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Pietro Invernizzi
Primary biliary cirrhosis
Hepatobiliary Immunopathology UnitIRCCS Istituto Clinico Humanitas,
Rozzano, Italy
A.I.S.F., Rome, 25 February 2010
Dept of Internal MedicineUniversity of California,
Davis, CA
CI I IISTITUTO CLINICO
HUMANITAS
2
Autoimmune liver diseasesPrimary target of immune-mediated injury
Primary biliary cirrhosis
Autoimmunehepatitis
CHOLANGIOCYTE HEPATOCYTE
OverlapsyndromePrimary sclerosing cholangitis
Invernizzi et al. Semin Liver Dis 2007
3
Outline
Genetics/environment
Female/male
Target organ
Novel biomarkers
Novel drugs
?
4
Etiopathogenesis of PBC
Autoimmunity
ENVIRONMENTALFACTORS
GENETICFACTORS
?
5
Geo-epidemiology of PBC prevalence
Local clustering
Risk factors
Experimental evidence for a role of xenobiotics, infectious agents
ENVIRONMENTALFACTORS
GENETICFACTORS
Etiopathogenesis of PBC
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The 2005 US PBC Epidemiology Group Study
1032 patients with PBC from US tertiary referral centers
1041 random-digit dialed healthy controls matched for race, sex, and telephone area code
Gershwin et al. Hepatology 2005
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PBC Risk FactorsUSA PBC Epidemiology Study vs. previous studies
-WeakHair dye use
Suggested
Yes
Yes
-
No
Suggested
No
No
No
Yes
Yes
Yes
PREVIOUS STUDIES
NOT CONFIRMED / DEBATED
NOVEL
CONFIRMED
YesYearly income
YesFamilial SLE
YesFamilial Sjogren
No
No
No
Breast cancer
Psoriasis
Eczema
YesFrequent nail polish use
YesUse of HRT
YesPregnancies/Age
YesSmoking habit
YesRecurrent UTIs
YesFamilial PBC
2005 UPEG
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Familial clustering (high risk for
PBC development within a
family)
High concordance rate of PBC
in monozygotic twins
Polymorphisms associated with
susceptibility and progression
ENVIRONMENTALFACTORS
GENETICFACTORS
Etiopathogenesis of PBC
9
Familial clustering (high risk
for PBC development within a
family)
High concordance rate of PBC
in monozygotic twins
Polymorphisms associated with
susceptibility and progression
ENVIRONMENTALFACTORS
GENETICFACTORS
Etiopathogenesis of PBC
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Country Year No. Of Familial ReferencePatients Prevalence
%
United States 1994 396 4.3 Bach
England 1995 736 1.33 Brind
England 1999 157 6.4 Jones
Sweden 1990 111 4.5 Danielsson
Italy 1997 156 3.8 Floreani
Japan 1999 156 5.1 Tsuji
United States 2005 1032 5.9 Gershwin
Familial PBC: epidemiological studies
11
Familial clustering (high risk for
PBC development within a
family)
High concordance rate of
PBC in monozygotic twins
Polymorphisms associated with
susceptibility and progression
ENVIRONMENTALFACTORS
GENETICFACTORS
Etiopathogenesis of PBC
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PBC concordance rate in twins
MZ Twins
5 out of 8 pairs concordant for PBC (CR 0.63)
DZ Twins
No pair [out of 9] concordant for PBC (CR 0)
Selmi et al. Gastroenterology 2004
13
Familial clustering (high risk for
PBC development within a
family)
High concordance rate of PBC
in monozygotic twins
Polymorphisms associated
with susceptibility and
progression
ENVIRONMENTALFACTORS
GENETICFACTORS
Etiopathogenesis of PBC
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Year Country Significant association with
1979 Spain DRw31983 Japan DR21987 England C4B21987 USA DR8 / DR5 (decreased in PBC)1990 USA DRw81991 Germany DRw8 / C4AQ01992 England DR81992 Denmark DR31993 Japan DQ3 / DPB1*0501 / DR52 (DRB3) decreased1994 Japan DRB1*0803 / DQA1*0103 / DQB1*06011994 USA DRB1*0801 / DRB1*0901 / DQA1*0401/0601
DQA1*0102 decreased / DQB1*0602 decreased1995 Germany DPB1*03012002 Sweden DRB1*0801 / DQB1*04022002 Canada DRB1*08 / DQB1*04
Polymorphisms of HLA genes
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Year Country Significant association with
1979 Spain DRw31983 Japan DR21987 England C4B21987 USA DR8 / DR5 (decreased in PBC)1990 USA DRw81991 Germany DRw8 / C4AQ01992 England DR81992 Denmark DR31993 Japan DQ3 / DPB1*0501 / DR52 (DRB3) decreased1994 Japan DRB1*0803 / DQA1*0103 / DQB1*06011994 USA DRB1*0801 / DRB1*0901 / DQA1*0401/0601
DQA1*0102 decreased / DQB1*0602 decreased1995 Germany DPB1*03012002 Sweden DRB1*0801 / DQB1*04022002 Canada DRB1*08 / DQB1*04
HLA DRB1*08
Polymorphisms of HLA genes
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HLA PBC Controls Pc Odds Ratio (95% C.I.)(n=186) (n=558)
(%) (%)
DRB1*08 6.7 5.3 N.S. - -
DRB1*11 10.7 27.6 0.000 0.3 0.2-0.5
Invernizzi et al. J Hepatol 2003
HLA polymorphisms in Italian PBC
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HLA polymorphisms in Italian PBCMulticenter Study
HLA PBC Controls Pc Odds Ratio (95% C.I.)(n=664) (n=1992)
(%) (%)
DRB1*08 7.2 2.3 0.000 3.3 2.4-4.5
DRB1*11 13.6 30.0 0.000 0.4 0.3-0.4
DRB1*13 8.6 11.2 0.000 0.7 0.3-0.9
Invernizzi et al. Hepatology 2008
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UK PBC Controls Pc Odds Ratio (95% C.I.)(n=412) (n=236)
DRB1*11 28% 47% 0.007 0.42 0.2-0.5DRB1*13 14% 20% 0.042 0.65 0.2-0.5
Donaldson et al. Hepatology 2006
FRANCE (n=358) (n=555)
DRB1*11 22% 38% 0.002 0.39 0.2-0.5DRB1*13 12% 17% 0.033 0.60 0.2-0.5
Poupon et al. Hepatology 2007 (abstract)
HLA protective variants
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Hirschfield et al. NEJM 2009
Genome-wide association study in PBC
536 Canadian & US PBC vs. 1536 controls (> 300.000 SNPs)
Risk variants:
HLA
IL12A
IL12RB2
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Risk variants:
HLA
IL12A
IL12RB2
IRF5
IKZF3/ORMDL3
SPIB
Manuscript submitted
536 Canadian & US PBC vs. 1536 controls (300K SNPs)
PLUS 457 Italian PBC vs. 947 controls (1Mb SNPs)
Genome-wide association study in PBC
21
HLA protection against infections
DRB1*11 human immunodeficiency virus PNAS 1994;91:11472Ann Intern Med 1990;112:3J Immunol 1999;162:6942
hepatitis C virus Gastroenterology 1997;113:1675Genes Immun 2004;5:237
human papilloma viruses J Gen Virol 1999;80 ( Pt 2):399
DRB1*13 human immunodeficiency virus J Clin Invest 2001;107:505
hepatitis B virus N Engl J Med 1995;332:1065J Hepatol 1997;26:503
hepatitis C virus Hepatology 2001;33:224
human papilloma viruses Virus Res 2002;89:229
malaria Nature 1991;352:595
22
Risk variants:
HLA
IL-12A
IL-12RB2
IRF5
IKZF3/ORMDL3
SPIB
Manuscript submitted
536 Canadian & US PBC vs. 1536 controls (300K SNPs)
PLUS 457 Italian PBC vs. 947 controls (1Mb SNPs)
Genome-wide association study in PBC
23
Antigenstimulation
p35
p40
IL-12P70
Dendriticcell
p19
p40
IL-23
IL12
Rββ ββ2
IL12
Rββ ββ1
IL23
R
IL12
Rββ ββ1
IL-12 IL-23
STAT4 STAT3
STAT4
+ +
TH1 cell T H17 cell Modified fromHepatology 2009;50:1347
24
Female preponderance
Sex chromosomes
22.3
22.1
21
11.4
11.2
11.3
21
2223
25262728
11.2
11.211.3
12
X
Y
22.2
25
Sex chromosomes and PBC
A considerable number of sex- and immune-related genes are located within the X chromosome
Major disorders of X chromosome, such as X-linked immunodeficiencies, Turner’s syndrome, as well as premature ovarian failure, may be accompanied by autoimmune features and by chronic cholestasis
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X monosomy in PBC
FISH on peripheral blood cell nuclei of a woman with PBC
A B
Pink dye: chromosome 15 Green dye: X chromosome
Invernizzi et al. Lancet 2004
27
X chromosome monosomyIn autoimmune diseases
Monosomy X(%)
PBC (n=100) 5.2 ± 1.7
Scleroderma (n=44) 6.2 ± 0.26
AI thyroiditis (n=44) 4.3 ± 0.26
Chronic Hep C (n=50) 3.2 ± 1.5
Healthy (n=73) 2.9 ± 0.20
Invernizzi et al. Lancet 2004Invernizzi et al. J Immunol 2005
28
X chromosome preferential loss in PBC
Miozzo et al. Hepatology 2007
0.001
8 (38%)
0
PBC
(n=21)
Controls
(n=27)
P valueImbalanced ratio
in ≥3 STR
Informative cases
29
The X chromosome in PBC: a unifying hypothesis
Haploinsufficiency related to X monosomy and preferential loss
unmasks PBC susceptibility genes
Miozzo et al. Hepatology 2007
30
Target organ of autoimmune aggression
Cholangiocytes
31
Apotopes and the biliary specificity of PBC
*
*
Apoptoticcells
Untreatedcells
HeLa
*
HIBEC
Human keratinocytes
**
Lleo et al. Hepatology 2009
32
Manuscript submitted
Biliary apotopes and AMA activate innate immune responses in PBC
PBC Healthy controls
33
Serum biomarkers
34
• More widespread resort to laboratory examinations led to PBC being diagnosed with increasing frequency during the earliest disease stages, when patients are asymptomatic and have not yet entered a phase of progressive bilirubin or Mayo score elevation
• New prognostic indicators are needed for asymptomatic patients
Natural history models in PBC
35
Prognostic role of AMA in PBCLiver failure-free survival
Invernizzi et al. Hepatology 1997
36
PBC-specific ANA
Rim like
Invernizzi et al. Semin Liver Dis 2005
Nuclear-dot
Sp100 and PMLNuclear porecomplex (NPC)gp210 and p62
37
YES1%65%Greece/Spain
2005
YES1%19%Italy2003
YES0%26%Japan 2003
YES3%27% Italy2001
YES0% 27%Japan 1996
NO15%30%US1994
NO-29%France1990
NO0.7%53%Spain1988
Association withmore advanced
disease
Prevalencein Controls
(n)
Prevalencein PBC
(n)
CountryYear
Cross-sectional studies of the clinical significance of anti-NPC in PBC
38
Prognostic role of anti-NPC in PBCMoratlity rate
Wesierska-Gadek et al. Hepatology 2006
39
Therapy
40
THERAPY – Recommendations (I)
Patients with PBC, including those with asymptomatic disease, should be treated with UDCA (13-15 mg/kg/d) (I / A1) on a long-term basis (II-2 / B1).
Favorable long-term effects of UDCA are observed in patients with early disease and in those with good biochemical response (II-2 / B1) which should be assessed after one year. A good biochemical response after one year of UDCA treatment is currently defined by a serum bilirubin < 1 mg/dL (17 mmol/L), AP <3 x ULN and AST < 2 x ULN (“Paris criteria”) or by a decrease of 40% or normalization of serum AP (“Barcelona criteria”) (II-2 / B1).
41
THERAPY – Recommendations (II)There is currently no consensus on how to treat patients with a suboptimal biochemical response to UDCA . One suggested approach is the combination of UDCA and budesonide (6 to 9 mg/d) in non-cirrhotic patients (stage 1-3) (III / C2). Further studies of this and other combination regimes should be a priority.
Liver transplantation should be strongly considered in patients with advanced disease as reflected by serum bilirubin exceeding 6 mg/dL (103 µmol/L) or decompensated cirrhosis with an unacceptable quality of life or anticipated death within a year due to treatment-resistant ascites and spontaneous bacterial peritonitis, recurrent variceal bleeding, encephalopathy or hepatocellularcarcinoma (II-2 / A1).
42
Murine models for PBC
dnTGFββββRII Ae2(a.b)-deficient
Gastroenterology2008;134:1482
J Immunol2006;177:1655
Xenobioticon C57BL/6
N. Aromaticivoranson NOD 1101
Cell Host Microbe2008;3:304
Hepatology2008;48:531
43
Anti-CD20 (Rituximab) for PBC
dnTGFββββRII Anti-CD20
less severe cholangitis
Moritoki et al. Hepatology 2009
44
Anti-CD20 (Rituximab) for PBC
dnTGFββββRII Anti-CD20
less severe cholangitis
Moritoki et al. Hepatology 2009
Xenobioticon C57BL/6
more severe cholangitis
Manuscript submitted
Anti-CD20 Xenobiotic
45
Anti-IL-6R (Tocilizumab) for PBC
dnTGFββββRII
Elevated serum levels of IL-6
46
Anti-IL-6R (Tocilizumab) for PBC
dnTGFββββRII IL-6-/-
dnTGFββββRII
Elevated serum levels of IL-6
47
Anti-IL-6R (Tocilizumab) for PBC
dnTGFββββRII IL-6-/-
more severe cholangitis
Hepatology 2010 in press
dnTGFββββRII
Elevated serum levels of IL-6
48
Hepatobiliary Immunopathology Unit
MEMBERSIRCCS Istituto Clinico HumanitasMauro PoddaFrancesca BernuzziIlaria BianchiCarlo SelmiLisa CaliariAna Lleo
San Paolo HospitalAndrea CrosignaniPier Maria BattezzatiEmanuela BertoliniChicca CamisascaPaola ZermianiMassimo Zuin
COLLABORATORSDomenico Alvaro (Rome ITA)Gianfranco Alpini (US)Antonio Benedetti (Ancona ITA)Ulrich Beuers (Holland)Kirsten Boberg (Norway)Dimitrios Bogdanos (UK)Eric Gershwin (US)Tom Karlsen (Norway)Keith Lindor (US)Haiying Liu (China)Ian Mackay (Australia)Marco Marzioni (Ancona ITA)Ken Setchell (US)Atsushi Tanaka (Japan)Diego Vergani (UK)Ren-Qian Zhong (China)
49
Thank you
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