differentiating between autoimmune hepatitis, pbc and overlap...
TRANSCRIPT
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
Contents
Why is differentiation necessary?
Why is differentiation difficult?
How can we differentiate?
AIH: pathogenesis
Un-resolving
inflammation of
the liver
Manns et al., AASLD practice guideline 2010 Kriese et al., Frontline Gastroenterology 2013;4:2
T-cell mediated
immune attack
Characteristics
Circulating autoantibodies
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
Asymptomatic (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%)
Jaundice (45.3%)
Fatigue (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 acute viral hepatitis (constitutional
symptoms, anorexia, nausea, and jaundice): 37%
Liver failure (3%)
Cirrhosis (23%)
Lim YS et al., J Hepatol 2008;48:133
PBC: pathogenesis
Jones Gut 2007;56:1615
Chronic
cholestatic liver
disease
Damage and loss of
biliary epithelial cells
lining small intrahepatic
bile ducts
Histology
Kaplan et al., N Engl J Med 2005;353:1261
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
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
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
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 azathioprine
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 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
Side effects can be fatal
20 days after discharge
Presented to emergency room with fever, diarrhea
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?
Pares et al., Gastroenterology 2006;130:715
Well-tolerated drug
High-dose UDCA, potentially harmful?
28-30 mg/kg/day for PSC
Lindor et al., Hepatology 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 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
Shared features
PBC
PSC
Cryptogenic Chronic
Hepatitis C
Autoimmune
Cholangitis
Autoimmune
hepatitis
10%
8%
13%
6%
11%
Czaja et al., Ann Intern Med 1996;125:588
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
Course
0
100
200
300
400
500
Pre_Tx ETR SVR 1m 4 years
AST
ALT
Peg-IFN + RBV
IgG = 3441 mg/dl FANA = 1:320 Anti-SM = positive AMA = negative Bx = Active cirrhosis, etiology undetermined, marked activity
Steroid + AZA
Variant forms of AIH
Syndrome Distinguishing features
Overlap syndromes
AIH & PBC
Mitochondiral antibodies Histologic cholangitis Cholestatic laboratory changes Responsiveness to corticosteroid therapy
AIH & PSC
Ulcerative colitis Histologic cholangitis Cholestatic laboratory changes Abnormal cholangiogram
AIH & viral hepatitis
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
AMA negative ANA, anti-SM positive Histologic features of bile duct injury Cholestatic laboratory changes Normal cholangiogram
Cryptogenic chronic hepatitis Absence of autoantibodies 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
SMA (33%)
ANA (13%)
Both (54%)
Czaja., J Hepatology 1999;30:394
107 patients, Caucasian 343, multicenter study1
ANA: 94%
SMA: 23%
Anti-LKM: 3%
AMA: 11%
86, single center study2
ANA: 81%
SMA: 44%
AMA: 3%
1Kim BH et al., J Gastroenterol Hepatol 2013;28:128
2Kil JS et al., J Korean Med Sci 2010;25:54
Simplified score
Hennes et al, Hepatology 2008;48:169
J Gastroenterol Hepatol 2013;28:128
Initially recruited AIH patients from 21
university hospital (n = 480)
IAHG or simplified criteria
(n = 343, 71.4%)
Simplified criteria Total
< 6 6 ≥ 7
Original criteria
< 10 - 21 13 34 (10%)
10-15 90 81 (24%) 53 (15%) 224
>15 3 30 (9%) 52 (15%) 85
Total 93 (27%) 132 118 343
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, alcohol use
Pattern of abnormal liver function tests
Hepatocellular pattern?
Cholestatic pattern?
Autoantibiodies, immunoglobulins
FANA, ASM, AMA, ANCA, IgG
Liver biopsy
How?
Disease presentation
Asymptomatic Symptomatic
(Failure)
Manns et al., AASLD practice guideline 2010
Toxic vs. Autoimmune
Sometimes time tells the truth!
Discontinuation of all drugs.
Early withdrawal of immunosuppresive agents and
watchful waiting for relapse.
Disease presentation
Asymptomatic
How?
Disease presentation
Symptomatic (Failure)
AI-ALF
Diagnostic criteria?
Histologic features
Type 4,5 massive hepatic necrosis
Lymphoid aggregates
Central perivenulitis
Plasma cell 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!