3’ Giornate
Gastro-Epatologiche Cuneesi
“Epatopatie Autoimmuni & Colestatiche:
uptodate
Vicoforte , 19-20 febbraio 2010
3 3 ’ ’ Giornate Giornate Gastro
Gastro - - Epatologiche Cuneesi Epatologiche Cuneesi
“Epatopatie Autoimmuni & Colestatiche: “ Epatopatie Autoimmuni & Colestatiche:
uptodate uptodate
Vicoforte , 19
Vicoforte , 19--20 febbraio 201020 febbraio 2010
Colangite
Sclerosante Primitiva
Colangite
Sclerosante Primitiva
F. Rosina
Presidio Sanitario Gradenigo Torino
F. Rosina
Presidio Sanitario Gradenigo
Torino
Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis
….. an immunemediated
inflammatory chronic cholestatic liver disease characterized by
obliterative fibrosis of the intra- and extra-hepatic bile ducts
….. an immunemediated
inflammatory chronic cholestatic liver disease characterized by
obliterative fibrosis of the intra- and extra-hepatic bile ducts
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Epidemiology: Prevalence
Primary Sclerosing Cholangitis
Epidemiology: Prevalence
• 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)
• 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)
Lee et al, N Engl J Med 1995
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Epidemiology: incidence
Primary Sclerosing Cholangitis
Epidemiology: incidence
Spain
1US
2UK
3Norway
4Incidence 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 9/12
Crohn Dis 1/20 3/16 3/33 2/12
Ind. Colitis 0 1/16 0 1/12
Spain
1US
2UK
3Norway
4Incidence 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 9/12
Crohn Dis 1/20 3/16 3/33 2/12
Ind. 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
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Etiology ...
Primary Sclerosing Cholangitis
Etiology ... ...
… unknown
… unknown
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Pathogenesis: Genetic susceptibility
Primary Sclerosing Cholangitis
Pathogenesis: Genetic susceptibility
Susceptibility: HLA A1-B8-DR3, DR6 & DR2 Protection: DR 4
Susceptibility Haplotypes Odds Ratio
B8-MICA*008-TNFA*2-DRB3*0101- 2,69
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
Susceptibility: HLA A1-B8-DR3, DR6 & DR2 Protection: DR 4
Susceptibility Haplotypes Odds Ratio
B8-MICA*008-TNFA*2-DRB3*0101- 2,69
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
Vicoforte, 19-20 febbraio 2010
Portal Space Portal Space Portal
Vein Portal
Vein
Bile
Duct
Bile
Duct
Gut –primed memory T lymphocytes
Dendritic cells Endothelial Cells
Gut –primed memory T lymphocytes
MADCAM 1 VCAM 1
Gut–primed memory T lymphocytes
CCL25
Gut–primed memory T lymphocytes
Gut–primed memory T lymphocytes
Gut–primed memory T lymphocytes
Apoptosis
Enteric bacterial PAMPs
(Pathogen associated
molecular patterns (LPS,
proteoglycans, etc)
Activation of Cholangiocytes Gene Expression Activation of Cholangiocytes Gene Expression
Kupffer stimulation:
TNF alpha
IL 1 beta, IL 6, IL 12
VCAM 1 CCL28
Primary Sclerosing Cholangitis
Pathogenesis: hypothetical model
Primary Sclerosing Cholangitis
Pathogenesis: hypothetical model
Focal Regurgitation of Bile Focal Regurgitation of Bile
Stellate cells – Fibroblast Activation Stellate cells – Fibroblast Activation
Concentric Periductular Fibrosis
Ischemic Atrophy of Cholangiocytes
Displacement of peri-biliary capillaries Displacement of peri-biliary capillaries
Fibrous Obliteration of Bile Ducts
Primary Sclerosing Cholangitis
Diagnosis
Primary Sclerosing Cholangitis
Diagnosis
• Symptoms (itching, right upper quadrant pain, jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT Bilirubin)
• Symptoms (itching, right upper quadrant pain, jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT Bilirubin)
•Autoantibodies
•Autoantibodies
Vicoforte, 19-20 febbraio 2010
PBC
PSC
AIH
0 10 20 30 40 50 60 70 80 90 100
pANCA
PBC PSC AIH
Healthy controls CBD obstruction
Bansi D, et al, J Hepatol, 1996
• reacts with a 50 kd nuclear protein
(Terjung B, Gastroenterology 2000)• identified as tubulin beta isotype 5
(Terjung B, Hepatology 2005)• cross reactive with microbial protein FtsZ
(Terjung B, Gut 20059)• no relationship with disease activity
• reacts with a 50 kd nuclear protein
(Terjung B, Gastroenterology 2000)• identified as tubulin beta isotype 5
(Terjung B, Hepatology 2005)• cross reactive with microbial protein FtsZ
(Terjung B, Gut 20059)• no relationship with disease activity
Primary Sclerosing Cholangitis
p-ANCA
Primary Sclerosing Cholangitis
p-ANCA
Primary Sclerosing Cholangitis
Diagnosis:MRCP or ERCP ?
Primary Sclerosing Cholangitis
Diagnosis:MRCP or ERCP ?
Pts Sensitivity Specificity Accuracy Ferrara et al
2002
21 81% 100% 85%
Angulo 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%
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Diagnosis: liver biopsy or liver stiffness ?
Primary Sclerosing Cholangitis
Diagnosis: liver biopsy or liver stiffness ?
• Liver Biopsy or….
•Transient Elastography
…. Liver stiffness correlated with fibrosis and histological stage in both PBC and PSC
(Corpechot et al, Hepatology 2006)
• Liver Biopsy or….
•Transient Elastography
…. Liver stiffness correlated with fibrosis and histological stage in both PBC and PSC
(Corpechot et al, Hepatology 2006)
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Differential Diagnosis
Primary Sclerosing Cholangitis
Differential Diagnosis
CAUSES of SSC
• Surgical trauma to bile ducts
• Ischemic injury (eg after OLT)
• Hepatic arterial chemotherapy (eg floxuridine)
• Intraductal gallstones
• Infections (eg CMV – criptosporidiosis)
• Caustic Injuries (eg formalin treatment of hydatid disease)
• Congenital abnormalities (eg cystic fibrosis – Caroli disease)
CAUSES of SSC
• Surgical trauma to bile ducts
• Ischemic injury (eg after OLT)
• Hepatic arterial chemotherapy (eg floxuridine)
• Intraductal gallstones
• Infections (eg CMV – criptosporidiosis)
• Caustic Injuries (eg formalin treatment of hydatid disease)
• Congenital abnormalities (eg cystic fibrosis – Caroli disease)
MIMICS of SSC
• Malignancy (eg metastatic carcinoma)
• Hypereosinophilic syndrome
• Choledocal cyst
• Autoimmune pancreatitis / IgG 4 associated
Cholangitis
MIMICS of SSC
• Malignancy (eg metastatic carcinoma)
• Hypereosinophilic syndrome
• Choledocal cyst
• Autoimmune pancreatitis / IgG 4 associated
Cholangitis
Vicoforte, 19-20 febbraio 2010
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
Vicoforte, 19-20 febbraio 2010
PSC AIP/SC
Male predominance yes yes
Cholestasis yes yes
Cholangiograph. changes yes yes
P-ANCA yes no
Serum IgG4 no yes
Cholangiocarcinoma yes no
Associated IBD yes no
Steroid response no yes
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
Vicoforte, 19-20 febbraio 2010
PSC AIP/SC
Male predominance yes yes
Cholestasis yes yes
Cholangiograph. changes yes yes
P-ANCA yes no
Associated IBD yes no
Cholangiocarcinoma yes no
Serum IgG4 no yes
Steroid response no yes
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
Vicoforte, 19-20 febbraio 2010
PSC AIP/SC
Male predominance yes yes
Cholestasis yes yes
Cholangiograph. changes yes yes
P-ANCA yes no
Associated IBD yes no
Cholangiocarcinoma yes no
Serum IgG4 no yes
Steroid response no yes
Primary Sclerosing Cholangitis
Natural History
Primary Sclerosing Cholangitis
Natural History
Wiesner RH, Hepatology 1989
Tischendorf JJ, Am J Gastroenterol 2006
Age,
Bilirubinemia Albumin
IBD
Histology
Independent predictors of high risk of dying
Age,
Bilirubinemia Albumin
IBD
Histology
Independent predictors of high risk of dying
Median survival: 11,9 yrs – Wiesner
9,6 yrs - Tischendorf
Histological Stage
1 2 3 4 Decompensated Cirrhosis
Bilirubin Bilirubin
DEATH DEATH
Bile Ducts
Bile Ducts
Histological Stage
1 2 3 4 Decompensated Cirrhosis
Bilirubin Bilirubin
DEATH DEATH
Acute
Cholangitis Acute
Cholangitis
Primary Sclerosing Cholangitis
Biliary strictures - Cholangitis
Primary Sclerosing Cholangitis
Biliary strictures - Cholangitis
Biliary strictures Cholangitis
Prevalence 20% 33%
Symptoms Jaundice Jaundice
Cholangitis Fever-Chills
Management Endoscopic Endoscopic
Dilation - Stent Ciprofloxacin 200 mg IV BID Biliary strictures Cholangitis
Prevalence 20% 33%
Symptoms Jaundice Jaundice
Cholangitis Fever-Chills Management Endoscopic Endoscopic
Dilation - Stent Ciprofloxacin 200 mg IV BID
Stiehl A, Sem Liv Dis 2006
Vicoforte, 19-20 febbraio 2010
Histological Stage
1 2 3 4 Decompensated Cirrhosis
Bilirubin Bilirubin
DEATH DEATH
Cholangiocarcinoma Cholangiocarcinoma
Acute
Cholangitis Acute
Cholangitis
Primary Sclerosing Cholangitis
Cholangiocarcinoma
Primary Sclerosing Cholangitis
Cholangiocarcinoma
• 10-15% lifetime risk (Lee and Kaplan NEJM 1995)
• Unknown risk factors (Bergquist, Hepatology 1998)
• 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, FISH, IGF-1 in bile (Alvaro et al, Ann Int med 2007) )
• Prognosis: poor (2 year survival: 10%; recurrence after OLT (Nichols, Mayo Clin Proc, 1993)
• 10-15% lifetime risk (Lee and Kaplan NEJM 1995)
• Unknown risk factors (Bergquist, Hepatology 1998)
• 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, FISH, IGF-1 in bile (Alvaro et al, Ann Int med 2007) )
• Prognosis: poor (2 year survival: 10%; recurrence after OLT (Nichols, Mayo Clin Proc, 1993)
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
CCC: ERCP or cholangioscopy ?
Primary Sclerosing Cholangitis
CCC: ERCP or cholangioscopy ?
Transpapillary ERCP Cholangioscopy
Sensitivity 92% 66%
Specificity 93% 51%
Accuracy 93% 55%
PPV 79% 29%
NPV 97% 84%
Transpapillary ERCP Cholangioscopy
Sensitivity 92% 66%
Specificity 93% 51%
Accuracy 93% 55%
PPV 79% 29%
NPV 97% 84%
Tischendorf et al, Endoscopy 2006
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Cholangiocarcinoma
Primary Sclerosing Cholangitis
Cholangiocarcinoma
Vicoforte, 19-20 febbraio 2010
Alvaro D et al, Ann Int Med 2007
Histological Stage
1 2 3 4 Decompensated Cirrhosis
Bilirubin Bilirubin
DEATH DEATH
Cholangiocarcinoma Cholangiocarcinoma
Acute
Cholangitis Acute
Cholangitis Colorectal cancer
Colorectal cancer
% 4 3 2 1 0
10 20 30 yrs
Cumulative Risk
UC + PSC
UC
P < 0,001
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
PSC and Colon cancer PSC
and Colon cancer
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Treatment
Primary Sclerosing Cholangitis
Treatment
UDCA …..
…… perhaps UDCA …..
…… perhaps
Vicoforte, 19-20 febbraio 2010
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 Cholangitis
UDCA – high dose
Primary Sclerosing Cholangitis
UDCA – high dose
Significantly improved - Serum APh
- Serum GGT
- Cholangiograms - Liver histology
- Expected survival
according to Mayo score Significantly improved
- Serum APh - Serum GGT
- Cholangiograms - Liver histology
- Expected survival
according to Mayo score
Mitchell S, Gastroenterology 2001 Harnois, Am J Gastroenterol 2001
Primary Sclerosing Cholangitis
UDCA – high dose
Primary Sclerosing Cholangitis
UDCA – high dose
Olsson, Gastroenterology 2005 Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis UDCA – high dose
Primary Sclerosing Cholangitis UDCA – high dose
Olsson, Gastroenterology 2005
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis UDCA – high dose
Primary Sclerosing Cholangitis UDCA – high dose
Olsson, Gastroenterology 2005 Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis UDCA – high dose
Primary Sclerosing Cholangitis UDCA – high dose
Olsson, Gastroenterology 2005
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis UDCA – high dose
Primary Sclerosing Cholangitis UDCA – high dose
Vicoforte, 19-20 febbraio 2010
Lindor, Hepatology 2005
Lindor, Hepatology 2009
Primary Sclerosing Cholangitis UDCA vs CRC prevention
Primary Sclerosing Cholangitis UDCA vs CRC prevention
Pardi, Gastroenterology 2003
Relative risk for
developing colorectal dysplasia or CRC
among UDCA treated pts: 0.26
Relative risk for
developing colorectal dysplasia or CRC
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
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis Steroids and ……
• 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 -
Intrabiliary application via nasobiliary tube seems to induce severe adverse events
(Cochrane Database Syst Rev 2004 - 2010)• 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 -
Intrabiliary application via nasobiliary tube seems to induce severe adverse events
(Cochrane Database Syst Rev 2004 - 2010)Vicoforte, 19-20 febbraio 2010
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)
(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)
• 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)
(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)
Vicoforte, 19-20 febbraio 2010
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)• 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)• 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)Vicoforte, 19-20 febbraio 2010
PSC TREAMENT
Liver Transplantation PSC TREAMENT
PSC TREAMENT
Liver Transplantation Liver Transplantation
0 1 2 3 4 5 6 7 yrs
100
80
60
40
20
0
OLT OLT
Predicted Mayo Score Survival Predicted Mayo Score Survival
Adapted from
Marcus et al, NEJM 1989
Survival %
PSC recurrence 20-40% (Gordon F, Liver Transpl 2006)
HLA-DR13 haplotype reduces graft survival (Futagawa Y et alLiver Traspl 2006)
PSC recurrence 20-40% (Gordon F, Liver Transpl 2006)
HLA-DR13 haplotype reduces graft survival (Futagawa Y et alLiver Traspl 2006)
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis Conclusion
• Likely a syndrome
• Etiology: unknown
• Pathogenesis: hypothetical
• Prognosis: ominous
• Medical & Endoscopic treatments: not effective
• OLT: the only Rx able to modify PSC natural history
• Likely a syndrome
• Etiology: unknown
• Pathogenesis: hypothetical
• Prognosis: ominous
• Medical & Endoscopic treatments: not effective
• OLT: the only Rx able to modify PSC natural history
Vicoforte, 19-20 febbraio 2010
SOSTITUIRE CON ERCP DA REVIEW R. CHAPMAN
Primary Sclerosing Cholangitis
Diagnosis
Primary Sclerosing Cholangitis
Diagnosis
• Symptoms (itching, right upper quadrant pain, jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT Bilirubin)
• Symptoms (itching, right upper quadrant pain, jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT Bilirubin)
•Autoantibodies
(P-ANCA 65-80%, SMA)
•Autoantibodies
(P-ANCA 65-80%, SMA)
P-ANNA (Antineutrophil Nuclear Antibodies)
Primary Sclerosing Cholangitis
Diagnosis
Primary Sclerosing Cholangitis
Diagnosis
• Symptoms (itching, right upper quadrant pain, jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT Bilirubin)
• Symptoms (itching, right upper quadrant pain, jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT Bilirubin)
•Autoantibodies
(P-ANCA 65-80%, SMA)
•Autoantibodies
(P-ANCA 65-80%, SMA)
P-ANNA (Antineutrophil Nuclear Antibodies)
Lindor, Hepatology 2005
Lindor, Hepatology 2005
Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis – Overlapping or separate diseases?
George J.M. Webster1, 2, , , Stephen P. Pereira1, 2 and Roger W.
Chapman3
Journal of Hepatology
Volume 51, Issue 2, August 2009, Pages 398-402
• Fig. 1. Histology from the liver hilum in a patient with complex hilar
stricturing and an associated mass. A diagnosis of IgG4-associated
cholangitis was made. (A) H + E showing extensive fibrous stroma, with associated plasma cell infiltrate.
(B) IgG4 immunostaining showing
>20 IgG4+ plasma cells per high
power film.
Autoimmune or
Immune-mediated ?
Autoimmune liver diseases & rheumatic diseases risk
Autoimmune liver diseases & rheumatic diseases risk
AIH PBC PSC
Female/male 8/1 9/1 1/2
AutoAb +++ +++ +
HLA +++ + +
Steroid response +++ - -
Age at onset 10 yrs 55 yrs 40 yrs
Acute onset 45% 0 30%
IV Corso AIGO di Epatologia – La Consulenza Epatologica – Napoli, 1 dicembre 2009
Autoimmune liver diseases & rheumatic diseases risk
AIH PBC PSC
Female/male 8/1 9/1 1/2
AutoAb +++ +++ +
HLA +++ + +
Steroid response +++ - -
Age at onset 10 yrs 55 yrs 40 yrs
Acute onset 45% 0 30%
IV Corso AIGO di Epatologia – La Consulenza Epatologica – Napoli, 1 dicembre 2009
Autoimmune liver diseases & rheumatic diseases risk
Autoimmune liver diseases & rheumatic diseases risk
AIH PBC PSC
Female/male 8/1 9/1 1/2
AutoAb +++ +++ +
HLA +++ + +
Steroid response +++ - -
Age at onset 10 yrs 55 yrs 40 yrs
Acute onset 45% 0 30%
IV Corso AIGO di Epatologia – La Consulenza Epatologica – Napoli, 1 dicembre 2009
Primary Sclerosing Cholangitis
Pathogenesis: the keystones of hypothetical model
Primary Sclerosing Cholangitis
Pathogenesis: the keystones of hypothetical model
MHC & non-MHC genetic susceptibility +
Circulating Gut-primed memory T cells +
Enteric Bacterial PAMPs in Portal Vein Blood MHC & non-MHC genetic susceptibility
+
Circulating Gut-primed memory T cells +
Enteric Bacterial PAMPs in Portal Vein Blood
Vicoforte, 19-20 febbraio 2010
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
Vicoforte, 19-20 febbraio 2010
PSC AIP/SC
Male predominance yes yes
Cholestasis yes yes
Cholangiograph. changes yes yes
P-ANCA yes no
Associated IBD yes no
Cholangiocarcinoma yes no
Serum IgG4 no yes
Steroid response no yes
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
PSC vs AIP/IgG4 associated Cholangitis A re they the same entitiy ?
Vicoforte, 19-20 febbraio 2010
PSC AIP/SC
Male predominance yes yes
Cholestasis yes yes
Cholangiograph. changes yes yes
P-ANCA yes no
Associated IBD yes no
Cholangiocarcinoma yes no
Serum IgG4 no yes
Steroid response no yes
Primary Sclerosing Cholangitis
Cholangiocarcinoma
Primary Sclerosing Cholangitis
Cholangiocarcinoma
• 10-15% lifetime risk (Lee and Kaplan NEJM 1995)
• Unknown risk factors (Bergquist, Hepatology 1998)
• 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, FISH, IGF-1 in bile (Alvaro et al, Ann Int med 2007) )
• Prognosis: poor (2 year survival: 10%; recurrence after OLT (Nichols, Mayo Clin Proc, 1993)
• 10-15% lifetime risk (Lee and Kaplan NEJM 1995)
• Unknown risk factors (Bergquist, Hepatology 1998)
• 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, FISH, IGF-1 in bile (Alvaro et al, Ann Int med 2007) )
• Prognosis: poor (2 year survival: 10%; recurrence after OLT (Nichols, Mayo Clin Proc, 1993)
Vicoforte, 19-20 febbraio 2010
Primary Sclerosing Cholangitis
Autoantibodies
Primary Sclerosing Cholangitis
Autoantibodies
Autoantibody Prevalence (%)
Anti-nuclear antibody (ANA) 7-77
Anti-smooth muscle antibody (ASMA) 13-20 Anti-endothelial cells antibody (AECA) 35
Anti-cardiolipin antibody 4-66
Thyroperoxidase 7-16
Thyroglobulin 4
Rheumatoid factor 15
Autoantibody Prevalence (%)
Anti-nuclear antibody (ANA) 7-77
Anti-smooth muscle antibody (ASMA) 13-20 Anti-endothelial cells antibody (AECA) 35
Anti-cardiolipin antibody 4-66
Thyroperoxidase 7-16
Thyroglobulin 4
Rheumatoid factor 15
Vicoforte, 19-20 febbraio 2010
