Pathogenesis and Classification of HBV-related Liver Failure Yuming Wang Department of Infectious...
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Transcript of Pathogenesis and Classification of HBV-related Liver Failure Yuming Wang Department of Infectious...
Pathogenesis and Classification of HBV-related Liver Failure
Yuming WangDepartment of Infectious Diseases
Southwest HospitalThird Military Medical University
Chongqing, P. R. China
Fig. Immune response from the host and viral adaptation
Host Factors Particularly in Genetics
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
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.
Yumoto E, et al. J Gastroenterol Hepatol 2002; 17: 285–294Deng 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
Fig. CXCL10 expression of the liver in a pt. with HBV- related ACLF
Deng G, et al. Gastroenterology 2008; 134(3): 716-726
Human CXCL10 gene SNP distribution
Human IL-10 gene SNP distribution
G-201A polymorphism is related with disease progression in HBV carriers
Non-progressed carriers(n=1253)
Progressed carriers(n=1147) P value OR ( 95%CI )
GG 1034 874
GA 205 248
AA 6 15
A Allele 0.087 0.122 < 0.001 1.5 (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)P OR (95% CI)
ATA/ATA 179 (0.488) 132 (0.382)
ATA / - - - 155 (0.422) 159 (0.461)0.0002 1.60 (1.25-2.07)
- - - / - - - 33 (0.090) 54 (0.157)
Association between IL-10 promoter haplotypes and HBV-related ALF
G-201A is regulatory SNP of CXCL10 gene
Deng G, et al. Gastroenterology 2008; 134(3): 716-726
Deng G, Yan ZH, Wang YM, et al. Gastroenterology 2008; 134(3): 716-726
Non-progressed (n=1253)Non-progressed (n=1253) Progressed carrier (n=1147)Progressed carrier (n=1147) P valueP value OR ( 95%CI )OR ( 95%CI )
GGGG 10341034 874874GAGA 205205 248248AAAA 66 1515
A AlleleA Allele 217(0.087)217(0.087) 278(0.122)278(0.122) < 0.001< 0.001 1.5 (1.2-1.9)1.5 (1.2-1.9)
CXCL10 gene mutation and disease progression
CXCL10 G-201A is closely related to disease progression
IL-10 -592A/C , -819T/Cis closely correlated with HBV-ALF
IL-10 gene mutation and HBV-related hepatitis exacerbation
alleleallele BD(2n = 828)BD(2n = 828) AsC (n =734)AsC (n =734) P ValueP Value ALF (n = 690)ALF (n = 690) P ValueP Value
T-819CT-819C
T allele, no.(%)T allele, no.(%) 612(8.0)612(8.0) 471(9.0)471(9.0) 428(15.7)428(15.7)C allele, no.(%)C allele, no.(%) 216(26.1)216(26.1) 203(27.7)203(27.7) 0.4850.485 262(38.0)262(38.0) 6.9×106.9×10-7-7
A-592CA-592CA allele, no.(%)A allele, no.(%) 612(8.0)612(8.0) 471(9.0)471(9.0) 42815.7)42815.7)C allele, no.(%)C allele, no.(%) 216(26.1)216(26.1) 203(27.7)203(27.7) 0.4850.485 262(38.0)262(38.0) 6.9×106.9×10-7-7
Deng G, Yan ZH, Wang YM, et al. J Viral Hepat. 2009 ,16,775-783
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 decompensationallele AsC(n = 857) ALF(n =359) P value HBV-LC(2n = 2570 P value
IVS1 T-401C(rs2234693, c.453-397T>C )T allele, no.(%)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.(%)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
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
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
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 flaresDeng 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
Viral Factors
Particularly in viral mutation
Fig. Hepatitis exacerbation in pts. with CHB using NUCsTang 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.
N Age SexDisease/therapy
Medicinepretherapy/post-treatment (HBV DNA)
ALTpeak
T.Bil /D.Bil peak
Therapy for viral reactivation
Outcome
1 33 F
chronic nephritis( uremia period ) /kidney transplantation
AZP, prednisone
HBsAg(+)/1.343×108 63
231.4/158.1
LAM death
2 46 M
nephritic syndrome/kidney transplantation
MePDNL, sirolimus, FK506
HBV DNA(-)/>1.00×107 665
522.5/305.9
ETVrecover after OLT
3 41 M CSH/OLTmedron 、 prednisone
HBVM(-)/(+)&HBV DNA 3.15×107 334
642.92/300.13
LAM Inefficacy
4 38 M
chronic nephritis( uremia period ) /kidney transplantation
Solu-Medrol, prednisoneFK506, CellCept
HBV DNA 0/2.88×103 154 none LAM improved
5 69 M eczema DEXHBV carrier/ HBV DNA1.303×106 2695
383.2/142.3
ETV deteriorate
#: 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
n agesexdisease/therapy
medicinepretherapy/post-treatment (HBV DNA)
ALTpeak
T.Bil /D.Bil peak
Therapy for viral reactivation
Outcome
6 40 F DLCFDB,DXM, MX HBV DNA 1×106
/6.88×107 38 LAM Inefficacy
7 47 MDecompensated cirrhosis, OTL
CsA, prednisone
HBV DNA(-)/4.693×107 78
394.2/263.5
LAM Inefficacy
8 40 MCRF/kidney transplantation
sirolimus, CsA, prednisone
HBV DNA 4.39×102/6.42×107 47 LAM Inefficacy
9 25 Muremia/kidney transplantation
FK506, CellCept 、Prednisone, DXM
anti-HCV(-)/HCV RNA 8.331×106269
186.7/110.9
---deteriorate (in treating)
10 45 M lymphomaVCR, EPI, IFO, SQS, Mabthera, MTX
HBV DNA 2.90×102
/2.792×109 1767484.5/266.47
LAM death
Tab. Viral-reactivation in Pts. with Chronic Viral Hepatitis (2)
Fan K, Wang YM, et al. 13th ISVHLD , 2009
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
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
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
0 100 200 300 400 500 600 700
0%
20%
40%
60%
80%
100%
Cum
Sur
viva
l
Survival Time(day)
treatment control
90d P<0.05
Fig. Survival rates in 215 pts. with liver failure
with hepatitis B after LAM treatmentZhang 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
Nomenclature and Classification of Liver Failure
Focal Point in Nomenclature
Europe & USA
Hepatic failure
Japan & China
Fulminant hepatitis
武藤 泰敏 . 肝胆膵 , 1995, 30(1):41
National Guideline for Nomenclature of Liver Failure
Nomenclature Definition
ALF* Acute onset, with liver failure in 2 weeks
SALF* Subacute onset, with liver failure in 15-168 days (24w)
ACLF Acute 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
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.
Nomenclature n %
ALF 116 10.88
ACLF 654 61.35
CLF 296 27.77
2003.2-2009.12 N=1 0662003.2-2009.12 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
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)
Past Now
Main onset form Acute or subacute Acute on chronic or chronic
Common disease duration
Short (1-4 weeks) Long (1-6 months)
Liver cirrhosis Few Majority
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
0. 00%
10. 00%
20. 00%
30. 00%
40. 00%
50. 00%
60. 00%
70. 00%
20002010
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 or
decompensation are relatively increasing than in
the pastLiu C, Wang YM, et al. World J Gastroenterol. 2011, 17(25): 3054-3059.
Conclusions
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
ProspectFrom 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 MembersDept. of Infectious Diseases, TMMU