Autoimmune Cholangiopathy

1. Autoimmune Cholangiopathy Joanna Leigh Siegel, MD December 13, 2004

3. Background PBC Addison and Gull, 1851- �On a Certain Affectation of the Skin- Vitiligoidea-alpha plana, beta tuberosa� Hanot, 1892- �La Cirrhosis hypertophique avec ictere and chroniqe� Ahrens, et al, 1950- �Primary Biliary Cirrhosis� A misnomer �Chronic non-suppurative granulomatous intrahepatic cholangiopathy�

4. Background T cell-mediated, apoptotic destruction of biliary epithelial cells (BECs) lining interlobular to septal intrahepatic bile ducts

5. Background- PBC Sherlock, 1959- 42 cases b/t 1944 and 1959 Dx usually made by laparotomy Walker, et al, 1965: Immunoflourescence test for AMA AMAs present in all PBC pts and in none of controls (CBD obstruction, drug-induced cholestasis, viral hepatitis, chronic cholestasis with UC) Rubin, et al, 1965: described spectrum of liver histology

6. Background- PBC Scheuer, 1967: 4 histologic stages 1. the florid duct lesion (pathognomonic) 2. ductular proliferation 3. fibrotic septa 4. cirrhosis Stage 1 is diagnostic; stages 2-4 are suggestive or compatible with diagnosis

7. Florid Duct Lesion

8. Florid Duct Lesion

9. Diagnosis of PBC Classic Diagnostic Triad Increased enzymes of cholestasis +AMA Diagnostic liver histology

10. Definite and probable PBC

11. AMA The Presentation and Diagnosis of 100 Patients with Primary Biliary Cirrhosis: 93/100 tests were AMA positive 5/7: diagnostic histology 2/7: compatible histology �Particular care has to be taken in making the diagnosis if the AMA is negative.�

12. AMA Directed against mitochondrial antigens localized to E2 subunit of PDH complex on inner mitochondrial membrane Not specific for PBC AIH, drug-induced hepatitis, PSC, syphilis, myocarditis 9 subtypes M2 most specific If AMA-, can check ELISA for M2

13. Overlap Syndromes A major source of diagnostic confusion 3 types Sequential autoimmune liver disease Simultaneous autoimmune liver disease One autoimmune disease with features of another Most common

14. Sequential autoimmune liver disease 56F with PBC and sprue (AMA+, bx-proven, stage 4 disease) who had response to UDCA 20 months later, increase in AST/ALT and alk phos AMA 1:320 -> undetectable ANA negative -> 1:1280 Prednisone 20mg -> improvement; tapering -> reactivation of disease Called �autoimmune cholangiopathy�

15. Sequential Autoimmune Liver Disease Transition from AIH to PSC difficult to document ?sequential disease or missed simultaneous disease No descriptions of PBC before or after PSC Look similar histologically and biochemically

16. Simultaneous Autoimmune Liver Diseases Most common is PSC and AIH in kids 32 pts with radiographically-proven PSC � had IBD 9/32: incr. IgG and AST/ALT, nL alk phos c/w AIH 6/9: tx w/ immunosupp, 0/6 improved 11/32: cirrhosis (more typical of AIH than PSC) 1/32 died, 10/32 listed during 15 years of observation (poor outcome more typical of PSC)

17. One Autoimmune Liver Disease With Features of Another Clinical Features Most asx at dx; fatigue most common sx Pruritus common in PBC, PSC, unusual in AIH Nonhepatic autoimmune diseases (UC, RA, thyroid) Biochemical Features Serologic Features AMA are not pathogenic Detection of autoantibodies which are atypical for a certain clinical syndrome is insufficient to declare it a variant form.

18. One Autoimmune Liver Disease With Features of Another AMA in AIH 20% of 187 AIH pts at Mayo Clinic ANA and SMA Anti-LKM1: seen in HCV pANCA and cANCA: frequently (> 50%) seen in AIH and sometimes in PBC

19. Autoimmune Cholangitis- History �Immune cholangitis� first mentioned by Brunner in 1987. 3 patients with clinical, biochemical, and histological characteristics of PBC who were AMA- and ANA+ Treated with corticosteroids and an improvement in biochemistry was said to occur

23. Treatment- Mayo Clinic > 200 patients referred for inclusion in UDCA study 9 excluded because AMA- 1 ultimately diagnosed with idiopathic adulthood ductopenia Treated with UDCA and results compared to the AMA+ PBC pts enrolled in the treatment arm with respect to death or OLTx, serial biochemical measurements, and withdrawal from UDCA Also assessed outcome of OLTx

24. Treatment- Mayo Clinic Outcomes: comparable to that of 89 AMA+ pts 1 died of colon CA 2 received OLTx 5 remained stable for 6-84 months on UDCA- No differences in sequential liver biochemistries between the two groups- both had improvements 2 pts who had initially been AMA- became AMA+, including one who underwent OLTx �When the potential risks and benefits of tx with prednisone vs. UDCA are considered, UDCA should be used first.�

25. Outcome of OLTx 6/85 pts who were transplanted for PBC were AMA- No significant differences in demographics, MRS, ANA, SMA, levels of aminotransferases, bili, IgM, gammaglobulin 5/6 were ANA+ and 2 of these 5 were SMA+

26. Outcome of OLTx Followed for median of 3 years post-tx All alive w/o retransplantation 1/6 developed histological lesions c/w recurrent PBC this pt was AMA+ at another institution, but repeatedly AMA- at Mayo Results at least as favorable as AMA+ counterparts In 12 AMA+ pts, AMA titer monitored in 11 and turned negative at least once in 6/11. In AMA- group, 1 pt, became AMA+ 4 years post OLTx

27. Problems with definition AMA fluctuates Sensitivity of AMA testing Histology not specific Lack of recognition of overlap syndromes

29. �What�s in a name? That which we call a rose by any other name would smell as sweet. -Romeo and Juliet William Shakespeare (1564-1616)