholar 

  108. Taylor-Robinson SD, Buckley C, Changani KK, Hodgson HJ, Bell JD. Cerebral proton and phosphorus-31 magnetic resonance spectroscopy in patients with subclinical hepatic encephalopathy. Liver 1999;19(5):389–398

    Article  PubMed  CAS  Google Scholar 

  109. Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002;35(2):433–439

    Article  PubMed  Google Scholar 

  110. Byrnes V, Miller A, Lowry D, Hill E, Weinstein C, Alsop D, et al. Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition. J Hepatol 2012;56(3):549–556

    Article  PubMed  CAS  Google Scholar 

  111. Kraus MR, Schafer A, Teuber G, Porst H, Sprinzl K, Wollschlager S, et al. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology 2013;58(2):497–504

    Article  PubMed  CAS  Google Scholar 

  112. Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, et al. HIV-associated neurocognitive disorder—pathogenesis and prospects for treatment. Nat Rev Neurol 2016;12(4):234–248

    Article  PubMed  PubMed Central  Google Scholar 

  113. Aznar-Bueno C, Abad-Alegria F, Amiguet JA. Early detection of neurophysiological abnormalities in infection by human immunodeficiency virus. Clin Electroencephalogr 2000;31(2):116–121

    Article  PubMed  CAS  Google Scholar 

  114. Rivera-Rivera Y, Vazquez-Santiago FJ, Albino E, Sanchez MD, Rivera-Amill V. Impact of depression and inflammation on the progression of HIV disease. J Clin Cell Immunol 2016;7(3). pii:423

  115. Langford D, Baron D, Joy J, Del Valle L, Shack J. Contributions of HIV infection in the hypothalamus and substance abuse/use to HPT dysregulation. Psychoneuroendocrinology 2011;36(5):710–719

    Article  PubMed  CAS  Google Scholar 

  116. Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 2005;111(2):194–213

    Article  PubMed  CAS  Google Scholar 

  117. Letendre SL, Cherner M, Ellis RJ, Marquie-Beck J, Gragg B, Marcotte T, et al. The effects of hepatitis C, HIV, and methamphetamine dependence on neuropsychological performance: biological correlates of disease. AIDS (London, England) 2005;19(Suppl 3):S72–S78

    Article  CAS  Google Scholar 

  118. Letendre S, Paulino AD, Rockenstein E, Adame A, Crews L, Cherner M, et al. Pathogenesis of hepatitis C virus coinfection in the brains of patients infected with HIV. J Infect Dis 2007;196(3):361–370

    Article  PubMed  CAS  Google Scholar 

  119. Tatro ET, Everall IP, Kaul M, Achim CL. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder. Brain Res 2009;1286:1–12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Tatro ET, Everall IP, Masliah E, Hult BJ, Lucero G, Chana G, et al. Differential expression of immunophilins FKBP51 and FKBP52 in the frontal cortex of HIV-infected patients with major depressive disorder. J Neuroimmune Pharmacol 2009;4(2):218–226

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia

    Sern Wei Yeoh & Amanda J. Nicoll

  2. Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia

    Alex C. N. Holmes & Ian P. Everall

  3. Melbourne School of Psychological Sciences, 12th Floor, Redmond Barry Building, Parkville Campus, University of Melbourne, Parkville, VIC, Australia, 3010

    Michael M. Saling

  4. Department of Clinical Neuropsychology, Austin Health, Heidelberg Repatriation Hospital, 300 Waterdale Rd, Ivanhoe, VIC, 3079, Australia

    Michael M. Saling

  5. Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Michael M. Saling

  6. Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London, SE5 8AF, UK

    Ian P. Everall

  7. South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, BR3 3BX, UK

    Ian P. Everall

  8. Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia

    Amanda J. Nicoll

Authors
  1. Sern Wei Yeoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alex C. N. Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael M. Saling
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ian P. Everall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amanda J. Nicoll
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sern Wei Yeoh.

Ethics declarations

Conflict of interest

Sern Wei Yeoh, Alex C. N. Holmes, Michael M. Saling, Ian P. Everall and Amanda J. Nicoll declare that they have no conflict of interests, funding sources or financial support relevant to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yeoh, S.W., Holmes, A.C.N., Saling, M.M. et al. Depression, fatigue and neurocognitive deficits in chronic hepatitis C. Hepatol Int 12, 294–304 (2018). https://doi.org/10.1007/s12072-018-9879-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-018-9879-5

Keywords

Search

Navigation