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
||Strength and Implications of Recommendation
|Randomized controlled trial
||Quality of evidence
||Balance of benefits and harms
Most people would want course
Most people should take course
Can be adapted as policy in most cases
||Patient values and preferences
||Resources and costs
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
||Characteristic histologic abnormalities (lymphoplasmacytic interface hepatitis), elevated AST, ALT, and total IgG and the presence of one or more characteristic autoantibodies
||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
||INR ≥ 2; hepatic encephalopathy within 26 weeks of onset of illness; no previously recognized liver disease100
||Normalization of serum AST, ALT, and IgG* levels
||Absence of inflammation in liver tissue after treatment
||Worsening laboratory or histological findings despite compliance with standard therapy
||Improvement of laboratory and histological findings that are insufficient to satisfy criteria for remission
||Exacerbation of disease activity after induction of remission and drug withdrawal (or nonadherence)
||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.
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
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
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.
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.
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
||Type 1 AIH
||Type 2 AIH
||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%
|Acute in 25%‐75%
|Acute severe in 2%‐6%
||IgA levels may be reduced153
|Concurrent immune diseases
|Autoimmune overlap with PSC (ASC in children)
||Common in children
|Overlap with PBC
||Seen in adults (not children)
|Cirrhosis at presentation
||Adults, 28%‐33% (especially elderly)
|Remission after drug withdrawal
||Rare, usually need long‐term immunosuppression
Abbreviations: GI, gastrointestinal; IgA, serum immunoglobulin A.
Table 4 -
Autoantibodies in the Diagnosis of AIH
||Type 1 AIH56
||Filamentous actin (F‐actin), vimentin, desmin81
||Type 1 AIH56
||Cytochrome P450 2D6 (CYP2D6)559
||Type 2 AIH153
||Sep (O‐phosphoserine) transfer RNA:Sec (selenocysteine) transfer RNA synthase560
||Type 1 AIH69
|Predicts relapse after treatment73
|Associated with poor outcome70
||Β‐tubulin isotype 577
||Type 1 AIH75
||Nuclear lamina proteins565
||Filamentous (F) actin81
||Type 1 AIH81
||Filamentous actin cross‐linking proteins568
||Type 1 AIH85
||UDP glucuronosyltransferase family 190
||Type 2 AIH90
||Type 2 AIH569
||Cytochrome P450 1A2572
||E2‐subunits of pyruvate dehydrogenase complex576
|PBC–AIH overlap syndrome177
|Type 1 AIH183
Abbreviations: APECED, autoimmune polyendocrinopathy‐candidias‐ectodermal dystrophy; UDP, uridine diphosphate.
ANA, SMA, and anti‐LKM1 constitute the conventional serological repertoire for the diagnosis of AIH (Table 4).2 ANA are detected in 80% of white North American adults with AIH at presentation, SMA are present in 63%, and anti‐LKM1 are present in 3%.61 Forty‐nine percent of patients with AIH have ANA, SMA, or anti‐LKM1 as an isolated serological finding at presentation; and 51% have multiple autoantibodies.61 ANA can also occur as an isolated serological finding in primary sclerosing cholangitis (PSC; 29%), chronic hepatitis C (26%), chronic hepatitis B (32%), nonalcoholic fatty liver disease (NAFLD; 34%), and chronic alcohol‐associated liver disease (21%); and SMA can occur as an isolated serological finding in PSC (6%), chronic hepatitis C (6%), and chronic alcohol‐associated liver disease (4%). ANA and SMA are concurrent in <10% of liver diseases outside of AIH, and the diagnostic accuracy for AIH improves from ~58% to 74% if two autoantibodies are detected at presentation.61
Anti‐LKM1 are commonly detected in the absence of ANA and SMA, and this observation has justified their assessment after first testing for ANA and SMA57 (Fig. 2). Furthermore, anti‐LKM1 have a low sensitivity for AIH in North American adults (1%),61 and their assessment after first demonstrating the absence of ANA and SMA is appropriate in these patients. Anti‐LKM1 are detected in 13%‐38% of British and Canadian children with AIH,13 and determinations of ANA, SMA, and anti‐LKM1 are usually made together at presentation. Autoantibody titers in adults and children roughly reflect disease severity and treatment response,63 but they are not established biomarkers of disease activity or treatment outcome.63
Antibodies to soluble liver antigen (anti‐SLA) are present in 7%‐22% of patients with type 1 AIH, and they have high specificity (99%) for the diagnosis65 (Table 4). Anti‐SLA have been the sole markers of AIH in 14%‐20% of patients,65 and they have been associated with severe disease and relapse after drug withdrawal.68 Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) are frequently present in patients with type 1 AIH (50%‐92%),75 but they lack diagnostic specificity, occurring in PSC, AIH–PSC overlap syndrome, ulcerative colitis (UC), and minocycline‐related liver injury.76 Occasionally atypical pANCA may be the only autoantibodies detected.56
Antibodies against filamentous (F) actin (antiactin) are a subset of SMA, and they are present in 86%‐100% of patients with AIH and SMA81 (Table 4). Antibody to alpha‐actinin (anti‐α‐actinin) is an investigational marker that is present in 42% of patients with AIH and 66% of patients with anti‐actin.84 Dual reactivity to anti‐actin and anti‐α‐actinin has been associated with severe acute AIH, incomplete treatment response, and relapse.84
Antibodies to liver cytosol type 1 (anti‐LC1) are present in 32% of patients with anti‐LKM1,87 and they occur mainly in children with severe liver disease87 (Table 4). Anti‐LKM3 are present in 17% of patients with type 2 AIH89 and may be useful in evaluating otherwise seronegative patients.90 Anti‐LC1 and anti‐LKM3 have not been rigorously assessed in the United States.94
Antibody determinations should be selective and consistent with the clinical phenotype being assessed. Additional serological markers may be sought depending on results of the earlier tests and in accordance with the evolving diagnostic possibilities (Fig. 2).
The diagnosis of AIH cannot be made without liver biopsy and compatible histological findings. Interface hepatitis is the histological hallmark of AIH, accompanied by plasma cell infiltration in 66% and lobular hepatitis in 47%.95 Centrilobular necrosis is also found in 29%,96 and it occurs with similar frequency in patients with and without cirrhosis.99 Emperipolesis is the penetration of one intact cell into another intact cell, with both cells retaining viability (as opposed to phagocytosis).101 Emperipolesis is present in 65% of patients with AIH, and hepatocyte rosettes are present in 33%103 (Fig. 3). None of the individual histological findings is specific for AIH, but the findings of interface hepatitis with portal lymphocytic or lymphoplasmacytic cells extending into the lobule, emperipolesis, and rosettes are considered typical of AIH.103
Cirrhosis is present in 28%‐33% of adults at presentation, especially in the elderly,9 as well as in 38% of children.13 Cirrhosis develops in 40% of adults with multilobular necrosis or bridging necrosis.105 The histological examination at presentation is essential to exclude alternative or concurrent diagnoses, grade the severity of inflammatory activity, and indicate the stage of fibrosis.111 IgG4‐positive plasma cells may be present in some patients with AIH,115 but the clinical impact of this finding remains unclear. Histological findings of NAFLD/nonalcoholic steatohepatitis (NASH) are present in 17%‐30% of patients with AIH,118 and liver tissue examination may identify patients with AIH and NASH who are at increased risk of liver‐related mortality (relative risk, 7.65) and adverse outcome (relative risk, 2.55).118
The histological features of AIH with ALF predominate in the centrilobular zone and consist of four principal features.100 Central perivenulitis is present in 65%, plasma cell–enriched inflammatory infiltrate in 63%, massive hepatic necrosis in 42%, and lymphoid follicles in 32%. Sixty‐six percent of patients with ALF will have two (21%), three (26%), or all four (19%) of these features.100
Diagnostic Scoring Systems
The diagnostic scoring system of the International Autoimmune Hepatitis Group (IAIHG) was created by an international panel in 1993,120 revised in 1999,56 and simplified in 2008121 (Supporting Table S2). The original revised scoring system has greater sensitivity for AIH compared to the simplified scoring system (100% versus 95%), whereas the simplified scoring system has superior specificity (90% versus 73%) and accuracy (92% versus 82%), using clinical judgment as the gold standard.122 The revised diagnostic scoring system is preferable for patients with complex or unusual features, whereas the simplified scoring system is most accurate for typical patients.122
Reassessment of patients with the revised scoring system should be considered whenever the simplified system yields a low score. In children, a meta‐analysis of four studies pertaining to the accuracy of the simplified criteria revealed a sensitivity of 77% and a specificity of 95%.123 In that study, false‐negative scores (~17%) were associated with seronegative AIH.
The revised original diagnostic scoring system can be applied to children and accepts lower autoantibody titers than in adults as having diagnostic significance.56 Substitution of the serum gamma‐glutamyltransferase (GGT) level for the serum alkaline phosphatase level in the ratio with the serum ALT or AST level may improve the specificity of the revised original scoring system for children by indicating the likelihood of biliary disease.124
Limitations to the revised original and simplified scoring systems include (1) lack of validation by prospective studies; (2) lack of accuracy in the setting of concurrent PSC, primary biliary cholangitis (PBC), NAFLD/NASH, LT, or fulminant liver failure125; (3) failure to include other serological markers, such as anti‐SLA56; and (4) dependence on autoantibody determinations by indirect immunofluorescence (titers) rather than by enzyme‐linked immunoassay (units).127 Diagnostic scoring systems can aid in establishing a diagnosis of AIH in challenging cases, but they are most useful in defining cohorts of patients with AIH for clinical studies.56
- The diagnosis of AIH requires compatible histological findings and is further supported by the following features: (1) elevated serum aminotransaminase levels; (2) elevated serum IgG level and/or positive serological marker(s); (3) exclusion of viral, hereditary, metabolic, cholestatic, and drug‐induced diseases that may resemble AIH.
- Initial serological testing should include determinations of ANA and SMA in adults and ANA, SMA, and anti‐LKM1 in children; consider additional autoantibody tests if warranted to secure the diagnosis.
- Diagnostically challenging cases should be reviewed by or referred to an experienced liver center prior to initiating therapy.
Most patients with AIH present after the development of chronic nonspecific symptoms (fatigue, malaise, arthralgias, or amenorrhea). Easy fatigability is the main complaint in 85% of patients, and jaundice may be present.128 Presence of pruritus or hyperpigmentation is inconsistent with the diagnosis,56 and weight loss suggests a serious complication (malignancy). Physical signs are usually absent, apart from signs of advanced chronic liver disease (spider nevi, caput medusa, splenomegaly, ascites, palmar erythema) or manifestations of extrahepatic autoimmune disease (vitiligo, inflammatory bowel disease [IBD]).129
AIH is asymptomatic in 25%‐34% of patients.60 Asymptomatic patients infrequently achieve spontaneous laboratory improvement (12%),131 may have histological findings similar to those of symptomatic patients,130 frequently develop symptoms within 2‐120 months (mean interval, 32 months; 26%‐70%),104 and experience a 10‐year survival that is less than that of treated patients with more severe disease (67% versus 98%).131 The absence of symptoms should not discourage treatment.130
Acute Severe Hepatitis and ALF
AIH presents with an acute onset (duration, <30 days) in 25%‐75% of patients.133 ALF associated with hepatic encephalopathy occurs in 3%‐6% of North American and European patients100 (see definitions in Table 2). Spontaneous exacerbation or a superimposed viral, toxic, or drug‐induced liver injury on previously undiscovered AIH (acute‐on‐chronic liver disease) must be excluded.138 ANA are absent or weakly positive in 29%‐39% of patients with acute severe AIH, and the serum IgG level is normal in 25%‐39%.140 Histological assessment is a key diagnostic test.141 Lobular hepatitis, lymphoplasmacytic infiltrate, and interface hepatitis support the diagnosis of acute AIH; and similar features in the presence of cirrhosis suggest exacerbated chronic disease.138 Central perivenulitis, lymphoplasmacytic infiltrate, lymphoid follicles, and massive hepatic necrosis can be found in AIH with ALF.100 Unenhanced computed tomography demonstrates heterogeneous hypoattenuated regions within the liver in 65% of patients with acute severe AIH and may be disease‐specific.142
ANA, SMA, and anti‐LKM1 are absent in 19%‐34% of North American and German patients originally diagnosed as cryptogenic hepatitis and then reclassified as AIH by the revised original diagnostic scoring system.143 Lower frequencies of autoantibody‐negative AIH have been reported in other ethnicities145 and by other diagnostic criteria, including clinical judgment and glucocorticoid responsiveness.146 ANA and SMA may be expressed later in the course of the disease,63 or the demonstration of SLA and atypical pANCA may direct the diagnosis to AIH148 (Fig. 2).
- The diagnosis of AIH must be considered in all patients presenting with acute or chronic liver disease, including patients with asymptomatic liver test abnormalities, ALF, and autoantibody‐negative hepatitis.
Concurrent Immune Diseases
Concurrent autoimmune diseases are present in 14%‐44% of patients with AIH,129 and they have been recognized with similar frequencies in patients with type 1 and type 2 disease.149 Autoimmune thyroid disease has been the most common concurrent autoimmune disease in type 1 AIH (10%‐18%),129 whereas type 1 diabetes,153 autoimmune thyroid disease,153 and autoimmune skin diseases (vitiligo, leucocytoclastic vasculitis, urticaria, alopecia areata) have been most common in type 2 AIH.152
Concurrent immune disease is commonly associated with few or no symptoms, but in rare instances, the severity of symptoms may obscure the underlying liver disease.129 but in rare instances, the severity of the concurrent disease may obscure the underlying liver disease.129 In 10%‐15% of children with APS‐1, AIH may accompany at least two of the three components of the syndrome (mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency).154
Extrahepatic autoimmune disease occurs most frequently in women,152 and the type varies by age group.156 Patients aged ≥60 years have autoimmune thyroid and rheumatic diseases more commonly than adults ≤30 years (42% versus 13%), whereas young adults more often have IBD and autoimmune hemolytic anemia (13% versus 0%).156 Furthermore, concurrent autoimmune disease is more common in patients with HLA DRB1*04:01156 or a family history of autoimmune disease in first‐degree relatives.152
The frequency of celiac disease in patients with AIH is higher than that in the general population (2.8%‐3.5%).160 Among Italian children with AIH, celiac disease was present in 16%.162 Both laboratory and serological features associated with celiac disease can be confused with AIH, and concurrent celiac disease may contribute to the degree of liver dysfunction in AIH.160 Pediatric patients with AIH and celiac disease who avoided gluten had higher frequencies of sustained remission after withdrawal of glucocorticoids than AIH children without celiac disease (33% versus 8%).166
- AIH patients should be screened for celiac and thyroid diseases at diagnosis.
- AIH patients should be assessed for rheumatoid arthritis, IBD, autoimmune hemolytic anemia, diabetes, and other extrahepatic autoimmune diseases based on symptomatology and medical provider concern.
Overlap Syndromes or Cholestatic Variants
Overlap syndromes between AIH and PBC or PSC are clinical descriptions and not validated pathological entities.126 Their major clinical value is to identify individuals who may not respond to conventional treatment for AIH.173
AIH–PBC Overlap Syndrome
The “Paris criteria” identify patients with overlapping features of AIH and PBC.177 Two of the following three criteria for PBC should be met: (1) serum alkaline phosphatase level ≥2‐fold the upper limit of normal (ULN) range or serum GGT level ≥5‐fold ULN, (2) presence of antimitochondrial antibodies (AMA), and (3) florid bile duct lesions on histological examination.126 Criteria for AIH in the setting of PBC (in addition to the presence of interface hepatitis) are (1) serum ALT level ≥5‐fold ULN and (2) serum IgG level ≥2‐fold ULN or presence of SMA.126 A single‐center comparison of the Paris criteria and the AIH scoring systems found that the Paris criteria were more reliable (sensitivity, 92%; specificity, 97%).181 Importantly, the Paris criteria may not capture all patients with the AIH–PBC overlap syndrome who have less pronounced cholestatic laboratory features.173
The IAIHG has emphasized that the criteria for the diagnosis of AIH–PBC have not been independently validated and that it is difficult to interpret the reported high sensitivity and specificity of the Paris criteria.126 They have also emphasized that the diagnostic scoring systems for AIH were not developed or validated for the diagnosis of the overlap syndromes and that they should not be used for this purpose.126
Antibodies to pyruvate dehydrogenase‐E2 (AMA) are present in 8%‐12% of patients with AIH in the absence of histological features of bile duct injury or loss.65 These patients respond well to glucocorticoid therapy, and they do not evolve into PBC.183 Liver tissue examination is required to exclude the AIH–PBC overlap syndrome, and the presence of AMA in patients with AIH is insufficient to make this diagnosis.
AIH–PSC Overlap Syndrome
Criteria for the diagnosis of AIH–PSC overlap syndrome (also known as autoimmune sclerosing cholangitis [ASC] in children108) include the presence of typical features of AIH, absence of AMA, and evidence of large‐duct PSC by endoscopic or magnetic resonance cholangiography or evidence of small‐duct PSC based on “onion skinning” periductal fibrosis on histology.173 Chronic UC is present in 16% of adults with AIH, and 42% of patients with AIH and concurrent UC have cholangiographic changes of PSC.184 UC is present in 20% of children with AIH, and it affects up to 45% with AIH–PSC overlap syndrome.108 Patients with cholestatic laboratory abnormalities, absence of AMA, histological features compatible with PSC or PBC, and normal cholangiograms may have small‐duct PSC185 or AMA‐negative PBC, respectively.186 The diagnosis of AIH–PSC overlap syndrome should be considered in all patients with AIH and chronic UC, unexplained cholestatic laboratory findings, or nonresponse to conventional glucocorticoid therapy.173
- Patients with AIH, cholestatic laboratory/histological findings consistent with PBC, and a positive AMA should be considered to have AIH–PBC overlap syndrome.
- Patients with AIH, cholestatic laboratory findings, histological features of bile duct injury or loss, and concurrent chronic UC should be evaluated for large‐duct PSC by cholangiography to determine whether they have the AIH–PSC overlap syndrome.
- The Paris criteria can aid in diagnosing the AIH–PBC overlap syndrome, but the criteria may exclude patients with AIH–PBC who have less severe cholestatic features.
- Neither the revised nor the simplified IAIHG diagnostic scoring systems for AIH should be used for assessing overlap syndromes.
Drug‐Induced AIH‐like Injury
Drug‐induced liver injury can mimic AIH,187 and an unpredictable idiosyncratic or hypersensitivity drug reaction has been implicated in 2%‐17% of patients with classical features of AIH.187 Minocycline,187 nitrofurantoin,187 and infliximab206 have been most commonly incriminated; and multiple other agents have been implicated (Table 5). Immune‐related adverse events, including hepatitis, have been reported with the use of immune activating agents, such as the checkpoint inhibitors.222 The liver injuries associated with the checkpoint inhibitors have usually improved with glucocorticoid therapy, but they have lacked the laboratory and histological features characteristic of AIH.225 Furthermore, some cases have been resistant to glucocorticoid therapy and associated with bile duct injury.230 The liver injuries associated with the checkpoint inhibitors should not be confused with AIH.
Table 5 -
Drugs Associated with Liver Injuries Resembling AIH
||Black cohosh (herbal medicine)599
||Dai‐saiko‐to (herbal medicine)604
||Germander (herbal medicine)606
||Hydroxycut (nutritional supplement)608
*Removed from marketplace.
Abbreviation: anti‐PD‐L1, antibody to programmed death protein ligand 1.
The clinical phenotype of drug‐induced AIH‐like injury is summarized in Table 6.56 The latency interval from drug exposure to disease onset ranges from 1‐8 weeks to 3‐12 months,231 but nitrofurantoin and minocycline can have latency periods that exceed 12 months.234 The clinical history should detail all previous exposures to drugs and supplements.
Table 6 -
Features of Drug‐Induced AIH‐Like Injury and AIH
||Drug Induced AIH‐Like Injury
||Female predominance, but men also affected2
|Hypersensitivity (fever, rash, eosinophilia)
||Up to 30%231
|Temporal relationship with drug
|HLA DRB1*03:01 or DRB1*04:01 association
|Concurrent autoimmune diseases
||Present in 14%‐44%129
|Cirrhosis at presentation
||Stop offending drug ± glucocorticoids187
||Glucocorticoids with AZA2
|Relapse after drug withdrawal
|Progression to cirrhosis
|Survival without transplantation
||10‐year survival, 89%‐91%105
The histological findings of interface hepatitis with portal and periportal infiltrates of lymphocytes, lobular hepatitis, plasma cells, and eosinophils are similar to those of classical AIH, except for the absence of advanced fibrosis or cirrhosis in most instances.187 Centrilobular zone 3 necrosis may be present,187 and bridging fibrosis (Ishak score ≥4) is rare.237
The diagnosis is supported by an acute onset, features of hypersensitivity, published literature on the implicated drug, latency period from drug exposure to liver injury, and absence of advanced fibrosis or cirrhosis at presentation.188 Liver tissue examination is warranted if the diagnosis is uncertain, laboratory findings indicate severe injury, or the institution of glucocorticoid therapy is being considered.
Treatment requires withdrawal of the offending agent with close monitoring until complete and sustained resolution of clinical and laboratory findings187 (Table 6). Resolution typically occurs within 1 month (rarely 3 months).187 In accordance with “Hy’s law,” serum aminotransferase levels >3‐fold ULN and total serum bilirubin level >2‐fold ULN increase the risk of death or need for LT in 9%‐12% of patients.240 Satisfaction of criteria for Hy’s law supports the institution of glucocorticoid therapy.187 Other reasons to consider glucocorticoid management are failure of the laboratory tests to improve after discontinuation of the medication or worsening of symptoms or laboratory tests at any time during the observation period.
Sustained biochemical resolution after glucocorticoid withdrawal strengthens the diagnosis of a self‐limited drug‐induced liver injury, whereas recrudescence of laboratory abnormalities is consistent with AIH.187 Recrudescent disease should be managed as AIH with immunosuppressive therapy.243 An algorithm based on the serum ALT level >17.3 ULN, total serum bilirubin level >6.6 ULN, and AST:ALT >1.5 has a sensitivity of 80% and specificity of 82% for drug‐induced ALF; this algorithm is a promising enhancement of Hy’s law.242
The outcome of drug‐induced AIH‐like injury has been excellent187 (Table 6). The infrequent exceptions have been reported mainly as case reports or abstracts,245 and idiosyncratic drug reactions do have a mortality of 5% and need for LT in 4.5%.234 The LiverTox website (https://livertox.nlm.nih.gov/aboutus.html) of the US Drug‐Induced Liver Injury Network is a valuable resource for evaluating suspected drug‐induced liver injury. It is a joint effort of the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases and the Division of Specialized Information Services of the National Library of Medicine, National Institutes of Health.
- Drug‐induced AIH‐like liver injury must always be considered in the differential diagnosis of AIH.
- The offending agent must be withdrawn and monitoring maintained to ensure laboratory resolution.
- Glucocorticoid therapy for drug‐induced AIH‐like injury should be instituted when symptoms or disease activity are severe (e.g., fulfill Hy’s law) or if symptoms and laboratory tests fail to improve or worsen after discontinuation of the offending drug.
- Laboratory flare after glucocorticoid withdrawal suggests underlying AIH and the need for immunosuppressive therapy.
Noninvasive Fibrosis Assessment
Noninvasive Assessment of Hepatic Fibrosis by Serum Biomarker Panels
Among 14 serum‐based biomarker panels for hepatic fibrosis, the FibroTest,247 the serum AST/platelet ratio index (APRI),250 the Fibrosis‐4 index (FIB‐4),251 and the enhanced liver fibrosis test253 have emerged as the better candidates in AIH.255 However, their role in AIH and their relative merit in assessing the progression or reversal of hepatic fibrosis, immediate and long‐term prognosis, risk of hepatocellular carcinoma (HCC), and treatment outcome remain unknown.259
Noninvasive Assessment of Hepatic Fibrosis by Liver Stiffness
Vibration‐Controlled Transient Elastography (or FibroScan)
Vibration‐controlled transient elastography (VCTE) or FibroScan correlates strongly with the histological stage of fibrosis in AIH,260 but its accuracy in quantifying fibrosis is impaired when undertaken within the first 3 months of treatment.260 Because liver stiffness estimated by VCTE is affected by both inflammation and fibrosis,260 the VCTE results at presentation correlate with histological grade of inflammation rather than stage of fibrosis.260 After at least 6 months of successful immunosuppressive therapy to reduce hepatic inflammation, VCTE can accurately diagnose cirrhosis and distinguish advanced stages of fibrosis (F3, F4) from less severe stages (F0‐F2).260 The cutoff values that best predicted fibrosis stages (defined as the highest sum of sensitivity plus specificity) were 5.8 kPa for F ≥ 2, 10.5 kPa for F ≥ 3, and 16 kPa for F ≥ 4.260 Improvements in liver stiffness correlate with biochemical remission, regression of fibrosis, and favorable prognosis when assessed after 6 months of treatment.265
Magnetic Resonance Elastography
The findings of magnetic resonance elastography (MRE) correlate strongly with fibrosis stage, and MRE appears to outperform VCTE for staging hepatic fibrosis in some studies performed in other liver diseases.266 Furthermore, MRE assessment of splenic stiffness can have prognostic value for predicting portal hypertension and esophageal varices.270 In AIH, the accuracy (97%), sensitivity (90%), specificity (100%), positive predictive value (100%), and negative predictive value (90%) of MRE for advanced hepatic fibrosis are excellent.269
MRE has outperformed conventional magnetic resonance imaging, the fibrosis scoring systems (FIB‐4, APRI), and the conventional laboratory tests (AST, ALT, international normalized ratio [INR], platelet count) for the diagnosis of cirrhosis in AIH.269 In one study, liver inflammation affected the assessment of fibrosis stage by MRE when the grade of fibrosis was ≤F2.271 In another study, liver stiffness in untreated patients with AIH was higher than that in treated patients (3.83 kPa versus 3.7 kPa, P = nonsignificant).269 This trend was seen at each fibrosis stage from F0 to F3 (F0, 3.1 kPa versus 2.61 kPa; F1, 2.94 kPa versus 2.74 kPa; F2, 3.2 kPa versus 2.63 kPa; F3, 4.1 kPa versus 3.99 kPa) and reversed in F4 (6.5 kPa versus 5.9 kPa).269 Differences in liver stiffness detected by MRE in untreated and treated patients with AIH have not been statistically significant, but the findings suggest that liver stiffness assessed by MRE can be influenced by therapy, possibly by reducing liver inflammation or hepatic fibrosis. MRE and VCTE have not been compared head‐to‐head in AIH.
Acoustic Radiation Force Impulse Imaging
Acoustic radiation force impulse imaging (ARFI) assesses liver stiffness by measuring changes in wave propagation speed, and displacements of short‐duration bursts of radiated sound waves are interpreted as changes in liver stiffness.256 The accuracy of ARFI for cirrhosis exceeds 90% (sensitivity, 93%; specificity, 85%),274 and results by meta‐analysis of 13 studies have been comparable to VCTE in predicting fibrosis stage ≥2 and cirrhosis.275 Splenic stiffness by ARFI has also correlated with the grade of esophageal varices, and ARFI may evolve as a method to assess manifestations of portal hypertension.276 ARFI can overestimate hepatic fibrosis in patients with massive hepatic necrosis, cholestasis, severe inflammation, and hepatic congestion.278
- Serum‐based biomarker panels for hepatic fibrosis are unestablished in AIH and should not be used.
- VCTE can identify advanced fibrosis or cirrhosis in patients with AIH with reasonable accuracy, but it should be deferred for at least 6 months after successful treatment of AIH in order to avoid the confounding effects of hepatic inflammation.
The aims of the pretreatment evaluation of patients with AIH are to limit treatment‐related complications and ensure an optimal therapeutic response.
Pretreatment Assessment of Thiopurine Methyltransferase Activity
Pretreatment testing of thiopurine methyltransferase (TPMT) activity identifies those rare patients with zero or near‐zero TPMT activity who are at risk for severe myelosuppression when treated with AZA or mercaptopurine (MP).279 Absent or near‐absent TPMT activity occurs in only 0.3%‐0.5% of the normal population,281 but the possibility of preventing severe bone marrow toxicity may warrant its use without an analysis of cost‐effectiveness.285 Genotypic and phenotypic screening for blood TPMT activity does not reduce the frequency of other common AZA or 6‐MP side effects such as nausea, rash, and arthralgias,289 and normal TPMT activity does not preclude the occurrence of dose‐dependent toxicities (including cytopenia) in AIH.291
- Consider screening patients with AIH for absent or near‐absent TPMT activity prior to initiating treatment with AZA.
Vaccination status should be reviewed and updated, ideally prior to the institution of immunosuppressive therapy.293 Live, attenuated vaccines are not recommended in persons on high doses of immunosuppression, whereas recombinant and inactivated vaccines are considered safe. Response rates to vaccines are lower in immunosuppressed patients but not so low as to preclude their use.
Patients unprotected against infections with hepatitis A virus (HAV) and hepatitis B virus (HBV) should undergo vaccination prior to immunosuppressive treatment if possible.294 Susceptibility to HAV infection (51%) and HBV infection (86%) has been demonstrated in most patients with autoimmune liver diseases, and the incidence of infection has been 1.3 (HAV infection) and 1.4 (HBV infection) per 1,000 person‐years.294 Protective antibodies have developed in all patients vaccinated for HAV and in 76% of patients vaccinated for HBV, with vaccination failures attributed mainly to concomitant immunosuppressive therapy.294
- Vaccines should be administered to all susceptible patients with AIH according to the age‐specific guidelines of the Centers for Disease Control and Prevention (https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html)
- Patients unprotected against HAV and HBV infection should undergo vaccination, preferably before immunosuppressive therapy.
Detection and Prevention of Reactivation of HBV Infection
Patients on immunosuppressive agents are at risk for reactivation of HBV infection, and guidelines have been developed recommending routine pretreatment screening of patients for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti‐HBc).296 Based on the serological profile (HBsAg‐positive versus HBsAg‐negative/anti‐HBc‐positive) and the type, dose, and duration of immunosuppressive therapy, the risk of HBV reactivation during treatment can be estimated as high (≥10%), moderate (1%‐10%), and low (<1%).298 Depending on the risk category, a preemptive treatment or monitoring strategy with the intent of on‐demand therapy can be developed.298 Prophylactic antiviral therapy, preferably with entecavir or tenofovir, during immunosuppressive treatment and for at least 6 months after treatment (or at least 12 months after treatment with anti‐CD20 agents) has been recommended for individuals at high to moderate risk of HBV reactivation. Watchful monitoring with intent of on‐demand therapy has been recommended for patients at low risk.298
The risk of HBV reactivation in patients with AIH who are treated with conventional regimens of prednisone or prednisolone in combination with AZA is unknown. Furthermore, the reported risk levels in glucocorticoid‐treated patients relate mainly to individuals with HBsAg who are at risk of developing viremia detected by HBV DNA.300 These patients warrant antiviral prophylaxis, but they constitute a small percentage of patients with AIH who would be considered for glucocorticoid therapy.296
HBsAg‐negative patients with anti‐HBc constitute another risk category for reactivation, but reverse seroconversion (appearance of HBsAg and HBV DNA in a previously HBsAg‐negative patient) has occurred mainly in patients treated with B cell–depleting agents, TNF inhibitors, and chemotherapeutic agents.300 Traditional immunosuppressive agents (AZA, 6‐MP) have been associated with a low risk (<1%) of reverse seroconversion, as has glucocorticoid therapy for ≥4 weeks for autoimmune disorders.296 Risk increases with the dose and duration of glucocorticoids, and moderate (10‐20 mg daily) to high (>20 mg daily) doses of glucocorticoids for ≥4 weeks have been associated with a risk of reverse seroconversion of 1%‐10%.298
Patients with AIH typically undergo serological testing for HBV (HBsAg, anti‐HBc, and antibodies to HBsAg) during the diagnostic phase of their evaluation, and individuals requiring close monitoring for HBV reactivation during glucocorticoid therapy can be identified prior to treatment. The goal of management is to achieve clinical and biochemical remission on low‐dose glucocorticoid regimens in combination with AZA, and close serological monitoring for reverse seroconversion is justified in these low‐risk patients. Assessments of serum HBV DNA and HBsAg at intervals of 1‐3 months has been suggested by the AASLD.299 High‐dose therapy or the institution of B cell–depleting agents, cytokine antagonists, calcineurin inhibitors, or other immune inhibitory agents may increase the risk of reverse seroconversion; and it is best avoided in these patients. Otherwise, the institution of preemptive antiviral therapy in these patients should be considered.
- Patients with AIH who are HBsAg‐negative/anti‐HBc‐positive during the diagnostic phase of their evaluation should undergo periodic serological testing (HBsAg, HBV DNA) during conventional therapy with prednisone or prednisolone in conjunction with AZA to detect HBV reactivation and the need for on‐demand antiviral therapy.
- Patients with serological evidence of previous HBV infection who are treated with high‐dose glucocorticoids or other immune modulators, especially B cell–depleting agents, are at moderate risk for HBV reactivation and should be considered for preemptive antiviral therapy.
Bone density assessments by dual‐energy X‐ray absorptiometry of lumbar vertebrae and hips should be performed at baseline in patients with risk factors for osteoporosis and every 2‐3 years in adult patients with ongoing risk factors for osteoporosis.301 The most common risk factors are past or prolonged use of glucocorticoids, postmenopausal status, history of low‐trauma fracture, and age (>65 years for women and >70 years for men).303 Elemental calcium (1,000‐1,200 mg daily) and vitamin D (at least 400‐800 IU daily) has been recommended for patients on glucocorticoid therapy.301
Vitamin D insufficiency (serum 25‐hydroxyvitamin D level, ≤29 ng/mL) occurs in 68%‐81% of patients with AIH,305 and severe vitamin D deficiency (serum 25‐hydroxyvitamin D level, <20 ng/mL) occurs in 20%.306 These findings justify assessment of the serum 25‐hydroxyvitamin D level in all patients at diagnosis and vitamin D supplementation as indicated clinically.307 Similar dosing and monitoring strategies are used in children.
Clinical trials support the use of bisphosphonates when osteoporosis is present.301 Regular weight‐bearing exercise can help control weight and eliminate immobility as a basis for bone loss.301
The metabolic syndrome is defined by a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus that may be aggravated or induced by prolonged glucocorticoid therapy, and its presence should be assessed prior to the institution of such therapy. The five principal components of the metabolic syndrome are hypertension, hypertriglyceridemia, low high‐density lipoprotein cholesterol level, fasting hyperglycemia, and central obesity (waist–hip ratio or body mass index >30 kg/m2).310 Three abnormal findings of the five possible manifestations justify the diagnosis. The presence of metabolic syndrome at presentation or during treatment might require modification of the glucocorticoid regimen and supplemental therapies and lifestyle adjustments (exercise, weight reduction).311
- Bone mineral densitometry should be performed at baseline in all adult patients with AIH who have risk factors for osteoporosis, and it should be repeated every 2‐3 years of continuous glucocorticoid treatment.
- Serum levels of 25‐hydroxyvitamin D should be determined at diagnosis and annually thereafter.
- Supplementation with elemental calcium (1,000‐1,200 mg daily) and vitamin D (at least 400‐800 IU daily) should be provided while on glucocorticoid therapy and supplemented as clinically indicated in patients with vitamin D insufficiency.
- Bisphosphonate therapy is indicated for patients with AIH and documented osteoporosis.
- Assessment for all features of metabolic syndrome should be performed prior to and during therapy, and its presence may require individualized treatment adjustments and lifestyle modifications.
Sufficient time should be spent prior to initiating treatment to ensure that patients understand not only the potential side effects of the medication but also the positive benefits of achieving therapeutic remission and the comparative risks associated with inadequately treated disease.312 Noncompliance or problematic adherence are commonplace among patients with chronic diseases, particularly among adolescents.312
Depression and anxiety are more common in patients with AIH than in the general population,314 mainly because of concerns about disease progression.316 Depression is moderate in 19% and moderately severe in 10% of patients, and it correlates strongly with physical fatigue.315 Anxiety relates mainly to misconceptions about the nature and outcome of the disease and its treatment, and it can predispose to nonadherence.312
Low scores on health‐related quality of life assessments have been strongly associated with glucocorticoid use.319 Pretreatment psychological disturbances, especially depression, may be intensified during glucocorticoid treatment.321 The combined effects of depression, anxiety, and glucocorticoid‐related emotional lability may impact on treatment outcome.322 Manifestations of depression and changes in the quality of life should be monitored throughout management of AIH as they may justify targeted counseling, individualized adjustments in the doses of glucocorticoids, or adjunctive antidepressive or antianxiety interventions.317 These manifestations can be assessed by structured, validated questionnaires such as the 12‐Item Short Form Survey, the depression module of the Patient Health Questionnaire, and the Generalized Anxiety Disorders Screener.316
- Potential barriers to long‐term medication compliance should be identified proactively and addressed at the start of treatment and monitored thereafter.
- Manifestations of depression and changes in the quality of life should be monitored throughout management of AIH, and they can be assessed objectively by structured, validated questionnaires.
The effects of AIH and its medications on fetal–maternal health should be discussed before pregnancy if possible. Data on risks and outcomes of pregnancy in AIH are derived from recent case series (2002‐2012) encompassing 142 conceptions.324 Amenorrhea and decreased fertility occur when AIH is poorly controlled,328 whereas menstruation signals improved overall health. Exact fertility rates are not known, but in 53 British women with AIH (81 pregnancies), 41% had cirrhosis.324
The live birth rate is 73% in mothers with AIH.324 The fetal loss and stillbirth rate of 27% is higher than that for the general population (7%‐15%) but similar to that for women with chronic disease (24%‐29%). Antiphospholipid antibodies are strongly associated with AIH,325 and they may be a separate, but related, cause of preterm delivery. Premature births occur in ~20% of pregnancies,324 but there are no specific birth defects associated with AIH.
The overall maternal complication rate during the pregnancy or within 12 months of delivery is 38%.324 Prematurity is primarily due to a flare in AIH. Flares occur mainly in patients who are not on therapy or who have not been in remission during the year prior to conception. Patients with AIH who are pregnant or planning pregnancy within the next year should be continued on treatment to reduce the risk of flare and hepatic decompensation. Flares are 3 times more common postpartum,327 and the low rate of flare during pregnancy may relate in part to the effects of pregnancy implantation factor.329
In pregnant patients with cirrhosis, progressive increase in blood volume can lead to an increased risk of variceal bleeding. Preemptive identification and eradication of varices with variceal ligation is necessary as β‐blockers and terlipressin have potential adverse effects in pregnancy (Table 7). The safety of endoscopy during pregnancy has been addressed in other guidelines.331
Table 7 -
Safety of Medications Commonly Used in the Pregnant Patient with AIH
||Safety Reports in Pregnancy
||No harmful effects noted
||Fetal bradycardia, fetal growth retardation
||No harmful effects noted
||No harmful effects noted but limited data
||Inconsistent association with cleft abnormalities
||Birth defects, spontaneous abortion
||Premature birth, transient neonatal renal dysfunction
Medication Safety in Pregnancy
Whereas data from 1997‐2002 suggested an increased risk of cleft lip and palate during the first trimester of pregnancy in glucocorticoid‐treated women, data from 2003‐2009 reported by the US National Birth Defects Prevention case–control study showed no association, presumably because of lower doses given in the latter era332 (Table 7). The placental enzyme 11‐beta‐hydroxysteroid dehydrogenase 2 converts prednisolone (the active drug) into prednisone (the inactive prodrug), and it may protect the fetus from high levels of glucocorticoids.
AZA‐related adverse events have not been reported in the pregnancy or baby. Initial concerns about possible teratogenicity were derived from animal studies that used supratherapeutic doses.333 A systematic review and meta‐analysis of 3,000 pregnant patients with IBD334 found no increase in the risk of low birth weight or birth defects in mothers taking AZA. However, the risk of preterm birth was increased (OR, 1.45) (Table 7). Small amounts of AZA are detectable in the milk of lactating mothers, and low levels of 6‐thioguanine nucleotide (6‐TGN) have been detected in newborns.335
Data from the National Transplantation Pregnancy Registry and postmarketing surveillance indicate that mycophenolate mofetil (MMF) use during pregnancy is associated with first‐trimester pregnancy loss and birth defects, most commonly ear, heart, and cleft defects336 (Table 7). Thus, MMF should be avoided during pregnancy. The Food and Drug Administration recommends a negative pregnancy test within 1 week of starting MMF and use of two effective methods of birth control for 4 weeks prior to and 6 weeks after use of MMF. Small amounts of MMF are detectable in the milk of lactating mothers.336
- Family planning should include the goal of achieving biochemical remission of AIH for 1 year prior to conception.
- Women of reproductive potential should receive prenatal counseling on the significant adverse effect of active AIH on pregnancy and the risk of flares during and after pregnancy.
- Maintenance doses of glucocorticoids and/or AZA should be continued throughout pregnancy.
- MMF is contraindicated during pregnancy, and women should be counseled about the adverse effects of MMF on pregnancy prior to initiating MMF treatment.
- Women with cirrhosis who are pregnant or plan to become pregnant within the next year should be screened for varices by endoscopy either prior to conception or during the second trimester of gestation and treated with band ligation.
- Women with AIH should be monitored closely for the first 6 months postpartum for early detection of a flare.
The objectives of first‐line therapy are to improve symptoms, control hepatic inflammation, achieve biochemical remission, prevent disease progression, and promote the regression of fibrosis at the lowest risk of drug‐induced complication. The ideal laboratory response is normalization of serum ALT, AST, and IgG levels.2 All patients with AIH are candidates for therapy except individuals with inactive disease by clinical, laboratory, and histological assessment.
Prednisone or Prednisolone With and Without AZA
Prednisone alone, 40‐60 mg daily in adults and 1‐2 mg/kg daily in children (maximum dose 40‐60 mg daily), or a lower dose of prednisone, 20‐40 mg daily, in combination with AZA (AZA adult dosing: United States, 50‐150 mg daily; Europe, 1‐2 mg/kg daily; pediatric, 1‐2 mg/kg daily), is administered with an antacid during an induction phase (Fig. 4). Some centers advocate using prednisone 1 mg/kg for adult patients and then reducing the dose once a response is documented. In Europe, prednisolone is preferred over prednisone, and equivalent or weight‐based doses of prednisolone (1 mg/kg daily) are administered in conjunction with weight‐based doses of AZA (1‐2 mg/kg daily). In some centers, AZA is started at the same time as glucocorticoids, whereas most centers recommend waiting 2 weeks before starting AZA to confirm steroid responsiveness, evaluate TPMT status, and assess treatment response by excluding the rare possibility of AZA‐induced hepatitis.
Once a biochemical remission has been achieved (see definition in Table 2), response‐guided therapy is advocated. The dose of prednisone or prednisolone is reduced gradually to 20 mg daily or a dose sufficient to achieve biochemical remission while monitoring laboratory tests every 2 weeks. Thereafter, a gradual taper is recommended (2.5‐5 mg every 2‐4 weeks) to achieve a lower dose of 5‐10 mg daily that maintains laboratory remission. Prednisone or prednisolone may then be discontinued completely, leaving the patient on only AZA or alternative glucocorticoid‐sparing drugs. Alternate‐day predniso(lo)ne is advocated by some because of fewer side effects, but this regimen may also reduce immunosuppression.339 In children, the goals of therapy are to eventually be glucocorticoid‐free and to prevent the multiple long‐term complications of glucocorticoids.
Treatment of AIH with prednisone monotherapy is appropriate for patients in whom the duration of treatment is expected to be <6 months (e.g., suspected drug‐induced AIH‐like injury) or AZA is contraindicated (known AZA intolerance or complete TPMT deficiency). In the setting of AZA intolerance, MMF is an acceptable alternative therapy to maintain remission. Prolonged prednisone monotherapy, especially at doses >10 mg daily, is frequently associated with well‐known drug toxicities and should be avoided341 (Table 8).
Table 8 -
Side Effects Associated with Prolonged First‐Line Treatment Drugs in AIH
Cosmetic: Facial rounding, hirsutism, alopecia, dorsal hump, striae
Systemic: Weight gain, glucose intolerance/diabetes, hypertension, fatty liver, osteoporosis, vertebral compression, cataracts, glaucoma, opportunistic infections
Quality of life: Emotional instability, psychosis, depression, anxiety
Actively taper to the lowest steroid dose needed for remission and attempt withdrawal after remission
Eye examinations for cataract and glaucoma
Lifestyle interventions for metabolic syndrome
Bone density monitoring
Vitamin D and calcium administration
Proactive screening and management for quality of life and mental health symptoms
Reduced intensity of the side effects from prednisone is possible despite first‐pass metabolism
Unable to reach the liver with portal hypertensive shunts
Portal vein thrombosis in cirrhosis
Hematologic: Mild cytopenia, severe leukopenia or bone marrow failure (rare)
Gastrointestinal: Nausea, emesis, pancreatitis
Neoplastic: Nonmelanoma skin cancer
Cholestatic liver damage (rare)
Check TPMT metabolizer status prior to prescribing
Monitor cell counts at least every 6 months
Reduce dose if mild cytopenia occurs
Discontinue in severe cytopenia
Discontinue in gastrointestinal intolerance
Avoid direct sunlight and have yearly dermatologic screening for skin cancer
Not recommended in decompensated cirrhosis or acute severe AIH
The typical starting dose of AZA is 50‐100 mg daily in adults and 1‐2 mg/kg daily in children. Evolving leukopenia or thrombocytopenia warrants dose reduction or drug withdrawal. AZA should be discontinued if the cytopenia does not recover in 1‐2 weeks. Most cases of cytopenia in AZA‐treated patients with AIH are associated with cirrhosis.290
The AZA dose can be further adjusted to achieve a therapeutic range and avoid toxicity by monitoring thiopurine metabolite levels.342 In children with AIH, the 6‐TGN level is titrated between 100 and 300 pmol/8 × 108 red blood cells (RBCs) to avoid bone marrow toxicity, and the 6‐methyl‐mercaptopurine level is kept <5700 pmol/8 × 108 RBCs to prevent hepatotoxicity.342 Nonadherence to treatment should be suspected in patients who fail to respond to induction therapy or in those who relapse. Text messaging347 and electronic monitoring348 may also be useful in reducing nonadherence in children. AZA should not be used in patients with active malignancy because it acts synergistically with ultraviolet light to enhance mutational damage.349
In adults with AIH, routine measurement of 6‐TGN levels in unselected patients has had limited value because 6‐TGN levels have been similar between patients with normalized serum aminotransferase levels and those with partial improvement.344 6‐TGN determinations might prove useful in assessing treatment compliance in adults and in developing management strategies for adults with an incomplete response (e.g., increasing the dose of AZA or adding allopurinol to the regimen).344
Budesonide and AZA
The efficacy and safety of budesonide (which has a 90% first‐pass effect on the liver) in combination with AZA was demonstrated in a randomized trial of newly diagnosed AIH which targeted laboratory remission after 6 months. Patients receiving budesonide (3 mg thrice daily, reduced to twice daily following remission) combined with weight‐based AZA (1‐2 mg/kg daily) achieved laboratory remission after 6 months more frequently (60% versus 39%) and with fewer steroid‐specific side effects (SSSE; 28% versus 53%) compared to prednisone (40 mg daily tapered to 10 mg daily) combined with weight‐based AZA.350 A potential long‐term benefit of budesonide therapy is preservation of the bone mineral density.351
Patients with ALF or cirrhosis were not included in this randomized trial of budesonide. Patients with cirrhosis should not receive budesonide because portosystemic shunting may reduce drug efficacy and promote SSSE by allowing budesonide to bypass the liver.353 Portal vein thrombosis has also been reported in patients with cirrhosis taking budesonide, albeit portal vein thrombosis is a known complication of cirrhosis independent of budesonide use355 (Table 8). Patients who fail to normalize their laboratory tests on prednisone therapy are also less likely to respond to budesonide treatment,351 and therefore the drug should not be used as a rescue therapy for steroid‐refractory AIH.352 The role of budesonide as first‐line treatment in acute severe AIH or ALF is unknown, and thus it is not recommended in these settings.
In a subgroup analysis, children receiving budesonide and AZA achieved laboratory remission after 6 months as frequently as those receiving prednisone and AZA. The occurrence of SSSE was lower but not statistically different between the groups, with the notable exception of lower weight gain in budesonide‐treated children.357 Budesonide with AZA may be considered in children with AIH, particularly if the disease is mild or if there are concerns that prednisone may worsen concurrent obesity, depression, or acne, thus potentially jeopardizing medication adherence.
Systematic Review and Meta‐Analysis of First‐Line Regimens
We performed a systematic review and meta‐analysis to investigate whether first‐line treatment with prednisone or prednisolone alone or in combination with AZA was superior to budesonide in combination with AZA in patients with newly diagnosed AIH. Outcomes were frequency of remission, interval to remission, frequency and type of medication‐associated side effects, and the frequency of death or LT. Out of 1,712 records that were identified in a database search, 578 were fully assessed for eligibility, five were included in a qualitative meta‐analysis,20 and two were included in a quantitative meta‐analysis.20
The meta‐analysis revealed that biochemical remission was more likely with the use of budesonide and AZA compared to prednisone and AZA (OR, 2.19; 95% confidence interval [CI], 1.30‐3.67) (high grade of evidence) (Table 9), but the analysis was based on a single randomized clinical trial.350 None of the studies reported on the time to remission or outcomes such as histological resolution, progression to cirrhosis, death, and transplantation. Furthermore, only one study reported a lower frequency of steroid‐related side effects in patients treated with budesonide and AZA (low grade of evidence).350 The individual determinants that constituted the strength assessment for the recommendation of either budesonide and AZA or prednisone and AZA as first‐line therapy (systematic review 1 [SR1]) are shown in Table 10.
Table 9 -
Evidence Profile and Results of Systematic Review and Meta‐analysis of First‐line Therapies for AIH
|Budesonide + AZA versus Predniso(ol)ne + AZA
||Grade of Evidence Quality
||Two studies (one RCT351 and one non‐RCT20)
|Rapidity of response
||No studies reported rapidity of response
|Side effects (bone disease, cytopenia, weight gain, portal vein thrombosis)
||One study351 reported more steroid‐specific side effects in prednisone group compared to budesonide group
||No studies reported death
||No studies reported LT
2 test of heterogeneity
2 = 0.0%, P = 0.495
|Meta‐analysis for biochemical remission
||OR, 2.19; 95% CI, 1.30‐3.67
||Few qualified studies
|Homogeneous test results between studies
|Current evidence insufficient to assess patient selection and long‐term outcome
|Budesonide and AZA favored for biochemical remission
|Conditional recommendation with low certainty for use of budesonide and AZA in children and adults without cirrhosis, acute severe hepatitis, or ALF
Abbreviation: RCT, randomized clinical trial.
Table 10 -
Determinants of Recommendation Strength by GRADE Assessment of Clinical Studies
||SR1: “First‐Line Treatment” (budesonide/AZA versus predniso(lo)ne/AZA
||SR2: “Second‐Line Treatment” (MMF versus TAC)
||SR3: “Steroid Withdrawal Post‐LT” (pred versus no pred)
|1. Benefits versus harms
||Budesonide > pred
||MMF > TAC
||No pred > pred
||High cost/copay for budesonide
|4. Patient values
||+MMF (ease of use)
||Copay may make it harder to get budesonide
||Copay may make it harder to get budesonide
Abbreviations: no pred, no predniso(lo)ne; pred, predniso(ol)ne.
- For children and adults who present with AIH who do not have cirrhosis or acute severe AIH, the AASLD suggests that budesonide and AZA or prednisone/prednisolone and AZA be used as first-line treatment.
- For children and adults with AIH who have cirrhosis or who present with acute severe AIH, the AASLD suggests that budesonide not be used (conditional recommendation, very low certainty).
Alternative First‐line Regimens
MMF has been used in place of AZA as a front‐line therapy in combination with prednisolone.360 A single‐center experience with MMF as front‐line treatment in combination with prednisone reported a remission rate of ~75% after 24 months.361 A recent meta‐analysis found few evaluable studies comparing MMF and prednisone with prednisone and AZA.362 MMF/prednisone was superior to prednisone/AZA in the normalization of serum ALT, AST, and IgG levels and in the rate of nonresponse. First‐line treatment with MMF seemed to be at least as effective as AZA when each was combined with prednisone, but data are insufficient to recommend its first‐line use.
Calcineurin inhibitors have been used to a limited extent as first‐line agents in AIH.16 Cyclosporine (CsA) has induced biochemical remission in children with AIH364 with good results during long‐term follow‐up.368 Trough levels of CsA are typically maintained higher initially (i.e., 150‐200 ng/mL) and then tapered to 50‐70 ng/mL after 1 year, providing the disease is in remission.368 Tacrolimus (TAC) reduced serum AST and ALT levels by 70% and 80% after 3 months,363 but this early promise has not been developed further. At this time, there are insufficient data to recommend calcineurin inhibitors as front‐line agents.
Special Consideration: Acute Severe AIH or ALF due to AIH
Patients presenting with acute severe AIH370 or ALF100 (see definitions in Table 2) constitute a management dilemma in which the potential advantages of glucocorticoid therapy must be balanced against the risks of the treatment, namely infection372 and delay of LT.373 Glucocorticoid therapy (usually prednisone or prednisolone alone, 0.5‐1 mg/kg daily in adults and up to 2 mg/kg in children) has been effective in 20%‐100% of patients with acute severe AIH and has not been associated with an increase in sepsis.136 In patients with AIH and ALF, glucocorticoid therapy has not been associated with improved overall survival, and survival has been less in treated patients with Model for End‐Stage Liver Disease scores >40.371 Reports of improvement in patients with ALF and mild encephalopathy have been sparse, and glucocorticoid therapy may be deleterious in patients with severe decompensation.370
The key to success in managing acute severe AIH is to abandon ineffective treatment quickly (within 1‐2 weeks depending on clinical status and treatment response) and to proceed to LT.370 Failure to improve any laboratory test reflective of liver inflammation or function, especially hyperbilirubinemia, or any evidence of clinical deterioration or hepatic encephalopathy during treatment justifies immediate consideration of LT.370 Hepatic encephalopathy at presentation defines AIH with ALF, and LT is more likely to improve survival than protracted glucocorticoid treatment.370
- Patients with acute severe AIH should receive a treatment trial with prednisone or prednisolone alone, whereas patients with AIH and ALF should be evaluated directly for LT.
- Patients with acute severe AIH who do not improve laboratory tests or clinically worsen within 1‐2 weeks of glucocorticoid therapy should be evaluated for LT.
Putative Predictors of Treatment Response
The rapidity of response to treatment is the most important index of outcome, and the serum aminotransferase levels should improve within 2 weeks.378 Elderly patients (≥60 years old) respond more quickly to treatment than young adults, and they are characterized by HLA DRB1*04:01.379 Biochemical remission that is achieved within 6 months is associated with a significantly lower frequency of progression to cirrhosis or need for LT, and individualized adjustments in therapy may be justified to improve the speed of response.379 Laboratory manifestations of cholestasis (increased serum alkaline phosphatase or GGT levels) have been associated with incomplete or delayed response and may indicate an alternative diagnosis (e.g., overlap syndrome).173
Other biomarkers predictive of response are evolving. In type 1 AIH, persistent production of SMA or antiactin in the setting of biochemical remission have been associated with histological features of active liver inflammation.381 Elevated ferritin levels (>2.1‐fold ULN) at the time of diagnosis have been associated with subsequent biochemical remission, and the predictive value of remission has increased when both elevated serum ferritin and low IgG values (<1.9‐fold ULN) have been present at baseline.382 Vitamin D deficiency at presentation has been associated with histological severity, poor treatment response, progression to cirrhosis, and increased mortality or need for LT305; and increased serum levels of angiotensin‐converting enzyme have correlated with fibrosis scores.383
Sustained normal serum levels of AST, ALT, and IgG for at least 2 years have been proposed as requisites before attempting treatment withdrawal.384 Patients with cirrhosis may have chronic elevation of the serum IgG level, and they are not excluded from treatment withdrawal if other tests are normal during a prolonged (≥2 years) period of stability.386 Restoration of the liver tissue to normal reduces the risk of subsequent relapse to 28%,386 and liver biopsy prior to drug withdrawal has been the preferred strategy.386 Liver biopsy, however, may not be mandatory before treatment withdrawal in all adults.384
In adult patients with and without prewithdrawal liver biopsy, the frequency of relapse (30% versus 21%, P = 0.57) was similar after treatment for at least 2 years, during which serum AST and ALT levels had been normal or near‐normal.389 Of 28 treated patients with AIH who were in biochemical remission for at least 2 years before withdrawal, 15 (54%) remained in biochemical remission after treatment withdrawal during a median follow‐up of 28 months (range, 17‐57 months).385 These patients were characterized by a serum ALT level <50% ULN and a normal serum IgG level <1,200 mg/dL.385 Liver biopsy was performed in 13 patients prior to drug withdrawal, and of the 11 patients with normal liver tests and normal liver tissue, 46% subsequently relapsed. These findings suggest that sustained normal liver tests during treatment may have gradations within the normal range that predict outcome, possibly better than liver tissue examination. Prewithdrawal liver biopsy is still strongly advised in children to ensure resolution of inflammation.108 In a retrospective study of 35 children with AIH, 16 (46%) had lack of inflammation on prewithdrawal liver biopsy after 2 years of biochemical remission and were weaned off of immunosuppression.384 Fourteen of these 16 patients (87%) had a sustained remission off immunosuppression, with a median follow‐up of 3.4 years.
VCTE is emerging as a noninvasive method that may also aid in the withdrawal decision.260 Patients achieving a complete biochemical remission decreased their liver stiffness by 7.5%/year (P = 0.003), whereas patients not achieving biochemical remission showed a slight but nonsignificant increase in liver stiffness by 1.7%/year.265 Patients achieving biochemical remission had an average liver stiffness measurement of 6.4 ± 3.2 kPa compared to the average liver stiffness measurement of 9.2 ± 9.1 kPa in the patients who did not achieve biochemical remission (P = 0.06).265 A liver stiffness threshold below which biochemical remission was expected was not determined. The findings of VCTE have not been correlated with outcome after treatment withdrawal or compared with histological examination in predicting sustained remission after treatment, and its role in predicting relapse after drug withdrawal is unknown.
Laboratory surveillance for relapse must be continued indefinitely at regular intervals of increasing length depending on test stability.390 Long‐term follow‐up studies in adults and children of at least 3 years’ duration have indicated that the frequency of achieving a treatment‐free remission is 19%‐40%.391
Relapse occurs in 50%‐87% of adults and 60%‐80% of children after drug withdrawal.244 In patients satisfying the remission criterion of biochemical normality for ≥2 years during treatment, the relapse frequency is 46% in adults385 and 80% in children.108 Long‐term biochemical remission has been possible in 20% of children with type 1 AIH but rarely in children with type 2 AIH.62
Relapse is typically asymptomatic, manifested by mild increases in serum AST or ALT level, and rapidly responsive to retreatment.394 Its main risks relate to delayed or failed detection, resulting in increased hepatic fibrosis in 10%243 and clinical deterioration in 3%.243 Fifty percent of all relapses occur within the first 3 months after drug withdrawal, and the frequency of relapse decreases after the first year to 3% per year over the next 3 years.390 Ninety percent of relapses occur within 28 months (mean interval, 5 ± 0.6 months; median, 3 months; range, 1‐28 months), but late relapses are possible (range, 49‐265 months after drug withdrawal).390
The principal predisposing factors for relapse are the duration and completeness of inactive disease prior to treatment withdrawal.385 Various other factors have been proposed, including psychological stress,323 concurrent autoimmune disease,244 treatment with multiple agents,244 increased serum ALT and IgG levels at drug withdrawal,106 portal plasma cells in the liver tissue prewithdrawal,106 delayed biochemical remission,396 and prednisolone monotherapy.397
Patients who relapse almost invariably respond to retreatment with the original regimen.244 Ninety‐four percent achieve laboratory resolution in 4 ± 1 months, and 59% achieve histological resolution in 8 ± 2 months.391 Subsequent attempts at drug withdrawal are commonly followed by another relapse,394 and adult patients should be treated long‐term after their first relapse. Cirrhosis develops more commonly in patients with repeated relapses after drug withdrawal than in patients who have relapsed once and been retreated (38% versus 10%, P = 0.02), and liver‐related death or LT is also more common (20% versus 3%, P = 0.02).243
Complete drug withdrawal has been possible in 12% of patients who have relapsed previously after 69 ± 8 months of retreatment, and it can be attempted in individuals with inactive disease for at least 24 months.387 In children with relapse and subsequent biochemical remission on retreatment, a second assessment to gauge histological remission and treatment withdrawal can be considered after an additional 2 years of normal laboratory tests.
Biochemical remission is induced with the standard glucocorticoid and AZA regimen, and then the dose of AZA is adjusted up to 2 mg/kg daily as the dose of prednisone or prednisolone is reduced to the lowest dose possible or fully withdrawn.398 Patients intolerant of AZA can be treated with MMF, or in adults, low‐dose predniso(lo)ne (≤7.5 mg daily) only can be instituted.400
- Drug withdrawal and achievement of a long‐term treatment‐free remission of AIH are possible in a minority of patients and should be considered in patients who have normalized serum aminotransferase and IgG levels for at least 2 years.
- Liver tissue examination prior to drug withdrawal is valuable in excluding unsuspected inflammation and reducing the frequency of relapse, but it is not mandatory in adults.
- Patients must be closely monitored for relapse with regular laboratory assessments during the first 12 months after treatment withdrawal and annually thereafter to cover for lifelong risk.
- Relapse requires prompt reinstitution of the original treatment until biochemical remission and subsequent transition to a long‐term maintenance regimen.
Second‐line therapies have been used to manage treatment failure, incomplete response, and drug intolerance402 (see definitions in Table 2). Treatment failure occurs in 7%‐9% of adults and is associated with increased risk of progression to cirrhosis and liver failure, with mortality rates as high as 30%.403 Second‐line therapies for treatment failure include MMF,404 calcineurin inhibitors (CsA411, TAC417), mercaptopurine421 and biologics (rituximab,423 infliximab424).
Incomplete response manifests as an improvement in laboratory findings but without complete normalization of serum AST, ALT, or IgG levels. Incomplete response occurs in ~15% of adults and children. Patients unable to normalize liver tests and liver tissue within 36 months have a higher frequency of cirrhosis and need for LT.379 Second‐line therapies for incomplete response include MMF and calcineurin inhibitors.
Treatment intolerance indicates the inability to continue therapy due to side effects of the drug.341 Treatment‐ending side effects occur in 13%. Some patients who cannot tolerate AZA will tolerate MP to maintain remission.421 Other therapies to consider are MMF and TAC.
MMF has been given to patients with AIH who are intolerant of AZA or have an incomplete response or treatment failure with glucocorticoid/AZA. In a meta‐analysis involving five studies and 309 patients,425 the pooled overall response rate was 58% (82% for AZA intolerance and 32% for treatment failure). MMF‐based therapies were well tolerated, with a pooled adverse event rate of 14%, leading to discontinuation in 8%. Another meta‐analysis426 based on 15 out of 1,532 studies indicated that the combination of MMF and prednisone was the most widely used second‐line treatment. The MMF regimen reduced serum AST and ALT levels in 79% and achieved histological remission in 89%.
The effectiveness of MMF as second‐line therapy has also been supported by a recent study indicating the induction of biochemical remission in 60%.427 As in previous studies, MMF therapy was more frequently effective in patients intolerant of primary therapy than in those with treatment failure to primary therapy (62% versus 38%). Predictors of a favorable response included older age and lower levels of IgG and INR.
Similar findings have been reported in pediatric patients with treatment failure.416 Normalization of serum ALT and AST levels by month 6 was achieved in 36% of children treated with MMF and 83% treated with CsA and in 50% of patients treated with TAC. MMF was well tolerated, and adverse events occurred in 45% compared to 78% treated with CsA and 42% treated with TAC.
Multiple studies on the use of TAC in the setting of treatment failure, incomplete response, and AZA intolerance have confirmed its moderate‐to‐high efficacy. TAC has been administered in combination with prednisone, budesonide, AZA, or MMF, with serum trough levels ranging from 1 to 10 ng/mL. Two single‐center studies reported normalization of serum aminotransferases in response to TAC in 91%‐92% of adult cases,417 and a third single‐center study showed normalization of either serum ALT or IgG level in 79%.420 A multicentered study of patients with either AZA intolerance or incomplete response/treatment failure documented normalization of serum aminotransferases in 73% (94% with AZA intolerance and 57% with incomplete response or treatment failure).418
Two meta‐analyses on the use of TAC in adults as second‐line therapy revealed improvement or normalization of serum aminotransferases in 75%‐94%.426 Similar response rates have been reported in single‐center studies in children.366 Side effects necessitating decreased dose or cessation of TAC occurred in ~25%. The most frequently reported side effects were neurologic symptoms (tremors, headaches), renal complications (hypertension, insufficiency), and hair loss. CsA may be considered as the second‐line therapy of choice for patients with concurrent diabetes when compared to TAC as diabetes can develop as a side effect of TAC.
Systematic Review and Meta‐Analysis of Second‐Line Regimens
We performed a systematic review to answer the question of whether 6‐MP, MMF, or a calcineurin inhibitor demonstrated superior efficacy in the setting of treatment failure or incomplete response in adults and children. A comprehensive search of several databases identified 1,712 records. After screening and exclusion of articles for various methodological reasons, four articles were included in a qualitative analysis and two in a quantitative meta‐analysis.407 Based on the available studies, a direct comparison was performed between MMF and TAC. There were insufficient data to evaluate the use of mercaptopurine as a second‐line therapy. No significant differences in outcome (remission rate, frequency of transplant or death) were reported between MMF and TAC therapies (Table 11). The individual determinants that constituted the strength assessment for the recommendation of preferred second‐line therapy (SR2) are shown in Table 10.
Table 11 -
Evidence Profile and Results of Systematic Review and Meta‐analysis of Second‐Line Therapies for AIH
|MMF versus TAC
||Grade of Evidence Quality
||Two retrospective studies418 reported no significant difference in frequency of biochemical remission
||One study418 reported drug intolerance and showed no significant difference between MMF and TAC in frequency of side effects
|Death or LT
||One study418 reported death or LT (together) and showed no significant difference in frequencies between MMF and TAC
2 test of heterogeneity
2 = 59.6%, P = 0.116
|Meta‐analysis: For biochemical remission
||OR, 1.95; 95% CI, 0.18‐20.81
||Few qualified studies
|Heterogeneous test results between studies
|Low‐quality evidence to assess differences in frequency of biochemical remission
|Very low‐quality evidence to assess differences in frequency of side effects, mortality, or need for LT
|Conditional recommendation with very low certainty that MMF be used over TAC based on ease of use and side effect profile
- In children or adults with AIH who have treatment failure, incomplete response, or drug intolerance to first‐line agents, the AASLD suggests the use of MMF or TAC to achieve and maintain biochemical remission (conditional recommendation, low certainty).
- Based on a superior ease of use and side‐effect profile, the AASLD suggests a trial of MMF over TAC as the initial second‐line agent in patients with AIH (conditional recommendation, very low certainty).
Evolving Salvage Therapies
Antibodies to TNF‐α
Monoclonal antibodies to TNF‐α (infliximab) are known to cause liver injury and may even cause drug‐induced AIH‐like injury.208 Anti‐TNF antibodies may also have a therapeutic role in AIH. In the largest single‐center retrospective analysis of infliximab therapy in AIH, 11 difficult‐to‐treat adult patients, including 7 with cirrhosis, received infusions of infliximab (5 mg/kg).424 Six patients normalized serum aminotransferase and IgG levels, 7 patients developed infectious complications, and 1 patient stopped treatment due to an allergic reaction and incomplete response.
Another single‐center retrospective analysis in 11 pediatric and adolescent patients with IBD and autoimmune liver disease included 2 patients with type 1 AIH and 9 with AIH–PSC overlap.434 Infliximab (5 mg/kg) was infused to treat the IBD, and 3 patients were later treated with adalimumab after infliximab intolerance or failure. The IBD improved in most patients, and liver enzymes improved in 5. The heterogeneity of the population and its principal goal of treating the IBD precluded conclusions about the role of anti‐TNF‐α agents in AIH. The weak evidence on efficacy and the increased risk of infection, especially in patients with cirrhosis, do not justify the use of anti‐TNF‐α agents as second‐line treatments.
Antibodies to CD20
Rituximab, a monoclonal antibody directed against the B‐cell surface receptor CD20, has been used to treat 2 children with AIH who were not responding to glucocorticoids/AZA; and both normalized serum AST and ALT levels.435 Rituximab has also been infused in 6 adult patients with AIH, including 3 with AZA intolerance and 3 who were nonresponders to glucocorticoids/AZA and MMF.423 Serum aminotransferases and IgG levels improved significantly in all patients, and biochemical remission was achieved in 67%. Evidence favoring the use of B cell–depleting antibodies is limited and does not justify their use as second‐line treatments. A prospective randomized clinical trial is ongoing that evaluates ianalumab (VAY736) in patients with AIH who are nonresponders or intolerant to glucocorticoids/AZA (NCT03217422).
Thioguanine is directly metabolized to 6‐TGN, which is the metabolically active metabolite of AZA.436 The 6‐thioguanine metabolites are responsible for the therapeutic immunosuppressive effect of AZA, but they can also cause myelosuppression, especially in the presence of TPMT deficiency. The methylated metabolites associated with the conversion of AZA to 6‐TGN have been associated with AZA intolerance, and the production of these methylated metabolites may be reduced by treatment with thioguanine.
Thioguanine has normalized serum aminotransferases in 64% of patients with AIH unresponsive to AZA, and the frequency of side effects (11%) has been less than those reported with the second‐line therapies of MMF or 6‐MP (12%‐50%).438 Of 38 patients treated for intolerable side effects of AZA, 29 (76%) were able to continue treatment with thioguanine and 24 (83%) achieved biochemical remission.439 Seven of 11 patients (64%) in one study439 and all 3 patients in another study440 with insufficient response to AZA improved after receiving thioguanine. The major concern about treatment with thioguanine has been liver toxicity, especially the development of nodular regenerative hyperplasia441; but dosing schedules of thioguanine not exceeding 25 mg daily have minimized this risk in patients with IBD.442
Thioguanine has been proposed as a second‐line treatment for patients with AIH who are intolerant of AZA, and it may also be considered in patients with nonresponse to thiopurine therapy (AZA, 6‐MP).438 The inclusion of thioguanine as a second‐line treatment for AIH awaits further demonstration of its safety and efficacy in a multicenter collaborative treatment trial.
- In children or adults with AIH who have nonresponse to first‐line treatment, the accuracy of the original diagnosis and medication adherence should be reevaluated.
- Anti‐TNF and anti‐CD20 are possible alternative therapies after first‐line and second‐line regimens have failed, but the data supporting their use are limited.
Treatment of Overlap Syndromes
Management of the overlap syndromes has been empiric and includes glucocorticoids, glucocorticoids in combination with AZA, ursodeoxycholic acid (UDCA), and glucocorticoids in combination with UDCA.126 The IAIHG advises that management be directed at the predominant manifestations of the overlap syndrome,126 and regimens directed at a single component of the overlap syndrome have been able to improve liver tests in patients with a predominant AIH or cholestatic phenotype. Patients with AIH–PBC who have not satisfied the Paris criteria175 have improved with conventional immunosuppressive therapy for AIH, and patients with predominantly PBC and background features of AIH have improved with UDCA alone.444 Early reports of the AIH–PSC overlap syndrome described responses to conventional immunosuppressive therapy for AIH.445 Regimens directed at a single predominant component of the overlap syndrome are based on the premise that these syndromes are single diseases with mixed atypical clinical features rather than concurrent diseases.446
Most reports have described combination regimens directed at both the AIH and cholestatic components. Prednisone or prednisolone (30 mg daily tapered over 4 weeks to 10 mg daily) in combination with UDCA (13‐15 mg/kg daily) has been superior to glucocorticoids alone and UDCA alone in patients satisfying the Paris criteria,177 and combination therapy has been advocated for patients satisfying the Paris criteria for the AIH–PBC overlap syndrome.126 Combination therapy has improved laboratory tests, stabilized hepatic fibrosis, and preserved the 5‐year transplant‐free (100%) and 10‐year overall survival (92%) in patients with AIH–PBC.181
Prednisone or prednisolone (0.5 mg/kg daily tapered to 10‐15 mg daily) with UDCA (13‐15 mg/kg daily) has improved survival and reduced frequency of transplantation compared to classical PSC,447 and this regimen has been advocated by the European and American liver societies for the AIH–PSC overlap syndrome.179 UDCA, 10 mg/kg twice daily (dose not exceeding 1.5‐2 g daily), in conjunction with prednisone or prednisolone has been used in children with AIH–ASC.62 Treatment outcomes have been variable in adults with AIH–PSC, and laboratory resolution has been less common than in AIH (22% versus 64%). Furthermore, treatment failure (33% versus 10%) and death from liver failure or need for LT (33% versus 8%) have been more common than in AIH.126
- Consider adding UDCA to prednisone or prednisolone in combination with AZA in adults and children with AIH and overlap syndromes.
The overall 10‐ and 20‐year survival rates of treated AIH in a nontransplant center are 91% and 70%, respectively; and the standardized mortality ratio is 1.63 for all‐cause death (95% CI, 1.25‐2.02) and 1.86 after inclusion of LT as “death” (95% CI, 1.49‐2.26).451 The 10‐year liver‐related mortalities in the United States range from 6.2% to 7.5%,105 and they are similar to those in the United Kingdom (9%)451 and Denmark (10.2%).11 Cirrhosis is present in 28%‐33% of patients at presentation, especially in patients aged ≥60 years156; and it may develop in 10%‐40% of treated patients.9 Cirrhosis has been associated with reduced survival,11 and LT has been necessary in 21% of steroid‐refractory patients.454 Factors that may affect the treatment response and long‐term outcome are age at onset, ethnicity, and malignancy.
Elderly patients with AIH frequently have advanced hepatic fibrosis at presentation, commonly have concurrent thyroid or rheumatic diseases, and tend to respond better to glucocorticoid therapy than adult patients aged <30 years.156 AIH occurs with similar frequency in all adult age groups, and the propensity for better treatment response among the elderly may be associated with immunosenescence and their higher frequency of HLA DRB1*04 (47% versus 13%).156 The findings suggest that AIH is undiagnosed at early fibrotic stages in the elderly and that age‐related genetic susceptibilities affect outcome.
Clinical phenotype, treatment response, and outcome can vary in different ethnic groups within the same geographical region.17 African American patients have more advanced stages of hepatic fibrosis at presentation than white American patients.452 They are younger at presentation, commonly have cirrhosis (57%‐85% versus 38%), have higher frequencies of liver failure (38% versus 9%), require LT more commonly (52% versus 23%), and have greater mortality (24% versus 6%).452 Asian Americans with AIH have a higher mortality (29%) than Hispanic Americans (5%) and white Americans (8%) with AIH, and hospitalizations for AIH have been more frequent for African Americans and Hispanics than for whites.458 In Europe, black patients with AIH have similar differences from white patients with AIH (younger age at presentation, increased risk of LT, and greater risk of liver‐related death). They differ by having similar responses to standard therapy and higher frequency of systemic lupus erythematosus.459
HCC and Extrahepatic Malignancies
HCC develops in 1%‐9% of patients with AIH and cirrhosis (annual incidence, 1.1‐1.9%).111 The standardized incidence ratio is 23.3 (95% CI, 7.5‐54.3),462 and the standardized mortality ratio is 42.3 (95% CI, 20.3‐77.9).463 Risk factors for HCC are cirrhosis ≥10 years, portal hypertension, continuous inflammation, and immunosuppressive therapy ≥3 years.113 Five percent of treated patients with AIH develop extrahepatic malignancies of diverse cell types (cervix, lymphatic tissue, breast, bladder, soft tissue, and skin).464 Nonmelanoma skin cancers are most common,465 and the standardized incidence ratio for extrahepatic malignancy is 2.7 (95% CI, 1.8‐3.9).463 These risks justify surveillance strategies that include hepatic ultrasonography, with or without serum alpha‐fetoprotein (AFP) level, every 6 months in patients with cirrhosis466 and adherence to standard guidelines for detection of extrahepatic malignancy.288
- Cancer surveillance should include hepatic ultrasonography, with or without serum AFP level, every 6 months in patients with cirrhosis and adherence to standard guidelines for detection of extrahepatic malignancy.
AIH is the indication for LT in 2%‐3% of recipients in Europe469 and approximately 5% of recipients in the United States.471 The number of new listings for LT for AIH in the United States is 0.5 per million population per year, but this number reflects an ongoing decrease in AIH listings of 0.012 listings per million population per year.472 Patient and graft survivals in European adults from 2000 to 2009 have been 88% and 84% at 1 year and 80% and 72% at 5 years, resepectively.470 In the United States, patient and graft survivals for children transplanted from 2002 to 2012 have been 95% and 91% at 1 year and 91% and 84% at 5 years, resepectively.473 The 5‐year patient and graft survivals for AIH in American adults are 80%‐90% and 74%, respectively.474 Patient survivals have been similar in pediatric and adult patients up to 50 years of age.475 Infection has been the most frequent cause of death within 30‐180 days after LT,476 especially during the early postoperative period for patients >50 years old.475
Acute (81% versus 47%) and steroid‐resistant (38% versus 13%) rejection after LT have occurred more frequently in adult patients transplanted for AIH than in patients transplanted for alcohol‐associated cirrhosis.477 Furthermore, the incidence of chronic rejection has been higher in patients transplanted for AIH (16%) than in patients transplanted for PBC (8.2%), PSC (5.2%), or alcohol‐associated cirrhosis (2%).478 More recent experience (2000‐2010) has demonstrated a frequency of late acute rejection of 9% in AIH.470 The frequency of chronic rejection has varied from 14% to 17% in AIH (versus 2% in alcohol‐associated cirrhosis).478 These findings continue to suggest an increased frequency of acute and chronic rejection in AIH compared to other liver diseases.
Continuation of glucocorticoid therapy after LT, rather than weaning patients to achieve a glucocorticoid‐free immunosuppressive regimen, has been touted to protect against rejection and recurrence of AIH.477 However, discontinuation of steroids after LT has been advocated to reduce risks of infection and steroid‐related side effects.485 The topic of long‐term use of corticosteroids after LT remains controversial, but the literature suggests that some patients can be safely weaned off of corticosteroids.
Systematic Review and Meta‐Analysis of Glucocorticoid Use After LT
We performed a systematic review and meta‐analysis to investigate whether continuous glucocorticoid treatment after LT was associated with fewer episodes of acute cellular rejection, recurrent AIH, graft loss, retransplantation, and better graft and patient survival compared to steroid withdrawal after LT. Out of 1,712 records that were identified in a database search, 578 were fully assessed for eligibility as full‐text articles, four were judged suitable for qualitative synthesis, and two were judged suitable for quantitative synthesis. The meta‐analysis was unable to establish a significant difference between each management strategy (Table 12). The individual determinants that constitute the strength assessment for the recommendation of glucocorticoid withdrawal versus continued glucocorticoid treatment (SR3) are shown in Table 10.
Table 12 -
Evidence Profile and Results of Systematic Review and Meta‐analysis for Continuation versus Discontinuation of Steroids after LT for AIH
|Continuation versus Discontinuation of Steroids After LT
||Grade of Evidence Quality
|Recurrent autoimmune hepatitis
||Two retrospective studies488 and one RCT489 reported no significant difference in recurrence of AIH after LT
|Acute cellular rejection
||No studies reported frequencies of acute cellular rejection
||No studies reported frequencies of graft loss
||One RCT489 reported no significant difference between the two groups
||No studies reported retransplantation
2 test of heterogeneity
2 = 38.6%, P = 0.202
|Meta‐analysis: For biochemical remission
||OR, 0.62; 95% CI, 0.19‐1.96
||Few qualified studies
|Heterogeneous test results between studies
|Low‐quality evidence to assess differences in frequency of recurrent AIH after LT
|Very low‐quality evidence to assess differences in mortality after LT
|Conditional recommendation of very low certainty that steroids be discontinued after LT
Abbreviation: RCT, randomized clinical trial.
- Based on limited data to support long‐term administration of glucocorticoids to prevent posttransplant rejection, graft loss, recurrent AIH, and reduced patient and graft survival in adults, the AASLD suggests that a gradual withdrawal of glucocorticoids be considered after LT (conditional recommendation, very low certainty).
Recurrent AIH After LT
AIH recurs in 8%‐12% of patients within the first year after LT and 36%‐68% after 5 years.471 The frequency of recurrent AIH has been similar (20%) in recipients of grafts from living‐related, living‐unrelated, and deceased donors.502 The diagnostic criteria for recurrent AIH are the same as for the original disease, albeit some features may be less pronounced or absent because of concurrent immunosuppressive therapy or short duration of disease.498 Recurrent AIH can sometimes be difficult to distinguish from alloimmune rejection. The laboratory profile and characteristic histological changes required for the diagnosis of recurrent AIH are detailed in Table 13. Histological features classically seen in rejection, including endothelialitis and bile duct damage, are usually absent in recurrent AIH. Standard glucocorticoid‐based therapy is used to treat recurrent AIH, along with the possible addition of AZA or MMF.
Table 13 -
Diagnostic Features, Treatment, and Outcome of Recurrent and De Novo
De Novo AIH
||Graft dysfunction at 2 months‐12 years471
||Indication for LT other than AIH503
|Asymptomatic to graft failure614
||Exclude plasma cell–rich rejection/plasma cell hepatitis521
|May be detected only by liver biopsy500
||Increased serum AST, ALT, IgG levels501
||Increased serum AST, ALT, IgG levels503
||Same antibodies as pre‐LT AIH617
||ANA, SMA, anti‐LKM1503
|ANA, SMA common617
||Lobular hepatitis, focal necrosis, pseudorosettes (early)620
|Interface hepatitis, lymphoplasmacytic infiltration (late)623
|Lobular collapse, confluent/bridging necrosis (severe)621
||Predniso(lo)ne, 30 mg daily, and AZA, 1‐2 mg/kg daily499
Predniso(lo)ne (1‐2 mg/kg, <60 mg daily) and AZA (1‐2 mg/kg daily)
Otherwise same as recurrent AIH adults501
Same as recurrent AIH
|Predniso(lo)ne dose reduction to 5‐10 mg daily in 4‐8 weeks624
|Predniso(lo)ne and AZA maintenance501
|Continue calcineurin inhibitor624
|Rescue regimens (empiric)
||MMF for AZA627
||MMF for AZA419
|Switch calcineurin inhibitor498
||5‐year patient survival, 86%‐100%500
||Better in children than adults 503
|Graft failure, 8%‐50%614
||Biochemical remission, 86%503
|Recurrent AIH in retransplanted liver, 33%‐100% 614
||Patient survival, 95%626
De Novo AIH
De novo AIH denotes the development of AIH in a patient transplanted for a disease other than AIH503 (Table 13). It was originally described in 4% of British children (median age, 10.3 years; range, 2‐19.4 years) who developed clinical and histological features of AIH 6‐45 months after LT for extrahepatic biliary atresia, Alagille syndrome, drug‐induced acute liver failure, and alpha 1‐antitrypsin deficiency.503 It has been reported subsequently in North American, South American, Japanese, and Korean children from 0.1 to 9 years after LT representing 1%‐7% of pediatric recipients.503De novo AIH has been described in adults after LT,510 especially in recipients transplanted for PBC511 or chronic hepatitis C.517 The estimated frequency of de novo AIH in transplanted adults ranges from 1% to 3% with an overall incidence of 4 cases per 1,000 patient‐years.520
The clinical features of de novo AIH are similar to those required for the diagnosis of AIH and recurrent AIH.2 The term “plasma cell hepatitis” was coined to describe the inflammatory infiltrates observed in adult LT recipients with recurrence of hepatitis C virus infection.522 The plasmacytic nature of the inflammation was thought to resemble AIH or “de novo AIH.”522 IgG4+ plasma cells have been identified in the infiltrates associated with severe portal, periportal, and perivenular necroinflammatory activity and fibrosis in adult patients, which could indicate alloimmune and/or autoimmune responses.523
The Banff working group on liver allograft pathology has proposed that “plasma cell–rich rejection” replace the terms “plasma cell hepatitis” and “de novo autoimmune hepatitis,” for graft dysfunction occurring >6 months after transplantation in association with severe lymphocytic cholangitis, plasma cell–rich central perivenulitis, and portal microvascular deposition of complement component 4d.524 This form of graft dysfunction has been described mainly in adult interferon‐treated recipients with chronic hepatitis C522 and distinguishes adults from children with de novo AIH.521 It may be prudent to separate de novo AIH from plasma cell hepatitis/rejection.521 Keys to the diagnosis and management of de novo AIH are provided in Table 13.
- Recurrent AIH or de novo AIH and plasma cell hepatitis/rejection must be suspected in LT recipients with laboratory changes of allograft injury.
- Liver biopsy, serum IgG level, and autoantibodies should be obtained to distinguish immune‐mediated disease from other causes of allograft dysfunction.
- Predniso(lo)ne with AZA should be added to the calcineurin inhibitor to achieve biochemical remission in recurrent AIH or de novo AIH.
Future Directions and Unmet Needs
The unmet clinical needs in AIH will drive studies that improve the outcomes of current management, enhance quality of life, prevent disease recurrence, improve management of atypical populations (especially overlap syndromes), and increase understanding of the epidemiology and pathophysiology of AIH through real‐world international databases.528
Pharmacological and biological agents that can restore homeostatic mechanisms that modulate immune responses,224 reduce oxidative and nitrosative stresses,532 or inhibit hepatic fibrosis533 will be evaluated to supplement or replace current treatments (Table 14). The ability to correct deficient immune cell mediators by the transfer of autologous expanded populations (Tregs, mesenchymal stromal cells, or myeloid‐derived suppressor cells) will be another promising investigational front.534
Table 14 -
Current and Potential Therapies for AIH Based on Evolving Knowledge of Immunopathogenic Mechanisms
||Mechanism of Action
||Status of Development
|Decrease the numbers and/or functions of autoimmune effector cells and pathogenic autoantibodies
||Immunosuppressive drugs: CNI, mTOR, antiproliferative agents
||Inhibit proliferation of autoantigen‐activated CD4 and CD8 T cells by reducing the amount and/or signaling of mitogenic IL‐2 or block completion of T‐cell division
||SOC in multiple AI diseases. Combination therapies using subtoxic doses of two or more agents attractive. Ongoing research into prevention and management of toxicities
||B‐cell depletion followed by mobilization of memory B cells from lymphoid tissue. Potent inhibition of BAFF signaling in activated T cells
||Off‐label use as alternative therapy in AIH
|Anti‐BAFF, followed by anti‐CD20
||SOC in SLE. Ongoing clinical trial in AIH
||Depletion of memory B cells mobilized from lymphoid tissues by anti‐BAFF
||Clinical trials planned in AI diseases
||Block CD40‐CD40L (CD154) costimulation of T cells and B cells
||POC. Clinical trial initiated in liver transplantation
|Inhibition of sphingosine‐1‐phosphate receptors
||First in class antibody fragment to block FcRn to increase IgG clearance and prevent IgG recycling
||POC to reduce pathogenic autoantibodies and Ig–autoantigen immune complexes
|Myeloid‐derived suppressor cells
||Prevent egress of activated T cells from lymph nodes into blood
||SOC in MS, new agents in development for other AI diseases
|Inhibit autoreactive T‐cell activation and proliferation
||POC in preclinical models. Clinical trials planned in RA
|Decrease and/or inhibit proinflammatory cytokines
||Anti‐TNFα or TNFα‐receptor
||Reduce TNFα‐mediated tissue injury and proinflammatory signaling pathways
||SOC in multiple AI diseases. Studied as an alternative therapy in AIH
|Anti‐IL‐6 or anti‐IL‐6R
||Reduce pathogenic effects of proinflammatory IL‐6 signaling in innate and adaptive immune responses
||SOC in RA, clinical trials ongoing in other AI diseases
|Anti‐IL‐12 (p40 subunit)
||Reduce pathogenic effects of proinflammatory IL‐12 signaling in innate and adaptive immune responses
||SOC in psoriasis and Crohn’s disease. Also blocks IL‐23 signaling
|Anti‐IL‐17a or Anti‐17R
||Reduce pathogenic effects of IL‐17
||SOC for psoriasis and psoriatic arthritis. Clinical trials planned in other AI diseases
||Reduce multiple pathogenic effects of IL‐21 in innate and adaptive immune responses
||Ongoing clinical trials in RA, T1DM, and Crohn’s disease
|Anti‐IL‐23 (p19 or p40 subunits)
||Reduce pathogenic effects of proinflammatory IL‐23 stimulation of Th17 cells
||SOC in psoriasis and Crohn’s disease
|Reduce pathogenic B‐cell selection, differentiation, and homeostasis
||SOC in SLE
|Inhibit signaling of proinflammatory cytokines
||Decrease proliferation of activated CD4 and CD8 T cells by inhibiting signaling of IL‐2
||SOC in solid organ transplantation and AI diseases. Alternative therapy in AIH
|Tofacitinib (JAK3 inhibitor of IL‐2 signaling)
||Decrease proliferation of activated CD4 and CD8 T cells by inhibiting signaling of IL‐2
||SOC in RA. Clinical trials planned
|Baricitinib (JAK1/2 inhibitor of IL‐6 and IFNγ signaling)
||Reduce pathogenic effects of proinflammatory IL‐6 signaling through IL‐6R in innate and adaptive immune responses and pathogenic effects of IFNγ signaling in NK, NK T, CD4, and CD8 T cells
||SOC in RA. Ongoing clinical trial in PBC
|Pacritinib (JAK2 inhibitor of IL‐12/IL‐23 signaling)
||Reduce proinflammatory IL‐12 and Il‐23 signaling that polarizes increases CD4 Th1 polarization, secretion of IFNγ and TNFα, cytotoxic activity of NK and CD8 CTLs, and differentiation of pathogenic Th17 cells
||POC established. Ongoing clinical trials
|Filotinib (JAK1 inhibitor of IFNα/IFNβ signaling)
||Reduce immunopathogenic gene expression induced by type 1 IFNs
||POC established. Ongoing clinical trials
|Upadacitinib (selective JAK1 inhibitor of IFNα/IFNβ signaling)
||Reduce immunopathogenic gene expression
||SOC for refractory RA
|Augment effects of immunosuppressant cytokines
||Reduce immunopathogenic effects of activated CD4 Th1 cells
||SOC to prevent pancreatitis post‐ERCP
|Trial in UC terminated for concern of Guillain‐Barré syndrome
|Inhibit transendothelial migration of effector cells from blood into tissues
||Inhibition of chemokine receptors or integrins
||Prevent tissue inflammation and injury by blocking transendothelial entry of effector cells from blood into target tissues
||SOC inhibition of α4/β7 integrin in UC. Clinical trial in PSC ineffective
|Prevent chemokine‐induced terminal differentiation of effector cells
||Potential for clinical trials of other Food and Drug Administration–approved chemokine/integrin inhibitors
|Establish immunoregulatory control
||Low‐dose IL‐2 infusion to increase autoantigen‐specific iTregs
||Expansion of preexisting autoantigen‐specific iTregs in vivo requires exposure to low concentrations of IL‐2
|Clinical trials ongoing
|Infusion of autoantigen‐specific iTregs generated ex vivo
Ex vivo generation of autologous autoantigen‐specific iTregs followed by infusion to immunologically control autoantigen‐specific CD4 Th‐cell subset responses
||POC of iTreg generation ex vivo established. Future clinical trials planned in AIH. Viability, function, and distribution of iTregs after infusion unknown
|Inhibition of bromodomain and extraterminal family of proteins
||Inhibition of disease‐specific epigenetic transcriptional enhancers, superenhancers, and enhancer RNA production to decrease autoimmune reactions
||POC established. Clinical trials ongoing
|Mesenchymal stem cells
||Inhibition of innate immune cells, effector T cells
||POC established. Clinical trials ongoing
|Induction of antigen‐specific iTregs
|Reduction of TNFα secretion
|Establish physiologic immunoregulatory state of pregnancy
||Creation of immunosuppressive and immunomodulatory environment of pregnancy
||Phase 1b trial of synthetic PIF in AIH completed. Ongoing clinical trial
Abbreviations: AI, autoimmune; BAFF, B cell–activating factor; Blys, B lymphocyte stimulator; CNI, calcineurin inhibitor; ERCP, endoscopic retrograde cholangiopancreatography; IFN, interferon; JAK, Janus kinase; MS, multiple sclerosis; mTOR, mechanistic target of rapamycin; PIF, preimplantation factor; POC, proof of concept; RA, rheumatoid arthritis; rHuIL‐10, recombinant, human IL‐10; SLE, systemic lupus erythematosus; SOC, standard of care regulatory approval; T1DM, type 1 diabetes mellitus.
Prognostic biomarkers that predict the risk of treatment failure, relapse, or progression to cirrhosis and therapeutic biomarkers that reflect biochemical and histological response are needed to individualize management strategies and establish endpoints of treatment.536 Antibodies to programmed cell death‐1 protein (PD‐1),537 soluble circulating PD‐1 levels,538 macrophage migration inhibitory factor,539 micro‐RNA‐21,541 and soluble CD163542 are evolving biomarkers that may guide future management. Similarly, metabolomic profiling may emerge as a means of distinguishing AIH from other liver diseases (drug‐induced liver injury, PBC)543 and assessing treatment outcome.545
Population‐based epidemiological studies that have demonstrated an increasing incidence of AIH in Spain, Denmark, and the Netherlands17 must energize efforts to understand the environmental risk factors for AIH in different geographical regions by promoting highly targeted, population‐based investigations. Key epitopes that might trigger the disease must be sought among environmental agents (infections, pharmaceuticals, diet, and pollutants)546 and within the intestinal microbiome.547
The intestinal microbiome is an underevaluated source of microbial antigens and activated immune cells that is actively being evaluated in diverse immune‐mediated diseases, including AIH.547 Intestinal dysbiosis, circulating gut‐derived lipopolysaccharides, and weakening of the intestinal mucosal barrier have already been described in patients with AIH548; and changes in the intestinal microbiome have been associated with female bias in autoimmune disease.550 Future investigations that reenforce and extend these observations in AIH may identify interventions that can reduce risk, severity, and relapse.547
The management and outcome of AIH and the overall well‐being of patients with AIH will continue to improve as understanding of its pathogenic mechanisms evolves, molecular interventions that counter its homeostatic disruptions emerge, and adjunctive measures tailored by greater awareness and responsiveness to individual need are instituted.
This work was produced in tandem with a de novo systematic review that was written by the same writing group, including M. Hassan Murad, M.D., M.P.H., who participated in the selection of the clinical questions and provided expertise regarding the GRADE approach. The AASLD Practice Guidelines Committee approved the scope, directed the development of the practice guideline and guidance, and provided the peer review that was led by Elizabeth C. Verna, M.D., M.S. Members of the AASLD Practice Guidelines Committee include George Ioannou, M.D., F.A.A.S.L.D. (chair); Rabab Ali, M.B.B.S.; Alfred Sidney Barritt IV, M.D., M.S.C.R.; James R. Burton, Jr., M.D.; Roniel Cabrera, M.D., M.S.; Michael F. Chang, M.D., M.Sc., M.B.A., F.A.A.S.L.D; Udeme Ekong, M.D., F.A.A.S.L.D.; Ruben Hernaez, M.D., M.P.H., Ph.D.; Whitney E. Jackson, M.D.; Binu John, M.D., M.P.H.; Patricia D. Jones, M.D., M.S.C.R.; Patrick S. Kamath, M.D.; David G. Koch, M.D.; Cynthia Levy, M.D., F.A.A.S.L.D.; Lopa Mishra, M.D., F.A.A.S.L.D. (board liaison); Daniel S. Pratt, M.D., F.A.A.S.L.D.; David J. Reich, M.D., F.A.C.S.; Barry Schlansky, M.D., M.P.H.; Amit G. Singal, M.D., M.S. (vice‐chair); James R. Spivey, M.D.; and Elizabeth C. Verna, M.D., M.S.
1. Merriman RB, Tran TT. AASLD practice guidelines: the past, the present, and the future. Hepatology 2016;63:31‐34.
2. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli‐Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193‐2213.
3. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924‐926.
4. Goldet G, Howick J. Understanding GRADE: an introduction. J Evid Based Med 2013;6:50‐54.
5. Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico‐laboratory and histological characteristics. World J Gastroenterol 2015;21:60‐83.
6. Palle SK, Naik KB, McCracken CE, Kolachala VL, Romero R, Gupta NA. Racial disparities in presentation and outcomes of paediatric autoimmune hepatitis. Liver Int 2019;39:976‐984.
7. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Taswell HF, Homburger HA. Evidence against hepatitis viruses as important causes of severe autoimmune hepatitis in the United States. J Hepatol 1993;18:342‐352.
8. Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33:99‐103.
9. Werner M, Prytz H, Ohlsson B, Almer S, Bjornsson E, Bergquist A, et al. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand J Gastroenterol 2008;43:1232‐1240.
10. Ngu JH, Bechly K, Chapman BA, Burt MJ, Barclay ML, Gearry RB, et al. Population‐based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroenterol Hepatol 2010;25:1681‐1686.
11. Gronbaek L, Vilstrup H, Jepsen P. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry‐based cohort study. J Hepatol 2014;60:612‐617.
12. van Gerven NM, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I, et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol 2014;49:1245‐1254.
13. Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20‐year experience. Hepatology 1997;25:541‐547.
14. Radhakrishnan KR, Alkhouri N, Worley S, Arrigain S, Hupertz V, Kay M, et al. Autoimmune hepatitis in children–impact of cirrhosis at presentation on natural history and long‐term outcome. Dig Liver Dis 2010;42:724‐728.
15. Deneau M, Jensen MK, Holmen J, Williams MS, Book LS, Guthery SL. Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. Hepatology 2013;58:1392‐1400.
16. Jimenez‐Rivera C, Ling SC, Ahmed N, Yap J, Aglipay M, Barrowman N, et al. Incidence and characteristics of autoimmune hepatitis. Pediatrics 2015;136:e1237‐e1248.
17. Czaja AJ. Global disparities and their implications in the occurrence and outcome of autoimmune hepatitis. Dig Dis Sci 2017;62:2277‐2292.
18. McFarlane IG. The relationship between autoimmune markers and different clinical syndromes in autoimmune hepatitis. Gut 1998;42:599‐602.
19. McFarlane IG. Autoimmune hepatitis: clinical manifestations and diagnostic criteria. Can J Gastroenterol 2001;15:107‐113.
20. Delgado JS, Vodonos A, Malnick S, Kriger O, Wilkof‐Segev R, Delgado B, et al. Autoimmune hepatitis in southern Israel: a 15‐year multicenter study. J Dig Dis 2013;14:611‐618.
21. Primo J, Merino C, Fernandez J, Moles JR, Llorca P, Hinojosa J. Incidence and prevalence of autoimmune hepatitis in the area of the Hospital de Sagunto (Spain). Gastroenterol Hepatol 2004;27:239‐243.
22. Primo J, Maroto N, Martinez M, Anton MD, Zaragoza A, Giner R, et al. Incidence of adult form of autoimmune hepatitis in Valencia (Spain). Acta Gastroenterol Belg 2009;72:402‐406.
23. Danielsson Borssen A, Marschall HU, Bergquist A, Rorsman F, Weiland O, Kechagias S, et al. Epidemiology and causes of death in a Swedish cohort of patients with autoimmune hepatitis. Scand J Gastroenterol 2017;52:1022‐1028.
24. Hurlburt KJ, McMahon BJ, Deubner H, Hsu‐Trawinski B, Williams JL, Kowdley KV. Prevalence of autoimmune liver disease in Alaska natives. Am J Gastroenterol 2002;97:2402‐2407.
25. Lee YM, Teo EK, Ng TM, Khor C, Fock KM. Autoimmune hepatitis in Singapore: a rare syndrome affecting middle‐aged women. J Gastroenterol Hepatol 2001;16:1384‐1389.
26. Chung HV, Riley M, Ho JK, Leung B, Jevon GP, Arbour LT, et al. Retrospective review of pediatric and adult autoimmune hepatitis in two quaternary care centres in British Columbia: increased prevalence seen in British Columbia's First Nations community. Can J Gastroenterol 2007;21:565‐568.
27. Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 1999;167:257‐274.
28. Fainboim L, Marcos Y, Pando M, Capucchio M, Reyes GB, Galoppo C, et al. Chronic active autoimmune hepatitis in children. Strong association with a particular HLA‐DR6 (DRB1*1301) haplotype. Hum Immunol 1994;41:146‐150.
29. Strettell MD, Donaldson PT, Thomson LJ, Santrach PJ, Moore SB, Czaja AJ, et al. Allelic basis for HLA‐encoded susceptibility to type 1 autoimmune hepatitis. Gastroenterology 1997;112:2028‐2035.
30. Goldberg AC, Bittencourt PL, Mougin B, Cancado EL, Porta G, Carrilho F, et al. Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus. Hum Immunol 2001;62:165‐169.
31. Djilali‐Saiah I, Fakhfakh A, Louafi H, Caillat‐Zucman S, Debray D, Alvarez F. HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis. J Hepatol 2006;45:844‐850.
32. van Gerven NM, de Boer YS, Zwiers A, Verwer BJ, Drenth JP, van Hoek B, et al. HLA‐DRB1*03:01 and HLA‐DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type‐1. Genes Immun 2015;16:247‐252.
33. Agarwal K, Czaja AJ, Jones DE, Donaldson PT. Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 2000;31:49‐53.
34. Cookson S, Constantini PK, Clare M, Underhill JA, Bernal W, Czaja AJ, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis. Hepatology 1999;30:851‐856.
35. Qin B, Li J, Liang Y, Yang Z, Zhong R. The association between cytotoxic T lymphocyte associated antigen‐4, Fas, tumour necrosis factor‐alpha gene polymorphisms and autoimmune hepatitis: a meta‐analysis. Dig Liver Dis 2014;46:541‐548.
36. Hiraide A, Imazeki F, Yokosuka O, Kanda T, Kojima H, Fukai K, et al. Fas polymorphisms influence susceptibility to autoimmune hepatitis. Am J Gastroenterol 2005;100:1322‐1329.
37. Agarwal K, Czaja AJ, Donaldson PT. A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis. Tissue Antigens 2007;69:227‐235.
38. Vogel A, Strassburg CP, Manns MP. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis. Hepatology 2002;35:126‐131.
39. Fan L, Tu X, Zhu Y, Zhou L, Pfeiffer T, Feltens R, et al. Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol 2005;20:249‐255.
40. Migita K, Nakamura M, Abiru S, Jiuchi Y, Nagaoka S, Komori A, et al. Association of STAT4 polymorphisms with susceptibility to type‐1 autoimmune hepatitis in the Japanese population. PLoS ONE 2013;8:e71382.
41. Paladino N, Flores AC, Fainboim H, Schroder T, Cuarterolo M, Lezama C, et al. The most severe forms of type I autoimmune hepatitis are associated with genetically determined levels of TGF‐beta1. Clin Immunol 2010;134:305‐312.
42. Bucala R. MIF, MIF alleles, and prospects for therapeutic intervention in autoimmunity. J Clin Immunol 2013;33(Suppl. 1):S72‐S78.
43. de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, et al. Genome‐wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014;147:443‐452.
44. Liu M, Zhu W, Wang J, Zhang J, Guo X, Wang J, et al. Interleukin‐23 receptor genetic polymorphisms and ulcerative colitis susceptibility: a meta‐analysis. Clin Res Hepatol Gastroenterol 2015;39:516‐525.
45. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet 1997;17:393‐398.
46. Christen U, Hintermann E. Pathogen infection as a possible cause for autoimmune hepatitis. Int Rev Immunol 2014;33:296‐313.
47. Floreani A, Leung PS, Gershwin ME. Environmental basis of autoimmunity. Clin Rev Allergy Immunol 2016;50:287‐300.
48. Oo YH, Hubscher SG, Adams DH. Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. Hepatol Int 2010;4:475‐493.
49. Trivedi PJ, Adams DH. Mucosal immunity in liver autoimmunity: a comprehensive review. J Autoimmun 2013;46:97‐111.
50. Floreani A, Restrepo‐Jimenez P, Secchi MF, De Martin S, Leung PSC, Krawitt E, et al. Etiopathogenesis of autoimmune hepatitis. J Autoimmun 2018;95:133‐143.
51. Sakkas LI, Daoussis D, Mavropoulos A, Liossis SN, Bogdanos DP. Regulatory B cells: new players in inflammatory and autoimmune rheumatic diseases. Semin Arthritis Rheum 2019;48:1133‐1141.
52. Kitz A, Singer E, Hafler D. Regulatory T cells: from discovery to autoimmunity. Cold Spring Harb Perspect Med 2018;8:a029041.
53. Saligrama N, Zhao F, Sikora MJ, Serratelli WS, Fernandes RA, Louis DM, et al. Opposing T cell responses in experimental autoimmune encephalomyelitis. Nature 2019;572:481‐487.
54. Chiba A, Murayama G, Miyake S. Mucosal‐associated invariant T cells in autoimmune diseases. Front Immunol 2018;9:1333.
55. Oo YH, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun 2010;34:45‐54.
56. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929‐938.
57. Czaja AJ, Manns MP. The validity and importance of subtypes in autoimmune hepatitis: a point of view. Am J Gastroenterol 1995;90:1206‐1211.
58. Muratori P, Granito A, Quarneti C, Ferri S, Menichella R, Cassani F, et al. Autoimmune hepatitis in Italy: the Bologna experience. J Hepatol 2009;50:1210‐1218.
59. Muratori P, Lalanne C, Fabbri A, Cassani F, Lenzi M, Muratori L. Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype. Aliment Pharmacol Ther 2015;41:1281‐1287.
60. Czaja AJ. Diagnosis and management of autoimmune hepatitis: current status and future directions. Gut Liv 2016;10:177‐203.
61. Czaja AJ. Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci 2011;56:545‐554.
62. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16‐year prospective study. Hepatology 2001;33:544‐553.
63. Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol 1999;30:394‐401.
64. Gregorio GV, McFarlane B, Bracken P, Vergani D, Mieli‐Vergani G. Organ and non‐organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease. Autoimmunity 2002;35:515‐519.
65. Czaja AJ, Carpenter HA, Manns MP. Antibodies to soluble liver antigen, P450IID6, and mitochondrial complexes in chronic hepatitis. Gastroenterology 1993;105:1522‐1528.
66. Kanzler S, Weidemann C, Gerken G, Lohr HF, Galle PR, Meyer zum Buschenfelde KH, et al. Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis. J Hepatol 1999;31:635‐640.
67. Ballot E, Homberg JC, Johanet C. Antibodies to soluble liver antigen: an additional marker in type 1 auto‐immune hepatitis. J Hepatol 2000;33:208‐215.
68. Baeres M, Herkel J, Czaja AJ, Wies I, Kanzler S, Cancado EL, et al. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut 2002;51:259‐264.
69. Eyraud V, Chazouilleres O, Ballot E, Corpechot C, Poupon R, Johanet C. Significance of antibodies to soluble liver antigen/liver pancreas: a large French study. Liver Int 2009;29:857‐864.
70. Montano‐Loza AJ, Shums Z, Norman GL, Czaja AJ. Prognostic implications of antibodies to Ro/SSA and soluble liver antigen in type 1 autoimmune hepatitis. Liver Int 2012;32:85‐92.
71. Efe C, Ozaslan E, Wahlin S, Purnak T, Muratori L, Quarneti C, et al. Antibodies to soluble liver antigen in patients with various liver diseases: a multicentre study. Liver Int 2013;33:190‐196.
72. Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002;35:658‐664.
73. Czaja AJ, Donaldson PT, Lohse AW. Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis. Am J Gastroenterol 2002;97:413‐419.
74. Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci 2010;55:2144‐2161.
75. Targan SR, Landers C, Vidrich A, Czaja AJ. High‐titer antineutrophil cytoplasmic antibodies in type‐1 autoimmune hepatitis. Gastroenterology 1995;108:1159‐1166.
76. Bansi D, Chapman R, Fleming K. Antineutrophil cytoplasmic antibodies in chronic liver diseases: prevalence, titre, specificity and IgG subclass. J Hepatol 1996;24:581‐586.
77. Terjung B, Sohne J, Lechtenberg B, Gottwein J, Muennich M, Herzog V, et al. p‐ANCAs in autoimmune liver disorders recognise human beta‐tubulin isotype 5 and cross‐react with microbial protein FtsZ. Gut 2010;59:808‐816.
78. Elkayam O, Levartovsky D, Brautbar C, Yaron M, Burke M, Vardinon N, et al. Clinical and immunological study of 7 patients with minocycline‐induced autoimmune phenomena. Am J Med 1998;105:484‐487.
79. Czaja AJ. Cryptogenic chronic hepatitis and its changing guise in adults. Dig Dis Sci 2011;56:3421‐3438.
80. Zachou K, Rigopoulou E, Dalekos GN. Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. J Autoimmune Dis 2004;1:2.
81. Czaja AJ, Cassani F, Cataleta M, Valentini P, Bianchi FB. Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 1996;24:1068‐1073.
82. Chretien‐Leprince P, Ballot E, Andre C, Olsson NO, Fabien N, Escande A, et al. Diagnostic value of anti‐F‐actin antibodies in a French multicenter study. Ann N Y Acad Sci 2005;1050:266‐273.
83. Frenzel C, Herkel J, Luth S, Galle PR, Schramm C, Lohse AW. Evaluation of F‐actin ELISA for the diagnosis of autoimmune hepatitis. Am J Gastroenterol 2006;101:2731‐2736.
84. Gueguen P, Dalekos G, Nousbaum JB, Zachou K, Putterman C, Youinou P, et al. Double reactivity against actin and alpha‐actinin defines a severe form of autoimmune hepatitis type 1. J Clin Immunol 2006;26:495‐505.
85. Zachou K, Oikonomou K, Renaudineau Y, Chauveau A, Gatselis N, Youinou P, et al. Anti‐alpha actinin antibodies as new predictors of response to treatment in autoimmune hepatitis type 1. Aliment Pharmacol Ther 2012;35:116‐125.
86. Renaudineau Y, Dalekos GN, Gueguen P, Zachou K, Youinou P. Anti‐alpha‐actinin antibodies cross‐react with anti‐ssDNA antibodies in active autoimmune hepatitis. Clin Rev Allergy Immunol 2008;34:321‐325.
87. Martini E, Abuaf N, Cavalli F, Durand V, Johanet C, Homberg JC. Antibody to liver cytosol (anti‐LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology 1988;8:1662‐1666.
88. Abuaf N, Johanet C, Chretien P, Martini E, Soulier E, Laperche S, et al. Characterization of the liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis. Hepatology 1992;16:892‐898.
89. Bachrich T, Thalhammer T, Jager W, Haslmayer P, Alihodzic B, Bakos S, et al. Characterization of autoantibodies against uridine‐diphosphate glucuronosyltransferase in patients with inflammatory liver diseases. Hepatology 2001;33:1053‐1059.
90. Obermayer‐Straub P, Manns MP. Cytochromes P450 and UDP‐glucuronosyl‐transferases as hepatocellular autoantigens. Baillieres Clin Gastroenterol 1996;10:501‐532.
91. Strassburg CP, Obermayer‐Straub P, Alex B, Durazzo M, Rizzetto M, Tukey RH, et al. Autoantibodies against glucuronosyltransferases differ between viral hepatitis and autoimmune hepatitis. Gastroenterology 1996;111:1576‐1586.
92. Obermayer‐Straub P, Manns MP. Cytochrome P450 enzymes and UDP‐glucuronosyltransferases as hepatocellular autoantigens. Mol Biol Rep 1996;23:235‐242.
93. Fabien N, Desbos A, Bienvenu J, Magdalou J. Autoantibodies directed against the UDP‐glucuronosyltransferases in human autoimmune hepatitis. Autoimmun Rev 2004;3:1‐9.
94. Czaja AJ, Shums Z, Norman GL. Nonstandard antibodies as prognostic markers in autoimmune hepatitis. Autoimmunity 2004;37:195‐201.
95. Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology 1993;105:1824‐1832.
96. Pratt DS, Fawaz KA, Rabson A, Dellelis R, Kaplan MM. A novel histological lesion in glucocorticoid‐responsive chronic hepatitis. Gastroenterology 1997;113:664‐668.
97. Kessler WR, Cummings OW, Eckert G, Chalasani N, Lumeng L, Kwo PY. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol 2004;2:625‐631.
98. Misdraji J, Thiim M, Graeme‐Cook FM. Autoimmune hepatitis with centrilobular necrosis. Am J Surg Pathol 2004;28:471‐478.
99. Miyake Y, Iwasaki Y, Terada R, Onishi T, Okamoto R, Takaguchi K, et al. Clinical features of Japanese type 1 autoimmune hepatitis patients with zone III necrosis. Hepatol Res 2007;37:801‐805.
100. Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011;53:517‐526.
101. Humble JG, Jayne WH, Pulvertaft RJ. Biological interaction between lymphocytes and other cells. Br J Haematol 1956;2:283‐294.
102. Rastogi V, Sharma R, Misra SR, Yadav L, Sharma V. Emperipolesis—a review. J Clin Diagn Res 2014;8:ZM01‐ZM02.
103. Balitzer D, Shafizadeh N, Peters MG, Ferrell LD, Alshak N, Kakar S. Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria. Mod Pathol 2017;30:773‐783.
104. Feld JJ, Dinh H, Arenovich T, Marcus VA, Wanless IR, Heathcote EJ. Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology 2005;42:53‐62.
105. Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology 1996;110:848‐857.
106. Verma S, Gunuwan B, Mendler M, Govindrajan S, Redeker A. Factors predicting relapse and poor outcome in type I autoimmune hepatitis: role of cirrhosis development, patterns of transaminases during remission and plasma cell activity in the liver biopsy. Am J Gastroenterol 2004;99:1510‐1516.
107. Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: current understanding. World J Hepatol 2016;8:1157‐1168.
108. Mieli‐Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, et al. Diagnosis and management of pediatric autoimmune liver disease: ESPGHAN Hepatology Committee position statement. J Pediatr Gastroenterol Nutr 2018;66:345‐360.
109. Schalm SW, Korman MG, Summerskill WH, Czaja AJ, Baggenstoss AH. Severe chronic active liver disease. Prognostic significance of initial morphologic patterns. Am J Dig Dis 1977;22:973‐980.
110. Davis GL, Czaja AJ, Ludwig J. Development and prognosis of histologic cirrhosis in corticosteroid‐treated hepatitis B surface antigen‐negative chronic active hepatitis. Gastroenterology 1984;87:1222‐1227.
111. Wang KK, Czaja AJ. Hepatocellular carcinoma in corticosteroid‐treated severe autoimmune chronic active hepatitis. Hepatology 1988;8:1679‐1683.
112. Park SZ, Nagorney DM, Czaja AJ. Hepatocellular carcinoma in autoimmune hepatitis. Dig Dis Sci 2000;45:1944‐1948.
113. Montano‐Loza AJ, Carpenter HA, Czaja AJ. Predictive factors for hepatocellular carcinoma in type 1 autoimmune hepatitis. Am J Gastroenterol 2008;103:1944‐1951.
114. Yeoman AD, Al‐Chalabi T, Karani JB, Quaglia A, Devlin J, Mieli‐Vergani G, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow‐up and screening. Hepatology 2008;48:863‐870.
115. Chung H, Watanabe T, Kudo M, Maenishi O, Wakatsuki Y, Chiba T. Identification and characterization of IgG4‐associated autoimmune hepatitis. Liver Int 2010;30:222‐231.
116. Umemura T, Zen Y, Hamano H, Joshita S, Ichijo T, Yoshizawa K, et al. Clinical significance of immunoglobulin G4–associated autoimmune hepatitis. J Gastroenterol 2011;46(Suppl. 1):48‐55.
117. Yada N, Kudo M, Chung H, Watanabe T. Autoimmune hepatitis and immunoglobulin G4–associated autoimmune hepatitis. Dig Dis 2013;31:415‐420.
118. De Luca‐Johnson J, Wangensteen KJ, Hanson J, Krawitt E, Wilcox R. Natural history of patients presenting with autoimmune hepatitis and coincident nonalcoholic fatty liver disease. Dig Dis Sci 2016;61:2710‐2720.
119. Takahashi A, Arinaga‐Hino T, Ohira H, Abe K, Torimura T, Zeniya M, et al. Non‐alcoholic fatty liver disease in patients with autoimmune hepatitis. JGH Open 2018;2:54‐58.
120. Johnson PJ, McFarlane IG. Meeting report: international autoimmune hepatitis group. Hepatology 1993;18:998‐1005.
121. Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008;48:169‐176.
122. Czaja AJ. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology 2008;48:1540‐1548.
123. Arcos‐Machancoses JV, Molera Busoms C, Julio Tatis E, Bovo MV, Martín de Carpi J. Accuracy of the simplified criteria for autoimmune hepatitis in children: systematic review and decision analysis. J Clin Exp Hepatol 2019;9:147‐155.
124. Ebbeson RL, Schreiber RA. Diagnosing autoimmune hepatitis in children: is the International Autoimmune Hepatitis Group scoring system useful? Clin Gastroenterol Hepatol 2004;2:935‐940.
125. Yatsuji S, Hashimoto E, Kaneda H, Taniai M, Tokushige K, Shiratori K. Diagnosing autoimmune hepatitis in nonalcoholic fatty liver disease: is the International Autoimmune Hepatitis Group scoring system useful? J Gastroenterol 2005;40:1130‐1138.
126. Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54:374‐385.
127. Vergani D, Alvarez F, Bianchi FB, Cancado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol 2004;41:677‐683.
128. Czaja AJ. Natural history, clinical features, and treatment of autoimmune hepatitis. Semin Liver Dis 1984;4:1‐12.
129. Muratori P, Fabbri A, Lalanne C, Lenzi M, Muratori L. Autoimmune liver disease and concomitant extrahepatic autoimmune disease. Eur J Gastroenterol Hepatol 2015;27:1175‐1179.
130. Kogan J, Safadi R, Ashur Y, Shouval D, Ilan Y. Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: a study of 68 patients. J Clin Gastroenterol 2002;35:75‐81.
131. Czaja AJ. Features and consequences of untreated type 1 autoimmune hepatitis. Liver Int 2009;29:816‐823.
132. Muratori P, Lalanne C, Barbato E, Fabbri A, Cassani F, Lenzi M, et al. Features and progression of asymptomatic autoimmune hepatitis in Italy. Clin Gastroenterol Hepatol 2016;14:139‐146.
133. Nikias GA, Batts KP, Czaja AJ. The nature and prognostic implications of autoimmune hepatitis with an acute presentation. J Hepatol 1994;21:866‐871.
134. Ferrari R, Pappas G, Agostinelli D, Muratori P, Muratori L, Lenzi M, et al. Type 1 autoimmune hepatitis: patterns of clinical presentation and differential diagnosis of the “acute” type. QJM 2004;97:407‐412.
135. Seo S, Toutounjian R, Conrad A, Blatt L, Tong MJ. Favorable outcomes of autoimmune hepatitis in a community clinic setting. J Gastroenterol Hepatol 2008;23:1410‐1414.
136. Czaja AJ. Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis Sci 2013;58:897‐914.
137. Lee WS, McKiernan P, Kelly DA. Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United kingdom. J Pediatr Gastroenterol Nutr 2005;40:575‐581.
138. Burgart LJ, Batts KP, Ludwig J, Nikias GA, Czaja AJ. Recent‐onset autoimmune hepatitis. Biopsy findings and clinical correlations. Am J Surg Pathol 1995;19:699‐708.
139. Anand L, Choudhury A, Bihari C, Sharma BC, Kumar M, Maiwall R, et al. Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy. Hepatology 2019;70:587‐596.
140. Yasui S, Fujiwara K, Yonemitsu Y, Oda S, Nakano M, Yokosuka O. Clinicopathological features of severe and fulminant forms of autoimmune hepatitis. J Gastroenterol 2011;46:378‐390.
141. Fujiwara K, Fukuda Y, Yokosuka O. Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute‐onset autoimmune hepatitis. J Gastroenterol 2008;43:951‐958.
142. Yasui S, Fujiwara K, Okitsu K, Yonemitsu Y, Ito H, Yokosuka O. Importance of computed tomography imaging features for the diagnosis of autoimmune acute liver failure. Hepatol Res 2012;42:42‐50.
143. Heringlake S, Schutte A, Flemming P, Schmiegel W, Manns MP, Tillmann HL. Presumed cryptogenic liver disease in Germany: high prevalence of autoantibody‐negative autoimmune hepatitis, low prevalence of NASH, no evidence for occult viral etiology. Z Gastroenterol 2009;47:417‐423.
144. Mehendiratta V, Mitroo P, Bombonati A, Navarro VJ, Rossi S, Rubin R, et al. Serologic markers do not predict histologic severity or response to treatment in patients with autoimmune hepatitis. Clin Gastroenterol Hepatol 2009;7:98‐103.
145. Miyake Y, Yamamoto K. Current status of autoimmune hepatitis in Japan. Acta Med Okayama 2008;62:217‐226.
146. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Homburger HA. The nature and prognosis of severe cryptogenic chronic active hepatitis. Gastroenterology 1993;104:1755‐1761.
147. Gassert DJ, Garcia H, Tanaka K, Reinus JF. Corticosteroid‐responsive cryptogenic chronic hepatitis: evidence for seronegative autoimmune hepatitis. Dig Dis Sci 2007;52:2433‐2437.
148. Czaja AJ. Autoantibody‐negative autoimmune hepatitis. Dig Dis Sci 2012;57:610‐624.
149. Bittencourt PL, Farias AQ, Porta G, Cancado EL, Miura I, Pugliese R, et al. Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis: effect of age, gender, and genetic background. J Clin Gastroenterol 2008;42:300‐305.
150. Teufel A, Weinmann A, Kahaly GJ, Centner C, Piendl A, Worns M, et al. Concurrent autoimmune diseases in patients with autoimmune hepatitis. J Clin Gastroenterol 2010;44:208‐213.
151. Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, et al. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol 2012;24:531‐534.
152. Wong GW, Yeong T, Lawrence D, Yeoman AD, Verma S, Heneghan MA. Concurrent extrahepatic autoimmunity in autoimmune hepatitis: implications for diagnosis, clinical course and long‐term outcomes. Liver Int 2017;37:449‐457.
153. Homberg JC, Abuaf N, Bernard O, Islam S, Alvarez F, Khalil SH, et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis. Hepatology 1987;7:1333‐1339.
154. Clemente MG, Meloni A, Obermayer‐Straub P, Frau F, Manns MP, De Virgiliis S. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology 1998;114:324‐328.
155. Lankisch TO, Jaeckel E, Strassburg CP. The autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy or autoimmune polyglandular syndrome type 1. Semin Liver Dis 2009;29:307‐314.
156. Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology 2006;43:532‐538.
157. Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology 1993;105:1502‐1507.
158. Czaja AJ, Strettell MD, Thomson LJ, Santrach PJ, Moore SB, Donaldson PT, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology 1997;25:317‐323.
159. Fogel R, Comerford M, Chilukuri P, Orman E, Chalasani N, Lammert C. Extrahepatic autoimmune diseases are prevalent in autoimmune hepatitis patients and their first‐degree relatives: survey study. Interact J Med Res 2018;7:e18.
160. Volta U, De Franceschi L, Molinaro N, Cassani F, Muratori L, Lenzi M, et al. Frequency and significance of anti‐gliadin and anti‐endomysial antibodies in autoimmune hepatitis. Dig Dis Sci 1998;43:2190‐2195.
161. van Gerven NM, Bakker SF, de Boer YS, Witte BI, Bontkes H, van Nieuwkerk CM, et al. Seroprevalence of celiac disease in patients with autoimmune hepatitis. Eur J Gastroenterol Hepatol 2014;26:1104‐1107.
162. Caprai S, Vajro P, Ventura A, Sciveres M, Maggiore G, SIGENP Study Group for Autoimmune Liver Disorders in Celiac Disease . Autoimmune liver disease associated with celiac disease in childhood: a multicenter study. Clin Gastroenterol Hepatol 2008;6:803‐806.
163. Volta U, De Franceschi L, Lari F, Molinaro N, Zoli M, Bianchi FB. Coeliac disease hidden by cryptogenic hypertransaminasaemia. Lancet 1998;352:26‐29.
164. Volta U, Granito A, De Franceschi L, Petrolini N, Bianchi FB. Anti tissue transglutaminase antibodies as predictors of silent coeliac disease in patients with hypertransaminasaemia of unknown origin. Dig Liver Dis 2001;33:420‐425.
165. Volta U. Pathogenesis and clinical significance of liver injury in celiac disease. Clin Rev Allergy Immunol 2009;36:62‐70.
166. Nastasio S, Sciveres M, Riva S, Filippeschi IP, Vajro P, Maggiore G. Celiac disease–associated autoimmune hepatitis in childhood: long‐term response to treatment. J Pediatr Gastroenterol Nutr 2013;56:671‐674.
167. Marciano F, Savoia M, Vajro P. Celiac disease–related hepatic injury: insights into associated conditions and underlying pathomechanisms. Dig Liver Dis 2016;48:112‐119.
168. Domschke W, Klein R, Terracciano LM, Jung P, Kirchner T, Berg PA, et al. Sequential occurrence of primary sclerosing cholangitis and autoimmune hepatitis type III in a patient with ulcerative colitis: a follow up study over 14 years. Liver 2000;20:340‐345.
169. Abdo AA, Bain VG, Kichian K, Lee SS. Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology 2002;36:1393‐1399.
170. Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology 2006;44:85‐90.
171. Gossard AA, Lindor KD. Development of autoimmune hepatitis in primary biliary cirrhosis. Liver Int 2007;27:1086‐1090.
172. Lindgren S, Glaumann H, Almer S, Bergquist A, Bjornsson E, Broome U, et al. Transitions between variant forms of primary biliary cirrhosis during long‐term follow‐up. Eur J Intern Med 2009;20:398‐402.
173. Czaja AJ. Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014;12:1430‐1438.
174. Czaja AJ. The variant forms of autoimmune hepatitis. Ann Intern Med 1996;125:588‐598.
175. Czaja AJ. Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 1998;28:360‐365.
176. Czaja AJ, Carpenter HA. Autoimmune hepatitis overlap syndromes and liver pathology. Gastroenterol Clin North Am 2017;46:345‐364.
177. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998;28:296‐301.
178. Farias AQ, Goncalves LL, Bittencourt PL, De Melo ES, Abrantes‐Lemos CP, Porta G, et al. Applicability of the IAIHG scoring system to the diagnosis of antimitochondrial/anti‐M2 seropositive variant form of autoimmune hepatitis. J Gastroenterol Hepatol 2006;21:887‐893.
179. Beuers U, Boberg KM, Chapman RW, Chazouilleres O, Invernizzi P, Jones DEJ, et al. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237‐267.
180. Beuers U, Gershwin ME, Gish RG, Invernizzi P, Jones DE, Lindor K, et al. Changing nomenclature for PBC: from “cirrhosis” to “cholangitis.” Hepatology 2015;62:1620‐1622.
181. Kuiper EM, Zondervan PE, van Buuren HR. Paris criteria are effective in diagnosis of primary biliary cirrhosis and autoimmune hepatitis overlap syndrome. Clin Gastroenterol Hepatol 2010;8:530‐534.
182. Bonder A, Retana A, Winston DM, Leung J, Kaplan MM. Prevalence of primary biliary cirrhosis–autoimmune hepatitis overlap syndrome. Clin Gastroenterol Hepatol 2011;9:609‐612.
183. O'Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long‐term follow‐up of antimitochondrial antibody–positive autoimmune hepatitis. Hepatology 2008;48:550‐556.
184. Perdigoto R, Carpenter HA, Czaja AJ. Frequency and significance of chronic ulcerative colitis in severe corticosteroid‐treated autoimmune hepatitis. J Hepatol 1992;14:325‐331.
185. Olsson R, Glaumann H, Almer S, Broome U, Lebrun B, Bergquist A, et al. High prevalence of small duct primary sclerosing cholangitis among patients with overlapping autoimmune hepatitis and primary sclerosing cholangitis. Eur J Intern Med 2009;20:190‐196.
186. Muratori P, Muratori L, Gershwin ME, Czaja AJ, Pappas G, MacCariello S, et al. “True” antimitochondrial antibody–negative primary biliary cirrhosis, low sensitivity of the routine assays, or both? Clin Exp Immunol 2004;135:154‐158.
187. Bjornsson E, Talwalkar J, Treeprasertsuk S, Kamath PS, Takahashi N, Sanderson S, et al. Drug‐induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010;51:2040‐2048.
188. Czaja AJ. Drug‐induced autoimmune‐like hepatitis. Dig Dis Sci 2011;56:958‐976.
189. Castiella A, Lucena MI, Zapata EM, Otazua P, Andrade RJ. Drug‐induced autoimmune‐like hepatitis: a diagnostic challenge. Dig Dis Sci 2011;56:2501‐2503.
190. deLemos AS, Foureau DM, Jacobs C, Ahrens W, Russo MW, Bonkovsky HL. Drug‐induced liver injury with autoimmune features. Semin Liver Dis 2014;34:194‐204.
191. Licata A, Maida M, Cabibi D, Butera G, Macaluso FS, Alessi N, et al. Clinical features and outcomes of patients with drug‐induced autoimmune hepatitis: a retrospective cohort study. Dig Liver Dis 2014;46:1116‐1120.
192. Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus‐like syndrome. BMJ 1996;312:169‐172.
193. Herzog D, Hajoui O, Russo P, Alvarez F. Study of immune reactivity of minocycline‐induced chronic active hepatitis. Dig Dis Sci 1997;42:1100‐1103.
194. Bhat G, Jordan J Jr., Sokalski S, Bajaj V, Marshall R, Berkelhammer C. Minocycline‐induced hepatitis with autoimmune features and neutropenia. J Clin Gastroenterol 1998;27:74‐75.
195. Teitelbaum JE, Perez‐Atayde AR, Cohen M, Bousvaros A, Jonas MM. Minocycline‐related autoimmune hepatitis: case series and literature review. Arch Pediatr Adolesc Med 1998;152:1132‐1136.
196. Goldstein NS, Bayati N, Silverman AL, Gordon SC. Minocycline as a cause of drug‐induced autoimmune hepatitis. Report of four cases and comparison with autoimmune hepatitis. Am J Clin Pathol 2000;114:591‐598.
197. Abe M, Furukawa S, Takayama S, Michitaka K, Minami H, Yamamoto K, et al. Drug‐induced hepatitis with autoimmune features during minocycline therapy. Intern Med 2003;42:48‐52.
198. Ramakrishna J, Johnson AR, Banner BF. Long‐term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. J Clin Gastroenterol 2009;43:787‐790.
199. Hatoff DE, Cohen M, Schweigert BF, Talbert WM. Nitrofurantoin: another cause of drug‐induced chronic active hepatitis? A report of a patient with HLA‐B8 antigen. Am J Med 1979;67:117‐121.
200. Sharp JR, Ishak KG, Zimmerman HJ. Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin. Ann Intern Med 1980;92:14‐19.
201. Stricker BH, Blok AP, Claas FH, Van Parys GE, Desmet VJ. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology 1988;8:599‐606.
202. Paiva LA, Wright PJ, Koff RS. Long‐term hepatic memory for hypersensitivity to nitrofurantoin. Am J Gastroenterol 1992;87:891‐893.
203. Amit G, Cohen P, Ackerman Z. Nitrofurantoin‐induced chronic active hepatitis. Isr Med Assoc J 2002;4:184‐186.
204. Fontana RJ, Seeff LB, Andrade RJ, Bjornsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in drug‐induced liver injury: summary of a clinical research workshop. Hepatology 2010;52:730‐742.
205. Appleyard S, Saraswati R, Gorard DA. Autoimmune hepatitis triggered by nitrofurantoin: a case series. J Med Case Rep 2010;4:311.
206. Germano V, Picchianti Diamanti A, Baccano G, Natale E, Onetti Muda A, Priori R, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis 2005;64:1519‐1520.
207. Tobon GJ, Canas C, Jaller JJ, Restrepo JC, Anaya JM. Serious liver disease induced by infliximab. Clin Rheumatol 2007;26:578‐581.
208. Ozorio G, McGarity B, Bak H, Jordan AS, Lau H, Marshall C. Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis. Med J Aust 2007;187:524‐526.
209. Marques M, Magro F, Cardoso H, Carneiro F, Portugal R, Lopes J, et al. Infliximab‐induced lupus‐like syndrome associated with autoimmune hepatitis. Inflamm Bowel Dis 2008;14:723‐725.
210. Carlsen KM, Riis L, Madsen OR. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept. Clin Rheumatol 2009;28:1001‐1003.
211. Fairhurst DA, Sheehan‐Dare R. Autoimmune hepatitis associated with infliximab in a patient with palmoplantar pustular psoriaisis. Clin Exp Dermatol 2009;34:421‐422.
212. Subramaniam K, Chitturi S, Brown M, Pavli P. Infliximab‐induced autoimmune hepatitis in Crohn's disease treated with budesonide and mycophenolate. Inflamm Bowel Dis 2011;17:E149‐E150.
213. Goldfeld DA, Verna EC, Lefkowitch J, Swaminath A. Infliximab‐induced autoimmune hepatitis with successful switch to adalimumab in a patient with Crohn's disease: the index case. Dig Dis Sci 2011;56:3386‐3388.
214. Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, presentation, and outcomes in patients with drug‐induced liver injury in the general population of Iceland. Gastroenterology 2013;144:1419‐1425.
215. Efe C. Drug induced autoimmune hepatitis and TNF‐alpha blocking agents: is there a real relationship? Autoimmun Rev 2013;12:337‐339.
216. Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, et al. Liver injury from tumor necrosis factor‐alpha antagonists: analysis of thirty‐four cases. Clin Gastroenterol Hepatol 2013;11:558‐564.
217. Dang LJ, Lubel JS, Gunatheesan S, Hosking P, Su J. Drug‐induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis. Australas J Dermatol 2014;55:75‐79.
218. Bjornsson ES, Gunnarsson BI, Grondal G, Jonasson JG, Einarsdottir R, Ludviksson BR, et al. Risk of drug‐induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol 2015;13:602‐608.
219. Rodrigues S, Lopes S, Magro F, Cardoso H, Horta e Vale AM, Marques M, et al. Autoimmune hepatitis and anti‐tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol 2015;21:7584‐7588.
220. French JB, Bonacini M, Ghabril M, Foureau D, Bonkovsky HL. Hepatotoxicity associated with the use of anti‐TNF‐alpha agents. Drug Saf 2016;39:199‐208.
221. Ricciuto A, Kamath BM, Walters TD, Frost K, Carman N, Church PC, et al. New onset autoimmune hepatitis during anti–tumor necrosis factor‐alpha treatment in children. J Pediatr 2018;194:128‐135.
222. Young A, Quandt Z, Bluestone JA. The balancing act between cancer immunity and autoimmunity in response to immunotherapy. Cancer Immunol Res 2018;6:1445‐1452.
223. Myers G. Immune‐related adverse events of immune checkpoint inhibitors: a brief review. Curr Oncol 2018;25:342‐347.
224. Czaja AJ. Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis. Autoimmunity 2019;52:144‐160.
225. Kleiner DE, Berman D. Pathologic changes in ipilimumab‐related hepatitis in patients with metastatic melanoma. Dig Dis Sci 2012;57:2233‐2240.
226. Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor‐associated colits and hepatitis. Clin Transl Gastroenterol 2018;9:180.
227. Reynolds K, Thomas M, Dougan M. Diagnosis and management of hepatitis in patients on checkpoint blockade. Oncologist 2018;23:991‐997.
228. Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug‐induced liver injury. Mod Pathol 2018;31:965‐973.
229. Nishida N, Kudo M. Liver damage related to immune checkpoint inhibitors. Hepatol Int 2019;13:248‐252.
230. Doherty GJ, Duckworth AM, Davies SE, Mells GF, Brais R, Harden SV, et al. Severe steroid‐resistant anti‐PD1 T‐cell checkpoint inhibitor–induced hepatotoxicity driven by biliary injury. ESMO Open 2017;2:e000268.
231. Lewis JH, Zimmerman HJ. Drug‐induced autoimmune liver disease. In: Krawitt EL, Wiesner RH, Nishioka K, eds. Autoimmune Liver Diseases. 2nd ed. Amsterdam: Elsevier Science; 1998:627‐649.
232. Liu ZX, Kaplowitz N. Immune‐mediated drug‐induced liver disease. Clin Liver Dis 2002;6:755‐774.
233. Watkins PB, Seeff LB. Drug‐induced liver injury: summary of a single topic clinical research conference. Hepatology 2006;43:618‐631.
234. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and outcomes of 899 patients with drug‐induced liver injury: the DILIN prospective study. Gastroenterology 2015;148:1340‐1352.
235. Ramachandran R, Kakar S. Histological patterns in drug‐induced liver disease. J Clin Pathol 2009;62:481‐492.
236. de Boer YS, Kosinski AS, Urban TJ, Zhao Z, Long N, Chalasani N, et al. Features of autoimmune hepatitis in patients with drug‐induced liver injury. Clin Gastroenterol Hepatol 2017;15:103‐112.
237. Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, et al. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug‐induced liver injury. Hepatology 2011;54:931‐939.
238. Bjornsson E, Kalaitzakis E, Av Klinteberg V, Alem N, Olsson R. Long‐term follow‐up of patients with mild to moderate drug‐induced liver injury. Aliment Pharmacol Ther 2007;26:79‐85.
239. Bjornsson E, Davidsdottir L. The long‐term follow‐up after idiosyncratic drug‐induced liver injury with jaundice. J Hepatol 2009;50:511‐517.
240. Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug‐induced liver disease. Hepatology 2005;42:481‐489.
241. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia‐Ruiz E, et al. Drug‐induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10‐year period. Gastroenterology 2005;129:512‐521.
242. Robles‐Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina‐Caliz I, Gonzalez‐Jimenez A, et al. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug‐induced liver injury. Gastroenterology 2014;147:109‐118.
243. Montano‐Loza AJ, Carpenter HA, Czaja AJ. Consequences of treatment withdrawal in type 1 autoimmune hepatitis. Liver Int 2007;27:507‐515.
244. van Gerven NM, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ, van Erpecum KJ, et al. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J Hepatol 2013;58:141‐147.
245. Castiella A, Zapata E, Lucena MI, Andrade RJ. Drug‐induced autoimmune liver disease: a diagnostic dilemma of an increasingly reported disease. World J Hepatol 2014;6:160‐168.
246. Fontana RJ, Hayashi PH, Gu J, Reddy KR, Barnhart H, Watkins PB, et al. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 2014;147:96‐108.
247. Ngo Y, Munteanu M, Messous D, Charlotte F, Imbert‐Bismut F, Thabut D, et al. A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C. Clin Chem 2006;52:1887‐1896.
248. Poynard T, Ngo Y, Perazzo H, Munteanu M, Lebray P, Moussalli J, et al. Prognostic value of liver fibrosis biomarkers: a meta‐analysis. Gastroenterol Hepatol (N Y) 2011;7:445‐454.
249. Poynard T, de Ledinghen V, Zarski JP, Stanciu C, Munteanu M, Vergniol J, et al. Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fibrosis in patients with chronic hepatitis C: a step toward the truth in the absence of a gold standard. J Hepatol 2012;56:541‐548.
250. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518‐526.
251. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317‐1325.
252. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1104‐1112.
253. Parkes J, Roderick P, Harris S, Day C, Mutimer D, Collier J, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut 2010;59:1245‐1251.
254. Parkes J, Guha IN, Roderick P, Harris S, Cross R, Manos MM, et al. Enhanced liver fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C. J Viral Hepat 2011;18:23‐31.
255. Poynard T, Morra R, Ingiliz P, Imbert‐Bismut F, Thabut D, Messous D, et al. Biomarkers of liver fibrosis. Adv Clin Chem 2008;46:131‐160.
256. Czaja AJ. Review article: prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014;39:385‐406.
257. Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008;47:455‐460.
258. Mayo MJ, Parkes J, Adams‐Huet B, Combes B, Mills AS, Markin RS, et al. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 2008;48:1549‐1557.
259. Wu S, Yang Z, Zhou J, Zeng N, He Z, Zhan S, et al. Systematic review: diagnostic accuracy of non‐invasive tests for staging liver fibrosis in autoimmune hepatitis. Hepatol Int 2019;13:91‐101.
260. Hartl J, Denzer U, Ehlken H, Zenouzi R, Peiseler M, Sebode M, et al. Transient elastography in autoimmune hepatitis: timing determines the impact of inflammation and fibrosis. J Hepatol 2016;65:769‐775.
261. Xu Q, Sheng L, Bao H, Chen X, Guo C, Li H, et al. Evaluation of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis. J Gastroenterol Hepatol 2017;32:639‐644.
262. Guo L, Zheng L, Hu L, Zhou H, Yu L, Liang W. Transient elastography (FibroScan) performs better than non‐invasive markers in assessing liver fibrosis and cirrhosis in autoimmune hepatitis patients. Med Sci Monit 2017;23:5106‐5112.
263. Sagir A, Erhardt A, Schmitt M, Haussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2008;47:592‐595.
264. Romanque P, Stickel F, Dufour JF. Disproportionally high results of transient elastography in patients with autoimmune hepatitis. Liver Int 2008;28:1177‐1178.
265. Hartl J, Ehlken H, Sebode M, Peiseler M, Krech T, Zenouzi R, et al. Usefulness of biochemical remission and transient elastography in monitoring disease course in autoimmune hepatitis. J Hepatol 2018;68:754‐763.
266. Huwart L, Sempoux C, Vicaut E, Salameh N, Annet L, Danse E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008;135:32‐40.
267. Venkatesh SK, Yin M, Ehman RL. Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J Magn Reson Imaging 2013;37:544‐555.
268. Loomba R, Wolfson T, Ang B, Hooker J, Behling C, Peterson M, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 2014;60:1920‐1928.
269. Wang J, Malik N, Yin M, Smyrk TC, Czaja AJ, Ehman RL, et al. Magnetic resonance elastography is accurate in detecting advanced fibrosis in autoimmune hepatitis. World J Gastroenterol 2017;23:859‐868.
270. Talwalkar JA, Yin M, Venkatesh S, Rossman PJ, Grimm RC, Manduca A, et al. Feasibility of in vivo MR elastographic splenic stiffness measurements in the assessment of portal hypertension. Am J Roentgenol 2009;193:122‐127.
271. Shi Y, Guo Q, Xia F, Dzyubak B, Glaser KJ, Li Q, et al. MR elastography for the assessment of hepatic fibrosis in patients with chronic hepatitis B infection: does histologic necroinflammation influence the measurement of hepatic stiffness? Radiology 2014;273:88‐98.
272. D'Onofrio M, Crosara S, De Robertis R, Canestrini S, Demozzi E, Gallotti A, et al. Acoustic radiation force impulse of the liver. World J Gastroenterol 2013;19:4841‐4849.
273. Bruno C, Minniti S, Bucci A, Pozzi MR. ARFI: from basic principles to clinical applications in diffuse chronic disease‐a review. Insights Imaging 2016;7:735‐746.
274. Piscaglia F, Salvatore V, Di Donato R, D'Onofrio M, Gualandi S, Gallotti A, et al. Accuracy of VirtualTouch acoustic radiation force impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography. Ultraschall Med 2011;32:167‐175.
275. Bota S, Herkner H, Sporea I, Salzl P, Sirli R, Neghina AM, et al. Meta‐analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int 2013;33:1138‐1147.
276. Ye XP, Ran HT, Cheng J, Zhu YF, Zhang DZ, Zhang P, et al. Liver and spleen stiffness measured by acoustic radiation force impulse elastography for noninvasive assessment of liver fibrosis and esophageal varices in patients with chronic hepatitis B. J Ultrasound Med 2012;31:1245‐1253.
277. Morishita N, Hiramatsu N, Oze T, Harada N, Yamada R, Miyazaki M, et al. Liver stiffness measurement by acoustic radiation force impulse is useful in predicting the presence of esophageal varices or high‐risk esophageal varices among patients with HCV‐related cirrhosis. J Gastroenterol 2014;49:1175‐1182.
278. Karlas TF, Pfrepper C, Rosendahl J, Benckert C, Wittekind C, Jonas S, et al. Acoustic radiation force impulse (ARFI) elastography in acute liver failure: necrosis mimics cirrhosis. Z Gastroenterol 2011;49:443‐448.
279. Bacon BR, Treuhaft WH, Goodman AM. Azathioprine‐induced pancytopenia. Occurrence in two patients with connective‐tissue diseases. Arch Intern Med 1981;141:223‐226.
280. Ben Ari Z, Mehta A, Lennard L, Burroughs AK. Azathioprine‐induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis. J Hepatol 1995;23:351‐354.
281. Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver‐erythrocyte correlation and presence of isozymes. Pharmacogenetics 1992;2:148‐159.
282. Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park‐Hah JO, et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther 1997;62:60‐73.
283. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, et al. Molecular diagnosis of thiopurine S‐methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997;126:608‐614.
284. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 2008;64:753‐767.
285. Regueiro M, Mardini H. Determination of thiopurine methyltransferase genotype or phenotype optimizes initial dosing of azathioprine for the treatment of Crohn's disease. J Clin Gastroenterol 2002;35:240‐244.
286. Lichtenstein GR. Use of laboratory testing to guide 6‐mercaptopurine/azathioprine therapy. Gastroenterology 2004;127:1558‐1564.
287. Richard VS, Al‐Ismail D, Salamat A. Should we test TPMT enzyme levels before starting azathioprine? Hematology 2007;12:359‐360.
288. Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013;38:343‐364.
289. Langley PG, Underhill J, Tredger JM, Norris S, McFarlane IG. Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis. J Hepatol 2002;37:441‐447.
290. Heneghan MA, Allan ML, Bornstein JD, Muir AJ, Tendler DA. Utility of thiopurine methyltransferase genotyping and phenotyping, and measurement of azathioprine metabolites in the management of patients with autoimmune hepatitis. J Hepatol 2006;45:584‐591.
291. Czaja AJ, Carpenter HA. Thiopurine methyltransferase deficiency and azathioprine intolerance in autoimmune hepatitis. Dig Dis Sci 2006;51:968‐975.
292. Ferucci ED, Hurlburt KJ, Mayo MJ, Livingston S, Deubner H, Gove J, et al. Azathioprine metabolite measurements are not useful in following treatment of autoimmune hepatitis in Alaska native and other non‐Caucasian people. Can J Gastroenterol 2011;25:21‐27.
293. Centers for Disease Control and Prevention . Vaccines & immunizations. www.cdc.gov/vaccines
. Published May 2016. Accessed December 2018.
294. Worns MA, Teufel A, Kanzler S, Shrestha A, Victor A, Otto G, et al. Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases. Am J Gastroenterol 2008;103:138‐146.
295. Danziger‐Isakov L, Kumar D; AST ID Community of Practice . Vaccination of solid organ transplant candidates and recipients: guidelines from the American society of transplantation infectious diseases community of practice. Clin Transplant 2019;33:e13563.
296. Perrillo RP, Gish R, Falck‐Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:221‐244.
297. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck‐Ytter YT. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:215‐219.
298. Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology 2017;152:1297‐1309.
299. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560‐1599.
300. Pattullo V. Prevention of hepatitis B reactivation in the setting of immunosuppression. Clin Mol Hepatol 2016;22:219‐237.
301. American Gastroenterological Association . American Gastroenterological Association medical position statement: osteoporosis in hepatic disorders. Gastroenterology 2003;125:937‐940.
302. Bernstein CN, Katz S. Guidelines for osteoporosis and inflammatory bowel disease. A guide to diagnosis and management for the gastroenterologist. Wolters Klumer Health. Bethesda, MD: American College of Gastroenterology; 2003.
303. Kornbluth A, Hayes M, Feldman S, Hunt M, Fried‐Boxt E, Lichtiger S, et al. Do guidelines matter? Implementation of the ACG and AGA osteoporosis screening guidelines in inflammatory bowel disease (IBD) patients who meet the guidelines' criteria. Am J Gastroenterol 2006;101:1546‐1550.
304. Long MD, Thiny MT, Sandler RS, Gangarosa LM. Bone health in a tertiary‐care gastroenterology and hepatology population. Dig Dis Sci 2010;55:2263‐2269.
305. Efe C, Kav T, Aydin C, Cengiz M, Imga NN, Purnak T, et al. Low serum vitamin D levels are associated with severe histological features and poor response to therapy in patients with autoimmune hepatitis. Dig Dis Sci 2014;59:3035‐3042.
306. Ebadi M, Bhanji RA, Mazurak VC, Lytvyak E, Mason A, Czaja AJ, et al. Severe vitamin D deficiency is a prognostic biomarker in autoimmune hepatitis. Aliment Pharmacol Ther 2019;49:173‐182.
307. Czaja AJ, Montano‐Loza AJ. Evolving role of vitamin D in immune‐mediated disease and its implications in autoimmune hepatitis. Dig Dis Sci 2019;64:324‐344.
308. Pares A, Guanabens N. Treatment of bone disorders in liver disease. J Hepatol 2006;45:445‐453.
309. Collier J. Bone disorders in chronic liver disease. Hepatology 2007;46:1271‐1278.
310. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640‐1645.
311. Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis 2017;11:215‐225.
312. Weiler‐Normann C, Lohse AW. Treatment adherence—room for improvement, not only in autoimmune hepatitis. J Hepatol 2012;57:1168‐1170.
313. Wusk B, Kullak‐Ublick GA, Rammert C, von Eckardstein A, Fried M, Rentsch KM. Therapeutic drug monitoring of thiopurine drugs in patients with inflammatory bowel disease or autoimmune hepatitis. Eur J Gastroenterol Hepatol 2004;16:1407‐1413.
314. Sockalingam S, Blank D, Abdelhamid N, Abbey SE, Hirschfield GM. Identifying opportunities to improve management of autoimmune hepatitis: evaluation of drug adherence and psychosocial factors. J Hepatol 2012;57:1299‐1304.
315. Janik MK, Wunsch E, Raszeja‐Wyszomirska J, Moskwa M, Kruk B, Krawczyk M, et al. Autoimmune hepatitis exerts a profound, negative effect on health‐related quality of life: a prospective, single‐centre study. Liver Int 2019;39:215‐221.
316. Schramm C, Wahl I, Weiler‐Normann C, Voigt K, Wiegard C, Glaubke C, et al. Health‐related quality of life, depression, and anxiety in patients with autoimmune hepatitis. J Hepatol 2014;60:618‐624.
317. Mieli‐Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, et al. Autoimmune hepatitis. Nat Rev Dis Primers 2018;4:18017.
318. Takahashi A, Moriya K, Ohira H, Arinaga‐Hino T, Zeniya M, Torimura T, et al. Health‐related quality of life in patients with autoimmune hepatitis: a questionnaire survey. PLoS One 2018;13:e0204772.
319. Gulati R, Radhakrishnan KR, Hupertz V, Wyllie R, Alkhouri N, Worley S, et al. Health‐related quality of life in children with autoimmune liver disease. J Pediatr Gastroenterol Nutr 2013;57:444‐450.
320. Trevizoli IC, Pinedo CS, Teles VO, Seixas R, de Carvalho E. Autoimmune hepatitis in children and adolescents: effect on quality of life. J Pediatr Gastroenterol Nutr 2018;66:861‐865.
321. Wong LL, Fisher HF, Stocken DD, Rice S, Khanna A, Heneghan MA, et al. The impact of autoimmune hepatitis and its treatment on health utility. Hepatology 2018;68:1487‐1497.
322. Bozzini AB, Neder L, Silva CA, Porta G. Decreased health‐related quality of life in children and adolescents with autoimmune hepatitis. J Pediatr (Rio J) 2019;95:87‐93.
323. Srivastava S, Boyer JL. Psychological stress is associated with relapse in type 1 autoimmune hepatitis. Liver Int 2010;30:1439‐1447.
324. Westbrook RH, Yeoman AD, Kriese S, Heneghan MA. Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun 2012;38:J239‐J244.
325. Terrabuio DR, Abrantes‐Lemos CP, Carrilho FJ, Cancado EL. Follow‐up of pregnant women with autoimmune hepatitis: the disease behavior along with maternal and fetal outcomes. J Clin Gastroenterol 2009;43:350‐356.
326. Schramm C, Herkel J, Beuers U, Kanzler S, Galle PR, Lohse AW. Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J Gastroenterol 2006;101:556‐560.
327. Buchel E, Van Steenbergen W, Nevens F, Fevery J. Improvement of autoimmune hepatitis during pregnancy followed by flare‐up after delivery. Am J Gastroenterol 2002;97:3160‐3165.
328. Waldenstrom J. Leber, Blutproteine und Nahrungseiweiss. Dtsch Gesellsch Verdau Stoffwechselkr 1950;15:113‐121.
329. Barnea ER, Kirk D, Ramu S, Rivnay B, Roussev R, Paidas MJ. Preimplantation factor (PIF) orchestrates systemic antiinflammatory response by immune cells: effect on peripheral blood mononuclear cells. Am J Obstet Gynecol 2012;207:313.
330. Barnea ER, Lubman DM, Liu YH, Absalon‐Medina V, Hayrabedyan S, Todorova K, et al. Insight into preimplantation factor (PIF*) mechanism for embryo protection and development: target oxidative stress and protein misfolding (PDI and HSP) through essential RIKP [corrected] binding site. PLoS One 2014;9:e100263.
331. Tran TT, Ahn J, Reau NS. ACG clinical guideline: liver disease and pregnancy. Am J Gastroenterol 2016;111:176‐194; quiz 196.
332. Centers for Disease Control and Prevention . National birth defects prevention study (NBDPS). https://www.cdc.gov/ncbddd/birthdefects/nbdps.html
. Accessed 2017.
333. Rosenkrantz JG, Githens JH, Cox SM, Kellum DL. Azathioprine (Imuran) and pregnancy. Am J Obstet Gynecol 1967;97:387‐394.
334. Akbari M, Shah S, Velayos FS, Mahadevan U, Cheifetz AS. Systematic review and meta‐analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:15‐22.
335. de Boer NK, Jarbandhan SV, de Graaf P, Mulder CJ, van Elburg RM, van Bodegraven AA. Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol 2006;101:1390‐1392.
336. Coscia LA, Armenti DP, King RW, Sifontis NM, Constantinescu S, Moritz MJ. Update on the teratogenicity of maternal mycophenolate mofetil. J Pediatr Genet 2015;4:42‐55.
337. Montano‐Loza AJ, Czaja AJ. Current therapy for autoimmune hepatitis. Nat Clin Pract Gastroenterol Hepatol 2007;4:202‐214.
338. Montano‐Loza AJ, Carpenter HA, Czaja AJ. Improving the end point of corticosteroid therapy in type 1 autoimmune hepatitis to reduce the frequency of relapse. Am J Gastroenterol 2007;102:1005‐1012.
339. Curtis JJ, Galla JH, Woodford SY, Saykaly RJ, Luke RG. Comparison of daily and alternate‐day prednisone during chronic maintenance therapy: a controlled crossover study. Am J Kidney Dis 1981;1:166‐171.
340. Summerskill WH, Korman MG, Ammon HV, Baggenstoss AH. Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut 1975;16:876‐883.
341. Czaja AJ. Safety issues in the management of autoimmune hepatitis. Expert Opin Drug Saf 2008;7:319‐333.
342. Rumbo C, Emerick KM, Emre S, Shneider BL. Azathioprine metabolite measurements in the treatment of autoimmune hepatitis in pediatric patients: a preliminary report. J Pediatr Gastroenterol Nutr 2002;35:391‐398.
343. Nguyen TM, Daubard M, Le Gall C, Larger M, Lachaux A, Boulieu R. Monitoring of azathioprine metabolites in pediatric patients with autoimmune hepatitis. Ther Drug Monit 2010;32:433‐437.
344. Hindorf U, Jahed K, Bergquist A, Verbaan H, Prytz H, Wallerstedt S, et al. Characterisation and utility of thiopurine methyltransferase and thiopurine metabolite measurements in autoimmune hepatitis. J Hepatol 2010;52:106‐111.
345. Sheiko MA, Sundaram SS, Capocelli KE, Pan Z, McCoy AM, Mack CL. Outcomes in pediatric autoimmune hepatitis and significance of azathioprine metabolites. J Pediatr Gastroenterol Nutr 2017;65:80‐85.
346. Rumbo C, Shneider BL, Emre SH. Utility of azathioprine metabolite measurements in post‐transplant recurrent autoimmune and immune‐mediated hepatitis. Pediatr Transplant 2004;8:571‐575.
347. Miloh T, Annunziato R, Arnon R, Warshaw J, Parkar S, Suchy FJ, et al. Improved adherence and outcomes for pediatric liver transplant recipients by using text messaging. Pediatrics 2009;124:e844‐e850.
348. Kerkar N, Annunziato RA, Foley L, Schmeidler J, Rumbo C, Emre S, et al. Prospective analysis of nonadherence in autoimmune hepatitis: a common problem. J Pediatr Gastroenterol Nutr 2006;43:629‐634.
349. Inman GJ, Wang J, Nagano A, Alexandrov LB, Purdie KJ, Taylor RG, et al. The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nat Commun 2018;9:3667.
350. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010;139:1198‐1206.
351. Manns MP, Jaeckel E, Taubert R. Budesonide in autoimmune hepatitis: the right drug at the right time for the right patient. Clin Gastroenterol Hepatol 2018;16:186‐189.
352. Czaja AJ, Lindor KD. Failure of budesonide in a pilot study of treatment‐dependent autoimmune hepatitis. Gastroenterology 2000;119:1312‐1316.
353. Geier A, Gartung C, Dietrich CG, Wasmuth HE, Reinartz P, Matern S. Side effects of budesonide in liver cirrhosis due to chronic autoimmune hepatitis: influence of hepatic metabolism versus portosystemic shunts on a patient complicated with HCC. World J Gastroenterol 2003;9:2681‐2685.
354. Efe C, Ozaslan E, Kav T, Purnak T, Shorbagi A, Ozkayar O, et al. Liver fibrosis may reduce the efficacy of budesonide in the treatment of autoimmune hepatitis and overlap syndrome. Autoimmun Rev 2012;11:330‐334.
355. Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in early‐ and late‐stage primary biliary cirrhosis. Hepatology 2003;38:196‐202.
356. Peiseler M, Liebscher T, Sebode M, Zenouzi R, Hartl J, Ehlken H, et al. Efficacy and limitations of budesonide as a second‐line treatment for patients with autoimmune hepatitis. Clin Gastroenterol Hepatol 2018;16:260‐267.
357. Woynarowski M, Nemeth A, Baruch Y, Koletzko S, Melter M, Rodeck B, et al. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr 2013;163:1347‐1353.
358. Dyson JK, Wong LL, Bigirumurame T, Hirschfield GM, Kendrick S, Oo YH, et al. Inequity of care provision and outcome disparity in autoimmune hepatitis in the United Kingdom. Aliment Pharmacol Ther 2018;48:951‐960.
359. Niederau C, Herden D, van Thiel I, Kautz A, Bemba G, Wohn HP, et al. Prospective survey of health and socioeconomical characteristics of 249 patients with autoimmune hepatitis. Verdauungskrankheiten 2013;31:55‐65.
360. Zachou K, Gatselis N, Papadamou G, Rigopoulou EI, Dalekos GN. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment‐naive patients. J Hepatol 2011;55:636‐646.
361. Zachou K, Gatselis NK, Arvaniti P, Gabeta S, Rigopoulou EI, Koukoulis GK, et al. A real‐world study focused on the long‐term efficacy of mycophenolate mofetil as first‐line treatment of autoimmune hepatitis. Aliment Pharmacol Ther 2016;43:1035‐1047.
362. Yu ZJ, Zhang LL, Huang TT, Zhu JS, He ZB. Comparison of mycophenolate mofetil with standard treatment for autoimmune hepatitis: a meta‐analysis. Eur J Gastroenterol Hepatol 2019;31:873‐877.
363. Van Thiel DH, Wright H, Carroll P, Abu‐Elmagd K, Rodriguez‐Rilo H, McMichael J, et al. Tacrolimus: a potential new treatment for autoimmune chronic active hepatitis: results of an open‐label preliminary trial. Am J Gastroenterol 1995;90:771‐776.
364. Alvarez F, Ciocca M, Canero‐Velasco C, Ramonet M, de Davila MT, Cuarterolo M, et al. Short‐term cyclosporine induces a remission of autoimmune hepatitis in children. J Hepatol 1999;30:222‐227.
365. Malekzadeh R, Nasseri‐Moghaddam S, Kaviani MJ, Taheri H, Kamalian N, Sotoudeh M. Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis. Dig Dis Sci 2001;46:1321‐1327.
366. Marlaka JR, Papadogiannakis N, Fischler B, Casswall TH, Beijer E, Nemeth A. Tacrolimus without or with the addition of conventional immunosuppressive treatment in juvenile autoimmune hepatitis. Acta Paediatr 2012;101:993‐999.
367. Nasseri‐Moghaddam S, Nikfam S, Karimiam S, Khashayar P, Malekzadeh R. Cyclosporine‐A versus prednisolone for induction of remission in auto‐immune hepatitis: interim analysis report of a randomized controlled trial. Middle East J Dig Dis 2013;5:193‐200.
368. Nastasio S, Sciveres M, Matarazzo L, Malaventura C, Cirillo F, Riva S, et al. Long‐term follow‐up of children and young adults with autoimmune hepatitis treated with cyclosporine. Dig Liver Dis 2019;51:712‐718.
369. Cuarterolo M, Ciocca M, Velasco CC, Ramonet M, Gonzalez T, Lopez S, et al. Follow‐up of children with autoimmune hepatitis treated with cyclosporine. J Pediatr Gastroenterol Nutr 2006;43:635‐639.
370. Yeoman AD, Westbrook RH, Zen Y, Bernal W, Al‐Chalabi T, Wendon JA, et al. Prognosis of acute severe autoimmune hepatitis (AS‐AIH): the role of corticosteroids in modifying outcome. J Hepatol 2014;61:876‐882.
371. Karkhanis J, Verna EC, Chang MS, Stravitz RT, Schilsky M, Lee WM, et al. Steroid use in acute liver failure. Hepatology 2014;59:612‐621.
372. Ichai P, Duclos‐Vallee JC, Guettier C, Hamida SB, Antonini T, Delvart V, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007;13:996‐1003.
373. Czaja AJ. Corticosteroids or not in severe acute or fulminant autoimmune hepatitis: therapeutic brinksmanship and the point beyond salvation. Liver Transpl 2007;13:953‐955.
374. Rahim MN, Liberal R, Miquel R, Heaton ND, Heneghan MA. Acute severe sutoimmune hepatitis: corticosteroids or liver transplantation? Liver Transpl 2019;25:946‐959.
375. Takikawa Y, Suzuki K. Clinical epidemiology of fulminant hepatitis in Japan. Hepatol Res 2008;38(Suppl. 1):S14‐S18.
376. Yeoman AD, Westbrook RH, Zen Y, Maninchedda P, Portmann BC, Devlin J, et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 2011;53:926‐934.
377. Sugawara K, Nakayama N, Mochida S. Acute liver failure in Japan: definition, classification, and prediction of the outcome. J Gastroenterol 2012;47:849‐861.
378. Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid‐treated severe autoimmune chronic active hepatitis. Gastroenterology 1988;95:448‐453.
379. Czaja AJ. Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol 2009;51:161‐167.
380. Chen J, Eslick GD, Weltman M. Systematic review with meta‐analysis: clinical manifestations and management of autoimmune hepatitis in the elderly. Aliment Pharmacol Ther 2014;39:117‐124.
381. Couto CA, Bittencourt PL, Porta G, Abrantes‐Lemos CP, Carrilho FJ, Guardia BD, et al. Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis. Hepatology 2014;59:592‐600.
382. Taubert R, Hardtke‐Wolenski M, Noyan F, Lalanne C, Jonigk D, Schlue J, et al. Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis. PLoS One 2017;12:e0179074.
383. Efe C, Cengiz M, Kahramanoglu‐Aksoy E, Yilmaz B, Ozseker B, Beyazt Y, et al. Angiotensin‐converting enzyme for noninvasive assessment of liver fibrosis in autoimmune hepatitis. Eur J Gastroenterol Hepatol 2015;27:649‐654.
384. European Association for the Study of the Liver . EASL Clinical Practice Guidelines : autoimmune hepatitis. J Hepatol 2015;63:971‐1004.
385. Hartl J, Ehlken H, Weiler‐Normann C, Sebode M, Kreuels B, Pannicke N, et al. Patient selection based on treatment duration and liver biochemistry increases success rates after treatment withdrawal in autoimmune hepatitis. J Hepatol 2015;62:642‐646.
386. Czaja AJ, Davis GL, Ludwig J, Taswell HF. Complete resolution of inflammatory activity following corticosteroid treatment of HBsAg‐negative chronic active hepatitis. Hepatology 1984;4:622‐627.
387. Czaja AJ, Menon KV, Carpenter HA. Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis. Hepatology 2002;35:890‐897.
388. Czaja AJ, Carpenter HA. Histological features associated with relapse after corticosteroid withdrawal in type 1 autoimmune hepatitis. Liver Int 2003;23:116‐123.
389. Guirguis J, Alonso Y, Lopez R, Carey W. Well‐controlled autoimmune hepatitis treatment withdrawal may be safely accomplished without liver‐biopsy guidance. Gastroenterol Rep (Oxf) 2018;6:284‐290.
390. Czaja AJ. Late relapse of type 1 autoimmune hepatitis after corticosteroid withdrawal. Dig Dis Sci 2010;55:1761‐1769.
391. Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment Pharmacol Ther 2014;39:1043‐1058.
392. Deneau M, Book LS, Guthery SL, Jensen MK. Outcome after discontinuation of immunosuppression in children with autoimmune hepatitis: a population‐based study. J Pediatr 2014;164:714‐719.
393. Czaja AJ, Beaver SJ, Shiels MT. Sustained remission after corticosteroid therapy of severe hepatitis B surface antigen–negative chronic active hepatitis. Gastroenterology 1987;92:215‐219.
394. Czaja AJ, Ammon HV, Summerskill WH. Clinical features and prognosis of severe chronic active liver disease (CALD) after corticosteroid‐induced remission. Gastroenterology 1980;78:518‐523.
395. Hegarty JE, Nouri Aria KT, Portmann B, Eddleston AL, Williams R. Relapse following treatment withdrawal in patients with autoimmune chronic active hepatitis. Hepatology 1983;3:685‐689.
396. Dhaliwal HK, Anderson R, Thornhill EL, Schneider S, McFarlane E, Gleeson D, et al. Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis. Hepatology 2012;56:1401‐1408.
397. Stellon AJ, Hegarty JE, Portmann B, Williams R. Randomised controlled trial of azathioprine withdrawal in autoimmune chronic active hepatitis. Lancet 1985;1:668‐670.
398. Johnson PJ, McFarlane IG, Williams R. Azathioprine for long‐term maintenance of remission in autoimmune hepatitis. N Engl J Med 1995;333:958‐963.
399. Harrison L, Gleeson D. Stopping immunosuppressive treatment in autoimmune hepatitis (AIH): is it justified (and in whom and when)? Liver Int 2019;39:610‐620.
400. Czaja AJ. Low‐dose corticosteroid therapy after multiple relapses of severe HBsAg‐negative chronic active hepatitis. Hepatology 1990;11:1044‐1049.
401. Seela S, Sheela H, Boyer JL. Autoimmune hepatitis type 1: safety and efficacy of prolonged medical therapy. Liver Int 2005;25:734‐739.
402. Parker R, Oo YH, Adams DH. Management of patients with difficult autoimmune hepatitis. Ther Adv Gastroenterol 2012;5:421‐437.
403. Selvarajah V, Montano‐Loza AJ, Czaja AJ. Systematic review: managing suboptimal treatment responses in autoimmune hepatitis with conventional and nonstandard drugs. Aliment Pharmacol Ther 2012;36:691‐707.
404. Devlin SM, Swain MG, Urbanski SJ, Burak KW. Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy. Can J Gastroenterol 2004;18:321‐326.
405. Aw MM, Dhawan A, Samyn M, Bargiota A, Mieli‐Vergani G. Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5‐year follow‐up. J Hepatol 2009;51:156‐160.
406. Inductivo‐Yu I, Adams A, Gish RG, Wakil A, Bzowej NH, Frederick RT, et al. Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol 2007;5:799‐802.
407. Hlivko JT, Shiffman ML, Stravitz RT, Luketic VA, Sanyal AJ, Fuchs M, et al. A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis. Clin Gastroenterol Hepatol 2008;6:1036‐1040.
408. Hennes EM, Oo YH, Schramm C, Denzer U, Buggisch P, Wiegard C, et al. Mycophenolate mofetil as second line therapy in autoimmune hepatitis? Am J Gastroenterol 2008;103:3063‐3070.
409. Baven‐Pronk AM, Coenraad MJ, van Buuren HR, de Man RA, van Erpecum KJ, Lamers MM, et al. The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes. Aliment Pharmacol Ther 2011;34:335‐343.
410. Fallatah HI, Akbar HO. Mycophenolate mofetil as a rescue therapy for autoimmune hepatitis patients who are not responsive to standard therapy. Expert Rev Gastroenterol Hepatol 2011;5:517‐522.
411. Hyams JS, Ballow M, Leichtner AM. Cyclosporine treatment of autoimmune chronic active hepatitis. Gastroenterology 1987;93:890‐893.
412. Person JL, McHutchison JG, Fong TL, Redeker AG. A case of cyclosporine‐sensitive, steroid‐resistant, autoimmune chronic active hepatitis. J Clin Gastroenterol 1993;17:317‐320.
413. Sherman KE, Narkewicz M, Pinto PC. Cyclosporine in the management of corticosteroid‐resistant type I autoimmune chronic active hepatitis. J Hepatol 1994;21:1040‐1047.
414. Jackson LD, Song E. Cyclosporin in the treatment of corticosteroid resistant autoimmune chronic active hepatitis. Gut 1995;36:459‐461.
415. Debray D, Maggiore G, Girardet JP, Mallet E, Bernard O. Efficacy of cyclosporin A in children with type 2 autoimmune hepatitis. J Pediatr 1999;135:111‐114.
416. Zizzo AN, Valentino PL, Shah PS, Kamath BM. Second‐line agents in pediatric patients with autoimmune hepatitis: a systematic review and meta‐analysis. J Pediatr Gastroenterol Nutr 2017;65:6‐15.
417. Aqel BA, Machicao V, Rosser B, Satyanarayana R, Harnois DM, Dickson RC. Efficacy of tacrolimus in the treatment of steroid refractory autoimmune hepatitis. J Clin Gastroenterol 2004;38:805‐809.
418. Efe C, Hagstrom H, Ytting H, Bhanji RA, Muller NF, Wang Q, et al. Efficacy and safety of mycophenolate mofetil and tacrolimus as second‐line therapy for patients with autoimmune hepatitis. Clin Gastroenterol Hepatol 2017;15:1950‐1956.
419. Efe C, Taii HA, Ytting H, Aehling N, Bhanji RA, Hagstrom H, et al. Tacrolimus and mycophenolate mofetil as second‐line therapies for pediatric patients with autoimmune hepatitis. Dig Dis Sci 2018;63:1348‐1354.
420. Than NN, Wiegard C, Weiler‐Normann C, Fussel K, Mann J, Hodson J, et al. Long‐term follow‐up of patients with difficult to treat type 1 autoimmune hepatitis on tacrolimus therapy. Scand J Gastroenterol 2016;51:329‐336.
421. Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6‐mercaptopurine after failure with azathioprine. Gastroenterology 1996;110:271‐274.
422. Hubener S, Oo YH, Than NN, Hubener P, Weiler‐Normann C, Lohse AW, et al. Efficacy of 6‐mercaptopurine as second‐line treatment for patients with autoimmune hepatitis and azathioprine intolerance. Clin Gastroenterol Hepatol 2016;14:445‐453.
423. Burak KW, Swain MG, Santodomingo‐Garzon T, Lee SS, Urbanski SJ, Aspinall AI, et al. Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy. Can J Gastroenterol 2013;27:273‐280.
424. Weiler‐Normann C, Schramm C, Quaas A, Wiegard C, Glaubke C, Pannicke N, et al. Infliximab as a rescue treatment in difficult‐to‐treat autoimmune hepatitis. J Hepatol 2013;58:529‐534.
425. Santiago P, Schwartz I, Tamariz L, Levy C. Systematic review with meta‐analysis: mycophenolate mofetil as a second‐line therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2019;49:830‐839.
426. De Lemos‐Bonotto M, Valle‐Tovo C, Costabeber AM, Mattos AA, Azeredo‐da‐Silva ALF. A systematic review and meta‐analysis of second‐line immunosuppressants for autoimmune hepatitis treatment. Eur J Gastroenterol Hepatol 2018;30:212‐216.
427. Nicoll AJ, Roberts SK, Lim R, Mitchell J, Weltman M, George J, et al. Beneficial response to mycophenolate mofetil by patients with autoimmune hepatitis, who have failed standard therapy, is predicted by older age and lower immunoglobulin G and INR levels. Aliment Pharmacol Ther 2019;49:1314‐1322.
428. Tannous MM, Cheng J, Muniyappa K, Farooq I, Bharara A, Kappus M, et al. Use of tacrolimus in the treatment of autoimmune hepatitis: a single centre experience. Aliment Pharmacol Ther 2011;34:405‐407.
429. Hanouneh M, Ritchie MM, Ascha M, Ascha MS, Chedid A, Sanguankeo A, et al. A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis. Scand J Gastroenterol 2019;54:76‐80.
430. Chatur N, Ramji A, Bain VG, Ma MM, Marotta PJ, Ghent CN, et al. Transplant immunosuppressive agents in non‐transplant chronic autoimmune hepatitis: the Canadian Association for the Study of Liver (CASL) experience with mycophenolate mofetil and tacrolimus. Liver Int 2005;25:723‐727.
431. Cravo M, Silva R, Serrano M. Autoimmune hepatitis induced by infliximab in a patient with Crohn's disease with no relapse after switching to adalimumab. BioDrugs 2010;24(Suppl. 1):25‐27.
432. Harada K, Akai Y, Koyama S, Ikenaka Y, Saito Y. A case of autoimmune hepatitis exacerbated by the administration of etanercept in the patient with rheumatoid arthritis. Clin Rheumatol 2008;27:1063‐1066.
433. Averbukh LD, Wu GY. Role of biologics in the development of autoimmune hepatitis: a review. J Clin Transl Hepatol 2018;6:402‐409.
434. Nedelkopoulou N, Vadamalayan B, Vergani D, Mieli‐Vergani G. Anti‐TNFalpha treatment in children and adolescents with combined inflammatory bowel disease and autoimmune liver disease. J Pediatr Gastroenterol Nutr 2018;66:100‐105.
435. D'Agostino D, Costaguta A, Alvarez F. Successful treatment of refractory autoimmune hepatitis with rituximab. Pediatrics 2013;132:e526‐e530.
436. Elion GB. The pharmacology of azathioprine. Ann N Y Acad Sci 1993;685:400‐407.
437. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos 2001;29:601‐605.
438. Legue C, Legros L, Kammerer‐Jacquet S, Jezequel C, Houssel‐Debry P, Uguen T, et al. Safety and efficacy of 6‐thioguanine as a second‐line treatment for autoimmune hepatitis. Clin Gastroenterol Hepatol 2018;16:290‐291.
439. van den Brand FF, van Nieuwkerk CMJ, Verwer BJ, de Boer YS, de Boer NKH, Mulder CJJ, et al. Biochemical efficacy of tioguanine in autoimmune hepatitis: a retrospective review of practice in the Netherlands. Aliment Pharmacol Ther 2018;48:761‐767.
440. de Boer NK, van Nieuwkerk CM, Aparicio Pages MN, de Boer SY, Derijks LJ, Mulder CJ. Promising treatment of autoimmune hepatitis with 6‐thioguanine after adverse events on azathioprine. Eur J Gastroenterol Hepatol 2005;17:457‐461.
441. Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, et al. 6‐Thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 2003;125:298‐303.
442. Seinen ML, van Asseldonk DP, Mulder CJ, de Boer NK. Dosing 6‐thioguanine in inflammatory bowel disease: expert‐based guidelines for daily practice. J Gastrointestin Liver Dis 2010;19:291‐294.
443. Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012;36:517‐533.
444. Joshi S, Cauch‐Dudek K, Wanless IR, Lindor KD, Jorgensen R, Batts K, et al. Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid. Hepatology 2002;35:409‐413.
445. McNair AN, Moloney M, Portmann BC, Williams R, McFarlane IG. Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases. Am J Gastroenterol 1998;93:777‐784.
446. Lohse AW, zum Buschenfelde KH, Franz B, Kanzler S, Gerken G, Dienes HP. Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals. Hepatology 1999;29:1078‐1084.
447. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, et al. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol 2005;100:1516‐1522.
448. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660‐678.
449. Al‐Chalabi T, Portmann BC, Bernal W, McFarlane IG, Heneghan MA. Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long‐term outcome and survival. Aliment Pharmacol Ther 2008;28:209‐220.
450. Czaja AJ. The overlap syndromes of autoimmune hepatitis. Dig Dis Sci 2013;58:326‐343.
451. Hoeroldt B, McFarlane E, Dube A, Basumani P, Karajeh M, Campbell MJ, et al. Long‐term outcomes of patients with autoimmune hepatitis managed at a nontransplant center. Gastroenterology 2011;140:1980‐1989.
452. Verma S, Torbenson M, Thuluvath PJ. The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology 2007;46:1828‐1835.
453. Wong RJ, Gish R, Frederick T, Bzowej N, Frenette C. The impact of race/ethnicity on the clinical epidemiology of autoimmune hepatitis. J Clin Gastroenterol 2012;46:155‐161.
454. Montano‐Loza AJ, Carpenter HA, Czaja AJ. Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end‐stage liver disease. Hepatology 2007;46:1138‐1145.
455. Czaja AJ. Clinical features, differential diagnosis and treatment of autoimmune hepatitis in the elderly. Drugs Aging 2008;25:219‐239.
456. Czaja AJ. Autoimmune hepatitis in diverse ethnic populations and geographical regions. Expert Rev Gastroenterol Hepatol 2013;7:365‐385.
457. Lim KN, Casanova RL, Boyer TD, Bruno CJ. Autoimmune hepatitis in African Americans: presenting features and response to therapy. Am J Gastroenterol 2001;96:3390‐3394.
458. Wen JW, Kohn MA, Wong R, Somsouk M, Khalili M, Maher J, et al. Hospitalizations for autoimmune hepatitis disproportionately affect black and Latino Americans. Am J Gastroenterol 2018;113:243‐253.
459. de Boer YS, Gerussi A, van den Brand FF, Wong GW, Halliday N, Liberal R, et al. Association between black race and presentation and liver‐related outcomes of patients with autoimmune hepatitis. Clin Gastroenterol Hepatol 2019;17:1616‐1624.
460. Wong RJ, Gish R, Frederick T, Bzowej N, Frenette C. Development of hepatocellular carcinoma in autoimmune hepatitis patients: a case series. Dig Dis Sci 2011;56:578‐585.
461. Czaja AJ. Hepatocellular cancer and other malignancies in autoimmune hepatitis. Dig Dis Sci 2013;58:1459‐1476.
462. Werner M, Almer S, Prytz H, Lindgren S, Wallerstedt S, Bjornsson E, et al. Hepatic and extrahepatic malignancies in autoimmune hepatitis. A long‐term follow‐up in 473 Swedish patients. J Hepatol 2009;50:388‐393.
463. Ngu JH, Gearry RB, Frampton CM, Stedman CA. Mortality and the risk of malignancy in autoimmune liver diseases: a population‐based study in Canterbury, New Zealand. Hepatology 2012;55:522‐529.
464. Wang KK, Czaja AJ, Beaver SJ, Go VL. Extrahepatic malignancy following long‐term immunosuppressive therapy of severe hepatitis B surface antigen–negative chronic active hepatitis. Hepatology 1989;10:39‐43.
465. Leung J, Dowling L, Obadan I, Davis J, Bonis PA, Kaplan MM, et al. Risk of non‐melanoma skin cancer in autoimmune hepatitis. Dig Dis Sci 2010;55:3218‐3223.
466. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, et al. Meta‐analysis: surveillance with ultrasound for early‐stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009;30:37‐47.
467. Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut 2011;60:1611‐1629.
468. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723‐750.
469. Adam R, Karam V, Delvart V, O'Grady J, Mirza D, Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675‐688.
470. Carbone M, Neuberger JM. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014;60:210‐223.
471. Mendes F, Couto CA, Levy C. Recurrent and de novo autoimmune liver diseases. Clin Liver Dis 2011;15:859‐878.
472. Webb GJ, Rana A, Hodson J, Akhtar MZ, Ferguson JW, Neuberger JM, et al. Twenty‐year comparative analysis of patients with autoimmune liver diseases on transplant waitlists. Clin Gastroenterol Hepatol 2018;16:278‐287.
473. Jossen J, Annunziato R, Kim HS, Chu J, Arnon R. Liver transplantation for children with primary sclerosing cholangitis and autoimmune hepatitis: UNOS database analysis. J Pediatr Gastroenterol Nutr 2017;64:e83‐e87.
474. Futagawa Y, Terasaki PI. An analysis of the OPTN/UNOS Liver Transplant Registry. Clin Transpl 2004;315‐329.
475. Schramm C, Bubenheim M, Adam R, Karam V, Buckels J, O'Grady JG, et al. Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry. Liver Transpl 2010;16:461‐469.
476. Baganate F, Beal EW, Tumin D, Azoulay D, Mumtaz K, Black SM, et al. Early mortality after liver transplantation: defining the course and the cause. Surgery 2018;164:694‐704.
477. Hayashi M, Keeffe EB, Krams SM, Martinez OM, Ojogho ON, So SK, et al. Allograft rejection after liver transplantation for autoimmune liver diseases. Liver Transpl Surg 1998;4:208‐214.
478. Milkiewicz P, Gunson B, Saksena S, Hathaway M, Hubscher SG, Elias E. Increased incidence of chronic rejection in adult patients transplanted for autoimmune hepatitis: assessment of risk factors. Transplantation 2000;70:477‐480.
479. Thurairajah PH, Carbone M, Bridgestock H, Thomas P, Hebbar S, Gunson BK, et al. Late acute liver allograft rejection; a study of its natural history and graft survival in the current era. Transplantation 2013;95:955‐959.
480. Vogel A, Heinrich E, Bahr MJ, Rifai K, Flemming P, Melter M, et al. Long‐term outcome of liver transplantation for autoimmune hepatitis. Clin Transplant 2004;18:62‐69.
481. Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ. Reasons for long‐term use of steroid in primary adult liver transplantation under tacrolimus. Transplantation 2001;71:1102‐1106.
482. Pelletier SJ, Nadig SN, Lee DD, Ammori JB, Englesbe MJ, Sung RS, et al. A prospective, randomized trial of complete avoidance of steroids in liver transplantation with follow‐up of over 7 years. HPB (Oxford) 2013;15:286‐293.
483. Krishnamoorthy TL, Miezynska‐Kurtycz J, Hodson J, Gunson BK, Neuberger J, Milkiewicz P, et al. Longterm corticosteroid use after liver transplantation for autoimmune hepatitis is safe and associated with a lower incidence of recurrent disease. Liver Transpl 2016;22:34‐41.
484. Theocharidou E, Heneghan MA. Con: steroids should not be withdrawn in transplant recipients with autoimmune hepatitis. Liver Transpl 2018;24:1113‐1118.
485. Everson GT, Trouillot T, Wachs M, Bak T, Steinberg T, Kam I, et al. Early steroid withdrawal in liver transplantation is safe and beneficial. Liver Transpl Surg 1999;5(Suppl. 1):S48‐S57.
486. Trouillot TE, Shrestha R, Kam I, Wachs M, Everson GT. Successful withdrawal of prednisone after adult liver transplantation for autoimmune hepatitis. Liver Transpl Surg 1999;5:375‐380.
487. Adams RW, Chapman RL, Smallwood GA. Steroid withdrawal in liver transplant recipients. Prog Transplant 2001;11:217‐223.
488. Heffron TG, Smallwood GA, Oakley B, Pillen T, Welch D, Martinez E, et al. Autoimmune hepatitis following liver transplantation: relationship to recurrent disease and steroid weaning. Transplant Proc 2002;34:3311‐3312.
489. Junge G, Neuhaus R, Schewior L, Klupp J, Guckelberger O, Langrehr JM, et al. Withdrawal of steroids: a randomized prospective study of prednisone and tacrolimus versus mycophenolate mofetil and tacrolimus in liver transplant recipients with autoimmune hepatitis. Transplant Proc 2005;37:1695‐1696.
490. Llado L, Xiol X, Figueras J, Ramos E, Memba R, Serrano T, et al. Immunosuppression without steroids in liver transplantation is safe and reduces infection and m