primary sclerosing cholangitis -clinical.PPT

primary sclerosing cholangitis

1. Primary Sclerosing Cholangitis
- Clinical Studies -
Oslo
14.6.2010
U. Beuers
Academic Medical Center, Univerity of Amsterdam, NL

2. Primary Sclerosing Cholangitis
Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
Immunologic bile duct injury
(Cytokine-mediated)
Pathogenetic model
m, 42 J.

3. •Study design, inclusion criteria, endpoints
•Medical approaches
• (3 min Christoph Schramm)
•Endoscopic approaches
• (3 min Cyriel Ponsioen)
•Surgical approaches
• (3 min Martti Faerkkila)
Primary Sclerosing Cholangitis

4. •Study design, inclusion criteria, endpoints
•Medical approaches
•Endoscopic approaches
•Surgical approaches
Primary Sclerosing Cholangitis

5. Treatment of Primary Sclerosing Cholangitis
Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
Immunologic bile duct injury
(Cytokine- mediated)
Pathogenetic model Placebo-contr.Studies Pilot studies
Cyclosporine
Methotrexate
Infliximab
D-Penicillamine
Colchicin
Budesonide
Cladribin
Etanercept
MMF
Nicotine
Pentoxifylline
Prednisone
Tacrolimus
Pirfenidone

6. Treatment of Primary Sclerosing Cholangitis
Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
Immunologic bile duct injury
(Cytokine- mediated)
Placebo-contr.Studies Pilot studies
Cyclosporine
Methotrexate
Infliximab
D-Penicillamine
Colchicin
Budesonide
Cladribin
Etanercept
MMF
Nicotine
Pentoxifylline
Prednisone
Tacrolimus
Pirfenidone
Pathogenetic model

7. Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
PSC : Therapy
Immunologic bile duct injury
(Cytokine- mediated)
Pathogenetic model
Ursodeoxycholic acid
(15-20 mg/kg/d)
?

8. Treatment of Primary Sclerosing Cholangitis with UDCA
- Serum liver tests -
Beuers et al., Hepatology 1992;16:707
Change
[%]
Bilirubin
Placebo
UDCA
Gamma - GT
Alk. Phosphatase
Months
P<0.05
P<0.01
P<0.01
n=14

9. Treatment of Primary Sclerosing Cholangitis with UDCA
- Placebo-controlled studies -
München Mayo Oxford ScandinaviaMayo
(1992) (1997)(2001) (2005) (2009)
Dose [mg/kg/d] 13-15 13-15 20 17-2328-30
(n=14) (n=105) (n=24) (n=219) (n=150)
Duration [years] 1 2.2 2 5 5
Symptoms - - - - -
Serum liver tests + + + - +
Histology + + - -
Beuers et al., Hepatology 1992;16:707
Lindor et al., New Engl J Med 1997;336:691
Mitchell et al., Gastroenterology 2001;121:900
Olsson et al. Gastroenterology 2005;129:1464
Lindor et al., Hepatology 2009;50:1

10. Olsson et al., Gastroenterology 2005;129:1464
[%]
Placebo (n=101)
UDCA (n=97)
Survival
without
liver
trans-
plantation
Study days
Power analysis a priori: n = 346
p = 0.37
Treatment of Primary Sclerosing Cholangitis with UDCA
- Transplant-free survival -

11. Cullen et al., J Hepatol 2008;48:792
Treatment of Primary Sclerosing Cholangitis with UDCA
Doubleblind, randomized, placebo-controlled dose finding study: Oxford/Munich
- Serum Alkaline Phosphatase -
* p<0.05

12. Lindor et al., Hepatology 2009;50:1 n=150
Treatment of Primary Sclerosing Cholangitis with UDCA
Double blind, randomized, placebo-controlled trial
- High dose UDCA (30 mg/kg/d) for 5 years -

13. Treeprasertsuk et al., Hepatology 2010:51:1302 n=150
Treatment of Primary Sclerosing Cholangitis with UDCA
Double blind, randomized, placebo-controlled trial
- High dose UDCA (30 mg/kg/d) for 5 years -
Patient population:
41.3% (62) Advanced liver fibrosis / cirrhosis
58.7% (88) Mild liver fibrosis

14. Treatment of PSC
EASL Clinical Practice Guidelines
• The available data base shows that UDCA (15-20 mg/kg/d)
improves serum liver tests and surrogate markers of prognosis
(I/B1), but does not reveal a proven benefit on survival (III/C2). The
limited data base does not yet allow a specific recommendation for
the general use of UDCA in PSC.
• I : Randomized, placebo-controlled trials, meta-analyses
• III : Opinion of respected authorities
• B1 : Moderate evidence – strong recommendation (GRADE)
• C2 : Weak evidence - weak recommendation (GRADE)
EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

15. Treatment of PSC
AASLD Clinical Practice Guidelines
• In adult patients with PSC, we recommend against the use of
UDCA as medical therapy (IA).
• In adult patients with PSC and overlap syndrome,we recommend
the use of corticosteroids and other immunosuppressive agents for
medical therapy (IC)
• I A : Strong recommendation – strong evidence
• I C : Strong recommendation – weak evidence
Chapman et al., AASLD PG PSC. Hepatology 2010;51:660

16. Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
PSC : Future Therapy
Immunologic bile duct injury
(Cytokine- mediated)
Pathogenetic model
Antibiotics ?
Docahexanoic acid ?
Immunosuppresive agents ?
Nor-Ursodeoxycholic acid ?
ACE Inhibitors ?
Nuclear receptor agonists ?
- PXR
- FXR
- VDR
- PPAR

17. •Study design, inclusion criteria, endpoints
•Medical approaches
•Endoscopic approaches
•Surgical approaches
Primary Sclerosing Cholangitis

18. Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
PSC : Therapy
Immunologic bile duct injury
(Cytokine- mediated)
Pathogenetic model
Endoscopic dilatation

19. Treatment of PSC
EASL Clinical Practice Guidelines
• Dominant bile duct strictures with significant cholestasis should be
treated with biliary dilatation (II-2/B1).
• Biliary stent insertion should be reserved for cases where stricture
dilatation and biliary drainage are unsatisfactory (III/C2).
• Prophylactic antibiotic coverage is recommended in this setting
(III/C1).
• II-2 : Cohort- and case-control studies
• III : Opinion of respected authorities
• B1 : Moderate evidence – strong recommendation (GRADE)
• C1/2 : Weak evidence - strong/weak recommendation (GRADE)
EASL Clinical Practice Guidelines, J Hepatol 2009;51:237

20. Treatment of PSC
AASLD Practice Guidelines
• In patients with increases in serum bilirubin and/or worsening
pruritus progressive bile duct dilatation on imaging studies, and/or
cholangitis, we recommend performing an ERC promptly to exclude
a dominant stricture (IB).
• In patients with dominant strictures from PSC, we recommend
initial management with endoscopic dilatation with or without
stenting (IB).
• We recommend antimicrobial therapy with correction of bile duct
obstruction in dominant strictures to effectively resolve cholangitis
(IA).
• IA : Strong recommendation – strong evidence (GRADE)
• IB : Strong recommendation – moderate evidence (GRADE)
Chapman et al., AASLD PG PSC. Hepatology 2010;51:660

21. •Study design, inclusion criteria, endpoints
•Medical approaches
•Endoscopic approaches
•Surgical approaches
Primary Sclerosing Cholangitis

22. Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
PSC : Therapy
Immunologic bile duct injury
(Cytokine- mediated)
Pathogenetic model
Liver transplantation

23. Recurrence of PSC after Liver Transplantation
Protection by Colectomy?
Alabraba et al., Liver Transpl 2009; 15: 330

24. Bile duct stenoses
Aggravation of injury by BA
Cholestasis with retention of
hydrophobic bile acids in liver
Liver cell damage, apoptosis,
necrosis, fibrosis, cirrhosis
Liver failure
PSC : Therapy
Immunologic bile duct injury
(Cytokine- mediated)
Pathogenetic model
Liver transplantation
Endoscopic dilatation
Ursodeoxycholic acid
(15-20 mg/kg/d)