Understanding Primary Biliary Cirrhosis (PBC): Diagnosis, Treatment, Prognosis & Management

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%