Καθηγητής Γεώργιος N. Νταλέκος Δ/ντής Παθολογικής Κλινικής και Ερευνητικού Εργαστηρίου Παθολογικής Κλινικής Π.Θ. Ιατρική Σχολή Πανεπιστήμιο Θεσσαλίας

Transcript

1 Αυτοάνοση ηπατίτιδα: διάγνωση και θεραπεία το 2010 Γαστρεντερολογική Διημερίδα Ηπατο-Γαστρεντερολογικής Μονάδας Α Παθολογικής Κλινικής Πανεπιστημίου Ιωαννίνων 8 & 9 Απριλίου 2011, Μέτσοβο Καθηγητής Γεώργιος N. Νταλέκος Δ/ντής Παθολογικής Κλινικής και Ερευνητικού Εργαστηρίου Παθολογικής Κλινικής Π.Θ. Ιατρική Σχολή Πανεπιστήμιο Θεσσαλίας

2 Κορίτσι 16 ετών με οξεία ικτερική ηπατίτιδα AST ALT ΙΟΛΟΓΙΚΟΣ & U/S: (-) Φάρμακα, οινόπνευμα: ΟΧΙ Υπερσφαιριναιμία: ΝΑΙ ΑΝΟΣΟΛΟΓΙΚΟΣ: αρνητικός?? Βιοψία ήπατος Νοε-08 Δεκ-08 Ιαν-09 Φεβ-09 Βιοψία ήπατος: αλλοιώσεις χρόνιας ηπατίτιδας με μέτρια φλεγμονώδη διήθηση από λεμφοκύτταρα, ηωσινόφιλα και λίγα πλασματοκύτταρα Αιτιολογία AST/ALT????

3 Κορίτσι 16 ετών: Νέο επεισόδιο ικτερικής ηπατίτιδας μετά από 20 μήνες!!! Ανοσολογικός έλεγχος Π.Θ ΑΝΟΣΟΚΑΤΑΣΤΟΛΗ AST ALT /7/ /7/ /7/2010 5/8/ /8/ /8/2010

4 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

5 EPIDEMIOLOGY OF AIH Autoimmune hepatitis is a rare disease in young women

6 Epidemiology of AIH: Age distribution at presentation Dalekos et al, unpublished prospective data Number of patients 20-25% males > 70 21

7 EPIDEMIOLOGY OF AIH Occurs in all countries and races Affects all age groups Prevalence: 17-20/ 10 5 population (N. Europe/ USA) Up to cases of AIH in USA (10-23% of CAH) 43/ 10 5 population in Alaska Natives!! Female predominance (F/M: 4-6/1) Different HLA-associations 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

8 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%??)

9 Laboratory Abnormalities in ΑIΗ There are no diagnostic abnormalities AST/ALT (0.5-50x UNL) Bilirubin (0.5-50x UNL) γ-globulins (IgG; x UNL)* ALP normal or moderate increase * Unfortunately their determination is usually forgotten; Normal values can be found in acute cases or in the elderly

10 AIH: Take home message (I) Zachou et al, J Autoimm Dis 04; Krawitt EL, N Engl J Med 06; Bogdanos & Dalekos, Cur Med Chem 08; Werner et al Scan J Gastr 08 AIH seems not to be so rare as previously believed There is no specific age of onset (most > 50 years) Both sexes can be affected although there is a clear predominance of females Clinical presentation is largely heterogeneous ranging from no symptoms to decompensated cirrhosis or even FHF Clinical course is characterized by fluctuating periods of decreased or increased activity

11 AIH: Take home message (II) Zachou et al, J Autoimm Dis 04; Krawitt EL, N Engl J Med 06; Bogdanos & Dalekos, Cur Med Chem 08; Werner et al Scan J Gastr 08 There is no characteristic laboratory abnormality Do not consider AIH only in patients with very high AST/ALT AST/ALT levels may fluctuate; thus consider previous values Icteric form is found in only 1/3 of AIH cases; do not consider AIH diagnosis only in patients with high bilirubin Do not forget the determination of γ-globulins and/or IgG The latter is the most missing laboratory evaluation!!!!

12 PROBLEMS IN THE DIAGNOSIS OF AIH Is AIH a rare disease? IAIHG does not believe that AIH is a rare disease - anti-sla Abs were detected in 1/3 of ALF cases of cryptogenic origin!! Bernal et al J Hepatol % of biopsies of ALF-explants of Lee W, AASLD 11/09 cryptogenic origin had indications of ΑIΗ!! Underdiagnosis, wrong and delay diagnosis are due to unfamiliar labs, clinicians & pathologists

13 AIH: Clinical example 2 Female 49y was referred with a diagnosis of NAFLD/NASH ΑST: U/L & ALT: 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???

14 AIH: Clinical example 2 1. Periodic testing by fibroscan only 2. Dietary and exercise modifications and follow-up 3. Serum IgG determination 4. Liver autoimmune serology (autoantibodies) 5. Immediate liver biopsy 6. Liver biopsy if IgG or autoantibodies are indicative

15 AIH: Clinical example 2 1. Periodic testing by fibroscan only 2. Dietary and exercise modifications and follow-up Serum IgG determination 3. Liver autoimmune serology (autoantibodies) 4. Immediate liver biopsy 5. Liver biopsy if IgG or autoantibodies are indicative

16 AIH: Clinical example 2 Hypergammaglobulinemia IgG: 2040 mg/dl Autoimmune serology C4: 18.7; ΑΝΑ 1/320 diffuse + fine speckled; HEp2 blot: anti- Ro (52 kda) SMA 1/160 VGT (Factin); anti-sla/lp (ELISA + liver blot +) Liver biopsy Typical findings of AIH

17 AIH: Clinical example 2

18 Decade 2000: NAFLD/NASH Why these subjects have by definition NAFLD/ NASH only? Is there any medical law which excludes concurrent AIH or even AIH only?

19 ΑIΗ: Clinical example 3 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 Off prednisolone 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 = definite AIH

20 AH: Κλινικό παράδειγμα 4 Γυναίκα 50 ετών check up Διακοπή κορτικοστεροειδών Θεράπων ιατρός καμία ενέργεια Αιτιολογία AST/ALT???? ΕΚΤΙΜΗΣΗ ΜΕΤΑ 10 ΜΗΝΕΣ!! ANA: 1/320 fine sp. SMA: 1/160 f-actin Anti-SLA/LP pos Anti-Ro52 pos Βιοψία ήπατος ευτυχώς ΟΧΙ κίρρωση ΑΛΛΑ αναγεννητικό παρέγχυμα

21 AH: Κλινικό παράδειγμα 4 Γυναίκα 50 ετών check up Βιοψία ήπατος ευτυχώς ΟΧΙ κίρρωση. ΑΛΛΑ periportal collapse με συνεχιζόμενη interface hepatitis με αναγεννητικό παρέγχυμα και rosetting

22 AH: Κλινικό παράδειγμα 5 Άνδρας 58 ys με τρανσαμινασαιμία (2-10x) υπερσφαιριναιμία από το 2002!!! Hx ΣΔ ΙΙ (91), κοιλιοκάκης (05) 3 (ΤΡΕΙΣ) βιοψίες ήπατος!!!! (2004, 2005 και 2007!!!!!) Ευτυχώς ΟΧΙ κίρρωση ΑΛΛΑ ήπια προς μέτρια ίνωση και νεκροφλεγμονώδη δραστηριότητα. ΑΠΟΥΣΙΑ ΣΤΕΑΤΩΣΗΣ!! Θεράποντες ιατροί καμία επικοινωνία και καμία ενέργεια!! Δίαιτα ελεύθερης γλουτένης Αιτιολογία AST/ALT & αύξησης των γ-σφαιρινών???? ΑΝΟΣΟΛΟΓΙΚΟΙ ΕΛΕΓΧΟΙ σε νοσοκομεία και ιδιωτικά κέντρα Αθηνών: NEG ΕΚΤΙΜΗΣΗ στο Τμήμα μας 9/08 ANA: 1/160 fine sp. In-house SMA: 1/320 f-actin panca/anna: 1/80 F-actin ELISA: high positive Anti-h-tTG/DGP screen: high pos Anti-h-tTG IgA: high positive Anti-gliadin deamidated: low pos ΤΕΛΙΚΗ ΔΙΑΓΝΩΣΗ: έξαρση παραμελημένης ΑΗ-1. Ύφεση CD

23 AH: Κλινικό παράδειγμα 6 Άνδρας 28 ετών με ιστορικό κιρσορραγιών, υπερσφαιριναιμία, υπερσπληνικές εκδηλώσεις, τρανσαμινασαιμία (3-5x) και χολόσταση από το 1998!!! Αντιμετώπιση κιρσών (banding για 5 έτη) Ιολογικός, φάρμακα, α1-ατ, γονιδιακός έλεγχος Wilson: (-). ΑΝΟΣΟΛΟΓΙΚΟΙ ΕΛΕΓΧΟΙ δεν αναφέρονται. MRCP: (-) Βιοψία (11/98): Αλλοιώσεις περισσότερο συμβατές με κίρρωση χολικού τύπου. Εφόσον ο λοιπός έλεγχος αποβεί αρνητικός τότε η κίρρωση πρέπει να χαρακτηριστεί κρυψιγενής!! Διάγνωση: Μη αντιρροπουμένη κρυψιγενής κίρρωση προς OLT ΕΚΤΙΜΗΣΗ τυχαία στο Τμήμα μας 10/2003 λόγω γαστρεντερίτιδας!! Ανοσολογικός: ANA, SMA, AMA θετικά με πολλαπλές μεθόδους. Hx θανάτου σε νεαρό αδελφό 12 ys λόγω ΗΚ ανεπάρκειας ΤΕΛΙΚΗ ΔΙΑΓΝΩΣΗ: Σίγουρη ΑΗ-1. Πιθανό overlap με PBC ΔΕΝ αποκλείεται

24

25 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)

26 Typical LC1 antibodies without LKM antibodies Κορίτσι 4ετών από 3μηνου AST/ALT: 153/281 Liver tissue only

27 Dalekos suggestion 1 SLA/LP, LC1, α-actinin Dalekos suggestion 2 1 st screening by IIF (in-house rat sections)

28

29 Autoimmune Hepatitis: Role of Liver Biopsy Although certain changes are characteristic, none of the findings is specific for AIH!!!! Acute Typical?? Typical?? Cirrhosis

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

31 Don t forget also occult or full-blown celiac disease Dalekos et al Liver Intern 2008

32

33 Simplified Criteria for AIH Diagnosis Take home message (III) AIH should be considered seriously in all cases of undefined acute or chronic liver disease 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 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

34 Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: a new or a complementary diagnostic score? Gatselis NK, Zachou K, Papamichalis P, Koukoulis GK, Gabeta S, Dalekos GN, Rigopoulou EI. Dig Liver Dis 2010 Nov; 42: RESULTS: The specificity of the simplified score was similar to that of the revised score (97% vs. 97.9%). The sensitivity in unmasking AIH in AIH/overlap syndromes was also similar in both systems (53.8% and 61.5%). Liver biopsy proved to be the only independent factor for unmasking AIH component among patients (p=0.003). CONCLUSION: The simplified score is a reliable and simple tool for excluding AIH. However, both systems cannot unmask AIH component efficiently in AIH patients with concurrent autoimmune or non-autoimmune liver diseases. This study also strongly reiterates the importance of liver biopsy in the work-up of patients.

35 AIH: Clinical example 8 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 elevated (2.5x UNL) Which is the most appropriate management next???

36 AIH: Clinical example 8 1. Liver autoimmune serology (autoantibodies) 2. Liver biopsy if autoantibodies tested positive 3. Liver biopsy irrespective of the presence of Abs

37 AIH: Clinical example 8 1. Liver autoimmune serology (autoantibodies) 2. Liver biopsy if autoantibodies tested positive 3. Liver biopsy irrespective of the presence of Abs

38 Autoimmune serology: ANA 1:2560; SMA 1:640 (VGT); F-actin Abs high pos; DR3+ and DR13+ AIH: Clinical example 8

39 AIH: Clinical example 9 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

40 Clinical example 9: 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

41 Clinical example 9: No association of biochemical with histologic activity; Note the interface activity and also the prominent plasma cells

42 AIH: Clinical example 10 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 gynecologists 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

43 ΑIΗ: We do need a prompt and timely diagnosis Hepatocellular necrosis No delay Liver Fibrosis Treatment Cirrhosis Liver-related death HCC Need for OLT

44

45 AIH: Treatment (I) The heterogeneity of AIH underscores the need for individualized therapy in adults and children Krawitt NEJM 06 Manns et al Hepatology 2010

46 AIH: Treatment (II) The magnitude of AST/ALT, Abs titers & IgG elevations does not necessarily correlate with the histologic extent of injury and provides little help with respect to the initiation of treatment or the dose of drugs used Krawitt NEJM 06 Manns et al Hepatology 2010

47

48 AIH: Treatment (III) Μonotherapy Prednisone or prednisolone mg/d Tapering Maintenance therapy Combination therapy Prednisone or Prednisolone mg/d+αζα 1-2 mg/kg/d Tapering of corticosteroids Maintenance therapy

49 AIH: Efficacy of Treatment Biochemical response (6-12 months) + Histological response (18-24 months) 85-90% ασθενών To be or not to be, that is the question Once the remission of the disease is achieved the physician should decide what to do: to stop completely treatment with the risk of relapse or to maintain low doses of steroids, able to control disease activity? >80% will relapse (4-12 mo)

50 Maintenance therapy: at least 2 years??? Monotherapy - prednizolone 5-15 mg/d or AZA mg/d Combination - prednizolone (5-10 mg/d) + ΑΖΑ mg/d

51 AIH: Treatment (IV) Whenever you have decided to stop therapy DON T forget: a liver biopsy is absolutely indicated before treatment withdrawal in which no activity should be present

52 ΑIΗ: Other Therapies (I) Budesonide Budesonide 3 mg tid in combination with AZA seems to be superior to prednisone 40 mg + AZA combination for induction of biochemical response IN NON-CIRRHOTICS!!!!!! BUT. complete response (normalization AST/ALT at 6 mo!!! w/o IgG!!): 60.2% (47% w/o prednisone complications) vs 38.8% (18.4% w/o complications)!!!!!!!!!! Manns et al Gastroenterology 2010

53 ΑIΗ: Other Therapies (II) Mycophenolate

54 ΑIΗ: Other Therapies (III) Mycophenolate (Zachou et al J Hepatol 2011)

55 ΑIΗ: Other Therapies (IV) Mycophenolate (Zachou et al J Hepatol 2011)

56 ΑIΗ: Potential Treatment by Molecular Interventions (I) Czaja AJ 2011

57 ΑIΗ: Potential Treatment by Molecular Interventions (II) Czaja AJ 2011

58 ΑIΗ: Potential Treatment by Molecular Interventions (III) Czaja AJ 2011

59 AIH: Follow-up Monitoring of AST/ALT levels and circulating globulins Follow-up for HCC development in cirrhotic AIH patients

60 Consider ΑIΗ... In all cases of acute or chronic liver diseases and particularly in undefined cases keep in mind that everything is liver autoimmunity otherwise proven something else...

61 Αυτοάνοση ηπατίτιδα: Διάγνωση και θεραπεία το 2010 Γαστρεντερολογική Διημερίδα Ηπατο- Γαστρεντερολογικής Μονάδας Α Παθολογικής Κλινικής Παν/μίου Ιωαννίνων 8 & 9 Απριλίου 2011, Μέτσοβο Merci beaucoup!!