Hepatites Non A-E
       Virus G et TTV …
et autres considérations métaboliques

          Vlad Ratziu,
     DU Hépatites ...
Evidence for Additional Hepatitis
             Agents
Prospective transfusion-associated hepatitis
  studies : 12%
Acute c...
VHG : GBV-C, 95 % homology
VHG : HCV, 29 % homology
HGV Epidemiology and Diagnosis


HGV transmission: parenteral +++; vertical
Risk groups: polytransfused, hemophiliacs,
hem...
HGV Epidemiology and Diagnosis


HGV prevalence :
  blood donors              1.5-2.5%
  chronic NA-NE hepatitis   10-13%
...
Prevalence of Serum HGVRNA in Acute
        Hepatitis of Viral Origin

                     %

 non A-E             9
 HBV...
HGV : is it an Hepatotropic Virus ?




                     Pessoa, Hepatology 1998
HGV : is it an Hepatotropic Virus ?

 low level of hepatic HGVRNA compared to
 HCVRNA
 no interaction of hepatic HCVRNA an...
HGV has no Pathogenic Role on the
   Course of Acute Hepatitis
No apparent effect on the clinical course of
acute disease ...
HGV and Transfusion associated
            Hepatitis (TAH)
HGV can be transmitted by transfusion +++
Protracted viremia po...
HGV in End-Stage Liver Disease
  and Liver Transplantation
HGV infection frequently present in end-stage
 liver disease (1...
Does HGV Impact on the Course
   of other Viral Infections?

           HCV
           HIV
No Histopathologic Impact of HGV on
           Chronic Hepatitis C
   Patients:
     Chronic HCV alone in 85 pts
     Chro...
Improved Survival in HGV-HIV
         Coinfection




                    Tillmann, NEJM 2001
Improved Survival in HGV-HIV
             Coinfection

Improved survival even after development of AIDS and
  introduction...
Multicenter AIDS Cohort Study
Baltimore, Chicago, Pittsburgh, LA
• Cohorte de patients homosexuels mâles
    infectés par ...
L’infection par le GBV-C Améliore
     la Survie des Patients VIH

                     SURVIE A 10 ANS          CD4+

GBV...
Inhibition of HIV Replication by
         HGV in PBMC

                    No effect on the entry
                    of H...
Molecular Interactions Between GBV-C and HIV
TT Virus and Transfusion
          Associated Hepatitis
Strong association with blood transfusion : risk
  increases with ...
TTV and Acute Viral Hepatitis
                        % with
Condition                TTV     No correlation
Controls (100...
Chronic TTV Carriage
Longitudinal study of 173 multiple transfused
patients
Prevalence of TTV : 28%
Chronic infection in 8...
TTV and Chronic Liver Disease
No significant differences in prevalence
between chronic HCV, HBV or cryptogenic
liver disea...
TTV, Chronic Hepatitis C and
          Response to IFN

 N=247 Japanese hepatitis C treated patients
 Prevalence of TTV : ...
Prognostic Significance of TTV
  in Patients with HIV Infection

High TTV viremia associated with :
     decreased surviva...
TTV - The Essentials
Transmission : parenteral route +++ ; fecal-
oral route ?
High prevalence in Japan
Replicates in the ...
Establishing Causality for New
              Viruses
Pathogen present in most cases of the disease
Pathogen found preferen...
Chronic Liver Disease - Beyond
        the Viruses ...

  Definition
  Etiologies
Etiologie de la Cirrhose (n=78)
     Etude Dionysos (Hepatology 1994)
                 HCV
                 28 %         H...
Factors Associated with ALT
           Levels
SEX            Cholesterol
BMI            Triglycerides
               Glyce...
What is a Normal ALT Value ?
“Normal” ALT ranges from
   26 UI/l (females, 95th percentile) to
   66 UI/l (males BMI > 26 ...
Clinical Implications of the Different
      Thresholds for Normal ALT

                        abnormal ALT
Blood donors
...
Chronic Liver Disease - Beyond the
            Viruses ...
Etiologies :
 Overweight, Diabetes +++
 Covert Alcohol
 Drugs
 ...
Impact of Overweight on Chronic
           Liver Disease
Dionysos Study, n = 1211 (6917 total)


BMI (kg/m2)     %       R...
Proportion of Patients With Cryptogenic
 Cirrhosis according to BMI - UNOS Database

N =19271                   HCV      A...
Obésité et Cirrhose Cryptogénétique

              Cirrhose X    NASH         Cirrhose C     CBP


N                70    ...
Liver Histology in Overweight
             Patients
n = 858 ; 9 studies, 1978 - 2002

Normal      :                  10 %
...
Prevalence of NASH/NAFLD
First (or second) cause of chronic liver disease in
  Western Countries

Prevalence among patient...
Hepatic Fibrosis in NASH
n= 572, 9 studies 1980 - 2001
                                %


 None or mild                  ...
Risk Factors for Severe Fibrosis
            in NASH
Age > 45-50 yrs
Diabetes
ALT>2N
BMI > 27 kg/m²
HTA
HyperTG
          ...
Abnormal Liver Function Tests
A frequent problem in clinical hepatology
New viruses : less of a problem
NAFLD : more of a ...
Viral Etiologies of Acute Hepatitis in the US
         (1985-1986 and 1991-1995)
 N=10 533
                          %

  ...
Ratziu HéPatites Nane Vhg Ttv Du 2010
Ratziu HéPatites Nane Vhg Ttv Du 2010
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Ratziu HéPatites Nane Vhg Ttv Du 2010

  1. 1. Hepatites Non A-E Virus G et TTV … et autres considérations métaboliques Vlad Ratziu, DU Hépatites Virales 2008 Hôpital Pitié Salpêtrière, Paris, France
  2. 2. Evidence for Additional Hepatitis Agents Prospective transfusion-associated hepatitis studies : 12% Acute cases of overt hepatitis : 20% Fulminant hepatitis : 25% Chronic liver disease : 20-30% Hepatitis-associated aplastic anemia : most of them
  3. 3. VHG : GBV-C, 95 % homology VHG : HCV, 29 % homology
  4. 4. HGV Epidemiology and Diagnosis HGV transmission: parenteral +++; vertical Risk groups: polytransfused, hemophiliacs, hemodialysis, patients infected with HIV, HCV, HBV Diagnosis: ongoing infection : HGVRNA without anti-E2 exposure with viral clearance : anti-E2 Ab
  5. 5. HGV Epidemiology and Diagnosis HGV prevalence : blood donors 1.5-2.5% chronic NA-NE hepatitis 10-13% cryptogenic cirrhosis 20% HCV infection 18-20% HBV infection 8-10%
  6. 6. Prevalence of Serum HGVRNA in Acute Hepatitis of Viral Origin % non A-E 9 HBV 32* HAV 25 HCV 20 * : p<0.05 vs HAV and HCV Alter M, NEJM 1997
  7. 7. HGV : is it an Hepatotropic Virus ? Pessoa, Hepatology 1998
  8. 8. HGV : is it an Hepatotropic Virus ? low level of hepatic HGVRNA compared to HCVRNA no interaction of hepatic HCVRNA and HGVRNA levels when patients with monoinfection are compared with those infected with both viruses Pessoa, Hepatology 1998
  9. 9. HGV has no Pathogenic Role on the Course of Acute Hepatitis No apparent effect on the clinical course of acute disease among the patients with hepatitis A, B or C No effect on the frequency or severity with which chronic hepatitis C develops Long-standing HGV viremia but no chronic hepatitis
  10. 10. HGV and Transfusion associated Hepatitis (TAH) HGV can be transmitted by transfusion +++ Protracted viremia possible (years) but 90% are mild Prevalence of HGV is not higher in non-A-C transfusion associated hepatitis than in HCV, minor ALT elevation or transfused patients with no hepatitis HGV milder forms than HCV; HCV-HGV not more severe than HCV A CAUSAL RELATION BETWEEN HGV AND TAH IS NOT ESTABLISHED Alter H, NEJM 1997
  11. 11. HGV in End-Stage Liver Disease and Liver Transplantation HGV infection frequently present in end-stage liver disease (13% in HCV, 22-64% in cryptogenic cirrhosis) HGV frequently present and/or acquired after liver transplantation HGV does not influence the clinical outcome after liver transplantation. Pessoa, Hepatology 1998 Fried, Hepatology 1997
  12. 12. Does HGV Impact on the Course of other Viral Infections? HCV HIV
  13. 13. No Histopathologic Impact of HGV on Chronic Hepatitis C Patients: Chronic HCV alone in 85 pts Chronic HCV-HGV in 17 pts No difference in the necroinflammatory grade, fibrosis stage, proportion of cirrhosis, steatosis or bile duct lesions HGV INFECTION DOES NOT MODIFY THE COURSE OF CHRONIC HCV INFECTION CONTRIBUTION TO LIVER DISEASE LESS THAN OTHER HEPATOTROPIC VIRUSES Bralet, Gastroenterology 1997
  14. 14. Improved Survival in HGV-HIV Coinfection Tillmann, NEJM 2001
  15. 15. Improved Survival in HGV-HIV Coinfection Improved survival even after development of AIDS and introduction of HAART Slower progression to AIDS Beneficial effect independent of age, sex, CD4+, CD8+ cell counts Inverse correlation HGV viral load- HIV viral load Under HAART, increase in HGV viral load while decrease in HIV viral load Tillmann, NEJM 2001
  16. 16. Multicenter AIDS Cohort Study Baltimore, Chicago, Pittsburgh, LA • Cohorte de patients homosexuels mâles infectés par le VIH et suivis avant 1996 • Recherche du VHG au moment de l’infection, 12 à 18 mois et 5 à 6 ans après la séroconversion VIH RT-PCR : infection en cours antiE2 : infection passée, disparition du virus Williams, NEJM 2004
  17. 17. L’infection par le GBV-C Améliore la Survie des Patients VIH SURVIE A 10 ANS CD4+ GBV-C pos 75% -26/mm3 GBV-C éliminé 39% -70/mm3 GBV-C neg 16% -107/mm3 Effet dépendant du taux de CD4 et virémie VIH Effet significatif pls années après primoinfection VIH Williams, NEJM 2004
  18. 18. Inhibition of HIV Replication by HGV in PBMC No effect on the entry of HIV into the cells No differences in expression of CD4, CXCR4 or CCR5 Xiang, NEJM 2001
  19. 19. Molecular Interactions Between GBV-C and HIV
  20. 20. TT Virus and Transfusion Associated Hepatitis Strong association with blood transfusion : risk increases with number of units Same prevalence in transfused patients regardless of the occurrence of transfusion associated hepatitis Same ALT level in transfusion associated hepatitis regardless of the presence of TTV Does not alter the course of hepatitis C Matsumoto, Hepatology 1999
  21. 21. TTV and Acute Viral Hepatitis % with Condition TTV No correlation Controls (100) 37 between TTV Acute hepatitis (125) 35 infection and clinical features of acute Acute HAV (28) 29 infection Acute HBV (29) 24 No effect on the Acute HCV (33) 42 clinical course of Acute NA-E (35) 43 HAV, HBV, HCV NO ETIOLOGIC ROLE ! Kanda, Hepatology 1999
  22. 22. Chronic TTV Carriage Longitudinal study of 173 multiple transfused patients Prevalence of TTV : 28% Chronic infection in 86% of TTV infected patients Persistence of TTV for a mean period of 3.1 years No biochemical evidence of liver disease for the majority of chronic TTV carriers Lefrere JJ, Blood 1999
  23. 23. TTV and Chronic Liver Disease No significant differences in prevalence between chronic HCV, HBV or cryptogenic liver disease No difference in genotype distribution according to the etiology of liver disease No association with hepatocellular carcinoma Tagger, Hepatology 1999 Kato, J Hepatol 1999 Nakano, J Hepatol 1999
  24. 24. TTV, Chronic Hepatitis C and Response to IFN N=247 Japanese hepatitis C treated patients Prevalence of TTV : 46% Same sustained HCV clearance rate in TTV negative and positive patients TTV clearance after IFN therapy was common (52%) TTV DOES NOT MODIFY CLINICAL FEATURES OF CHRONIC HEPATITIS C OR RESPONSE TO IFN Hagiwara, J Viral Hepat 1999
  25. 25. Prognostic Significance of TTV in Patients with HIV Infection High TTV viremia associated with : decreased survival lower CD4+ T cell counts higher HIV viral load proportion of patients with AIDS Christensen, J Inf Dis, 2000 Shibayama, AIDS 2001
  26. 26. TTV - The Essentials Transmission : parenteral route +++ ; fecal- oral route ? High prevalence in Japan Replicates in the liver Role in post transfusion hepatitis not confirmed Does not aggravate chronic HCV or HBV Negligible role in the etiology of chronic liver disease (the role of certain genotypes cannot be excluded…)
  27. 27. Establishing Causality for New Viruses Pathogen present in most cases of the disease Pathogen found preferentially in the target organ Should not be significantly detectable in subjects without the disease Copy number should decrease or become undetectable with resolution of the disease Copy number should correlate with disease severity Alter, Postgraduate Course, AASLD 2000
  28. 28. Chronic Liver Disease - Beyond the Viruses ... Definition Etiologies
  29. 29. Etiologie de la Cirrhose (n=78) Etude Dionysos (Hepatology 1994) HCV 28 % HBV+ ALCOOL 3 % HBV 9 % HCV+ ALCOOL 3% HEMO CHROMATOSE 1% ALCOOL 26 % CRYPTOGENIC CBP 24 % 1%
  30. 30. Factors Associated with ALT Levels SEX Cholesterol BMI Triglycerides Glycemia Oral contraceptives Smoking Age Physical exercise Medications Piton, Hepatology 1998 Prati, Ann Intern Med 2002
  31. 31. What is a Normal ALT Value ? “Normal” ALT ranges from 26 UI/l (females, 95th percentile) to 66 UI/l (males BMI > 26 kg/m²) New definitions of normal ALT (no overweight, lipid, carbohydrate alterations) : 30 UI/l for men 19 UI/l for women Piton, Hepatology 1998 Prati, Ann Intern Med 2002
  32. 32. Clinical Implications of the Different Thresholds for Normal ALT abnormal ALT Blood donors male donors : 4 - 20% female donors : 1.5 - 16% HCV infection males : 13 - 22 % females : 20 - 45 % Piton, Hepatology 1998
  33. 33. Chronic Liver Disease - Beyond the Viruses ... Etiologies : Overweight, Diabetes +++ Covert Alcohol Drugs Seronegative autoimmune liver diseases Vascular liver diseases Celiac disease Occult HBV
  34. 34. Impact of Overweight on Chronic Liver Disease Dionysos Study, n = 1211 (6917 total) BMI (kg/m2) % Relative Risk (CI 95%) < 25 32 0.3 (0.32-0.33) 25-27 25 1.16 (1.15-1.17) > 27 45 1.83 (1.81-1.85) (Bellentani Hepatology 1994)
  35. 35. Proportion of Patients With Cryptogenic Cirrhosis according to BMI - UNOS Database N =19271 HCV Alcohol Cryptogenic % 40 35 30 25 20 15 10 5 0 < 25 25 - 30 30 - 35 35 - 40 > 40 BMI (Nair, Hepatology 2002)
  36. 36. Obésité et Cirrhose Cryptogénétique Cirrhose X NASH Cirrhose C CBP N 70 50 39 33 Age 63(+/- 11) 49(+/-14) 60(+/-7) 54(+/-10) Femmes (%) 70 56 36 100 Obésité (%) 47 64 3 15 Diabète (%) 53 42 25 15 Caldwell, Hepatology 1999
  37. 37. Liver Histology in Overweight Patients n = 858 ; 9 studies, 1978 - 2002 Normal : 10 % Steatosis alone : 48 % Steatohepatitis : 42 %
  38. 38. Prevalence of NASH/NAFLD First (or second) cause of chronic liver disease in Western Countries Prevalence among patients with abnormal LFTs of undetermined etiology (n=673, 5 studies) steatosis alone : 30% steatohepatitis : 26%
  39. 39. Hepatic Fibrosis in NASH n= 572, 9 studies 1980 - 2001 % None or mild 65 Severe (cirrhosis excepted) 20 Cirrhosis 15
  40. 40. Risk Factors for Severe Fibrosis in NASH Age > 45-50 yrs Diabetes ALT>2N BMI > 27 kg/m² HTA HyperTG Angulo, Hepatology 1999 AST/ALT > 1 Ratziu, Gastroenterology 2000 Dixon, Gastroenterology 2001
  41. 41. Abnormal Liver Function Tests A frequent problem in clinical hepatology New viruses : less of a problem NAFLD : more of a problem Identifying patients at risk of liver disease - that is the problem !
  42. 42. Viral Etiologies of Acute Hepatitis in the US (1985-1986 and 1991-1995) N=10 533 % HAV 48 HBV 34 HCV 15 non A-E 3 Alter, NEJM 1997

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