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Thomas Hargrave M.D. November 20, 2009

Autoimmune Hepatitis. Thomas Hargrave M.D. November 20, 2009. Autoimmune Hepatitis. Autoimmune Hepatitis. Autoimmune Hepatitis. Intermittently progressive inflammatory liver disease of presumed autoimmune etiology High gamma globulins, autoantibodies

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Thomas Hargrave M.D. November 20, 2009

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  1. Autoimmune Hepatitis Thomas Hargrave M.D. November 20, 2009

  2. Autoimmune Hepatitis Autoimmune Hepatitis Autoimmune Hepatitis Intermittently progressive inflammatory liver disease of presumed autoimmune etiology • High gamma globulins, autoantibodies • Predominately periportal plasma cell hepatitis • Usually responds favorably to corticosteroids or immnomodulators

  3. Often Unrecognized Features Autoimmune Hepatitis Autoimmune Hepatitis • First described by Waldenstrom in 1950 in a young woman with idiopathic chronic hepatitis • Now recognized as a chronic multisystem disorder that occurs in males and females of all ages. • AIH can co-exist with other liver diseases (hepatitis C) and can be triggered by drugs (minocycline) and herbal agents

  4. Often Unrecognized Features Autoimmune Hepatitis Autoimmune Hepatitis • Annual incidence in North America of 1.9/100,000 • Prevalence 16.9/100,000 • Accounts for 6% of liver transplantations • Affects all ages and ethnic groups • 70-80% of AIH are women but men may predominate over the age of 70

  5. Often Unrecognized Features Autoimmune Hepatitis Autoimmune Hepatitis • Characterized by considerable heterogeniety and fluctuating disease activity over time • Liver injury is the result of cell-mediated immunologic attack against genetically predisposed hepatocytes • HLA association with B8, B14,DR3,Dr4, Dw3 • There is little evidence that the autoantibodies have a role in the pathogenesis of AIH

  6. Clinical Features Autoimmune Hepatitis Clinical Features: Classic • 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

  7. Clinical Features Autoimmune Hepatitis Clinical Features: Highly Variable • Asymptomatic abnormal LFTs: up to 50% • Acute hepatitis 18-30% • Chronic fatigue, viral-like illness • Fulminant hepatic failure (rare) • Many patients found to have established cirrhosis during initial acute presentation (20%) • Long periods of sub-clinical disease may occur both before and after presentation

  8. Often Unrecognized Features Autoimmune Hepatitis Often Unrecognized Features • May occur in men, children, or elderly • Auto-antibodies may be absent or only transient • Responses to immunosuppressive therapy may be delayed or inadequate • May have an acute presentation with no laboratory, clinical or histological features indicating chronicity

  9. Autoimmune Hepatitis Differential Diagnosis: Acute Hepatitis • Viral Hepatitis • Drug induced • Herbal medications • Wilson’s Disease: F:M 4:1, KF Rings, Ceruloplasmin<20 • Cirrhosis • Chronic active hepatitis, • Fulminant hepatic failure.

  10. Inflixamab INH Statins (unmask AIH) Allopurinol Aldomet Autoimmune Hepatitis Often Unrecognized Features Differential Diagnosis • Drug-induced Autoimmune Hepatitis • Minocycline • Nitrofurantoin • Orlistat • Meloxicam • Herbal medications • Echinacea • Noni Juice • Black cohosh • Chaparral leaf • Kava Kava • Valerian • St. John’s Wort

  11. Sub-Types of Autoimmune Hepatitis Autoimmune Hepatitis Sub-Types of Autoimmune Hepatitis Type 1Type 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%

  12. Auto-Antibodies in AIH Autoimmune Hepatitis Auto-Antibodies in AIH Antibody Target Antigen Prevalence ANA Multiple nuclear 60-80% proteins SMA Actin 60-80% pANCA Lactoferrin, Other 65-90% unknown antigen LKM-1 CYP 2D6 ≈ 4% US/20% EU SLA/LP UGA repressor 10-30% (high tRNA-associated specificity) protein

  13. Other Causes of AIH-Associated Auto-Antibodies Autoimmune Hepatitis 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

  14. Prevalence of ANA in Liver Disease Autoimmune Hepatitis Prevalence of ANA in Liver Disease 100 80 60 % Positive 40 20 0 AIH PBC PSC NAFLD HCV HBV ALD

  15. Utility of ANA Testing in Patients with Elevated Transaminases Autoimmune Hepatitis ANA Testing in Patients with Elevated Transaminases Has Low Specifcity 80 200 60 150 Percent ANA (+) ANA (+) Patients / 100,000 40 100 20 50 16 0 0 AIH NAFLD HCV *Sem. Liv. Dis 2002, 22:339Amer. J. Gastro 2004, 99:1316 Hepatology 1995, 21:613 **J. Gastro. Hepatol. 2003 18:1118 Hepatology 2004, 40:1387 NEJM 1999, 341:556

  16. Recognition and Diagnosis of AIH Autoimmune Hepatitis Extrahepatic Manifestations • Concurrent immunologic disease present in 38% of patients with AIH • Celiac disease 10% • Thyroiditis/ Graves Disease • Ulcerative Colitis • Uveitis • Rheumatoid arthritis • Up to 18% overlap syndromes: AIH/PBC, AIH/PSC

  17. Recognition and Diagnosis of AIH Autoimmune Hepatitis Diagnosis of AIH • Should be considered in patient with elevated AST/ALT or cirrhosis of uncertain etiology • The diagnosis of AIH must be based on a constellation of clinical and lab findings • ANA, SMA and other autoantibody tests are poor “screening tests” • A diagnosis of AIH is often a “work in progress”

  18. Autoimmune Hepatitis Laboratory Features • In general, transaminase elevations (5-10x) are more impressive than alkaline phosphatase or bilirubin elevations: Alt averages 200-300 U/L • Occasional cholestatic presentation with high conjugated bilirubin and alkaline phosphatase • IgG polyclonal hypergammaglobulinemia almost universal: AIH highly improbable with normal globulins • Gamma globulin typically 3-4 g/dl • IgA deficiency common in children with both type I and type II AIH

  19. IgG Polyclonal Hypergammaglobulinemia

  20. Criteria for Definite Autoimmune Hepatitis Autoimmune Hepatitis Criteria for Definite Autoimmune Hepatitis • 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

  21. Female sex +2 ALP/ALT Ratio <1.5: +2 1.5-3.0: 0 >3.0: -2 Globulinn >2x: +3 1.5-2.0x: +2 1.0-1.5X: +1 ANA/ASMA/LKM >1:80 +3 1:80: +2 1:40 +1 <1:40 0 AMA + -4 Negative HBV/HCV +1 ETOH < 25gm/d +2 Other autoimmune +2 Response to steroids Complete +2 Relapse +3 Liver Biopsy Interface hepatitis +3 Lymphoplasmacytic +1 Neither -5 International AIH Scoring System Pre-treatment Score > 15 : Definite AIH (>17 post-Rx) Score 10-15: Prob. AIH (12-17 post-Rx)

  22. Recognition and Diagnosis of AIH Autoimmune Hepatitis Diagnosis of AIH • Liver biopsy essential in confirming the clinical diagnosis of AIH and stage degree of liver injury • Interface hepatitis is the hallmark of the disease • Plasma cell infiltration typical • Neither finding is disease specific • Absence of plasma cells does not exclude the disease

  23. Not All Cases With ANA Will Have Autoimmune Hepatitis Not All Cases With ANA Will Have Autoimmune Hepatitis ANA positive steatohepatitis ANA positive, Near normal biopsy Dig Dis Sci 2003; 48:2173

  24. Interface Hepatitis of AIH • Portal tract expanded with mononuclear inflitrate • Limiting plate disrupted • Inflammation extends into acinus

  25. Portal Tract Inflammation Histology Plasma cells Plasma cell cluster; occasional eosinophils

  26. Natural History of Untreated Autoimmune Hepatitis Autoimmune Hepatitis Natural History of Untreated Autoimmune Hepatitis 100 80 60 % Survival 40 20 0 0 1 2 3 5 4 Years of follow-up Kirk AP, Jain S, Pocock S, Thomas HC & Sherlock S, Gut, 1980, 21:78

  27. Autoimmune Hepatitis 10-Year Survival for Treated AIH 90%

  28. Autoimmune Hepatitis Treatment • Appropriate management can: • Improve quality of life • Prolong survival/ Delay need for liver transplant • Treated patients have a life-expectancy similar to age and gender matched controls followed up to 20 years • After > 3 decades, prednisone and azathioprine remain the mainstays of treatment AASLD Practice Guidelines, Hepatology 2002, 36:479

  29. Indications for Treatment Based on the results of Autoimmune Hepatitis 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

  30. Therapy in Adults Autoimmune Hepatitis Therapy in Adults Combination Therapy Monotherapy Interval Prednisone Prednisone Azathrioprine mg/d mg/d mg/d Week 1 60 30 50 Week 2 40 20 50 Week 3 30 15 50 Week 4 30 15 50 Daily until 20 10 50 endpoint AASLD Practice Guidelines, Hepatology 2002, 36:479

  31. Reasons for Selecting Treatment Regimens Autoimmune Hepatitis Reasons for Selecting Treatment Regimens Prednisone Monotherapy • Severe cytopenia • TPMT deficiency • Prior Aza intolerance • Pregnancy • Malignancy Combination (Pred+Aza) • Postmenopausal state • Osteoporosis • Brittle diabetes • Obesity • Acne • Emotional lability • Hypertension AASLD Practice Guidelines, Hepatology 2002, 36:479

  32. Autoimmune Hepatitis Reasons for Selecting Treatment Regimens Toxicity of Azathioprine/6-MP • The toxicity of AZA/6-MP is related to their metabolites • Two important enzymes • Thiopurine methyltranferase (TPMT) • Hypoxanthine phosphoribosyl tranferase (HPRT) • The toxicity of AZA/6-MP is predominantly related to the activity of TPMT • 11% of the population is heterozygous and 0.3% homozygous for TPMT deficiency • Testing for TPMT before initiating AZA/6MP becoming the standard of care AASLD Practice Guidelines, Hepatology 2002, 36:479

  33. HPRT TPMT

  34. Autoimmune Hepatitis Definition of Remission Response To Treatment • 90% of adults have improvement in bilirubin, transaminases, and globulin levels within 2 weeks • Histologic improvement lags behind laboratory improvement by 3-6 months • Remission is rarely achieved in less than 12 months • 65% remission at 18 months • 80% remission at 3 years • 13% partial response • 9% treatment failure

  35. Definition of Remission Autoimmune Hepatitis Definition of Remission All of the following: • Disappearance of symptoms • Normal serum bilirubin, g-globulin • AST, AST < 2x normal • Normal hepatic histology or minimal inflammation, no interface hepatitis

  36. Maintenance Therapy Autoimmune Hepatitis Maintenance Therapy • Lowest effective dose for Prednisone ≤ 10 mg/d • Azathioprine, 1.5-2.0 mg/kg/d • Low dose Prednisone ≤10mg/d plus Azathioprine 50 mg/d or or • 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

  37. Autoimmune Hepatitis Maintenance Therapy • Prednisone taper 2.5 mg/mo. until lowest dose reached which maintains clinical remission • 87% can be maintained on </= 10 mg/day • Azathioprine 2.0 mg/kg monotherapy also 87% effective in maintaining remissions for up to 67 months

  38. Autoimmune Hepatitis Should Therapy Be Discontinued? • Once remission is achieved steroids should first be tapered and eventually discontinued, followed by azathioprine 50 mg/12 weeks • Between 10-40% can be withdrawn from treatment for up to 5 years • Liver biopsy assessment is preferred, but not essential, prior withdrawing patients from therapy • Relapse occurs in 20-90% of AIH depending on the histologic findings at time of withdrawal

  39. End of Therapy Liver Histology Predicts Relapse Autoimmune Hepatitis 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

  40. Options When Conventional Treatments Fail Autoimmune Hepatitis 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

  41. Pregnancy Autoimmune Hepatitis Pregnancy and AIH • If AIH in remission, pregnancy well tolerated unless complications of portal hypertension are present • Increased frequency of prematurity and fetal loss • Pregnancy or planned pregnancy are not a contraindication to immunosuppression • Teratogenicity observed with azathioprine treatment in mice but little evidence for teratogenicity in humans • Many reports of AIH flares post-partum, but AIH also may exacerbate or present during pregnancy

  42. Pitfalls in Therapy of AIH Autoimmune Hepatitis 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

  43. Liver Transplantation Autoimmune Hepatitis 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

  44. Liver Transplantation Autoimmune Hepatitis AIH Treatment: Summary • Treatment Indications: • ALT> 10 fold • ALT>5 fold with hyper globulinemia • ALT <5x with symptoms • Bridging necrosis or multiacinar necrosis • Interface hepatitis without necrosis does not compel treatment

  45. Liver Transplantation Autoimmune Hepatitis AIH Treatment: Summary • Start therapy with prednisone alone, adding azathioprine/6MP if remission not achieved within 3 months • Test for TPMT before starting azathioprine/6-MP • Maintain fixed daily dose of medication until remission • Continue treatment until remission, treatment failure or drug toxicity

  46. Liver Transplantation Autoimmune Hepatitis AIH Treatment: Summary • Vaccination for for HBV and HAV recommended • Drug withdrawal should be attempted once remission obtained, preferably based on liver biopsy findings • 10-40% can eventually be maintained off medication but multiple relapses may occur before sustained remission achieved

  47. What are Overlap Syndromes? Overlap Syndromes What are Overlap Syndromes? • Two simultaneous autoimmune liver diseases AIH/PBC, AIH/PSC • Two sequential autoimmune liver diseases • One autoimmune liver disease with features of another

  48. Diagnostic Criteria Overlap Syndromes Diagnostic Criteria AIH PBC PSC Symptoms malaise, fatigue, fatigue jaundicepruritus pruritus Asymptomatic occasionally often often Gender female>male female>male female>male Biochemistry ALT ALP ALP and/or GGT Immunoglobulins IgG IgM IgM/IgG (low Ig A type2) Autoantibodies SMA/anti LKM1 AMA none specific ERC/MRC overlap PSC normal Diagnostic (young)hallmark

  49. What are Overlap Syndromes? Overlap Syndromes How to Treat Overlap Syndromes

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