严重乙肝相关肝病发病机理和治疗英文版.ppt

HBV-associated Severe Liver Diseases: Progress on Pathogenesis and Treatment,Yuming Wang Institute for Infectious Diseases of PLA Southwest Hospital Third Military Medical University Chongqing, P. R. China,The Progress of Pathogenesis Viral Factors,Evidence 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 paralysis,HBV 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: 326-334,Outcome 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 mutation,Ozasa A, et al. Hepatology. 2006, 44: 326-334,Pathogenesis of Special Fulminant Hepatitis- Immunosuppression-induced ALF (Fibrosing Cholastatic Hepatitis, FCH),Fig. Hepatitis reactivation after chemotherapy,Time after exposure (w),0,4,8,12,16,20,24,28,32,36,52,100,chemotherapy,Meuleman P, et al. J Virol, 2006, 80(6):2797-2807.,Actually there are 2 kinds of responses: immune rebound and immune paralysis,Ocama P, et al. Am J Med, 2005, 118, Dec:e15-1413.e22,Fig. Overwhelming HBV infection with immnosuppression,A-D ALF after chemotherapy in 1 case of non-Hodgkin lymphoma E, F a case with CHB,HBcAg,Why 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 virus,Medical 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 necrosis,The Progress of Treatment Antiviral therapy by NA,Hospitalized pts. with HBV-associated hepatic failure in Our Dept. through 1991-2005,Fig. Hospitalized liver failure patient of hepatitis B and nucleoside analogue usage in South-West hospital,Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Outcome of severe hepatitis patients after LAM treatment,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,Tab. Curative effect of 810 liver failure patients of hepatitis B after nucleoside analogue treatment,Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Fig.1 Survival Curve of 215 liver failure of hepatitis B after lamivudine treatment,Zhang 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 hospital,Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Fig. Anti-HBV therapy by NA of 276 liver failure patients of Hepatitis after anti-HBV therapy by NA,Zhang 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,LAM,liver failure,peritonitis,death,admission,Zhang X, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,HBV DNA (log10 copies/ml),100,200,300,400,500,600,700,800,IU/ml,LAM 100mg/d 36m,LAM 50mg/d,6m,LAM,停药后复发,month,ETV,ADV,Fig. One pts. with decompensated liver cirrhosis showed multi-drug resistance,YVDD,Wang Y, et al. unpublished data,Target 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 included,Fig. Nested-PCR for the amplification of P Rt sequence,Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Agarose gel electrophoresis of PCR products,TA cloning,PCR verification of white colonies,Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Patient I,Dynamics of serum HBV DNA, ALT and HBV quasispecies population,Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,VM breakthrough,Quasispecies memory,Patient J,Dynamics of serum HBV DNA, ALT and HBV quasispecies population,VM breakthrough,Quasispecies memory,Liu L et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Antiviral therapy before and After OLTx in Pts. with Severe Hepatitis,Terrault N, et al. Liver Transpl, 2005, 11: 716-732,Fig. 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 patients,Xia J, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007,Conclusion: Progress of Pathogenesis,viral factors are emphasized now, which have been demonstrated by the efficacy of antiviral therapy by nucleoside analogues Immunosuppression induced liver failure is associated with immune polarization and viral replication,NA has been shown to be effective and safe in patients with hepatitis B including fulminant hepatitis and decompensated liver cirrhosis could effectively suppress HBV-induced liver inflammation and necrosis in short term, and preven