Pathogenesis and Classification of HBV-related Liver Failure Yuming Wang Department of Infectious Diseases Southwest Hospital Third Military Medical University Chongqing, P. R. China
Host Factors Particularly in Genetics
、IL-10,IL-12 Fig. Role of natural killer (NK) and natural killer T (NKT) cells in mediating acute liver injury Antoniades CG, et al. J Hepatol. 2008,49: 845–861
Fig. Serum levels of IL-12 in chronic hepatitis B patients with different ALT levels He DM, Yan GH, Wang YM. Cell Immunol, 2011, 272：162-165.
Fig. Correlation between serum levels of IL-12 and ALT He DM, Yan GH, Wang YM. Cell Immunol, 2011, 272：162-165.
Fig. Serum IL-10 and CXCL10 in pts. with HBV- related liver failure During hepatitis exacerbation, serum cytokines including CXCL10(IP-10) ,TH1 type, and IL10, TH2 type, significantly increased Yumoto E, et al. J Gastroenterol Hepatol 2002; 17: 285–294Deng G, et al. Gastroenterology 2008; 134(3): 716-726
Fig. CXCL10 expression of the liver in a pt. with HBV- related ACLF Deng G, et al. Gastroenterology 2008; 134(3): 716-726
HumanCXCL10 gene SNPdistribution HumanIL-10 gene SNPdistribution
G-201A polymorphism is related with disease progression in HBV carriers Association between IL-10 promoter haplotypes and HBV-related ALF Deng GH, Wang YM, et al. Gastroenterology 2008; 134(3): 716-726 Yan ZH, Deng GH, Wang YM, et al. J Viral Hepatitis 2009; 16: 775-783
G-201A is regulatory SNP of CXCL10 gene Deng G, et al. Gastroenterology 2008; 134(3): 716-726
CXCL10 gene mutation and disease progression CXCL10 G-201A is closely related to disease progression Deng G, Yan ZH, Wang YM, et al. Gastroenterology 2008; 134(3): 716-726
IL-10 gene mutation and HBV-related hepatitis exacerbation IL-10 -592A/C，-819T/Cis closely correlated with HBV-ALF Deng G, Yan ZH, Wang YM, et al.J Viral Hepat. 2009 ,16,775-783
ESR1 gene mutation and HBV-related chronic hepatitis and liver decompensation ESR1 T29C、IVS1 T-401Care closely correlated to HBV-ALFand LC Yan ZH, Deng G, Wang YM, et al. Human Mutation. 2011 , 32(10): 1128-1136
ICAM-1 gene mutation and HBV-related liver decompensation ICAM-1 G241R & E469K mutationare closely correlated with liver decompensation ICAM-1R241-E469 haplotype is closely correlated with liver decompensation Zhang XQ et al，J Viral Hepat 2008; 15:173-178
TBX21 gene mutation and HBV-related chronic hepatitis liver decompensation TBX21 SNPis correlated with HBVpersistent infection Chen S，Zhao WL, Deng G, Wang YM, et al. Hepatol Res. 2009; 39: 716-723
SNP of CXCL10, IL-10and ESR1: significance • Above-mentioned SNPsare all located in promoter area • SNP distributions in human being are constant • The expression of genes will change when response happens • Both SNPs and expression of genes are all of importance in explore the mechanisms of hepatitis flares Deng GH, Wang YM, et al. Gastroenterology 2008; 134(3): 716-726 Yan ZH, Deng GH, Wang YM, et al. J Viral Hepatitis 2009; 16: 775-783 Morley M, et al. Nature 2004; 430: 743-747 Ge B, Pastinen T, et al. Nat Genet 2009; 41: 1216-1224
Fig. Hepatitis exacerbation in pts. with CHB using NUCs Tang YZ, Wang YM, et al. Antiv Res, 2011, 90(3): 116-125.
Fig. Nucleotide (nt) polymorphism along the HBV genome in pts with hepatitis exacerbation Tang YZ, Wang YM, et al. Antiv Res, 2011, 90(3): 116-125.
Tab. Viral-reactivation in Pts. with Chronic Viral Hepatitis (1) #: f: female; m: male; LT: Liver transplantation Fan K, Wang YM, et al. 13th ISVHLD , 2009
Tab. Viral-reactivation in Pts. with Chronic Viral Hepatitis (2) Fan K, Wang YM, et al. 13th ISVHLD , 2009
The patient stopped using LAM Fig. Case 1 with HBV-reactivation during Steroid Therapy after Renal Transplantation Using LAM for 7 m and HBV DNA was under detection, reactivated after stopping the drug. Refused to use LAM plus ADV, and died with liver failure Fan K, Wang YM, et al. 13th ISVHLD , 2009
Fig. Case 2 with HBV-reactivation after Renal Transplantation Using ETV after HBV-reactivation and recovered by OTLx Fan K, Wang YM, et al. 13th ISVHLD , 2009
Summary：Liver Failure/severe Hepatitis by HBV-reactivation • Immune inhibitors: strong precipitating factors of viral-reactivation • Occurrence: in any HBV infected pts • Pathogenesis: hepatocyte nutrient depletion due to extensive viral replication • Immune paralysis: other than immune tolerance is the key precondition • Management: prevention is more important than treatment
Fig. Survival rates in 215 pts. with liver failure with hepatitis B after LAM treatment Zhang N, et al. Oral presentation at the Annual Conference of APASL, Kyoto 2007 Tang YZ, Liu L, Zhou X, Wang YM Antiv Res 2011; 90(3): 116-125
Fig. Choice of NUCs in 178 cases of HBV-related Liver Failure in Our Dept. (2008-2010)
Choice of NUCs for HBV-related Liver Failure • With resistance (with LAMR or ADVR) - LAM+ADV or ETV+ADV or LdT+ADV for LAMR - ETV for ADVR • Without resistance - Rapid progression and high replication： ETV or LdT (+ADV) or LAM (+ADV) - Slow progression and low replication: ADV *TDF is unvailable in China Tang YZ, Liu L, Zhou X, Wang YM Antiv Res 2011; 90(3): 116-125
Focal Point in Nomenclature Japan & China Europe & USA Hepatic failure Fulminanthepatitis 武藤 泰敏. 肝胆膵, 1995, 30(1):41
National Guideline for Nomenclature of Liver Failure * With or without chronic liver disease, can be divided into 2 subtypes: HE and non-HE ▲ T.Bil＜171μmol/L，the other types: T.Bil≥171μmol/L National guideline for diagnostic and treatment of liver failure. Chin J Hepatol, 2008
Classification of Liver Failure • Acute Liver Failure (ALF) Encephalopathy within 8 wks of onset disease • Acute-on-Chronic Liver Failure (A-CLF) precipitated by sepsis, bleeding, alcohol • Chronic decompensation (CLF) progression of end stage liver disease • Clinical manifestations similar – encephalopathy, jaundice, hepatorenal syndrome, systemic vasodilatation, but differences in severity & in patho-physiol. disturbance Roger Willianms, International and national symposium for Liver Failure. Chongqing 2007.3
Summary for Nomenclature of liver failure • Liver failure is currently divided into 2 groups in China and some countries: - ALF/SALF manifested by necrosis - ACLF/CLF manifested by decompensation • We suggest to rename “CLF” as “end-stage liver failure (ELF)”, so as to avoid the confusion of ACLF and CLF • History is not necessary to distinguish the 2 groups - When there is an abrupt onset a in a patient from immune tolerance stage, the diagnosis should be “acute” other than “chronic”
Tab. HBV-related Liver Failure in Our Dept. 2003.2-2009.12 N=1 066 ACLFand CLFusually manifested liver decompensation after effective treatment in-hospital Liu C, Wang YM, et al. World J Gastroenterol. 2011, 17(25): 3054-3059.
Onset Patterns of HBV-related Liver Failure Flare form: Abrupt and progressive hepatitis flares on the basis of immune tolerance stage Relapse form: hepatitis activation and reactivation intermittently Insidious form: there is no any obvious onset in the past and gradually liver decompensation occurred Precipitation form: acute liver decompensation occurred due to precipitation factors (sepsis)
Tab. The Changing Patterns of Liver Failure in China ACLFand CLFusually manifested liver decompensation after effective treatment in-hospital Liu C, Wang YM, et al. World J Gastroenterol, 2011, 17(25): 3054-3059.
Fig. The comparision of HE occurrence in different year Yan GH, Wang YM, et al. 1st CCIFLDI. 2012.
The Reasons for Changing Patterns of HBV-related Liver Failure in China • Real acute HBV infection induced liver failure is rare, majority of pts. are infected by vertical transmission, who usually develop to liver failure by one to several hepatitis flares • Timely and effective antiviral therapy especially by using NUCs in CHB in recent ~ 10 years have significantly reduced HBV-related liver failure • Pts with liver cirrhosis with compensation ordecompensation are relatively increasing than in the past Liu C, Wang YM, et al. World J Gastroenterol. 2011, 17(25): 3054-3059.
Conclusions (1) • Both host and viral factors play important roles in the pathogenesis of HBV-related liver failure • IL-12, G-201A from CXCL10, -592C and -819C from IL-10 are closely related to hepatitis exacerbation and liver failure • Quasispecies studies during antiviral therapy by using NUCs are quite important
Conclusions (2) • Viral reactivation in immunosuppressed statues can induce FCH, manifested by 2 forms: high and low ALT level, which suggests different mechanisms • For HBV-related liver failure, there are 2 strategies for the NUC therapy: single and combination • According to pathogenesis, liver failure is currently divided into 2 groups: ALF/SALF manifested by necrosis and ACLF/CLF manifested by decompensation
Prospect From mechanisms to nomenclature To explore the mechanisms of liver injuries with different etiology, so as to provide evidences for clinical nomenclature of liver failure From management to mechanisms To test mechanisms by effects of different managements, so as to improve the level of diagnosis and treatment of liver failure
Whole Members Dept. of Infectious Diseases, TMMU