Differentiating between autoimmune hepatitis, PBC and ... Hepatology Update 1/3... ·...

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!