Download Slide 1

Primary Sclerosing
Cholangitis and Primary
Biliary Cirrhosis


Registrar teaching July 2007
Paul Frankish
Primary Biliary Cirrhosis
PBC-introduction






Slowly progressive autoimmune liver disease
90% females
Peak incidence in 40’s
Portal inflammation and autoimmune
destruction of intrahepatic bile ducts
Leads to cirrhosis and liver failure
90-95% have antimitochondrial antibody
Clinical features




~50% asymptomatic at diagnosis
Fatigue and pruritus most commonn
symptoms~20%
Hyperlipidaemia,hypothyroidism,osteo
penia,autoimmune diseases
Portal hypertension ,liver failure,HCC
Physical examination





Often normal
Spiders and skin excoriations
Xanthelasmas
Hepatomegaly ~70%
Jaundice (late)
Diagnosis
3 criteria
Positive AMA
Abnormal LFT
Compatible biopsy
Pathological Stages (4)




1 Destruction of bile ducts in portal
tracts
2 Inflammation beyond portal tracts
3 fibrous septa link portal triads
Cirrhosis
Epidemiology and Genetic
factors




Most prevalent in Nth Europe.10 fold
variation
More common in first degree relatives
Molecular mimicry to certain bacteria
or viruses
Environmental chemical exposure
Autoimmune responses






Targets of antimitichondrial antibodies
4 autoreactive mitochondrial antigens
Pyruvate dehydrogenase E2 complex PDCE2
E-3 binding protein E3-BP
Ketoglutaric acid dehydrogenase E2 complex
OGDC-E2
2 oxo-aciddehydrogenaseE-2 complex
BCKD-E2
T cell response


T cells infiltrating the liver are specific
for PDC-E2
Nature of bile duct injury not fully
elucidated
Treatment:Ursodeoxycholic acid
UDCA
Given in dose 12-15 mg/kg
Reduces bilirubin,ALP,AST,ALT cholesterol and
IgM
Meta-analysis of 3 trials 548 patients UDCA
reduced risk of liver transplantation or death
over 4 years
Delays fibrosis and varices
Does not work in advanced disease
Other drugs



Colchicine
Methotrexate
Budesoide
Liver transplantation



Only effective Rx for liver failure
Survival is excellent 85% at 5 years
CAN RECUR IN GRAFT-30% AT 10
YEARS
Primary Sclerosing
Cholangitis PSC
Definition
A chronic inflammatory cholestatic
disease
Progressive destruction of bile
ducts
May progress to cirrhosis
Aetiology unknown
Epidemiology,Natural
History and Prognosis






Prevalence 6-8/100000
Usually diagnosed in 20s and 30s
Male predominance ~3:1
80% have IBD –usually UC
~44% asymptomatic at diagnosis
Median survival ~ 12 years
IBD and PSC



Mainly associated with UC ~85%-the
rest Crohns or indeterminate colitis
4% UC patients will develop PSC
No correlation between activity of IBD
and PSC
Aetiology and
Pathogenesis



Familial incidence
HLA associationsB8,DR3,DRw52a,DR2,DR4
Polymorphism of TNF gene
Immune factors



frequency autoimmune disorders
T cells in blood and liver
circulating immune complexes
Autoantibodies




95% patients with PSC have at least
one autoantibody
85% +ve ANCA
50% +ve ANA
25% +ve SMA
Pathogenesis



Association between PSC and UC
suggests a pathogenic interaction
?bacteria or toxic substances absorbed
via inflammed mucosa
Bile duct injury suggest ischaemic
injury ?immune complex mediated
Clinical Manifestations



44% asymptomatic but most develop
symptoms over time
Pruritis,jaundice,pain and fatigue are
common symptoms
Later on develop symptoms of
cirrhosis and portal hypertension
Cholangiocarcinoma




Lifetime prevalence of 10-30%
Annual risk 1.5% per year
Difficult to diagnose
Patients also have late risk of HCC
PSC and Bowel cancer



25% PSC develop cancer or dysplasia
cf 5.6% with UC alone
Cancers associated with PSC tend to
be more proximal,are more advanced
at diagnosis and mre likely to be fatal
Need aggressive colonoscopic
surveillance
Diagnosis


Cholangiography-either MRCP or ERCP
Clinical,biochemical and histological
features
ERCP and MRCP

Typical features:multifocal strictures and dilatation
usually affects both intra and
extrahepatic ducts
MRCP image of PSC
ERCP image
MRCP-PSC
ERCP-PSC
Liver biopsy



Useful for staging disease
“Onion skin fibrosis” only in ~10%
biopsies
~5% patients have typical biopsy
features with a normal cholangiogram
PSC-onion skin
appearance
PSC-cirrhosis
Lab tests

LFTs-cholestatic pattern:ALP 3-5x ULN
-AST/ALT slightly elevated only
-raised bilirubin may occur with
advanced disease,dominant
stricture,cholangioca,stones,cholangitis
Management

Many strategies tried but only
transplantation shown to improve
survival
Ursodeoxycholic acid





Causes significant biochemical
improvement
Little symptomatic or clinical benefit
May need high doses
Major role may be to reduce bowel
cancer risk in patients with PSC/UC
Not funded in NZ !
Steroids




No long term data
Serious risk of bone disease
Colchicine, D-Penicillamine, Nicotine of no
benefit
Combination Rx with UDCA Aza and steroids
showed clinical and biochemical
improvement in a small trial
Endoscopic treatment



Direct injection of steroids into biliary
tree ineffective
Balloon dilation or stenting can
improve clinical,biochemical and
cholangiographic appearances
Some reports of survival advantages
and delay to liver transplantation
Liver Transplant





Only treatment to improve overall
survival
Improves quality of life in 80%
patients
10 year survival post OLT ~70%
Aim to transplant before cholangica
Recurrent PSC in ~ 4% of grafts