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 • “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
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
Etiopathogenesis of PSC? ?
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
PSC, and Inflammatory Bowel Disease • PSC -uncommon ? -7 -9/100, 000 pop 1993 -21/100, 00 pop 2006 q PSC -70 -80% have associated IBD in Northern Europe ERCP q PSC -occurs in 5 -10% of Total UC -underestimate? q PSC- 20 -30% normal LFTs MRCP
Frequency of IBD in Pts with PSC different parts of the world First author country No IBD of pt [%] UC Crohn’s [%] Schrumpf Norway 77 96 75 14 Broome Sweden 305 81 72 Farrant UK 126 73 71 Wiesner US 174 71 Olikosany Italy 117 54 36 10 Escorell Spain 43 46 44 2 Kocher India 18 50 Takikawa Japan 192 21 20 1
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
“PSC-IBD” • Does the IBD associated with PSC differ from UC?
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
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
PSC-IBD • Genetic differences between PSC-IBD and pan ulcerative colitis – Lower carriage of B*44 and DRB 1*0103 (associated with peripheral arthritis and severe disease) – Lower carriage of TNF-1031 C (associated with erythema nodosum)
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
Susceptibility to PSC • • Male gender Inflammatory bowel disease Non cigarette smoking Immunogenetics -MHC genes -Non-MHC immunoregulatory genes • Cystic fibrosis genes
PSC : Male Predominance !!
Relationship between smoking habit & appendicectomy in 170 pts with PSC* PSC UC Controls pvalue never 66% 52% 39% <0. 001 ever 34% 48% 61% <0. 001 former 27% 36% <0. 05 current 7% 25% <0. 001 no 86% 88% 87% yes 14% 12% 13% smoking appendicectomy *Mitchell et al; GUT 2002*
Smoking habits in PSC with and without IBD* PSC with IBD PSC without Controls IBD never 65% 68% 37% ever 35% 32% 63% former 27% 37% current 8% 5% 26% *Mitchell et al : Gut 2002
? PSC Appears protective!
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
Pathogenesis of PSC Hypotheses/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
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
Key HLA Susceptibilty Haplotypes assoc with PSC* Haplotype Significance in PSC B 8 -TNF*2 -DR 3*0101 -DRB 1*0301 DQA 1*0501 -DQB 1*0201 DR 3 Strong association; “autoimmune haplotype” DRB 3*0101 -DRB 1*1301 -DQA 1*0103 - Strong association DQB 1*0603 DR 6 DRB 5*0101 -DRB 1*1501 -DQA 1*0102 - Weak association DQB 1*0602 DR 15 DRB 4*0103 -DRB 1*0401 -DQA 1*03 DQB 1*0302 DR 4 Strong association with disease protection *Cullen S &Chapman R: Autoimmune Reviews 2003
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 B 8 &TNFA) : occurs in 2 of key candidate haplotypes • Could all be linkage disequilibrium *Cullen S & Chapman R: Autoimmune Reviews 2003
Is PSC an Autoimmune disease? Evidence for immune dysfunction • Autoimmunity HLA DR 3 DQ 2 haplotype Autoimmune disease associations 2: 1 male to female Poor response to immunosuppression
Evidence for immune dysfunction Autoantibodies found in PSC Antibody Prevalence Atypical p-ANCA 33 -87% Antinuclear antibody 7 -77% Anti smooth muscle antibody 13 -20% Anti-endothelial cell antibody 35% Anti-cardiolipin antibody 4 -66% Thyroperoxidase 7 -16% Thyroglobulin 4% Rheumatoid factor 15%
Evidence for immune dysfunction • • Autoantibodies Indicate an altered state of immune responsiveness. Low prevalence and low titres No help in determining prognosis Functional significance?
ANCA control ANCA positive Alcohol fixed normal neutrophils
Diagnostic Role of ANCA in PSC* Number of pts tested Prim Scl Chol % ANCA positive 80 70 78% 0 EH bile duct obstruction 21 0 Hepatitis C 38 56 96 48 0 42% 34% 4% Prim Bil Cirr Autoimmune Hep Ulcerative colitis Crohn’s disease *Bansi D & Chapman R Gut 1996
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
Evidence for immune dysfunction - cellular immune abnormalities Infiltration of portal tract with lymphocytes (monoclonal antibody stain for CD 3)
Features of PSC cp Classical Autoimmune disease Characteristic Classical Primary Sclerosing autoimmune disease Cholangitis Age Children and adults Sex Female predominance Male Predominance Assoc AI Disease Yes HLA Association(Class I & II ) Yes Usually good Response to Immunosuppression Good in children Poor in most adults
Role of biliary epithelial cells in the immune process? Target of immune attack AND Participant in immune response HLA expression on bile duct epithelium
Biliary epithelial cells Aberrant expression of HLA Class II antigens Allows binding of autoantigens or exogenous antigens Present peptides to Class II restricted T-lymphocytes Immune response
Bacteria, Infective Agents and PSC • Do bacteria / other infective agents gain access to portal circulation via inflamed and leaky bowel wall?
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
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)
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
The role of viruses , unlikely bacteria, and protozoans in the pathogenesis of PSC?
PROTOZOANS in PSC • Cryptosporidium parvum implicated in AID’s & inherited immunodeficiency syndromes (eg CD 40 ligand deficiency) • Causes papillary stenosis and SC* • Evidence in PSC is lacking! *Cello et al. 1990 ? PSC ? SSC Adult with CD 40 ligand def
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?
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 p. SC
Candidate Viruses in PSC Ponsioen CW et al; Eur J Gastroenterol/Hepatol 2000; 14: 641 -6 CONCLUSION : No evidence of higher titres of any virus tested
Candidate viruses in PSC conclusion • 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”
Unlikely Bacteria and PSC* *Eur J Gastroenterol & Hepatol 2000; 14: 641 -648
Chlamydia in PSC Ponsioen CW et al; Eur J Gastroenterol/Hepatol 2000; 14: 641 -6
Chlamydia in PSC Broad LPS assay % positive sera per immunoglobulin subclass NB anti –LPS immunohistochemical staining neg in 14 PSC livers tested
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 Gastro. Hepatol 2000
Helicobacter & PSC • Isolated from chronic cholangitis pts (in Chile); H. hepaticus and H bilis • Helicobacter sp in 50% of bile and liver from PSC patients (also PBC) -however results not confirmed Helicobacter hepaticus
Helicobacter and PSC Wadstrom, Ljungh & Willen; Gut 2001 Helicobacter pylori in liver • Helicobacter species may invade human biliary tree and liver • New species of Helicobacter in cotton top tamarinds • “Helicobacter may play a role in pathogenesis of PSC and biliary malignancy” PSC
Can lymphocytes from the gut explain PSC?
Pathogenesis of PSC : Hypothesis • • Known Factors Immune mediated Genetic predisposition Environmental Factors eg nonsmoking (cp PBC) Hypothesis 1. Bacterial Ag’s access from leaky colon 2. Shared colonic /biliary antigens attacked by T lymphocytes
Summary of pathogenesis of PSC • Good evidence of immune dysregulation • Circumstantial evidence of bacterial involvement • No evidence for viruses/protozoaans • Memory T lymphocytes might also be the link between the gut and the liver
Conclusion • No convincing evidence of any single factor in triggering or maintaining the pathogenetic process in PSC • Unlikely that “the Holy Grail” will ever be found
Can lymphocytes from the gut explain PSC? • Assoc between PSC and IBD may be explained by adhesion molecules that direct and regulate lymphocyte trafficking to tissues • Gut lymphocytes express chemokine receptor CCR 9 and alpha 4 beta 7 integrins ie post code to gut • Specific gut ligands are CCL 25 and MAd. CAM 25 • Aberrantly expressed in PSC
Normal Gut ligand expression PSC: Aberrant expression on Explanation for aberrant liver expression in PSC is unknown
In PSC: Homing of gut derived lymphocytes to aberrant ligand expression on liver endothelium Gut derived Chemokine receptor integrins
Unifying hypothesis for pathogenesis of PSC 2 AJ Grant (Lancet 2002) Enterohepatic circulation of lymphocytes • Active inflammation in gut produces mucosal lymphocytes • Some persist as memory T cells which could circulate through the liver • Activation of memory T cells could cause hepatic inflammation
Potential therapy for IBD and PSC Inhibition of adhesion molecules monoclonal. AB, natalizumab, inhibits a 4 subunit of a 4 b 7 integrin Clinical efficacy shown in Crohn’s ? PSC
Unifying hypothesis for pathogenesis of PSC 2 AJ Grant et al (Lancet 2002) • Explains independent course of inflammation in gut and PSC • Explains occurrence of PSC after colectomy
Clinical Presentation of PSC Changing Spectrum PSC circa 1979 PSC circa 2005
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
Direction for future work • Look more closely at HLA associations of PSC • Collaborative international efforts eg European Study Group • Careful phenotyping of disease to clarify results
Pathogenesis of PSC Outline of presentation – Evidence for immune dysfunction – Role of bacteria in pathogenesis – Role of viruses /unusual organisms – Unifying hypotheses for pathogenesis of PSC
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
PSC phenotype “Small duct” PSC
Retroviruses in PSC Results/Conclusion* • HIV-1 p 24 gag seropositivity in 35% PBC and in 39% PSC /biliary atresia • HIAP (human intra cisternal A-type particle) prev found in Sjogren’s salivary glands 75%PBC 39% PSC • Conclusion: HIV-1 & HIAP Ab reactivity Ø ? autoimmune response to viral protein Ø ? immune response to uncharacterised viral proteins crossreacting with HIV-1 And HIAP *Mason et al Lancet 1998
• CMV DNA 0/19 control liver 1/37 PSC liver • CMV replication reactivation • CMVNOT implicated in progression of PSC
“Small duct” PSC • Not necessarily associated with IBD • Better long term prognosis • Just an early stage of large duct disease? – Same age of onset – Similar follow - up period – Only 20% progress to large duct disease
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