Ratziu HéPatites Nane Vhg Ttv Du 2010
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Transcript of Ratziu HéPatites Nane Vhg Ttv Du 2010
HepatitesNon A-E
Virus G et TTV …et autres considérations métaboliques
Vlad Ratziu,
DU Hépatites Virales 2008
Hôpital Pitié Salpêtrière,
Paris, France
Evidencefor Additional HepatitisAgents
Prospective transfusion-associated hepatitisstudies : 12%
Acute cases of overt hepatitis : 20%
Fulminant hepatitis : 25%
Chronic liver disease : 20-30%
Hepatitis-associated aplastic anemia : most ofthem
VHG : GBV-C, 95 % homology
VHG : HCV, 29 % homology
HGV Epidemiologyand 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
HGV Epidemiologyand 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%
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
HGV : is it an HepatotropicVirus ?
Pessoa, Hepatology 1998
HGV : is it an HepatotropicVirus ?
� 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
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
HGV and Transfusion associatedHepatitis (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 elevationor 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
HGV in End-StageLiver Disease and Liver Transplantation
HGV infection frequently present in end-stageliver disease (13% in HCV, 22-64% incryptogenic cirrhosis)
HGV frequently present and/or acquired afterliver transplantation
HGV does not influence the clinical outcomeafter liver transplantation.
Fried, Hepatology 1997Pessoa, Hepatology 1998
DoesHGV Impact on theCourse of other Viral Infections?
� HCV
� HIV
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, fibrosisstage, proportion of cirrhosis, steatosis or bile ductlesions
HGV INFECTION DOES NOT MODIFY THE COURSE OF CHRONIC HCV INFECTION
CONTRIBUTION TO LIVER DISEASE LESS THAN OTHER HEPATOTROPIC VIRUSES
Bralet, Gastroenterology 1997
Improved Survival in HGV -HIV Coinfection
Tillmann, NEJM 2001
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 whiledecrease in HIV viral load
Tillmann, NEJM 2001
Multicenter AIDS Cohort StudyBaltimore, 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
L’infection par le GBV-C Améliore la Survie des Patients VIH
GBV-C pos
GBV-C éliminé
GBV-C neg
SURVIE A 10 ANS CD4+
75%
39%
16%
-26/mm3
-70/mm3
-107/mm3
Effet dépendant du taux de CD4 et virémie VIH
Effet significatif pls années après primoinfection VIH
Williams, NEJM 2004
Inhibition of HIV Replicationby HGV in PBMC
� No effect on the entryof HIV into the cells
� No differences in expression of CD4, CXCR4 or CCR5
Xiang, NEJM 2001
Molecular Interactions BetweenGBV-C and HIV
TT Virus and Transfusion AssociatedHepatitis
Strong association with blood transfusion :riskincreases with number of units
Same prevalencein transfused patients regardlessof the occurrence of transfusion associatedhepatitis
Same ALT levelin transfusion associated hepatitisregardless of the presence of TTV
Does not alter thecourse of hepatitis C
Matsumoto, Hepatology 1999
TTV and Acute Viral Hepatitis
Controls(100) 37
Acute hepatitis(125) 35
Acute HAV (28) 29
Acute HBV (29) 24
Acute HCV (33) 42
Acute NA-E (35) 43
� No correlationbetween TTV infection and clinicalfeatures of acute infection
� No effect on theclinical course ofHAV, HBV, HCV
% withTTVCondition
Kanda, Hepatology 1999
NO ETIOLOGIC ROLE !
ChronicTTV Carriage
� Longitudinal study of 173 multiple transfusedpatients
� Prevalence of TTV : 28%
� Chronic infection in 86% of TTV infectedpatients
� 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
TTV and ChronicLiver Disease
� No significant differences in prevalencebetween chronic HCV, HBV or cryptogenicliver disease
� No difference in genotype distribution according to the etiology of liver disease
� No association with hepatocellularcarcinoma
Tagger, Hepatology 1999
Kato, J Hepatol 1999
Nakano, J Hepatol 1999
TTV, ChronicHepatitis C and Responseto 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 FEATURESOF CHRONIC HEPATITIS C OR RESPONSE TO IFN
Hagiwara, J Viral Hepat 1999
PrognosticSignificanceof TTV in Patients withHIV Infection
High TTV viremia associated with :
� decreased survival
� lower CD4+ T cell counts
� higher HIV viral load
� proportion of patients with AIDS
Shibayama, AIDS 2001
Christensen, J Inf Dis, 2000
TTV - TheEssentials
� Transmission : parenteral route +++ ; fecal-oral route ?
� High prevalence in Japan
� Replicates in the liver
� Role in post transfusion hepatitisnotconfirmed
� Does not aggravatechronic HCV or HBV
� Negligible role in the etiology ofchronic liverdisease(the role of certain genotypes cannotbe excluded…)
EstablishingCausalityfor 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 becomeundetectable with resolution of the disease
� Copy number should correlate with diseaseseverity
Alter, Postgraduate Course, AASLD 2000
ChronicLiver Disease - BeyondtheViruses...
� Definition
� Etiologies
Etiologie de la Cirrhose (n=78) Etude Dionysos (Hepatology 1994)
HCV28 %
HBV 9 %
HBV+ALCOOL 3 %
HEMOCHROMATOSE
1 %
ALCOOL26 %
CBP1 %
HCV+ALCOOL 3%
CRYPTOGENIC24 %
Factors Associated with ALT Levels
� SEX
� BMI
� Cholesterol
� Triglycerides
� Glycemia
� Oral contraceptives
� Smoking
� Age
� Physical exercise
� Medications
Piton, Hepatology 1998Prati, Ann Intern Med 2002
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 1998Prati, Ann Intern Med 2002
Clinical Implications of the Different Thresholds for Normal ALT
Blood donors � male donors : 4 - 20%
� female donors : 1.5 - 16%
HCV infection � males : 13 - 22 %
� females : 20 - 45 %
Piton, Hepatology 1998
abnormal ALT
Chronic Liver Disease - BeyondtheViruses ...
� Etiologies :� Overweight, Diabetes +++
� Covert Alcohol
� Drugs
� Seronegative autoimmune liver diseases
� Vascular liver diseases
� Celiac disease
� Occult HBV
Impact of Overweight on ChronicLiver Disease
< 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)
BMI (kg/m2) % Relative Risk (CI 95%)
Dionysos Study, n = 1211 (6917 total)
(Bellentani Hepatology 1994)
Proportion of Patients With Cryptogenic Cirrhosis according to BMI - UNOS Database
0
5
10
15
20
25
30
35
40
> 40 BMI35 - 4030 - 3525 - 30< 25
HCV Alcohol CryptogenicN =19271
%
(Nair, Hepatology 2002)
0
5
10
15
20
25
30
35
40
Obésité et Cirrhose Cryptogénétique
Cirrhose X NASH Cirrhose C CBP
N
Age
Obésité(%)
Femmes (%)
Diabète(%)
70 50 39 33
63(+/- 11) 49(+/-14) 60(+/-7) 54(+/-10)
70 56 36 100
47 64 3 15
53 42 25 15
Caldwell, Hepatology 1999
Normal : 10 %
Steatosis alone : 48 %
Steatohepatitis : 42 %
Liver Histology in OverweightPatients
n = 858 ; 9 studies, 1978 - 2002
Prevalence of NASH/NAFLD
First (or second) cause of chronic liver disease in Western Countries
Prevalence among patients with abnormal LFTsof undetermined etiology (n=673, 5 studies)
steatosis alone : 30%
steatohepatitis : 26%
Hepatic Fibrosis in NASH
None or mild 65Severe (cirrhosis excepted) 20Cirrhosis 15
%
n= 572, 9 studies 1980 - 2001
Risk Factors for Severe Fibrosis in NASH
Age > 45-50 yrs
Diabetes
ALT>2N
BMI > 27 kg/m²
HTA
HyperTG
AST/ALT > 1Ratziu, Ratziu, GastroenterologyGastroenterology 20002000
AnguloAngulo, , HepatologyHepatology 19991999
Dixon, Dixon, GastroenterologyGastroenterology 20012001
Abnormal Liver FunctionTests
A frequent problemin clinical hepatology
New viruses : less of a problem
NAFLD : more of a problem
Identifying patients at risk of liver disease -that is the problem!
Viral Etiologies of Acute Hepatitis in the US(1985-1986 and 1991-1995)
� HAV 48
� HBV 34
� HCV 15
� non A-E 3
%
Alter, NEJM 1997
N=10 533