Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis

1. Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis • Registrar teaching July 2007 • Paul Frankish

2. 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

3. Clinical features • ~50% asymptomatic at diagnosis • Fatigue and pruritus most commonn symptoms~20% • Hyperlipidaemia,hypothyroidism,osteopenia,autoimmune diseases • Portal hypertension ,liver failure,HCC

4. Physical examination • Often normal • Spiders and skin excoriations • Xanthelasmas • Hepatomegaly ~70% • Jaundice (late)

5. Diagnosis 3 criteria Positive AMA Abnormal LFT Compatible biopsy

6. Pathological Stages (4) • 1 Destruction of bile ducts in portal tracts • 2 Inflammation beyond portal tracts • 3 fibrous septa link portal triads • Cirrhosis

9. 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

10. 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

11. T cell response • T cells infiltrating the liver are specific for PDC-E2 • Nature of bile duct injury not fully elucidated

12. 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

13. Other drugs • Colchicine • Methotrexate • Budesoide

15. Liver transplantation • Only effective Rx for liver failure • Survival is excellent 85% at 5 years • CAN RECUR IN GRAFT-30% AT 10 YEARS

16. Primary Sclerosing Cholangitis PSC

17. Definition A chronic inflammatory cholestatic disease Progressive destruction of bile ducts May progress to cirrhosis Aetiology unknown

18. 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

19. 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

20. Aetiology and Pathogenesis • Familial incidence • HLA associations-B8,DR3,DRw52a,DR2,DR4 • Polymorphism of TNF gene

21. Immune factors • frequency autoimmune disorders • T cells in blood and liver • circulating immune complexes

22. Autoantibodies • 95% patients with PSC have at least one autoantibody • 85% +ve ANCA • 50% +ve ANA • 25% +ve SMA

23. 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

24. 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

25. Cholangiocarcinoma • Lifetime prevalence of 10-30% • Annual risk 1.5% per year • Difficult to diagnose • Patients also have late risk of HCC

26. 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

27. Diagnosis • Cholangiography-either MRCP or ERCP • Clinical,biochemical and histological features

28. ERCP and MRCP • Typical features:- multifocal strictures and dilatation usually affects both intra and extrahepatic ducts

29. MRCP image of PSC

30. ERCP image

31. MRCP-PSC

32. ERCP-PSC

33. Liver biopsy • Useful for staging disease • “Onion skin fibrosis” only in ~10% biopsies • ~5% patients have typical biopsy features with a normal cholangiogram

34. PSC-onion skin appearance

35. PSC-cirrhosis

36. 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

37. Management • Many strategies tried but only transplantation shown to improve survival

38. 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 !

39. 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

40. 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

41. 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