Autoimmune Hepatitis- Better

Autoimmune Hepatitis- Better Understanding 9 : 3 SG Maity, Kolkata Introduction & Definition Autoimmune Hepatitis () is generally considered un-resolving inflammation of liver of unknown cause. Pathologic mechanism postulates environmental triggers, failure of immune tolerance mechanisms, genetic pre-disposition collaborate to induce T-Cell mediated immune attack upon liver antigen leading to progressive necroinflammatory and fibrotic process in the liver (Figure 1). Onset is frequently insidious with non-specific symptoms such as fatigue, jaundice, nausea, abdominal pain and arthralgias, but clinical spectrum is wide ranging from asymptomatic presentation to an acute severe disease. Diagnosis is based on histologic abnormalities, characteristic clinical and laboratory findings, abnormal level of globulin and the presence of one or more characteristic auto antibodies. It is one of the important causes of chronic liver disease and diagnosed after exclusion of other causes like chronic viral hepatitis, wilson s disease, drug induced liver disease, NAFLD (Non alcoholic fatty liver disease), PBC (Primary biliary cirrhosis) and PSC (Primary sclerosing cholangitis). Diagnosis The diagnostic criteria for and diagnostic scoring system were co-defined by an international panel in 1993 and revised in 1999. The clinical criteria for the diagnosis are sufficient to make or exclude definite or probable in the majority of patients: Definitive diagnosis of : Require exclusion of other similar diseases, lab findings which indicate substantial immuno reactivity and on histology interface hepatitis. Probable diagnosis: It is justified when findings are compatible with but insufficient for definitive diagnosis. Patients who lack conventional autoantibody but who are seropositive for investigational markers e.g., Antibodies to ASGRP, SLA, actin or LC1, are classified as probable diagnosis. Diagnosis requires predominant elevation of serum aminotrans- ferase level, exclusion of other similar disorders (e.g., Wilson s disease, drug induced hepatitis and viral hepatitis), ANA (antinuclear antibody), SMA (smooth muscle antibody), anti-lkm1 (antibodies to liver kidney microsome type 1) Scoring Criteria: The original scoring system proposed by International Autoimmune Hepatitis group accommodates the diverse manifestation of and render an aggregate score that reflects the net strength of the diagnosis before and after glucocorticoid treatment (Table 1). A simplified scoring system has been developed to ease clinical application. The original scoring system has greater sensitivity for diagnosis than simplified system (100% vs. 95%) but the simplified system has greater specificity (90% vs. 73%) and predictability (92% vs. 82%). 463

Medicine Update 2012 Vol. 22 Elevated serum AST and gamma globulin levels AST: alkaline phosphatase >3 AMA negative Ceruloplasmin normal Normal α1 antitrypsin phenotype Normal or near-normal serum iron HBsAG, anti-hcv, IgM anti-hav negative Liver biopsy Interface hepatitis ± lobular hepatitis Definite Probable Gamma globulin level 1.5 normal ANA, SMA, or anti-lkm1 1:80 No exposure to drugs or blood products Alcohol intake < 25 g/day Gamma globulin level < 1.5 normal ANA, SMA, or anti-lkm1 1:40 Previous drugs or blood products Alcohol use Other liver- related auto antibodies Type 1 Type 2 ANA and/or SMA+ Anti-LKM1 + Fig. 1 : Diagnostic algorithm for 464

Autoimmune Hepatitis - Better Understanding Table 1 : Simplified scoring system for diagnosis of : Category Variable Score Auto antibodies ANA or SMA 1:40 +1 Antibodies to liver- kidney > 1:80 +2 microsome type 1 1:40 +2 Antibodies to soluble liver antigen Positive +2 Immunoglobulin Level Immunoglobulin G > upper limit of normal +1 1:1 times upper limit of normal +2 Histological findings Morphologic features Compatible with autoimmune hepatitis +1 Typical of autoimmune hepatitis +2 Viral Disease Absence of viral hepatitis No viral markers +2 Pre-treatment aggregate score Definite diagnosis 7 Probable diagnosis 6 Table 2 : Auto-antibodies in the diagnosis of : Antibody Target Antigen(s) Liver Disease Value in ANA Multiple targets including Chromatin Rhibo nucleoprotein Rhibo nucleoprotein complex PBC PSC Drug induced Chr. Hep C Chr. Hep B NAFLD SMA Microfilaments (filamentous action) LKM1 Cytochromac P-450 Type II Chr. Hep C panca Nuclear lamina Protein PSC Diagnosis of type I Diagnosis of type I Diagnosis of type II Diagnosis of type I SLA trnp Diagnosis of type I LKM3 Family I UDP Type II Gencoronosyc Transference (UGTIA) Diagnosis of type II ASGPR Asialoglycoprotein Prognostic implication Pathogenesis The pathogenic mechanism for is unknown. Popular hypothesis- includes triggering agent, genetic predeposition and various determinants of auto-antigen display, immunocyte activation, and effector cell expansion. Proposed triggering factor include infectious agent, drug and toxins. Clinical & Lab features Histology Treatment Table 3 : Variant forms of AH + PBC + PSC + Cholestatic features Features of AMA+ Cholangitis Cholestasis if AP 2x ULN & UDCA if AP>2x ULN and/or florid duct lesion. features ulcerative colitis AMA- Abnormal Cholangiogram Cholangitis Cholestasis & UDCA ANA and or SMA + AMA- No ulcerative colitis Normal cholangiogram Cholangitis Cholestasis and or UDCA depending on AP level & histology features. Auto-antibody negative features No autoantibody HLA-DR3 or DR4 Interface Hepatitis Conventional regimen for CD4+ helper T-Cell is the principle effector cell and its activation is the initial step in the pathogenic pathway. Classification- Two types of with distinct serologic profile have been identified (Table 2): Type I- Autoimmune Hepatitis- Type I is characterized by SMA, ANA or both. Antibodies to action have greater specificity but less sensitivity. A typical P-ANCA is found as many as 90% in type I. Type II- Autoimmune Hepatitis- Type II is characterized by the expression of Anti- LKM1. Most affected person is children between ages of 2 to 14 yrs. Variant Forms Patients who have atypical features of currently lack an official designation and confident treatment strategy (Table 3). Autoantibody- Negative Autoimmune hepatitis Thirteen percent of adult with chronic hepatitis of undermined cause satisfy international criteria for diagnosis of but lack of the characteristic auto-antibodies. These pts commonly designated as cryptogenic chronic hepatitis. Auto-antibody negative pts are similar in age, female predominant, frequency of concurrent immunology diseases, histologic features and laboratory findings of classic. They are similar frequency of HLA-B8, HLA-DR3 and HLA-A1 B8 DR3 and respond to glucocorticoid treatment. 465

Medicine Update 2012 Vol. 22 Table 4 : Clinical features Occurrence (%) Symptoms Fatigue 86 Jaundice 77 Upper abdominal discomfort 48 Pruritus (mild) 36 None (at presentation) 25-34 Anorexia 30 Myalgias 30 Diarrhea 28 Cushingoid features 19 Fever ( 40 C) 18 Physical Findings Hepatomegaly Jaundice Spider angiomata Concurrent immune disease Splenomegaly None Ascites Encephalopathy Laboratory Features Elevated aspartate aminotransferase level Hypergammaglobulinemia Increased immunoglobulin G level Hyperbilirubinemia Alkaline phosphatase level 2-fold normal Immunoserologic Markers SMA, ANA, or anti-lkm1 Atypical panca Anti-asialoglycoprotein receptor Anti-actin Anti-chromatin Anti- liver cytosol 1 Anti- soluble liver antigen and Chronic hepatitis: 78 69 58 38 32 <25 20 14 100 92 91 83 33 100 92 (type 1 only) 82 74 42 (ANA+ only) 32 (type 2 only) 11-17 About 8% of white North American adult with classic have concurrent HCV infection and 52% pts of chronic hepatitis C have auto-antibodies concurrent immune disease or both. It is important to identify to one or other group because interferon therapy can enhance immune manifestations of persons with and concurrent HCV infection and immunosuppressive treatment can increase serum viral level with chronic hepatitis C. Clinical features of - The clinical features of frequently reflect the inflammatory activity of the liver disease or complication of cirrhosis (Table 4). Severe or Fulminant presentation have an acute severe or fulminant presentation that can be mistaken for acute viral or toxic hepatitis and mis-diagnosis can delay life saving therapy. Glucocorticoid therapy can be effective in suppressing the inflammatory activity in 36-100% of pts, whereas delay in treatment lead to negative outcome. Treatment of (Table 5) A. Absolute indication of treatment Three randomized, controlled trails have demonstrated that pts with serum AST level at-least 10-fold of upper limit of normal (ULN) or more than 5-fold of ULN is associated with serum y-globulin level more than 2-fold ULN have high mortality (60% at 6 months), if untreated. Further histological findings of bridging necrosis or multilobular necrosis at presentation progress to cirrhosis is 82% in untreated pts and are associated with 5 yr mortality of 45%. These laboratory & histologic findings at presentation are absolute indication n of corticosteroid treatment. B. Uncertain indications In pts who have no or only mild symptoms and with mild lab & histologic findings & prospective & randomized controlled treatment trails not performed, their indication for treatment remains uncertain & highly unindividualized. Asymptomatic individuals with inactive cirrhosis may have an excellent immediate survival without corticosteroid treatment. There is no definite guideline to identify the safe population who require no therapy. Spontaneous resolution is possible in some asymptomatic pts with mild disease but these pts improve less commonly and more slowly than treated pts. Since mild autoimmune hepatitis can progress and a rapid & complete response to a normal end point can be anticipated, corticosteroid therapy is favored in asymptomatic mild disease, especially in young who can tolerate the medication satisfactorily. Corticosteroid therapy is effective only in pts with clinical, laboratory or histological features of active liver inflammation (Table 6). Pts with inactive or burned out cirrhosis cannot benefit from therapy and increased risk of drug-induced side effects. Pts with brittle diabetes, vertebral compression, pyschosis or severe osteoporosis must be critically analyzed for treatment benefit before corticosteroid administration. Treatment indication in children Treatments of children are similar to those of adults (Table 7). 466

Autoimmune Hepatitis - Better Understanding Table 5 : Indications for Treatment in Autoimmune Hepatitis Indications Findings Absolute Relative None Clinical Incapacitating symptoms Relentless clinical progression Mild or no symptoms Asymptomatic with minimal laboratory changes. Previous intolerance of prednisone and/or azathioprine Laboratory Histologic AST 10-fold ULN AST 5-fold ULN and gamma globulin 2-fold ULN Bridging necrosis Multilobular necrosis AST 3- to 9.9-fold ULN AST 5-fold ULN and gamma globulin <2-fold ULN Interface hepatitis AST <3-fold ULN Severe cytopenia Inactive cirrhosis Portal hepatitis Decompensated cirrhosis with vericeal bleeding. Prednisone only* (mg/ day) Prednisone* (mg/day) USA (mg/ day) EU (mg/kg/ day) Table 6 : Immunosuppressive Treatment Regimens for Adults in Monotherapy Combination Therapy Azathioprine Week 1 60 30 50 1.2 Week 2 40 20 50 1.2 Week 3 30 15 50 1.2 Week 4 30 15 50 1.2 Maintenance Until endpoint 20 and below 10 50 1.2 Reasons for preference Cytopenia Post menopausal state Thiopurin methyltransferase deficiency Osteoporosis Brittle diabetes Obesity Pregnancy Acne Malignancy Emotional lability Shot course ( months) Hypertension * can be used in place of prednisone in equivalent doses. Treatment Regimens Treatment Regimen in Adults: Two treatment regimens are advocated and are equally effective in severe. Prednisone alone (60 mg daily), or lower dose of prednisone (30 mg daily) with azathioprine (50 mg daily or 1-2 mg/kg Table 7 : Immunosuppressive Treatment Regimens for Children in Initial Regimen Maintenance Regimen Endpoint Prednisone, 1.2 mg/kg Prednisone taper over 6 Normal liver tests for 1 daily (up to 60 mg/day), 8 weeks to 0.1 0.2 mg/ 2 yrs during treatment. for two weeks either kg daily or 5 mg daily alone or in combination with azathioprine, 1.2 mg/kg daily. Azathioprine at constant No flare during entire dose if added ini- interval tially. Continue daily prednisone Liver biopsy examina- dose with or tion discloses no in- without azathioprine flammation. or switch alternate day prednisone dose adjusted to response with or without azathioprine body wt daily). Prednisone is tapered down to the individual sufficient to maintain remission with 20 mg daily, reduction of dose done by 5 mg every week until 10 mg/day and even further reduction of dose to 2.5 mg/week. The maintenance regimen is continued until resolution of disease, or treatment failure or drug intolerance. The combination of prednisone and azathioprine is associated with lower occurrence of corticosteroid related side-effects, than higher dose of prednisone & its preferred treatment. Treatment Regimen in Children: Treatment regimen is less rigorously established in children than adults & reflects the preferences of individual centres. But several report shows, children show similar efficacy as adults. Prednisone is the mainstay in virtually all reported regimen, at the dose of 1.2mg/kg of body wt daily. Tapering schedule vary widely. Recommendations Diagnosis of should be made when compatible clinical signs & symptoms, lab abnormalities, serological and histological findings are present and other conditions that can cause chronic hepatitis including viral, hereditary, metabolic, and cholestatic & drug induced disease have been excluded. Diagnostically challenging cases that have few or atypical clinical, laboratory, serological or histological findings should be assessed by the diagnostic scoring system. In pts negative for conventional auto-antibodies in is suspected, other serological marker e.g. Anti-SLA and atypical panca, should be tested. 467

Medicine Update 2012 Vol. 22 In pts with & multiple endocrine disorders, the APECED syndrome must be excluded by testing for typical mutation in the AIRE gene. Classification of into two types based on the presence of ANA and SMA (type 1 ) or anti-lkm1 and anti LCI (type 2 ) Diagnosis of should be considered in all pts with acute or chr. Hepatitis of undermined cause including pts with acute severe hepatitis. Cholangiographic studies should be considered to exclude PSC in adults if no response to corticosteroid therapy after 3 months. All children with and all adult with both & IBD should undergo cholangiographic studies to exclude PSC. Immunosuppressive treatment should be instituted in pts with serum AST or ALT level 10-fold ULN, at least 5-fold ULN in connection with serum x-globulin level, at-least 2-fold ULN, and/or histological features of bridging necrosis or multilobular necrosis. Immunosuppressive treatment may be considered in adult pts without symptoms & mild laboratory and histologic changes, but the decision is individualized & against possible risk. Immunosuppressive treatment should not be instituted in pts with minimal or no disease activity or inactive cirrhosis, but pts should follow closely. Immunosuppressive therapy should not be given in pts with serious pre-existent co-morbid condition (psychosis, vertebral compression, brittle diabetes, uncontrolled hypertension). Azathioprine should not be started in pts with severe pre-treatment cytopenia. Immunosuppressive treatment should be started in children at the time of diagnosis regardless of symptoms. Treatment should start with prednisone (starting with 30 mg daily & tapering down to 10 mg daily within 4 wks) in combination with azathioprine (50 mg daily or 1-2 mg/ kg body wt wkly. Combination regimen is preferred. In children prednisone (1-2 mg/kg daily, max 60 mg daily with azathioprine (1-2 mg/kg daily) or 6 mercaptopurine (1.5 mg/kg daily) Pts on long term corticosteroid should monitor for bone disease at base line and then annually & pre-treatment vaccination against HAV & HBV to be given. Pts to be counseled for risk of azathioprine in pregnancy & should be discontinued. Improvements of serum AST or ALT level, and also total bilirubin concentration & y-globulin or IgG level should be monitored at 3-6 months interval during treatment. Treatment should be continued until normal AST or ALT level, total bilirubin, y-globulin or IgG level and normal liver histology. 1 st relapse after drug withdrawal should be retreated with combination of prednisone plus azathioprine with same treatment regimen. Treatment failure in adults should be managed with high dose prednisone (60 mg daily) or 30 mg daily in combination with azathioprine (150 mg daily).other alternative medication e.g., mycofenolate mofetil, cyclosporine mycophenolate mofetil (2 gm daily orally) is the most promising agent. Liver transplantation should be considered in pts with acute liver failure, decompensated cirrhosis or HCC. References: 1. Alverez F, Berg P, Bianchi F et al, International Autoimmune Hepatitis group report: Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31:929-38. 2. Czaja AJ. Auto antibodies in autoimmune liver disease. Adv Clin Chem 2005; 40: 127-64. 3. Czaja AJ. Autoimmune hepatitis: Diagnosis. 4. Hennes EM, Zeniya M, Czaja AJ. Simplified diagnostic criteria for autoimmune hepatitis. Hepatology 2008; 48:169-76. 5. Micheal P Mannas, Albert J Czaja, James D Gorhametal Hepatology, vol 51, No 6, 2010. AASLD Practice Guidelines, Diagnosis and management of Autoimmune hepatitis. 6. Sleisenger and Fordtran s Gastrointestinal and Liver disease. Pathophysiology/ Diagnosis/ Management 9e vol-2. Chap 88 P-1461-1476, 2010. 7. Honnes EM, zenia M, Czaja AJ et al. Simplified diagnostic criteria for autoimmune hepatitis. Hepatology 2008; 48: 169-76. 468