1. Pathogenesis and Classification of HBV-related Liver Failure Yuming Wang Department of Infectious Diseases Southwest Hospital Third Military Medical University Chongqing, P. R. China

2. Fig. Immune response from the host and viral adaptation

3. Host Factors Particularly in Genetics

4. 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 、 IL-10,IL-12

5. 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.

6. Fig. Correlation between serum levels of IL-12 and ALT He DM, Yan GH, Wang YM. Cell Immunol, 2011, 272 ： 162-165.

7. Yumoto E, et al. J Gastroenterol Hepatol 2002; 17: 285–294 Deng G, et al. Gastroenterology 2008; 134(3): 716-726 During hepatitis exacerbation, serum cytokines including CXCL10(IP- 10),TH1 type, and IL10, TH2 type, significantly increased Fig. Serum IL-10 and CXCL10 in pts. with HBV- related liver failure

8. Fig. CXCL10 expression of the liver in a pt. with HBV- related ACLF Deng G, et al. Gastroenterology 2008; 134(3): 716-726

9. Human CXCL10 gene SNP distribution Human IL-10 gene SNP distribution

10. G-201A polymorphism is related with disease progression in HBV carriers Non-progressed carriers (n=1253) Progressed carriers (n=1147) P valueOR ( 95%CI ) GG1034874 GA205248 AA615 A Allele0.0870.122< 0.0011.5 (1.2-1.9) 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 IL10 promoter haplotype AsC (n = 367) HBV-ALF (n = 345) POR (95% CI) ATA/ATA179 (0.488)132 (0.382) ATA / - - -155 (0.422)159 (0.461) 0.00021.60 (1.25-2.07) - - - / - - -33 (0.090)54 (0.157) Association between IL-10 promoter haplotypes and HBV-related ALF

11. G-201A is regulatory SNP of CXCL10 gene Deng G, et al. Gastroenterology 2008; 134(3): 716-726

12. Deng G, Yan ZH, Wang YM, et al. Gastroenterology 2008; 134(3): 716-726 Non-progressed (n=1253) Progressed carrier (n=1147) P value OR ( 95%CI ) GG1034874 GA205248 AA615 A Allele 217(0.087)278(0.122) < 0.001 1.5 (1.2-1.9) CXCL10 gene mutation and disease progression CXCL10 G-201A is closely related to disease progression

13. IL-10 -592A/C ， -819T/Cis closely correlated with HBV-ALF IL-10 gene mutation and HBV-related hepatitis exacerbationallele BD(2n = 828) AsC (n =734) P Value ALF (n = 690) P Value T-819C T allele, no.(%) 612(8.0)471(9.0)428(15.7) C allele, no.(%) 216(26.1)203(27.7)0.485262(38.0) 6.9×10 -7 A-592C A allele, no.(%) 612(8.0)471(9.0)42815.7) C allele, no.(%) 216(26.1)203(27.7)0.485262(38.0) 6.9×10 -7 Deng G, Yan ZH, Wang YM, et al. J Viral Hepat. 2009,16,775-783

14. Yan ZH, Deng G, Wang YM, et al. Human Mutation. 2011, 32(10): 1128-1136 ESR1 gene mutation and HBV-related chronic hepatitis and liver decompensation allele AsC(n = 857)ALF(n =359)P valueHBV-LC(2n = 2570P value IVS1 T-401C(rs2234693, c.453-397T>C ) T allele, no.(%) 1086(62.4)400(55.7)1361(53.0) C allele, no. (%)632 (36.9)318 (44.3)5.37×10 -6 1209 (47.0)2.0×10 -8 T29C(rs2077647, c.30T>C) T allele, no.(%) 1184 (11.7)446(62.1)1441 (60.0) C allele, no. (%)296 (31.6)272 (37.9)8.65×10 -4 1029 (40.0)4.2×10 -8 ESR1 T29C 、 IVS1 T-401Care closely correlated to HBV-ALF and LC

15. Zhang XQ et al ， J Viral Hepat 2008; 15:173-178 ICAM-1 gene mutation and HBV-related liver decompensation ICAM-1 G241R & E469K mutation are closely correlated with liver decompensation ICAM-1 R241-E469 haplotype is closely correlated with liver decompensation

16. TBX21 SNP is correlated with HBV persistent infection Chen S ， Zhao WL, Deng G, Wang YM, et al. Hepatol Res. 2009; 39: 716-723 TBX21 gene mutation and HBV-related chronic hepatitis liver decompensation

17. SNP of CXCL10, IL-10 and ESR1: significance  Above-mentioned SNPs are 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

18. Viral Factors Particularly in viral mutation

19. Fig. Hepatitis exacerbation in pts. with CHB using NUCs Tang YZ, Wang YM, et al. Antiv Res, 2011, 90(3): 116-125.

20. 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.

21. NAgeSex Disease /therapy Medicine pretherapy/ post-treatment (HBV DNA) ALT peak T.Bil /D.Bil peak Therapy for viral reactivation Outcome 133F chronic nephritis （ uremia period ） /kidney transplantation AZP, prednisone HBsAg(+) /1.343×10 8 63 231.4 /158.1 LAMdeath 246M nephritic syndrome/ kidney transplantation MePDNL, sirolimus, FK506 HBV DNA (-)/>1.00×10 7 665 522.5 /305.9 ETV recover after OLT 341MCSH/OLT medron 、 prednisone HBVM(-)/(+)&HBV DNA 3.15×10 7 334 642.92 /300.13 LAMInefficacy 438M chronic nephritis （ uremia period ） /kidney transplantation Solu-Medrol, prednisone FK506, CellCept HBV DNA 0 /2.88×10 3 154noneLAMimproved 569MeczemaDEX HBV carrier/ HBV DNA1.303×10 6 2695 383.2 /142.3 ETVdeteriorate #: f: female; m: male; LT: Liver transplantation Tab. Viral-reactivation in Pts. with Chronic Viral Hepatitis (1) Fan K, Wang YM, et al. 13th ISVHLD, 2009

22. nagesex disease /therapy medicine pretherapy/ post-treatment (HBV DNA) ALT peak T.Bil /D.Bil peak Therapy for viral reactivation Outcome 640FDLC FDB, DXM, MX HBV DNA 1×10 6 /6.88×10 7 38LAMInefficacy 747M Decompensated cirrhosis, OTL CsA, prednisone HBV DNA (-)/4.693×10 7 78 394.2/ 263.5 LAMInefficacy 840M CRF /kidney transplantation sirolimus, CsA, prednisone HBV DNA 4.39×10 2 /6.42×10 7 47LAMInefficacy 925M uremia/kidney transplantation FK506, CellCept 、 Prednisone, DXM anti-HCV(-)/ HCV RNA 8.331×10 6 269 186.7/ 110.9 --- deteriorat e (in treating) 1045Mlymphoma VCR, EPI, IFO, SQS, Mabthera, MTX HBV DNA 2.90×10 2 /2.792×10 9 1767 484.5/ 266.47 LAMdeath Tab. Viral-reactivation in Pts. with Chronic Viral Hepatitis (2) Fan K, Wang YM, et al. 13th ISVHLD, 2009

23. 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 The patient stopped using LAM

24. 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

25. 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

26. 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

27. Fig. Choice of NUCs in 178 cases of HBV-related Liver Failure in Our Dept. (2008-2010)

28. Choice of NUCs for HBV-related Liver Failure  With resistance (with LAM R or ADV R ) - LAM+ADV or ETV+ADV or LdT+ADV for LAM R - ETV for ADV R  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

29. Nomenclature and Classification of Liver Failure

30. Focal Point in Nomenclature Europe & USA Hepatic failure Japan & China Fulminant hepatitis 武藤 泰敏. 肝胆膵, 1995, 30(1):41

31. National Guideline for Nomenclature of Liver Failure NomenclatureDefinition ALF*Acute onset, with liver failure in 2 weeks SALF*Subacute onset, with liver failure in 15- 168 days (24w) ACLFAcute liver decompensation on the basis of chronic liver disease CLF ▲ Chronic liver decompensation on the basis of end stage liver disease * 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

32. 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

33. 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”

34. Tab. HBV-related Liver Failure in Our Dept. Nomenclature n % ALF 116 10.88 ACLF 654 61.35 CLF 296 27.77 2003.2-2009.12 N=1 066 Liu C, Wang YM, et al. World J Gastroenterol. 2011, 17(25): 3054-3059. ACLF and CLF usually manifested liver decompensation after effective treatment in-hospital

35. 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)

36. PastNow Main onset formAcute or subacuteAcute on chronic or chronic Common disease duration Short (1-4 weeks)Long (1-6 months) Liver cirrhosisFewMajority Main HE type HE occurrence Type A High Type C Low Liu C, Wang YM, et al. World J Gastroenterol, 2011, 17(25): 3054-3059. ACLF and CLF usually manifested liver decompensation after effective treatment in-hospital Tab. The Changing Patterns of Liver Failure in China

37. Fig. The comparision of HE occurrence in different year Yan GH, Wang YM, et al. 1st CCIFLDI. 2012.

38. 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 or decompensation are relatively increasing than in the past Liu C, Wang YM, et al. World J Gastroenterol. 2011, 17(25): 3054-3059.

39. Conclusions

40. 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

41. 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

42. 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

43. Whole Members Dept. of Infectious Diseases, TMMU