Primary Sclerosing Primary Sclerosing Cholangitis and Primary Cholangitis and Primary Biliary CirrhosisBiliary Cirrhosis

Registrar teaching July 2007Registrar teaching July 2007 Paul FrankishPaul Frankish

Primary Biliary Primary Biliary Cirrhosis PBC-Cirrhosis PBC-introductionintroduction Slowly progressive autoimmune liver Slowly progressive autoimmune liver

diseasedisease 90% females90% females Peak incidence in 40’sPeak incidence in 40’s Portal inflammation and autoimmune Portal inflammation and autoimmune

destruction of intrahepatic bile ductsdestruction of intrahepatic bile ducts Leads to cirrhosis and liver failureLeads to cirrhosis and liver failure 90-95% have antimitochondrial 90-95% have antimitochondrial

antibodyantibody

Clinical featuresClinical features

~50% asymptomatic at diagnosis~50% asymptomatic at diagnosis

Fatigue and pruritus most Fatigue and pruritus most commonn symptoms~20%commonn symptoms~20%

Hyperlipidaemia,hypothyroidism,oHyperlipidaemia,hypothyroidism,osteopenia,autoimmune diseasessteopenia,autoimmune diseases

Portal hypertension ,liver Portal hypertension ,liver failure,HCC failure,HCC

Physical examinationPhysical examination

Often normalOften normal Spiders and skin excoriationsSpiders and skin excoriations XanthelasmasXanthelasmas Hepatomegaly ~70%Hepatomegaly ~70% Jaundice (late)Jaundice (late)

DiagnosisDiagnosis

3 criteria3 criteria

Positive AMAPositive AMA

Abnormal LFTAbnormal LFT

Compatible biopsyCompatible biopsy

Pathological Stages (4)Pathological Stages (4)

1 Destruction of bile ducts in 1 Destruction of bile ducts in portal tractsportal tracts

2 Inflammation beyond portal 2 Inflammation beyond portal tractstracts

3 fibrous septa link portal triads3 fibrous septa link portal triads CirrhosisCirrhosis

Epidemiology and Epidemiology and Genetic factorsGenetic factors Most prevalent in Nth Europe.10 Most prevalent in Nth Europe.10

fold variationfold variation More common in first degree More common in first degree

relativesrelatives Molecular mimicry to certain Molecular mimicry to certain

bacteria or virusesbacteria or viruses Environmental chemical exposureEnvironmental chemical exposure

Autoimmune Autoimmune responsesresponses Targets of antimitichondrial antibodiesTargets of antimitichondrial antibodies 4 autoreactive mitochondrial antigens4 autoreactive mitochondrial antigens Pyruvate dehydrogenase E2 complex Pyruvate dehydrogenase E2 complex

PDC-E2PDC-E2 E-3 binding protein E3-BPE-3 binding protein E3-BP Ketoglutaric acid dehydrogenase E2 Ketoglutaric acid dehydrogenase E2

complex OGDC-E2complex OGDC-E2 2 oxo-aciddehydrogenaseE-2 complex 2 oxo-aciddehydrogenaseE-2 complex

BCKD-E2BCKD-E2

T cell responseT cell response

T cells infiltrating the liver are T cells infiltrating the liver are specific for PDC-E2specific for PDC-E2

Nature of bile duct injury not fully Nature of bile duct injury not fully elucidatedelucidated

Treatment:-Treatment:-Ursodeoxycholic acid Ursodeoxycholic acid UDCAUDCAGiven in dose 12-15 mg/kgGiven in dose 12-15 mg/kgReduces bilirubin,ALP,AST,ALT Reduces bilirubin,ALP,AST,ALT

cholesterol and IgMcholesterol and IgMMeta-analysis of 3 trials 548 patients Meta-analysis of 3 trials 548 patients

UDCA reduced risk of liver UDCA reduced risk of liver transplantation or death over 4 yearstransplantation or death over 4 years

Delays fibrosis and varicesDelays fibrosis and varicesDoes not work in advanced diseaseDoes not work in advanced disease

Other drugsOther drugs

ColchicineColchicine MethotrexateMethotrexate BudesoideBudesoide

Liver transplantationLiver transplantation

Only effective Rx for liver failureOnly effective Rx for liver failure Survival is excellent 85% at 5 Survival is excellent 85% at 5

yearsyears CAN RECUR IN GRAFT-30% AT 10 CAN RECUR IN GRAFT-30% AT 10

YEARSYEARS

Primary Sclerosing Primary Sclerosing Cholangitis PSCCholangitis PSC

DefinitionDefinition

A chronic inflammatory A chronic inflammatory cholestatic diseasecholestatic diseaseProgressive destruction of bile Progressive destruction of bile ductsductsMay progress to cirrhosisMay progress to cirrhosisAetiology unknownAetiology unknown

Epidemiology,Natural Epidemiology,Natural History and PrognosisHistory and Prognosis Prevalence 6-8/100000Prevalence 6-8/100000 Usually diagnosed in 20s and 30sUsually diagnosed in 20s and 30s Male predominance ~3:1Male predominance ~3:1 80% have IBD –usually UC80% have IBD –usually UC ~44% asymptomatic at diagnosis~44% asymptomatic at diagnosis Median survival ~ 12 yearsMedian survival ~ 12 years

IBD and PSCIBD and PSC

Mainly associated with UC ~85%-Mainly associated with UC ~85%-the rest Crohns or indeterminate the rest Crohns or indeterminate colitiscolitis

4% UC patients will develop PSC4% UC patients will develop PSC No correlation between activity of No correlation between activity of

IBD and PSCIBD and PSC

Aetiology and Aetiology and PathogenesisPathogenesis Familial incidenceFamilial incidence HLA associations-HLA associations-

B8,DR3,DRw52a,DR2,DR4B8,DR3,DRw52a,DR2,DR4 Polymorphism of TNF genePolymorphism of TNF gene

Immune factorsImmune factors

frequency autoimmune disordersfrequency autoimmune disorders

T cells in blood and liverT cells in blood and liver

circulating immune complexescirculating immune complexes

AutoantibodiesAutoantibodies

95% patients with PSC have at 95% patients with PSC have at least one autoantibodyleast one autoantibody

85% +ve ANCA85% +ve ANCA 50% +ve ANA50% +ve ANA 25% +ve SMA25% +ve SMA

PathogenesisPathogenesis

Association between PSC and UC Association between PSC and UC suggests a pathogenic interactionsuggests a pathogenic interaction

?bacteria or toxic substances ?bacteria or toxic substances absorbed via inflammed mucosaabsorbed via inflammed mucosa

Bile duct injury suggest ischaemic Bile duct injury suggest ischaemic injury ?immune complex injury ?immune complex mediatedmediated

Clinical ManifestationsClinical Manifestations

44% asymptomatic but most 44% asymptomatic but most develop symptoms over timedevelop symptoms over time

Pruritis,jaundice,pain and fatigue Pruritis,jaundice,pain and fatigue are common symptomsare common symptoms

Later on develop symptoms of Later on develop symptoms of cirrhosis and portal hypertensioncirrhosis and portal hypertension

CholangiocarcinomaCholangiocarcinoma

Lifetime prevalence of 10-30%Lifetime prevalence of 10-30% Annual risk 1.5% per yearAnnual risk 1.5% per year Difficult to diagnoseDifficult to diagnose Patients also have late risk of HCCPatients also have late risk of HCC

PSC and Bowel cancerPSC and Bowel cancer

25% PSC develop cancer or 25% PSC develop cancer or dysplasia cf 5.6% with UC alonedysplasia cf 5.6% with UC alone

Cancers associated with PSC tend Cancers associated with PSC tend to be more proximal,are more to be more proximal,are more advanced at diagnosis and mre advanced at diagnosis and mre likely to be fatallikely to be fatal

Need aggressive colonoscopic Need aggressive colonoscopic surveillancesurveillance

DiagnosisDiagnosis

Cholangiography-either MRCP or Cholangiography-either MRCP or ERCPERCP

Clinical,biochemical and Clinical,biochemical and histological featureshistological features

ERCP and MRCPERCP and MRCP

Typical features:-Typical features:-

multifocal strictures and multifocal strictures and dilatationdilatation

usually affects both intra and usually affects both intra and

extrahepatic ducts extrahepatic ducts

MRCP image of PSCMRCP image of PSC

ERCP imageERCP image

MRCP-PSCMRCP-PSC

ERCP-PSCERCP-PSC

Liver biopsyLiver biopsy

Useful for staging diseaseUseful for staging disease ““Onion skin fibrosis” only in Onion skin fibrosis” only in

~10% biopsies~10% biopsies ~5% patients have typical biopsy ~5% patients have typical biopsy

features with a normal features with a normal cholangiogramcholangiogram

PSC-onion skin PSC-onion skin appearanceappearance

PSC-cirrhosisPSC-cirrhosis

Lab testsLab tests

LFTs-cholestatic pattern:ALP 3-5x LFTs-cholestatic pattern:ALP 3-5x ULNULN

-AST/ALT slightly elevated -AST/ALT slightly elevated onlyonly

-raised bilirubin may occur -raised bilirubin may occur with advanced disease,dominant with advanced disease,dominant stricture,cholangioca,stones,cholastricture,cholangioca,stones,cholangitisngitis

ManagementManagement

Many strategies tried but only Many strategies tried but only transplantation shown to improve transplantation shown to improve survivalsurvival

Ursodeoxycholic acidUrsodeoxycholic acid

Causes significant biochemical Causes significant biochemical improvementimprovement

Little symptomatic or clinical Little symptomatic or clinical benefitbenefit

May need high dosesMay need high doses Major role may be to reduce bowel Major role may be to reduce bowel

cancer risk in patients with PSC/UCcancer risk in patients with PSC/UC Not funded in NZ !Not funded in NZ !

SteroidsSteroids

No long term dataNo long term data Serious risk of bone diseaseSerious risk of bone disease

Colchicine, D-Penicillamine, Nicotine of Colchicine, D-Penicillamine, Nicotine of no benefitno benefit

Combination Rx with UDCA Aza and Combination Rx with UDCA Aza and steroids showed clinical and steroids showed clinical and biochemical improvement in a small biochemical improvement in a small trialtrial

Endoscopic treatmentEndoscopic treatment

Direct injection of steroids into Direct injection of steroids into biliary tree ineffectivebiliary tree ineffective

Balloon dilation or stenting can Balloon dilation or stenting can improve clinical,biochemical and improve clinical,biochemical and cholangiographic appearancescholangiographic appearances

Some reports of survival Some reports of survival advantages and delay to liver advantages and delay to liver transplantationtransplantation

Liver TransplantLiver Transplant

Only treatment to improve overall Only treatment to improve overall survivalsurvival

Improves quality of life in 80% Improves quality of life in 80% patientspatients

10 year survival post OLT ~70%10 year survival post OLT ~70% Aim to transplant before Aim to transplant before

cholangicacholangica Recurrent PSC in ~ 4% of graftsRecurrent PSC in ~ 4% of grafts