Primary Sclerosing Cholangitis

- Clinical Studies -

Oslo14.6.2010

U. Beuers Academic Medical Center, Univerity of Amsterdam, NL

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.

• 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

• Study design, inclusion criteria, endpoints

• Medical approaches

• Endoscopic approaches

• Surgical approaches

Primary Sclerosing Cholangitis

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

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

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)

?

Treatment of Primary Sclerosing Cholangitis with UDCA - Serum liver tests -

Beuers et al., Hepatology 1992;16:707

Change[%]

BilirubinPlacebo

UDCA

Gamma - GT

Alk. Phosphatase

Months

P<0.05

P<0.01

P<0.01

n=14

Treatment of Primary Sclerosing Cholangitis with UDCA - Placebo-controlled studies -

München Mayo Oxford Scandinavia Mayo(1992) (1997) (2001) (2005) (2009)

Dose [mg/kg/d] 13-15 13-15 20 17-23 28-30(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;16:707Lindor et al., New Engl J Med 1997;336:691Mitchell et al., Gastroenterology 2001;121:900Olsson et al. Gastroenterology 2005;129:1464Lindor et al., Hepatology 2009;50:1

Olsson et al., Gastroenterology 2005;129:1464

[%] Placebo (n=101)

UDCA (n=97)

Survivalwithout

livertrans-

plantation

Study daysPower analysis a priori: n = 346

p = 0.37

Treatment of Primary Sclerosing Cholangitis with UDCA - Transplant-free survival -

Cullen et al., J Hepatol 2008;48:792

Treatment of Primary Sclerosing Cholangitis with UDCADoubleblind, randomized, placebo-controlled dose finding study: Oxford/Munich

- Serum Alkaline Phosphatase -

* p<0.05

Lindor et al., Hepatology 2009;50:1 n=150

Treatment of Primary Sclerosing Cholangitis with UDCADouble blind, randomized, placebo-controlled trial

- High dose UDCA (30 mg/kg/d) for 5 years -

Treeprasertsuk et al., Hepatology 2010:51:1302 n=150

Treatment of Primary Sclerosing Cholangitis with UDCADouble 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

Treatment of PSCEASL 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

Treatment of PSCAASLD 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

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

• Study design, inclusion criteria, endpoints

• Medical approaches

• Endoscopic approaches

• Surgical approaches

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

PSC : Therapy

Immunologic bile duct injury

(Cytokine- mediated)

Pathogenetic model

Endoscopic dilatation

Treatment of PSCEASL 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

Treatment of PSCAASLD 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

• Study design, inclusion criteria, endpoints

• Medical approaches

• Endoscopic approaches

• Surgical approaches

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

PSC : Therapy

Immunologic bile duct injury

(Cytokine- mediated)

Pathogenetic model

Liver transplantation

Recurrence of PSC after Liver TransplantationProtection by Colectomy?

Alabraba et al., Liver Transpl 2009; 15: 330

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)