Download Pathogenesis of PSC

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
 PSC -70-80% have associated
IBD in Northern Europe
ERCP
 PSC -occurs in 5-10% of
Total UC
-underestimate?
 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 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
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%
36%
<0.05
current
7%
25%
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%
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
B8-TNF*2-DR3*0101-DRB1*0301DQA1*0501-DQB1*0201
DR3
Strong association;“autoimmune haplotype”
DRB3*0101-DRB1*1301-DQA1*0103- Strong association
DQB1*0603
DR6
DRB5*0101-DRB1*1501-DQA1*0102- Weak association
DQB1*0602
DR15
DRB4*0103-DRB1*0401-DQA1*03DQB1*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
• Autoimmunity
HLA DR3 DQ2 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 CD3)
Features of PSC cp Classical
Autoimmune disease
Characteristic
Classical
Primary Sclerosing
autoimmune disease 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
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 CD40 ligand
deficiency)
• Causes papillary stenosis and
SC*
• Evidence in PSC is lacking!
*Cello et al.1990
?PSC ?SSC
Adult with CD40 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 pSC
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 GastroHepatol 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 CCR9
and alpha 4 beta 7 integrins ie post code to gut
• Specific gut ligands are CCL25 and MAdCAM25
• 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
monoclonalAB,
natalizumab,
inhibits
a4subunit of
a4b7 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 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
• 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