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

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Presentation on theme: "Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis Registrar teaching July 2007 Registrar teaching July 2007 Paul Frankish Paul Frankish."— Presentation transcript:

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

2 Primary Biliary Cirrhosis PBC-introduction Slowly progressive autoimmune liver disease Slowly progressive autoimmune liver disease 90% females 90% females Peak incidence in 40’s Peak incidence in 40’s Portal inflammation and autoimmune destruction of intrahepatic bile ducts Portal inflammation and autoimmune destruction of intrahepatic bile ducts Leads to cirrhosis and liver failure Leads to cirrhosis and liver failure 90-95% have antimitochondrial antibody 90-95% have antimitochondrial antibody

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

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

5 Diagnosis 3 criteria Positive AMA Abnormal LFT Compatible biopsy

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

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9 Epidemiology and Genetic factors Most prevalent in Nth Europe.10 fold variation Most prevalent in Nth Europe.10 fold variation More common in first degree relatives More common in first degree relatives Molecular mimicry to certain bacteria or viruses Molecular mimicry to certain bacteria or viruses Environmental chemical exposure Environmental chemical exposure

10 Autoimmune responses Targets of antimitichondrial antibodies Targets of antimitichondrial antibodies 4 autoreactive mitochondrial antigens 4 autoreactive mitochondrial antigens Pyruvate dehydrogenase E2 complex PDC- E2 Pyruvate dehydrogenase E2 complex PDC- E2 E-3 binding protein E3-BP E-3 binding protein E3-BP Ketoglutaric acid dehydrogenase E2 complex OGDC-E2 Ketoglutaric acid dehydrogenase E2 complex OGDC-E2 2 oxo-aciddehydrogenaseE-2 complex BCKD-E2 2 oxo-aciddehydrogenaseE-2 complex BCKD-E2

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

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15 Liver transplantation Only effective Rx for liver failure Only effective Rx for liver failure Survival is excellent 85% at 5 years Survival is excellent 85% at 5 years CAN RECUR IN GRAFT-30% AT 10 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/ Prevalence 6-8/ Usually diagnosed in 20s and 30s Usually diagnosed in 20s and 30s Male predominance ~3:1 Male predominance ~3:1 80% have IBD –usually UC 80% have IBD –usually UC ~44% asymptomatic at diagnosis ~44% asymptomatic at diagnosis Median survival ~ 12 years Median survival ~ 12 years

19 IBD and PSC Mainly associated with UC ~85%-the rest Crohns or indeterminate colitis Mainly associated with UC ~85%-the rest Crohns or indeterminate colitis 4% UC patients will develop PSC 4% UC patients will develop PSC No correlation between activity of IBD and PSC No correlation between activity of IBD and PSC

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

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

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

23 Pathogenesis Association between PSC and UC suggests a pathogenic interaction Association between PSC and UC suggests a pathogenic interaction ?bacteria or toxic substances absorbed via inflammed mucosa ?bacteria or toxic substances absorbed via inflammed mucosa Bile duct injury suggest ischaemic injury ?immune complex mediated Bile duct injury suggest ischaemic injury ?immune complex mediated

24 Clinical Manifestations 44% asymptomatic but most develop symptoms over time 44% asymptomatic but most develop symptoms over time Pruritis,jaundice,pain and fatigue are common symptoms Pruritis,jaundice,pain and fatigue are common symptoms Later on develop symptoms of cirrhosis and portal hypertension Later on develop symptoms of cirrhosis and portal hypertension

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

26 PSC and Bowel cancer 25% PSC develop cancer or dysplasia cf 5.6% with UC alone 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 Cancers associated with PSC tend to be more proximal,are more advanced at diagnosis and mre likely to be fatal Need aggressive colonoscopic surveillance Need aggressive colonoscopic surveillance

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

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

29 MRCP image of PSC

30 ERCP image

31 MRCP-PSC

32 ERCP-PSC

33 Liver biopsy Useful for staging disease Useful for staging disease “Onion skin fibrosis” only in ~10% biopsies “Onion skin fibrosis” only in ~10% biopsies ~5% patients have typical biopsy features with a normal cholangiogram ~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 LFTs-cholestatic pattern:ALP 3-5x ULN -AST/ALT slightly elevated only -AST/ALT slightly elevated only -raised bilirubin may occur with advanced disease,dominant stricture,cholangioca,stones,cholangitis -raised bilirubin may occur with advanced disease,dominant stricture,cholangioca,stones,cholangitis

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

38 Ursodeoxycholic acid Causes significant biochemical improvement Causes significant biochemical improvement Little symptomatic or clinical benefit Little symptomatic or clinical benefit May need high doses May need high doses Major role may be to reduce bowel cancer risk in patients with PSC/UC Major role may be to reduce bowel cancer risk in patients with PSC/UC Not funded in NZ ! Not funded in NZ !

39 Steroids No long term data No long term data Serious risk of bone disease Serious risk of bone disease Colchicine, D-Penicillamine, Nicotine of no benefit Colchicine, D-Penicillamine, Nicotine of no benefit Combination Rx with UDCA Aza and steroids showed clinical and biochemical improvement in a small trial 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 Direct injection of steroids into biliary tree ineffective Balloon dilation or stenting can improve clinical,biochemical and cholangiographic appearances Balloon dilation or stenting can improve clinical,biochemical and cholangiographic appearances Some reports of survival advantages and delay to liver transplantation Some reports of survival advantages and delay to liver transplantation

41 Liver Transplant Only treatment to improve overall survival Only treatment to improve overall survival Improves quality of life in 80% patients Improves quality of life in 80% patients 10 year survival post OLT ~70% 10 year survival post OLT ~70% Aim to transplant before cholangica Aim to transplant before cholangica Recurrent PSC in ~ 4% of grafts Recurrent PSC in ~ 4% of grafts

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