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Possible Causes of Primary Sclerosing Cholangitis
+ web-based presentation
Kurdistan Board GEH/GIT Surgery weekly J Club:Supervised by:
Professor Dr.Mohamed AlshekhaniMBChB-CABM,FRCP,EBGH.
Introduction:• It is idiopathic, heterogeneous, cholestatic liver disease characterized
by persistent, progressive, biliary inflammation &fibrosis. • There is no effective medical therapy.• ESLD necessitating liver transplantation may ultimately develop.• The cause & pathogenesis are unclear, but genetic / environment
contribute to development, progression&outcomes.• It is strongly associated with IBD (70 -80% have both)&it is a risk
factor for colon, BD,GB cancers.• PSC is a poorly understood disease for which medical therapy is
lacking.
ERCPNormal 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 Normal ERCPERCP
Abnormal Liver Abnormal Liver biopsybiopsy
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
Frequency of IBD in Pts with PSC different parts of the world
First author country No of pt
IBD[%]
UC[%]
Crohn’s[%]
Schrumpf Norway 77 96 75 14Broome Sweden 305 81 72Farrant UK 126 73 71Wiesner US 174 71Olikosany Italy 117 54 36 10Escorell Spain 43 46 44 2Kocher India 18 50Takikawa 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 PSC is premalignant conditioncondition
“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 DRB1*0103
(associated with peripheral arthritis and severe disease)
– Lower carriage of TNF-1031C (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
Relationship between smoking habit & appendicectomy in 170 pts with PSC*
PSC UC Controls pvalue
smoking
never 66% 52% 39% <0.001ever 34% 48% 61% <0.001
former 27% 36% 36% <0.05
current 7% 25% 25% <0.001
appendicectomy
no 86% 88% 87%
yes 14% 12% 13%*Mitchell et al;GUT 2002*
Smoking habits in PSC with and without IBD*
PSC withIBD
PSC without IBD
Controls
never 65% 68% 37%
ever 35% 32% 63%
former 27% 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 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
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
B8-TNF*2-DR3*0101-DRB1*0301-DQA1*0501-DQB1*0201 DR3
Strong association;“auto-immune haplotype”
DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603 DR6
Strong association
DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 DR15
Weak association
DRB4*0103-DRB1*0401-DQA1*03-DQB1*0302 DR4
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 B8 &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
• AutoimmunityHLA DR3 DQ2 haplotype
Autoimmune disease associations
2:1 male to female
Poor response to immunosuppression
Evidence for immune dysfunction
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%
Autoantibodies found in PSC
Evidence for immune dysfunction
Autoantibodies• Indicate an altered state of immune
responsiveness.• Low prevalence and low titres• No help in determining prognosis• Functional significance?
ANCAcontrol ANCA positive
Alcohol fixed normal neutrophils
Diagnostic Role of ANCA in PSC*
Number of pts tested
% ANCA positive
Prim Scl Chol 80 78%Prim Bil Cirr 70 0EH bile duct obstruction
21 0
Hepatitis C 38 0Autoimmune Hep 56 42%Ulcerative colitis 96 34%Crohn’s disease 48 4%
*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 antibodystain for CD3)
Features of PSC cp Classical Autoimmune disease
Characteristic Classical autoimmune disease
Primary Sclerosing Cholangitis
Age Children and adults Children and adults
Sex Female predominance Male Predominance
Assoc AI Disease Yes Yes
HLA Association(Class I & II )
Yes Yes
Response to Immunosuppression
Usually good Good in childrenPoor 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
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
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 Normal ERCPERCP
Abnormal Liver Abnormal Liver biopsybiopsy
PSC phenotype“Small duct” PSC
Retroviruses in PSCResults/Conclusion*
• HIV-1 p24 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 ? autoimmune response to viral protein ? immune response to uncharacterised viral
proteins crossreacting with HIV-1 And HIAP
*Mason et al Lancet 1998
“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
Management:drugs• No effective treatment but we control the
complications.• UDCA decreases liver enzymes, but not survival & high dose
increased the risk of death, liver transplantation, minimal listing criteria for liver transplantation, cirrhosis, esophageal or gastric varices, & cholangiocarcinoma.
• May be given at a dose of 13 -15 mg/ kilogram) for 6 months & If no decrease in alkaline phosphatase suggest discontinuation.
Management: survielance• Even if patients with IBD have undergone liver transplantation, they
should undergo annual colonoscopy with surveillance biopsies, given the increased risk of CRC.
• Patients who do not have evidence of IBD should undergo colonoscopy every 5 years, given their risk of colonic lesions.
• An annual GB U/S for assessment of polyps or other mass lesions is also recommended & any masses of any size should undergo cholecystectomy.
• 65% 5-year recurrence-free survival rate among selected patients with PSC & perihilar cholangiocarcinoma who have undergone liver transplantation after neoadjuvant chemotherapy/radiation.
Management:transplantation• 40% will ultimately require liver transplantation, 6% of all liver
transplantations.• 1-year survival 85% & 5-year survival 72%.• 25% recurs after transplantation diagnosed by cholangiographic
evidence in the absence of chronic liver rejection or vascular offenses (such as ischemia).
• Colectomy before liver transplantation in IBD may decrease the frequency of recurrence after transplantation.
Management: new drugs trials• Obeticholic acid is a semisynthetic analogue of chenodeoxycholic acid ,
a potent ligand for the farsenoid X receptor that has an antifibrotic effect.
• 24-nor -ursodeoxycholic acid, a synthetic bile acid that produce a bile acid–dependent bicarbonate-rich choleresis, may have beneficial effects.
• Apical sodium-dependent bile acid transporter inhibitor.• Vancomycin alter the gut microbiota & reduce innate immune
responses.• Intestinal microbiome may be involved, a pilot study of fecal
microbiota transplantation is underway.