“Management of Autoimmune Hepatitis”

Early Morning Workshop, April 1, 2011

“Management of Autoimmune Hepatitis”

The International Liver CongressTM 2011

46th Annual Meeting of EASL, March 30- April 3, 2011, Berlin

George N. Dalekos, MD, PhD

Professor of Medicine

Head, Department of Medicine

and Research Laboratory of

Internal Medicine, Medical

School, University of Thessaly

Larissa, Greece

Prof. Dr. Christoph Schramm

I. Medizinische Klinik und

Poliklinik, Universitatsklinikum

Hamburg-Eppendorf,

Hamburg

Germany

Early Morning Workshop, April 1, 2011

“Management of Autoimmune Hepatitis”

The International Liver CongressTM 2011

46th Annual Meeting of EASL, March 30- April 3, 2011, Berlin

DISCLOSURE SLIDE

“Nothing to disclose”

George N. Dalekos

Professor of Medicine

AUTOIMMUNE HEPATITIS (AIH)

Definition

A chronic (or acute) hepatitis of unknown cause

Progressive Usual Increased

destruction progression mortality

of the liver to cirrhosis (if untreated)

Krawitt E N Engl J Med 2006, Zachou et al J

Autoimm Dis 04, Dalekos et al Eur J Gastro

Hepatol 02, Eur J Intern Med 02, J Hepatol 98

Manns MP et al Hepatology 2010, Czaja et al

Gastroenterology 2010

Autoimmune hepatitis is a rare disease

in young women

EPIDEMIOLOGY OF AIH

32

21

31

23

18

14

7

0

5

10

15

20

25

30

35

0-19 20-29 30-39 40-49 50-59 60-69 > 70

Number ofpatients

Epidemiology of AIH: Age distribution at presentation

Dalekos et al, unpublished prospective data 2010

20-25% males

• Occurs in all countries and races

• Affects all age groups

• Prevalence: 17-20/ 105 population (N. Europe/ USA)

• Up to 200.000 cases of AIH in USA (10-23% of CAH)

• 43/ 105 population in Alaska Natives !!

• Female predominance (F/M: 4-6/1)

• Different HLA-associations

EPIDEMIOLOGY OF AIH

Boberg KM Clin Liver Dis 02; Hurlburt et al AJG 02; Muratori et al Mol

Asp Med 08; Gupta et al JGH 01; Choudhuri et al BMC Gastro 05;

Werner et al Scan J Gastro 08; Koay et al Dig Dis Sci 06

AIH: Clinical Characteristics

There is no characteristic clinical sign or symptom

• Most cases (60%) have an insidious onset with one

or more of non-specific symptoms and fluctuating

course like arthralgias, fatigue, acne, weight loss,

malaise, anorexia or low-grade fever

• Acute hepatitis (20-30%) or FHF (rarely)

• Asymptomatic disease (10-20% ??)

Laboratory Abnormalities in ΑIΗ

There are no diagnostic abnormalities

AST/ALT (0.5 - 50x UNL)

Bilirubin (0.5 - 50x UNL)

γ-globulins (IgG; 1.1 – 5.0x UNL)*

ALP normal or moderate increase

* Unfortunately their determination is usually forgotten; Normal

values can be found in acute cases or in the elderly

AIH: Clinical example 1

• Female 49y was referred with a diagnosis of NAFLD/NASH

• ΑST: 67-180 U/L & ALT: 53-359 U/L at least for 1y (check-up)

• BMI: 32.2, CHOL +TRIG: normal, Diabetes mellitus (-)

• No alcohol, no drugs, no symptoms; HΑV, HBV, HCV: (-)

• U/S: NAFLD

How will you

manage the

patient ???


1. Testing by fibroscan only and follow-up

2. Dietary and exercise modifications

3. Serum IgG determination

4. Liver autoimmune serology (autoantibodies)

5. Immediate liver biopsy

6. Liver biopsy if IgG or autoantibodies are indicative


• Autoimmune serology

C4: 18.7; ΑΝΑ 1/320 diffuse +

fine speckled; HEp2 blot: anti-

Ro (52 kDa) SMA 1/160 VGT (F-

actin); anti-SLA/LP (ELISA +

liver blot +)

• Liver biopsy

Typical findings of AIH

• Hypergammaglobulinemia

IgG: 2040 mg/dl

Decade 2000: NAFLD/NASH

Why these subjects

have by definition

NAFLD/ NASH only?

Is there any “medical

low” which excludes

concurrent AIH or

even AIH only?

AIH Classification and Autoantibodies Dalekos et al, Eur J Intern Med 02

Krawitt E, N Engl J Med 06; Bogdanos and Dalekos Curr Med Chem 08

Zachou et al, J Autoimm Dis 04, Czaja et al Gastroenterology 2010

AIH-1

• ANA

• SMA

• ANCA

• anti - ASGP-R

• anti - SLA/LP

AIH-2

• anti - LKM-1

• anti - LKM-3

• anti - LC1

• anti - ASGP-R

ΑIΗ in APS-1: anti – LM (anti-CYP1A2)

Autoimmune Hepatitis:

Although certain changes are characteristic,

none of the findings is specific for AIH diagnosis !!!!

Role of Liver Biopsy

Acute Typical?? Typical?? Cirrhosis

DESCRIPTIVE CRITERIA

FOR ΑIΗ DIAGNOSIS

• Increased LFTs (predominance of AST/ALT)

• Hypergammaglobulinemia (in particular IgG)*

• Positive autoantibody serology*

• Histologic lesions of chronic/acute hepatitis

• Absence of viral hepatitis markers

• Exclusion of other causes of acute or chronic

hepatitis

IAIHG Report, J Hepatol 1999 *Usually these issues are largely underestimated

• AIH should be considered seriously in all ca-

ses of undefined acute or chronic liver disea-

se independently of the age, the gender, Abs

titers, the presence or absence of symptoms

and under some circumstances even when

other liver disease has been established

Simplified Criteria for AIH Diagnosis

Take home message

Be careful !! The coincidence of ΑIΗ with ANY kind of liver

diseases CANNOT be excluded Papamichalis et al J Autoimmune Dis 07

Gatselis et al Dig Liver Dis 2010

Can you recognize

autoimmune hepatitis?

Edward L. Krawitt, Postgrad Med 1998; NEJM 2006

Be careful: Underdiagnosis of AIH is mainly due to unfamiliar

labs, clinicians and pathologists !!!!!!!!!!!!!!!!!!

• Female 67ys referred with a diagnosis of SLE based on

high ANA titer and anti-dsDNA (ELISA) and a past

history of acute anicteric hepatitis 4 months ago........

• LFTs were normal (under Medrol 8 mg/d)

HOWEVER......

IgG levels were still elevated (2.5x UNL)


Which is the most

appropriate

management next ??


1. Liver autoimmune serology (autoantibodies)

2. Liver biopsy if autoantibodies tested positive

3. Liver biopsy irrespective of the presence of Abs


Autoimmune serology: ANA 1:2560; SMA 1:640 (VGT);

F-actin Abs high pos; DR3+ and DR13+

AIH: Clinical example 2; Note the presence of emperipolesis (one arrow) and of peripolesis (two arrows)

• Female 17ys; Mild general symptoms 3-4 mo

• AST/ALT: 48/52 U/L twice (UNL=40)

• Physical examination: Normal; Viral serology (-)

• No drugs; no alcohol abuse

• a1-antithrypsin, ceruloplasmin, ferritin: normal

• IgG levels x1.5 UNL


Clinical example 3: No association of biochemical with histologic activity; a portal area

with remarkable inflammation and ongoing interface necroinflammatory activity

Autoimmune serology: anti-SLA/LP high positive; all other Abs

tested negative

Clinical example 3: No association of biochemical with histologic activity; Note the

interface activity and also the prominent plasma cells

ΑIΗ: Clinical example 4

A 67 years old male with acute

relapsing hepatitis

γ-globulins: 5 g/dL; ANA:

1/160; viral hepatitis: (-)

Biopsy: periportal severe

necroinflammatory activity

by lymphocytes, plasma

cells and eosinophils Immunosupression

in our department

• ANA: 1/320

• SMA: 1/1280 VGT pattern

• F-actin: high pos

• p-ANCA/ANNA: 1/320

• HLA-typing: A1-B8-DR3

• IgG: 2100 mg/dL

• Anti-TPO Abs: very high

• Simplified score: 7 (defini-

te AIH)

Off prednisolone

• AST/ALT levels = 5-10X UNL>3 ys

• Polish nationality; always

negative HBV/HCV profile

• Asymptomatic BUT high INR,

splenomegaly, low PLT, varices,

spiders & menstrual cycle

disorders (amenorrhea)

• She had participated by the gyne-

cologists in two programs of

assisted reproduction !!!!!!!!!!!!!

• High IgG; high SMA titers; anti-

SLA/LP & Ro-52 pos

• Diagnosis: AIH-1-related cirrhosis

• Immunosuppression: CR for 11

years; 2 successful pregnancies


“Management of Autoimmune Hepatitis”

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