Neurological manifestations of HCV infection appear to be under-recognized in clinical practice despite the majority of HCV-infected patients experiencing symptoms such as fatigue, depression and cognitive dysfunction. There is also growing evidence for a link between HCV infection and an increased risk of Parkinson's disease. The mechanism underpinning the association between HCV and these neuropsychiatric syndromes still requires further investigation. Here we review the pre-clinical and clinical evidence for a link between HCV and effects on the central nervous system leading to neuropsychiat-ric syndromes. Lastly, we describe how improvements in neuro psychiatric manifestations of HCV following treatment have been observed, which is subsequently refected in an overall improvement in health-related quality of life.
References
1.
Polaris Observatory HCV Collaborators.Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.Lancet Gastroenterol Hepatol2017; 2: 161–176.
2.
Forton DM, Thomas HC, Taylor-Robinson SD.Quality of life and cognitive function in chronic hepatitis C - what to measure?J Hepatol2003; 39: 272–274.
3.
LangC.A., ConradS., GarrettL.Symptom prevalence and clustering of symptoms in people living with chronic hepatitis C infection.J Pain Symptom Manage2006; 31: 335–344.
4.
KahlounA., BabbaT., FathallahB.Prevalence of extra-hepatic manifestations in infection with hepatitis C virus: study of 140 cases.Tunis Med2011; 89: 557–560.
5.
AASLD and IDSA.HCV guidance: recommendations for testing, managing, and treating hepatitis C.2017. (Updated 21 September 2017. Accessed November 2017.) Available from http://www.hcvguidelines.org/.
6.
HeerenM., SojrefF., SchuppnerR.Active at night, sleepy all day–sleep disturbances in patients with hepatitis C virus infection.J Hepatol2014; 60: 732–740.
7.
MonacoS., FerrariS., GajofattoA., ZanussoG., MariottoS.HCV-related nervous system disorders.Clin Dev Immunol2012; 2012: 236148.
8.
DusheikoG.The impact of antiviral therapy for hepatitis C on the quality of life: a perspective.Liver Int2017; 37: 7–12.
9.
TelepL., MuamotoD., OsinusiA., BrainardD.M., SingerA.W., ChokkalingamA P.. Risk of Parkinson's disease in hepatits C patients following exposure to direct-acting antiviral treatment: an analysis of US administrative claims data.Hepatology2017; 66: 520A–521A.
10.
WijarnpreechaK., ChesdachaiS., JaruvongvanichV., UngprasertP.Hepatitis C virus infection and risk of Parkinson disease: a systematic review and meta-analysis.Hepatology2017; 66: 475A–476A.
11.
LaskusT., RadkowskiM., BednarskaA.Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid.J Virol2002; 76: 10064–10068.
12.
RadkowskiM., WilkinsonJ., NowickiM.Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication.J Virol2002; 76: 600–608.
13.
FortonD.M., KarayiannisP., MahmudN., Taylor-RobinsonS.D., ThomasH.C.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 Virol2004; 78: 5170–5183.
14.
FishmanS.L., MurrayJ.M., EngF.J., WalewskiJ.L., MorgelloS., BranchA.D.Molecular and bioinformatic evidence of hepatitis C virus evolution in brain.J Infect Dis2008; 197: 597–607.
15.
TullyD.C., HjerrildS., LeutscherP.D.Deep sequencing of hepatitis C virus reveals genetic compartmentalization in cerebrospinal fluid from cognitively impaired patients.Liver Int2016; 36: 1418–1424.
16.
WilkinsonJ., RadkowskiM., LaskusT.Hepatitis C virus neuroinvasion: identification of infected cells.J Virol2009; 83: 1312–1319.
17.
WilkinsonJ., RadkowskiM., EschbacherJ.M., LaskusT.Activation of brain macrophages/microglia cells in hepatitis C infection.Gut2010; 59: 1394–1400.
18.
PaulinoA.D., UbhiK., RockensteinE.Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling.J Neurovirol2011; 17: 327–340.
19.
FletcherN.F., YangJ.P., FarquharM.J.Hepatitis C virus infection of neuroepithelioma cell lines.Gastroenterology2010; 139: 1365–1374.
20.
FletcherN.F., WilsonG.K., MurrayJ.Hepatitis C virus infects the endothelial cells of the blood-brain barrier.Gastroenterology2012; 142: 634–643.e6.
21.
MillerD.S., BauerB., HartzA.M.S.Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve CNS pharmacotherapy.Pharmacol Rev2008; 60: 196–209.
22.
McQuaidT., SaviniC., SeyedkazemiS.Sofosbuvir, a significant paradigm change in HCV treatment.J Clin Transl Hepatol2015; 3: 27–35.
23.
PoynardT., CacoubP., RatziuV.Fatigue in patients with chronic hepatitis C.J Viral Hepat2002; 9: 295–303.
24.
McDonaldJ., JayasuriyaJ., BindleyP., GonsalvezC., GluseskaS.Fatigue and psychological disorders in chronic hepatitis C.J Gastroenterol Hepatol2002; 17: 171–176.
25.
GlackenM., CoatesV., KernohanG., HegartyJ.The experience of fatigue for people living with hepatitis C.J Clin Nurs2003; 12: 244–252.
26.
HilsabeckR.C., HassaneinT.I., CarlsonM.D., ZieglerE.A., PerryW.Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C.J Int Neuropsychol Soc2003; 9: 847–854.
27.
ZalaiD., ShermanM., McShaneK., ShapiroC.M., CarneyC.E.The importance of fatigue cognitions in chronic hepatitis C infection.J Psychosom Res2015; 78: 193–198.
28.
YarlottL., HealdE., FortonD.Hepatitis C virus infection, and neurological and psychiatric disorders - a review.J Adv Res2017; 8: 139–148.
29.
DirksM., PflugradH., HaagK.Persistent neuropsychiatric impairment in HCV patients despite clearance of the virus?!J Viral Hepat2017; 24: 541–550.
30.
BarkhuizenA., RosenH.R., WolfS., FloraK., BennerK., BennettR.M.Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients.Am J Gastroenterol1999; 94: 1355–1360.
31.
GohJ., CoughlanB., QuinnJ., O'KeaneJ.C., CroweJ.Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection.Eur J Gastroenterol Hepatol1999; 11: 833–838.
32.
DwightM.M., KowdleyK.V., RussoJ.E., CiechanowskiP.S., LarsonA.M., KatonW.J.Depression, fatigue, and functional disability in patients with chronic hepatitis C.J Psychosom Res2000; 49: 311–317.
33.
HuckansM., FullerB.E., OlavarriaH.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 Behav2014; 4: 123–142.
34.
KrausM.R., SchaferA., CsefH., ScheurlenM., FallerH.Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C.Psychosomatics2000; 41: 377–384.
35.
FontanaR.J., HussainK.B., SchwartzS.M., MoyerC.A., SuG.L., LokA.S.Emotional distress in chronic hepatitis C patients not receiving antiviral therapy.J Hepatol2002; 36: 401–407.
36.
FortonD.M., ThomasH.C., MurphyC.A.Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease.Hepatology2002; 35: 433–439.
37.
SchaeferM., CapuronL., FriebeA.Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement.J Hepatol2012; 57: 1379–1390.
38.
YounossiZ., ParkH., HenryL., AdeyemiA., StepanovaM.Extrahepatic manifestations of hepatitis C: a meta-analysis of prevalence, quality of life, and economic burden.Gastroenterology2016; 150: 1599–1608.
39.
PawlowskiT., RadkowskiM., MalyszczakK.Depression and neuroticism in patients with chronic hepatitis C: correlation with peripheral blood mononuclear cells activation.J Clin Virol2014; 60: 105–111.
40.
HughesE., BassiS., GilbodyS., BlandM., MartinF.Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness: a systematic review and meta-analysis.Lancet Psychiatry2016; 3: 40–48.
41.
JohnsonM.E., FisherD.G., FenaughtyA., ThenoS.A.Hepatitis C virus and depression in drug users.Am J Gastroenterol1998; 93: 785–789.
42.
GoldenJ., ConroyR.M., O'DwyerA.M.Reliability and validity of the Hospital Anxiety and Depression Scale and the Beck Depression Inventory (Full and FastScreen scales) in detecting depression in persons with hepatitis C.J Affect Disord2007; 100: 265–269.
43.
WeissenbornK., KrauseJ., BokemeyerM.Hepatitis C virus infection affects the brain-evidence from psychometric studies and magnetic resonance spectroscopy.J Hepatol2004; 41: 845–851.
44.
HilsabeckR.C., PerryW., HassaneinT.I.Neuropsychological impairment in patients with chronic hepatitis C.Hepatology2002; 35: 440–446.
45.
CórdobaJ., FlaviaM., JacasC.Quality of life and cognitive function in hepatitis C at different stages of liver disease.J Hepatol2003; 39: 231–238.
46.
McAndrewsM.P., FarcnikK., CarlenP.Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors.Hepatology2005; 41: 801–808.
47.
AbrantesJ., TorresD.S., de MelloC.E.Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function.Postgrad Med J2013; 89: 433–439.
48.
SoogoorM., LynnH.S., DonfieldS.M.Hepatitis C virus infection and neurocognitive function.Neurology2006; 67: 1482–1485.
49.
MorgelloS., EstanislaoL., RyanE.Effects of hepatic function and hepatitis C virus on the nervous system assessment of advanced-stage HIV-infected individuals.AIDS2005; 19: S116–S122.
50.
AronowH.A., WestonA.J., PezeshkiB.B., LazarusT.S.Effects of coinfection with HIV and hepatitis C virus on the nervous system.AIDS Read2008; 18: 43–48.
51.
MartinE.M., NovakR.M., FendrichM.Stroop performance in drug users classified by HIV and hepatitis C virus serostatus.J Int Neuropsychol Soc2004; 10: 298–300.
52.
ChangL., ErnstT., Leonido-YeeM., WalotI., SingerE.Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex.Neurology1999; 52: 100–108.
53.
ZahrN.M., MayerD., RohlfingT., SullivanE.V., PfefferbaumA.Imaging neuroinflammation? A perspective from MR spectroscopy.Brain Pathol2014; 24: 654–664.
54.
FortonD.M., AllsopJ.M., MainJ., FosterG.R., ThomasH.C., Taylor-RobinsonS.D.Evidence for a cerebral effect of the hepatitis C virus.Lancet2001; 358: 38–39.
55.
Taylor-RobinsonS.D., BuckleyC., ChanganiK.K., HodgsonH.J., BellJ.D.Cerebral proton and phosphorus-31 magnetic resonance spectroscopy in patients with subclinical hepatic encephalopathy.Liver1999; 19: 389–398.
56.
FortonD.M., HamiltonG., AllsopJ.M.Cerebral immune activation in chronic hepatitis C infection: a magnetic resonance spectroscopy study.J Hepatol2008; 49: 316–322.
57.
ThamesA.D., CastellonS.A., SingerE.J.Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C.Neurol Neuroimmunol Neuroinflamm2015; 2: e59.
58.
BokemeyerM., DingX.Q., GoldbeckerA.Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.Gut2011; 60: 370–377.
59.
BladowskaJ., ZimnyA., KnyszB.Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: a pilot study.J Hepatol2013; 59: 651–657.
60.
BladowskaJ., KnyszB., ZimnyA.Value of perfusion-weighted MR imaging in the assessment of early cerebral alterations in neurologically asymptomatic HIV-1-positive and HCV-positive patients.PLoS One2014; 9: e102214.
61.
KumarA., DeepA., GuptaR.K., AtamV., MohindraS.Brain microstructural correlates of cognitive dysfunction in clinically and biochemically normal hepatitis C virus infection.J Clin Exp Hepatol2017; 7: 198–204.
62.
GroverV.P., PaveseN., KohS.B.Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation.J Viral Hepat2012; 19: e89–e96.
63.
PflugradH., MeyerG.J., DirksM.Cerebral microglia activation in hepatitis C virus infection correlates to cognitive dysfunction.J Viral Hepat2016; 23: 348–357.
64.
HeerenM., WeissenbornK., ArvanitisD.Cerebral glucose utilisation in hepatitis C virus infection-associated encephalopathy.J Cereb Blood Flow Metab2011; 31: 2199–2208.
65.
KrausM.R., SchaferA., TeuberG.Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C.Hepatology2013; 58: 497–504.
66.
CacoubP., RatziuV., MyersR.P.Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C.J Hepatol2002; 36: 812–818.
67.
ByrnesV., MillerA., LowryD.Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition.J Hepatol2012; 56: 549–556.
68.
PflugradH., DingX.Q., TillmannH.L., WeissenbornK.Neuroinflammation in HCV-infection - peril or protection?J Hepatol2012; 57: 921–922.
69.
WuW.Y., KangK.H., ChenS.L.Hepatitis C virus infection: a risk factor for Parkinson's disease.J Viral Hepat2015; 22: 784–791.
70.
TsaiH.H., LiouH.H., MuoC.H., LeeC.Z., YenR.F., KaoC.H.Hepatitis C virus infection as a risk factor for Parkinson disease: a nationwide cohort study.Neurology2016; 86: 840–846.
71.
PakpoorJ., NoyceA., GoldacreR.Viral hepatitis and Parkinson disease: a national record-linkage study.Neurology2017; 88: 1630–1633.
72.
FosterG.R., GoldinR.D., ThomasH.C.Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis.Hepatology1998; 27: 209–212.
73.
BonkovskyH.L., WoolleyJ.M.Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group.Hepatology1999; 29: 264–270.
74.
WareJ.E.Jr., BaylissM.S., MannocchiaM., DavisG.L.Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. The Interventional Therapy Group.Hepatology1999; 30: 550–555.
75.
McHutchisonJ.G., WareJ.E.Jr., BaylissM.S.The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity.J Hepatol2001; 34: 140–147.
76.
BernsteinD., KleinmanL., BarkerC.M., RevickiD.A., GreenJ.Relationship of health-related quality of life to treatment adherence and sustained response in chronic hepatitis C patients.Hepatology2002; 35: 704–708.
77.
ChongC.A., GulamhusseinA., HeathcoteE.J.Health-state utilities and quality of life in hepatitis C patients.Am J Gastroenterol2003; 98: 630–638.
78.
HassaneinT., CooksleyG., SulkowskiM.The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C.J Hepatol2004; 40: 675–681.
79.
von WagnerM., LeeJ.H., KronenbergerB.Impaired health-related quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels.J Viral Hepat2006; 13: 828–834.
80.
John-BaptisteA.A., TomlinsonG., HsuP.C.Sustained responders have better quality of life and productivity compared with treatment failures long after antiviral therapy for hepatitis C.Am J Gastroenterol2009; 104: 2439–2448.
81.
StraussE., Porto-FerreiraF.A., de Almeida-NetoC., TeixeiraM.C.Altered quality of life in the early stages of chronic hepatitis C is due to the virus itself.Clin Res Hepatol Gastroenterol2014; 38: 40–45.
82.
FerreiraF.A., de Almeida-NetoC., TeixeiraM.C., StraussE.Health-related quality of life among blood donors with hepatitis B and hepatitis C: longitudinal study before and after diagnosis.Rev Bras Hematol Hemoter2015; 37: 381–387.
83.
Nuño SolinísR., Arratibel UgarteP., RojoA., Sanchez GonzalezY.Value of treating all stages of chronic hepatitis C: a comprehensive review of clinical and economic evidence.Infect Dis Ther2016; 5: 491–508.
84.
CacoubP., BourlièreM., AsselahT.French hepatitis C patients treated with anti-viral combinations containing pegylated interferon (IFN), ribavirin (RBV), sofosbuvir, ledipasvir, velpatasvir and/or voxilaprevir: the impact of treatment on patient-reported outcomes (PROs).Hepatology2017; 66: 390A.
85.
YounossiZ.M., StepanovaM., AsselahT.Hepatitis C in patients without fibrosis or with minimal fibrosis: the impact of treatment and sustained virologic response on patient-reported outcomes.Hepatology2017; 66: 526A.
86.
CarrieriM.P., ProtopopescuC., YounossiZ.Health-related quality of life in chronic HCV-infected patients switching to pegylated-interferon-free regimens (ANRS CO20 CUPIC Cohort Study and SIRIUS Trial).Patient2017; 10: 605–614.
87.
YounossiZ.M., StepanovaM., FeldJ.Sofosbuvir/ velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 placebo-controlled trial.J Hepatol2016; 65: 33–39.
88.
YounossiZ.M., StepanovaM., ZeuzemS.Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin: the VALENCE study.J Hepatol2014; 61: 228–234.
89.
YounossiZ.M., StepanovaM., NaderF.Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with sofosbuvir-containing regimens.Hepatology2014; 59: 2161–2169.
90.
YounossiZ.M., StepanovaM., JacobsonI.M.Sofosbuvir and velpatasvir with or without voxilaprevir in direct- acting antiviral-naive chronic hepatitis C: patient-reported outcomes from POLARIS 2 and 3.Aliment Pharmacol Ther2018; 47: 259–267.
91.
YounossiZ.M., StepanovaM., AfdhalN.Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir.J Hepatol2015; 63: 337–345.
92.
YounossiZ.M., StepanovaM., FeldJ.Sofosbuvir and velpatasvir combination improves patient-reported outcomes for patients with HCV infection, without or with compensated or decompensated cirrhosis.Clin Gastroenterol Hepatol2017; 15: 421–430.e6.
93.
YounossiZ.M., StepanovaM., SulkowskiM.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 Dis2016; 63: 1042–1048.
94.
YounossiZ.M., StepanovaM., HenryL., NaderF., HuntS.An in-depth analysis of patient-reported outcomes in patients with chronic hepatitis C treated with different anti-viral regimens.Am J Gastroenterol2016; 111: 808–816.
