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Possible Causes of Primary Sclerosing Cholangitis London 2006

Possible Causes of Primary Sclerosing Cholangitis London 2006. Roger Chapman John Radcliffe Hospital, Oxford ,UK. Results of 30 years research in pathogenesis of PSC?. “The Scream”. ERCP Normal bile ducts Scleros Cholangitis. Liver histology in PSC.

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Possible Causes of Primary Sclerosing Cholangitis London 2006

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  1. Possible Causes of Primary Sclerosing CholangitisLondon 2006 Roger Chapman John Radcliffe Hospital, Oxford ,UK

  2. Results of 30 years research in pathogenesis of PSC? “The Scream”

  3. ERCPNormal bile ducts Scleros Cholangitis

  4. Liver histology in PSC • “Onion skin fibrosis” • Atrophy and eventual bile duct loss. • Ludwig Stage 1 = portal hepatitis with little or no periportal inflammation and fibrosis • Ludwig Stage 4 = frank biliary cirrhosis

  5. Causes of Secondary Sclerosing cholangitis • Biliary Calculi • Biliary stricture • Biliary Atresia • Bile duct malformations • Biliary infections -Cytomegalovirus -Cryptosporidium -Ascariasis -Asc cholangitis • Chemotherapy eg FUDR • Formalin treatment for Hydatid cysts

  6. Etiopathogenesis of PSC? ?

  7. Small Duct PSC • Three recent studies • Rarely progresses to large duct PSC (< 25% over 10 yrs) • No cases of cholangioca • Urso - no evidence of benefit • Effect on UC/dysplasia unknown • Abandon the term“pericholangitis” Normal ERCP Abnormal Liver biopsy

  8. PSC, and Inflammatory Bowel Disease • PSC -uncommon ? -7-9/100,000 pop 1993 -21/100,00 pop 2006 • PSC -70-80% have associated IBD in Northern Europe • PSC -occurs in 5-10% of Total UC -underestimate? • PSC- 20-30% normal LFTs ERCP MRCP

  9. Frequency of IBD in Pts with PSC different parts of the world

  10. Cancer in PSC-conclusions • Risk of hepatobiliary cancer is constant at 1.5% per year • Overall prevalence of 30 % • Cancer is now commonest mode of death in PSC • Increased risk of colonic cancer • Pancreatic cancer may also be increased • ?shared colonic /hepatobiliary risk of malignancy • Mechanism is unknown cp chronic inflammation PSC is premalignant condition

  11. “PSC-IBD” • Does the IBD associated with PSC differ from UC?

  12. Clinical Features of UC assoc with PSC -“PSC-UC” – Different clinical phenotype? • Male predominance [2:1] cp UC alone [1:1.1] • Total in distribution – but symptomatically mild • Rectal sparing in 23% -cp 5% of UC alone • Backwash Ileitis in 64%-cp 18% of UC alone -backwash ileitis assoc with colon ca /dysplasia • Increased rate of pouchitis post colectomy

  13. Clinical Features of UC assoc with PSC -“PSC-UC” – Different clinical phenotype? • Male predominance [2:1] cp UC alone [1:1.1] • Total in distribution – but symptomatically mild • Rectal sparing in 23% -cp 5% of UC alone • Backwash Ileitis in 64%-cp 18% of UC alone -backwash ileitis assoc with colon ca /dysplasia • Extra colonic manifestations are different -rheumatoid arthritis cp seroneg arthropathy, & rare skin or eye involvement in PSC/IBD • Increased rate of pouchitis post colectomy

  14. PSC-IBD • Genetic differences between PSC-IBD and pan ulcerative colitis • Lower carriage of B*44 and DRB1*0103 (associated with peripheral arthritis and severe disease) • Lower carriage of TNF-1031C (associated with erythema nodosum)

  15. PSC-IBD: Conclusions • PSC-IBD is characterized by • Extensive disease • Mild symptoms • High colorectal carcinoma rate • Low incidence of IBD-associated EIMS • High incidence of rheumatoid arthritis • Lower rates of extraintestinal manifestations in PSC-IBD are reflected in lower carriage rates of HLA alleles associated with these EIMs

  16. Susceptibility to PSC • Male gender • Inflammatory bowel disease • Non cigarette smoking • Immunogenetics -MHC genes -Non-MHC immunoregulatory genes • Cystic fibrosis genes

  17. PSC :Male Predominance !!

  18. Relationship between smoking habit & appendicectomy in 170 pts with PSC* *Mitchell et al;GUT 2002*

  19. Smoking habits in PSC with and without IBD* *Mitchell et al :Gut 2002

  20. ?PSC Appears protective!

  21. Protective effect of smoking in PSC? • Powerful effect • Mechanism in PSC (as for IBD) is unknown • Theories: - alteration in mucosal blood flow -effect on immune system - effect on mucus

  22. Pathogenesis of PSCHypotheses/considerations Strong association with IBD partic UC but the paradox: • PSC can occur many years before development of UC • PSC can occur many years after colectomy • Clinical activities of colitis and PSC not related unlike other EIM’s ie Skin,eyes, seronegative arthropathies

  23. Pathogenesis of PSC What are the possible pathogenic mechanisms? Non-Immune portal bacteremia portal endotoxemia absorbed colonic toxins toxic bile acids copper accumulation/toxicity viral infections ischaemic damage Immune Mediated

  24. Key HLA Susceptibilty Haplotypes assoc with PSC* *Cullen S &Chapman R: Autoimmune Reviews 2003

  25. MHC Susceptibility Genes in PSC* Complex disease –not attributable to single gene locus • 3 key haplotypes associated with PSC • Responsible for 90% of all PSC pts • ?common susceptibility allele for all 3 • Candidate is MICA*008 (mapping on HLA Class I /Class II boundary between B8 &TNFA) : occurs in 2 of key candidate haplotypes • Could all be linkage disequilibrium *Cullen S & Chapman R:Autoimmune Reviews 2003

  26. Is PSC an Autoimmune disease?Evidence for immune dysfunction • Autoimmunity HLA DR3 DQ2 haplotype Autoimmune disease associations 2:1 male to female Poor response to immunosuppression

  27. Evidence for immune dysfunction Autoantibodies found in PSC

  28. Evidence for immune dysfunction Autoantibodies • Indicate an altered state of immune responsiveness. • Low prevalence and low titres • No help in determining prognosis • Functional significance?

  29. ANCA control ANCA positive Alcohol fixed normal neutrophils

  30. Diagnostic Role of ANCA in PSC* *Bansi D & Chapman R Gut 1996

  31. Evidence for immune dysfunction-Autoantibodies • Atypical p-ANCA • most common autoantibody found in PSC • Sensitive not specific:overlap with AIH • Antigen(s) not yet clear but may be neutrophil nuclear protein* • Limited diagnostic role *Terjung &Worman 2005

  32. Evidence for immune dysfunction- cellular immune abnormalities Infiltration of portal tract with lymphocytes (monoclonal antibody stain for CD3)

  33. Features of PSC cp Classical Autoimmune disease

  34. Role of biliary epithelial cells in the immune process? • Target of immune attack AND Participant in immune response HLA expression on bile duct epithelium

  35. Biliary epithelial cells Aberrantexpression of HLA Class II antigens Allows binding of autoantigens or exogenous antigens Present peptides to Class II restricted T-lymphocytes Immune response

  36. Bacteria,Infective Agents and PSC • Do bacteria / other infective agents gain access to portal circulation via inflamed and leaky bowel wall?

  37. Bacteria/Infective agents – evidence • Portal bacteraemia • Found in 25% of colectomy patients in 1960’s • Confounded by introduction of bacteria during ERCP • Animal studies eg bacterial peptides in rectum of rats /rabbits with colitis appear in bile and initiate a small duct cholangitis

  38. Bacteria - evidence • Portal bacteraemia • Presence of intact colon in male patients at time of liver transplant for PSC may be a risk factor for recurrence of PSC in the allograft. (Vera et al,Lancet 2003)

  39. Unifying hypothesis for pathogenesis of PSC 1(JM Vierling) Immunogenetically susceptible host Bacterial antigens Kupfer cell activation Cytokine and chemokine secretion Neutrophils, monocytes,lymphocytes and fibroblasts Concentric fibrosis around bile ducts Ischaemia and atrophy of BEC Cholestasis,fibrosis and biliary cirrhosis

  40. The role of viruses ,unlikely bacteria,and protozoans in the pathogenesis of PSC?

  41. PROTOZOANS in PSC?PSC ?SSC • Cryptosporidium parvum implicated in AID’s & inherited immunodeficiency syndromes (eg CD40 ligand deficiency) • Causes papillary stenosis and SC* • Evidence in PSC is lacking! *Cello et al.1990 Adult with CD40 ligand def

  42. Viruses and Etiology PSC • Virus “small piece of bad news wrapped up in a protein coat” Sir Peter Medawer • Evidence for viral infection in PSC?

  43. Candidate Viruses in PSC • Reovirus type 3 - neonatal biliary atresia - not found in PSC/PBC tissue Minuk et al,J Hepatol 1987 • Cytomegalovirus - cholestatic hepatitis in immunocompromised pts /AID’s SC - not confirmed in PSC • Retroviuses-not confirmed in pSC

  44. Candidate Viruses in PSCPonsioen CW et al;Eur J Gastroenterol/Hepatol 2000; 14: 641-6 CONCLUSION : No evidence of higher titres of any virus tested

  45. Candidate viruses in PSCconclusion • NO consisent or reproduceable data to support role of viruses in on going pathogenesis of PSC • Possible that micro-organism need no longer to be present once pathologenetic process is activated “hit and run phenomenon”

  46. Unlikely Bacteria and PSC* *Eur J Gastroenterol & Hepatol 2000;14:641-648

  47. Chlamydia in PSCPonsioen CW et al;Eur J Gastroenterol/Hepatol 2000; 14: 641-6

  48. Chlamydia in PSCBroad LPS assay% positive sera per immunoglobulin subclass NB anti –LPS immunohistochemical staining neg in 14 PSC livers tested

  49. Chlamydia in PSC*Conclusion • Increased seroprevalence of chlamydia –LPS compared with controls • “Chlamydia may be inciting noxious agent in PSC” HOWEVER • NO increase or correlation with specific C.trachomatis and C.pneumoniae assays • NO chlamydial bodies found in PSC liver tissue Further confirmatory studies needed *Ponsioen et al Eur J GastroHepatol 2000

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