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 40s 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 symptoms20% 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 criteriaPositive 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 disordersT cells in blood and livercirculating 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 dilatationusually 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 diseaseColchicine, 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,