Hepatites Non A-EVirus G et TTV …

et autres considérations métaboliques

Vlad Ratziu, DU Hépatites Virales 2008Hôpital Pitié Salpêtrière,

Paris, France

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

VHG : GBV-C, 95 % homology

VHG : HCV, 29 % homology

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

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%

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 Hepatotropic Virus ?

Pessoa, Hepatology 1998

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

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 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

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.

Fried, Hepatology 1997Pessoa, Hepatology 1998

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 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

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 while decrease in HIV viral load

Tillmann, NEJM 2001

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

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 VIHEffet significatif pls années après primoinfection

VIHWilliams, NEJM 2004

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

Molecular Interactions Between GBV-C and HIV

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

severityAlter, Postgraduate Course, AASLD 2000

Chronic Liver Disease - Beyond the Viruses ...

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 1998

Prati, 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 - Beyond the Viruses ...

Etiologies : Overweight, Diabetes +++ Covert Alcohol Drugs Seronegative autoimmune liver diseases Vascular liver diseases Celiac disease Occult HBV

Impact of Overweight on Chronic Liver 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 Overweight Patients

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 LFTs of undetermined etiology (n=673, 5 studies)

steatosis alone : 30%

steatohepatitis : 26%

Hepatic Fibrosis in NASH

None or mild 65

Severe (cirrhosis excepted) 20

Cirrhosis 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, Gastroenterology 2000Ratziu, Gastroenterology 2000

Angulo, Hepatology 1999Angulo, Hepatology 1999

Dixon, Gastroenterology 2001Dixon, Gastroenterology 2001

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 !

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