严重乙肝相关肝病发病机理和治疗英文版

HBV-associated Severe Liver Diseases:Progress on Pathogenesis and Treatment Yuming WangInstitute for Infectious Diseases of PLASouthwest HospitalThird Military Medical UniversityChongqing,P.R.ChinaThe Progress of Pathogenesis Viral FactorsEvidence for the role of viral factors Long-term follow-up studies demonstrated the close relationship between disease severity and viral factors NA has been showed to be effective in prevention and treatment of hepatitis exacerbation HBV mutation and genotypes are closely related to disease severity Immune suppressed ALF:overwhelming viral replication and immune paralysisHBV mutation and genotyping is closely related to disease severity Precore(G1896A)mutation/core-promoter(G1762T/G1764A)mutations PreS2 mutations HBV genotypes Fig.Frequencies of Precore/C-promoter mutations compared between pts.with FH and self-limited acute hepatitis who were infected with HBV/Bj or Ce Ozasa A,et al.Hepatology.2006,44:326-334Outcome of acute hepatitis B virus infection Pts with FH were older(34y)FH was frequent(13%)and associated with Bj and Ce Lack of HBeAg High replication due to precore mutationOzasa A,et al.Hepatology.2006,44:326-334Pathogenesis of Special Fulminant Hepatitis-Immunosuppression-induced ALF(Fibrosing Cholastatic Hepatitis,FCH)Fig.Hepatitis reactivation after chemotherapyTime after exposure(w)0481216202428323652100Immuno-suppressionMeuleman P,et al.J Virol,2006,80(6):2797-2807.Actually there are 2 kinds of responses:immune rebound and immune paralysisOcama P,et al.Am J Med,2005,118,Dec:e15-1413.e22 Fig.Overwhelming HBV infection with immnosuppressionA-D ALF after chemotherapy in 1 case of non-Hodgkin lymphoma E,F a case with CHBHBsAgHBcAgExtensivePositive HBsAgExtensive hepatocyte injury and inflamationSevere architectural disruption with fibrosis and necrosisHBcAgWhy do the pts.in tolerance stage have no FCH manifestations?Immune tolerance immune paralysis Immune tolerance：virus and host have a relationship of mutually restriction immune paralysis:host loses its restriction to the virusMedical strategy for two categories of ALF Immune suppression induced ALF -Inhibition of virus Immune mediated ALF -Immune suppression by using steroids -Inhibition of virus,ceasing of Immune mediated liver necrosisThe Progress of Treatment Antiviral therapy by NAHospitalized pts.with HBV-associated hepatic failure in Our Dept.through 1991-2005 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005(人人)6194974100167189212777.2%13.9%22.3%42.3%57.5%68.7%76.2%77.7%92.3%83137220175174243248273831999200020012002200320042005200620070%20%40%60%80%100%percentage(%)nucleoside analogue use none nucleoside analogue(1-3)Fig.Hospitalized liver failure patient of hepatitis B and nucleoside analogue usage in South-West hospitalZhang N,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Outcome of severe hepatitis patients after LAM treatment Cases495（control）541（treatment）p0.0001Cure or improved（%）291（58.8）389（71.9）Inefficacy or death（%）204（41.2）152（28.1）Zhang N,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Fig.Patients condition and prognosis of anti-HBV therapy within 1 week after onset of symptoms*P=0.000张绪清，等，待发表张绪清，等，待发表Year(n)2000(19)2001(49)2002(74)2003(100)2004(167)2005(189)improvement/total(%)stage：early2/5(40.0)6/15(40.0)12/24(50.0)15/31(48.4)28/52(53.9)31/51(56.1)40/69(58.0)late2/14(14.3)4/34(11.8)7/50(14.0)16/69(23.1)29/115(25.2)39/132(29.5)49/143(34.3)1.86845.104811.01296.349713.05445.0975P0.17170.02380.00090.01170.00030.02402Tab.Curative effect of 810 liver failure patients of hepatitis B after nucleoside analogue treatmentZhang N,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 01002003004005006007000%20%40%60%80%100%Cum SurvivalSurvival Time(day)treatment control90d P0.05Fig.1 Survival Curve of 215 liver failure of hepatitis B after lamivudine treatmentZhang N,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Fig.liver failure of Chronic Hepatitis B Virus Infection After Withdrawal of Lamivudine Therapy in South-West hospital1372201751742432482738303261314151120002001200220032004200520062007050100150200250In patient of liver failure total LAM withdrawal(1-3)Zhang N,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 0w2w4w8w4.55.05.56.06.57.07.5BV DNA(Log10copies/ml)LAM ETV ADVFig.Anti-HBV therapy by NA of 276 liver failure patients of Hepatitis after anti-HBV therapy by NAZhang N,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Fig.The disease cause of 1 patients with severe hepatitis B after treatment 38y male；HBsAg(+)4 years,jaundice for 2 weeks was transferred to our department after 8 weeks treatment from local hospital LAMliver failureperitonitisdeath admissionZhang X,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007HBV DNA(log10 copies/ml)100200300400500600700800IU/mlLAM 100mg/d 36mLAM50mg/d6mLAM停药后复发停药后复发monthETVADVFig.One pts.with decompensated liver cirrhosis showed multi-drug resistanceYVDDWang Y,et al.unpublished dataTarget sequence:394 bp.located in the Rt region of the polymerase gene in HBV genome All known mutation loci associated with nucleoside analog resistance were includedLAMADVETVL-dTI169TV173LL180MA181VT184ACFGILMSS202CGIM204IM204VN236TM250ILVFig.Nested-PCR for the amplification of P Rt sequenceXia J,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Agarose gel electrophoresis of PCR productsTA cloningPCR verification of white coloniesXia J,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Patient IDynamics of serum HBV DNA,ALT and HBV quasispecies population Liu L et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007VM breakthroughQuasispecies memoryPatient JDynamics of serum HBV DNA,ALT and HBV quasispecies population VM breakthroughQuasispecies memoryLiu L et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007Antiviral therapy before and After OLTx in Pts.with Severe HepatitisTerrault N,et al.Liver Transpl,2005,11:716-732Fig.Prevention and Treatment of HBV Reinfection in OLTx Patients HBV recurrence rate between HBV DNA(+)and HBV DNA(-)pre-OLT patients（）8.2（7/85）2.3（2/88）31.5（17/54）12.7（7/55）51.4（19/37）20.6（7/37）P0.01(post-OLT)Xia J,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Mechanism for HBV recurrence post-OLTx Without anti-virus treatment pre-OLT in HBV DNA(-)patients Insufficient anti-viral treatment pre-OLT HBV mutations(LAM-R)pre-OLT has not been detected by real-time PCR Be short of profession doctors guidance,and insufficient follow-up system The problem in compliance of patientsXia J,et al.Oral presentation at the Annual Conference of APASL,Kyoto 2007 Conclusion:Progress of Pathogenesislviral factors are emphasized now,which have been demonstrated by the efficacy of antiviral therapy by nucleoside analogues lImmunosuppression induced liver failure is associated with immune polarization and viral replicationlNA has been shown to be effective and safe in patients with hepatitis B including fulminant hepatitis and decompensated liver cirrhosis lcould effectively suppress HBV-induced liver inflammation and necrosis in short term,and prevent hepatitis flares lmore experience has been accumulated in LAM and ADV,latter is suitable for the patients with slow progression Conclusion:the Progress of Antiviral Therapy by NA(1)lETV and LdT will have potential application owing to their strong potency;iii)antiviral indication can be extended to acute course lviral load can be flexible,and duration is indefinite(except for patients with acute infection)lviral resistance is not common and multi-drug resistance is rare,but more attention should be paid,due to the resistance related hepatitis reactivation Conclusion:the Progress of Antiviral Therapy by NA(1)50-year Anniversary of Dept.of Infectious Diseases,TMMU in 2005