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