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Dalekos et al, unpublished prospective data 2010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 ???
AIH: Clinical example 1
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
AIH: Clinical example 1
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
AIH: Clinical example 1
• 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
AIH: Clinical example 1
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)
AIH: Clinical example 2
Which is the most
appropriate
management next ??
AIH: Clinical example 2
1. Liver autoimmune serology (autoantibodies)
2. Liver biopsy if autoantibodies tested positive
3. Liver biopsy irrespective of the presence of Abs
AIH: Clinical example 2
1. Liver autoimmune serology (autoantibodies)
2. Liver biopsy if autoantibodies tested positive
3. Liver biopsy irrespective of the presence of Abs
AIH: Clinical example 2
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
AIH: Clinical example 3
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
AIH: Clinical example 5
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