Front. Med. DOI 10.1007/s11684-015-0386-y

REVIEW

Autoimmune hepatitis Farhad Sahebjam, John M. Vierling (

✉)

Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St. Luke’s Medical Center, Houston, TX 77030, USA

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2015

Abstract Autoimmune hepatitis is a chronic liver disease putatively caused by loss of tolerance to hepatocytespecific autoantigens. It is characterized by female predilection, elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. It is currently divided into types 1 and 2, based on expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2. Although autoimmune hepatitis occurs in childhood, this review focuses on disease in adults. In the absence of pathognomonic biomarkers, diagnosis requires consideration of clinical, biochemical, serological and histological features, which have been codified into validated diagnostic scoring systems. Since many features also occur in other chronic liver diseases, these scoring systems aid evaluation of the differential diagnosis. New practice guidelines have redefined criteria for remission to include complete biochemical and histological normalization on immunosuppressive therapy. Immunosuppression is most often successful using prednisone or prednisolone and azathioprine; however, the combination of budesonide and azathioprine for non-cirrhotic patients offers distinct advantages. Patients failing standard immunosuppression are candidates for alternative immunosuppressive regimens, yet none of the options has been studied in a randomized, controlled trial. Overlap syndromes with either primary sclerosing cholangitis or primary biliary cirrhosis occur in a minority. Liver transplantation represents a life-saving option for patients presenting with acute liver failure, severely decompensated cirrhosis or hepatocellular carcinoma. Transplant recipients are at risk for recurrent autoimmune hepatitis in the allograft, and de novo disease may occur in patients transplanted for other indications. Patients transplanted for AIH are also at risk for recurrent or de novo inflammatory bowel disease. Progress in our understanding of the immunopathogenesis should lead to identification of specific diagnostic and prognostic biomarkers and new therapeutic strategies. Keywords autoimmune hepatitis; autoantibodies; diagnosis; immunological diseases; drug-induced liver injury; therapy; immunosuppression; outcomes; hepatocellular carcinoma; liver transplantation

Introduction Autoimmune hepatitis (AIH) is a chronic hepatocellular disease putatively caused by a loss of tolerance to hepatocyte-specific autoantigens [1–3]. The syndrome of AIH is characterized by elevated levels of aminotransferases, non-species specific autoantibodies, elevated γglobulin and/or IgG levels and interface hepatitis on liver biopsy. In accord with other autoimmune diseases, AIH is a global disease that afflicts children and adults of all ethnicities and races. The etiology of AIH is undefined but appears to require immunogenetic susceptibility and

Received May 16, 2014; accepted November 28, 2014 Correspondence: [email protected]

environmental triggers that result in an unregulated immunological attack against hepatocytes. AIH is a rare cause of acute liver failure (ALF) but more often presents as an indolent, chronic liver disease. In untreated patients, AIH progresses at variable rates to cirrhosis with subsequent risks of complications of portal hypertension, liver failure or hepatocellular carcinoma (HCC). Patients who achieve remission using immunosuppressive drugs have an excellent prognosis [1–3]. In contrast, patients presenting with ALF and those presenting with or developing severe complications of cirrhosis or HCC require life-saving orthotopic liver transplantation (OLT) [4]. A minority of patients transplanted for AIH develop recurrent AIH in the allograft [4]. In 2010, the American Association for the Study of Liver Diseases (AASLD) practice guideline (2010 PG) on

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Autoimmune hepatitis

the diagnosis and management of AIH were revised [1]. The most important changes in the 2010 PG definition of remission were normalization of aminotransferase levels and resolution of histologic inflammation (Table 1). In contrast, the 2002 AASLD practice guideline (2002 PG) had defined remission on the basis of a reduction of aminotransferase levels and elimination of interface hepatitis (Table 1) [5]. Evidence indicated that the new 2010 PG definition of remission resulted in better clinical outcomes. A clinically important consequence of the redefinition of remission is an expected increase in the proportion of patients who fail to achieve remission using corticosteroids and/or azathioprine and require alternative immunosuppressive therapies [6]. The purpose of this review is to summarize advances in our understanding of AIH with particular emphasis on diagnosis and treatment of adults with AIH.

Epidemiology AIH is a disease of female predilection that occurs in both children and adults world-wide among all ethnicities and races [1,3]. In the absence of validated diagnostic biomarkers, AIH has been classified into type 1 and type 2, based on differences in the expression of autoantibodies and other features (Table 2). Thus, our understanding of epidemiology is based on recognition of types 1 and 2 AIH in persons with different ethnicities and races in diverse geographic areas. In Caucasian Europeans and North Americans, the point prevalence of AIH is 16.9 per 100 000 and the average annual incidence ranges from 0.1 to 1.9 per 100 000 [7,8]. A 15-year prospective, multicenter study in Israel reported an annual incidence of 0.67 per 100 000 and an average annual prevalence of 11 per 100 000 [9]. The annual incidence is much lower in Japan [7]. In contrast, the point prevalence among Alaskan natives is much higher (42.9 per 100 000) [10]. Early reports indicated that incident cases occurred in a bimodal age distribution with the first peak between 10 and 30 years

of age and the second between 40 and 50 years of age; however, these findings may have reflected referral bias in tertiary care centers [11]. The peak incidence of AIH type 2 occurs in young persons [12]; however, the incidence of AIH type 2 varies geographically. AIH type 2 is reported more commonly in Europe than either the USA or Japan [7], but the prevalence in the USA remains unknown, in part, due to infrequent testing for type 2 AIH. In adults, the frequency of type 2 AIH varies within Europe, being more common in the South than in the North [7]. It is noteworthy that the female to male ratio varies from 4:1 in type 1 AIH up to 10:1 in type 2 AIH (Table 2) [13]. Japanese patients typically present with late-onset AIH [14]. In New Zealand, the majority of newly diagnosed patients are older women with type 1 AIH [15]. Clinical presentations and outcomes vary among geographic regions and ethnicities and races, even within the same country [16]. It remains unclear how genetics, environmental exposures, responsiveness to medications, socioeconomics and access to healthcare contribute to these differences. In Europe, AIH patients of African, Middle Eastern or Asian race or ethnicity presented at younger ages, had higher frequencies of cholestatic features biochemically and histologically and responded less frequently to immunosuppression than Caucasian patients [17]. At presentation in the USA, AfricanAmerican patients had higher rates of cirrhosis (56%– 85%) than Caucasian patients of European ancestry (38%) [18,19]. In addition, African Americans were more likely to fail immunosuppressive therapy and had higher mortality than Caucasian patients [16]. In Japan patients present with AIH as older adults [14] and often respond to ursodeoxycholic therapy, regarded as having only modest immunosuppressive activity [20]. A retrospective study in a tertiary referral center compared the clinical presentations and outcomes for Hispanic, Asian and Caucasian patients with AIH [21]. The sex ratio and age at diagnosis were similar among the groups. At presentation, Hispanic and Asian patients had greater elevations of PT INR than Caucasians. Hispanics also had a greater frequency of

Table 1 Comparison of AASLD 2002 and 2010 autoimmune hepatitis practice guidelines 2002 practice guideline

2010 practice guideline

Goal

Reduce mortality and symptoms

Prevent progression of disease and need for OLT

Biochemistry

Reduce AST/ALT to 1.5 – 2  ULN

Normalize ALT

Histology

Eliminate interface hepatitis Confine inflammation to portal tracts

Eliminate interface hepatitis Eliminate lymphoplasmacytic inflammatory infiltrates in portal tracts

Clinical outcome

Reduce rate of progression to cirrhosis

Prevent development of cirrhosis Prevent progression of established cirrhosis

Immunosuppressive therapy

Minimize immunosuppression to decrease serious adverse events

Combine immunosuppressive drugs to minimize adverse events

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal range; OLT, orthotopic liver transplantation. Assembled from references [1,5].

Farhad Sahebjam and John M. Vierling

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Table 2 Comparison of autoimmune hepatitis type 1 and type 2 Signature autoantibodies

AIH type 1

AIH type 2

ANA, ASM, Anti-f-actin*

Anti-LKM1, Anti-LC1, Anti-LKM3

Overlapping autoantibodies

Anti-SLA/LP

Anti-SLA/LP

Geographic distribution

Global

Global but with geographic differences in adult prevalence: Europe>USA 10 to 1

Female to male ratio

4 to 1

Age distribution

Infancy to elderly adulthood

Childhood to young adulthood

Clinical presentation and course

Indolent>>Severe

Severe

Histology at presentation

Spectrum ranging from mild disease to cirrhosis to High grade inflammation cirrhosis common ALF with massive hepatocellular necrosis

Treatment failure

Uncommon

Common

Requirement for long-term immunosuppression

Majority

Universal

*Up to 20% negative for all autoantibodies. Abbreviations: ANA, anti-nuclear antibody; ASM, anti-smooth muscle antibody; f-actin, filamentous actin; LKM, liver-kidney-microsomal; LC-1, liver cytosol-1; SLA, soluble liver antigen; LP, liver-pancreas.

hypoalbuminemia and higher prevalence of biopsy-proven cirrhosis than Caucasians or Asian. Paradoxically, Hispanics had the highest survivals on therapy, followed by Caucasians and Asians. In China, elderly patients were more often asymptomatic than younger patients but less likely to respond to immunosuppressive therapy [22]. A meta-analysis of clinical manifestations and outcomes in elderly patients with AIH showed that they were more likely to present asymptomatically with cirrhosis and less likely to relapse after withdrawal of immunosuppressive therapy than younger patients [23].

Immunopathogenesis The pathogenesis of AIH is incompletely understood [3,24,25]. This is particularly true of type 1 AIH, since hepatospecific autoantigenic epitopes recognized by the T cell receptors of autoreactive CD4 and CD8 T cells remain undefined. However, evidence of oligoclonality of the T cell receptor repertoire among liver infiltrating T cells suggests the autoantigenic epitopes exist and are few in number [26]. In contrast, the autoantigenic epitopes recognized by both B cells and the T cell receptors of CD4 and CD8 T cells have been defined in type 2 AIH as components of cytochrome P450 2D6 (CYP2D6) [24]. Although a detailed summary of research on the etiopathogenesis of AIH is beyond the scope of this review, it is useful to consider a postulated theory of immunopathogenesis that incorporates current concepts (Fig. 1) [24,27,28]. AIH may be triggered in genetically susceptible persons by viral infections or exposures to drugs or xenobiotics, either through molecular mimicry of autoantigens or as a result of presentation of hepatic autoantigens concentrated within apoptotic bodies from dying hepatocytes [27]. Viruses associated with the onset of AIH include: HAV, HCV, HEV, EBV, HSV and measles

[3,24,27,28]. Drug-induced liver injury (DILI) can mimic, trigger or unmask AIH [29,30], and distinction between DILI and AIH can be challenging [30–33]. Multiple genetic polymorphisms may confer susceptibility or resistance to AIH [24,27,28]. To date, studies of susceptibility and resistance have focused on HLA alleles and geographic differences (Table 3). Type 1 AIH has strong HLA associations with three HLA haplotypes in Northern Europe and North America: (1) HLA-DR3 (encoded by DRBI*0301) and DR4 (encoded by DRB1*0401) confer susceptibility; and (2) DRB1*1501 confers resistance. The class II HLA-DR3 alleles associated with AIH susceptibility have strong linkage disequilibrium with class I HLA-A, HLA-Cw and HLAB molecules. The extended haplotype of the linked alleles are HLA A*0101-Cw*0701-B*0801-DRB1*0301DQA1*0501-DQB1*0201. A recent Dutch genome-wide association study [34] associated a variant in the HLA region at rs2187668 with type 1 AIH (P = 1.5  10–78). The variant was a primary susceptibility genotype in patients with HLA-DRBI*0301 and a secondary susceptibility genotype in patients with HLA-DRB1*0401. Patients with HLA-DR3 share common class I HLA alleles that may affect cytotoxic T lymphocyte (CTL) effector cell function. In Japan, China and Mexico, susceptibility to AIH type 1 is associated with the DRB1 alleles DRB1*0405 and DRB1*0404. DRB1*1301 is associated with AIH in Argentine children and Brazilians and appears to be associated with protracted HAV infections [27]. A meta-analysis of Latin American data concluded that reported HLA DQ2 and DR52 (DQB1*02, DQB1*0603, DRB1*0405 and DRB1*1301) as susceptibility loci and HLA DR5 and DQ3 (DQB1*0301 and DRB1*1302) as protective loci [35]. Susceptibility to type 2 AIH in Germany, Britain and Brazil is associated with HLA-DR7 (DRB1*0701), but in Spain it is associated with DR3 (DRB1*0301) [27]. That

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Autoimmune hepatitis

Fig. 1 Hypothetical sequence of events in the immunopathogenesis of autoimmune hepatitis.

Table 3 HLA DRB1 alleles associated with autoimmune hepatitis susceptibility and resistance in different geographic areas Susceptibility alleles

Geographic area

DRB1*0301

North America and Europe

DRB1*0401

North America and Europe

DRB1*0404

Japan, China and Mexico (Mestizo)

DRB1*0405

Japan, China and Argentina (adults)

Resistance alleles DRB1*1501

North and South America, Europe, Japan

DRB1*1302

South America

DQB1*0301

South America

both DRB1*0701 and DRB1*0301 have strong linkage disequilibrium with DQB1*0201 may explain this apparent paradox. Thus, DQB1*0201 may confer susceptibility, while DRB1*0701 might be related to disease severity and progression. It is important to note that HLA alleles explain less than 50% of the susceptibility to AIH type 1, which emphasizes the importance of polygenetic factors. Class I MICA or MICB genes produce highly polymorphic ligands expressed by cells exhibiting stress, infection or neoplasia [27]. The killer receptor NKG2D on NK cells, NKT cells, macrophages, γ/δ T cells and CD8 T cells binds to MICA and MICB causing apoptosis of the

target cell. MICA and MICB map between the class I HLA B and class III TNF loci. Although MICA alleles are not associated with AIH, they are associated with primary sclerosing cholangitis, suggesting a role for MICA in the pathogenesis of the PSC-AIH overlap syndrome [27]. The mechanism(s) involved in the loss of tolerance in AIH remain unknown [24,27,28]. Recent studies suggested that the pathogenic activities of effector T cells in both types 1 and 2 AIH result from decreases in quantities and functional capacities of autoantigen-specific CD4 T regulatory (Treg) cells required to inhibit the autoimmune effector cell response(s) [36–38]. However, the role of Treg dysfunction remains controversial, since others failed to detect dysfunctional Tregs in AIH [39]. The ability to generate autoantigen-specific CD4 Tregs from peripheral blood lymphocytes holds promise as a potential autoantigen-specific therapy for AIH in the future [40]. This underscores the importance of defining the autoantigenic CD4 and CD8 T cell epitopes in type 1 AIH [27].

Differential diagnostic considerations AIH should be considered in the differential diagnosis of all patients presenting with acute or chronic liver disease, including acute liver failure (ALF), acute hepatitis, chronic hepatitis or cirrhosis regardless of the presence or absence

Farhad Sahebjam and John M. Vierling

of symptoms. Presentation of AIH as ALF (defined as elevated aminotransferases, jaundice, coagulopathy and hepatic encephalopathy) is extremely rare [41–43], and presentation as an acute icteric hepatitis is uncommon [43]. Approximately 70%–80% of adults present with chronic liver disease, and up to 40%–50% have cirrhosis in the absence of symptoms or jaundice [6]. The frequency of cirrhosis at the time of presentation attests to the facts that: (1) AIH can progress insidiously as an asymptomatic disease; and (2) patients with AIH and abnormal liver enzymes remain undiagnosed and untreated for protracted periods. Thus, the clinician must consider and exclude acute and chronic viral hepatitis caused by HAV, HBV with or without HDV, HCV, HEV or viruses causing hepatic necrosis, such as EBV, CMV and HSV. The differential diagnosis should include primary biliary cirrhosis and primary sclerosing cholangitis, since AIH overlap syndromes occur with these diseases. Wilson disease is a particularly important consideration, since it can mimic AIH biochemically, serologically and histologically [44– 46]. In patients with Wilson disease, ceruloplasmin screening can be unreliable because the serum ceruloplasmin level is often elevated as an acute phase reactant stimulated by hepatic inflammation [44]. The most diagnostically helpful tests are hepatic copper concentration and 24 h urinary copper excretion [44,45]. Distinction between ALF due to AIH vs. Wilson disease is particularly difficult, since ALF is associated with low serum ceruloplasmin levels as a result of massive hepatocellular necrosis [47]. Drug-induced liver injury is also an important consideration in the differential diagnosis [29–32,48,49]. Since DILI can mimic, trigger or unmask AIH, distinction between DILI with features of AIH and true AIH requires scrutiny of clinical and histological differences [30– 33,48,49].

Diagnostic criteria The diagnosis of AIH is based on a composite of clinical, biochemical, serological and histological features, each of which can be observed individually or collectively in other liver diseases. The International Autoimmune Hepatitis Group (IAIHG) published revised diagnostic criteria (RDC) in 1999 that were designed to ensure enrollment of comparable patient groups in clinical trials [50]. By providing a systematic, comprehensive assessment, RDC became widely used clinically to establish a diagnosis of AIH with high sensitivity, specificity and accuracy (Table 4). The RDC, however, does not discriminate among diseases with clinical, biochemical, serological or histological features similar to AIH. Thus, the diagnostic utility of the RDC for AIH requires specific testing to

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exclude other etiologies for acute and chronic liver diseases, especially those with high levels of necroinflammatory activity and interface hepatitis on biopsy. The most important diseases to exclude are acute and chronic viral hepatitis A, B, D, C and E and Wilson disease. Subsequently, the IAIHG developed simplified diagnostic criteria (SDC) (Table 4) to facilitate greater clinical application [51]. Both the RDC and SDC use the titer of autoantibodies detected using immunofluoresence microscopy, but the increasing use of ELISA for detection of ANA, SMA, anti-f-actin and anti-LKM1 in the USA negates utilization of titers [52]. Anti-SLA detection is based on ELISA or radioimmunoassay; it is not detectable using immunofluorescence [52]. To date, ELISA units for autoantibodies used to diagnose AIH have not been correlated with immunofluoresence titers, but should be. The RDC and SDC should be viewed as complimentary. The comprehensive RDC is advantageous for establishing a diagnosis of AIH in patients with paucity of typical features of AIH. In contrast, the SDC is most useful in establishing a diagnosis of AIH in patients with typical features of AIH and in excluding AIH in the differential diagnosis. A pre-treatment RDC score of 15 designates a “definite” diagnosis of AIH (sensitivity 95%, specificity 97% and accuracy 94%). A diagnosis of “probable” AIH is denoted by a pre-treatment RDC score ≥ 10 or ≥ 12 in a responder to empiric corticosteroid therapy. A RDC score of 10 prior to treatment has a sensitivity of 100%, specificity of 73% and accuracy of 67%. RDC and SDC scoring systems have been compared in several studies [52–55,56]. Specificities of the SDC and RDC were 97% vs. 97.9%, respectively in a large, retrospective study [53]. Another study of 185 adult patients assessed the performance of the RDC and SDC at presentation [54] and found that 17/185 (9%) had “probable” AIH using the RDC score, while 28/185 (15%) had “probable” AIH using the SDC score. Patients with “probable” AIH differed from patients with “definite” by being more likely male, having more immune-associated diseases, lower levels of γglobulin or IgG and lower titers of autoantibodies. Regardless of whether the RDC or SDC scores indicated “definite” or “probable” AIH, patients responded similarly to steroids. RDC and SDC scores were concordant in 79% and discordant in 21% of patients. Among the 39 patients with discordant RDC and SDC scores, 5 who were scored as “definite” using RDC scored as “probable” using SDC. SDC scored 12 patients as non-diagnostic due to their lower γ-globulin and IgG levels and autoantibody titers < 1:80. In contrast, RDC scored 6 as “definite” and the other 6 as “probable.” When 8 of the 12 were treated with steroids, 5 (62%) responded. The SDC has been validated in Chinese patients [57]. Comparison of the RDC and SDC in China showed that the RDC was superior to the SDC in the diagnosis of AIH, due to its inclusion of concurrent

Table 4 Diagnostic criteria for scoring systems in autoimmune hepatitis Revised original scoring system1 +2

Autoantibodies

>3

–2

ANA or SMA

2

+3

1.5–2.0

+2

Drugs

Autoantibodies ≥1:40

+1

≥1:80

+2

LKM-1

≥1:40

+2

Anti-SLA

Positive

+2

ANA, SMA, LKM1, Anti-SLA, anti-f-actin Histopathological features  massive hepatic necrosis  lymphoid follicles

1.0–1.5

+1

Immunoglobulin level

ULN

+1

g-globulin

>1.1  ULN

+2

 plasma cell-enriched

>1:80 + 3

+3

1:80

+2

Histological features

1:40

+1

Compatible with AIH

+1

15

Probable diagnosis

10–15

Post-treatment aggregate score Definite diagnosis

>17

Probable diagnosis

12–17

Abbreviations: Alk Phos, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ANA, antinuclear antibody; SMA, antismooth muscle antibody; LKM1, anti-liver-kidney microsome-1 antibody; f-actin, anti-f-actin antibody; SLA, soluble liver antigen; pANCA, perinuclear neutrophil cytoplasmic antibody. *Typical histological features are those contained in the Revised Diagnostic Criteria, principally interface hepatitis. 1 [50]; 2[51]; 3[41].

Farhad Sahebjam and John M. Vierling

immunological diseases in the score (OR = 7.25, 95% CI 1.41–37.29; P = 0.018) [56]. Cumulatively, these data allow the following conclusions. First, both the RDC and SDC are accurate and concordant for patients with “definite” or “probable” scores. Second, RDC should be used to reassess all patients with SDC scores of “probable” or non-diagnostic. Third, clinicians must recognize the limitations of both the RDC and SDC and regard them as diagnostic aids and not rigid standards [52,58]. For example, AIH patients without autoantibodies may not achieve “probable” or “definite” scores and require empiric immunosuppression to establish a diagnosis of AIH [52,58]. In a retrospective Chinese study, 17 (10.2%) of 167 patients were autoantibody negative [59]. Using RDC, 6 were “definite” and 11 “probable” scores for AIH. In contrast, the SDC identified only 3 of the 17 as “probable” AIH and none as “definite.” It is also important to note that neither the RDC nor the SDC have been validated in patients with putative overlap syndromes [60,61].

Autoantibodies Serum autoantibodies have played an important historic role in the detection and diagnosis of AIH [1–3]. In the absence of other biomarkers, AIH is currently classified on the basis of the signature expression of autoantibodies (Tables 2 and 5) into Type 1 (ANA and/or SMA) and Type 2 (LKM-1) [1,62]. SMA should be tested along with anti-factin because they are complimentary and may have prognostic value [63]. Clinicians should not accept ELISA testing for anti-f-actin as the equivalent of testing for SMA. Additional autoantibodies with defined autoantigenic targets are also associated with AIH (Table 5) [1,62]. If ANA, SMA and anti-LKM1 are absent, testing for pANCA, anti-SLA/LP, anti-LC-1 and anti-LKM-3 should be performed (Fig. 2, Table 5). A minority of patients express only these autoantibodies [62]. If all autoantibodies are absent but the RDC are compatible with the diagnosis of AIH, empiric treatment with steroids should be considered and the RDC score should be recalculated on the basis of the response to immunosuppression [64]. Retesting of autoantibodies during therapy should be considered, since some patients without autoantibodies prior to therapy paradoxically express them during immunosuppression [1,52,64]. The clinical performance of autoantibody testing has been studied in detail [65,66]. Comparison of autoantibody tests in 265 adults with AIH and 342 adults with other chronic liver diseases showed that the sensitivities of standard autoantibodies were poor: ANA (32%), SMA (16%) and LKM1 (1%). Diagnostic accuracy was poor, ranging from 56%–61%. Multiple autoantibodies were detected in 51% of patients with AIH, but in only 8% of patients with other liver diseases. Having both ANA and

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SMA increased sensitivity to 43% and specificity to 99%. When having both ANA and SMA was compared to having either autoantibody alone, the presence of both had a 97% positive predictive value, 69% negative predictive value and a 74% diagnostic accuracy. This study highlights the fact that ANA and SMA are expressed commonly in a variety of acute and chronic liver diseases other than AIH. Thus, clinicians must not over interpret autoantibody results but use them within the RDC and SDC scoring systems (Table 5). Among autoantigens detected as ANA are Sp100 and gp210, which are uniquely found in primary biliary cirrhosis (PBC) [67]. The autoantigenic epitopes recognized by anti-SLA/LP are components of the UGA suppressor tRNA-associated antigenic protein (tRNASer/Sec), now known as SepSecS. SLA/LP autoantibodies occur in a minority of patients, predominantly with type 1 AIH, but are highly specific for the diagnosis of AIH [3,24,27,28]. SepSecS shares amino acid sequences with asialoglycoprotein receptor (ASGPR), an autoantigen protein expressed primarily by the membranes of periportal hepatocytes [3,24,27,28], suggesting a possible role in pathogenesis. Anti-LKM1 autoantibodies react with defined CYP2D6 epitopes, and shared amino acid sequences have been identified in proteins encoded by HCV that are produced during infection [3,24,27,28]. In addition to their role in establishing a diagnosis of AIH, specific autoantibodies have prognostic implications [68]. Autoantibodies reacting with SLA/LP, smooth muscle f-actin, LC-1, ASGPR, chromatin, cyclic citrullinated peptide and uridine glucuronosyltranferase are indicators of severity and increased probability of progression [68]. New autoantibodies being assessed in AIH include those reacting with α-actinin, a ubiquitous cytoskeletal cross-linking protein within the family of filamentous actin (f-actin) [69]; phosphoenolpyruvate carboxykinase 2 (PCK2) [70]; ribosomal P [71]; nucleosome [72]; programmed cell death-1 (PD-1) [73]; and interleukin-4 receptor (IL-4R) [74]. Their diagnostic roles have not been determined.

Histopathology and the role of liver biopsy in diagnosis Currently, a liver biopsy is mandatory for the diagnosis of AIH [41,75]. In coagulopathic patients with ALF, a transjugular liver biopsy can be safely performed. Several histopathological features, including interface hepatitis, are scored in the RDC system, and interface hepatitis is the key histopathological feature in the SDC scoring system (Table 4). Non-invasive, surrogate tests for hepatic inflammation and fibrosis are not substitutes for a biopsy, since they cannot identify interface hepatitis, lymphoplasmacytic infiltrates or rosettes, the key histological features of chronic AIH (Fig. 3). However, clinicians must recognize that the histological features of AIH are not pathognomic;

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Autoimmune hepatitis

Table 5 Autoantibodies and the differential diagnosis of AIH Autoantibody

Target antigen(s)

Liver diseases

Diagnostic value

ANA

Multiple antigens: chromatin, ribonucleoproteins, ribonucleoprotein complexes

AIH, PBC, PSC, DILI, chronic Compatible with type 1 AIH, but not diagnostic HBV, HCV infections, NAFLD

SMA

Microfilaments: filamentous actin (f-actin) Intermediate filaments: vimentin, desmin

AIH, PBC, PSC, DILI, HBV, HCV, NAFLD

Compatible with type 1 AIH, but not diagnostic

pANCA

β-tubulin isotype 5, cross reacts with bacterial precursor protein FtsZ

AIH, PSC, IBD

Compatible with diagnosis of type 1 AIH but not diagnostic

LKM-1

Cytochrome P450 2D6 (CYP2D6)

AIH, chronic HCV infection, halothane-induced hepatitis

Diagnostic of type 2 AIH in absence of HCV infection

LC-1

Formiminotransferase cyclodeaminase (FTCD)

AIH type 2

Liver specific Diagnostic of type 2 AIH

LKM-3

Family 1 UDP-glucuronosyltransferases (UGT1A)

AIH, chronic HDV

Diagnostic of type 2 AIH in absence of chronic HDV infection

SLA

tRNA-selenocysteinyl-tRNA synthase (SepSecS protein)

AIH type 1 or 2 HCV infection?

Liver specific Diagnostic of AIH in absence of HCV infection Prognostic for severe disease, relapse after withdrawal of immunosuppression

ASGPR

Asialoglycoprotein receptor

AIH, PBC, DILI, chronic HBV, Liver specific HCV, HDV infections Compatible with type 1 or 2 AIH Prognostic for severe disease, histopathological activity and relapse after withdrawal of immunosuppression

Type 1

Type 2

Type 1 or 2

Abbreviations: ANA, antinuclear antibody; SMA, anti-smooth muscle antibody; LKM-1, anti-liver-kidney microsome-1 antibody; LC-1, anti-liver cytosol type 1 antibody; LKM-3, anti-liver-kidney microsome-3 antibody; SLA, anti-soluble liver antigen; pANCA, perinuclear neutrophil cytoplasmic antibody; ASGPR, anti-asialoglycoprotein receptor antibody; UDP, uridine diphosphate; UGT, uridine diphosphate glucuronosyltransferase; tRNA, tRNA; DILI, drug-induced liver injury; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; NAFLD, non-alcoholic fatty liver disease.

thus, histology alone does not establish the diagnosis. Histological features suggestive of AIH must be considered in the context of the clinical, biochemical and serological features (Table 4). While interface hepatitis is the key histological feature in AIH, it also occurs in HBV (with or without HDV), HCV and HEV infections, Wilson disease and drug-induced liver injury [33,46,76,77]. In contrast, central zonal necrosis and perivenulitis of the central vein (Fig. 3) are now recognized as a primary histological feature of AIH presenting as acute hepatitis or ALF (Table 4) [41,75]. However, similar lesions can be observed in biopsies of AIH patients with chronic disease [78,79]. If a biopsy report contains insufficient information for RDC or SDC scoring, the clinician should ask the pathologist to score the biopsy or seek outside consultation. The histopathological features of a biopsy can usually be classified as typical, compatible or incompatible with AIH by an experienced pathologist [75]. The necessity of a liver biopsy for the diagnosis of AIH has been challenged [80]. The similarity of laboratory findings in AIH patients with either atypical histology (5%) or compatible histology (95%) led to the conclusion

that AIH can be diagnosed accurately without a biopsy. However, 77% of the patients had “probable” and 22% had “nondiagnostic” scores using the SDC system. In these 22% of patients, RDC scoring of histological features would be required for diagnostic accuracy. In the future, biomarkers specific for type 1 or 2 AIH may eliminate the need for a diagnostic biopsy. If that becomes possible, non-invasive tests for inflammation and fibrosis would suffice for detection of fibrosis stage and identification of patients with cirrhosis.

Presentation as acute liver failure or acute hepatitis Diagnostic criteria for AIH presenting as ALF have been proposed by the NIH Acute Liver Failure Study Group (Table 4) but have not been validated [41]. The criteria include the presence of autoantibodies and compatible histopathological features, especially central zonal necrosis and perivenulitis of the central vein. The essential role of histopathology in these proposed criteria requires a transjugular liver biopsy [41,75]. A retrospective report of clinicopathological features in

Farhad Sahebjam and John M. Vierling

9

Fig. 2 Diagnosis and treatment of autoimmune hepatitis. Abbreviations: RDC, revised diagnostic criteria [50]; SDC, simplified diagnostic criteria [51]. *Clinical trials in USA proved that azathioprine at a fixed dose of 50 mg/d was safe and effective when combined with prednisone to induce remission in AIH. Clinical trials in the European Union proved that azathioprine dosages of 1–2 mg/(kg$d) also were safe and effective when combined with prednisone to induce remission in AIH. Thus, both are evidence-based induction regimens [1]. ** Budesonide is appropriate only for patients without cirrhosis.

28 AIH patients admitted to hospital with severe acute hepatitis or ALF [81] showed that 100% had a positive ANA, 29% had a low titer of ≤ 1:40 and only 75% had an elevated IgG level. Histologically, 95% had necroinflammation and 86% had lobular hepatitis. Central zonal lesions, multilobular necrosis and lobular collapse were prominent. Seventeen patients (68%) responded to steroids, but 11 (32%) did not. Responders to steroids were younger and had more severe coagulopathy. The rapid deterioration of patients with ALF potentially caused by AIH often requires consideration of empiric steroid therapy before autoantibody test results return or a transjugular liver biopsy can be performed [82,83]. Reported outcomes for patients empirically treated with steroids vary. In a report of 9 patients, 4 responded and recovered, while 2 died and 3 underwent OLT [84]. No patient with a MELD score ≥ 28 responded to steroids in 2 other reports [83,85]. Another report concluded that steroid treatment was ineffective, unless total bilirubin and

coagulopathy stabilized or improved by day 3 of therapy [86]. Since infection is the major contraindication for OLT in patients with ALF, clinicians must weigh the increased risk of infection with steroid therapy against the potential benefit [82,83]. The above results indicate that steroids should be avoided in critically ill ALF patients in urgent need of OLT.

Presentation with extrahepatic immune disorders Patients with AIH may present with signs or symptoms of extrahepatic autoimmune or immune-mediated disorders [1]. Astute clinicians should assess liver enzyme and bilirubin levels when evaluating such patients. The spectrum of extrahepatic immune disorders includes: thyroiditis, hyperthyroidism, hypothyroidism, vitiligo, celiac sprue, diabetes mellitus, rheumatoid arthritis,

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Autoimmune hepatitis

Fig. 3 Histopathology of acute and chronic autoimmune hepatitis. (A) Photomicrograph showing lymphoplasmacytic portal inflammation and interface hepatitis in chronic autoimmune hepatitis. (B) Photomicrograph showing central zonal necrosis and perivenulitis of the terminal hepatic venule in acute autoimmune hepatitis.

mixed connective tissue disease, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, polymyositis, uveitis, sicca syndrome, systemic lupus erythematosus and ulcerative colitis. AIH may develop later, even in patients with established connective-tissue diseases [87]. Thus, serial monitoring of liver tests should be performed routinely in patients with diseases associated with AIH [87].

Concomitant autoimmune hepatitis and other chronic liver diseases AIH does not preclude the concomitant presence of or the future risk of acquiring a comorbid, chronic liver disease. In the USA, the increasing prevalence of obesity and the metabolic syndrome confer significant risks for nonalcoholic fatty liver disease, which can be associated with autoantibodies and portal inflammation [88,89]. Chronic HBV or HCV infections are particularly problematic because chronic viral hepatitis is exclusionary for AIH in either RDC or SDC scoring systems. Yet patients with AIH have risks for parenteral transmission of HBV or HCV infection similar to those in the general population. Expert interpretation of histology is essential in such patients, since grade 3 inflammation in chronic viral hepatitis denotes “interface hepatitis.” The issue of overlap syndromes of AIH and PSC or PBC is discussed later. Whether intense interface hepatitis in HCV infected

patients is caused by concurrent AIH was retrospectively studied [90]. In 92 patients with HCV infection, only 2% of biopsies had intense interface hepatitis and other histological findings typical of AIH. However, only 1% had a “definite” AIH score. Frequencies for autoantibodies in these 92 patients were low: ANA = 12%, SMA = 5% and LKM-1 = 0%. These results indicate that patients with chronic HCV infection and biopsy evidence of intense interface hepatitis are unlikely to have concomitant AIH. This has therapeutic importance for patients who are eligible for treatment regimens using pegylated interferon, which would be contraindicated by concurrent AIH [1,6]. The performance of the RDC and SDC scoring systems was assessed in a retrospective review of 25 patients with concurrent AIH and chronic HCV (n = 20, 80%) and HBV (n = 5, 20%) infections [76]. None of the patients were scored as “definite” using either RDC or SDC. The RDC scored 18 (72%) as probable, while the SDC scored 12 (48%) as probable. Each of the patients with AIH and HCV infection were sequentially treated with immunosuppression, followed by antiviral regimens with interferon once biochemical remission of AIH was achieved. In contrast, patients with AIH and HBV infection were treated first with oral antiviral agents and then with immunosuppression. In the era of direct acting antiviral regimens for HCV that do not require interferon, it is likely that HCV can be eradicated prior to using immunosuppression for AIH. De novo onset of AIH has been reported in patients with Alagille syndrome, cystic fibrosis or sickle cell hepato-

Farhad Sahebjam and John M. Vierling

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pathy, respectively [91]. Each patient was a young female presenting with acute icteric hepatitis, fatigue and abdominal pain. Unexplained onset or worsening of symptoms or development of jaundice in a patient with chronic liver disease requires consideration of AIH in the differential diagnosis. However, the frequency of diagnosing AIH in patients with other liver diseases would be expected to be quite rare. Acute HEV infections usually resolve spontaneously; however, chronic HEV infections have been reported in chronically immunosuppressed post-transplant patients [92,93]. To determine the serological prevalence of HEV infection in AIH, testing was performed in patients with AIH (n = 208), rheumatoid arthritis (n = 114), either chronic HCV or HBV infections (HCV-HBV, n = 109) and healthy adults (n = 537) [77]. AIH patients had a significantly higher prevalence of anti-HEV antibodies (n = 16, 7.7%) compared to healthy adult controls (n = 11, 2%), patients with rheumatoid arthritis (n = 4, 3.5%) and HCVHBV (n = 2, 1.8%). Only one immunosuppressed patient with AIH had an active infection with detectable HEV RNA, and the infection spontaneously resolved after reduction of the dosages of immunosuppressive agents. Importantly, 100% of the anti-HEV positive AIH patients had HEV-specific proliferative T cell responses, indicating prior HEV infection. These findings indicate that AIH patients with incomplete responses to immunosuppression should be tested for active HEV infection using PCR. Since DILI may mimic, trigger or unmask AIH, it must be considered in the assessment of concomitant diseases [29,30,43]. Complimentary and alternative medications have also been associated with AIH, and clinicians must inquire about them because patients often do no regard them as medications [29,30,43].

large cohort of patients with AIH at a single center, and associations with demographic, clinical, and laboratory features were analyzed [98]. HCC developed in 15 of 243 (6.2%) patients with type 1 AIH, which equated to 1090 cases per 100 000 patient follow-up years. HCC occurred in females and males in equal frequency (6.1% vs. 6.4%, P = 0.95). Risk factors for HCC included cirrhosis at presentation (9.3% vs. 3.4%, P = 0.048) or presentation with variceal bleeding (20% vs. 5.3%, P = 0.003). The median interval from confirmation of cirrhosis to diagnosis of HCC was 102.5 months (range, 12–195 months). In patients with HCC diagnosed by surveillance, the median survival was superior: 19 months (range, 6–36 months) compared with 2 months (range 0–14 months) for patients with symptomatic presentations (P = 0.042). The calculated incidence of HCC in AIH with cirrhosis was 1.1% per year and did not vary between men or women. The range of the annual incidence of HCC meets criteria for surveillance imaging of cirrhotic patients with AIH using ultrasound every 6 months [94,95,98]. Surveillance has been validated by evidence that patients with HCC detected using surveillance have greater life expectancy [98]. This follows from the fact that therapeutic options for HCC vary according to the size and number of lesions and whether or not metastatic disease is present. Early detection of HCC is critical for survival.

Hepatocellular carcinoma

Overlap syndromes

Cirrhosis, regardless of etiology, is a risk factor for development of hepatocellular carcinoma (HCC) [94,95]. The frequency of HCC in patients with cirrhosis due to AIH ranges from 1% to 9%, and the incidence is 1.1%– 1.9% per year [96]. The standardized incidence ratio (ratio of observed rate of HCC in AIH to the age-adjusted expected rate in the general population) in Sweden is 23.3 (95% CI 7.5–54.3). Significant risk factors include: cirrhosis for ≥ 10 years, decompensation with complications of portal hypertension, chronic hepatic inflammation and immunosuppression for ≥ 3 years. A Japanese national survey showed that HCC developed in 5.1% of patients with AIH [97]. The mean age at diagnosis was 69 years, the female to male ratio was 5.7:1 and the mean duration of AIH was 8 years. Cirrhosis was present in 78% and 62% were Child-Pugh class A. The incidence of HCC was prospectively evaluated in a

Patients with AIH and cholestatic features have characteristics of autoimmune diseases with cholestatic phenotypes, such as PBC or PSC [60,99,100]. Diagnosis of overlap syndromes of AIH with PBC or with PSC is problematic, and the criteria are controversial in the absence of validated diagnostic criteria or defined immunopathogenic mechanisms [60,61,101,102]. The IAIHG’s critical review of overlap syndromes concluded that current diagnostic criteria for overlap were arbitrary, lacked discriminated power and made inappropriate use of RDC and SDC scoring for the diagnosis of AIH [61]. They concluded that SDC scoring for diagnosis of AIH overlap syndromes had a low utility, which is contrary to the conclusion of another study [103]. The IAIHG recommended that patients with autoimmune liver diseases (AILDs) be classified as having AIH, PBC or PSC (including small duct variant) based on which was the predominant disease [61]. This recommendation is based on

Extrahepatic malignancies The most common extrahepatic malignancies in patients with AIH are non-melanoma skin cancers [96]. All immunosuppressed AIH patients should have annual skin examinations.

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the view that the AIH overlap syndromes are not defined pathological entities, and the dominant component of the disease should determine its diagnostic designation and therapy [99,100]. In AIH, cholestatic features alter the response to immunosuppressive therapy [60,99,100]. The central question is whether pathogenic mechanisms of each AILD are part of the continuum of mechanisms capable of producing all AILDs or whether overlap syndromes reflect sequentially acquired, distinct AILDs. Better understanding of the immunopathogenesis of each AILD is required to answer this fundamental question. AIH overlap syndromes should be considered in patients with cholestatic findings, those with incomplete responses to immunosuppression and in those with inflammatory bowel disease [60,99,100]. Despite the limitations of imprecise definitions, AIH overlap syndromes are encountered by clinicians and require diagnosis and therapy [60,99,100]. AIH-PBC overlap syndrome Criteria have been developed to aid in the diagnosis of AIH-PBC overlap; yet, no “gold standard” exists to validate the criteria [61]. A retrospective analysis of the Paris criteria [104] showed a sensitivity of 92% and specificity of 97% for the diagnosis of AIH-PBC overlap [105]. In accord with the IAIHG’s conclusions, the sensitivity and specificity of both the RDC and SDC were low. Based on publications in the MEDLINE database from 1984 to 2013, the frequency of AIH-PBC overlap ranged from 7% to 13% [100]. A retrospective, single center study assessed development of AIH during long-term follow-up of 1476 PBC patients and identified only 8 cases (0.54%) [101]. Among 16 Japanese patients with AIH-PBC overlap syndrome, evidence of PBC preceded development of AIH in 6 patients, and AIH and PBC were diagnosed simultaneously in the remaining 10 [106]. Thirteen of 16 responded well to combination therapy with immunosuppressive drugs and ursodeoxycholic acid, normalizing aminotransferase and alkaline phosphatase levels. The remaining 3 patients, treated with steroid or ursodeoxycholic acid monotherapy progressed to decompensated cirrhosis or died of liver-related causes after 5, 12 or 14 years of follow-up. Another retrospective study compared clinical, biological, and histological features and treatment responses in 115 consecutive patients with AIH (n = 48), AIH-PBC overlap syndrome (n = 15) or PBC (n = 52) diagnosed in 5 centers [107]. Patients with AIH-PBC were significantly younger than those with PBC (median age: 44 vs. 59 years). Overlap patients presented with cholestatic features of jaundice (20%) and pruritus (20%), and levels of aminotransferase and γ-globulin levels significantly higher than those in patients with PBC. Conversely, levels

Autoimmune hepatitis

of alkaline phosphatase, γ-glutamyl-transpeptidase and IgM were significantly higher in overlap patients than in patients with AIH. Liver biopsies in overlap patients showed interface hepatitis in 86% and destructive cholangitis in 93% of the overlap syndrome group. Only 6 of 11 overlap patients had complete responses to ursodeoxycholic acid or immunosuppressives alone, but all 7 patients treated with combination therapy responded: 5 to steroids-azathioprine-ursodeoxycholic acid and 2 to cyclosporine-ursodeoxycholic acid. A recent Japanese study reported the outcomes of PBC patients with features of AIH treated with steroids [108]. Among 280 PBC patients treated with ursodeoxycholic acid, 28 (10%, 26 women) had features of AIH (high levels of aminotransferases and IgG, ANA or SMA positivity and moderate to severe interface hepatitis or lobular hepatitis). Steroids were added to ursodeoxycholic acid in 20 of 28 patients; 15 responded and 5 did not. Factors predictive of failure to respond to steroids included high alkaline phosphatase levels, absence of SMA and positive gp210 autoantibodies. Steroid responders had an excellent prognosis, while the 8 ineligible for steroid treatment and the 5 non-responders to steroids had poor outcomes. Another retrospective study identified 12 patients with AIH-PBC overlap syndrome and 10 with AIH-PSC overlap syndrome [109]. Three patients with AIH-PBC overlap were treated with ursodeoxycholic acid alone and 9 received combination immunosuppression and ursodeoxycholic acid. During follow-up, 6 of the 12 patients progressed to liver failure (including patients treated with ursodeoxycholic acid with and without immunosuppression). A comparison of 26 patients with AIH-PBC overlap syndrome and 109 PBC patients without overlap showed that patients with overlap had worse outcomes [110]. Overlap was associated with significantly higher rates of portal hypertension (P = 0.01), esophageal varices (P < 0.01), gastrointestinal bleeding (P = 0.02), ascites (P < 0.01), death and/or OLT (P < 0.05). In addition to adverse outcomes, the AIHPBC overlap syndrome is more frequently associated with extrahepatic autoimmune diseases [111]. Assessment of 71 patients with AIH-PBC overlap syndrome showed that 31 (43.6%) patients had extrahepatic autoimmune diseases, including autoimmune thyroid diseases (n = 13, 18%), Sjögren syndrome (n = 6, 8%), celiac disease (n = 3, 4%), psoriasis (n = 3, 4%), rheumatoid arthritis (n = 3, 4%), vitiligo (n = 2, 3%), and systemic lupus erythematosus (n = 2, 3%). Autoimmune disorders, each occurring in a single patient (1.4%) included: autoimmune hemolytic anemia, multiple sclerosis, membranous glomerulonephritis, sarcoidosis, systemic sclerosis, antiphospholipid syndrome and temporal arteritis. Patients often had multiple autoimmune diseases: 40 patients (56%) had two, 23 (32%) had three and eight (11%) had four. These results indicate a need for screening for concomitant autoimmune diseases

Farhad Sahebjam and John M. Vierling

during follow-up and support the notion of diverse susceptibility to autoimmunity in AIH-PBC overlap patients. An increased frequency of HLA-DR7 in patients considered to have AIH-PBC overlap has been interpreted as evidence of susceptibility to overlap [112]. A recent cross-sectional study reported that Hispanic patients with PBC had a significantly increased prevalence of overlap syndrome compared with non-Hispanic PBC patients (31% vs. 13%; P = 0.002) [113], suggesting an ethnic predisposition. Immunohistochemical staining of plasma cells expressing IgG or IgM in liver biopsies has been proposed as an aid in the diagnosis of AIH-PBC overlap [114,115]. Plasma cells predominantly express IgG in AIH and IgM in PBC; thus, concurrent expression of both would suggest overlap. Unfortunately, results of staining for IgG and IgM in putative cases AIH-PBC overlap were inconsistent, and the specificity and sensitivity of immunostaining to detect AIH or PBC were low [114]. Importantly, PBC was exclusively associated with a ratio of IgG to IgM expressing plasma cells < 1, while a ratio > 1 was present in the patients with putative AIH overlap [115]. AIH-PSC overlap syndrome Review of the MEDLINE database from 1984 to 2013 indicated that 6% to 11% of AIH patients are reported to have features of PSC [60,100]. RDC scores were assessed in 211 PSC patients: 3 (1.4%) scored as “definite” AIH, 13 (6%) scored as “probable” AIH, and AIH was excluded in 195 (93%) [116]. Patients considered to have AIH-PSC overlap differed from those with PSC alone by having higher levels of total globulins (P = 0.01), IgG (P = 0.001), autoantibody titers (P < 0.001) and histological score (P < 0.001). In a study of 118 AIH patients, 24 (20%) with cholestatic liver tests were evaluated for possible PSC using magnetic resonance cholangiography [117]. These 24 patients had lower AST (P = 0.012) and higher IgM levels (P = 0.002) and some developed ulcerative colitis. AIH-PSC overlap was diagnosed in 12 of the 24 (10% of the 118 AIH patients). To evaluate the AIH-PSC overlap syndrome, 7 of 41 (17%) PSC patients fulfilling criteria for overlap were compared to the 34 “classical” PSC patients [118]. The overlap group significantly differed from the “classical” PSC group by having a lower mean age at presentation (21.4  5.0 vs. 32.3  10 years, P < 0.01), higher ALT (357  26.5 vs. 83.7  60.7 U/L, P < 0.005) and higher IgG level (25.6  4.7 vs. 12.9  6.0 mg/dl, P < 0.0001). During an average follow-up of 93 vs. 98 months, OLT was performed in 1 of 7 overlap patients and 6 of 34 PSC patients. Deaths and malignancies occurred exclusively in the “classical” PSC group. In a retrospective study of overlap syndromes, survival was significantly higher in the 10 patients with AIH-PSC overlap than in the

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12 patients with AIH-PBC overlap (90% vs. 50%, P = 0.045) [109]. The above findings support the conclusion that patients with AIH-PSC overlap syndromes and cholestatic AIH patients without diagnostic features of PSC should be treated with a combination of immunosuppressive therapy and ursodeoxycholic acid. However, it is important to note that the efficacy of combination therapy varies with the severity of cholestasis, ranging from 20% to 100% [99,100]. Variant AIH overlap syndromes Several variants of the overlap syndromes have been identified: small duct PSC, antimitochondrial antibodynegative PBC, autoimmune sclerosing cholangitis, IgG4associated secondary sclerosing cholangitis and IgG4associated AIH [60,119–121]. To study the possible pathogenic role of IgG4 in type 1 AIH [122], 60 patients meeting diagnostic criteria for AIH had IgG4 measured in the serum and IgG4-expressing plasma cells quantified within portal tracts. Elevations in serum levels and numbers of IgG4 expressing plasma cells were detected in 2/60 (3.3%). Steroid therapy normalized both ALT and histology, and serum IgG4 concentrations decreased. Five years later, 1 of the patients developed IgG4-associated secondary sclerosing cholangitis. Identification of these patients is important because of their responsiveness to steroid therapy and association with secondary, in contrast to primary, sclerosing cholangitis. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid has had variable efficacy; empiric cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients [60,100].

AIH and drug-induced liver injury Drug induced liver injury (DILI) has been associated with AIH, both as a mimic of clinical, biochemical and serological phenotype of AIH as well as a trigger of true AIH [29]. Contrary to the expectation that DILI might induce a type 2 AIH based on the metabolism of drugs by CYP isoforms, the vast majority of patients with AIH associated with DILI have type 1 disease. It is estimated that 9%–10% of patients with classical features of type 1 AIH may have DILI-related AIH [29]. DILI-related AIH caused by minocycline or nitrofurantoin account for 90% of current cases [29,30,123,124]. However, multiple drugs have been reported to cause AIH (Table 6). Complimentary and alternative medications associated with AIH include: melatonin and dai-taiko (da chai hu tang), glucosamine chondroitin sulfate, a combination herbal in Korea and green tea [3,24,27,28,125,126]. Standardized case definitions for AIH related to DILI have been proposed [127].

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Autoimmune hepatitis

Table 6 Prescription drugs reported to cause autoimmune hepatitis Prescription drug

Multiple reports?

Minocycline

Yes

Nitrofurantoin

Yes

Propylthiouracil

Yes

Diclofenac

Yes

Tienilic acid

Yes

Alpha-methyldopa

Yes

Stains

Yes

Pemoline

Yes

Ornidazole

Yes

Clometazine

No

Infliximab

Yes

Adalimumab

Yes

Natalizumab

No

Ramelton

Yes

All clinicians should report drugs or complimentaryalternative medications suspected of causing DILI to their national regulatory agency.

Management of autoimmune hepatitis The 2010 PG redefined remission in AIH as normal levels of AST, ALT, total bilirubin, γ-globulin or IgG and absence of inflammatory activity on liver biopsy (Table 1) [1]. Based on the 2002 PG of remission, approximately 80% of patients met criteria for “remission” within 3 years of immunosuppression, and approximately 20% of jaundiced patients failed to achieve remission and required alternative therapy or OLT [128]. Using the more stringent definition of remission in the 2010 PG would be expected to reduce the frequency of remissions using standard of care steroids and/or azathioprine. Conversely, it would likely increase the proportion of patients in need of alternative therapies to achieve remission. Prospective studies are needed to assess the impact of the clinical consequences of the 2010 PG. However, a retrospective report of 163 consecutive Italian AIH patients provided support for this expectation [129]. Using the 2002 PG criteria, 119 of the 163 patients (73%) achieved remission. As predicted, 36 of 66 patients (54.5%) whose AST/ALT did not normalize had histological progression during follow-up. Only 42 of 163 patients (26%) achieved remission using the stringent 2010 PG definition. During a mean follow-up of 8.33 years, AIH progressed in 1 of 23 patients (4%), which validated the central thesis of the 2010 PG that biochemical and histological normalization would result in absence or reduction of clinical progression. A combined retrospective-prospective study of the 2010 PG criteria proposed by the IAIHG aims to define the proportion of patients who achieve remission with steroids

and/or azathioprine, the proportion of patients placed on alternative immunosuppressive therapies and the frequency of remission on alternative therapies. Induction of immunosuppression Fig.2 shows 3 induction regimens for adults that have demonstrated safety and efficacy in AIH [1,130]. Prednisone monotherapy (or an equivalent doses of prednisolone), is particularly advantageous for patients with cytopenias, thiopurine methytransferase (TPMT) deficiency, pregnancy or malignancy. Azathioprine can always be added later in patients without contraindications to intensify immunosuppression and/or facilitate dose reduction of steroid to prevent adverse events associated with chronic steroid use. Induction with a combination of prednisone (or prednisolone) and azathioprine is the preferred regimen in the 2010 PG. Dosing of prednisone is identical in the US and EU combination regimens; however, they differ with respect to the dosing of azathioprine (Fig. 2). In the US regimen, azathioprine is initiated at a dose of 50 mg daily, regardless of body weight. In contrast, the EU regimen uses weight-based dosing of 1–2 mg/(kg$d). For a 70 kg patient, the azathioprine dose in the EU regimen would be at least 40% higher than the US regimen’s dose of 50 mg/d. Since randomized, controlled trials have shown that both are safe and effective, both regimens are evidenced-based. Increases in azathioprine dosages should be made in a step-wise manner to achieve optimal efficacy with the minimum effective dose. The upper limit should not exceed 2 mg/(kg$d). In patients who are not responding to azathioprine, it is important to ascertain compliance and perform TPMT testing for metabolites (see below). The combination steroid and azathioprine regimen is particularly suitable for patients benefited by reducing the dose of prednisone, such as patients who are post-menopausal or those having obesity, diabetes mellitus, hypertension, osteopenia, emotional lability or acne. Of note, a systematic review of randomized controlled trials of prednisone and azathioprine therapy showed that induction with prednisone alone or combination of prednisone and azathioprine achieved equivalent results [131]. However, the combination of prednisone and azathioprine was superior for maintaining remission. In addition, low dose maintenance with a combination of prednisone and azathioprine was equivalent to azathioprine monotherapy. The third induction regimen (Fig. 2), using a combination of budesonide and azathioprine [130] had not been published at the time the 2010 PG was developed. It is suitable only for non-cirrhotic patients and is discussed in detail below. The 2010 PG recommends that immunosuppression not be used in AIH patients with normal AST/ALT and γglobulin levels, mild portal inflammation without interface

Farhad Sahebjam and John M. Vierling

hepatitis, inactive cirrhosis or in those with significant contraindications for steroids. Steroids are also contraindicated for patients with brittle diabetes mellitus, uncontrolled hypertension, history of intolerance to steroids, osteopenic vertebral compression fractures and psychosis. Contraindications for azathioprine include TPMT deficiency, leukopenia or thrombocytopenia. Long-term steroid treatment requires maintenance of sufficient 25-OH vitamin D levels and adequate dietary or supplemental calcium intake. Baseline bone mineral densitometry should be performed to determine the risk of osteopenia or detect the presence of unsuspected osteopenia or osteoporosis. Patients with osteoporosis should be treated with vitamin D, calcium and a bisphosphonate. Long-term adverse effects of steroids are the primary reason for suboptimal immunosuppression of patients with AIH and failure to achieve and maintain remission. For non-cirrhotic patients, the results of the randomized, controlled trial of budesonide and azathioprine vs. prednisolone and azathioprine offer new hope. The third induction regimen [130] (Fig. 2) uses budesonide, a steroid that is avidly extracted from portal venous blood by the liver [6,132]. This first pass hepatic extraction significantly reduces entry of budesonide into the systemic circulation, minimizing the risk of steroid side effects [133]. In cirrhosis, unfortunately, abnormal hepatic metabolism and portal systemic shunting significantly reduce first pass hepatic extraction, and circulating budesonide can cause systemic steroid effects [134]. The results of a multicenter, randomized, controlled trial conducted in the EU showed that budesonide and azathioprine induced remission more effectively than prednisone and azathioprine for noncirrhotic patients with AIH [130]. The trial was conducted in 2 phases. The first phase was a 6-month prospective, double-blind, randomized, active controlled, multi-center phase 2b trial comparing budesonide 3 mg TID with prednisone 40 mg daily tapered to 10 mg daily in combination with azathioprine 1–2 mg/(kg$d). Neither budesonide nor prednisone was used as monotherapy. In the second phase, all patients received open label budesonide and azathioprine. The primary endpoint was a composite that included: (1) complete biochemical remission (normal AST /ALT levels) and (2) absence of predefined steroid-specific side effects at 6 months. A significantly higher proportion of patients treated with budesonide and azathioprine achieved the composite primary endpoint (47%) than did patients treated with prednisone and azathioprine (18.4%). At the end of 6 months, 60% of patients receiving budesonide and azathioprine had a complete biochemical remission compared to only 38.8% of patients treated with prednisone and azathioprine. Steroid-specific side effects occurred in only 28% of patients treated with budesonide, which was significantly lower than the rate of 53% in patients on prednisone. Steroid-specific side effects in

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patients treated with prednisone decreased significantly to 26.4% after being switched to budesonide. Thus, the combination of budesonide and azathioprine therapy induced and maintained remission in non-cirrhotic patients with AIH and minimized steroid-specific side effects. Evidence of reactivation of AIH in a patient treated with budesonide monotherapy illustrates the importance of combining budesonide with azathioprine [135]. Remission and withdrawal of immunosuppressive therapy The 2010 PG recommended that all adult patients be considered potential candidates for withdrawal of immunosuppressive therapy after achieving a sustained remission documented by normalization of biochemical tests and liver biopsy [1]. Permanent withdrawal of immunosuppression is a desirable outcome but has been achieved only in a minority of patients with AIH [136]. The risk of relapse after withdrawal of immunosuppression in AIH patients after ≥ 2 years of clinical and biochemical remission was studied retrospectively in 7 academic and 14 regional centers in the Netherlands [136]. A total of 131 patients met criteria for withdrawal of immunosuppression among 844 patients with AIH. During follow-up, 117 (89%) patients relapsed or lost remission during weaning. Sixty patients had fully discontinued immunosuppression, while 57 patients flared during withdrawal. Retreatment with immunosuppression was required in 59% 1 year after withdrawal, 73% 2 years after withdrawal and 81% 3 years after withdrawal. Risk factors for failure of withdrawal included previous combination therapy with steroids and azathioprine, concomitant autoimmune diseases and younger age at time of withdrawal. Reattempts to discontinue immunosuppression resulted in relapse. This retrospective analysis indicates that the occurrence of relapse is virtually universal. In contrast, a recent review of studies cited in PubMed from 1972 to 2014 for AIH treatment, relapse, remission and outcome reported that 19% to 40% of patients remained off immunosuppression for ≥ 3 years after withdrawal [137]. These patients were characterized by having complete normalization of laboratory tests and normal liver biopsies prior to drug withdrawal. However, liver biopsies reverted to normal in only 22% of patients during conventional corticosteroid therapy. Patients who developed cirrhosis during immunosuppressive therapy were prone to relapse after withdrawal of immunosuppression. Sustained remission is unlikely with < 12–24 months of therapy, and histological normalization may lag biochemical normalization by ≥ 8 months. Significant increases in AST/ALT while reducing doses of immunosuppression constitute a failure and full dose therapy should be restarted. Relapse after full withdrawal of immunosuppression requires retreatment, beginning with an induction regimen (Fig.2). Patients who

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fail multiple attempts to withdraw immunosuppression have increased rates of progression to cirrhosis (38% vs. 4%) and deaths due to liver failure or need for OLT (20% vs. 0%) [138]. Thus, reattempts to withdraw immunosuppression should be avoided. Achieving the 2010 PG goals of normalization of liver enzymes and liver histology during immunosuppressive therapy may increase the frequency of successful withdrawal. Testing for thiopurine methyltransferase and azathioprine metabolites Routine TPMT screening prior to treatment with azathioprine in AIH is not obligatory, since the frequency of severe TPMT deficiency is only 0.3%–0.5% in the general population and its presence does not universally result in azathioprine-induced bone marrow toxicity [139–141]. The presence of advanced fibrosis predicts the risk of azathioprine toxicity better than either TPMT genotype or activity [142]. Azathioprine is non-enzymatically converted to 6-mercaptopurine, and the subsequent metabolism of 6-MP by 3 enzymes determines the effectiveness of immunosuppression. The enzyme hypoxanthine phosphoribosyltransferase generates 6-thioguanine nucleotides (6TGN), which mediate immunosuppression. In contrast, the enzymes TPMT and xanthine oxidase enzymatically convert 6-MP to 6-thiouric acid and 6-methylmercaptopurine nucleotides (6-MMP), respectively. A study comparing TPMT activity with 6-TGN and 6-MMP showed that metabolite concentrations did not differ between patients in remission and those with active disease [143]. Checking the level of the immunosuppressive 6TGN is useful in monitoring compliance and can aid in the individualized dosing of azathioprine [144]. A minority of patients with poor clinical responsiveness to azathioprine have low levels of 6-TGN due to preferential metabolism of 6-MP by xanthine oxidase and formation of nonimmunosuppressive 6-thiouric acid. Addition of allopurinol to inhibit xanthine oxidase can restore immunosuppressive 6-TGN to effective levels [145]. Thus, the results of TPMT testing should be assessed before concluding that an individual is a non-responder to azathioprine. In Native Alaskan Americans and other non-Caucasian patients with AIH, 6-TGN and 6-MMP levels correlated with the dose of azathioprine only when TPMT enzyme activity was normal [146]. The frequency of normal TPMT enzyme activity was similar in patients with azathioprineinduced leukopenia and in patients without leukopenia. Patients with modestly decreased TPMT activity (usually heterozygotes) can tolerate doses of azathioprine of 50 – 150 mg/d. Treatment of overlap syndromes As noted above, a minority of patients have overlap

Autoimmune hepatitis

syndromes with AIH-PSC overlap being much more common than AIH-PBC overlap. Treatment of patients with mixed hepatocellular-cholestatic biochemical patterns (i.e., patients with true or suspected overlap syndromes) has been empiric, as discussed in detail above. AIH patients with cholestatic features or those suspected of AIH-PBC or AIH-PSC overlap syndromes have had ursodeoxycholic acid added to their immunosuppressive regimens [60,61,99,109,147,148]. However, the use of ursodeoxycholic acid in this setting is not evidenced-based [60,99]. Conversely, immunosuppressive therapy is often used for patients with PBC or PSC who have features of AIH, again in the absence of proven efficacy [60,61,99]. Clinicians must remember that PBC is associated with AMA, ANA and SMA autoantibodies; thus, clinicians must not misinterpret the presence of ANA or SMA as evidence of AIH overlap [60]. Clinicians must also know that the natural histopathological progression of PBC includes a phase of interface hepatitis, and its presence is not diagnostic of AIH overlap [149,150]. Finally, it is noteworthy that steroids can be efficacious in PBC [151], while azathioprine is not [152]. Conventional immunosuppressive therapy is associated with a higher frequency of drug-induced complications in patients with cirrhosis (25%) than in patients without cirrhosis (8%) [1]. Hypersplenism with cytopenias may contraindicate the use of azathioprine, favoring prednisone monotherapy for initiation (Fig. 2). Budesonide cannot be used in cirrhotics because of ineffective metabolism and portal systemic shunting [130,134]. Patients with cirrhosis and cytopenias should have TPMT testing prior to initiation of azathioprine to ensure safety. Before concluding that a patient is unresponsive to azathioprine, TPMT testing for azathioprine metabolites should be performed. Two centers have reported retrospectively their experiences with treatment regimens using mycophenolate mofetil (MMF; see “Alternative immunosuppressive therapies” below) in patients with AIH overlap syndromes. MMF therapy in 16 patients with AIH or AIH-PBC or AIH-PSC overlap syndromes resulted in 5 (31%) achieving biochemical remission according to the 2002 PG, while 7 (44%) had partial remission, 2 (12.5%) had incomplete responses and 2 (12.5%) had treatment failure [153]. MMF had been used instead of azathioprine due to intolerance to azathioprine, failure to respond to prednisone plus azathioprine or physician preference. The Dutch Autoimmune Hepatitis Group cohort assessed the efficacy of MMF as second line treatment for azathioprine intolerance or nonresponse in 45 patients with AIH or AIH overlap syndromes [154]. In AIH overlap syndromes, rates of remissions or responses induced by MMF were 57% vs. 14% in patients nonresponsive to azathioprine and 63% vs. 25% in patients intolerant of azathioprine. Adverse events occurred in 33% and 13% discontinued MMF. Decompensated cirrhosis, OLT and death occurred exclusively

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among AIH patients nonresponsive to azathioprine. Randomized, controlled trials enrolling patients with well established clinical phenotypes are required to define the role of MMF therapy in either AIH or AIH overlap syndromes.

Management of autoimmune hepatitis in pregnancy Pregnancy in women with AIH occurs, including in some with cirrhosis. It represents a therapeutic challenge because the clinician is responsible for the health of both the woman and her fetus. AIH influences the outcomes of pregnancy, and, conversely, pregnancy also affects AIH [155]. Thus, all pregnancies in women with AIH must be regarded as high risk pregnancies and followed closely by skilled obstetricians. In unplanned pregnancies, conception and embryogenesis often occur during treatment with azathioprine, raising the prospect of teratogenicity. One Swedish study investigated how women with AIH contemplate pregnancies, how they are advised by physicians, how they are pharmacologically treated during pregnancy and what are the outcomes [156]. A questionnaire was mailed to 128 women with AIH diagnosed during their childbearing years and data from the Swedish National Birth Register was obtained for matched controls. Responses were obtained from 106 women with AIH (83%), and 35 women reported having 63 pregnancies. Fifty-one women (48%) did not consult a physician prior to pregnancy. Over 50% of the women reduced or stopped their immunosuppression during pregnancy or during breastfeeding. Some had been advised to abstain from pregnancy or have an abortion. Women with AIH had a higher rate of Caesarean sections than the matched controls: 16% vs. 6.5%, P < 0.01. No significant differences were noted between the 2 groups with respect to the number of stillborns or neonates with congenital malformations. Postpartum flares of AIH occurred in 32 women. In general, the outcomes of the pregnancies were favorable, and immunosuppressive therapies, including azathioprine, at the time of conception appeared to be safe. Better communication between women with AIH who are planning to become pregnant and their physicians might improve outcomes and prevent postpartum flares associated with ineffective dosing of immunosuppression. Several studies have provided important data regarding the course of AIH in pregnant women and the outcomes of their pregnancies. A retrospective study in 4 liver centers sought to identify AIH-related risk factors for adverse outcomes in 42 pregnancies in 22 women with AIH [155]. Adverse outcomes of pregnancy occurred in 11 (26%) pregnancies; however, a medical cause was identified in only 4 of the 11 pregnancies. Serious maternal complications occurred in 4 pregnancies (9%). An interesting

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feature of the 7 women with unexplained adverse outcomes was a high frequency of anti-SLA/LP (OR 51; P < 0.003) and Ro/SSA (OR 27; P < 0.02). Postpartum flares of AIH occurred in 22 of the pregnancies (52%). There were 35 live births, and 32 infants survived. Childhood development was normal in 30 of the 32 of the surviving infants that during observation for nearly 5 years. The two infants with abnormal development included one with Smith-Lemli-Opitz syndrome (autosomal recessive disorder of cholesterol metabolism) and one with spastic quadraparesis complicating preterm delivery. Eleven of these children had been exposed to azathioprine in utero. Prospective studies are needed to determine whether anti-SLA/LP or Ro/SSA autoantibodies represent biomarkers of risk for adverse outcomes. A single center analysis sought to identify pre-conception factors predictive of adverse outcomes in pregnant women with AIH [157]. They studied 81 pregnancies in 53 women, and 33 pregnancies (41%) occurred in women with cirrhosis. At conception, 61 patients (75%) were being immunosuppressed for AIH. Live births occurred in only 59 of the 81 pregnancies (73%). Twelve of the 59 live births (20%) were premature, and 6 of the 59 neonates (11%) required intensive care. The live birth rate in mothers with cirrhosis at the time of conception was significantly lower (P = 0.02) and the need for neonatal intensive care was higher. Maternal complications occurred in 31 of the 81 pregnancies (38%). AIH flared in 26 of the 81 (33%) pregnancies. Serious maternal adverse events of death or need for OLT occurred in 9 of 81 pregnancies (11%) either during the pregnancy or ≤ 12 months postpartum. Hepatic decompensation during pregnancy or ≤ 3 months postpartum was significantly more common in women with cirrhosis (P = 0.028). Immunosuppressive therapy did not significantly impact the rate of live birth, elective abortion, miscarriage rate or duration of gestation. However, flares of AIH were more common in women who were off immunosuppressive therapy (P = 0.048) or women who had had a flare of AIH during the year prior to conception (P = 0.03). Hepatic decompensation occurred significantly more often in women with a flare of AIH during pregnancy (P = 0.01). Another retrospective analysis of 54 pregnancies (3 ongoing at the time of publication) in 39 women with AIH patients was performed to assess clinical management and maternal and fetal outcomes [158]. Cirrhosis was present in 27 of the women at conception (68.4%). Prior to conception and during the first trimester, 19 (48.1%) were being treated with prednisone and azathioprine. When pregnancy was identified, 11 patients (80%) discontinued azathioprine and switched to prednisone monotherapy, while 8 patients (20%) stopped immunosuppression. Fetal loss occurred in 15 pregnancies (29.4%, 13 miscarriages, 1 still birth, 1 ectopic pregnancy). There were 36 live births (67%), and 12% were premature births. Acute fetal distress

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occurred in 2 pregnancies, and 2 neonates had congenital malformations (4%). However, there was no clear relationship between azathioprine use and either premature birth or congenital malformations. Serious maternal complications occurred in 7.8%; none was fatal. Only 41% of pregnancies were free of flares; ALT elevations occurred in 55% with postpartum flares of AIH in 31.4%. The issue of the safety of azathioprine at the time of conception and during pregnancy was investigated by determining the intrauterine exposure to maternal azathioprine [159]. Three women with AIH and Crohn’s disease were treated with azathioprine throughout their pregnancies. 6-TGN and 6MMP metabolites of azathioprine were measured in the mother and neonate immediately after delivery. Immunosuppressive 6-TGN metabolites were present in both mother and neonate, and the concentrations were slightly lower in the neonate than the mother. No 6-MMP metabolites were detected in the neonates, indicating that the placenta restricts intrauterine exposure to 6-TGN metabolites. Another study of 14 pregnancies in 5 women with AIH and 1 with AIH-PSC overlap syndrome reported that AIH improved markedly in the second trimester of pregnancy, permitting decreased dosages of immunosuppressive therapy [160]. Azathioprine appeared to be safe during pregnancy. After delivery in 13 pregnancies or stillbirth in 1, AIH flared in 12 instances. These findings indicated a need for preemptive increases in the doses of immunosuppressive drugs soon after delivery. The phenomenon of AIH first presenting in the early postpartum period was assessed in a case series of 5 women who developed severe AIH ≤ 4 months postpartum [161]. All patients met diagnostic criteria as “definite” AIH. All patients achieved remission using conventional immunosuppressive therapy. Clinicians should be suspicious of AIH in any postpartum woman presenting with clinical or laboratory evidence of hepatitis. The cumulative results of studies of AIH and pregnancy lead to several firm conclusions. First, the optimal outcome of an elective pregnancy requires that AIH be well controlled for at least 1 year before conception. Second, all pregnancies in women with AIH must be regarded as high risk and need the attention of knowledgeable obstetricians. Thus, all women with AIH should be treated with immunosuppression during pregnancy. While azathioprine appears to be safe, the more judicious approach would be prednisone monotherapy. There are no data regarding the safety and effectiveness of budesonide, and the randomized, controlled trial indicating safety and efficacy was conducted with coadministration of azathioprine [130]. Fourth, the risk of postpartum flares of AIH is substantial and warrants careful monitoring and increased dosages of immunosuppression postpartum. This may be achieved by resuming azathioprine, although its safety in breast feeding is unknown. Fifth, all women of

Autoimmune hepatitis

childbearing age should be informed of the potential for adverse outcomes of pregnancy in AIH. Finally, effective birth control should be provided to women with AIH to prevent unplanned pregnancies.

Alternative immunosuppressive therapies Alternative immunosuppressive therapies should be used to achieve remission in AIH patients who fail to respond to conventional immunosuppression or are ineligible for or cannot tolerate steroids or azathioprine (Fig.2). Publications, comprised of anecdotal reports and small series of highly selected patients, have reported the safety and efficacy of 6-mercaptopurine (6-MP), cyclosporine (CSA), tacrolimus (TAC), sirolimus, mycophenolate mofetil (MMF) or mycophenolic acid (MA), ursodeoxycholic acid, methotrexate, cyclophosphamide, anti-TNFα agents, rituximab and abatacept as alternative therapies in AIH. The details of these alternative therapies have been the subject of recent reviews [6,120,131,133,147,162–176]. To date, no randomized controlled trials of alternative therapies in AIH have been conducted. As discussed earlier, the proportion of patients requiring alternative therapies will be expected to increase using the more stringent definition of remission in the 2010 PG. Prospective studies are required to determine the precise proportion of newly diagnosed patients who achieve remission according to the 2010 PG. Before resorting to alternative therapies, however, it is important that clinicians note that the 2010 PG recommended that non-responders to conventional immunosuppression be treated with a course of intensified conventional therapy. Clinicians can choose between two intensified regimens: (1) prednisone 60 mg/d; or (2) prednisone 30 mg/d and azathioprine 150 mg/d. Azathioprine is the prodrug of 6-MP; thus, 6-MP may be more effective than azathioprine in some patients and should be considered before abandoning azathioprine. Failure to achieve normalization using either regimen indicates a need for alternative therapies. TPMT testing should be performed in patients with an inadequate response to azathioprine to detect non-compliance and potential need for allopurinol (see above). Ursodeoxycholic acid and budesonide as alternative therapies Randomized, controlled trials have shown that neither ursodeoxycholic acid nor budesonide is an effective alternative therapy for patients refractory to or intolerant of standard immunosuppression [177,178]. The lack of effect is not unexpected for ursodeoxycholic acid, since it is a very weak immunosuppressant. Similarly, budesonide’s ineffectiveness should be expected, since it acts on

Farhad Sahebjam and John M. Vierling

the same corticosteroid receptors stimulated by prednisone and prednisolone. Mycophenolate mofetil or mycophenolic acid Mycophenolate mofetil (MMF) is a prodrug that is converted to mycophenolic acid (MA) in the liver. Both MMF and MA are approved for use as immunosuppressive medications for recipients of solid organ transplants. Both MMF and MA are attractive alternatives to azathioprine because their antiproliferative effects are more lymphocytepecific for B and T cells than those of azathioprine [179]. In a retrospective report of 21 patients treated with MMF (12 (57%) for treatment failure and 9 (43%) for drug intolerance) sustained remissions occurred in 8 (88%) of the 9 patients with drug intolerance but in none (0%) of the 12 treatment failure patients [179]. In another series, 29 patients received MMF (12 were switched to MMF for intolerance or nonresponse to prednisone and azathioprine, and 17 received MMF with or without prednisone as initial therapy [180]. Ten of the 29 treated with MMF therapy (34%) discontinued MMF due to adverse events. Sixteen (84%) of the remaining 19 treated patients achieved remission using the 2002 PG definition. A small study compared the outcomes of 8 patients treated with MMF for 19  7 months as initial therapy or after adverse events on conventional steroid treatment with those of 17 patients treated with high-dose steroids after treatment failure [181]. Remission based on 2002 PG criteria was achieved in only 64% on MMF compared to 100% of patients treated with intensive steroids. Normalization of laboratory tests occurred in none of the patients treated with MMF and in 6 (35%) of the steroid treated patients. Steroids could not be withdrawn in the patients treated with MMF but withdrawal was achieved in 7 (41%) of the comparison group. None of the patients treated with MMF had histological resolution and 2 patients had progressive fibrosis. Thus, MMF did not induce laboratory resolution, prevent progressive fibrosis, or allow steroid withdrawal. The Dutch Autoimmune Hepatitis Group cohort ranked the efficacy of MMF as second line treatment for azathioprine intolerance or nonresponse in AIH or AIH overlap syndromes [154]. In AIH, remission or response was achieved in only 13% vs. 27% in patients unresponsive to azathioprine compared to 67% vs. 0% in those with azathioprine intolerance (P = 0.008). The multicenter Canadian experience with MMF in AIH patients who had not responded to or were intolerant of conventional immunosuppression reported results in 11 patients [182]. Complete sustained normalization of aminotransferases occurred in 7 (64%). Another retrospective study reported outcomes of 15 AIH patients treated an average of 41 months with MMF (monotherapy or in combination with prednisone) after failure or intolerance [183]. ALT levels, histological inflammatory scores and Ishak fibrosis scores

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significantly decreased without serious side effects. More data are required to identify the characteristics of patients who may benefit from MMF therapy. However, current data indicate that MMF or MA may not be effective in AIH patients who are nonresponsive to azathioprine. Conversely, MMF and MA are more likely to be effective in patients intolerant of azathioprine. Cyclosporine and tacrolimus Both calcineurin inhibitors, cyclosporine (CSA) or tacrolimus (TAC), are beneficial alternative therapies and have been endorsed by the 2010 AASLD PG [1, 147, 167, 168]. Both CSA and TAC inhibit the calcineurin-dependent pathways required to generate nuclear factor for activated T cells (NFAT). NFAT promotes transcription and translation of the potent T cell mitogen IL-2 and other growth factors. Thus, calcineurin inhibition prevents activation and maturation of deleterious effector mechanisms of CD4 and CD8 effector T cells in AIH. Cyclosporine Several reports of empiric therapy indicate that CSA is efficacious and safe when used as an alternative therapy for AIH in adults. A retrospective study reported the efficacy and safety of CSA therapy (3mg/(kg$d)) in 4 adult patients with type 1 AIH (one with a possible AIH-PSC overlap syndrome) who had failed treatment with steroids or steroids and azathioprine [184]. All 5 had experienced significant side effects with conventional immunosuppressive therapy. ALT normalized or nearly normalized in 5 (83%) within 10 weeks with CSA trough level targets of ~200 ng/ml. All responders achieved sustained biochemical remissions for periods of up to 1 year. Liver biopsies were performed in 3 patients who responded to CSA, and all showed histological improvement. In addition, symptoms improved in all responders. Adverse events occurred in 33%. Another study described the outcomes of 5 adult AIH patients treated with low dose CSA (2–3 mg/(kg$d)) (compared to induction dosing of 4 mg/(kg$d) in solid organ transplantation) after they had failed to respond to conventional steroids and azathioprine [185]. The dosage of CSA was reduced after achieving biochemical remission, usually with trough levels of 100–200 ng/ml. Liver tests normalized in 4 (80%) within 3 months, fulfilling the 2010 PG definition of remission. One of the responders relapsed twice within 1 month of discontinuing CSA, but liver tests normalized promptly after resumption of CSA. Two maintained remission on CSA monotherapy. The patient who failed to respond underwent OLT. CSA was generally well tolerated, and no renal insufficiency occurred. In another retrospective review 12 patients were treated with CSA: 8 patients with AIH, 2 with

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autoimmune cholangitis and 2 with giant cell hepatitis [186]. CSA was used in 4 with treatment failure and in 8 who refused steroids or had steroid contraindications. CSA was administered for a mean of 35.6 months (range, 8–89 months), and the median follow-up was 6.5 years (range, 1.5–15 years). All patients achieved complete remission in a median of 4.5 weeks (range, 2–12 weeks). Three patients with severe liver impairment were treated with a combination of CSA and conventional immunosuppression. CSA was well tolerated, and no patient discontinued CSA due to side-effects. One patient had transiently elevated serum creatinine. In another series, 19 AIH patients (9 treatment-naïve, 10 non-responders) were treated with low dose CSA in an open label trial for 26 weeks [187]. Four patients did not complete therapy. The mean ALT level decreased from 454.8  354 to 78.5  40.3 (P < 0.001). The hepatic activity index of inflammation on liver biopsy decreased from 15.2  3.16 to 7.14  4.01 (P < 0.005). Serum creatinine levels did not increase. Overall, the empiric, uncontrolled experiences with CSA therapy for AIH patients, especially those failing to respond to conventional steroids and azathioprine, indicate that CSA is a safe and effective alternative therapy [171,188–192]. A potential advantage of CSA is that it has a wider therapeutic range of effective serum concentrations than tacrolimus, which facilitates adjustment of doses to achieve maximum efficacy with optimal safety. Tacrolimus Tacrolimus (TAC) has also been used empirically to treat patients with AIH who failed to respond to or were intolerant of conventional immunosuppression [163,169– 171,188,190–192]. In one case series, full dose TAC (6 mg/d) was used as initial therapy for 21 adults with AIH [193]. The dose of TAC was adjusted using plasma trough levels. After 3 months of TAC and a median serum trough level 0.5 ng/dl, the ALT levels were reduced by 80%. Modest changes in the leukocytes and platelet counts were observed. TAC caused mild azotemia with increases in median BUN level from 12 to 18 mg/dl and serum creatinine from 0.9 to 1.3 mg/dl. No significant adverse events occurred. A retrospective study evaluated the efficacy of very low dose TAC (1 mg/d) in 11 adult patients with steroid refractory AIH [194]. The median duration of steroid treatment prior to TAC was 9 months. The median duration of TAC therapy was 25 months, and the median follow-up was 16 months. Median baseline levels of ALT decreased significantly from 77 U/L to 21 U/L at end of follow-up (P = 0.005). TAC also induced histological remission. Low dose TAC was also safe and well tolerated. Retrospective analysis of 222 patients with AIH at a single center identified 13 with type 1 AIH who

Autoimmune hepatitis

were treated with TAC at doses of 2–6 mg/d with average TAC serum trough levels of 6 ng/ml [195]. Histologically, 36% had cirrhosis, 58% had bridging fibrosis and 60% had confluent multilobular necrosis. ALT and AST normalized in 12 (92%) during treatment, which ranged from 1 to 65 months. One patient developed hemolytic uremic syndrome after 4 weeks and discontinued TAC; another patient discontinued TAC after 12 months due to squamous cell carcinoma. The multicenter Canadian retrospective study reported only 3 patients treated with TAC monotherapy and 2 with the combination of MMF and TAC [182]. TAC doses varied from 1 to 4 mg/d. Only 1 of the 5 patients (20%) had a biochemical response, and 1 had adverse events. Another single center study reported the outcomes of 9 patients treated with low dose TAC (2 mg/d) for steroid refractory AIH. The median duration of TAC treatment was 18 months (range, 12–37 months). Patients had been maintained previously on prednisolone at doses of 20–80 mg/d, but TAC allowed reduction to 7.5 (5–12.5) mg/d (P = 0.004). ALT levels decreased significantly during TAC therapy (P = 0.007) from 154 U/L (range, 100–475 U/L) to 47 U/L (22–61 U/L). IgG levels also fell significantly (P = 0.032) from 16 g/L (range, 10–30 g/L) to 14.5 g/L (range, 8.4–20 g/L). Histological improvements were noted in hepatic inflammatory activity (P = 0.016), and the Ishak fibrosis score (P = 0.049). The cumulative reports indicate that low dose TAC therapy can result in biochemical and histological remissions as initial therapy or as alternative therapy for steroid and azathioprine refractory AIH. Low dose TAC therapy also permitted steroid dose reductions in patients requiring high doses. Despite the fact that CSA and TAC have been used empirically since the 1990s, no multicenter, randomized controlled trials of these drugs have been conducted in AIH patients. Randomized, controlled trials of calcineurin inhibitors will require a multicenter, international approach. However, the advent of the 2010 PG definition of remission should increase the proportion of patients considered failures with conventional steroid and azathioprine therapy, which would correspondingly make enrollment of such studies practical. Impediments to such randomized, controlled trials include differences of opinion about which alternative therapies should be studied, the design of studies (e.g., addition of investigational drug to standard of care therapy vs. substitution of standard of care therapy), concern that patients in need of alternative therapy might be disadvantaged were they to be randomized to the control group, and the complexity and cost of conducting a multinational, multicenter study. Currently, the International Autoimmune Hepatitis Group is creating a database of all patients treated with alternative immunosuppression to assess anecdotal outcomes on different regimens to aid in design of future multicenter pivotal trials of alternative therapies.

Farhad Sahebjam and John M. Vierling

Sirolimus Sirolimus and everolimus inhibit the mammalian target of rapamycin (mTOR), preventing its activation by mitogenic IL-2 signaling through its T cell receptor (CD25). Inhibition of the mTOR activation pathway can prevent proliferation and maturation required for the deleterious actions of CD4 and CD8 effector T cells in AIH [1,147,167,168]. Based on the mechanisms of action, the option exists to use calcineurin and mTOR inhibitors concurrently; however, no reports of combined use have been published. Sirolimus and everolimus immunosuppression protects renal function in recipients of solid organ transplants; thus, they have a role alone or in combination with reduced doses of calcineurin inhibitors in the prevention of chronic renal insufficiency. Since low dose calcineurin inhibition is sufficient for the treatment of AIH and does not compromise renal function, little need exists for sirolimus or everolimus. Sirolimus and everolimus have been used successfully in the treatment of recurrent AIH or interferon-induced AIH after OLT (see below) [196,197]. Methotrexate Methotrexate inhibits the metabolism of folic acid, resulting in antiproliferative effects on lymphocytes in immune-mediated and autoimmune diseases. In 1998 the successful use of methotrexate was reported in a middleaged woman presenting with jaundice and type 1 AIH. Liver enzymes normalized, and histology improved on a dose of 7.5 mg per week. In 2011 a case of AIH in an adult on long-term methotrexate for rheumatoid arthritis was reported [198]. The authors speculated that AIH developed as a result of a breakdown of immune tolerance induced by methotrexate. Other reviews have focused on evidence of hepatotoxicity of methotrexate in patients treated for inflammatory bowel disease [199]. Overall, there are no compelling data to justify methotrexate as an alternative treatment when better agents are available. Rituximab Rituximab is a monoclonal antibody against the CD20 molecule expressed on the surface of mature B cells. It is extensively used to deplete B cells in the treatment of B cell lymphomas and to treat antibody-mediated autoimmune diseases. A recent, open-label, single-center pilot study was performed to assess the safety and efficacy of rituximab in AIH patients refractory to standard immunosuppression [173]. Six patients with AIH who had failed prednisone and azathioprine treatment received 2 infusions of rituximab two weeks apart. Rituximab was well tolerated and no serious adverse events occurred. By week 24, mean (  SD) levels of AST significantly

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decreased (90.0  23.3 U/L vs. 31.3  4.2 U/L; P = 0.03). Mean levels of IgG decreased but the difference was not statistically significant (16.4  2.0 g/L vs. 11.5  1.1 g/L; P = 0.056). Three of 4 were successfully weaned off prednisone; AIH flared during prednisone taper in one patient. Repeat liver biopsies at week 48 showed improved inflammation in all 4 patients. FoxP3-positive Tregs decreased in parallel with reduced hepatic inflammatory activity in the follow-up biopsies. No significant changes were noted in serum levels of chemokines or cytokine levels from baseline to week 24. Several individual case reports of empiric rituximab use in AIH also indicated that it was well tolerated and improved liver enzymes but the reduction of immunoglobulins increased the risk of infections. A middle-aged woman with AIH-PBC overlap syndrome entered remission using prednisone and azathioprine [200]. She appeared to relapse on therapy, but did not respond to intensified prednisone, azathioprine or MMF. Shortly thereafter she developed autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura consistent with Evans syndrome. She was treated with rituximab and MMF was discontinued. Liver enzymes significantly improved after only one infusion of rituximab, and Evans syndrome completely resolved with normal hemoglobin and platelet levels after 4 doses. Aminotransferase levels decreased to < 2  the upper limit of normal. Rituximab was successful in another woman with AIH and concomitant idiopathic thrombocytopenic purpura that were non-responsive to steroids [201]. Her platelet count rapidly improved and liver enzymes normalized without relapse over the next 5 months. Another woman with AIH and a history of B cell lymphoma was successfully treated with rituximab [202]. She had failed to respond to steroid before being treated with rituximab for 8 weeks. On rituximab both liver enzymes and histological findings marked improved. An elderly woman with progressive AIH despite high-dose prednisone was also treated with rituximab [203]. She experienced rapid clinical and biochemical improvement. These results support further investigation of rituximab as a treatment for AIH, especially in patients with concurrent antibody-mediated autoimmune diseases, such as autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura. Prospective randomized studies of rituximab are unlikely to be performed due to the high response rates observed for other therapies. Infliximab Infliximab is a monoclonal antibody directed against TNFα that has been used in the treatment of immune-mediated inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and psoriasis. It has also been used successfully as rescue therapy in refractory AIH

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[204,205]. Infliximab induced remission in a young woman with AIH and Still’s disease who was refractory to steroid therapy [205]. A single center successfully used off-label infliximab as an alternative therapy for 11 AIH patients who failed to achieve remission with standard immunosuppression. Infliximab (used for a minimum of 6 months) significantly decreased AST levels from a pretreatment mean of 475  466 U/L to a mean during treatment of 43  32 U/L [204]. Similarly, mean pretreatment levels of IgG fell from 24.8  10.1 mg/dl to a mean during treatment of 17.38  6 mg/dl. Seven of 11 (64%) experienced infectious complications. Overall, the published results indicate that infliximab can be considered as an alternative theapy for AIH patients who do not achieve remission with standard therapy. However, the clinician must be aware of the high rates of infections and institute careful monitoring of patients on therapy. Of significant concern are multiple reports indicating that infliximab therapy may actually trigger de novo onset of AIH or a disease closely resembling it. The reported characteristics included female predilection, positive ANA and anti-double-stranded DNA autoantibodies resembling systemic lupus erythematosus [206–208]. Whether infliximab induces AIH remains controversial [209], especially in light of recent reports of its efficacy as an alternative therapy for refractory AIH [204,205]. Clinicans using infliximab should be aware of the potential for an AIH-like complication and monitor liver enzymes to detect it. Prospective clinical trials are needed, not only of alternative immunosuppressive therapies but also of regimens of prednisone and azathioprine optimized to achieve normal aminotransferase levels. Randomized, controlled clinical trials of alternative therapies are desireable; however, the low prevalence of refractory AIH will likely necessitate multicenter, multinational designs with high financial costs.

Orthotopic liver transplantation OLT is performed for the indication of AIH in approximately 4% of adults in the US and Europe [4,210]. OLT is indicated in AIH for patients with ALF, decompensated cirrhosis with MELD scores ≥ 15 and patients with hepatocellular carcinoma who meet criteria for OLT. The therapeutic goal of the 2010 PG was to reduce the need for OLT using either conventional or alternative therapies to achieve complete biochemical and histological remission to prevent progress to cirrhosis or to prevent decompensation of established cirrhosis [1]. OLT remains necessary for AIH patients presenting with ALF due to insufficient time to properly diagnose and assess responses to immunosuppression. Other factors contribute to the need for OLT in AIH, including failure to diagnose and treat AIH (especially patients with compensated cirrhosis), noncom-

Autoimmune hepatitis

pliance with or intolerance of immunosuppression, inadequate response to conventional immunosuppression, reluctance to use alternative immunosuppression or failure of alternative therapies. OLT for AIH is associated with excellent 5-year and 10year survivals of > 70% [4,210]. Analysis of the European Transplant Registry showed that the 5-year survival of patients undergoing OLT for AIH (n = 827) was 73% (95% CI, 67%–77%) [210]. While this survival was comparable to that of patients undergoing OLT for alcoholic cirrhosis (n = 6424) of 74% (95% CI, 72%– 76%), it was significantly inferior to the survival of patients undergoing OLT for PBC (n = 1588) of 83% (95% CI, 80%–85%). An increased rate of fatal infections in patients transplanted for AIH (compared to those transplanted for PBC) contributed to a decreased survival in AIH (HR, 1.8, P = 0.002). The age of patients with AIH at the time of OLT was inversely related to post-OLT survival. The 5year survival of AIH patients transplanted after 50 years of age was only 61% (95% CI, 51%–70%), which was significantly lower than the 5-year survival of adults 18– 34 years of age transplanted for AIH of 78% (95% CI, 70%–86%). Recurrent autoimmune hepatitis after transplantation AIH can recur in the transplanted donor allograft, despite the absence of intentional HLA matching between donor and recipient in OLT [4,211,212]. The occurrence of AIH in a recipient mismatched for the HLA alleles of the donor allograft appears to violate the dictum that autoreactive T cells are restricted to autoantigens presented by self-HLA molecules on hepatocytes [213,214]. This raised the possibility that AIH post-OLT represents a different disease or results from alternative pathogenic mechanisms than those of the original disease. However, the repopulation of the donor liver with recipient Kupffer cells and dendritic cells allows presentation of recipient hepatospecific peptide antigens to donor CD4 and CD8 T cells by self-HLA molecules. Although donor hepatic target cells would continue to express hepatospecific antigens in mismatched donor HLA molecules, studies of recurrent HCV infection post-OLT have shown HCV-antigenspecific responses of recipient T cells to HCV antigens expressed by HLA-mismatched donor target cells [215]. Reported rates of AIH recurrence after OLT have varied between 12%–50% after 8–10 years of follow-up with a median time to diagnosis of recurrence of 2 years [216– 219]. The cumulative prevalence of recurrent AIH increased from 12% at 1 year to 36% after 5 years. A systematic review of recurrent AIH calculated a weighted recurrence rate of 22% by correcting for factors, such as publication bias [220]. No differences in the rates of AIH recurrence were observed between patients immunosuppressed with TAC vs. CSA. Recurrent AIH infrequently

Farhad Sahebjam and John M. Vierling

progresses to cirrhosis or allograft failure because recurrent AIH has generally responded to intensified immunosuppression [216]. Arbitrary, diagnostic criteria have been proposed for recurrent AIH [4,211,212]. These criteria include: (1) OLT performed for either AIH or cryptogenic cirrhosis; (2) elevated AST/ALT levels; (3) persistence of autoantibodies present prior to OLT; (4) hypergammaglobulinemia and/or elevated IgG; (5) compatible histology; (6) exclusion of alternative etiologies; and (7) responsiveness to intensification of steroid or doses and calcineurin inhibitor immunosuppression or reintroduction of steroid. Protocol biopsies showed evidence of histopathological changes preceding biochemical evidence of recurrence; however, most transplant hepatologists await evidence of increased aminotransferase enzymes before performing a liver biopsy [218]. Recurrent AIH has been treated empirically with increased doses of steroid or reintroduction of steroids following withdrawal. In addition, calcineurin inhibitor immunosuppression has usually been intensified. Remission is common after reintroduction of steroids and optimization of calcineurin inhibitor doses [221,222]. As a result, there has been no need for randomized, controlled trials of therapy. Refractory patients have achieved remission by adding azathioprine [223] or using sirolimus [196]. The risk of retransplantation for recurrent AIH is very low, yet when retransplantation has been performed, recurrent AIH in the second allograft has been observed [224]. De novo autoimmune hepatitis after transplantation AIH is unique among autoimmune liver diseases because it can occur as a de novo disease in allografts of children or adults who underwent OLT for other disease indications [1,225–227]. De novo AIH has been reported in adults transplanted for chronic hepatitis C, Wilson disease, PBC, PSC, alcoholic cirrhosis, and ALF [1,225]. De novo AIH must be included in the differential diagnostic considerations of post-OLT patients with abnormal aminotransferase levels and liver biopsy features of interface hepatitis [228]. Successful treatments have been reported using intensified dosing or reintroduction of steroids and optimizing dosages of calcineurin or mTOR inhibitors [4,211,212]. Refractory patients may benefit from the addition of azathioprine (1–2 mg/(kg$d)) or MMF. Sirolimus has been used to treat recurrent AIH, which suggests that it would be effective in de novo AIH in adults [196]. Five of 21 patients treated with prednisone plus azathioprine or addition of MMF to calcineurin inhibitors failed to respond. These 5 patients and one newly diagnosed patient were treated with sirolimus. All 6 patients responded, but sirolimus was discontinued in one. Minimal adverse events were noted. Everolimus was successfully used to treat 3

23

patients with de novo AIH generated by pegylated interferon treatment of recurrent HCV after OLT [197]. One patient had a sustained viral response; the other 2 were nonresponders. Initial therapy with prednisone and azathioprine stabilized the patients, and everolimus was introduced for long-term management. One patient died of repeated cerebral hemorrhages. HCV did not progress, and prednisone was withdrawn. Inflammatory bowel disease after orthotopic liver transplantation for autoimmune hepatitis Inflammatory bowel disease (IBD), principally ulcerative colitis, occurs after solid organ transplantation, despite immunosuppression to prevent allograft rejection [229,230]. In one series, recurrent IBD was more common than de novo IBD, and the 10-year cumulative risks after OLT were 70% and 30%, respectively [230]. The incidence of IBD following solid organ transplantation was estimated to be 206 cases/100 000/year, which is ten times higher than the 20 cases/100 000/year expected in the general population. IBD was more common after OLT than transplantation of other solid organs, which may reflect the known association between IBD and both PSC and AIH. The clinical course of recurrent IBD was more severe than de novo IBD, and patients with recurrent IBD often required colectomy. Risk factors for post-transplant IBD included: CMV infection and tacrolimus-based immunosuppression. A retrospective study of 91 patients undergoing OLT for either PSC or AIH with intact colons sought to define the incidence of recurrent and de novo colitis and analyze the risk factors associated with colitis [229]. Sixty patients were transplanted for PSC and 31 for AIH. IBD activity before and after OLT and other risk factors were analyzed in a multivariate model. Forty-nine of 91 patients (54%) had IBD prior to OLT. Active IBD occurred in 40 of 91 patients (44%) after OLT: recurrent IBD in 32 and de novo IBD in 8. The cumulative risk for IBD was 15% at year 1, 39% at year 5 and 54% at year 10 after OLT. In 59% of patients with recurrent IBD, the disease was more severe than it had been prior to OLT. Risk factors for recurrent IBD included symptomatic IBD at time of OLT, short duration of IBD before OLT, CMV positive donor and negative recipient and tacrolimus immunosuppression. Empiric use of 5-aminosalicylates protected patients from recurrence. Clinicians should be aware of the risk for recurrent and de novo IBD when caring for AIH patients with symptoms of diarrhea with blood or mucus post-OLT.

Future therapies The immunopathogenesis of AIH is incompletely understood (Fig. 1), and the absence of a refined understanding

24

Autoimmune hepatitis

of the pathogenic mechanisms hinders the search for specific therapies [27]. This is particularly germane for type 1 AIH where no hepatospecific autoantigenic epitopes recognized by the T cell receptors of autoreactive CD4 and CD8 T cells or autoantibodies secreted by B cells have been identified. In contrast, the well defined autoantigenic epitopes in type 2 AIH for both autoantibodies and the T cell receptors of CD4 and CD8 T cells have led to innovative transgenic animal models and new concepts of therapy. Future therapies can be conceptually categorized (Table 7) : (1) new immunosuppressive agents with greater specificity for pathogenic mechanisms in AIH to control effector mechanisms of hepatic destruction; (2) antifibrotic agents to prevent progression to or even reverse established cirrhosis; (3) antigen-specific restoration of immunoregulatory control over the generation and deleterious functions of autoreactive CD4 and CD8 T cells; (4) restoration of antigen-specific tolerance; and (5) tolerogenic immunization of young children to

autoantigens associated with AIH to prevent future loss of self-tolerance. A body of recent work indicates that the deleterious pathogenic functions of effector T cells in type 1 and 2 AIH may result from a failure of autoantigen-specific T regulatory (Treg) cells to control effector cells [24,231]. A recent study showed that autoantigen-specific Treg cells can be generated from peripheral blood leukocytes of patients with type 2 AIH, and that these Treg cells can inhibit the effector functions of autoreactive CD4 and CD8 T cells [232]. It is a plausible hypothesis that infusion of autologous, hepatic autoantigen-specific Treg cells could control or extinguish the effector mechanisms of AIH [233–235]. However, multiple obstacles need to be overcome before the therapeutic potential of such Treg cells can be explored in patients with type 2 AIH [40]. Identification of the autoantigen(s) involved in type 1 AIH is a prerequisite for pursuit of this approach in type 1 AIH [27].

Table 7 Conceptual approaches to future therapies for autoimmune hepatitis Therapeutic approaches

Comments

New immunosuppressive agents

Belatacept is a protein created by fusion of the Fc fragment of a human IgG1 immunoglobulin linked and the extracellular domain of CTLA-4, a homolog of CD28 on T cells. It binds to B7.1/7.2 (CD80/CD86), blocking CD80/CD86 costimulation of T cells required for T cell proliferation and development of effector cell functions. It is a promising agent for pilot studies in refractory AIH. Leflunomide inhibits pyrimidine synthesis required for lymphocytes proliferation. In addition, it interferes with T cell transendothelial migration and modulates cytokine production, effector cell functions and production of metalloproteinases. Fingolimod causes sequestration of lymphocytes in lymphoid tissue and the thymus, preventing the lymphocyte circulation and transendothelial migration into tissue. Cumulative consequences include modulation of monocytic dendritic cell functions, lymphocyte apoptosis, inhibition of transendothelial migration of activated T cells, prevention of activation of tissue-infiltrating lymphocytes, and inhibition of germinal centers with suppression of humoral immunity. Clonal T cell activation, proliferation and differentiation of effector functions remain unaltered. It has been used to prevent experimental AIH. Chemokine receptor inhibitors have potential to treat AIH. Chemokines promote transendothelial migration of activated leukocytes bearing specific chemokine receptors. Chemokine gradients within tissue chemoattract leukocytes and induce effector functions. Thus, chemokines produced by activated leukocytes and epithelial cells within tissue and organs control the composition, quantity and functions of inflammatory cells migrating to a site of inflammation. Multiple inhibitors of chemokine receptors have been identified, including antagonists of CCR1, CCR3, CCR5, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR6. Preliminary studies indicate the potential therapeutic value of chemokine receptor inhibition in hepatic inflammatory diseases. CD4 T helper 1 cells mediating immunopathology predominantly express the chemokine receptor CXCR3. CXCR3 ligands CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (ITAC) are generated by leukocytes and epithelial cells in sites of inflammation. CXCR3 antagonists are candidates for pilot studies in AIH.

Antifibrotic agents

Antifibrotic strategies are appealing to prevent progression of chronic AIH to cirrhosis. Antifibrotics appear most applicable as a concomitant therapy with immunosuppression to reduce inflammation and the associated cytokines responsible for fibrogenesis and proliferation of activated myofibroblasts. Simtuzamab, a humanized monoclonal antibody against lysl-oxidase like-2 that prevents cross-linkage of collagen, is being studied as an antifibrotic agent in clinical trials for NASH and PSC.

Autoantigen-specific immunoregulation

Antigen-specific T regulatory cells appear to be the most promising candidates to inhibit antigen-specific effector functions of CD4 T cells. See text for further discussion.

Restoration of tolerance to autoantigens

Re-establishing self-tolerance to autoantigens in autoimmune diseases is a primary goal of research in immunology. To date, no strategies applicable to AIH have been proposed.

Prevention with tolerogenic immunization

Ingestion of an antigen leads to induction of antigen-specific tolerance in the liver and prevents systemic responses when the antigen is subsequently administered. Oral administration of autoantigens responsible for the autoimmune diseases type 1 diabetes mellitus and multiple sclerosis has been proposed to prevent these diseases. Autoantigens responsible for type 2 AIH are also potential candidates for oral tolerance.

Farhad Sahebjam and John M. Vierling

Conclusions AIH is a chronic liver disease putatively caused by loss of tolerance to hepatocyte-specific autoantigens. It is characterized by female predilection, elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. AIH presents rarely as ALF. Approximately 70%–80% of patients have established chronic disease at the time of diagnosis, and approximately 33% of them have cirrhosis [1,5], which indicates that substantial numbers of patients with AIH remain undiagnosed and untreated for prolonged periods. Untreated AIH progresses to cirrhosis, complications of portal hypertension and risks of hepatocellular carcinoma and hepatic failure. It is currently divided into two types, based on expression of autoantibodies. Autoantigenic epitopes have been identified only for type 2 AIH. In the absence of pathognomic biomarkers, diagnosis requires consideration of clinical, biochemical, serological and histological features, which have been codified into validated diagnostic scoring systems. Since many features occur in other chronic liver diseases, these scoring systems aid evaluation of the differential diagnosis. Adult diagnostic criteria for AIH are well established, as are the indications and contraindications for immunosuppressive therapy. The landmark 2010 PG redefined therapeutic remission as the complete normalization of AST/ALT, γglobulin and IgG levels and hepatic histology. Preliminary evidence indicates that patients meeting the new criteria for remission criteria may not progress. Because new definition of remission is stringent, a smaller proportion of patients will likely achieve remission. Hence, more patients will require alternative immunosuppressive therapies. OLT is a life-saving option for AIH patients with ALF, decompensated cirrhosis or hepatocellular carcinoma. Post-OLT outcomes are excellent, but recurrent AIH can compromise allograft survival. AIH is unique among AILDs in its capacity to occur de novo in patients transplanted for other indications. Patients transplanted for AIH are also at risk for recurrent or de novo ulcerative colitis. No randomized, controlled therapeutic trials of alternative therapies have been conducted in patients who fail to respond to or tolerate conventional steroids and azathioprine. Progress in our understanding of the immunopathogenesis of AIH should lead to identification of specific diagnostic and prognostic biomarkers and new therapeutic strategies.

Compliance with ethics guidelines Farhad Sahebjam, MD has no conflict of interest. John M. Vierling, MD makes the following disclosures. He is co-author of Immunosuppression in Liver Transplantation in Up-to-Date. He has been a principal investigator in clinical trials of antiviral agents for HCV

25 infection sponsored by Roche, the maker of mycophenolate mofetil and Novartis, the maker of mycophenolic acid, sirolimus and everolimus. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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