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

Funding for the development of this Practice Guideline and Guidance was provided by the American Association for the Study of Liver Diseases.

Potential conflict of interest: Dr. Mack consults for Albireo. Dr. Kerkar advises High Tide and received royalties from Elsevier. Dr. Manns consults for, is on the speakers’ bureau for, and received grants from Falk. He consults for and received grants from Novartis. Dr. Vierling advises and received grants from CymaBay, Enanta, Genkyotex, Intercept, Lilly, Novartis, and TaiwanJ. He advises Arena, BioIncept, Blade, and GlaxoSmithKline and received grants from Allergan and NGM.

What’s New Since 2010 Guidelines?

• Histological features of NAFLD are present in 17%‐30% of adult patients with AIH, and concurrent NAFLD may influence response to therapy.
• Diagnostic scoring systems should be used only to support clinical judgment in challenging cases of AIH and to define AIH cohorts for clinical studies.
• Immune checkpoint inhibitors have been associated with immune‐mediated liver injury and are frequently steroid‐responsive, but the liver injury lacks autoantibodies and typical histological features of AIH.
• Elastography may be used to assess the stages of hepatic fibrosis noninvasively.
• Testing for TPMT activity prior to AZA treatment is encouraged in all patients.
• Budesonide and AZA or predniso(lo)ne and AZA are recommended as first‐line AIH treatments in children and adults who do not have cirrhosis, acute severe hepatitis, or ALF.
• AZA can be continued throughout pregnancy, whereas the use of MMF is contraindicated in pregnancy.
• Liver tissue examination prior to drug withdrawal in individuals with ≥2 years of biochemical remission is preferred but not mandatory in adults and required in children.
• MMF or TAC can be used as second‐line treatment in children and adults with AIH who have failed to respond to first‐line therapy.
• Patients with acute severe AIH should receive predniso(lo)ne followed by LT if no improvement within 2 weeks, whereas patients with AIH and ALF should be evaluated directly for LT.
• Glucocorticoids can be discontinued after LT and patients monitored for recurrence of AIH.

Purpose and Scope

The objectives of this document are to provide guidance in the diagnosis and management of autoimmune hepatitis (AIH) based on current evidence and expert opinion and to present guidelines to clinically relevant questions based on systematic reviews of the literature and the quality of evidence.¹ This practice guideline/guidance constitutes an update of the guidelines on AIH published in 2010 by the American Association for the Study of Liver Diseases (AASLD).² It updates the epidemiology, diagnosis, management, and outcomes of AIH in adults and children.

The document is divided into “guideline recommendations” and “guidance statements.” Guideline recommendations were based on evidence derived from systematic reviews of the medical literature and supported, if appropriate, by meta‐analyses. The systematic reviews and meta‐analyses were conducted independently by the Mayo Clinic Evidence‐Based Practice Center. Findings were analyzed and interpreted by a multidisciplinary panel of experts, including both content and methodology experts, who rated the quality of evidence and determined the strength of each recommendation. The quality of clinical evidence was determined by its source (e.g., randomized controlled trial or observational study), and the strength of the recommendation was determined by assessing the quality of evidence, balance of benefits and harms, patient values and preferences, and use of resources and costs. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to categorize each recommendation as strong or conditional (Table 1).³ Details of the methodology, systematic reviews, and meta‐analyses are published separately. The guideline recommendations focus on pertinent management issues for which sufficient evidence was available to render a recommendation. They address glucocorticoid and azathioprine therapy as first‐line management, second‐line medications after failure of first‐line therapy, and maintenance management after liver transplantation (LT; see Supporting Table S1 for patient/intervention/comparison/outcome questions related to systematic reviews).

Table 1 - GRADE Assessment of Clinical Studies

Study Design	Rating Quality	Strength Determinants	Strength and Implications of Recommendation
Randomized controlled trial	High	Quality of evidence	Strong
	Moderate	Balance of benefits and harms	Most people would want course Most people should take course Can be adapted as policy in most cases
	Low	Patient values and preferences
Observational	Very low	Resources and costs	Conditional
		Feasibility	Many people would select course Requires decision aids and shared decision‐making Debatable policy choice
		Acessibility
		Equity

Quality downgrades: selection bias, inconsistency, imprecision, indirectness, publication bias. Quality upgrades: large effect, very large effect, dose–response gradient, confounders produce no effect.

“Guidance statements” were developed by consensus of an expert panel based on formal review and analysis of the published literature on the topic. The quality (level) of evidence and the strength of each guidance statement were not formally rated for the guidance statements. “Guidance statements” were used to address topics for which a sufficient number of randomized controlled trials were not available to justify a systematic review and meta‐analysis. The “guidance statements” and “guideline recommendations” were also reviewed by members of the AIH Association, a 501(c)(3) nonprofit organization, in order to incorporate patient and public perspectives. “Guidance statements” and “guideline recommendations” are intended to provide health care practitioners with updated information and rigorously assessed, evidence‐based recommendations. They are intended to aid, not supersede, clinical judgment. For ease of reading this AIH guidance/guidelines document, a glossary of definitions is provided in Table 2.

Table 2 - Definitions of AIH and Its Treatment Outcomes

Condition	Definition
AIH	Characteristic histologic abnormalities (lymphoplasmacytic interface hepatitis), elevated AST, ALT, and total IgG and the presence of one or more characteristic autoantibodies
Inactive cirrhosis	Absence of inflammatory infiltrates in both portal tracts and fibrous bands in cirrhosis
Acute severe AIH	Jaundice, INR > 1.5 < 2, no encephalopathy; no previously recognized liver disease370
ALF	INR ≥ 2; hepatic encephalopathy within 26 weeks of onset of illness; no previously recognized liver disease100
Biochemical remission	Normalization of serum AST, ALT, and IgG* levels
Histological remission	Absence of inflammation in liver tissue after treatment
Treatment failure	Worsening laboratory or histological findings despite compliance with standard therapy
Incomplete response	Improvement of laboratory and histological findings that are insufficient to satisfy criteria for remission
Relapse	Exacerbation of disease activity after induction of remission and drug withdrawal (or nonadherence)
Treatment intolerance	Inability to continue maintenance therapy due to drug‐related side effects

^*Patients with cirrhosis in biochemical remission may have persistent elevation of IgG.

AIH is an immune‐mediated inflammatory liver disease of uncertain cause which affects all ages, both genders, and all ethnicities. Patients may be asymptomatic, be chronically ill, or present with acute liver failure (ALF); and the diagnosis must be considered in all patients with acute or chronic liver inflammation, including patients with graft dysfunction after LT. AIH does not have a signature diagnostic feature, and the diagnosis requires the presence of a constellation of typical features which can vary between patients with the same disease and can occur in other liver diseases. Progression to advanced hepatic fibrosis, cirrhosis, death from liver failure, or LT are possible outcomes. Treatment with immunosuppressive agents has been life‐saving, but management regimens may be long‐term, associated with serious side effects, and variably effective.

Background

Epidemiology

AIH occurs at all ages and within all ethnic groups, and its manifestations appear to vary by race and ethnicity. Alaskan Natives have a high frequency of icteric AIH at presentation, Hispanics more commonly present with cirrhosis, and African Americans have accelerated progression of disease and a higher rate of recurrence after LT compared to other races.⁵ Female predominance occurs in adults (71%‐95% women)⁷ and children (60%‐76% girls).¹³ Early epidemiological reports suggested that the onset of AIH had age peaks at 10‐30 and 40‐60 years, but the findings may have been influenced by referral bias.¹⁷ Older peak ages at onset (>60 years) have been reported in Denmark¹¹ and New Zealand.¹⁰

The estimated incidence of AIH varies worldwide depending on the region and the age at onset. Incidence rates in adults range from 0.67 (southern Israel) to 2 cases per 100,000 person‐years (Canterbury region of New Zealand).¹⁰ Pediatric incidences are lower, ranging from 0.23 (Canada)¹⁶ to 0.4 per 100,000 person‐years (United States).¹⁵ Over the past few decades there has been a near 50% increase in incidence in Spain, Denmark, Sweden, and the Netherlands.¹¹ The prevalence of AIH in adults ranges from 4 (Singapore) to 42.9 (Alaska natives) per 100,000 persons.¹⁷ The prevalence in children ranges from 2.4 (non‐native Canadian children)²⁶ and 3 per 100,000 persons (United States)¹⁵ to 9.9 per 100,000 persons (native Canadian children).¹⁷

Genetic Predispositions

In common with other autoimmune diseases, the primary genetic associations in AIH involve major histocompatibility complex loci. Human leukocyte antigen (HLA) associations cluster within the conserved 8.1 ancestral haplotype which defines the alleles carried by most Caucasians²⁷ and results from linkage disequilibrium within HLA class I, II, and III loci: HLA‐A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*03:01, DRB1*04:01, DRB1*13:01, DRB3*01:01, DQA1*05:01, DQB1*02:01.²⁸HLA‐DRB1*03:01 haplotypes associated with AIH are the result of additional genetic recombinations.

AIH also has non‐HLA genetic associations, but the odds ratios (ORs) for risk of AIH are far lower than those for HLA alleles. Susceptibility for AIH has been associated with genetic polymorphisms encoding cytotoxic T lymphocyte antigen‐4 (CTLA‐4),³³ tumor necrosis factor‐alpha (TNF‐α),³⁴ Fas (cluster of differentiation 95 [CD95] or apoptosis antigen‐1),³⁶ vitamin D receptor,³⁸ signal transducer and activator of transcription 4,⁴⁰ transforming growth factor‐beta 1,⁴¹ macrophage migration inhibitory factor,⁴² SH2B adapter protein 3,⁴³ caspase recruitment domain family member 10,⁴³ and the interleukin‐23 (IL‐23) receptor.⁴⁴ Dysfunctional products of genetic variants or deficient levels of gene product may disrupt homeostatic mechanisms that affect the proliferation and survival of autoreactive T and B cells, regulate cytokine production, and modulate inflammatory and immune responses.

AIH is a complex genetic disease that requires interplay among genetic, epigenetic, immunologic, and environmental factors. A rare exception is AIH associated with an autosomal recessive mutation in the autoimmune regulator gene on chromosome 21q22.3, which has been associated with autoimmune polyglandular syndrome type 1 (APS‐1).⁴⁵ Environmental exposures play greater roles than genetics in shaping the immune repertoire, and specific environmental factors, such as viral infections or xenobiotic exposures, can act as environmental triggers for loss of self‐tolerance to autoantigens in persons genetically susceptible to AIH.⁴⁶

Pathogenesis

Autoreactive CD4 and CD8 T cells break self‐tolerance to hepatic autoantigens as the result of environmental triggers and inability of autoantigen‐specific natural T regulatory cells (nTregs) and inducible T regulatory cells (iTregs) to prevent autoreactivity⁴⁸ (Fig. 1). Concurrently, in the absence of effective B regulatory cell (Breg) inhibition, autoreactive B cells produce autoantibodies.⁵¹ Peptide autoantigens are presented by class II and class I HLA alleles to autoreactive T‐cell receptors on CD4 T helper (Th) cells and CD8 cytotoxic T lymphocytes (CTLs), respectively. Binding of different autoantigens to B‐cell receptors initiates secretion of specific autoantibodies.

Figure 1: Current concepts of the immunopathogenesis of AIH. Current knowledge supports a multistep working model of the immunopathogenesis of AIH, in which a break in self‐tolerance to hepatocyte autoantigens initiates immunological responses causing progressive hepatic necroinflammation and fibrogenesis.⁵⁰ In the first step, thymic autoantigen‐specific nTregs are incapable of preventing immune responses to hepatic autoantigens during hepatic or systemic immune responses to environmental triggers, such as viral infections or xenobiotics. In the second step, professional antigen‐presenting cells (APCs) present autoantigenic peptides to autoreactive α/β T cell receptors (TCRs) on naive CD4⁺ Th cells, and CD8⁺ T cells and APCs activate MAIT cells by presenting bacterially processed vitamin B antigens to MAIT cell TCRs.⁵⁴ Costimulation is a crucial third step, which induces expression of T‐cell genes required for proliferation, differentiation, and maturation of autoantigen‐specific CD4⁺ Th subsets (e.g., Th1, Th2, Th3, Th9, Th17, iTregs, Tr1, Tfh cells) and both CD8⁺ CTLs and CD8⁺ Tregs. In the fourth step, secretion of specific cytokines by subsets of CD4⁺ Th cells produces a variety of immunological sequelae, including CD4⁺ Th2 cytokine stimulation of B‐cell autoantibody production, CD4⁺ Tfh‐cell activation of B cells into antibody‐secreting plasma cells, Treg stimulation of Breg development through IL‐35 mechanisms and cytokine‐activated macrophages, and CD4⁺ Th17 cell–mediated pathogenic cytotoxicity. The fifth step is the cumulative failure of CD4⁺ and CD8⁺ Tregs and Bregs to control autoantigen‐specific effector mechanisms causing hepatic injury.⁵³ Moreover, exposure of CD4⁺ iTregs to specific cytokines can transform them from regulatory cells into pathogenic CD4⁺ Th17 cells.⁵² The sixth step is the generation of complex portal inflammatory infiltrates of effector cells that cause cytotoxicity of periportal and lobular hepatocytes. Necroinflammatory destruction of hepatocytes results in activation of periportal stellate cells, which amplify local immune responses through contact‐dependent and independent mechanisms and cause progressive portal fibrosis, culminating in cirrhosis in the absence of effective immunosuppressive therapy. Abbreviations: Ag, antigen; IFN, interferon; TGF, transforming growth factor.

The composition of the local cytokine milieu dictates CD4 Th cells to differentiate into Th1, Th2, Th9, Th17, iTregs, and T follicular helper (Tfh) cell subsets in the presence of costimulatory signaling.⁵⁰ CD4 Th1 cells secrete cytokines that promote proliferation of autoantigen‐specific CD8 CTLs and activation of macrophages. CD4 Th2 cytokines augment immunoglobulin production by B cells, while cytokines produced by Tfh cells induce their conversion to immunoglobulin G (IgG)–secreting plasma cells. CD4 Th17 cells intensify inflammation and tissue injury.

Autoantigen‐specific iTregs can down‐regulate the proliferation and functions of all CD4 Th subtypes, and inadequate numbers and/or dysfunction of CD4 iTregs may play a key role in AIH.⁵² Cytokine‐mediated transformation of CD4 iTregs into pathogenic CD4 Th17 cells also promotes perpetuation of AIH. Low doses of IL‐2 preferentially stimulate proliferation and function of CD4 iTregs, while high doses promote production of other pathogenic CD4 Th subsets.

Mucosal invariant T (MAIT) cells that react with bacterially processed vitamin B antigens presented by major histocompatibility complex class I–related molecules congregate in the peribiliary region in AIH.⁵⁴ MAIT cells can express characteristics of CD4 Th1 and Th17 cells, and they may transform CD4 iTregs into proinflammatory CD4 Th17 cells. Inflammatory infiltrates composed of CD4 Th subsets, CD8 CTLs, MAIT cells, B cells, plasma cells, and innate immune cells, including natural killer (NK) and NK T cells and activated macrophages, can accumulate within the portal tracts.

Adhesion molecules and chemokines mediate transendothelial migration of immune cells into tissues.⁵⁰ Extension of inflammation into periportal hepatocytes (interface hepatitis) and lobular hepatitis causes apoptosis of hepatocytes and fibrogenesis in untreated patients with AIH. Uptake and processing of immune complexes of autoantigen and immunoglobulin by antigen‐presenting cells greatly increases activation of autoantigen‐specific CD8 CTLs, and autoantibodies may enhance CD8 CTL cytotoxicity of hepatocytes.

Diagnosis

Diagnostic Requisites and Subtypes

The diagnosis of AIH is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (elevated serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels and increased serum IgG concentration), and the presence of one or more characteristic autoantibodies.² AIH lacks a signature diagnostic marker, and the diagnosis requires characteristic features and the exclusion of other diseases that may resemble it (e.g., viral hepatitis, drug‐induced liver injury, Wilson’s disease, hereditary hemochromatosis).⁵⁶

There are two types of AIH, based on the specific autoantibodies that are present. Type 1 is characterized by antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA)/anti‐actin antibodies, and type 2 is characterized by antibodies to liver kidney microsome type 1 (anti‐LKM1), usually in the absence of ANA and SMA.⁵⁷ The characteristic clinical features of these two types are presented in Table 3. In addition, up to 20% of AIH cases are negative for ANA, SMA, and LKM1 autoantibodies, despite the presence of other characteristic features of AIH (seronegative AIH). If seronegative AIH is suspected, other autoantibodies may be sought, as indicated in Table 4 and Fig. 2. Classification of AIH into types assists in management and aids in predicting outcomes in children, but it may be less informative in adults.⁵⁸

Table 3 - Characteristic Features of Type 1 and Type 2 AIH

Features	Type 1 AIH	Type 2 AIH
Frequency	US adults, 96%61	US children, 9%‐12%14
		UK children, 38%13
Age at presentation	Peripubertal and adults	Usually under 14 years153
Mode of presentation	Chronic symptoms common	Acute onset (~40%)
	Ascites or GI bleeding rare	Acute liver failure possible555
	Asymptomatic in 25%‐34%	Relapse frequent108
	Acute in 25%‐75%
	Acute severe in 2%‐6%
Laboratory features	Hypergammaglobulinemia	IgA levels may be reduced153
Autoantibodies	ANA	Anti‐LKM1
	SMA, anti‐actin	[Anti‐LC1, Anti‐LKM3]
	SLA
Concurrent immune diseases	Autoimmune thyroiditis	Autoimmune thyroiditis
	Rheumatic diseases	Diabetes mellitus
	IBD	Vitiligo
Autoimmune overlap with PSC (ASC in children)	Common in children	Rare
	Atypical pANCA‐positive	Atypical pANCA‐negative
Overlap with PBC	Seen in adults (not children)	Not reported
Cirrhosis at presentation	Adults, 28%‐33% (especially elderly)	Rare
	Children, ≤33%
Remission after drug withdrawal	Possible	Rare, usually need long‐term immunosuppression

Abbreviations: GI, gastrointestinal; IgA, serum immunoglobulin A.

Table 4 - Autoantibodies in the Diagnosis of AIH

Antibody	Target Antigen	Diagnostic Value
ANA	Chromatin, ribonucleoproteins557	Type 1 AIH56
SMA	Filamentous actin (F‐actin), vimentin, desmin81	Type 1 AIH56
LKM1	Cytochrome P450 2D6 (CYP2D6)559	Type 2 AIH153
SLA	Sep (O‐phosphoserine) transfer RNA:Sec (selenocysteine) transfer RNA synthase560	Type 1 AIH69
		Severe AIH70
		Predicts relapse after treatment73
		Associated with poor outcome70
p‐ANCA (atypical)	Β‐tubulin isotype 577	Type 1 AIH75
	Nuclear lamina proteins565	PSC566
		ASC108
Actin	Filamentous (F) actin81	Type 1 AIH81
α‐Actinin	Filamentous actin cross‐linking proteins568	Investigational84
		Type 1 AIH85
		Prognostic biomarker85
LKM3	UDP glucuronosyltransferase family 190	Type 2 AIH90
		Hepatitis D90
LC‐1	Formiminotransferase cyclodeaminase569	Type 2 AIH569
LM	Cytochrome P450 1A2572	Dihydralazine‐induced hepatitis574
		APECED hepatitis575
AMA	E2‐subunits of pyruvate dehydrogenase complex576	PBC576
		PBC–AIH overlap syndrome177
		Type 1 AIH183

Abbreviations: APECED, autoimmune polyendocrinopathy‐candidias‐ectodermal dystrophy; UDP, uridine diphosphate.

Figure 2: Diagnostic algorithm for the evaluation of suspected AIH after exclusion of viral, drug‐induced, hereditary, and metabolic diseases. ANA and SMA should be assessed in adults (green panel), and antibodies to LKM1 should be assessed later if ANA and SMA are absent. ANA, SMA, and LKM1 should be assessed in all pediatric patients at presentation (green panel). The findings of the liver biopsy (dark blue panels) could support the diagnosis of AIH (dark red panel) or suggest alternative diagnoses that might include an overlap syndrome, PBC, PSC, AIH with NAFLD, or NASH (brown panels). The absence of ANA, SMA, and LKM1 justifies additional serological tests (green panel) that can include antibodies to SLA, atypical pANCA, tissue transglutaminase, and AMA. Seropositivity for one of these autoantibodies could support the diagnosis of AIH (dark red panels) or suggest other diagnoses including celiac disease (dark brown panels). Abbreviations: Peds, pediatric patients; tTG, tissue transglutaminase.

Autoantibodies

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).

Histological Findings

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

Figure 3: Histological features characteristic of AIH. (A) Lymphoplasmacytic inflammatory infiltration of the portal tract and interface hepatitis involving >50% of the portal tract circumference (arrows; hematoxylin and eosin; magnification, ×200). (B) Plasma cell predominance in a portal inflammatory infiltrate (hematoxylin and eosin; magnification, ×600). (C) Perivenulitis of a central vein (hematoxylin and eosin; magnification, ×400). (D) A hepatocyte undergoing emperipolesis (arrows; hematoxylin and eosin; magnification, ×600). (E) Rosettes of regenerating hepatocytes (arrows; hematoxylin and eosin; magnification, ×600). Photomicrographs are courtesy of Sadhna Dhingra, M.D., Department of Pathology, Baylor College of Medicine, Houston, TX.

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

Guidance Statements

• 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.

Clinical Manifestations

Presentations

Symptomatic

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

Asymptomatic

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

Autoantibody‐Negative Hepatitis

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).

Guidance Statement

• 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

Guidance Statements

• 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

Guidance Statements

• 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

Definite Association	Probable Association	Possible Association
Minocycline187	Propylthiouracil579	Ipilimumab (anti‐CTLA‐4)581
Nitrofurantoin187	Isoniazid582	Tremelimumab (anti‐CTLA‐4)581
Infliximab206	Diclofenac583	Nivolumab (anti‐PD‐1)581
Alpha‐methyldopa585	Etanercept216	Pembroluzimab (anti‐PD‐1)230
Adalimumab216	Atorvastatin592	Atezolizumab (anti‐PD‐L1)581
Halothane596	Rosuvastatin598	Black cohosh (herbal medicine)599
Oxyphenisatin*601	Clometacine602	Dai‐saiko‐to (herbal medicine)604
Dihydralazine*573		Germander (herbal medicine)606
Tienilic acid*607		Hydroxycut (nutritional supplement)608
		Trichloroethylene (toxin)609
		Papaverine610
		Indomethacin611
		Imatinab612

^*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

Clinical Features	Drug Induced AIH‐Like Injury	AIH
Gender	Mainly women187	Female predominance, but men also affected2
Acute onset	Majority (>60%)231	<20%2
Hypersensitivity (fever, rash, eosinophilia)	Up to 30%231	Unusual2
Temporal relationship with drug	Positive231	Negative2
HLA DRB1*03:01 or DRB1*04:01 association	None236	Common29
Concurrent autoimmune diseases	Unusual187	Present in 14%‐44%129
Cirrhosis at presentation	Rare187	28%‐33%9
Management	Stop offending drug ± glucocorticoids187	Glucocorticoids with AZA2
Relapse after drug withdrawal	Rare187	60%‐87%243
Progression to cirrhosis	Rare187	7%‐40%105
Survival without transplantation	90%‐100%187	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.

Guidance Statements

• 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

Guidance Statements

• 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.

Pretreatment Evaluation

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

Guidance Statement

• Consider screening patients with AIH for absent or near‐absent TPMT activity prior to initiating treatment with AZA.

Vaccinations

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

Guidance Statements

• 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.

Guidance Statements

• 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 Maintenance

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

Metabolic Syndrome

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

Guidance Statements

• 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.

Pretreatment Counseling

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

Guidance Statements

• 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.

Pregnancy Counseling

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

Fetal Complications

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.

Maternal complications

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

Medication	Safety Reports in Pregnancy
Terlipressin	Uterine ischemia
Octreotide	No harmful effects noted
Beta‐blockers	Fetal bradycardia, fetal growth retardation
Lactulose	No harmful effects noted
Rifaximin	No harmful effects noted but limited data
Corticosteroids	Inconsistent association with cleft abnormalities
AZA	Premature birth
MMF	Birth defects, spontaneous abortion
TAC	Premature birth, transient neonatal renal dysfunction

Medication Safety in Pregnancy

Glucocorticoids

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

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

Mycophenolate Mofetil

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

Guidance Statements

• 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.

First‐Line Treatments

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.

Figure 4: First‐line treatment of AIH in adults and children, recognizing adjustments based on the presence of cirrhosis or an acute severe presentation.

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

Drug	Side Effects	Management Options
Predniso(lo)ne	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
Budesonide	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	Taper budesonide to the lowest effective dose and attempt withdrawal after remission Do not prescribe in cirrhosis and acute severe AIH
AZA	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
Outcome	Results	Grade of Evidence Quality
Biochemical remission	Two studies (one RCT351 and one non‐RCT20)	High
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	Low
Death	No studies reported death
Liver transplantation	No studies reported LT
Meta‐analysis: I 2 test of heterogeneity	I 2 = 0.0%, P = 0.495
Meta‐analysis for biochemical remission	OR, 2.19; 95% CI, 1.30‐3.67
Meta‐analysis: Conclusions	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

Strength Determinant	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
2. Certainty	Limited	Limited	Limited
3. Cost	High cost/copay for budesonide	+MMF	No pred
4. Patient values	Budesonide	+MMF (ease of use)	No pred
		+TAC (pregnancy)
5. Feasibility	Copay may make it harder to get budesonide	Equal	Equal
6. Accessibility	Copay may make it harder to get budesonide	Equal	Equal
7. Equity	Equal	Equal	Equal

Abbreviations: no pred, no predniso(lo)ne; pred, predniso(ol)ne.

Guideline Recommendations

1. 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.
2. 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

Guidance Statements

• 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

Treatment Withdrawal

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

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

Guidance Statements

• 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 Treatments

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

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.

Calcineurin Inhibitors

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
Outcome	Results	Grade of Evidence Quality
Biochemical remission	Two retrospective studies418 reported no significant difference in frequency of biochemical remission	Low
Drug intolerance	One study418 reported drug intolerance and showed no significant difference between MMF and TAC in frequency of side effects	Very low
Death or LT	One study418 reported death or LT (together) and showed no significant difference in frequencies between MMF and TAC	Very low
Meta‐analysis: I 2 test of heterogeneity	I 2 = 59.6%, P = 0.116
Meta‐analysis: For biochemical remission	OR, 1.95; 95% CI, 0.18‐20.81
Meta‐analysis: Conclusions	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

Guideline Recommendations

1. 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).
2. 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

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.

Guidance Statements

• 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

Guidance Statement

• Consider adding UDCA to prednisone or prednisolone in combination with AZA in adults and children with AIH and overlap syndromes.

Long‐Term Outcomes

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.

Age‐Related Impact

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.

Ethnicity

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

Guidance Statement

• 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.

LT

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
Outcome	Results	Grade of Evidence Quality
Recurrent autoimmune hepatitis	Two retrospective studies488 and one RCT489 reported no significant difference in recurrence of AIH after LT	Low
Acute cellular rejection	No studies reported frequencies of acute cellular rejection
Graft loss	No studies reported frequencies of graft loss
Death	One RCT489 reported no significant difference between the two groups	Very low
Re‐transplantation	No studies reported retransplantation
Meta‐analysis: I 2 test of heterogeneity	I 2 = 38.6%, P = 0.202
Meta‐analysis: For biochemical remission	OR, 0.62; 95% CI, 0.19‐1.96
Meta‐analysis: Conclusions	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.

Guideline Recommendation

1. 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 AIH

Categories	Recurrent AIH	De Novo AIH
Clinical findings	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
Laboratory findings	Increased serum AST, ALT, IgG levels501	Increased serum AST, ALT, IgG levels503
Serological markers	Same antibodies as pre‐LT AIH617	ANA, SMA, anti‐LKM1503
	ANA, SMA common617
	Anti‐LKM1 rare618
Histologic findings	Lobular hepatitis, focal necrosis, pseudorosettes (early)620	Interface hepatitis521
	Interface hepatitis, lymphoplasmacytic infiltration (late)623	Lymphoplasmacytic infiltrates521
	Lobular collapse, confluent/bridging necrosis (severe)621
Treatment	Predniso(lo)ne, 30 mg daily, and AZA, 1‐2 mg/kg daily499	Children501 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	Rapamycin629
	Rapamycin628
Outcomes	5‐year patient survival, 86%‐100%500	Better in children than adults 503
	Graft failure, 8%‐50%614	Biochemical remission, 86%503
	Retransplantation, 33%‐60%614	Retransplantation, 8%508
	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.

Guidance Statements

• 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

Goal	Treatment	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
	Anti‐CD20	B‐cell depletion
	Anti‐BAFF	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
	Anti‐CD40	Depletion of memory B cells mobilized from lymphoid tissues by anti‐BAFF	Clinical trials planned in AI diseases
	Efgartigimod	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
	Anti‐IL‐21	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
	Anti‐Blys	Reduce pathogenic B‐cell selection, differentiation, and homeostasis	SOC in SLE
Inhibit signaling of proinflammatory cytokines	mTOR inhibition	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	rHuIL‐10	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	POC established
			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	PIF	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.