ACCME/Disclosures. The Overlap Syndromes: Do They Exist? Key Points and Questions 4/6/2016. Hans Popper Hepatopathology Society

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1 ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Kay Washington declares she has no conflict(s) of interest to disclose. V A N D ER B I L T U N I V E R SI T Y The Overlap Syndromes: Do They Exist? Kay Washington, MD, PhD Vanderbilt University Medical Center March 13, 2016 Hans Popper Hepatopathology Society Key Points and Questions Some patients with autoimmune liver disease present with overlapping features, mostly between AIH PBC and AIH PSC. Standardized definitions of these overlap syndromes are lacking. Should these cases be classified as separate diagnostic entities? (Even classical AIH, PBC, PSC cases are not homogenous disorders.) What are the clinical implications of a diagnosis of overlap syndrome? 1

2 Variants of Autoimmune Liver Disease Overlap Syndromes Outlier Syndrome Sequential Syndromes AIH-PBC AIC (AMA negative AIH PBC PBC) AIH-PSC AIH PSC AIH-AIC Demographics and Clinical Features Feature AIH PBC PSC Gender 60 75% >90% female 30 35% female female Age All age groups Cholangiography Normal or signs of cirrhosis Inflammatory Bowel Disease Other autoimmune disorders Typically middleaged (30 to 65 years). Not seen in children. Normal or signs of liver cirrhosis All age groups; typically years Characteristic findings, diagnostic of PSC. May be normal in small duct PSC. Rarely associated Rarely associated Up to 80% Raynaud s phenomenon, sicca syndrome, scleroderma, CREST syndrome predominantly related to PBC Adapted from Boberg KM, et al. J Hepatol 2011;54: Laboratory Tests Feature AIH PBC PSC Aminotransferases Elevated, often 3 to 10x ULN, but may be normal Alkaline May be elevated phosphatase Normal or slightly elevated Bilirubin Variable Variable; usually normal at diagnosis Normal or slightly elevated Moderately to Usually at least 3 x markedly elevated ULN Variable; may be normal at diagnosis Immunoglobulins Elevated IgG Elevated IgM IgG increased in up to 61%. IgM increased in up to 45% Overlapping Autoantibody Profiles Autoantibodies AIH PBC PSC ANA Significant titers of ANA ANA >30% ANA in 8 77% SMA +/ SMA in 70 80% May be present SMA in 0 83% LKM 3 to 4% SLA/LP 10 30% May be detected May be detected panca 50 96% 26 94% AMA Occasionally, low titer (anti PDC E2 pattern rarely detected) 90 95% (anti PDC E2 is highly specific) Occasionally positive Adapted from Boberg KM, et al. J Hepatol 2011;54: Adapted from Boberg KM, et al. J Hepatol 2011;54:

3 Overlap Syndromes of Autoimmune Liver Diseases 8 14% AIH 6 8% PBC PSC Possible Relationships between Autoimmune Liver Diseases Sequential presentation Concomitant presence of 2 distinct disorders (if you have one autoimmune disease, you are at risk for others) Continuum of changes without strict boundaries Distinct clinical entities on their own The presence of one primary disorder with one or more characteristics of another 3

4 Zone 3 Inflammation in AIH Regenerative Rosette in AIH Lobular Plasma Cells in AIH Emperipolesis in Autoimmune Hepatitis 4

5 Revised AIH Scoring System: Positive Weighting Revised AIH Scoring System: Negative Weighting Female sex Low alk phos:ast ratio Increased IgG Autoantibodies Negative viral serology Positive treatment response Negative drug history Low alcohol consumption Interface hepatitis Concurrent autoimmune disorders + for relevant HLA haplotypes High alk phos:ast ratio AMA + Positive viral serology Positive drug history High alcohol consumption Bile duct damage Definite AIH if score > 15 before treatment, 17 after treatment Probable AIH if score before treatment, after treatment Alvarez et al. J Hepatol 1999;31: Simplified Diagnostic Criteria for AIH Feature Cutoff Points ANA or SMA + >1:40 1 ANA or SMA + >1:80 2* OR LKM >1:40 OR SLM Positive IgG > Upper limit of normal 1 >1.1 x upper limit of normal 2 Liver histology Compatible with AIH 1 Typical AIH 2 Absence of viral hepatitis yes 2 >6: probable AIH *Addition of points achieved for all antibodies (max 2 points) >7 definite AIH Categories for Weighting Histology Typical histology (2 points) Interface hepatitis (lymphocytes +/ plasma cells) Emperipolesis Hepatocyte rosette formation Histology compatible with AIH (1 point) Chronic hepatitis pattern of injury but lacking some typical features Atypical histology Features suggestive of other diagnoses Hennes EM, et al. Hepatology 2008; 48:

6 Pathology of PBC Florid duct lesion: inflammation injury to bile duct epithelium disruption of basement membrane 40 to 80 microns bile ducts Segmental destruction LOBULAR PLASMA CELLS IN PBC 6

7 AIH PBC 84 patients with definite or probable AIH 20/84 (24%) had bile duct injury or loss 4 with ductopenia 6 with destructive cholangitis 10 with non destructive cholangitis No difference in response to treatment or clinical outcome Hepatology 2001;34: Case 1 29 year old woman with asthma and celiac disease 3 week hx nausea, vomiting; 12 weeks postpartum Liver tests checked elevated US showed normal appearing liver and contracted gallbladder Viral serologies negative Transaminases previously in the 100s range, diagnosed with fatty liver disease Liver tests normalized after diagnosis of celiac disease when gluten free diet started Liver Tests Alk Phos AST ALT Liver biopsy 7

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9 Liver Tests Alk Phos AST ALT Final Diagnosis: AIH/PBC Overlap Initial clinical impression autoimmune hepatitis; started on 40 mg prednisone, with planned prolonged taper and azathioprine Added UDCA Latest lab values: Alk phos 182 (40 150) AST 45 (5 40) ALT 81 (0 55) T. bili 0.3 ANA +, >1:160; F actin IgG + Liver bx AMA +, 1:160 AIH PBC Overlap Most reports are retrospective Defined in several ways in the literature: Paris criteria Histologic finding of interface hepatitis is mandatory Prevalence depends upon cohort Prevalence among PBC patients is 4.8 to 9.2% If IAIHG scoring system is used, range is 2.1 to 19%. (4% if other autoimmune diseases or gender is excluded.) IAIHG scoring system includes parameters common to both PBC and AIH and thus cannot discriminate Paris Criteria At least 2 of the following criteria for each diagnosis: AIH ALT >5 x ULN IgG levels >2 x ULN or positive SMA Liver biopsy with periportal interface hepatitis PBC Alkaline phosphatase >2 x ULN or GGT >5 x ULN Positive AMA Liver biopsy with florid duct lesions Chazouillères O. et al. Hepatology 1998;28:

10 Problems with AIH PBC Overlap Disease features can change over time in the individual patient and may be modified by treatment AMA in AIH is usually low titer and non specific Florid duct lesions in only ~ 1/3 of PBC Severe interface hepatitis in up to 30% of PBC Incidental bile duct injury is common in AIH (~ 25%) Clinical Considerations for PBC with Features of AIH Severity of interface hepatitis and lobular inflammation in PBC is associated with progression of fibrosis when treated with UDCA Hispanic patients more likely to have AIH PBC OS (31%, compared to 13%), less likely to respond to UDCA alone (60% vs 88%)* Features of AIH may be transient in patients with PBC AIH overlap syndrome *Levy C, et al. Clin Gastroenterol Hepatol 2014;12(8): IgG and IgM in AIH IgG IgM Fig. 1. Clinical significance of IgG elevation for the diagnosis of corticosteroid-responsive PBC-AIH overlap syndrome. (Panel A) Serum IgG elevations (xuln) in AIH, PBC and corticosteroid-responsive PBC-AIH overlap syndrome. (Panel B) Among patients with PBC, the area under ROC curve is to identify corticosteroid-response OS. Wang Q, et al. Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis. Journal of Autoimmunity, Volume 41, 2013,

11 IgG IgG and IgM in PBC IgM AMA Negative PBC Identical to PBC except for lack of AMA Similar response to UDCA More sensitive AMA tests may detect AMA Autoimmune Cholangitis Lack of uniform criteria for diagnosis Most commonly characterized as a variant of PBC (AMAnegative PBC) Patients typically have high ANA titers, no AMA Histology is often similar to PBC May represent an early stage of disease in evolution (AMA titers may fluctuate) 11

12 Diagnosis of PSC Gold standard is cholangiography (MRCP) Multifocal stricturing and beading Involves both extra and intrahepatic ducts in typical case Gallbladder and cystic duct are involved in ~15% Duct Lesions in PSC Periductal edema Periductal fibrosis Duct distortion Duct loss Often minimal inflammation 12

13 Interface Hepatitis in PSC 13

14 Case 2 11 year old girl, diagnosed with ulcerative colitis One year later, elevated liver tests prompted liver biopsy AST 199 ALT 138 GGT 2 64 (normal 2 40) Alk phos 517 Also: anti SMA 1:80; ANA 1:80 Biopsy # 1 (Age 11) Biopsy # 2 (Age 13) 14

15 Biopsy # 3 (age 18) Autoimmune Hepatitis versus PSC Distinguishing PSC from autoimmune hepatitis is more commonly a problem in pediatric patients Alkaline phosphatase may be normal for age Cholangiographic findings more subtle Concentric periductal fibrosis is rare; usual pattern is loss of small bile ducts Portal inflammation may mimic AIH 15

16 PSC AIH Overlap Usual case: Confirmed dx of PSC, with concurrent features of AIH Particularly common in children and with small duct PSC Using IAIHG scoring system, up to 19% score as probable AIH PSC strongly associated with IBD, AIH is not. PSC AIH OS concordance with IBD is similar to PSC. Consider PSC in AIH patients with pruritis, cholestatic liver tests, bile duct injury on histology, and poor response to treatment. 55 children with AIH followed for 16 years 27 developed bile duct changes of PSC 1/3 of these had only small duct disease 35% had ERCP but not histologic changes of PSC IBD more common in this group than in AIH More commonly p ANCA + Younger than classic PSC patients, more likely to be female Term autoimmune sclerosing cholangitis proposed Hepatology 33:544-53, 2001 PSC AIH Overlap in Children ASC may be the childhood counterpart of PSC AIH overlap in adults. PSC in children is skewed towards a hepatitic presentation, instead of cholestatic profile in adults. Possibility of PSC should be considered in all children (but not in all adults) with AIH. Prognosis is better than classic PSC; better in children than adults EASL, AASLD recommend combination therapy Sequential Syndromes Relatively rare; multiple liver biopsies Usually AIH PBC or AIH PSC Diagnosis of AIH usually precedes PSC 16

17 Can Genetic Studies Help? AIH, PBC, PSC are all associated with HLA genes on chromosome 6 Conflicting data, but probably reflect broad phenotypic themes with shared risk factors for autoimmunity and not the clinical manifestations of the primary disease Different autoantibody profiles? Is there a marker? AMA and anti ds DNA found in 47% of PBC/AIH overlaps compared to 2% of controls Tension between clinical practice and research needs Clinical: small number of categories, simple diagnostic criteriadiagnosis should be easy and reproducible Research: strict classification is needed, so dx is unquestionable Given current state of knowledge, criteria for OS are arbitrary Use of IAIHG scoring system is inappropriate Classifying most patients according to the dominant features seems appropriate; combo tx can still be used. Is Diagnosis of OS Important for Therapy? AIH immunosuppression PBC UDCA PSC treatment of strictures Treatment is based on retrospective reports and common practice (not evidence based) Recent EASL guidelines suggest combined therapy for PBC AIH OS Or, can try UDCA, add immunosuppression if inadequate response at 3 months A minority achieve complete response with UDCA alone, based on biochemistry and stable or decreased fibrosis Boberg et al. J Hepatology 2011;54:

18 Final Thoughts on Overlap Syndromes Drop use of overlap syndrome term Classify according to dominant pattern of autoimmune liver disease (e.g., AIH with features of PBC) But histologic features of some cases are in the middle. Maybe we should drop syndrome (implies distinct clinical entities). Classify autoimmune liver disease according to the dominant pattern Don t overinterpret Minor bile duct injury in AIH Interface hepatitis and plasma cells in PBC Remember Low titer AMA can be found in AIH PSC may present in children with a hepatitic pattern When possible, use published or standard criteria Paris criteria for AIH PBC overlap syndrome are a good starting point J Hepatology 2011;54:

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