Autoimmune Hepatitis in Clinical Practice

1 Autoimmune Hepatitis in Clinical Practice Atif Zaman, MD MPH Professor of Medicine Senior Associate Dean for Clinical and Faculty Affairs School of Medicine Oregon Health & Science University Disclosure Nothing to disclose Objectivces Delineate the hepatic manifestations of various autoimmune diseases Outline the diagnostic approach to a patient with autoimmune hepatic diseases Discuss the management approach to autoimmune hepatic diseases

2 Intermittently progressive inflammatory liver disease of presumed autoimmune etiology High gamma globulins, autoantibodies Predominately periportal hepatitis Usually responds favorably to corticosteroids Pathogenesis Most of the evidence supports a central role for an alteration in T cell function in the pathogenesis of AIH although abnormalities in B cell function also may be important. Implicit in this loss of tolerance is an escape from normal suppression of selfreactive T cells, which results in ongoing inflammation and necrosis. Pathogenesis Another hypothesis: environmental trigger in a genetically predisposed individual. The exact relationships between the genes and the autoimmune process remain largely undefined at the molecular level, they are thought to involve the antigen, the major histocompatibility complex, and the T cell receptor

3 Pathogenesis Form a ternary complex in which short segments called complementary determining regions (CDR) identify and contact the antigen-mhc complex Viruses, drugs, herbs, and immunizations have been suggested as triggering agents Contrasting Features of Viral and Contrasting Features of Viral and Viral Autoimmune Prevalence: High, >1% in many Low, ~0.02% countries Diagnostic Tests: Highly specific No single screening and pathognomonic confirmatory tests marker Therapy: Subject of ongoing, Based on RCT large, multicenter completed > 30 yrs trials ago! Natural History of Untreated Autoimmune Hepatitis 100 Natural History of Untreated 80 % Survival 60 40 20 0 0 1 2 3 4 5 Years of follow-up Kirk AP, Jain S, Pocock S, Thomas HC & Sherlock S, Gut, 1980, 21:78

4 Benefits of Prednisolone Therapy Benefits of Prednisolone Therapy 100 80 Prednisolone (15 mg/d) % Survival 60 40 20 No therapy, yrs. 0-5 0 0 2 4 6 8 10 Years of follow-up Kirk AP, Jain S, Pocock S, Thomas HC & Sherlock S, Gut, 1980, 21:78 Clinical Features Clinical Features Middle-aged (or teenage) woman, non-drinker without viral hepatitis Fatigue, arthralgias/myalgias, oligomenorrhea, jaundice Increased ALT, AST, gamma globulins Positive ANA and SMA Interface hepatitis with lymphoplasmacytic infiltrate Responds to corticosteroids Often Unrecognized Features Often Unrecognized Features May occur in men, children, or elderly Auto-antibodies may be absent or only transient Minimal overlap with lupus erythematosus Responses to immunosuppressive therapy may be delayed or inadequate May have an acute presentation with no laboratory, clinical or histological features indicating chronicity

5 Auto-Antibodies in AIH Auto-Antibodies in AIH Antibody Target Antigens Prevalence Other Disease ANA Multiple nuclear 60-80% PBC, PSC, HCV, proteins NAFLD SMA Actin 60-80% HCV, NAFLD, Acute viral hepatitis panca Lactoferrin, Other 65-90% PSC, PBC unknown Ag LKM-1 CYP 2D6 4% HCV SLA/LP UGA repressor 10-30% HCV trna-associated protein Other Causes of AIH-Associated Auto-Antibodies Other Causes of AIH-Associated Auto-Antibodies Other Disease Antibody Associations Drug ANA PBC, PSC, HCV, nitrofurantoin, NAFLD minocycline and methyldopa SMA HCV, NAFLD, nitrofurantoin, Acute viral methyldopa and germander hepatitis panca PSC, PBC propylthiouracil, and minocycline LKM HCV dihydralazine, halothane and ticrynafen SLA/LP HCV Portal Tract Inflammation Histology Plasma cells Plasma cell cluster; occasional eosinophils

6 Prevalence of ANA in Liver Disease Prevalence of ANA in Liver Disease 100 80 % Positive 60 40 20 0 AIH PBC PSC NAFLD HCV HBV ALD Sub-Types of Sub-Types of Type 1 Type 2 Age at Presentation Any age Predominantly children Female:Male 4:1 8:1 Ig G Levels Elevated IgG Variable Ig G Ig A Levels Normal +/- Low IgA Auto-antibodies ANA, SMA LKM-1 Cirrhosis at 3 yrs ~ 40% ~ 80% Recognition and Diagnosis of AIH Recognition and Diagnosis of AIH Should be considered in patient with elevated AST/ALT or cirrhosis of uncertain etiology ANA, SMA and other autoantibody tests are poor screening tests The diagnosis of AIH must be based on a constellation of findings A diagnosis of AIH is often a work in progress

7 Criteria for Definite Criteria for Definite Not all cases are straight-forward Elevated AST, ALT, IgG ANA, SMA or anti-lkm-1 1:80 ( 1:20 in children) Liver biopsy showing interface hepatitis with no biliary lesions, granulomas, or prominent steatosis Absence of: Genetic liver disease HCV RNA HBV DNA, IgM anti-hav Alcohol, drugs, toxins International Group Scoring System: Patient History International Group Scoring System: Patient History Favor AIH Favor other diagnosis Gender Female (+2) Male (0) Alcohol < 25 g/d (+2) > 60 g/d ( 2) Hepatotoxic drugs None (+1) Present (-4) Other autoimmune Present (+2) None (0) diseases International Group Scoring System: Biochemistries International Group Scoring System: Biochemistries Favor AIH Favor other diagnosis Alkaline phosphatase < 1.5 (+2) > 3.0 (-2) elevation: ALT elevation Serum globulins, > 2 x normal (+3) Normal (0) globulin or IgG >1.5-2 x normal (+2) > 1-1.5 x normal (+1)

8 International Group Scoring System: Serologies International Group Scoring System: Serologies Favor AIH Favor other diagnosis ANA, SMA or LKM-1 > 1:80 (+3) < 1:40 (0) 1:80 (+2) 1:40 (+1) AMA Negative (0) Positive (-4) Hepatitis Markers Negative (+3) Positive (-3) Other autoantibodies Present (+2) Absent (0) HLA-DR3 or DR4 Present (+1) Absent (0) International Group Scoring System: Histology International Group Scoring System: Histology Favor AIH Favor other diagnosis Interface Hepatitis +3 Lymphoplasmacytic +1 Infiltrate Rosetting of liver cells +1 None of Above -5 Biliary Changes -3 Other changes -3 International Group Scoring System: Response to Therapy International Group Scoring System: Response to Therapy Favor AIH Complete Remission (normal ALT, IgG, +2 bilirubin within 12 mo and for >6 month duration or: all tests > 50% improved in 1 mo. and AST/ALT < 2x normal within 6 mos. or: liver biopsy with minimal activity) Remission with relapse (return of +3 symptoms, abnormal biopsy and /or > 2 x normal AST/ALT)

9 - Criteria Interpretation of International Group Score Interpretation of International Autoimmune Hepatitis Group Score Score Interpretation Pre-therapy: >15 Definite AIH 10-15 Probable AIH Post-therapy: >17 Definite AIH 12-17 Probable AIH A Simplified Criteria Autoantibodies: assign one point if the ANA or ASMA are 1:40 OR assign two points if the ANA or ASMA are 1:80 (OR if the LKM 1:40 OR if the SLA is positive). IgG: assign one point if the IgG is > the upper limit of normal OR assign two points if the IgG is >1.10 times the upper limit of normal. Liver histology (evidence of hepatitis is a mandatory condition): assign one point if the histological features are compatible with autoimmune hepatitis OR two points if the histological features are typical of autoimmune hepatitis. Absence of viral hepatitis: assign two points if viral hepatitis has been excluded. A probable diagnosis of autoimmune hepatitis is made if the total points are six, while a definite diagnosis is made if the total points are seven. Indications for Treatment Based on the results of Indications for Treatment Absolute Relative None AST 10x normal Symptoms No symptoms AST 5x normal AST < 5x normal Inactive and -globulin -globulin cirrhosis 2x normal < 2x normal Bridging necrosis Interface Portal hepatitis hepatitis AASLD Practice Guidelines, Hepatology 2002, 36:479

10 Comparison of Various Treatments Comparison of Various Treatments 60 Placebo % Treatment failures 40 20 0 0 1 2 3 Years Adapted from Soloway, et al, Gastroenterology 1972; 63:828 Azathioprine Prednisone Pred + Aza Definition of Remission Definition of Remission All of the following: Disappearance of symptoms Normal serum bilirubin, -globulin ALT, AST < 2x normal Normal hepatic histology or minimal inflammation, no interface hepatitis Histology lags biochemical remission by ~6 months Managing Patients in Remission Managing Patients in Remission Gradual withdrawal of corticosteroids Discontinuation of azathioprine Long term, regular monitoring for expected relapse

11 End of Therapy Liver Histology Predicts Relapse End of Therapy Liver Histology Predicts Relapse Normal Histology Interface Hepatitis Inactive Cirrhosis Portal Plasma Cells 0 20 40 60 80 100 Risk of Relapse (%) Czaja, AJ, Davis, GL, Ludwig, J, Taswell, HF. Hepatology 1984, 4:622 Czaja, AJ, Carpenter, HA. Liver International 2003, 23:116 Maintenance Therapy Maintenance Therapy Lowest effective dose for Prednisone 10 mg/d or Azathioprine, 1.5-2.0 mg/kg/d or Low dose Prednisone 10mg/d plus Azathioprine 50 mg/d Add Vitamin D (50,000 U/wk) and Ca (1-1.5 g/d) to Prednisone Monitor for hypertension, cataracts, glaucoma, bone disease in Prednisone recipients Monitor WBC, platelets in Azathioprine recipients Options When Conventional Treatments Fail Options When Conventional Treatments Fail Treatment failures: Prednisone 60 mg/d or Prednisone 30 mg/d + Azathioprine 150 mg/d Drug intolerance or treatment failure: Mycophenolate mofetil (1 g BID) Tacrolimus (4 mg BID, trough level = 6-10 ng/ml) Cyclosporin (5-6 mg/kg/d, trough level = 200-250 ng/ml) Heneghan MA, McFarlane, IG. Hepatology 2002, 35:7 Cjaga, AJ. Seminars in Liv. Dis., 2002, 22:365

12 Pitfalls in Therapy of AIH Pitfalls in Therapy of AIH Inadequate initial therapy (histological remission lags behind biochemical remission) Failure to consider steroid-sparing (or steroid free) regimens Initiation of therapy without appropriate indication (mild hepatitis, inactive cirrhosis, wrong disease) Persistent ( lifelong ) therapy in those in first complete remission with benign follow-up biopsies Liver Transplantation Liver Transplantation Overall 5-year survival rates 80-90% Increased frequency of acute allograft rejection AIH recurrence in 30-40% Surveillance liver biopsies may be warranted Manage with corticosteroids