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PBC and PSC

PBC and PSC. Michael Nunez, MD September 20, 2004. Cholestatic Liver Disease. medication induced TPN infections sepsis choledocholithiasis pancreatic malignancy pregnancy related infiltrative liver diseases primary biliary cirrhosis (PBC) primary sclerosing cholangitis (PSC)

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PBC and PSC

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  1. PBC and PSC Michael Nunez, MD September 20, 2004

  2. Cholestatic Liver Disease • medication induced • TPN • infections • sepsis • choledocholithiasis • pancreatic malignancy • pregnancy related • infiltrative liver diseases • primary biliary cirrhosis (PBC) • primary sclerosing cholangitis (PSC) • secondary sclerosing cholangitis • graft vs. host disease

  3. Autoimmune Liver/Biliary Diseases • PBC • PSC • autoimmune hepatitis • autoimmune cholangitis (AMA-negative PBC)

  4. Primary Biliary Cirrhosis • misnomer – actually a nonsuppurative autoimmune cholangitis • autoimmune disease of the liver • predominantly affects middle-aged women • results in destruction of interlobular bile ducts • causes cholestasis and, eventually, cirrhosis • no cure

  5. PBC: Epidemiology • worldwide distribution • 90% of patients are female (9:1 ratio) • median age at presentation is 50 years (range 21-91) • prevalence of 20-400 patients per million population • up to 650 per million in US women • possible genetic association based on familial studies

  6. PBC: Pathogenesis • cause or trigger remains unknown (alloantigen?) • immune (T-cell) mediated attack that targets the epithelial cells of interlobular bile ducts • see B-cell elaboration of autoantibodies that may not be pathogenic • AMA is not pathogenic • intrahepatic bile duct destruction leads to cholestasis and fibrosis

  7. Normal Liver Biopsy

  8. PBC: Pathology damaged septal bile duct damaged interlobular bile duct

  9. PBC: Pathology bridging fibosis missing interlobular bile duct (ductopenia)

  10. PBC: Clinical Presentation

  11. PBC: Associated Diseases

  12. PBC: Diagnosis • abnormal liver function tests • alkaline phosphatase usually 3-4 times elevated • normal or minimally elevated transaminases (<3x) • elevated serum cholesterol and IgM often seen • jaundice, hypoalbuminemia, and coagulopathy seen in later stages of the disease • serologic testing • AMA present in 90-95% (the best have sens=98%, spec=96%) • RF found in 70% • ASMA in 66% • anti-thyroid in 40% • ANA in 35%

  13. PBC: Diagnosis • liver biopsy • gold standard to make diagnosis and exclude other diagnoses • stage 1 - portal triad inflammation • stage 2 - parenchymal (interface) hepatitis • stage 3 - fibrosis • stage 4 – cirrhosis • imaging studies • main utility in excluding biliary obstruction • can see increased hepatic echogenicity • can see lymphadenopathy in 25%

  14. PBC: Natural History and Prognosis • AMA positive with normal LFTs and asymptomatic • 29 patients followed (18 years average) • 24 with PBC on biopsy (83%) • 2 with normal biopsies • 24 developed abnormal LFTs at average of 5.6 years • 22 developed symptomatic disease • no progression to cirrhosis or death from liver disease • asymptomatic PBC (AMA and biopsy) with abnormal LFTs • 40% develop symptoms in 5-7 years • once symptomatic, life expectancy falls (median survival 10 years but a large range)

  15. PBC: Natural History and Prognosis • symptomatic PBC patients • independent predictors of poor prognosis • advanced age • bilirubin level (>10 portends 2 year avg. survival) • poor synthetic function • hepatomegaly • ascites or edema • variceal bleed • advanced biopsy stage • prognostic models have been developed and validatedhttp://www.mayoclinic.org/gi-rst/mayomodel2.html

  16. PBC: Treatment • traditional glucocorticoids • one controlled trial with benefits on biochemistry and histology • no change in mortality • colchicine • in 3 controlled trials, no prognostic or survival benefit • azathioprine • 248 patients without biochemical, histologic or survival benefit • cyclosporine • 349 patients without histologic or survival benefit • methotrexate • only one controlled trial with worse outcomes at 6 years

  17. PBC: Treatment • ursodeoxycholic acid (UDCA) • improves biochemistry, histology, and survival • 13-15 mg/kg/day divided TID • FDA approved for PBC • budesonide and UDCA • well studied only in UDCA non-responders; no benefit in prognosis models • in naïve patients, improved biochemistry and histology (vs. UDCA alone), but no information on prognosis AMA-negative PBC seems to behave and respond the same as PBC, but may overlap with autoimmune hepatitis.

  18. PBC: Management • osteopenia and osteoporosis • lose bone mass at twice rate of controls • risk of osteoporosis 8 times matched controls • 50% of post transplant PBC patients suffer fractures • treatment: exercise, calcium and vitamin D (25,000-100,000 IU/week) • bisphosphonates need further study • fat soluble vitamins • monitor vitamins D, A and E • trial of vitamin K for prolonged prothrombin time • pruritus • cholestyramine 4-16 gm/day divided before and after breakfast • rifampin or oral naltrexone can be useful in non-responders • can require transplantation

  19. PBC: Transplantation • survival is better if transplanted before a life-threatening complication or patient is on life support • common indications • portal hypertensive bleeding • refractory ascites • encephalopathy • hepatorenal syndrome • disabling fatigue • disabling pruritus • severe muscle wasting • one-year survival rates 90%; 5-year >80% • post-transplant recurrence (by biopsy) in 30-50% by 10 years but usually takes a benign course

  20. Primary Sclerosing Cholangitis • most common type of sclerosing cholangitis in U.S. • autoimmune disease of the biliary tree • chronic inflammation and fibrosis of the bile ducts • may occur in association with other diseases (IBD, scleroderma, SLE, sprue…) • but lacks a specific etiology (AIDS infections, parasites, operative injury, cystic fibrosis, RPC…) • no cure

  21. PSC: Epidemiology • prevalence of 6-8 per 100,000 • up to 44% are asymptomatic at diagnosis • 80% of patients have concomitant IBD and 90% of those have ulcerative colitis (some years before symptoms) • 3-6% of UC patients and 1% of Crohn’s patients have PSC • PSC and IBD progress independently • median age at diagnosis is 39 (neonates to octogenarians) • male:female ~ 1.5:1

  22. PSC: Pathogenesis • theory: unknown trigger (toxin, infection, ischemia) in a genetically susceptible host • familial clustering reported • class II and III HLA associations • common autoantibodies (ANCA in 65-85%) • humoral and cellular immune dysfunction • intra- and extra-hepatic bile duct inflammation and fibrosis • stricture formation and obliteration • intra- and extra-hepatic ducts usually involved • 5% predominantly extra-hepatic • 25% predominantly intra-hepatic • leads to cholestasis and cirrhosis

  23. PSC: Pathology normal liver “onion skin fibrosis” in PSC

  24. PSC: Pathology bile duct distortion fibrous obliteration

  25. PSC: Clinical Presentation Course may be very variable with spontaneous remission for prolonged periods.

  26. PSC: Diagnosis • symptoms • high index of suspicion in IBD patients • physical findings • hepatomegaly • splenomegaly • laboratory • alkaline phosphatase elevation (usually 3-fold or higher) • 6% have normal alkaline phosphatase • modest transaminase elevations (usually < 3-fold) • bilirubin may be normal • small subset have marked eosinophilia • 65-85% are ANCA positive

  27. PSC: Diagnosis • liver biopsy • “onion skin” fibrosis is most common (50% patients) • “obliterative fibrous cholangitis” is pathognomonic (10%) • most findings can be confused with chronic hepatitis or auto-immune hepatitis • imaging studies • non-specific findings variably present • dilated intra-hepatic ducts may be seen • cholangiography • ERCP considered the “gold standard” • MRCP reported to have PPV of 90% and sens/spec of ~85% compared to ERCP • 75% will have strictures at the bifurcation

  28. PSC: Cholangiography MRCP ERCP

  29. PSC: Cholangiography MRCP ERCP

  30. PSC: Cholangiography MRCP ERCP

  31. PSC: Natural History and Prognosis • median survival or time to transplant is 12 years, but very variable and less predictable than PBC • some predictors of poor prognosis (Mayo model) • advanced age • degree of bilirubin elevation • low albumin • high AST level • variceal bleeding • Child-Pugh classification is used by UNOS (transplant listing) • class A: 90% 7 year survival • class B: 68% 7 year survival • class C: 25% 7 year survival

  32. PSC: Natural History and Prognosis • malabsorption • steatorrhea • calcium malabsorption and osteoporosis • fat-soluble vitamin deficiencies • portal hypertension • bleeding • ascites • cholangiocarcinoma • median survival of 5 months • diagnosed in 3-20% of patients • found in 30-40% of PSC patients at autopsy • found in 23-33% of PSC patients at transplant • tumor markers unproven as screening tools

  33. PSC: Management • medical palliation • pruritus • cholestyramine • cholestipol • rifampin • bacterial cholangitis • antibiotics (gram neg bacilli,enterococci, bacteroides) • steatorrhea • fat-soluble vitamins • medium-chain triglycerides • interventional palliation • ERCP • dilation of dominant strictures • short-term stenting (7-14 days) • stone removal

  34. PSC: Transplantation • indications • complications of portal hypertension • hepatic dysfunction • disabling refractory symptoms • recurrent cholangitis • usually done with a Roux-en-Y biliary anasamosis • excellent patient and graft survival rates • if cholangiocarcinoma is found in native liver, survival drops to 30% at one year • PSC recurs in 15-20%

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