Autoimmune Hepatitis. Stephan Kanzler II. Department of Medicine Leopoldina Hospital Schweinfurt, Germany

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1 Autoimmune Hepatitis Stephan Kanzler II. Department of Medicine Leopoldina Hospital Schweinfurt, Germany Falk Symposium 160, Portoroz

2 Autoimmune Liver Diseases AIH OVERLAP PBC/ PSC

3 Autoimmune Hepatitis Inactive hepatitis Chronic active hepatitis Acute hepatitis Fulminant hepatitis Intensity of immune response

4 Immunopathogenesis of AIH (Excessive autoimmune response in genetically predisposed subjects - reason??) HLA German type 1 AIH (n = 156) Italian type 1 AIH (n= 57) North American type I AIH (n=149) B8 64 (41%) 18 (32%) 73 (49%) DR3 70 (45%) 17(30%) 77 (52%) DR4 68 (44%) 13 (23%) 64 (43%) DR7 20 (13%) 9 (16%) 23 (15%) DR11 17 (11%) 10 (18%) 11 (7%) DR13 17 (11%) 15 (26%) 24 (16%) DQ2 42 (27%) 30 (53%) 84 (57%) B8-DR3- DQ2 28 (18%) 17 (30%) 70 (48%) Teufel et al. WJG 2006

5 Undulating spontaneous course of AIH AST Bilirubine Prednisolone Azathioprine

6 Significantly reduced life expectancy in patients with untreated AIH!! Royal Free Hospital Trial 1972

7 Epidemiology of AIH Prevalent in all countries and races Prevalence in europe: about 1 : % women Age of manifestation: 2-75 years, median 45

8 Age distribution of AIH-patients at initial diagnosis Absolute frequency Age in years

9 Autoimmune Hepatitis: clinical aspects Frequently slow onset, however: 25 % with acute (icteric) onset Fluctuating course Arthalgias and fatigue Further autoimmunopathies in personal or family history

10 Differential diagnosis Toxic liver damage Hepatitis B Hepatitis C Fatty liver disease Wilson disease Hämochromatosis... PSC PBC There is no single test prooving the diagnosis of AIH (exception SLA/LP?)!

11 Diagnosis of AIH: Scoring-System of the IAIHG Alvares et al. J Hepatol Female gender + 2 AP : AST-ratio < 1, ,5-3 0 > 3-2 IgG / γ-globuline elevation > , ,5 + 1 < 1 0

12 Diagnosis of AIH: Scoring-System of the IAIHG Alvares et al. J Hepatol ANA, SMA or LKM-1 > 1 : : : < 1 : 40 0 AMA > 1 : 40-4 Viral hepatitis (HBsAg, anti-hcv) positive - 3 negative + 3

13 Diagnosis of AIH: Scoring-System of the IAIHG Alvares et al. J Hepatol Use of medicaments Positive - 4 Negative + 1 Consumption of alcohol < 25 g / d + 2 > 60 g / d - 2 Other autoantibodies (SLA/LP, ANCA, LC1) + 2 HLA-DR3 or DR4 + 2 Other autoimmune diseases (patient/family) + 2

14 Diagnosis of AIH: Scoring-System of the IAIHG Alvares et al. J Hepatol Liver histology Interface hepatitis + 3 Lymphoplasmacellular infiltrates + 1 Rosetting of hepatocytes + 1 No of the above changes - 5 Bile duct pathologies - 3 Success of therapy Complete + 2 Relapse after withdrawal + 3

15 Diagnosis of AIH: Scoring-System of the IAIHG Alvares et al. J Hepatol Before treatment (immunosuppression): Definite AIH Probable AIH > 15 points points After treatment (immunosuppression): Definite AIH > 17 points Probable AIH points

16 Diagnose der AIH: vereinfachte Hauptkriterien Selektive IgG Erhöhung Autoantikörper (ANA, SMA, SLA/LP, LKM) Histologie einer chronischen Hepatitis Ausschluß Virushepatitis 3 von 4 Kriterien sollten erfüllt sein

17 Diagnosis of AIH: Simplified main criteria I IgG (γ-globuline) elevation 1 IgG > 18.5 g/l 2 ANA, SMA, LKM > 1:40 1 ANA, SMA, LKM > 1:80 2 Histology compatible with AIH 1 Histology typical for AIH 2 Exclusion of viral hepatitis 2 > 5 points = AIH probable Hennes et al. for the IAHG; AASLD 2005

18 Diagnosis of AIH: Simplified main criteria II Response to immunosuppressive therapy Relapse after discontinuation of immunosuppressive therapy Hennes et al. for the IAHG; AASLD 2005

19 Autoantibodies in AIH ANA: SMA: LKM: Anti-Nuclear Antibodies Smooth Muscle Antibodies Liver Kidney Microsomal Antibodies SLA/LP: Soluble Liver Antigen/Liver-Pancreas Other: (ANCA, ASGPR, LC1,...) - unspecific

20 Autoantibodies in patients with hepatitis (839 consecutive outpatients, I. Dept. of Medicine, Mainz) AIH Hepatitis B Hepatitis C ANA SMA ANA + SMA LKM SLA SLA + andere keine Lohse et al.; Z. Gastroenterol. 1995

21 ANA Anti-Nuclear Antibodies Found in 40-50% of all AIH-patients Against multiple antigens High titers (> 1:80) and / or combination with SMA diagnostically helpful Immunofluorescence is gold standard

22 Immunofluorescence: ANA

23 SMA Anti-Smooth Muscle Antibodies Found in about 40% of all AIH-patients Main antigen: F-actin High titers (> 1:80) or combination with ANA dignostically helpful Immunofluorescence is gold standard

24 LKM Liver-Kidney-Microsomal Antibodies Rare! (<< 5%) Mostly in childhood Target antigen: cytochrome p450 2D6 Immunofluorescence and ELISA Type II AIH; run a more severe course?

25 Immunohistology: LKM

26 SLA/LP Anti-Soluble Liver Antigen / Liver Pancreas LP antibodies first descibed in 1981 (Berg et al.) SLA antibodies first described in 1987 (Manns et al.) SLA and LP are the same antigen (Wies et al. 2000) About % of all AIH-patients Very high disease specificity (type III AIH)

27 Prevalence of SLA/LP autoantibodies in AIH USA n = 149 Brazil n = % 83% 15% 17% 81% 93% SLA/LP-positive SLA/LP-negative 7% 19% Germany n = 108 Japan n = 30 Baeres et al. Hepatology 2000; 32: 238 Kanzler et al. J Hepatol 1999; 31: 635

28 Staging (mini-)laparoscopy in patients with AIH Low complication rate / high diagnostic yield

29 About 30 % of all AIH-patients have liver cirrhosis at initial diagnosis!

30 Autoimmune Hepatitis = Chronic Disease

31 Aim of treatment Normalisation of transaminases + IgG Histologically no or minimal disease activity No significant side effects of therapy!

32 Therapy of AIH: Induction therapy Prednisolone Initially 1 mg / kg weekly reduction from 20 mg/d on reduction in 4-weekly interval Vit. D + calcium Azathioprine mg /kg

33 Response to immunosuppressive therapy (after 6 months, n = 103) Complete Remission 91.2 % Incomplete Remission 6.9% No Remission 1.9% Kanzler et al. Z Gastroenterol 2001.

34 AIH - Maintenance therapy 50 (-100) mg Azathioprine / d +/- 5 (-10) mg Prednisolone / d or mg Azathioprine / d Johnson et al.: NEJM 1995

35 Relapse under maintenance therapy (Mean observation period 95 months, n = 103) Remission 64.1% Relapse 35.9% Kanzler et al. Z Gastroenterol 2001.

36 Relapse after discontinuation of immunosuppressive therapy (n = 28) Stable Remissio n Relaps e Kanzler et al. Z Gastroenterol 2001.

37 Relapse of AIH after discontinuation of immunsuppressive therapy Probability of stable remission after discontinuation of immunosuppressive therapy (%) Duration of stable remission 2-4 years 1-2 years 17 % 10 % > 4 years 67 % n = 10 n = 12 n = 6 Kanzler et al. Z Gastroenterol 2001.

38 Alternative therapeutic options in AIH Mofetilmycofenolate (MMF) 1-2 g / d Hennes et al. submitted Cyclophosphamide 1-2 mg / kg / d Kanzler et al. Z Gastroenterol 1997 Budenoside?? (not in cirrhotics!) Wiegand et al. Liver International 2005 Large international multicenter-study recently closed CsA, FK 506 Anti-TNF therapy (??)

39 AIH and HepatoCellular Carcinoma (HCC) Follow-up of 278 patients with AIH in Mainz 89 Patienten (32%) with liver cirrhosis 431 observation years of AIH-associated liver cirrhosis: No patient developed HCC (despite of immunosuppression)! Since 1990 referal of three patients with AIH and HCC (exclusion of concomittant liver disease) Teufel et al. Submitted

40 Survival of AIH-patients under immunosuppressive therapy (103 patients, mean observation period 95 months) AIH-patients Survival rate [%] General population Years Kanzler et al.: Z Gastroenterol 2001; 39:

41 Overlap-Syndromes: Therapy AIH OVERLAP PBC/ PSC Activity of AIH determines the intensity of immunosuppressive therapy, since untreated AIH has the worst prognosis

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