Master Rosina Marzo 09 (1)

XIII Congresso Nazionale delle XIII Congresso Nazionale delle

Malattie DigestiveMalattie Digestive

Corso AIGOCorso AIGO--SIGESIGE

“Hot “Hot topicstopics in Gastroenterologia”in Gastroenterologia”

XIII Congresso Nazionale delle XIII Congresso Nazionale delle

Malattie DigestiveMalattie Digestive

Corso AIGOCorso AIGO--SIGESIGE

“Hot “Hot topicstopics in Gastroenterologia”in Gastroenterologia”

“Up date” su …. Colangite Sclerosante “Up date” su …. Colangite Sclerosante Colangite Sclerosante PrimitivaColangite Sclerosante Primitiva

F. RosinaPresidio Sanitario GradenigoTorino

F. RosinaPresidio Sanitario GradenigoTorino

Primary Sclerosing CholangitisPrimary Sclerosing Cholangitis

….. an immune-mediated

inflammatory chronic cholestatic

….. an immune-mediated

inflammatory chronic cholestatic

Palermo , 3 ottobre 2007

liver disease characterized by

obliterative fibrosis of the intra- and

extra-hepatic bile ducts

liver disease characterized by

obliterative fibrosis of the intra- and

extra-hepatic bile ducts

Primary Sclerosing CholangitisEpidemiology. PrevalencePrimary Sclerosing CholangitisEpidemiology. Prevalence

• UC prevalence in US: 40-225 / 100.000

• PSC in Ulcerative Colitis: 2,4-7,5%

• UC prevalence in US: 40-225 / 100.000

• PSC in Ulcerative Colitis: 2,4-7,5%

• US estimated PSC prevalence : 1- 6 / 100.000(but 20-40% of PSC occur in non IBD pts)

• Male/female : 2 /1

• Age of onset : mean 40 yrs (range 1 -90 yrs)

• US estimated PSC prevalence : 1- 6 / 100.000(but 20-40% of PSC occur in non IBD pts)

• Male/female : 2 /1

• Age of onset : mean 40 yrs (range 1 -90 yrs)

Lee et al, N Engl J Med 1995


Primary Sclerosing CholangitisEpidemiology: incidencePrimary Sclerosing CholangitisEpidemiology: incidence

Spain 1 US2 UK3 Norway 4

Incidence 0.07 0,9 0,91 1,31(100.000-yr)

Spain 1 US2 UK3 Norway 4

Incidence 0.07 0,9 0,91 1,31(100.000-yr)

IBD 20/43 16/22 33/53 12/17(47%) (73%) (62%) (71%)

UC 19/20 12/16 30/33 9/12Crohn Dis 1/20 3/16 3/33 2/12Ind. Colitis 0 1/16 0 1/12

IBD 20/43 16/22 33/53 12/17(47%) (73%) (62%) (71%)

UC 19/20 12/16 30/33 9/12Crohn Dis 1/20 3/16 3/33 2/12Ind. Colitis 0 1/16 0 1/12

1) Escorsell et al, J Hepatology 1994, 2) Kingham et al, Gastroenterology 2004,3) Bambha et al, Gastroenterology 2003, 4) Boberg et al, Scan d J Gastroenterol 1998


Primary Sclerosing CholangitisEtiology ............Primary Sclerosing CholangitisEtiology ............

… unknown… unknown


Primary Sclerosing CholangitisPathogenesis: Genetic susceptibilityPrimary Sclerosing CholangitisPathogenesis: Genetic susceptibility

Susceptibility: HLA A1-B8-DR3, DR6 & DR2Protection: DR 4

Susceptibility Haplotypes Odds Ratio

B8-MICA*008-TNFA*2-DRB3*0101- 2,69DRB1*0301- DQA1*0501 - DQB1*0201

Susceptibility: HLA A1-B8-DR3, DR6 & DR2Protection: DR 4

Susceptibility Haplotypes Odds Ratio

B8-MICA*008-TNFA*2-DRB3*0101- 2,69DRB1*0301- DQA1*0501 - DQB1*0201DRB1*0301- DQA1*0501 - DQB1*0201

DRB3*0101- DRB1*0301-DQA1*0103-DQB1*0603 3,80

MICA*008-DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 1,52

MICA*008 homozygosity 5,01

Resistance Haplotypes

DRB4*-DRB1*0401-DQA1*0301-DQB1*0302 0,26

DRB4*-DRB1*0701-DQA1*0201-DQB1*0303 0,15

MICA*002 0,12

DRB1*0301- DQA1*0501 - DQB1*0201

DRB3*0101- DRB1*0301-DQA1*0103-DQB1*0603 3,80

MICA*008-DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 1,52

MICA*008 homozygosity 5,01

Resistance Haplotypes

DRB4*-DRB1*0401-DQA1*0301-DQB1*0302 0,26

DRB4*-DRB1*0701-DQA1*0201-DQB1*0303 0,15

MICA*002 0,12

Primary Sclerosing CholangitisPathogenesis: the keystones of hypothetical modelPrimary Sclerosing CholangitisPathogenesis: the keystones of hypothetical model

MHC & non-MHC genetic susceptibility

+

MHC & non-MHC genetic susceptibility

+

Circulating Gut-primed memory T cells

+

Enteric Bacterial PAMPS in Portal Vein Blood

Circulating Gut-primed memory T cells

+

Enteric Bacterial PAMPS in Portal Vein Blood


Portal Bile

Portal Space

Portal Vein

Bile Duct

Gut –primed memory T lymphocytes

Dendritic cells Endothelial CellsDendritic cells Endothelial Cells

Gut –primed memory T lymphocytes

MADCAM 1 VCAM 1

Gut–primed memory T lymphocytes

CCL25CCL25




ApoptosisApoptosis

Enteric bacterial PAMPs(Pathogen associated molecular patterns (LPS, proteoglycans, etc)

Kupffer stimulation:TNF alpha

Activation of Cholangiocytes Gene Expression

TNF alphaIL 1 beta, IL 6, IL 12

VCAM 1 CCL28

Primary Sclerosing CholangitisPathogenesis: hypothetical modelPrimary Sclerosing CholangitisPathogenesis: hypothetical model

Focal Regurgitation of BileFocal Regurgitation of Bile

Stellate cells – Fibroblast ActivationStellate cells – Fibroblast Activation

Concentric Periductular FibrosisConcentric Periductular Fibrosis

Ischemic Atrophy of Cholangiocytes

Displacement of peri-biliary capillariesDisplacement of peri-biliary capillaries

Fibrous Obliteration of Bile Ducts

Primary Sclerosing CholangitisDiagnosisPrimary Sclerosing CholangitisDiagnosis

• Symptoms (itching, right upper quadrant pain,

jaundice, fatigue)

• Symptoms (itching, right upper quadrant pain,

jaundice, fatigue)

• Abnormal LFT (increased GGT, APh, ALTBilirubin)

• Abnormal LFT (increased GGT, APh, ALTBilirubin)

•Autoantibodies(P-ANCA 65-80%, SMA)

•Autoantibodies(P-ANCA 65-80%, SMA)

P-ANNA (Antineutrophil Nuclear Antibodies)

Primary Sclerosing CholangitisDiagnosis:MRCP or ERCP ?Primary Sclerosing CholangitisDiagnosis:MRCP or ERCP ?

Pts Sensitivity Specificity Accuracy

Ferrara et al 2002

21 81% 100% 85%

Angulo et al, 2000Angulo et al, 2000 73 NR NR 90%

Textor et al, 2002

150 88% 99% NR

Weber et al, 2003

55 97% 64% 84%

Berstad et al, 2006

67 80% 87% 83%


Primary Sclerosing CholangitisDiagnosis: liver biopsy or liver stiffness ?Primary Sclerosing CholangitisDiagnosis: liver biopsy or liver stiffness ?

• Liver Biopsy or….• Liver Biopsy or….

•Transient Elastography…. Liver stiffness correlated with fibrosis and histological stage in both PBC and PSC(Corpechot et al, Hepatology 2006)

•Transient Elastography…. Liver stiffness correlated with fibrosis and histological stage in both PBC and PSC(Corpechot et al, Hepatology 2006)


Primary Sclerosing CholangitisNatural HistoryPrimary Sclerosing CholangitisNatural History

Age,BilirubinemiaAlbuminIBD

Age,BilirubinemiaAlbuminIBD

Wiesner RH, Hepatology 1989Tischendorf JJ, Am J Gastroenterol 2006

IBDHistology

Independent predictors of high risk of dying

IBDHistology

Independent predictors of high risk of dying

Median survival: 11,9 yrs – Wiesner

9,6 yrs - Tischendorf

DEATHDEATH

Bile DuctsBile Ducts

Histological Stage

1 2 3 4 DecompensatedCirrhosis

BilirubinBilirubin

DEATHDEATH

Acute CholangitisAcute Cholangitis

Histological Stage


BilirubinBilirubin

Primary Sclerosing CholangitisBiliary strictures - CholangitisPrimary Sclerosing CholangitisBiliary strictures - Cholangitis

Biliary strictures Cholangitis

Prevalence 20% 33%

Biliary strictures Cholangitis

Prevalence 20% 33%

Symptoms Jaundice JaundiceCholangitis Fever-Chills

Management Endoscopic EndoscopicDilation - Stent Ciprofloxacin

200 mg IV BID

Symptoms Jaundice JaundiceCholangitis Fever-Chills

Management Endoscopic EndoscopicDilation - Stent Ciprofloxacin

200 mg IV BID

Stiehl A, Sem Liv Dis 2006


DEATHDEATH


Histological Stage


BilirubinBilirubin

CholangiocarcinomaCholangiocarcinoma

Primary Sclerosing CholangitisCholangiocarcinomaPrimary Sclerosing CholangitisCholangiocarcinoma

• 10-15% lifetime risk (Lee and Kaplan NEJM 1995)

• Unknown risk factors (Bergquist, Hepatology 1998)

• Diagnosis: difficult

• 10-15% lifetime risk (Lee and Kaplan NEJM 1995)

• Unknown risk factors (Bergquist, Hepatology 1998)

• Diagnosis: difficult• Diagnosis: difficult (cholangiography + brushing, CT,

MR, CEA, CA 19-9, US or CT guided percutaneous biopsy, PET

(sens. 90%, Spec 78%), Combined radiological & molecular

tecniques)

• Prognosis: poor (2 year survival: 10%; recurrence after

OLT (Nichols, Mayo Clin Proc, 1993)

• Diagnosis: difficult (cholangiography + brushing, CT,

MR, CEA, CA 19-9, US or CT guided percutaneous biopsy, PET

(sens. 90%, Spec 78%), Combined radiological & molecular

tecniques)

• Prognosis: poor (2 year survival: 10%; recurrence after

OLT (Nichols, Mayo Clin Proc, 1993)


Primary Sclerosing CholangitisCCC: ERCP or cholangioscopy ?Primary Sclerosing CholangitisCCC: ERCP or cholangioscopy ?

Transpapillary ERCP

Cholangioscopy

Sensitivity 92% 66%

Transpapillary ERCP

Cholangioscopy

Sensitivity 92% 66%Sensitivity 92% 66%

Specificity 93% 51%Accuracy 93% 55%PPV 79% 29%NPV 97% 84%

Sensitivity 92% 66%

Specificity 93% 51%Accuracy 93% 55%PPV 79% 29%NPV 97% 84%


Tischendorf et al, Endoscopy 2006

DEATHDEATH


Colorectal cancerColorectal cancer

Histological Stage


BilirubinBilirubin

CholangiocarcinomaCholangiocarcinoma

%

4

3

2

Cumulative Risk

UC + PSCP < 0,001

PSC and Colon cancer

PSC and Colon cancer

1

0

10 20 30 yrs

UC

Broome et al,Hepatology 1995

…… history of pseudopolyps, smoking, steroids, ASA, NSAIDS and mesalazine but not PSC are associated with colon cancer risk

Velayos et al, Gastroenterology 2006

…… history of pseudopolyps, smoking, steroids, ASA, NSAIDS and mesalazine but not PSC are associated with colon cancer risk

Velayos et al, Gastroenterology 2006


Primary Sclerosing CholangitisTreatmentPrimary Sclerosing CholangitisTreatment

UDCA …..UDCA …..

…… perhaps…… perhaps

Palermo, 3 ottobre 2007

pts RCT yrs Dose Lab Hist Sympt ERCP Surv

Chazoulliers 15 - 0,5 1250 + NE 0 NE NE

O’Brien 12 - 1,5 10/kg + NE + NE NE

Beuers 14 + 1 15/kg + + 0 NE -

Stiehl 27 - 1 750 + NE + NE NE

De Maria 40 + 2 600 0 NE 0 0 0

Lindor 102 + 2,2 15/kg + 0 0 NE 0

Hoogstraten 48 - 2 10/kg + 0 0 0 0

Mitchell 26 + 2 20/kg + + 0 NE NE

Harnois 30 - 1 30/kg + NE NE NE +

Okolicsanyi 86 - 4 13/kg + + NE NE NE

Farkila 80 + 3 15/kg + + NE 0 0

Stiehl 65 - 4 750 + NE NE 0 +

Sterling 25 - 2 15/kg 0 0 0 0 0

Primary Sclerosing CholangitisUDCA – high dosePrimary Sclerosing CholangitisUDCA – high dose

Significantly improved

- Serum APh

- Serum GGT

Significantly improved

- Serum APh

- Serum GGT- Serum GGT

- Cholangiograms

- Liver histology

- Expected survival

according to Mayo score

- Serum GGT

- Cholangiograms

- Liver histology

- Expected survival

according to Mayo score

Mitchell S, Gastroenterology 2001Harnois, Am J Gastroenterol 2001


Olsson, Gastroenterology 2005







Primary Sclerosing CholangitisUDCA vs CRC preventionPrimary Sclerosing CholangitisUDCA vs CRC prevention

Relative risk for

developing colorectal

dysplasia or CRC

Relative risk for

developing colorectal

dysplasia or CRC

Pardi, Gastroenterology 2003

among UDCA treated

pts: 0.26

among UDCA treated

pts: 0.26

Retrospective/Cohort study…. No significant difference in cumulative incidence of

cancer and dysplasia in UC/PSC treated with UDCA.Wolf JM et al, Aliment Pharmacol Ther 2005


Primary Sclerosing CholangitisSteroids and ……

• Responders to steroids have stigmata of AIH or AIP overlap (Boberg, Scand J Gastroenterol 2003; van Buuren et

al, Scand J Gastroenterol 2006 )

• Responders to steroids have stigmata of AIH or AIP overlap (Boberg, Scand J Gastroenterol 2003; van Buuren et

al, Scand J Gastroenterol 2006 )

• Budesonide decreases AST, APh and Portal Inflammation but increases Bilirubin and Mayo score (Angulo, Am J Gastroenterol, 2000)

• No evidence to support or refute oral steroids (Cochrane Database Syst Rev 2004)

• Budesonide decreases AST, APh and Portal Inflammation but increases Bilirubin and Mayo score (Angulo, Am J Gastroenterol, 2000)

• No evidence to support or refute oral steroids (Cochrane Database Syst Rev 2004)


Primary Sclerosing Cholangitis….further and ….

• Pirfenidone: ineffective / side effects (Angulo Dig Dis Sci 2002)

• Mycophenolate mofetil: minimal APH decrease, side effects (Talwalkar JA Am J Gastroenterol 2005)

• Mycophenolate mofetil + UDCA: no additional effect over UDCA)

• Pirfenidone: ineffective / side effects (Angulo Dig Dis Sci 2002)

• Mycophenolate mofetil: minimal APH decrease, side effects (Talwalkar JA Am J Gastroenterol 2005)

• Mycophenolate mofetil + UDCA: no additional effect over UDCA) UDCA) (Sterling, Alim Pharmacol Ther, 2004)

• Metronidazole & UDCA: biochemical, ERCP and Mayo improvement, no improvement on histology (Farkkila M, Hepatology 2004)

• Pentoxyphillin: no effect on LFT & symptoms (Bharucha, Am J Gastroenterol, 2000)

• Etanercept : pruritus improved, no effects on other parameter (Epstein MP, Dig Dis Sci 2004)

UDCA) (Sterling, Alim Pharmacol Ther, 2004)

• Metronidazole & UDCA: biochemical, ERCP and Mayo improvement, no improvement on histology (Farkkila M, Hepatology 2004)

• Pentoxyphillin: no effect on LFT & symptoms (Bharucha, Am J Gastroenterol, 2000)

• Etanercept : pruritus improved, no effects on other parameter (Epstein MP, Dig Dis Sci 2004)


Primary Sclerosing Cholangitis….further ineffective drugs

• Colchicine: 1 mg/day ineffective (Olsson, Gastroenterology, 1995)

• Methotrexate: decreases APh (Knox, Gastroenterology, 1994)

• Methotrexate & UDCA: no additional effect over UDCA (Lindor, Am J Gastroenterol, 1996)

• Colchicine: 1 mg/day ineffective (Olsson, Gastroenterology, 1995)

• Methotrexate: decreases APh (Knox, Gastroenterology, 1994)

• Methotrexate & UDCA: no additional effect over UDCA (Lindor, Am J Gastroenterol, 1996)

• Penicillamine: no evidence to support or refute (Cochrane Data Base Syst Rev, 2006)

• FK506: biochemical response (Van Thiel, Am J Gastroenterol, 1995)

• Tacrolimus: marginal biochemical response (Liver int 2007)

• Bezafibrate: decreases GGT and APh (Kita R, J Gastroenterol 2006)

• Penicillamine: no evidence to support or refute (Cochrane Data Base Syst Rev, 2006)

• FK506: biochemical response (Van Thiel, Am J Gastroenterol, 1995)

• Tacrolimus: marginal biochemical response (Liver int 2007)

• Bezafibrate: decreases GGT and APh (Kita R, J Gastroenterol 2006)


PSC TREAMENTPSC TREAMENTLiver TransplantationLiver Transplantation

PSC TREAMENTPSC TREAMENTLiver TransplantationLiver Transplantation

100

80

60

Survival %

0 1 2 3 4 5 6 7 yrs

60

40

20

0

OLTOLTPredicted Mayo Score SurvivalPredicted Mayo Score Survival

Adapted from Marcus et al, NEJM 1989PSC recurrence 20-40% (Gordon F, Liver Transpl 2006)

HLA-DR13 haplotype reduces graft survival (Futagawa Y et al Liver Traspl 2006)

PSC recurrence 20-40% (Gordon F, Liver Transpl 2006)

HLA-DR13 haplotype reduces graft survival (Futagawa Y et al Liver Traspl 2006)

Primary Sclerosing CholangitisConclusion

• Likely a syndrome• Etiology: unknown• Pathogenesis: hypothetical

• Likely a syndrome• Etiology: unknown• Pathogenesis: hypothetical • Prognosis: ominous• Medical & Endoscopic treatments:

not effective• OLT: the only treatment able to modify

the ominous natural history of PSC

• Prognosis: ominous• Medical & Endoscopic treatments:

not effective• OLT: the only treatment able to modify

the ominous natural history of PSC


Health & Medicine

Master Rosina Marzo 09 (1)