自身免疫性肝炎 AASLD 2010

AASLD PRACTICE GUIDELINES Diagnosis and Management of Autoimmune Hepatitis Michael P. Manns,1 Albert J. Czaja,2 James D. Gorham,3 Edward L. Krawitt,4 Giorgina Mieli-Vergani,5 Diego Vergani,6 and John M. Vierling7 This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the Association. 1. Preamble Clinical practice guidelines are defined as ‘‘systemati- cally developed statements to assist practitioner and patient decisions about appropriate heath care for spe- cific clinical circumstances.’’1 These guidelines on autoimmune hepatitis provide a data-supported approach to the diagnosis and management of this dis- ease. They are based on the following: (1) formal review and analysis of the recently-published world lit- erature on the topic [Medline search]; (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines;2 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy State- ment on Guidelines;3 and (4) the experience of the authors in the specified topic. These recommendations, intended for use by physi- cians, suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in ev- ery case. Specific recommendations are based on rele- vant published information. To more fully characterize the quality of evidence supporting the recommenda- tions, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommenda- tion.4 The grading system applied to the recommenda- tions has been adapted from the American College of Cardiology and the American Heart Association Prac- tice Guidelines, and it is given below (Table 1). 2. Introduction Autoimmune hepatitis (AIH) is a generally unresolv- ing inflammation of the liver of unknown cause. A working model for its pathogenesis postulates that environmental triggers, a failure of immune tolerance mechanisms, and a genetic predisposition collaborate to induce a T cell–mediated immune attack upon liver antigens, leading to a progressive necroinflammatory and fibrotic process in the liver.5,6 Onset is frequently insidious with nonspecific symptoms such as fatigue, jaundice, nausea, abdominal pain, and arthralgias at presentation,7 but the clinical spectrum is wide, rang- ing from an asymptomatic presentation8,9 to an acute severe disease.10,11 The diagnosis is based on histologic abnormalities, characteristic clinical and laboratory findings, abnormal levels of serum globulins, and the presence of one or more characteristic autoantibod- ies.12-16 Women are affected more frequently than men (sex ratio, 3.6:1).17-19 and the disease is seen in all ethnic groups20-34 and at all ages.21,35-44 There are no robust epidemiological data on AIH in the United States. In Norway and Sweden, the mean incidence is 1 to 2 per 100,000 persons per year, and its point prevalence is 11 to 17 per 100,000 persons per year.45,46 A similar incidence and prevalence can be All AASLD Practice Guidelines are updated annually. If you are viewing a Practice Guideline that is more than 12 months old, please visit www.aasld.org for an update in the material. Abbreviations: AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; CYP1A2, cytochrome P450 1A2; HCV, hepatitis C virus; IBD, inflammatory bowel disease; IgG, immunoglobulin G; LKM-1, liver/kidney microsome type 1; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SMA, smooth muscle antibodies. From the 1Medical School of Hannover, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany; 2Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Rochester, MN; 3Dartmouth Medical School, Department of Pathology, Lebanon, NH; 4University of Vermont College of Medicine, Department of Medicine, Given Building, Burlington, VT; 5Pediatric Liver Centre and 6Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London, UK; and 7Baylor Liver Health, Baylor College of Medicine, Houston, TX. Received January 22, 2010; accepted January 25, 2010. Address reprint requests to: Michael P. Manns, M.D., Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany. E-mail: manns. michael@mh-hannover.de; fax: þ49 511 532-4896. Copyright VC 2010 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23584 Potential conflict of interest: Michael Manns has received research support, lecture fees and took part in clinical trials for Falk Pharma GmbH, Freiburg, Germany, and Roche Pharma, Basel, Switzerland. 1 assumed for the Caucasian population of North America. Data on the natural progression of untreated disease are derived principally from experiences published prior to the widespread use of immunosuppressive agents for AIH and before the detection of the hepati- tis C virus (HCV).47-54 These studies showed that as many as 40% of patients with untreated severe disease died within 6 months of diagnosis,47,49 and that survi- vors frequently developed cirrhosis, esophageal varices and subsequent hemorrhage.47,49,50,55 An acute onset of illness is common (�40%),56-63 and an acute severe presentation, characterized by hepatic encephalopathy within 8 weeks of clinical symptoms, is sometimes seen.10,11,58,64-68 Three randomized, controlled treatment trials estab- lished that prednisone alone or in combination with azathioprine improved symptoms, laboratory tests, his- tological findings, and immediate survival.48-50 These studies led to the acceptance of immunosuppressive regimens as the standard in treatment, and supported an autoimmune pathogenesis of the disease. However, these studies were completed decades ago before the discovery of HCV. Therefore, HCV infection could not be excluded in these studies and one can assume that several of these patients were indeed infected with HCV. Liver transplantation has also evolved as an effective treatment for the decompensated patient, and the 5-year patient and graft survivals now exceed 80%.69-74 3. Diagnosis: Criteria and Methods The diagnostic criteria for AIH and a diagnostic scoring system were codified by an international panel in 199375 and revised in 199913 (Table 2). The clinical criteria for the diagnosis are sufficient to make or exclude definite or probable AIH in the majority of patients. The revised original scoring system was devel- oped as a research tool by which to ensure the compa- rability of study populations in clinical trials (Table 3),13 and can also be applied in diagnostically challeng- ing cases not readily captured by the descriptive crite- ria.13 The treatment response is graded in the revised original scoring system, and a score can be rendered both before and after treatment (Table 3).13 A pretreat- ment score of 10 points or higher, or a posttreatment score of 12 points or higher, indicate ‘‘probable’’ AIH at presentation. A pretreatment score of 10 points has a sensitivity of 100%, a specificity of 73%, and diagnos- tic accuracy of 67%.76 A pretreatment score of 15 points, indicative of ‘‘definite AIH’’ has a sensitivity of 95%, a specificity of 97%, and a diagnostic accuracy of 94%.76 A retrospective study supports the usefulness of the revised original system in children with AIH.77 A simplified scoring system has been proposed recently to ease clinical application78 and is based on the presence and level of autoantibody expression by indirect immunofluorescence, serum immunoglobulin G (IgG) concentration, compatible or typical histologi- cal features, and the absence of viral markers (Table 3).78 In three recent retrospective studies, the simpli- fied scoring system performed with high sensitivity and specificity in the diagnosis of AIH, but it has yet to be validated in prospective studies.76,79,80 3.1. Clinical, Laboratory, and Histological Assessment The diagnosis of AIH requires the presence of charac- teristic clinical and laboratory features, and the exclu- sion of other conditions that cause chronic hepatitis and cirrhosis (Table 2).13 The clinical assessment should include an evaluation of alcohol consumption and the use of drugs known to be hepatotoxic. The laboratory assessment should include determinations of the levels of serum alanine (ALT) or aspartate (AST) aminotrans- ferases, alkaline phosphatase (AP), albumin, total or c-globulin, IgG, and bilirubin (conjugated and uncon- jugated). AIH can be asymptomatic in 34%-45% of patients.8,9,269 Typically, these patients are men and have significantly lower serum ALT levels at presenta- tion than do symptomatic patients.8 Histological find- ings, including the frequency of cirrhosis, are similar Table 1. Description of Grading System Used to Assign Class and Level of Evidence Classification Description Class I Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful, and effective Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure or treatment Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy Class IIb Usefulness/efficacy is less well established by evidence/opinion Class III Conditions for which there is evidence and/or general agreement that a diagnostic evaluation/procedure/treatment is not useful/effective and in some cases may be harmful Level of Evidence Description Level A Data derived from multiple randomized clinical trials or meta analyses Level B Data derived from a single randomized trial, or nonrandomized studies Level C Only consensus opinion of experts, case studies, or standard of care 2 MANNS ET AL. HEPATOLOGY, June 2010 between asymptomatic patients and symptomatic patients. Because as many as 70% of asymptomatic patients become symptomatic during the course of their disease,8,9 asymptomatic patients must be followed life- long, preferably by an expert, to monitor for changes in disease activity. In children, the gamma glutamyl transferase level may be a better discriminator of biliary disease, Table 2. Codified Diagnostic Criteria of the International Autoimmune Hepatitis Group Features Definite Probable Liver histology Interface hepatitis of moderate or severe activity with or without lobular hepatitis or central portal bridging necrosis, but without biliary lesions or well defined granulomas or other prominent changes suggestive of a different etiology Same as for ‘‘definite’’ Serum biochemistry Any abnormality in serum aminotransferases, especially if the serum alkaline phosphatase is not markedly elevated. Normal serum concentrations of alpha antitrypsin, copper and ceruloplasmin. Same as for ‘‘definite’’ but patients with abnormal serum concentrations of copper or ceruloplasmin may be included, provided that Wilson disease has been excluded by appropriate investigations Serum immunoglobulins Total serum globulin or c globulin or IgG concentrations greater than 1.5 times the upper normal limit Any elevation of serum globulin or c globulin or IgG concentrations above the upper normal limit Serum autoantibodies Seropositivity for ANA, SMA, or anti LKM 1 antibodies at titers greater than 1:80. Lower titers (particularly of anti LKM 1) may be significant in children. Seronegativity for AMA. Same as for ‘‘definite’’ but at titers of 1:40 or greater. Patients who are seronegative for these antibodies but who are seropositive for other antibodies specified in the text may be included. Viral markers Seronegativity for markers of current infection with hepatitis A, B, and C viruses Same as for ‘‘definite’’ Other etiological factors Average alcohol consumption less than 25 g/day. No history of recent use of known hepatotoxic drugs. Alcohol consumption less than 50 g/day and no recent use of known hepatotoxic drugs. Patients who have consumed larger amounts of alcohol or who have recently taken potentially hepatotoxic drugs may be included, if there is clear evidence of continuing liver damage after abstinence from alcohol or withdrawal of the drug. Adapted from Alvarez F, Berg PA, Bianchi FB, et al. J Hepatol 1999;31:929 938. Table 3. Revised Original Scoring System of the International Autoimmune Hepatitis Group Sex Female þ2 HLA DR3 or DR4 þ1 AP:AST (or ALT) ratio >3 2 Immune Disease Thyroiditis, colitis, others þ2 <1.5 þ2 c globulin or IgG level above normal >2.0 þ3 Other markers Anti SLA, anti actin, anti LC1, pANCA þ2 1.5 2.0 þ2 1.0 1.5 þ1 <1.0 0 ANA, SMA, or anti LKM1 titers >1:80 þ3 Histological features Interface hepatitis þ3 1:80 þ2 Plasmacytic þ1 1:40 þ1 Rosettes þ1 <1:40 0 None of above 5 Biliary changes 3 Other features 3 AMA Positive 4 Treatment response Complete þ2 Relapse þ3 Viral markers Positive 3 Negative þ3 Drugs Yes 4 Pretreatment aggregate score: No þ1 Definite diagnosis >15 Probable diagnosis 10 15 Alcohol <25 g/day þ2 Posttreatment aggregate score: >60 g/day 2 Definite diagnosis >17 Probable diagnosis 12 17 Adapted from Alvarez F, Berg PA, Bianchi FB, et al. J Hepatol 1999;31:929 938. AMA, antimitochondrial antibody; anti LC1, antibody to liver cytosol type 1; anti LKM1, antibody to liver/kidney microsomes type 1; anti SLA, antibody to soluble liver antigen; ANA, antinuclear antibody; AP:AST (or ALT) ratio, ratio of alkaline phosphatase level to aspartate or alanine aminotransferase level; HLA, human leuko cyte antigen; IgG, immunoglobulin G; pANCA, perinuclear anti neutrophil cytoplasmic antibody; SMA, smooth muscle antibody. HEPATOLOGY, Vol. 51, No. 6, 2010 MANNS ET AL. 3 specifically primary sclerosing cholangitis (PSC), than the AP level, which can be elevated due to bone activ- ity in the growing child.77 Neither the gamma glu- tamyl transferase nor AP levels, however, discriminate between the presence or absence of cholangiopathy in children with AIH.36 The conventional serologic markers of AIH should also be assessed, including an- tinuclear antibody (ANA), smooth muscle antibody (SMA), antibody to liver/kidney microsome type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) (Table 4).12-16 Diagnostic evaluations should be under- taken to exclude hereditary diseases (Wilson disease and alpha 1 antitrypsin deficiency), viral hepatitis, stea- tohepatitis and other autoimmune liver diseases that may resemble AIH specifically primary biliary cirrho- sis (PBC) and PSC.12,13,36,81,82 Liver biopsy examination at presentation is recom- mended to establish the diagnosis and to guide the treatment decision.12,13,15,16 In acute presentation unavailability of liver biopsy should not prevent from start of therapy. Interface hepatitis is the histological hallmark (Fig. 1), and plasma cell infiltration is typical (Fig. 2).83-87 Neither histological finding is specific for AIH, and the absence of plasma cells in the infiltrate does not preclude the diagnosis.84 Eosinophils, lobular inflammation, bridging necrosis, and multiacinar ne- crosis may be present.55,86,87 Granulomas rarely occur. The portal lesions generally spare the bile ducts. In all but the mildest forms, fibrosis is present and, with advanced disease, bridging fibrosis or cirrhosis is seen.55,83-85 Occasionally, centrizonal (zone 3) lesions exist (Fig. 3),10,60-62,88-91 and sequential liver tissue examinations have demonstrated transition of this pat- tern to interface hepatitis in some patients.62 The his- tological findings differ depending on the kinetics of the disease. Compared to patients with an insidious onset, patients with acute severe hepatic failure exhibit more interface and lobular hepatitis, lobular disarray, hepatocyte necrosis, central necrosis and submassive necrosis, but less fibrosis and cirrhosis.10,92,93 Table 4. Autoantibodies in the Diagnosis of Autoimmune Hepatitis Antibody Target Antigen(s) Liver Disease Value in AIH ANA* Multiple targets including: AIH Diagnosis of type 1 AIH � chromatin, PBC � ribonucleoproteins PSC � ribonucleoprotein complexes Drug induced Chronic hepatitis C Chronic hepatitis B Nonalcoholic fatty liver disease SMA* Microfilaments (filamentous actin) and intermediate filaments (vimentin, desmin) Same as ANA Diagnosis of type 1 AIH LKM 1* Cytochrome P450 2D6 (CYP2D6) Type 2 AIH Diagnosis of type 2 AIH Chronic hepatitis C LC 1* Formiminotransferase cyclo deaminase (FTCD) Type 2 AIH Diagnosis of type 2 AIH Chronic hepatitis C Prognostic implications Severe disease pANCA (atypical) Nuclear lamina proteins AIH Diagnosis of type 1 AIH PSC Re classification of cryptogenic chronic hepatitis as type 1 AIH SLA tRNP(SER)Sec AIH Diagnosis of AIH Chronic hepatitis C Prognostic implications Severe disease Relapse Treatment dependence LKM 3 family 1 UDP glucuronosyl transferases (UGT1A) Type 2 AIH Diagnosis of type 2 AIH Chronic hepatitis D ASGPR Asialoglycoprotein receptor AIH Prognostic implications PBC Severe Disease Drug induced hepatitis Histological activity Chronic hepatitis B, C, D Relapse LKM2 Cytochrome P450 2C9 Ticrynafen induced hepatitis None, does not occur after withdrawal of ticrynafen LM Cytochrome P450 1A2 Dihydralazine induced hepatitis Diagnosis of APECED hepatitis APECED hepatitis *Antibodies highlighted as bold letters indicate the conventional serological repertoire for the diagnosis of AIH. The other autoantibodes may be useful in patients who lack the conventional autoantibody markers. AIH, autoimmune hepatitis; ANA, antinuclear antibody; APECED, autoimmune polyendocrinopathy candidias ectodermal dystrophy; ASGPR, antibody to asialoglycoprotein receptor; LC1, liver cytosol type 1; LKM, liver kidney/microsome; LM, liver microsome antibody; pANCA, perinuclear anti neutrophil cytoplasmic antibody; PBC, primary bili ary cirrhosis; PSC, primary sclerosing cholangitis; SLA, soluble liver antigen; SMA, smooth muscle antibody; UGT, uridine diphosphate glucuronosyltransferase. 4 MANNS ET AL. HEPATOLOGY, June 2010 Some patients exhibit features of both AIH and another disorder such as PSC, PBC, or autoimmune cholangitis, a variant syndrome.94-100 Certain histo- logic changes such as ductopenia or destructive cholan- gitis may indicate the presence of one of these variant types.101 In these cases, the revised original scoring sys- tem can be used to assist in diagnosis (Table 3).13,76 The findings of steatosis or iron overload may suggest alternative or additional diagnoses, such as nonalco- holic fatty liver disease, Wilson disease, chronic hepatitis C, drug toxicity, or hereditary hemochromatosis.84,85,101 Differences between a definite and probable diagno- sis of AIH by the diagnostic scoring system relate mainly to the magnitude of serum IgG elevation, titers of autoantibodies, and extent of exposures to alcohol, medications, or infections that could cause liver injury.13,76,78 There is no time requirement to establish chronicity, and cholestatic clinical, laboratory, and his- tologic changes generally preclude the diagnosis. If the conventional autoantibodies are not detected, a proba- ble diagnosis can be supported by the presence of other autoantibodies such as atypical perinuclear anti- neutrophil cytoplasmic antibody (atypical pAN