1 Differentiating between autoimmune hepatitis, primary biliary cirrhosis and overlap syndrome Dong Hyun Sinn, M.D., Ph.D. Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea
2 Contents Why is differentiation necessary? Why is differentiation difficult? How can we differentiate?
3 AIH: pathogenesis T-cell mediated immune attack Un-resolving inflammation of the liver Kriese et al., Frontline Gastroenterology 2013;4:2 Manns et al., AASLD practice guideline 2010
5 Autoantibodies Manns et al., AASLD practice guideline 2010
6 Histology Manns et al., AASLD practice guideline 2010
7 Diagnosis Manns et al., AASLD practice guideline 2010
8 Characteristics of AIH in Korean Mean age = 52.8 years (19-87) 88% female Multicenter, 343 patients Mostly type I AIH Presentation Asymptomatic (30.6%) Cirrhotic (22.7%) Decompensation (4.3%) Kim BH et al., J Gastroenterol Hepatol 2013;28:128
9 Characteristics of AIH in Korean Single-center, 86 patients Mean age: 51 years (17 79 years) Female: 83.7% Presentation Asymptomatic (37.2%) Jaundice (45.3%) Fatigue (16.3%) Kil JS et al., J Korean Med Sci 2010;25:54
10 Characteristics of AIH in Korean Single-center, 62 patients Mean age: 50 years (20 76) Female: 90% Presentation Indistinguishable from acute viral hepatitis (constitutional symptoms, anorexia, nausea, and jaundice): 37% Liver failure (3%) Cirrhosis (23%) Lim YS et al., J Hepatol 2008;48:133
11 PBC: pathogenesis Damage and loss of biliary epithelial cells lining small intrahepatic bile ducts Chronic cholestatic liver disease Jones Gut 2007;56:1615
12 Histology Kaplan et al., N Engl J Med 2005;353:1261
13 Diagnosis 1. Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation. 2. Presence of AMA 3. Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts When two of the three criteria are met, the diagnosis of PBC can be established Lindor et al., AASLD Practice guideline, 2010
14 Characteristics of PBC in Korea Multicenter, 251 patients Age = 55 Female = 87% Presentation Asymptomatic = 61% Systemic symptoms = 27% Decompensation = 12% AMA positive = 98% Jung HE et al., Clin Mol Hepatol 2012;18:375
15 AIH-PBC overlap syndrome AIH PBC AIH ALT > 5 X UNL IgG > 2 X UNL, ASM (+) Compatible liver biopsy PBC AP > 2 X UNL or rgt > 5 X UNL AMA 1:40 Compatible liver biopsy
16 Characteristics of PBC in Korea Single center, 24 patients Age = 50 years Female = 95.8% Presentation Asymptomatic = 56% Pruritus = 29% Jaundice = 25% AIH overlap syndrome = 5/24 (20.8%) Jung HE et al., Clin Mol Hepatol 2012;18:375
17 Contents Why is differentiation necessary? Why is differentiation difficult? How can we differentiate?
18 Why is differentiation necessary? Different treatment AIH: steroid and/or azathioprine PBC: UDCA Treatment with potential side effects
19 Treatment-related side effects from AIH Manns et al., AASLD practice guideline 2010
20 Side effects can be fatal F/58 Known DM Abnormal LFT Bilirubin: 3.7, AST/ALT: 423/541 Liver biopsy: interface hepatitis, periportal fibrosis, moderate lobular and porto-poriportal activity Serum IgG = 2500 ANA = 1:40, anti-sm = positive Steroid + Azathioprine started LFT improved (bilirubin: 2.5, AST/ALT: 44/151) Discharged
21 Side effects can be fatal 20 days after discharge Presented to emergency room with fever, diarrhea CBC: 330 (seg = 0%) k Bilirubin = 1.3, AST/ALT: 22/45 Septic shock (E.coli) Expired 8 days later due to multi-organ failure and septic shock.
22 What about high-dose UDCA? Well-tolerated drug Pares et al., Gastroenterology 2006;130:715
23 High-dose UDCA, potentially harmful? mg/kg/day for PSC Lindor et al., Hepatology 2009;50:808
24 Why is differentiation necessary? Treatment with rare, but serious side effects. Risk-benefit assessment.
25 Contents Why is differentiation necessary? Why is differentiation difficult? How can we differentiate?
26 Autoimmune liver disease Represent about 5% of all chronic liver disease Sub-category Autoimmune hepatitis (AIH) Primary biliary cirrhosis (PBC) Primary sclerosing cholangitis (PSC) IgG4-associated cholangitis Etc Pathogenesis: unknown Diagnosis Based on reasonable exclusion + compatible findings No single test (eg., pathology) confirms the diagnosis Jeong SH, KASL meeting 2011:S44
27 Shared features PBC 8% Autoimmune Cholangitis 10% Autoimmune hepatitis 6% PSC 11% Chronic Hepatitis C 13% Cryptogenic Czaja et al., Ann Intern Med 1996;125:588
28 Overlap (?) with viral hepatitis 61/F 8 years ago, chronic hepatitis C diagnosed Rheumatoid arthritis Lab Genotype 2a/2c RNA: 30,780 copies/ml Peg-interferon + Ribavirin for 24 weeks
29 Course Peg-IFN + RBV IgG = 3441 mg/dl FANA = 1:320 Anti-SM = positive AMA = negative Bx = Active cirrhosis, etiology undetermined, marked activity Steroid + AZA AST ALT Pre_Tx ETR SVR 1m 4 years
30 Variant forms of AIH Syndrome Overlap syndromes AIH & PBC AIH & PSC AIH & viral hepatitis Distinguishing features Mitochondiral antibodies Histologic cholangitis Cholestatic laboratory changes Responsiveness to corticosteroid therapy Ulcerative colitis Histologic cholangitis Cholestatic laboratory changes Abnormal cholangiogram High autoantibody titer (AIH) Interface hepatitis, plasma cells (AIH) Low autoantibody titer (viral) Portal lymphoid aggregates, steatosis, bile duct injury (viral) Outlier syndrome Autoimmune cholangitis Cryptogenic chronic hepatitis AMA negative ANA, anti-sm positive Histologic features of bile duct injury Cholestatic laboratory changes Normal cholangiogram Absence of autoantibodies Histologic findings identical to AIH Responsiveness to cortocosteroid therapy Czaja et al., Ann Intern Med 1996;125:588
31 Consecutive PBC/AIH
32 AMA-negative PBC/AMA-positive AIH
33 Why is differentiation difficult? Diagnosis of exclusion Highly sensitive and specific test do not exist. Shared features Changing features
34 Scoring system for AIH Manns et al., AASLD practice guideline 2010
35 Suk KT et al, Am J Gastroenterol 2012
36 Forms of etiology Suk KT et al, Am J Gastroenterol 2012
37 Drug-induced hepatitis vs. AIH Ju HY et al., Clin Mol Hepatol 2012;18:213
38 More concerns Nguyen et al., Hepatology 2008;47:1058
39 Scoring system for AIH Manns et al., AASLD practice guideline 2010
40 Differences in genetic susceptability Lim YS et al., J Hepatol 2008;48:133
41 Difference in autoantibodies 107 patients, Caucasian ANA (13%) Both (54%) SMA (33%) 343, multicenter study 1 ANA: 94% SMA: 23% Anti-LKM: 3% AMA: 11% 86, single center study 2 ANA: 81% SMA: 44% AMA: 3% 1 Kim BH et al., J Gastroenterol Hepatol 2013;28:128 Czaja., J Hepatology 1999;30:394 2 Kil JS et al., J Korean Med Sci 2010;25:54
42 Simplified score Hennes et al, Hepatology 2008;48:169
43 Initially recruited AIH patients from 21 university hospital (n = 480) Simplified criteria < Total Original criteria < (10%) (24%) 53 (15%) 224 > (9%) 52 (15%) 85 IAHG or simplified criteria (n = 343, 71.4%) Total 93 (27%) J Gastroenterol Hepatol 2013;28:128
44 Scoring system for AIH Manns et al., AASLD practice guideline 2010
45 Why if treatment response is incomplete? Kil JS et al., J Korean Med Sci 2010;25:54
46 Why is differentiation difficult? Diagnosis of exclusion Gold standard does not exist Few Korean data Clinical features can be shared or even may change
47 Contents Why is differentiation necessary? Why is differentiation difficult? How can we differentiate?
48 How can we differentiate? In any unexplained suspected liver disease (asymptomatic ~ liver failure), always think about the possibility of autoimmune liver disease. Use detailed history, serologic markers, laboratory patterns, histology and changes after time course, to differentiate the autoimmune liver disease.
49 Tools that can be used History Chronicity Drug, alcohol use Pattern of abnormal liver function tests Hepatocellular pattern? Cholestatic pattern? Autoantibiodies, immunoglobulins FANA, ASM, AMA, ANCA, IgG Liver biopsy
50 How? Disease presentation Asymptomatic Symptomatic (Failure) Manns et al., AASLD practice guideline 2010
51 Toxic vs. Autoimmune Disease presentation Asymptomatic Sometimes time tells the truth! Discontinuation of all drugs. Early withdrawal of immunosuppresive agents and watchful waiting for relapse.
52 How? Disease presentation AI-ALF Diagnostic criteria? Histologic features Symptomatic (Failure) Type 4,5 massive hepatic necrosis Lymphoid aggregates Central perivenulitis Plasma cell enrichment Stravitz et al., Hepatology 2011;53:517
53 Take home message Differentiating between autoimmune hepatitis, primary biliary cirrhosis and overlap syndrome Tools are used to differentiate History, lab pattern, autoantibodies, biopsy Clinical course Clinical suspicions is most important step in the differentiation!
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