Autoimmune Hepatitis

Transcription

1 Autoimmune Hepatitis Robert H. Squires, Jr., MD Professor of Pediatrics Children s Hospital of Pittsburgh Northwest Pediatric Liver Disease Symposium April 11,12, 2008 Seattle, Washington

2 Common Liver Tests Hepatocellular Damage AST, ALT Can be elevated in patients with myopathy Cholestasis Bilirubin, GGTP, serum bile acids Alkaline phosphatase (not helpful in children) Note: benign elevation of alkaline phosphatase Liver function tests PT, INR, albumin, glucose, factor VII, ammonia

3 Interpretation of Liver Tests Must be in placed in clinical context Signs/symptoms of chronic liver disease Hepatic failure Incidental finding Risk factors Viral hepatitis Alcohol Obesity Medications

4 Costs of Selected Tests (US dollars, 2001) AST, ALT, alkaline phosphatase, bilirubin Prothrombin time GGTP Hep A-IgM HBsAg HBV-DNA Hep C Ab HCV-RNA (Quant) HCV-genotype ANA Smooth Muscle Ab Anti-LKM Alpha-1 antitrypsin Ceruloplasmin Abdominal sono 600 Liver biopsy 1,500 Gastroenterology 2002;123:

5 Proposed Healthy Ranges of ALT Prati D et al Ann Intern Med 2002:137:1-9

6 Variation in serum Alkaline Phosphatase by age Reichling JJ et al Diges Dis Sci 1988:33:

7 Prevalence of elevated ALT among US adolescents: NHANES Fraser A, et al Gastroenterology 2007;133:1814

8 Isolated Unconjugated Hyperbilirubinemia Gilbert s syndrome Neonatal jaundice Hemolysis, blood transfusion Resorption of a large hematoma Crigler-Najjar syndrome Shunt hyperbilirubinemia

9 Evaluation of Abnormal Liver Tests Mild elevation (< 2x ULN) Variation of normal Follow clinically, if no sign of chronic liver disease Look for simple things: medications, obesity, myopathy, viral exposure, history of autoimmune disease, celiac disease Consider further evaluation if aminotransferase levels increase or persist beyond 4-6 months, despite lifestyle changes Would check aminotransferase levels between 3-6 weeks after initial elevation in the asymptomatic patient, or sooner as clinical circumstances change.

10 Evaluation of Abnormal Liver Tests Moderate elevation (< 5x ULN) Infection Hep B, C, EBV, CMV Fatty liver/steatohepatitis Medications/toxins Meds: Acetaminophen, NSAID s, augmentin, anti-fungal, analeptics Herbs: Germander, Jin Bu Huan, Senna, Vitamin A Illicit drugs: Anabolic steroids, cocaine, ecstasy, phencyclidine Toxins: Alcohol, mushroom Autoimmune hepatitis Alpha-1 antitrypsin deficiency Wilson disease Celiac disease Non-hepatic Hemolysis, myopathy, thyroid disease, strenuous exercise

11 Evaluation of Abnormal Liver Tests Severe elevation (>15 x ULN) Infection Viral A-E, Herpes Medications/Toxins Vascular injury to the liver Ischemic hepatitis Acute Budd-Chiari syndrome Hepatic artery ligation Autoimmune hepatitis Wilson disease Acute bile duct obstruction

12 AST/ALT elevation in skeletal muscle diseases Nathwani RA et al Hepatology 2005:41:380-82

13 Unusual causes of elevated AST/ALT AST macroenzyme Fortunato G et.al. J Pediatrics 1998;133:286 Subclinical Addison s Disease Boulton R, et al Gastroenterology 1995;109:1324 Rotavirus Grimwood K, et al J Pediatrics 1988;112:597

14 Autoimmune Hepatitis in Children 2-5% of chronic liver disease in children Phenotypic variability Acute hepatitis (most common) 25-56% Indolent presentation over some months Acute liver failure Cryptogenic cirrhosis Associated immune-mediated disorders Thyroiditis -- Hypereosinophilic syndrome Ulcerative colitis -- Hemolytic anemia Celiac disease -- Diabetes mellitus Vitiligo -- Myasthenia gravis

15 Diagnosis of Autoimmune Hepatitis Elevated aminotransferase levels Elevated serum globulin Autoantibodies ANA, SMA, anti-lkm1, SLA Absence of viral markers for hepatitis Histologic evidence of interface hepatitis Absence of other conditions Infection, toxic injury, metabolic defect

16 Clinical and Immunological Features Clinical Features Type 1 Type 2 Type 3 Autoantibodies SMA/ANA LKM-1 SLA Age (yr) 10-20; Women (%) Elevated Gamma Globulin HLA Association B8, DR3, DR4 B14, DR3, C4AQO Other immune disease(%) Steroid response Progress to cirrhosis (%) ?

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18 Interface Hepatitis Multinucleated cells Plasma cells Cholestasis

19 Autoimmune Hepatitis in Children Gregorio GV, et.al. Hepatology 1997;25: patients from with autoimmune liver disease 21 sclerosing cholangitis were excluded 52 with autoimmune hepatitis were evaluated SEROLOGICAL MARKERS AT THE TIME OF PRESENTATION Marker Titer # Comments ANA 1: SMA 1: ANA + SMA 14 Anti-LSP 1: Weak ANA=2; ANA + after 1,3 mo LKM-1 1: LKM + ANA 1 No marker 1 3 y/o spherocytosis; +LKM/SMA

20 Autoimmune Hepatitis in Children ANA/SMA LKM-1 p-value (N = 32) N = (20) Age (yr) 10.5 ( ) 7.4 ( ) Female 24 (75%) 15 (75%) 1.00 Length of illness* 4 ( ) 1.7 ( ) 0.06 Fulminant failure 1 (3%) 5 (25%) 0.05 Autoimmune disorders (AD) First degree relative with AD 7 (22%) 4 (20%) (43%) 8 (40%) 0.81 * Months Gregorio GV, et.al. Hepatology 1997;25:541

21 AIH in Children: Laboratory ANA/SMA LKM-1 p-value N = 32 N = 20 T.Bili µmol/l (< 20) 62 (6/462) 188 (13-773) AST IU/L (< 50) 632 ( ) 1146 ( ) GGT IU/L (< 50) 126 (11-871) 91 (36-299) SAP IU/L (< 350) 376 ( ) 377 ( ) INR ( ) 1.6 (1-2.5) 1.6 (1-8.6) 0.39 IgG g/l (5-15) 28 ( ) 21 ( ) 0.06 Alb g/l (35-50) 32 (20-43) 38 (25-54) 0.02 ANA titer (N=20) 120 ( ) NA SMA titer (N=26) 160 ( ) NA LKM1 titer (N=19) NA 640 ( ) Gregorio GV, et.al. Hepatology 1997;25:541

22 47 medical Rx 52 patients (20 LKM) 6 fulminant failure (5 LKM) 3 elevated AST 1 Rx steroids 4 OTLTx 1 died 9 OTLTx 2 died 15mo 5 OTLTx 3 died 44 remission (13 LKM) 7mo (1 wk-7yr) 6 pred 35 pred + Aza 3 other 13 (4 LKM) ended Rx 6 (0 LKM) success Lasting 9-13 yr 7 (4 LKM) relapse 2 mo (1-15 ) Gregorio, 1997

23 Observations Excluding ALF, Type 1 and Type 2 have similar presentation and initial response to therapy Most require treatment life-long, particularly LKM Standard autoantibodies may be absent initially 56% of patients present with acute hepatitis Normal IgG in 20% Cirrhosis at presentation is more common in ANA/SMA +ve patients

24 Management of AIH in Children Standard immunosuppression Prednisone Azathioprine Calcineurin Inhibitors Cyclosporine FK 506 Antimetabolites Mycophenolate mofetil Cyclophosphamide Methotrexate Other Ursodeoxycholic acid D-Penicillamine Liver transplantation

25 Overlap Syndromes AIH and Primary Biliary Cirrhosis AMA +ve; elevated AST/ALT/GGT/SAP Biliary damage, piecemeal necrosis Steroids and UDCA AIH and Primary Sclerosing Cholangitis panca +ve; elevated AST/ALT/GGT/SAP Abnormal cholangiogram; associated with IBD Cholangitis, piecemeal necrosis Steroids AIH and Hepatitis C ANA and/or SMA and/or anti-lkm1 +ve; Hep C Ab +ve Portal lymphocytic infiltrate, steatosis, bile duct injury Treatment is problematic

26 Variant Syndromes Autoimmune cholangitis ANA and/or SMA +ve; AMA absent Cholestasis; normal cholangiogram Biliary damage Prednisone and/or UDCA response is poor Cryptogenic cirrhosis Autoantibody negative Histologic features of AIH Good response to Prednisone

27 Autoimmune Hepatitis/Sclerosing Cholangitis in Childhood: 16 yr study Gregorio GV, et al Hepatology 2001;33: patients with liver disease and circulating antibodies 21 too ill to undergo cholangiography 55 underwent cholangiography (ERCP = 51), 54 had sigmoidoscopy / bx Recruited Followed through patients were antibody positive Sclerosing cholangitis (AIH-SC) 27 Normal cholangiogram (AIH) patient with sclerosing cholangitis from other causes during the study (not included) Primary immunodeficiency 6 Langerhan cell histiocytosis 2 Neonatal sclerosing cholangitis 5 Primary sclerosing cholangitis 9

28 OLS AIH-SC in Children: Demographics OCS AIH-SC AIH p-value (N = 27) (N = 28) Age (yr) 11.8 (2.3-16) 10.5 (2.2-14).16 Female 15 (55%) 22 (79%).12 Jaundice 15 (56%) 19 (68%) NS Pruritis 2 (7%) 7 (25%).08 IBD 12 (44%) 5 (18%).03 Immune disorders 13 (48%) 11 (39%) NS Gregorio GV,et.al Hepatology 2001:33:544

29 OLS AIH-SC in Children: Laboratory OLS AIH-SC AIH p-value (N = 27) (N = 28) T.Bili (µmol/l) 20 (4-178)* 35 (4-306).04 AST (IU/L) 102 ( ) 333 ( ).002 GGT (IU/L) 129 (13-948) 76 (29-333) NS SAP (IU/L) 303 ( ) 356 ( ) NS INR 1.1 (.9-1.6) 1.2 ( ).009 IgG (g/l) 19.4 ( ) 24 ( ) NS Alb (g/l) 39 (27-54) 35 (25-47).051 ANA +ve SMA +ve LKM1 +ve panca +ve 74% 36% * = median (range) Gregorio GV,et.al Hepatology 2001:33:544

30 OLS AIH-SC in Children: Time to Normalization* of Lab AIH-SC AIH p-value AST 2.1 (.2-107) 6 (.8-25) NS GGT 7 (1-96) 12 (1-40) NS SAP 2 (1-40) 5 (1-48).015 T. Bili 1.5 (.5-12) 1.25 (.25-16) NS Alb 0.5 (.5-1) 2 (.25-8).016 INR 1 (1-6) 6 (.5-15).021 * In months Gregorio GV,et.al Hepatology 2001:33:544

31 OLS AIH-SC and AIH in Children: Conclusions Sclerosing cholangitis is present in 50% of children with typical AIH Normal SAP can be present in children, onion-skin fibrosis is rare Biochemical markers do not predict bile duct disease Concordance between histology and radiographic findings is poor Response to immunosuppression is good in both conditions AIH and ASC appear to constitute a spectrum of the same disease

32 Primary Sclerosing Cholangitis in Children (N = 9) Autoantibody negative; abnl bile ducts Male predominance (6/9) Associated immune disorders (4/9) Ulcerative colitis (3/4) Presenting symptoms similar to AIH Diarrhea (6/9) and hematochezia (3/6) Jaundice is infrequent at presentation (8/9)

33 Pediatric Variants Autoimmune polyendocrinopathy-candidiasisectodermal dysplasia (APECED) Celiac disease and chronic hepatitis Hyper-eosinophilic syndrome and CAH Neonatal liver disease and placental transfer of AMA De novo autoimmune hepatitis after liver transplant Autoimmune lymphoproliferative syndrome (ALPS) and AIH

34 Autoimmune Polyendocrinopathycandidiasis-ectodermal dysplasia (APECED) Mutation of autoimmune regulator (AIRE) gene located on chromosome 22q22.3 Transcription factor expressed in the thymus Associated autoimmune conditions Hypoparathyroidism -- Hepatitis (10-20%) Addison s disease -- Diabetes Autoimmune enteropathy -- Graves disease Clinical features Variable; Onset in the first decade of life, but can occur anytime Anti-CYP1A2 specific but insensitive marker Responds to immunosuppressive medications Eisenbarth GS NEJM 2004:350:

35 Autoimmune Polyglandular Syndrome type 1 (APS 1) Also known as: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) Autoimmune polyendocrine syndrome type I Characterized by the presence of 2 of 3 major clinical manifestations: Chronic mucocutanous candidiasis Hypoparathyroidism Addison disease APS type II includes Addison disease Autoimmune thyroid disease And/or type 1 diabetes mellitus

36 Clinical Features Candidiasis is usually the first clinical manifestation (initial manifestation in 60%) Typically followed by hypoparathyroidism (79%) Addison disease (72%) All components present together in about half of patients 3 main diseases develop in first 20yrs with accompanying diseases appearing until at least 5 th decade

37 Clinical Features Type I diabetes mellitus Autoimmune thyroid disease Primary hypogonadism Chronic atrophic gastritis Autoimmune Hepatitis 10-20% lifetime risk Pernicious anemia Ectodermal Dystrophy Keratocojunctivitis Autoimmune skin diseases Vitiligo Alopecia Pituitary Defects

38 Autoimmune Regulator Gene (AIRE) AIRE teaches self AIRE regulates transcription of peripheral tissue-restricted antigens in thymic medullary epithelial cells. Knock out mice have defined autoimmune diseases In vitro studies show increased T cell thymic survival in absence of AIRE.

39 Celiac Disease and Chronic Hepatitis Gluten Hepatitis up to 60% of children Transient, no associated symptoms Resolves within 2-8 weeks of gluten-free diet Nonspecific reactive hepatitis Celiac disease may be silent Autoimmune hepatitis Rare Associated with elevated IgG, compatible histology Type 1 markers, or marker negative Responds to immunosuppressive medications Rubio-Tapia A and Murray JA Hepatology 2007:46:

40 Celiac disease and cryptogenic ALT elevation Volta U et al Lancet 1998;352:26-29

41 Hyper-eosinophilic Syndrome and Clinical features Chronic Hepatitis Asymptomatic or mild systemic symptoms Mild lymphadenopathy Eosinophilia (20-77%) Elevated IgG (50%), ALT , total bili <5.0 Type 1 markers; compatible histology Treatment Histology, symptoms, and biochemical markers improved with prednisone and azathioprine Relapse may be heralded by rise in eosinophil count Digest Dis Sci 1988;33:233 Hepatology 1991;13:1090

42 Molecular Mimicry and AIH Type 2 CYP2D6 is the microsomal target of LKM-1 antibody Peptide sequence between 193 and 212 was the target in 12/13 patients Within one hexameric aminoacid sequence of the CYP2D6 protein: 5/6 aminoacids were shared with HCV 6/6 aminoacids were shared with CMV Conclude: Multiple exposures to viruses mimicking self may represent an important pathway to the development of autoimmunity. Kerkar N. J Immunology 2003; 170:1481

43 Final Take on AIH in Children An animal model is desperately needed. If it is not in the differential, you will not make the diagnosis. Prednisone and Azathioprine work pretty well, but are there other treatment strategies we should consider? It is time to initiate a multi-center approach to the diagnosis, management, and pathophysiological understanding of AIH in children.