“Up date” su …. Colangite Sclerosante Primitiva

1. XIII Congresso Nazionale delle
Malattie Digestive
Corso AIGO-SIGE
AIGO-
“Hot topics in Gastroenterologia”
“Up date” su ….
Colangite Sclerosante
Primitiva
F. Rosina
Presidio Sanitario Gradenigo
Torino

2. Primary Sclerosing Cholangitis
….. an immune-mediated
inflammatory chronic cholestatic
liver disease characterized by
obliterative fibrosis of the intra- and
extra-hepatic bile ducts
Palermo , 3 ottobre 2007

3. 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)
Lee et al, N Engl J Med 1995
Palermo , 3 ottobre 2007

4. Primary Sclerosing Cholangitis
Epidemiology: incidence
Spain1 US2 UK3 Norway4
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 9/12
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
Palermo , 3 ottobre 2007

5. Primary Sclerosing Cholangitis
Etiology ......
… unknown
Palermo , 3 ottobre 2007

6. 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

7. 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
Palermo , 3 ottobre 2007

8. Portal Bile
Vein Duct
Portal Space

9. Gut –primed memory T lymphocytes
Dendritic cells Endothelial Cells

10. Gut –primed memory T lymphocytes
MADCAM 1 VCAM 1

11. Gut–primed memory T lymphocytes
CCL25

12. Gut–primed memory T lymphocytes

13. Gut–primed memory T lymphocytes

14. Gut–primed memory T lymphocytes
Apoptosis

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

16. Kupffer stimulation:
TNF alpha
IL 1 beta, IL 6, IL 12
Activation of Cholangiocytes Gene Expression

17. CCL28
VCAM 1

19. Primary Sclerosing Cholangitis
Pathogenesis: hypothetical model
Focal Regurgitation of Bile
Stellate cells – Fibroblast Activation
Concentric Periductular Fibrosis
Displacement of peri-biliary capillaries
Fibrous Obliteration of Bile Ducts
Ischemic Atrophy of Cholangiocytes

21. Primary Sclerosing Cholangitis
Diagnosis
• Symptoms (itching, right upper quadrant pain,
jaundice, fatigue)
• Abnormal LFT
(increased GGT, APh, ALT
Bilirubin)
•Autoantibodies
(P-ANCA 65-80%, SMA)
P-ANNA (Antineutrophil Nuclear Antibodies)

22. Primary Sclerosing Cholangitis
Diagnosis:MRCP or ERCP ?
Pts Sensitivity Specificity Accuracy
Ferrara et al 21 81% 100% 85%
2002
Angulo et al, 2000 73 NR NR 90%
Textor et al, 150 88% 99% NR
2002
Weber et al, 55 97% 64% 84%
2003
Berstad et al, 67 80% 87% 83%
2006
Palermo , 3 ottobre 2007

23. 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)
Palermo , 3 ottobre 2007

24. Primary Sclerosing Cholangitis
Natural History
Age,
Bilirubinemia
Albumin
IBD
Histology
Independent
Median survival: 11,9 yrs – Wiesner
9,6 yrs - Tischendorf predictors of
high risk of
dying
Wiesner RH, Hepatology 1989
Tischendorf JJ, Am J Gastroenterol 2006

25. DEATH
Bile Ducts
Bilirubin
1 2 3 4 Decompensated
Cirrhosi
Histological Stage
s

26. DEATH
Acute
Cholangitis
Bilirubin
1 2 3 4 Decompensated
Cirrhosi
Histological Stage
s

27. 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
Stiehl A, Sem Liv Dis 2006
Palermo , 3 ottobre 2007

28. DEATH
Acute
Cholangitis
Cholangiocarcinoma
Bilirubin
1 2 3 4 Decompensated
Cirrhosi
Histological Stage
s

29. 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)
• Prognosis: poor (2 year survival: 10%; recurrence after
OLT (Nichols, Mayo Clin Proc, 1993)
Palermo , 3 ottobre 2007

30. 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%
Tischendorf et al, Endoscopy 2006
Palermo , 3 ottobre 2007

31. DEATH
Colorectal cancer
Acute
Cholangitis
Cholangiocarcinoma
Bilirubin
1 2 3 4 Decompensated
Cirrhosi
Histological Stage
s

32. Cumulative Risk
%
PSC
and
4
Colon
UC + PSC
3
P < 0,001
cancer
2
1 UC
0
10 20 30 yrs 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
Palermo , 3 ottobre 2007

33. Primary Sclerosing Cholangitis
Treatment
UDCA …..
…… perhaps
Palermo, 3 ottobre 2007

34. 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

35. Primary Sclerosing Cholangitis
UDCA – high dose
Significantly improved
- Serum APh
- Serum GGT
- Cholangiograms
- Liver histology
- Expected survival
according to Mayo score
Mitchell S, Gastroenterology 2001
Harnois, Am J Gastroenterol 2001

36. Primary Sclerosing Cholangitis
UDCA – high dose
Olsson, Gastroenterology 2005

37. Primary Sclerosing Cholangitis
UDCA – high dose
Olsson, Gastroenterology 2005

38. Primary Sclerosing Cholangitis
UDCA – high dose
Olsson, Gastroenterology 2005

39. Primary Sclerosing Cholangitis
UDCA – high dose
Olsson, Gastroenterology 2005

40. Primary Sclerosing Cholangitis
UDCA vs CRC prevention
Relative risk for
developing colorectal
dysplasia or CRC
among UDCA treated
pts: 0.26
Pardi, Gastroenterology 2003
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

41. 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 (Cochrane Database Syst Rev 2004)
Palermo, 3 ottobre 2007

42. 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)
Palermo, 3 ottobre 2007

43. 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)
Palermo, 3 ottobre 2007

44. PSC TREAMENT
Liver Transplantation
100
Survival %
80
60
40
OLT
20
Predicted Mayo
Score Survival
00 1 2 3 4 5 6 7 yrs
Adapted from
Marcus et al, NEJM 1989
PSC recurrence 20-40% (Gordon F, Liver Transpl 2006)
HLA-DR13 haplotype reduces graft survival (Futagawa Y et al Liver Traspl 2006)

45. Primary Sclerosing Cholangitis
Conclusion
• 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
Palermo, 3 ottobre 2007