sign in sign up
<<
Home , Autoimmune hepatitis, Hepatitis C, Viral hepatitis

Differentiating between autoimmune , primary biliary and

Dong Hyun Sinn, M.D., Ph.D.

Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea Contents

. Why is differentiation necessary?

. Why is differentiation difficult?

. How can we differentiate? AIH: pathogenesis

T-cell mediated immune attack

Un-resolving inflammation of the

Kriese et al., Frontline 2013;4:2 Manns et al., AASLD practice guideline 2010 Characteristics

. Circulating

. Elevated immunoglobulins

. Dramatic response to immune suppression

Jeong SH, KASL meeting 2011:S44 Autoantibodies

Manns et al., AASLD practice guideline 2010 Histology

Manns et al., AASLD practice guideline 2010 Diagnosis

Manns et al., AASLD practice guideline 2010 Characteristics of AIH in Korean

Mean age = 52.8 years (19-87) 88% female . Multicenter, 343 patients . Mostly type I AIH . Presentation . (30.6%) . Cirrhotic (22.7%) . Decompensation (4.3%)

Kim BH et al., J Gastroenterol Hepatol 2013;28:128 Characteristics of AIH in Korean

. Single-center, 86 patients . Mean age: 51 years (17 – 79 years) . Female: 83.7% . Presentation . Asymptomatic (37.2%) . (45.3%) . (16.3%)

Kil JS et al., J Korean Med Sci 2010;25:54 Characteristics of AIH in Korean

. Single-center, 62 patients . Mean age: 50 years (20 – 76) . Female: 90% . Presentation . Indistinguishable from (constitutional symptoms, , , and jaundice): 37% . (3%) . Cirrhosis (23%)

Lim YS et al., J Hepatol 2008;48:133 PBC: pathogenesis

Damage and loss of biliary epithelial cells lining small intrahepatic bile ducts

Chronic cholestatic

Jones Gut 2007;56:1615 Histology

Kaplan et al., N Engl J Med 2005;353:1261 Diagnosis

1. Biochemical evidence of 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 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 AIH-PBC overlap syndrome

AIH PBC

. AIH . PBC . ALT > 5 X UNL . AP > 2 X UNL or rGT > 5 X UNL . IgG > 2 X UNL, ASM (+) . AMA ≥ 1:40 . Compatible . Compatible liver biopsy

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 Contents

. Why is differentiation necessary?

. Why is differentiation difficult?

. How can we differentiate ? Why is differentiation necessary?

. Different treatment . AIH: steroid and/or . PBC: UDCA

. Treatment with potential side effects Treatment-related side effects from AIH

Manns et al., AASLD practice guideline 2010 Side effects can be fatal…

. F/58 . Known DM . Abnormal LFT . Bilirubin: 3.7, AST/ALT: 423/541 . Liver biopsy: interface hepatitis, periportal , moderate lobular and porto-poriportal activity . IgG = 2500 . ANA = 1:40, anti-SM = positive . Steroid + Azathioprine started . LFT improved (bilirubin: 2.5, AST/ALT: 44/151) . Discharged Side effects can be fatal

. 20 days after discharge . Presented to emergency room with , . CBC: 330 (seg = 0%) – 9.3 – 13k . Bilirubin = 1.3, AST/ALT: 22/45 . Septic shock (E.coli)

. Expired 8 days later due to multi-organ failure and septic shock.

What about high-dose UDCA?

Well-tolerated drug

Pares et al., Gastroenterology 2006;130:715 High-dose UDCA, potentially harmful?

. 28-30 mg/kg/day for PSC

Lindor et al., 2009;50:808 Why is differentiation necessary?

. Treatment with rare, but serious side effects.

. Risk-benefit assessment. Contents

. Why is differentiation necessary?

. Why is differentiation difficult?

. How can we differentiate ? Autoimmune liver disease

. Represent about 5% of all . Sub-category . (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 Shared features

PBC

8%

Autoimmune Cholangitis 10% PSC Autoimmune 6% hepatitis

11% 13%

Chronic Cryptogenic

Czaja et al., Ann Intern Med 1996;125:588 Overlap (?) with viral hepatitis

. 61/F . 8 years ago, chronic hepatitis C diagnosed . . Lab . Genotype 2a/2c . RNA: 30,780 copies/ml . Peg- + for 24 weeks

Course

IgG = 3441 mg/dl FANA = 1:320 Anti-SM = positive AMA = negative Bx = Active cirrhosis, etiology undetermined, marked activity Peg-IFN + RBV 500 Steroid + AZA

400

300 AST 200 ALT

100

0 Pre_Tx ETR SVR 1m 4 years Variant forms of AIH

Syndrome Distinguishing features Overlap syndromes Mitochondiral Histologic cholangitis AIH & PBC Cholestatic laboratory changes Responsiveness to therapy Ulcerative Histologic cholangitis AIH & PSC Cholestatic laboratory changes Abnormal cholangiogram High titer (AIH) Interface hepatitis, plasma cells (AIH) AIH & viral hepatitis Low autoantibody titer (viral) Portal lymphoid aggregates, , injury (viral)

Outlier syndrome AMA negative ANA, anti-SM positive Autoimmune cholangitis Histologic features of bile duct injury Cholestatic laboratory changes Normal cholangiogram Absence of autoantibodies Cryptogenic chronic hepatitis Histologic findings identical to AIH Responsiveness to cortocosteroid therapy Czaja et al., Ann Intern Med 1996;125:588 Consecutive PBC/AIH AMA-negative PBC/AMA-positive AIH Why is differentiation difficult?

. Diagnosis of exclusion . Highly sensitive and specific test do not exist. . Shared features . Changing features

Scoring system for AIH

Manns et al., AASLD practice guideline 2010 Suk KT et al, Am J Gastroenterol 2012 Forms of etiology

Suk KT et al, Am J Gastroenterol 2012 Drug-induced hepatitis vs. AIH

Ju HY et al., Clin Mol Hepatol 2012;18:213 More concerns

Nguyen et al., Hepatology 2008;47:1058 Scoring system for AIH

Manns et al., AASLD practice guideline 2010 Differences in genetic susceptability

Lim YS et al., J Hepatol 2008;48:133 Difference in autoantibodies

107 patients, Caucasian . 343, multicenter study1 . ANA: 94% ANA . SMA: 23% (13%) . Anti-LKM: 3%

SMA . AMA: 11% (33%) . 86, single center study2 Both . ANA: 81% (54%) . SMA: 44% . AMA: 3%

1Kim BH et al., J Gastroenterol Hepatol 2013;28:128 Czaja., J Hepatology 1999;30:394 2Kil JS et al., J Korean Med Sci 2010;25:54 Simplified score

Hennes et al, Hepatology 2008;48:169 Initially recruited AIH patients from 21 Simplified criteria Total university hospital (n = 480) < 6 6 ≥ 7

< 10 - 21 13 34 (10%) Original 10-15 90 81 (24%) 53 (15%) 224 criteria >15 3 30 (9%) 52 (15%) 85

IAHG or simplified Total 93 (27%) 132 118 343 criteria (n = 343, 71.4%)

J Gastroenterol Hepatol 2013;28:128 Scoring system for AIH

Manns et al., AASLD practice guideline 2010 Why if treatment response is incomplete?

Kil JS et al., J Korean Med Sci 2010;25:54 Why is differentiation difficult?

. Diagnosis of exclusion . Gold standard does not exist . Few Korean data . Clinical features can be shared or even may change

http://www.desicomments.com/babies/the-more-i-think-the-more-confused-i-get/ Contents

. Why is differentiation necessary?

. Why is differentiation difficult?

. How can we differentiate ? 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. Tools that can be used

. History . Chronicity . Drug, use . Pattern of abnormal . Hepatocellular pattern? . Cholestatic pattern? . Autoantibiodies, immunoglobulins . FANA, ASM, AMA, ANCA, IgG . Liver biopsy How?

Disease presentation

Symptomatic Asymptomatic (Failure)

Manns et al., AASLD practice guideline 2010 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.

How?

Disease presentation

Symptomatic (Failure) . AI-ALF . Diagnostic criteria? . Histologic features . Type 4,5 massive hepatic . Lymphoid aggregates . Central perivenulitis . enrichment

Stravitz et al., Hepatology 2011;53:517 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!