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 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