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,osteopenia,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 PDC-E2 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 associations-B8,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