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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
Palermo , 3 ottobre 2007
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
Palermo , 3 ottobre 2007
Primary Sclerosing CholangitisEtiology ............Primary Sclerosing CholangitisEtiology ............
… unknown… unknown
Palermo , 3 ottobre 2007
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
Palermo , 3 ottobre 2007
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
Gut–primed memory T lymphocytes
Gut–primed memory T lymphocytes
Gut–primed memory T lymphocytes
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%
Palermo , 3 ottobre 2007
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)
Palermo , 3 ottobre 2007
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
1 2 3 4 DecompensatedCirrhosis
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
Palermo , 3 ottobre 2007
DEATHDEATH
Acute CholangitisAcute Cholangitis
Histological Stage
1 2 3 4 DecompensatedCirrhosis
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)
Palermo , 3 ottobre 2007
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%
Palermo , 3 ottobre 2007
Tischendorf et al, Endoscopy 2006
DEATHDEATH
Acute CholangitisAcute Cholangitis
Colorectal cancerColorectal cancer
Histological Stage
1 2 3 4 DecompensatedCirrhosis
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
Palermo , 3 ottobre 2007
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
Primary Sclerosing CholangitisUDCA – high dosePrimary Sclerosing CholangitisUDCA – high dose
Olsson, Gastroenterology 2005
Primary Sclerosing CholangitisUDCA – high dosePrimary Sclerosing CholangitisUDCA – high dose
Olsson, Gastroenterology 2005
Primary Sclerosing CholangitisUDCA – high dosePrimary Sclerosing CholangitisUDCA – high dose
Olsson, Gastroenterology 2005
Primary Sclerosing CholangitisUDCA – high dosePrimary Sclerosing CholangitisUDCA – high dose
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
Palermo, 3 ottobre 2007
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)
Palermo, 3 ottobre 2007
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)
Palermo, 3 ottobre 2007
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)
Palermo, 3 ottobre 2007
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
Palermo, 3 ottobre 2007
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