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Evidence for a cerebral effect of the hepatitis C virus

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  • claudine intexas
    from Jules Levin, NATAP Evidence for a cerebral effect of the hepatitis C virus This report appears as a Research Letter in Lancet, which is not the same as a
    Message 1 of 1 , Aug 4, 2001
      from Jules Levin, NATAP

      Evidence for a cerebral effect of the hepatitis C
      virus

      This report appears as a Research Letter in Lancet,
      which is not the same as a peer reviewed study.
      Nonetheless, although early research, the report is
      creditable to me, and further research attention is
      needed. This report appears to be a follow-up to
      poster/abstract these researchers reported at EASL
      2000. This was the subject of my report HCV & the
      Brain. Below is the entire article without the tables.
      Starting off below is the abstract and a few
      highlights before the entire article.

      Here is the link to the NATAP called HCV & Brain
      Dysfunction report from EASL 2000 on DM Horton's
      initial presentation which I viewed:
      <A HREF="http://www.natap.org/2000/ddw/rpt_11.htm">
      http://www.natap.org/2000/ddw/rpt_11.htm</A>

      Research letters
      Lancet 2001; 358: 38-39

      Daniel M Forton, Joanna M Allsop, Janice Main, Graham
      R Foster, Howard C Thomas, Simon D Taylor-Robinson

      --We considered that HCV infection itself may affect
      cerebral function
      and
      looked at cerebral choline/creatine ratios with proton

      magnetic-resonance
      spectroscopy (1H MRS) in patients and controls

      --30 patients with histologically defined mild chronic
      HCV infection
      were
      randomly selected. Liver biopsies showed mild
      inflammation only, with
      no
      cirrhosis or significant fibrosis (table 1). 1H MRS
      was also performed
      in 29
      age-matched and sex-matched healthy controls and in 12
      patients with
      chronic
      hepatitis B. 20 (67%) patients with HCV infection, but
      no healthy
      controls or
      patients with hepatitis B infection, gave ahistory of
      intravenous drug
      use
      (IVDU)

      --Patients with significant fibrosis or cirrhosis were
      excluded from
      the
      study so we can conclude that the findings are not due
      to minimal
      hepatic
      encephalopathy.

      -- A neuroradiologist reviewed the MR images. the
      Cho/Cr ratios were
      significantly higher in the white matter and basal
      ganglia of the HCV
      group
      compared with both the hepatitis B group and healthy
      volunteers

      --There were no statistically significant differences
      in the ratios
      between
      the HCV patients with a history of IVDU and those
      without. There was
      also no
      association between viral genotype or liver biopsy
      score and the
      cerebral
      metabolite ratios.

      --In 1H MRS the choline resonance mainly reflects
      intracerebral
      phospholipid
      cell membrane precursor and degradation products and
      is increased in
      conditions where there is cellular proliferation, most
      notably in
      inflammatory or infective conditions such as multiple
      sclerosis, or HIV
      infection.

      --Similar metabolite abnormalities in the same spatial
      distribution to
      those
      reported here have been extensively documented in
      cerebral HIV
      infection, in
      patients both with and without neurological symptoms

      --Infection of cerebral microglia by HIV, possibly via
      infected
      monocytes,
      and subsequent microglial activation are thought to
      underlie the MRS
      changes.
      There is good evidence to suggest that HCV infects
      cells of monocytic
      lineage,5 raising the possibility that HCV too may
      infect the brain

      --There is good evidence to suggest that HCV infects
      cells of monocytic
      lineage,5 raising the possibility that HCV too may
      infect the brain. An
      alternative explanation for these findings is a
      centrally mediated
      effect of
      peripherally derived cytokines, either via their
      transfer across the
      blood-brain barrier or through an interaction with the
      cerebral
      vascular
      endothelium and the generation of secondary
      messengers. Our preliminary
      data
      suggest that there is altered cerebral metabolism in
      patients with
      chronic
      HCV infection which cannot be explained by hepatic
      encephalopathy or a
      history of drug use.


      ABSTRACT: Patients with hepatitis C virus (HCV)
      infection frequently
      complain
      of symptoms
      akin to the chronic fatigue syndrome and score worse
      on health-related
      quality of
      life indices than matched controls. We address the
      hypothesis that HCV
      itself
      affects cerebral function. Using proton
      magnetic-resonance spectroscopy
      we
      have
      shown elevations in basal ganglia and white matter
      choline/creatine
      ratios in
      patients with histologically-mild hepatitis C,
      compared with healthy
      volunteers and
      patients with hepatitis B. This elevation is unrelated
      to hepatic
      encephalopathy or
      a history of intravenous drug abuse, and suggests that
      a biological
      process
      underlies the extrahepatic symptoms in chronic HCV
      infection.

      Report:
      Several studies have shown that patients with chronic
      hepatitis C virus
      (HCV)
      infection score worse than matched controls on
      health-related quality
      of life
      indices and that their scores improve with successful
      antiviral
      treatment.1
      These findings agree with the clinical observation
      that such patients
      frequently complain of fatigue, lassitude, impaired
      memory ("brain
      fog") and
      a perceived inability to function effectively, even in
      the absence of
      clinically significant liver disease. It is not known
      whether social,
      psychological, or biological factors cause these
      complaints.

      We considered that HCV infection itself may affect
      cerebral function
      and
      looked at cerebral choline/creatine ratios with proton

      magnetic-resonance
      spectroscopy (1H MRS) in patients and controls. 30
      patients with
      histologically defined mild chronic HCV infection were
      randomly
      selected.
      Liver biopsies showed mild inflammation only, with no
      cirrhosis or
      significant fibrosis (table 1). 1H MRS was also
      performed in 29
      age-matched
      and sex-matched healthy controls and in 12 patients
      with chronic
      hepatitis B.
      20 (67%) patients with HCV infection, but no healthy
      controls or
      patients
      with hepatitis B infection, gave ahistory of
      intravenous drug use
      (IVDU).

      All subjects underwent cerebral MRS, using a 1�5T
      Eclipse spectroscopy
      system
      (Marconi Medical Systems, Cleveland, OH, USA). We
      used T1-weighted
      magnetic-resonance (MR) images to exclude organic
      brain disease and
      to
      position the voxels of interest. We positioned three 8
      cm3 voxels; in
      the
      basal ganglia, in the white matter at the level of the
      centrum
      semiovale,
      and in the occipital grey matter. We then performed
      single voxel 1H MRS
      examinations with an automated PRESS sequence (TR/TE
      1500/135 ms, 128
      acquisitions). MR spectra were analysed by a single
      blinded observer.
      Peak
      areas were measured for choline (Cho), creatine (Cr)
      and
      N-acetylaspartate
      (NAA). Ratios for NAA/Cr and Cho/Cr were calculated
      and compared with a
      one-way analysis of variance (ANOVA) with post-hoc
      comparisons, using
      contrasts (SPSS version 9).

      A neuroradiologist reviewed the MR images. One patient
      had an arachnoid
      cyst.
      There
      was no evidence of cerebral vasculitis or white-matter
      abnormalities in
      any
      of the patients or controls. The metabolite ratios
      were normally
      distributed.
      There were no differences in the grey matter
      metabolite ratios between
      the
      patients with HCV, healthy controls, and hepatitis B
      controls. However,
      the
      Cho/Cr ratios were significantly higher in the white
      matter and basal
      ganglia
      of the HCV group compared with both the hepatitis B
      group and healthy
      volunteers (table 2).

      Groups were compared with a one-way ANOVA and between
      group comparisons
      performed using post-hoc contrasts with a Bonferroni
      adjustment for
      multiple
      comparisons. p values greater than 1�00 are rounded
      down to 1�00.

      A second ANOVA was performed to compare the Cho/Cr
      ratios in HCV
      patients
      with and without a history of IVDU with the control
      groups. There were
      no
      statistically significant differences in the ratios
      between the HCV
      patients
      with a history of IVDU and those without. The mean
      alanine
      aminotransferase
      concentration was higher in the hepatitis B group than
      in the HCV group
      (93
      vs 47 IU/L respectively, p<0�03), but no association
      was found between
      the
      concentration of alanine aminotransferase and the
      metabolite ratios in
      the
      HCV or hepatitis B group. There was also no
      association between viral
      genotype or liver biopsy score and the cerebral
      metabolite ratios.

      These data demonstrate cerebral 1H MRS metabolite
      abnormalities in
      patients
      with histologically defined mild HCV infection.
      Patients with
      significant
      fibrosis or cirrhosis were excluded from the study so
      we can conclude
      that
      the findings are not due to minimal hepatic
      encephalopathy. Indeed,
      spectroscopic studies of hepatic encephalopathy show
      globally reduced
      Cho/Cr
      ratios.2 We found no statistically significant
      differences in 1H MRS
      between
      HCV patients with or without a history of IVDU.

      A number of cerebral MRS studies have investigated the
      effect of
      illicit drug
      use, but
      neither chronic use of cocaine or heroin has been
      found to increase
      cerebral
      choline-containing compounds.3 It is therefore
      unlikely that a history
      of
      IVDU underlies the
      MR abnormalities in the HCV group. In 1H MRS the
      choline resonance
      mainly
      reflects intracerebral phospholipid cell membrane
      precursor and
      degradation
      products and is increased in conditions where there is
      cellular
      proliferation, most notably in inflammatory or
      infective conditions
      such as
      multiple sclerosis, or HIV infection.

      Similar metabolite abnormalities in the same spatial
      distribution to
      those
      reported here have been extensively documented in
      cerebral HIV
      infection, in
      patients both with and without neurological
      symptoms.4 Infection of
      cerebral
      microglia by HIV, possibly via infected monocytes, and
      subsequent
      microglial
      activation are thought to underlie the MRS changes.
      There is good
      evidence to
      suggest that HCV infects cells of monocytic lineage,5
      raising the
      possibility
      that HCV too may infect the brain. An alternative
      explanation for these
      findings is a centrally mediated effect of
      peripherally derived
      cytokines,
      either via their transfer across the blood-brain
      barrier or through an
      interaction with the cerebral vascular endothelium and
      the generation
      of
      secondary messengers. Our preliminary data suggest
      that there is
      altered
      cerebral metabolism in patients with chronic HCV
      infection which cannot
      be
      explained by hepatic encephalopathy or a history of
      drug use. These
      findings
      have implications for the direction of future research
      and ultimately
      for
      patient
      treatment.

      We thank Mark Wright, Peter Karayiannis of the
      Hepatology section, ICSM
      and
      Glyn
      Coutts, Alison Fletcher, Serena Counsell, and Louise
      Goff of the Robert
      Steiner MR Unit, Hammersmith Hospital for their help
      with this study.
      We are
      also thank Professor Graeme Bydder for
      neuroradiological advice. This
      work
      was partly supported by Marconi Medical Systems
      International
      (Cleveland, OH,
      USA) and the Medical Research Council, UK.

      1 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: 264-70. [PubMed]

      2 Taylor-Robinson SD, Sargentoni J, Marcus CD, Morgan
      MY, Bryant DJ.
      Regional
      variations in cerebral proton spectroscopy in patients
      with chronic
      hepatic
      encephalopathy.
      Metab Brain Dis 1994; 9: 347-59. [PubMed]

      3 Haselhorst R, Dursteler K, Scheffler K, et al.
      Effect of chronic
      opioid
      abuse on the NAA concentration in the human frontal
      cortex as detected
      by 1H
      MRS. Proc Int Soc Magn
      Reson Med 1999; 2: 1407.

      4 Meyerhoff DJ, Bloomer C, Cardenas V, Norman D,
      Weiner MW, Fein G.
      Elevated
      subcortical choline metabolites in cognitively and
      clinically
      asymptomatic
      HIV+ patients.
      Neurol 1999; 52: 995-1003. [PubMed]

      5 Afonso AM, Jiang J, Penin F, et al. Nonrandom
      distribution of
      hepatitis C
      virus
      quasispecies in plasma and peripheral blood
      mononuclear cell subsets.
      J Virol
      1999; 73: 9213-21. [PubMed]


      Hepatology Section, Division of Medicine, Imperial
      College School of
      Medicine, St
      Mary's Hospital, London (D M Forton MRCP, J Main FRCP,
      G R Foster FRCP,
      H C
      Thomas FRCP, S D Taylor-Robinson MRCP); Robert Steiner
      Magnetic
      Resonance
      Unit, Clinical Sciences Centre, Hammersmith Hospital,
      London W12 0HS,
      UK (D M
      Forton MRCP, J M Allsop DCR, S D Taylor-Robinson MRCP)

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