1. Autoimmune Hepatitis

2. Case Presentation ► 54 yo woman with abnormal liver function test  9 years ago patient with ele lfts  No complaints  PMH: migraine headaches, arthritis, bilateral tubal ligation, repair of ganglion cyst  Meds: Prempro, Imitrex  SH: rare alcohol, no tobacco  FH: no history of liver disease  PE: weight 104 lbs, no stigmata of Chronic liver disease

3. Laboratory Data AST214 ALT272 Alk Phos 74 Total Bili 0.6 Total Protein 8.0 Alb3.0 ANA1:1280 ASMA1:80 AMA- Viral Serologies - Ferritin75

4. Other Data ► Sono: 3 mm CBD, normal gallbladder, increase echogeneity c/w fatty liver ► Liver Biopsy: moderate piecemeal necrosis with early fibrosis, expanded portal tracts with plasma cells ► DX: Autoimmune Hepatitis ► RX: Steroids and Imuran

5. Definition ► Self perpetuating hepatocellular inflammation of unknown cause ► Characterized by the presence of:  periportal hepatitis  Hypergammaglobulinemia  Serum liver-associated autoantibodies ► Exclusion of other chronic liver diseases

6. Epidemiology ► 1.9 cases per 100,000 incidence of Autoimmune Hepatitis in western Europe ► Frequency of AIH among patients with chronic liver disease is 11% ► Accounts for 5.9% of transplantations in the US Boberg K. 1998: Scad J Gastro;33:99-103

7. Background ► 40% of patients with untreated severe disease die within 6 mos of dx ► 40% develop cirrhosis  54% develop esophageal varices ► 20% die of hemorrhage ► An acute onset of illness is seen in 40% patients ► Prednisone and azathioprine are mainstay of treatment

8. Clinical Manifestations ► Symptoms  Fatigue 85%  Jaundice 77%  Abdominal pain 48%  Pruritus 36%  Anorexia 30%  Polymyalgias 30%  Diarrhea 28%  Fevers 18%

9. Clinical Manifestations ► Physical Findings  Hepatomegaly 78%  Jaundice 69%  Splenomegaly 32%  Spider nevi 58%  Ascites 20%  Encephalopathy 14%  Concurrent immune disease 48%

10. Clinical Manifestations ► Laboratory features  Elevated AST 100%  Hypergammaglobulinemia 92%  Inc immunoglobulin G level 91%  Hyperbilirubinemia 83%  Alk Phos >2x 33%

11. Differential Diagnosis ► Wilson’s disease ► A1AT deficiency ► Hemochromatosis ► Viral hepatitis ► Drug induced hepatitis

12. Liver Histology

13. Autoimmune Histology

14. Diagnosis

15. Diagnostic Criteria ► Clinical criteria  Presence of characteristic clinical features  Liver histology  Exclusion of other diseases ► Scoring criteria  Assess the strength of the diagnosis  Pretreatment and post-treatment  Helpful with variant or atypical forms of AIH

16. Diagnostic Scoring System for Atypical Autoimmune Hepatitis CategoryFactorScoreCategoryFactorScore Genderfemale+2 Other immune Non-hepatic of immune nature +2 AP:AST>3<1.5-2+2autoabs Anti- SLA/LP,actin,LC1 +2 glob>2.01.5-2.01.0-1.5<1.0+3+2+10histology Interface hepatitis Plasma cells Rosettes None of above +3+1+1-5 ANA,SMA, LKM1 >1:801:801:40<1:40+3+2+10HLA DR3 or DR4 +1 AMApositive-4 Rx response Remission alone Remission w/relapse +2+3 Viral markers Positivenegative-3+3Pretreatment definite dx definite dx probable dx probable dx>1510-15 drugsYesno-4+1Post-treatment definite dx definite dx probable dx probable dx>1712-17 alcohol <25 gm/d >60 gm/s +2-2

17. Subclassification of AIH ► Type I ► Type II ► Type III

18. Type 1 AIH ► Diagnostic autoantibodies: ANA, ASMA ► Age: Bidmodal (10-20 and 45-70) ► % Women: 78 ► % Concurrent immune diseases: 41 ► Elevated gamma globulin: +++ ► Steroid responsiveness: +++ ► Progression to cirrhosis (%): 45

19. Type II AIH ► Diagnostic autoantibodies: LKM1 ► Age: Pediatric (2-14), rare adults (4%) ► % Women: 89 ► % Concurrent autoimmune disease: 34 ► Elevated gamma-globulins: + ► Steroids responsive: ++ ► % progression to cirrhosis: 82

20. Type III AIH ► Diagnostic autoantibodies: SLA and LP ► Age: adults (30-50) ► % Women: 90 ► % Concurrent autoimmune disease: 58 ► Elevated gamma-globulin: ++ ► Steroid responsive: +++ ► % progression to cirrhosis: 75

21. Prognostic Indices ► Laboratory findings at presentation  AST>10x nl: 50%, 3-year mortality  AST>5x nl + GGT>2x; 90%, 10-yr mortality  AST<10x nl + GGT<2x; 49%, cirrhosis at 15 yr; 10% 10-yr mortality ► Histologic findings at presentation  Periportal hepatitis: 17%,cirrhosis at 5 yr; Nl 5 yr survival  Bridging necrosis: 82%, cirrhosis of 5 yr; 45%, 5-yr mortality  Cirrhosis: 58%, 5 yr-mortality

22. Recommendations ► Diagnosis of AIH requires aminotransferase and globulin levels; detection of ANA +/or SMA, anti-LKM1; and histology ► Diagnostic criteria for AIH should be applied to all patients ► If the diagnosis is not clear, a scoring method should be used

23. Treatment

24. Indications for Treatment AbsoluteRelative Serum AST>10x uln Symptoms (fatigue, arthralgia, jaundice) Serum AST>5x uln and globulin >2x nl Serum AST and globulin less than absolute criteria Bridging necrosis or multiacinar necrosis Interface hepatitis

25. Treatment Regimens Prednisone only Combination (Pred + AZA) Week 1 60 mg 30 mg+50 mg Week 2 40 mg 20 mg+50 mg Week 3 30 mg 15 mg+50 mg Week 4 30 mg 15 mg+50 mg Maintenance until endpoint 20 mg 10mg+50 mg

26. Reasons for Preference ► Prednisone  Cytopenia  TPMT deficiency  Pregnancy  Malignancy  Short course <6 mos ► Combination  Postmenopausal state  Osteoporosis  Brittle diabetes  Obesity  Acne  Emotional Lability  Hypertension

27. Treatment Endpoints ► Remission  10-40% of patients ► Treatment Failure ► Incomplete Response ► Drug Toxicity

28. Remission ► Criteria  Disappearance of symptoms  Normal bilirubin + globulin levels  Transaminases normal or less than 2x  Normal histology or minimal inflammation ► Action  Gradual withdrawal of prednisone  Discontinuation of azathioprine  Regular monitoring for relapse

29. Treatment Failure ► Criteria  Worsening clinical, labs and histology despite compliance  Inc transaminasis by 67%  Development of jaundice, ascites or hepatic encephalopathy ► Action  Pred 60 mg/d or pred 30 mg/d with aza 150 mg/d x 1 mo  Reduction of the dose each month of improvement until maintenance levels

30. Incomplete Response ► Criteria  Some or no improvement in clinical,labs and histology during therapy  Failure to achieve remission after 3 years  No worsening of condition ► Action  Reduction of dose to lowest levels possible to prevent worsening  Indefinite treatment

31. Management of Relapse after Drug Withdrawal ► Relapse at least twice  Indefinite low dose prednisone  Indefinite low dose azathioprine

32. Management of Suboptimal Response to Initial Therapy ► Alternative medications  Cyclosporine, 6MP, ursodeoxycholic acid, budesonide, methotrexate, cyclophosphamide and mycophenolate mofetil ► Liver Transplantation  5 year graft survival 83-92%  Disease recurrence is mild and easily managed

33. Hepatocellular Carcinoma ► Uncommon in the absence of cirrhosis or coexisting hepatitis B or C ► If cirrhosis  RUQ ultrasound  Alfa fetoprotein every 6-12 months

34. Recommendations ► High dose prednisone alone or prednisone and aza should be used in treatment failures ► Corticosteroid therapy should be considered in the decompensated patient ► Liver transplantation should be considered in the decompensated patient unable to undergo salvage therapy

35. Case Presentation AST19 ALT12 AP54 Total protein/albumin 7.3/4.6 Total bilirubin 0.6 What would do next?