Colestasis autoinmunes: Nuevos conceptos patogénicos y...
Transcript of Colestasis autoinmunes: Nuevos conceptos patogénicos y...
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Albert Parés
Unidad de Hepatología
Hospital Clínic, IDIBAPS, CIBERehd
Universidad de Barcelona, Barcelona.
Colestasis autoinmunes: Nuevos conceptos patogénicos y terapéuticos
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Enfermedades autoinmunes colestásicas
Colangitis biliar Colangitis esclerosante
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Colangitis biliar primaria. Patogenia
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Fibrosis
Respuestainmune
Colestasis
Colangitis biliar primaria. Patogenia
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UDCA compared to placebo:
Ø Decreases serum bilirubin (9 trials) and alkaline phosphatases (9 trials).
Ø Improves gGT, AST/ALT, total cholesterol, and IgM concentration.
Ø Have a beneficial effect on worsening of histological stage (7 trials).
Ø No changes in the intervention effects on all-cause mortality, or on all-cause mortality or liver transplantation
AUDC en la CBP: Revisión Cochrane
Rudic JS, Poropat G, KrsticMN, Bjelakovic G, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis (Review). Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD000551. DOI: 10.1002/14651858.CD000551.pub3.
Endpoint RR (95% CI)
All-cause mortality 0.97(0.67−1.42)
All-cause mortality or liver transplantation
0.96(0.74−1.25)
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0
0.5
1
1.5
2
2.5
Histological
stage
Portal
inflammation
Piecemeal
necrosis
Lobular
necrosis
Ductular
proliferation
Cholestasis
Bile duct/portal
tract
**
* *
***
UDCA Placebomean score
Efecto del ácido ursodeoxicólico sobre la histología hepática en la colangitis biliar primaria
Parés et al. J Hepatol 2000;; 32(4):561-6.
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Respuesta bioquímica al AUDC en la CBP
Parés et al Gastroenterology 2006;; 2006;;130:715-720
Response 61% Suboptimal response 39%
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Criterios de respuesta bioquímica al AUDC en la CBP
Criteria Evaluation
time
Biochemical response to UDCA
Barcelona1 1 year AP <1 x ULN and decrease in AP >40%
Paris I2 1 year AP < 3 x ULN or AST > 2 x ULN or bilirubin < 1mg/dL
Rotterdam3 1 year Abnormal bilirubin and/or albumin
Toronto4 2 years AP >1.67 x ULN
Paris II5 1 year AP < 1.5 x ULN or AST < 1.5 x ULN or bilirubin < 1mg/dL
Beijing6 6 months ALP < 3 ULN, increased bilirubin, decreased albumin
AP, alkaline phosphatase;; AST, aspartate aminotransferase;; UDCA, ursodeoxycholic acid;; ULN, upper limit of normal. 1. Parés A, et al. Gastroenterology. 2006;;130:715-720. 2. Corpechot C, et al. Hepatology. 2008;;48:871-877. 3. Kuiper EM, et al. Gastroenterology. 2009;;136:1281-1287. 4. Kumagi T, et al. Am J Gastroenterol. 2010;;105:2186-2194. 5. CorpechotC. J Hepatol. 2011;;55:1361-1367. 6. Zhang LN, et al. Hepatology. 2013;;58:264-272.
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Colestasis
Fibrosis
Respuesta inmune
Colangitis biliar primaria
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Tratamientos dirigidos a la respuesta inmune
• Prednisolona
• Budesonida
• Rituximab
• Ustekinumab
• Otros anticuerpos monclonales:
• Anti TNFα, adalinumab, abatecept.
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Tratamientos dirigidos a la respuesta inmune
• Prednisolona
• Budesonida
• Rituximab
• Ustekinumab
• Otros anticuerpos monclonales:
• Anti TNFα, adalinumab, abatecept.
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Autor año n casos aleatorio duración resultados
Leuschner M 1999 20 yes 2 yrs LFT + histology
Angulo P 2000 22 no 46 mo no effect
Rautiainen H 2005 77 yes 3 yrs histology
Rabahi N 2010 15 No, MFM + 3 yrs LFT + histology
Budesonida en la colangitis biliar primarias
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Rituximab en la colangitis biliar primaria
Myers RP et al. 2013;;108(6):933-41
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Ustekinumab en la colangitis biliar primaria
Hirschfield G, et al Hepatology2016 Jul;;64(1):189-99
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Tratamientos dirigidos a la respuesta inmune
• Prednisolona
• Budesonida
• Rituximab
• Ustekinumab
• Otros anticuerpos monclonales:
• Anti TNFα, adalinumab, abatecept.
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Colestasis
Fibrosis
Respuesta inmune
Colangitis biliar primaria
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Tratamientos dirigidos a la colestasis
• Ácido obeticólico
• Fibratos
• Otros:
• ASBT
• FGF19 recombinante
• Nor-UDCA.
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FXR
FXR
FXR
FXR
Trauner M et al Gastroenterology. 2011;;140(4):1120-1125
Vias del receptor Farnesoide X (FXR)
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OCA6α-‐ethyl chenodeoxycholic acid
CDCAchenodeoxycholic acid
UDCAursodeoxycholic acid
FXR EC50(agonist) 0.099 µM 8.66 µM No activity
~100x h FXR agonism
Ácido obeticólico (OCA)
Pelliciari R et al. J Med Chem. 2002;;45(17):3569-72.
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Ácido obeticólico en la colangitis biliar primaria
Hirschfield G et al Gastroenterology 2015;;148(4):751-61
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Hirschfield G et al Gastroenterology 2015;;148(4):751-61
Ácido obeticólico en la colangitis biliar primaria
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NevensF et N Engl J Med. 2016;;375(7):631-43
Ácido obeticólico en la colangitis biliar primaria. Ensayo POISE
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Cambios en la fosfatasa alcalina
KowdleyC et al. J Hepatol (submitted)
Monoterapia con ácido obeticólico en la colangitis biliarprimaria.
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Potenciales mecanismos de acción de los fibratos
GhonemNS et al Hepatology 2015;;62(2):635-43
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Author Country Year Fibrate(mg)
UDCA (mg)
n months Outcomes Improvement Adverse events
BezafibrateNakai Japan 2000 400 600 10 12 AP, ALT, gGT, IgM no
Kurihara Japan 2000 400 12 12 AP, ALT, gGT, IgM no
Kanda Japan 2002 400 600 11 6 AP no
Akbar Japan 2005 400 600 10 12 AP, ALT, gGT, IgM, Chol no
Kita R Japan 2006 400 600 22 6 AP, gGT no
Hazzan Israel 2010 400 900-1500 8 4 to 12 AP, gGT No
Lens Spain 2013 400 13-15/kg 30 12 AP, gGT, ALT, Chol, TGR heartburn
Honda Japan 2013 400 600 19 3 AP,gGT,ALT,Chol, TGR, IgM No
Reig Spain 2015 400 13-16/kg 48 38 AP, gGT, ALT, Chol, TGR No
Hosonuma Japan 2015 400 12-15/jg 12 96 AP, Mayo score Renal dysfunction
FenofibrateOhira Japan 2002 150 to 200 600-900 7 6 AP, gGT, IgM No
Walter UK 2009 134 to 200 16 3 to 4 AP, IgM No
Liberopoulus Greece 2010 200 600 6 2 AP, gGT No
Levy USA 2010 160 13-15/kg 20 12 AP, AST, IgM, IL-1, IL-6 Esophagitis, ALT
increase
Fibratos in la colangitis biliar primaria
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Efecto del bezafibato en la colangitis biliar primaria
Lens S et al Liver Int. 2014;;34(2):197-203
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Bezafibrate 400 mg/d
100
75
50
25
0
%
Alkaline Phosphatase
Normalización de fosfatasa alcalina con bezafibrato en la colangitis biliar primaria
Lens S et al Liver Int. 2014;;34(2):197-203
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Alk
alin
e p
ho
sph
ata
se (x
UN
L)
012345678910
basal final0
1
2
3
4
5
6
7
8
9
10
basal final
Responders to therapy
Si26 (54%)
No22 (46%)
Fosf
ata
sa a
lca
lina
(U x
LA
N)
Reig A et al. EASL 2015
Efecto a largo plazo del bezafibrato sobre la fosfatasa alcalina en la colangitis biliar primaria
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Respondedores No respondedores
Tratamiento (meses) 36.2 ± 2.9 36.9 ± 3.0
Exitus 0 1 (4.5%)
Trasplante 0 3 (14.0%)
Hepatocarcinoma 0 1 (4.5%)
Total 0 5 (23%)*
Progresión de la CBP tras tratamiento combinado de AUDC y bezafibrato en la cholangitis biliar primaria
Reig A et al. EASL 2015
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Author Country Year Fibrate(mg)
UDCA (mg)
n months Outcomes Improvement Adverse events
BezafibrateNakai Japan 2000 400 600 10 12 AP, ALT, gGT, IgM no
Kurihara Japan 2000 400 12 12 AP, ALT, gGT, IgM no
Kanda Japan 2002 400 600 11 6 AP no
Akbar Japan 2005 400 600 10 12 AP, ALT, gGT, IgM, Chol no
Kita R Japan 2006 400 600 22 6 AP, gGT no
Hazzan Israel 2010 400 900-1500 8 4 to 12 AP, gGT No
Lens Spain 2013 400 13-15/kg 30 12 AP, gGT, ALT, Chol, TGR heartburn
Honda Japan 2013 400 600 19 3 AP,gGT,ALT,Chol, TGR, IgM No
Reig Spain 2015 400 13-16/kg 48 38 AP, gGT, ALT, Chol, TGR No
Hosonuma Japan 2015 400 12-15/jg 12 96 AP, Mayo score Renal dysfunction
FenofibrateOhira Japan 2002 150 to 200 600-900 7 6 AP, gGT, IgM No
Walter UK 2009 134 to 200 16 3 to 4 AP, IgM No
Liberopoulus Greece 2010 200 600 6 2 AP, gGT No
Levy USA 2010 160 13-15/kg 20 12 AP, AST, IgM, IL-1, IL-6 Esophagitis, ALT
increase
Fibratos in la colangitis biliar primaria
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NGM282, a novel variant of FGF-19, in primary biliary cholangitis
-19.2
-1.2
-15.8
-25
-20
-15
-10
-5
0
5
Baseline Day 7 Day 14 Day 21 Day 28 Day 42
Mean
+SE
Abs
olut
e Cha
nge
in A
LP (IU
/L)
NGM282 3 mg Placebo NGM282 0.3 mg
p = 0.0092
p = 0.0025
Mayo M et al AASLD 2015
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Colangitis esclerosante primaria
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Weissmuler T et al. Gastroenterology 2017
Colangitis esclerosante primaria. Supervivencia
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Hypothesis EvidencesAutoimmunity Autoantibodies
HLA associations
Other autoimmune diseases
T-cell infiltrates
Toxic bile abcb4 -/- mice
Adults with ABCB4 mutations
PSC like changes cystic fibrosis
UDCA improvement
Leaky gut Bacterial translocation in rats
LPS activates toll-like receptors on BEC
Antibiotic effects
Aberrant homing
Pollheimer et al. Best Pract Res Clin Gss 2011Karlsen et al Dig Liv Dis 2010
Colangitis esclerosante primaria. Patogenia
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Autor año Dosis diaria pacientes Tipo estudio Mejoría síntomas
Mejoría bioquímica
Mejoría histológica
O’Brien
Beuers
Stiehl
De Maria
Lindor
Van Hoostraten
Mitchell
Harnois
Okolicsanyi
Olsson
Lindor
1991
1992
1994
1996
1997
1998
2001
2001
2002
2005
2009
10 mg/kg
13-15 mg/kg
750 mg
600 mg
13-15 mg/kg
10 mg/kg
20-25 mg/kg
25-30 mg/kg
8-13 mg/kg
17-23 mg/kg
28-30 mg/kg
12
6
20
59
105
48
26
30
86
110
76
Abierto
DC, plac
DC, plac
DC, plac
DC, plac
DC
DC, plac
Abierto
DC, plac
DC, plac
DC, plac
SI
NO
NO
-
NO
NO
NO
-
NO
NO
NO
SI
SI
SI
NO
SI
SI
SI
SI
SI
SI
NO
-
SI
SI
-
NO
-
SI
-
NO
-
-
Tratamiento de la colangitis esclerosante primaria con ácido ursodeoxicólico
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Tratamiento de la colangitis esclerosante primaria con dosis altas de ácido ursodeoxicólico
Olsson et al, Gastroenterology, 2005
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Tratamiento de la colangitis esclerosante primaria con dosis muy altas de ácido ursodeoxicólico
Lindor et al, Hepatology 2009
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Colangitis esclerosante primaria. Recomendación AUDC
Sintomática o FA > 1.5 VVN
Descartar estenosis dominante
AUDC 17-23 mg/kg/d
ToleranciaFA > 40 %
Mejora síntomas
FA > 40 % a 1 año
Seguir tratamiento
Suspender AUDC
Suspender AUDC Tratamiento alternativo
Si No
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Tratamiento de la colangitis esclerosante primaria con antibióticos
Culver et al. Alim Pharmacol Ther 2011
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norUDCA Bile acid (BA)Detoxification &Alternative Export
HCO3-
Anti-proliferative
Anti-inflammatory
Anti-fibrotic
OH
HO
COO-BA
CholehepaticShunting
DuctalTargeting
IntrahepaticEnrichement
Hepatocyte
Bile DuctRenal
Elimination
BicarbonateUmbrella
NorUDCA. Mecanismos de acción
Gentileza del Prof. M. Trauner
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Efecto del norAUDC sobre la fosfatasa alcalina en la colangitis esclerosante primaria
-50
-40
-30
-20
-10
0
Change in ALP (%
)PLACEBO(N=40)
NU 500mg(N=39)
NU 1000mg(N=41)
NU 1500mg(N=39)
p = 0.0029
p = 0.0003
p < 0.0001
+1.2%
-12.3%
-17.3%
-26%
Ø norUDCA (NU) reduces ALP in a dose-dependent fashion
Values (%) are means(SD)
Trauner M, et al. J Hepatol (submitted)
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Efecto del norAUDC sobre la fosfatasa alcalina en la colangitis esclerosante primaria
-50
-40
-30
-20
-10
0
Change in ALP (%
)PLACEBO(N=40)
NU 500mg(N=39)
NU 1000mg(N=41)
NU 1500mg(N=39)
p = 0.0029
p = 0.0003
p < 0.0001
+1.2%
-12.3%
-17.3%
-26%
Ø norUDCA (NU) reduces ALP in a dose-dependent fashion
Values (%) are means(SD)
Trauner M, et al. J Hepatol (submitted)
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ü Se ha demostrado la eficacia de nuevos fármacos para eltratamiento de la colangitis biliar primaria en pacientes conrespuesta bioquímica insuficiente al ácido ursodeoxicólico.
ü Los tratamientos dirigidos a modificar el estado inmunitario nohan mostrado efectos positivos.
ü El ácido ursodeoxicólico sigue siendo un tratamiento aconsiderar en la colangitis esclerosante primaria.
ü Hay datos atractivos sobre el efecto del norursodeoxicólico en lacolangitis esclerosante primaria.
Sumario
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