PBC and PSC: Back to Basics grace.kim@ucsf.edu Outline Case 1 - PowerPoint PPT Presentation

5/27/2016 Disclosure No financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in this presentation. PBC and PSC: Back to Basics grace.kim@ucsf.edu Outline Case 1 clinical history • In chronic cholestatic liver disease, liver biopsy • 54 year old woman, asymptomatic, plays a supporting role incidentally discovered to have elevated alkaline phosphatase (ALP) and positive anti- • Case-based discussion mitochondrial antibodies (AMA) • Clinical information, including laboratory • Liver biopsy performed findings and radiographic features, must be integrated for diagnosis 1

5/27/2016 What finding would you like to see on AASLD and EASL recommendations biopsy so you can diagnosis it as PBC? A. Portal and lobular inflammation • 2 of 3 required criteria for PBC diagnosis B. Infiltrate with easily identified plasma cells – Presence of antimitochondrial antibodies (AMA) C. Florid duct lesion – Alkaline phosphatase (ALP) at least 1.5 times D. Ductular reaction upper limit of normal for >24 weeks E. Ductopenia – Histologic evidence of PBC, specifically F. Periportal copper deposition nonsuppurative cholangitis and duct injury G. CK7 positive periportal hepatocytes H. Nodular regenerative hyperplasia I. Biliary pattern of cirrhosis Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4. Lindor KD, et al. Primary biliary cirrhosis. Hepatology 2009;50:291–308. EASL. Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. AASLD and EASL recommendations Antimitochondrial antibodies (AMA) • 2 of 3 required criteria for PBC diagnosis • Major autoantigen target by PBC patient sera – Presence of antimitochondrial antibodies (AMA) – M2 antigen fraction • E2 subunits of – Alkaline phosphatase (ALP) at least 1.5 times – Pyruvate dehydrogenase complex ( PDC-E2 ) upper limit of normal for >24 weeks – Branched chain 2-oxo-acid dehydrogenase complex ( BCOADC- – Histologic evidence of PBC, specifically E2 ) nonsuppurative cholangitis and duct injury – 2-oxo glutarate dehyrogenase complex ( OGDC-E2 ) • E1 α and E3 binding protein of PDC Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4. Lindor KD, et al. Primary biliary cirrhosis. Hepatology 2009;50:291–308. EASL. Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. Muratori L, et al. Antimitochondrial Antibodies and Other Antibodies in Primary Biliary Cirrhosis: Diagnostic and Prognostic Value. Clin Liver Dis 2008 May;12(2):261-76. 2

5/27/2016 Venn diagram of serum reactivity of PBC AMA test methodology patients • Indirect immunofluorescence assay (IFA) – Positive titer is ≥ 1:40 – Sensitivity 70-90% • Enzyme-linked immunosorbent assay (EIA) – AMA-M2 antibodies is most frequently used • First generation utilized PDC-E2 – 10% of PBC pts only react to BCOADC-E2 and/or OGDC-E2 • MIT3 or BPO expresses BCOADC-E2, PDC-E2 and OGDC- E2 epitopes – Sensitivity 94% Dähnrich C, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009 May;55(5):978-85. Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011 May 7;377(9777):1600-9. Dähnrich C, et al. New ELISA for detecting primary biliary cirrhosis-specific antimitochondrial antibodies. Clin Chem. 2009 May;55(5):978-85. AMA positive also in… AASLD and EASL recommendations • <1% of healthy adults • 2 of 3 required criteria for PBC diagnosis – Possibly early preclinical stage – Presence of antimitochondrial antibodies (AMA) • Patients with other diseases – Alkaline phosphatase (ALP) at least 1.5 times – 10-20% of AIH upper limit of normal for >24 weeks – <10% of HCV – Histologic evidence of PBC, specifically – <1% of steatohepatitis nonsuppurative cholangitis and duct injury – Rare reports associated with DILI – ~20% of pts have other autoimmune diseases – Infection mycobacteria and E.coli (cross reactivity) O'Brien C, et al. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology. 2008 Aug;48(2):550-6. Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4. Ravi S, et al. Autoimmune Markers Do Not Impact Clinical Presentation or Natural History of Steatohepatitis-Related Liver Disease. Dig Dis Sci. 2015 Dec;60(12):3788-93. Lindor KD, et al. Primary biliary cirrhosis. Hepatology 2009;50:291–308. Chantran Y, et al. Autoantibodies in primary biliary cirrhosis: antimitochondrial autoantibodies. Clin Res Hepatol Gastroenterol. 2013 Sep;37(4):431-3. EASL. Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. 3

5/27/2016 • 7829 new requests of autoantibody screen • 10-year follow-up of cohort – 29 pts had • Conclusion • Incidental finding of +AMA by IFA, titer ≥ 1:40 – Patients with AMA but no other signs or • Normal serum bilirubin, ALP, and transaminase symptoms of PBC seem to have slow disease • “Diagnostic” liver histology of PBC at presentation in progression 40% of cases – Liver histology was diagnostic of or compatible with PBC in 24 pts and normal in only 2 pts (7%) Florid duct lesion AASLD and EASL recommendations aka chronic nonsuppurative cholangitis Lymphohistiocytic • 2 of 3 required criteria for PBC diagnosis inflammation centered on – Presence of antimitochondrial antibodies (AMA) an interlobular bile duct (<100 µ m) and is – Alkaline phosphatase (ALP) at least 1.5 times associated with bile duct upper limit of normal for >24 weeks epithelial damage and – Histologic evidence of PBC, specifically epithelial reactive nonsuppurative cholangitis and duct injury changes. Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4. Lindor KD, et al. Primary biliary cirrhosis. Hepatology 2009;50:291–308. EASL. Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. 4

5/27/2016 The name PBC Acronym PBC • First described - 1851 • Xanthomatous biliary cirrhosis - 1949 – Xanthoma seen in 15-50% of pts and first finding • Primary biliary cholangitis 2015 in <1% – Name change approved by EASL, AASLD, AGA • Primary biliary cirrhosis - 1950 – Expected survival no different from the general population in 2 of 3 patients diagnosed and treated with UDCA and only a minority will ever develop cirrhosis Addison T, Gull W. On a certain affection of the skin – vitiligoidea a plana, b tuberosa. Guy’s Hospital Reports 1851;7:265–276. Hanot V. Étude sur une forme de cirrhose hypertrophique du foie [cirrhose hypertrophique avec ictere chronique]. Paris: JBBaillère,1876. Sherlock S. Primary billiary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterology. 1959 Nov;37:574-86. Macmahon HE, Thannhauser SJ. Xanthomatous biliary cirrhosis; a clinical syndrome. Ann Intern Med. 1949 Jan;30(1):121-79. Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis. Chronic non-suppurative destructive cholangitis. Am J Pathol. 1965 Mar;46:387-407. Corpechot C, et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology. 2005 Feb;128(2):297-303. Beuers U, et al. Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. Hepatology. 2015 Nov;62(5):1620-2 Case 1 pathologic diagnosis Case 1 treatment • Feature consistent with primary biliary • Ursodeoxycholic acid (UDCA) cirrhosis/primary biliary cholangitis – FDA approved drug for PBC since 1998 – Meets all three criteria – Well-tolerated – Better prognosis when given at early stage 5

5/27/2016 Emphasize Case 2 not much clinical history • Diagnostic criteria • 55 year old woman with elevated LFT • Patchy distribution and range of histologic • Liver biopsy performed features • Stains supportive of chronic biliary disease Case 2 pathologic diagnosis • Portal and lobular inflammation or mild nonspecific changes. • Do you then . . . 1. Go on to next case? 2. Send it to UCSF GI/Hepatobiliary Pathology Consult Service? 3. Inquire about laboratory results? 6

5/27/2016 Diagnostic approach to cholestasis in adult patients We called for laboratory test results • Elevated ALP (264) 2 • Mildly elevated AST (62) and ALT (51) • Positive AMA (M2 157.7) EASL. Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. Case 2 clinical history and labs Case 2 clinical history and labs Scenario A Scenario B • If ALP elevated and AMA negative • ALP elevated and AMA positive • Other characteristic clinical features • Diagnosis: Portal and lobular inflammation; – PBC-specific ANAs (Sp100 and gp210) see comment. – Elevated serum IgM – Comment: Describe features, state this can – Hypercholesterolemia/Xanthomas represent an early manifestation of PBC – Sicca syndrome – Pruritus – Fatigue Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014 Apr-May;13(4-5):441-4. 7