Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases

Funding for the development of this Practice Guideline and Guidance was provided by the American Association for the Study of Liver Diseases. Potential conflict of interest: Dr. Mack consults for Albireo. Dr. Kerkar advises High Tide and received royalties from Elsevier. Dr. Manns consults for, is on the speakers' bureau for, and received grants from Falk. He consults for and received grants from Novartis. Dr. Vierling advises and received grants from CymaBay, Enanta, Genkyotex, Intercept, Lilly, Novartis, and TaiwanJ. He advises Arena, BioIncept, Blade, and GlaxoSmithKline and received grants from Allergan and NGM. What's New Since 2010 Guidelines? Histological features of NAFLD are present in 17%‐30% of adult patients with AIH, and concurrent NAFLD may influence response to therapy. Diagnostic scoring systems should be used only to support clinical judgment in challenging cases of AIH and to define AIH cohorts for clinical studies. Immune checkpoint inhibitors have been associated with immune‐mediated liver injury and are frequently steroid‐responsive, but the liver injury lacks autoantibodies and typical histological features of AIH. Elastography may be used to assess the stages of hepatic fibrosis noninvasively. Testing for TPMT activity prior to AZA treatment is encouraged in all patients. Budesonide and AZA or predniso(lo)ne and AZA are recommended as first‐line AIH treatments in children and adults who do not have cirrhosis, acute severe hepatitis, or ALF. AZA can be continued throughout pregnancy, whereas the use of MMF is contraindicated in pregnancy. Liver tissue examination prior to drug withdrawal in individuals with ≥2 years of biochemical remission is preferred but not mandatory in adults and required in children. MMF or TAC can be used as second‐line treatment in children and adults with AIH who have failed to respond to first‐line therapy. Patients with acute severe AIH should receive predniso(lo)ne followed by LT if no improvement within 2 weeks, whereas patients with AIH and ALF should be evaluated directly for LT. Glucocorticoids can be discontinued after LT and patients monitored for recurrence of AIH. Purpose and Scope The objectives of this document are to provide guidance in the diagnosis and management of autoimmune hepatitis (AIH) based on current evidence and expert opinion and to present guidelines to clinically relevant questions based on systematic reviews of the literature and the quality of evidence.1 This practice guideline/guidance constitutes an update of the guidelines on AIH published in 2010 by the American Association for the Study of Liver Diseases (AASLD).2 It updates the epidemiology, diagnosis, management, and outcomes of AIH in adults and children. The document is divided into "guideline recommendations" and "guidance statements." Guideline recommendations were based on evidence derived from systematic reviews of the medical literature and supported, if appropriate, by meta‐analyses. The systematic reviews and meta‐analyses were conducted independently by the Mayo Clinic Evidence‐Based Practice Center. Findings were analyzed and interpreted by a multidisciplinary panel of experts, including both content and methodology experts, who rated the quality of evidence and determined the strength of each recommendation. The quality of clinical evidence was determined by its source (e.g., randomized controlled trial or observational study), and the strength of the recommendation was determined by assessing the quality of evidence, balance of benefits and harms, patient values and preferences, and use of resources and costs. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to categorize each recommendation as strong or conditional (Table 1).3 Details of the methodology, systematic reviews, and meta‐analyses are published separately. The guideline recommendations focus on pertinent management issues for which sufficient evidence was available to render a recommendation. They address glucocorticoid and azathioprine therapy as first‐line management, second‐line medications after failure of first‐line therapy, and maintenance management after liver transplantation (LT; see Supporting Table S1 for patient/intervention/comparison/outcome questions related to systematic reviews). Table 1 - GRADE Assessment of Clinical Studies Study Design Rating Quality Strength Determinants Strength and Implications of Recommendation Randomized controlled trial High Quality of evidence Strong Moderate Balance of benefits and harms Most people would want course Most people should take course Can be adapted as policy in most cases Low Patient values and preferences Observational Very low Resources and costs Conditional Feasibility Many people would select course Requires decision aids and shared decision‐making Debatable policy choice Acessibility Equity Quality downgrades: selection bias, inconsistency, imprecision, indirectness, publication bias. Quality upgrades: large effect, very large effect, dose–response gradient, confounders produce no effect. "Guidance statements" were developed by consensus of an expert panel based on formal review and analysis of the published literature on the topic. The quality (level) of evidence and the strength of each guidance statement were not formally rated for the guidance statements. "Guidance statements" were used to address topics for which a sufficient number of randomized controlled trials were not available to justify a systematic review and meta‐analysis. The "guidance statements" and "guideline recommendations" were also reviewed by members of the AIH Association, a 501(c)(3) nonprofit organization, in order to incorporate patient and public perspectives. "Guidance statements" and "guideline recommendations" are intended to provide health care practitioners with updated information and rigorously assessed, evidence‐based recommendations. They are intended to aid, not supersede, clinical judgment. For ease of reading this AIH guidance/guidelines document, a glossary of definitions is provided in Table 2. Table 2 - Definitions of AIH and Its Treatment Outcomes Condition Definition AIH Characteristic histologic abnormalities (lymphoplasmacytic interface hepatitis), elevated AST, ALT, and total IgG and the presence of one or more characteristic autoantibodies Inactive cirrhosis Absence of inflammatory infiltrates in both portal tracts and fibrous bands in cirrhosis Acute severe AIH Jaundice, INR > 1.5 < 2, no encephalopathy; no previously recognized liver disease370 ALF INR ≥ 2; hepatic encephalopathy within 26 weeks of onset of illness; no previously recognized liver disease100 Biochemical remission Normalization of serum AST, ALT, and IgG* levels Histological remission Absence of inflammation in liver tissue after treatment Treatment failure Worsening laboratory or histological findings despite compliance with standard therapy Incomplete response Improvement of laboratory and histological findings that are insufficient to satisfy criteria for remission Relapse Exacerbation of disease activity after induction of remission and drug withdrawal (or nonadherence) Treatment intolerance Inability to continue maintenance therapy due to drug‐related side effects *Patients with cirrhosis in biochemical remission may have persistent elevation of IgG. AIH is an immune‐mediated inflammatory liver disease of uncertain cause which affects all ages, both genders, and all ethnicities. Patients may be asymptomatic, be chronically ill, or present with acute liver failure (ALF); and the diagnosis must be considered in all patients with acute or chronic liver inflammation, including patients with graft dysfunction after LT. AIH does not have a signature diagnostic feature, and the diagnosis requires the presence of a constellation of typical features which can vary between patients with the same disease and can occur in other liver diseases. Progression to advanced hepatic fibrosis, cirrhosis, death from liver failure, or LT are possible outcomes. Treatment with immunosuppressive agents has been life‐saving, but management regimens may be long‐term, associated with serious side effects, and variably effective. Background Epidemiology AIH occurs at all ages and within all ethnic groups, and its manifestations appear to vary by race and ethnicity. Alaskan Natives have a high frequency of icteric AIH at presentation, Hispanics more commonly present with cirrhosis, and African Americans have accelerated progression of disease and a higher rate of recurrence after LT compared to other races.5 Female predominance occurs in adults (71%‐95% women)7 and children (60%‐76% girls).13 Early epidemiological reports suggested that the onset of AIH had age peaks at 10‐30 and 40‐60 years, but the findings may have been influenced by referral bias.17 Older peak ages at onset (>60 years) have been reported in Denmark11 and New Zealand.10 The estimated incidence of AIH varies worldwide depending on the region and the age at onset. Incidence rates in adults range from 0.67 (southern Israel) to 2 cases per 100,000 person‐years (Canterbury region of New Zealand).10 Pediatric incidences are lower, ranging from 0.23 (Canada)16 to 0.4 per 100,000 person‐years (United States).15 Over the past few decades there has been a near 50% increase in incidence in Spain, Denmark, Sweden, and the Netherlands.11 The prevalence of AIH in adults ranges from 4 (Singapore) to 42.9 (Alaska natives) per 100,000 persons.17 The prevalence in children ranges from 2.4 (non‐native Canadian children)26 and 3 per 100,000 persons (United States)15 to 9.9 per 100,000 persons (native Canadian children).17 Genetic Predispositions In common with other autoimmune diseases, the primary genetic associations in AIH involve major histocompatibility complex loci. Human leukocyte antigen (HLA) associations cluster within the conserved 8.1 ancestral haplotype which defines the alleles carried by most Caucasians27 and results from linkage disequilibrium within HLA class I, II, and III loci: HLA‐A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*03:01, DRB1*04:01, DRB1*13:01, DRB3*01:01, DQA1*05:01, DQB1*02:01.28HLA‐DRB1*03:01 haplotypes associated with AIH are the result of additional genetic recombinations. AIH also has non‐HLA genetic associations, but the odds ratios (ORs) for risk of AIH are far lower than those for HLA alleles. Susceptibility for AIH has been associated with genetic polymorphisms encoding cytotoxic T lymphocyte antigen‐4 (CTLA‐4),33 tumor necrosis factor‐alpha (TNF‐α),34 Fas (cluster of differentiation 95 [CD95] or apoptosis antigen‐1),36 vitamin D receptor,38 signal transducer and activator of transcription 4,40 transforming growth factor‐beta 1,41 macrophage migration inhibitory factor,42 SH2B adapter protein 3,43 caspase recruitment domain family member 10,43 and the interleukin‐23 (IL‐23) receptor.44 Dysfunctional products of genetic variants or deficient levels of gene product may disrupt homeostatic mechanisms that affect the proliferation and survival of autoreactive T and B cells, regulate cytokine production, and modulate inflammatory and immune responses. AIH is a complex genetic disease that requires interplay among genetic, epigenetic, immunologic, and environmental factors. A rare exception is AIH associated with an autosomal recessive mutation in the autoimmune regulator gene on chromosome 21q22.3, which has been associated with autoimmune polyglandular syndrome type 1 (APS‐1).45 Environmental exposures play greater roles than genetics in shaping the immune repertoire, and specific environmental factors, such as viral infections or xenobiotic exposures, can act as environmental triggers for loss of self‐tolerance to autoantigens in persons genetically susceptible to AIH.46 Pathogenesis Autoreactive CD4 and CD8 T cells break self‐tolerance to hepatic autoantigens as the result of environmental triggers and inability of autoantigen‐specific natural T regulatory cells (nTregs) and inducible T regulatory cells (iTregs) to prevent autoreactivity48 (Fig. 1). Concurrently, in the absence of effective B regulatory cell (Breg) inhibition, autoreactive B cells produce autoantibodies.51 Peptide autoantigens are presented by class II and class I HLA alleles to autoreactive T‐cell receptors on CD4 T helper (Th) cells and CD8 cytotoxic T lymphocytes (CTLs), respectively. Binding of different autoantigens to B‐cell receptors initiates secretion of specific autoantibodies.Figure 1: Current concepts of the immunopathogenesis of AIH. Current knowledge supports a multistep working model of the immunopathogenesis of AIH, in which a break in self‐tolerance to hepatocyte autoantigens initiates immunological responses causing progressive hepatic necroinflammation and fibrogenesis.50 In the first step, thymic autoantigen‐specific nTregs are incapable of preventing immune responses to hepatic autoantigens during hepatic or systemic immune responses to environmental triggers, such as viral infections or xenobiotics. In the second step, professional antigen‐presenting cells (APCs) present autoantigenic peptides to autoreactive α/β T cell receptors (TCRs) on naive CD4+ Th cells, and CD8+ T cells and APCs activate MAIT cells by presenting bacterially processed vitamin B antigens to MAIT cell TCRs.54 Costimulation is a crucial third step, which induces expression of T‐cell genes required for proliferation, differentiation, and maturation of autoantigen‐specific CD4+ Th subsets (e.g., Th1, Th2, Th3, Th9, Th17, iTregs, Tr1, Tfh cells) and both CD8+ CTLs and CD8+ Tregs. In the fourth step, secretion of specific cytokines by subsets of CD4+ Th cells produces a variety of immunological sequelae, including CD4+ Th2 cytokine stimulation of B‐cell autoantibody production, CD4+ Tfh‐cell activation of B cells into antibody‐secreting plasma cells, Treg stimulation of Breg development through IL‐35 mechanisms and cytokine‐activated macrophages, and CD4+ Th17 cell–mediated pathogenic cytotoxicity. The fifth step is the cumulative failure of CD4+ and CD8+ Tregs and Bregs to control autoantigen‐specific effector mechanisms causing hepatic injury.53 Moreover, exposure of CD4+ iTregs to specific cytokines can transform them from regulatory cells into pathogenic CD4+ Th17 cells.52 The sixth step is the generation of complex portal inflammatory infiltrates of effector cells that cause cytotoxicity of periportal and lobular hepatocytes. Necroinflammatory destruction of hepatocytes results in activation of periportal stellate cells, which amplify local immune responses through contact‐dependent and independent mechanisms and cause progressive portal fibrosis, culminating in cirrhosis in the absence of effective immunosuppressive therapy. Abbreviations: Ag, antigen; IFN, interferon; TGF, transforming growth factor.The composition of the local cytokine milieu dictates CD4 Th cells to differentiate into Th1, Th2, Th9, Th17, iTregs, and T follicular helper (Tfh) cell subsets in the presence of costimulatory signaling.50 CD4 Th1 cells secrete cytokines that promote proliferation of autoantigen‐specific CD8 CTLs and activation of macrophages. CD4 Th2 cytokines augment immunoglobulin production by B cells, while cytokines produced by Tfh cells induce their conversion to immunoglobulin G (IgG)–secreting plasma cells. CD4 Th17 cells intensify inflammation and tissue injury. Autoantigen‐specific iTregs can down‐regulate the proliferation and functions of all CD4 Th subtypes, and inadequate numbers and/or dysfunction of CD4 iTregs may play a key role in AIH.52 Cytokine‐mediated transformation of CD4 iTregs into pathogenic CD4 Th17 cells also promotes perpetuation of AIH. Low doses of IL‐2 preferentially stimulate proliferation and function of CD4 iTregs, while high doses promote production of other pathogenic CD4 Th subsets. Mucosal invariant T (MAIT) cells that react with bacterially processed vitamin B antigens presented by major histocompatibility complex class I–related molecules congregate in the peribiliary region in AIH.54 MAIT cells can express characteristics of CD4 Th1 and Th17 cells, and they may transform CD4 iTregs into proinflammatory CD4 Th17 cells. Inflammatory infiltrates composed of CD4 Th subsets, CD8 CTLs, MAIT cells, B cells, plasma cells, and innate immune cells, including natural killer (NK) and NK T cells and activated macrophages, can accumulate within the portal tracts. Adhesion molecules and chemokines mediate transendothelial migration of immune cells into tissues.50 Extension of inflammation into periportal hepatocytes (interface hepatitis) and lobular hepatitis causes apoptosis of hepatocytes and fibrogenesis in untreated patients with AIH. Uptake and processing of immune complexes of autoantigen and immunoglobulin by antigen‐presenting cells greatly increases activation of autoantigen‐specific CD8 CTLs, and autoantibodies may enhance CD8 CTL cytotoxicity of hepatocytes. Diagnosis Diagnostic Requisites and Subtypes The diagnosis of AIH is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (elevated serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels and increased serum IgG concentration), and the presence of one or more characteristic autoantibodies.2 AIH lacks a signature diagnostic marker, and the diagnosis requires characteristic features and the exclusion of other diseases that may resemble it (e.g., viral hepatitis, drug‐induced liver injury, Wilson's disease, hereditary hemochromatosis).56 There are two types of AIH, based on the specific autoantibodies that are present. Type 1 is characterized by antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA)/anti‐actin antibodies, and type 2 is characterized by antibodies to liver kidney microsome type 1 (anti‐LKM1), usually in the absence of ANA and SMA.57 The characteristic clinical features of these two types are presented in Table 3. In addition, up to 20% of AIH cases are negative for ANA, SMA, and LKM1 autoantibodies, despite the presence of other characteristic features of AIH (seronegative AIH). If seronegative AIH is suspected, other autoantibodies may be sought, as indicated in Table 4 and Fig. 2. Classification of AIH into types assists in management and aids in predicting outcomes in children, but it may be less informative in adults.58 Table 3 - Characteristic Features of Type 1 and Type 2 AIH Features Type 1 AIH Type 2 AIH Frequency US adults, 96%61 US children, 9%‐12%14 UK children, 38%13 Age at presentation Peripubertal and adults Usually under 14 years153 Mode of presentation Chronic symptoms common Acute onset (~40%) Ascites or GI bleeding rare Acute liver failure possible555 Asymptomatic in 25%‐34% Relapse frequent108 Acute in 25%‐75% Acute severe in 2%‐6% Laboratory features Hypergammaglobulinemia IgA levels may be reduced153 Autoantibodies ANA Anti‐LKM1 SMA, anti‐actin [Anti‐LC1, Anti‐LKM3] SLA Concurrent immune diseases Autoimmune thyroiditis Autoimmune thyroiditis Rheumatic diseases Diabetes mellitus IBD Vitiligo Autoimmune overlap with PSC (ASC in children) Common in children Rare Atypical pANCA‐positive Atypical pANCA‐negative Overlap with PBC Seen in adults (not children) Not reported Cirrhosis at presentation Rare after drug withdrawal usually Abbreviations: serum immunoglobulin Table 4 - Autoantibodies in the Diagnosis of AIH Diagnostic ANA Type 1 Type 1 LKM1 Type 2 SLA Type 1 after with Type 1 Type 1 Type 1 family Type 2 Type 2 of overlap Type 1 Abbreviations: autoimmune Diagnostic for the of AIH after exclusion of and diseases. ANA and should be in adults and antibodies to LKM1 should be if ANA and are ANA, SMA, and LKM1 should be in all patients at presentation The findings of the liver support the diagnosis of AIH or that an overlap AIH with or The absence of ANA, SMA, and LKM1 additional that can antibodies to tissue and for one of these autoantibodies support the diagnosis of AIH or other including disease Abbreviations: tissue ANA, SMA, and the for the diagnosis of AIH (Table ANA are in of American adults with AIH at presentation, are present in and are present in of patients with AIH have ANA, SMA, or as an at and have ANA can also occur as an in primary chronic hepatitis chronic hepatitis B liver disease and chronic liver disease and can occur as an in PSC chronic hepatitis and chronic liver disease ANA and are concurrent in of liver diseases of AIH, and the diagnostic for AIH from to if two autoantibodies are at Anti‐LKM1 are commonly in the absence of ANA and SMA, and this has their after first for ANA and (Fig. have a low for AIH in American adults and their after first the absence of ANA and is in these patients. Anti‐LKM1 are in of and Canadian children with and of ANA, SMA, and are usually at in adults and children disease and treatment but they are not of disease activity or treatment to liver antigen are present in of patients with type 1 AIH, and they have high for the (Table have been the of AIH in of and they have been associated with severe disease and after drug Atypical antibodies are frequently present in patients with type 1 AIH but they diagnostic in overlap and liver may be the only autoantibodies are a of SMA, and they are present in of patients with AIH and (Table to is an that is present in of patients with AIH and of patients with to anti‐actin and has been associated with severe acute AIH, treatment and to liver type 1 are present in of patients with and they occur in children with severe liver (Table are present in of patients with type 2 and may be in seronegative and have not been rigorously in the should be and with the clinical may be depending on results of the and in with the diagnostic (Fig. Histological Findings The diagnosis of AIH be liver and histological hepatitis is the histological of AIH, by plasma cell in and lobular hepatitis in necrosis is also in and it occurs with frequency in patients with and is the of one cell into with both cells to is present in of patients with AIH, and hepatocyte are present in (Fig. of the histological findings is specific for AIH, but the findings of interface hepatitis with portal or cells into the and are considered typical of Histological features characteristic of AIH. inflammatory of the portal and interface hepatitis of the portal and cell predominance in a portal inflammatory and of a and A hepatocyte and of hepatocytes and are of of of is present in of adults at presentation, in the as as in of Cirrhosis in of adults with necrosis or The histological examination at presentation is to or concurrent the of inflammatory and the of plasma cells may be present in patients with but the clinical of this Histological findings of are present in 17%‐30% of patients with and liver tissue examination may patients with AIH and who are at increased risk of and The histological features of AIH with ALF in the and of is present in plasma inflammatory in hepatic necrosis in and in of patients with ALF have two or all of these Diagnostic The diagnostic scoring system of the Autoimmune was by an panel in in and in Table The scoring system has greater for AIH compared to the scoring system whereas the scoring system has and clinical judgment as the The diagnostic scoring system is for patients with complex or whereas the scoring system is most for typical of patients with the scoring system should be considered the system a low In children, a of to the of the criteria a of and a of In that were associated with seronegative AIH. The diagnostic scoring system can be to children and lower autoantibody than in adults as diagnostic of the serum for the serum in the with the serum or may the of the scoring system for children by the of to the and scoring systems of by