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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 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 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 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 Liver biopsy 60-104 29-44 28-65 79-111 55-58 250-300 92-104 327-340 578-590 58-113 73-117 136-205 83-99 65-78 600 1,500 Gastroenterology 2002;123:1367-84 Proposed “Healthy Ranges” of ALT Prati D et al Ann Intern Med 2002:137:1-9 Variation in serum Alkaline Phosphatase by age Reichling JJ et al Diges Dis Sci 1988:33:1601-14 Prevalence of elevated ALT among US adolescents: NHANES 1999-2004 Fraser A, et al Gastroenterology 2007;133:1814 Isolated Unconjugated Hyperbilirubinemia • • • • • • Gilbert’s syndrome Neonatal jaundice Hemolysis, blood transfusion Resorption of a large hematoma Crigler-Najjar syndrome “Shunt” hyperbilirubinemia 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. 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 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 AST/ALT elevation in skeletal muscle diseases Nathwani RA et al Hepatology 2005:41:380-82 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 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 Ulcerative colitis Celiac disease Vitiligo ----- Hypereosinophilic syndrome Hemolytic anemia Diabetes mellitus Myasthenia gravis 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 Clinical and Immunological Features Clinical Features Type 1 Type 2 Autoantibodies SMA/ANA LKM-1 Age (yr) 10-20; 45-75 2-14 Women (%) 78 89 Elevated Gamma Globulin +++ + HLA Association B8, DR3, DR4 B14, DR3, C4AQO Other immune disease(%) 41 34 Steroid response +++ ++ Progress to cirrhosis (%) 45 82 Type 3 SLA 10-50 90 ++ ? 58 +++ 75 Interface Hepatitis Multinucleated cells Plasma cells Cholestasis Autoimmune Hepatitis in Children Gregorio GV, et.al. Hepatology 1997;25:541 • 73 patients from 1973-1993 with autoimmune liver disease • 21 sclerosing cholangitis were excluded • 52 with autoimmune hepatitis were evaluated SEROLOGICAL MARKERS AT THE TIME OF PRESENTATION Marker Titer # ANA 1:80-320 4 SMA 1:40-2560 10 ANA + SMA Comments 14 Anti-LSP 1:400-1300 4 LKM-1 1:40-10400 18 LKM + ANA 1 No marker 1 Weak ANA=2; ANA + after 1,3 mo 3 y/o spherocytosis; +LKM/SMA Autoimmune Hepatitis in Children ANA/SMA (N = 32) LKM-1 N = (20) p-value Age (yr) 10.5 (2.3-14.9) 7.4 (0.8-14.2) 0.011 Female 24 (75%) 15 (75%) 1.00 Length of illness* 4 (.2-24.6) 1.7 (.03-15.4) 0.06 Fulminant failure 1 (3%) 5 (25%) 0.05 Autoimmune disorders (AD) 7 (22%) 4 (20%) 0.85 First degree relative with AD 13 (43%) 8 (40%) 0.81 * Months Gregorio GV, et.al. Hepatology 1997;25:541 AIH in Children: Laboratory ANA/SMA LKM-1 N = 32 N = 20 62 (6/462) 188 (13-773) 0.007 AST IU/L (< 50) 632 (81-2500) 1146 (93-2440) 0.047 GGT IU/L (< 50) 126 (11-871) 91 (36-299) 0.055 SAP IU/L (< 350) 376 (131-1578) 377 (102-1677) 0.087 1.6 (1-2.5) 1.6 (1-8.6) 0.39 IgG g/L (5-15) 28 (13.4-73.3) 21 (10.2-40) 0.06 Alb g/L (35-50) 32 (20-43) 38 (25-54) 0.02 ANA titer (N=20) 120 (10-5120) NA SMA titer (N=26) 160 (10-2560) NA LKM1 titer (N=19) NA 640 (40-10400) T.Bili µmol/L (< 20) INR (0.9-1.2) p-value Gregorio GV, et.al. Hepatology 1997;25:541 52 patients (20 LKM) 6 fulminant failure (5 LKM) 47 medical Rx 1 Rx steroids 4 OTLTx 1 died 3 elevated AST 2 died 9 OTLTx 5 OTLTx 1 @ 15mo 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 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 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 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 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 Autoimmune Hepatitis/Sclerosing Cholangitis in Childhood: 16 yr study Gregorio GV, et al Hepatology 2001;33:544 • 76 patients with liver disease and circulating antibodies • 21 too ill to undergo cholangiography • 55 underwent cholangiography (ERCP = 51), 54 had sigmoidoscopy / bx • Recruited 1984-1997 • Followed through 1999 •55 patients were antibody positive • Sclerosing cholangitis (AIH-SC) • Normal cholangiogram (AIH) 27 28 • 22 patient with sclerosing cholangitis from other causes during the study (not included) • • • • Primary immunodeficiency Langerhan cell histiocytosis Neonatal sclerosing cholangitis Primary sclerosing cholangitis 6 2 5 9 OLS AIH-SC in Children: Demographics Age (yr) OCS AIH-SC AIH (N = 27) (N = 28) 11.8 (2.3-16) 10.5 (2.2-14) p-value .16 Female 15 (55%) 22 (79%) .12 Jaundice 15 (56%) 19 (68%) NS 2 (7%) 7 (25%) .08 IBD 12 (44%) 5 (18%) .03 Immune disorders 13 (48%) 11 (39%) NS Pruritis Gregorio GV ,et.al Hepatology 2001:33:544 OLS AIH-SC in Children: Laboratory OLS AIH-SC AIH (N = 27) (N = 28) 20 (4-178)* 35 (4-306) .04 AST (IU/L) 102 (18-1215) 333 (24-4830) .002 GGT (IU/L) 129 (13-948) 76 (29-333) NS SAP (IU/L) 303 (1.4-1710) 356 (131-878) NS 1.1 (.9-1.6) 1.2 (.96-2.5) .009 IgG (g/L) 19.4 (7.8-70.8) 24 (7.8-73.3) NS Alb (g/L) 39 (27-54) 35 (25-47) .051 ANA +ve 20 18 SMA +ve 20 13 LKM1 +ve 1 8 74% 36% T.Bili (µmol/L) INR pANCA +ve * = median (range) p-value .014 Gregorio GV ,et.al Hepatology 2001:33:544 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 T. Bili 2 (1-40) 1.5 (.5-12) 5 (1-48) 1.25 (.25-16) .015 NS Alb INR 0.5 (.5-1) 1 (1-6) 2 (.25-8) 6 (.5-15) .016 .021 * In months Gregorio GV ,et.al Hepatology 2001:33:544 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 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) 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 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 – Addison’s disease – Autoimmune enteropathy -- Hepatitis (10-20%) -- Diabetes -- 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 2004:350:2068-79 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 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 5th decade 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 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. 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 2007:46:1650-58 Celiac disease and cryptogenic ALT elevation Volta U et al Lancet 1998;352:26-29 Hyper-eosinophilic Syndrome and Chronic Hepatitis • Clinical features – – – – – Asymptomatic or mild systemic symptoms Mild lymphadenopathy Eosinophilia (20-77%) Elevated IgG (50%), ALT 150-1700, 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 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 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.