Clinical Gastroenterology and Hepatology 2015;13:2088–2108
Autoimmune Hepatitis and Overlap Syndromes: Diagnosis
and Management
John M. Vierling
Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke’s Medical Center, Houston, Texas
Keywords: Autoimmune Hepatitis; Acute Liver Failure; Hepatocellular Carcinoma
utoimmune hepatitis (AIH) occurs globally and
A afflicts children and adults of all ethnicities and
races.1,2 The current hypothesis is that AIH results
from hepatocyte injury (caused by environmental
exposure to viruses or xenobiotics) that triggers a
dysregulated, adaptive immune attack against hepa-
tocyte autoantigens in immunogenetically suscepti-
ble persons.3–5 AIH is characterized by female
predilection, elevated aminotransferases, non-
species or organ-specific autoantibodies, increased
levels of g-globulin or immunoglobulin (Ig) G, and
interface hepatitis on liver biopsy.1,3,6 AIH presents
rarely as acute liver failure (ALF) and infrequently as
acute hepatitis. At diagnosis, 70%–80% of patients
have chronic hepatitis, and approximately 33% have
cirrhosis,1,7 indicating that AIH commonly pro-
gresses undiagnosed and untreated for prolonged
periods. Cirrhotic patients are at risk for complica-
tions of portal hypertension, liver failure, and, in a
minority, hepatocellular carcinoma (HCC).
AIH is divided into types 1 and 2 (Table 1), which
are based on signature expressions of autoantibodies
(Table 2). Autoantigenic B- and T-cell epitopes have
been identified only for the less frequent type 2.
Type 1 AIH can present at any age but is increasingly
diagnosed in older women.8 In contrast, the peak
incidence of type 2 AIH occurs in children and ado-
lescents.9 In European adults, the prevalence of type
2 AIH is higher in the South than in the North.10
Neither the incidence nor prevalence of type 2 AIH
in the United States is known, largely because of
failure to test for anti–liver-kidney microsomal anti-
body 1 (LKM1).3 A minority of AIH patients develop
putative overlap syndromes (OS) with the cholestatic
diseases primary biliary cirrhosis (PBC) or primary
sclerosing cholangitis (PSC),3,6,11 but both diagnostic
criteria and therapy remain controversial.12
The absence of pathognomic biomarkers for AIH ne-
cessitates a systematic approach to diagnosis. Validated
diagnostic criteria should be used to assess the diagnostic
probability of AIH on the basis of clinical, biochemical,
serologic, and histologic features and response to empiric
immunosuppression (Table 3).13,14 Acute and chronic dis-
eases with features similar to AIH must be excluded,
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especially acute and chronic viral hepatitis, other autoim-
mune liver diseases (AILDs) with similar autoantibodies,
drug-induced liver injury (DILI), and Wilson disease (WD).
Indications and contraindications for immunosuppressive
therapy in AIH are well-established (Figure 1).1,3,15 The
landmark American Association for the Study of Liver Dis-
eases (AASLD) 2010 Practice Guideline (PG) (Table 4)1
redefined therapeutic remission as normalization of
aspartate aminotransferase (AST)/alanine aminotrans-
ferase (ALT), g-globulin, and IgG levels and absence of he-
patic inflammation on liver biopsy. Stringent criteria for
remission may increase the proportion of nonresponders to
standard immunosuppression. Both nonresponders and
patients intolerant of standard immunosuppressive drugs
should be treated with alternative therapies (Figure 1). The
choice remains empiric, because no alternative therapies
have been studied in randomized controlled trials. Ortho-
topic liver transplantation (OLT) is a life-saving option for
AIH patients with ALF, decompensated cirrhosis, or HCC.1,3
Allograft and patient survivals are excellent; however, AIH
recurs in the allograft in a minority.16
The goal of this review is to update clinicians regarding
the advances in the diagnosis and management of adult
patients with AIH and putative AIH-PBC and AIH-PSC OS.
Rigorous application of our current knowledge, especially
appropriate use of alternative therapies, can improve
outcomes. Future elucidation of the immunopathogenesis
Abbreviations used in this paper: AASLD, American Association for the
Study of Liver Diseases; AIH, autoimmune hepatitis; AILD, autoimmune liver
disease; ALF, acute liver failure; ALT, alanine aminotransferase; AMA, anti-
mitochondrial antibody; ANA, antinuclear antibody; AST, aspartate amino-
transferase; AZA, azathioprine; CNI, calcineurin inhibitor; CSA, cyclosporine;
CVS, cholestatic variant syndrome; DILI, drug-induced liver injury; EVR,
everolimus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV,
hepatitis C virus; HEV, hepatitis E virus; IAIHG, International Autoimmune
Hepatitis Group; IG, immunoglobulin; LKM, liver-kidney microsomal anti-
body; MMF, mycophenolate mofetil; MA, mycophenolic acid; 6-MMP, 6-
methylmercaptopurine nucleotide; 6-MP, 6-mercaptopurine; NAFLD, non-
alcoholic fatty liver disease; OLT, orthotopic liver transplantation; OS,
overlap syndrome; PBC, primary biliary cirrhosis; PG, practice guideline;
PSC, primary sclerosing cholangitis; RDC, research diagnostic criteria; RIT,
rituximab; SDC, simplified diagnostic criteria; SIR, sirolimus; SLA/LP, soluble
liver antigen/liver-pancreas; SMA, smooth muscle antibody; TAC, tacroli-
mus; 6-TGN, 6-thioguanine nucleotide; TPMT, thiopurine methyltransferase;
UDCA, ursodeoxycholic acid; WD, Wilson disease.
Most current article
© 2015 by the AGA Institute
1542-3565/$36.00
http://dx.doi.org/10.1016/j.cgh.2015.08.012
November 2015 Autoimmune Hepatitis and Overlap Syndromes 2089

Table 1. Comparison of Type 1 and Type 2 AIH

Type 1 Type 2

Female to male ratio 4:1 10:1

Age distribution Infancy to elderly adulthood Childhood to young adulthood
Geographic distribution Global Global but with geographic differences in adult
prevalence: Southern Europe > Northern
Europe and Europe > United Statesa
Clinical presentation and course ALF rare ALF rare
Indolent presentation more frequent Severe presentation, especially in children
than severe presentation and adolescents
Signature autoantibodies ANA Anti-LKM1
SMA Anti-LC1
Anti–F-actinb Anti-LKM3
Overlapping autoantibodies Anti-SLA/LP Anti-SLA/LP
Anti-ASGPR Anti-ASGPR
Histology at presentation Spectrum ranging from ALF with ALF with massive hepatocellular necrosis rare
massive hepatocellular necrosis, Often high-grade inflammation
mild disease to active cirrhosis Cirrhosis common
Response to steroid and AZA Excellent in majority Excellent in minority
Failure in minority Failure common
Requirement for long-term Sustained withdrawal successful Sustained withdrawal rare
immunosuppression in minority
Majority require long-term therapy Nearly universal need for long-term therapy

NOTE. Adapted from reference 3 with permission.

ASGPR, asialoglycoprotein receptor; F-actin, filamentous actin component of smooth muscle; LC1, liver cytosol type 1.
a
Prevalence of anti-LKM1 unclear in United States because of infrequent testing.
b
Up to 20% test negative for all autoantibodies.

of AIH should drive discovery of diagnostic and prognostic
biomarkers as well as novel therapeutic strategies.
Diagnosis of Autoimmune Hepatitis
Diagnostic Criteria
The International Autoimmune Hepatitis Group
(IAIHG) published revised diagnostic criteria (RDC) for
AIH in 199913 and validated simplified diagnostic criteria
(SDC) in 2008 (Table 3).14 Neither the RDC nor SDC
distinguish AIH from diseases with similar biochemical,
serologic, or histologic features. Both the RDC and SDC
require liver biopsy. Both also use autoantibody titers for
scoring, which disadvantages clinicians in the United
States where enzyme-linked immunosorbent assay is
used to detect antinuclear antibody (ANA), smooth
muscle antibody (SMA), anti–F-actin, anti-LKM1, and
anti–soluble liver antigen/liver-pancreas (SLA/LP).17
Without titers, RDC and SDC scores are likely
underestimates.
Differential Diagnosis
AIH should be considered in the differential diagnosis
of adult patients presenting with ALF, acute or chronic
hepatitis, or cirrhosis. Presentation of AIH as ALF is
extremely rare,18–20 and presentation as an acute, icteric
hepatitis is uncommon.20 Up to 80% of adults with AIH
present with chronic liver disease, and 33% have
cirrhosis,7 even in the absence of symptoms or jaundice.21
Diagnosis of AIH requires exclusion of acute and
chronic diseases, including hepatitis A virus, hepatitis B
virus (HBV) with or without hepatitis D virus (HDV),
hepatitis C virus (HCV), hepatitis E virus (HEV), Epstein-
Barr virus, cytomegalovirus and herpes simplex virus,
PBC, PSC, DILI, and WD. Exclusion of WD is crucial
because biochemical, serologic, and histologic features
can be indistinguishable from AIH,22–24 and serum ceru-
loplasmin levels can be within normal in WD patients
with hepatic inflammation because of stimulated synthe-
sis as an acute phase reactant protein.22 Hepatic copper
concentrations >200 mg/g dry weight are diagnostic of
WD, and 24-hour urinary copper is usually
100 mg/24
h.22,23 Ceruloplasmin levels are low in ALF regardless of
etiology because of multilobular hepatic necrosis.25
Use and Interpretation of Diagnostic Criteria
The RDC and SDC are complementary (Table 3).3,26
The RDC is more accurate for the diagnosis of AIH in
patients with atypical features than the SDC. In
contrast, the SDC and RDC have identical diagnostic
accuracies for patients with typical features of AIH.
Thus, the SDC are well-suited for assessment of typical
patients. A very low SDC score excludes AIH from the
differential diagnosis.
A pretreatment RDC score of 15 (definite AIH diag-
nosis) has a sensitivity of 95%, a specificity of 97%, and
an accuracy of 94%.13 A pretreatment RDC score of 10
(probable AIH diagnosis) has a sensitivity of 100% and a
specificity of 73% but an accuracy of only 67%.

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2090 John M. Vierling Clinical Gastroenterology and Hepatology Vol. 13, No. 12

Table 2. Autoantibodies and Differential Diagnosis of AIH

Autoantibody Autoantigen Liver diseases Utility

ANA Chromatin, ribonucleoproteins, AIH, PBC, PSC, DILI, chronic Compatible with type 1 AIH
ribonucleoprotein complexes (gp210 and HBV, HCV infections, WD, Must exclude other diseases
Sp100 in PBC) NAFLD
SMA Microfilaments: filamentous actin (F-actin), AIH, PBC, PSC, DILI, HBV, HCV, Compatible with type 1 AIH
intermediate filaments: vimentin, desmin WD, NAFLD Must exclude other diseases
pANCA Beta-tubulin isotype 5, mimicry with AIH, PSC, IBD Compatible with type 1 AIH
bacterial precursor protein FtsZ AIH-PSC OS? AIH-PSC OS?
Must exclude other diseases
AMA 2-oxo-acid dehydrogenase complex (E2 PBC, rarely AIH Rarely observed in type 1 AIH
subunit lipodryl domains) AIH-PBC OS? AIH-PBC OS?
LKM-1 Epitopes of cytochrome P450 2D6 AIH, chronic HCV infection, Diagnostic of type 2 AIH if HCV
(CYP2D6) halothane-induced hepatitis infection excluded
LKM-3 Family 1 UDP-glucuronosyltransferases AIH, chronic HDV Diagnostic of type 2 AIH if chronic
(UGT1A) HDV infection excluded
LC-1 Formiminotransferase cyclodeaminase AIH type 2 Diagnostic of type 2 AIH
(FTCD) Liver specific
LM Epitopes of cytochrome P450 2A6 (CYP2A6) APECED APECED
HCV Must exclude HCV infection
SLA/LP tRNA-selenocysteinyl-tRNA synthase AIH type 1 or 2 Diagnostic of AIH
(SepSecS protein) Compatible with either type 1 or 2
AIH
Prognostic for severe disease,
relapse after withdrawal of
immunosuppression, fetal loss
ASGPR Asialoglycoprotein receptor AIH, PBC, DILI, chronic HBV, Liver specific
HCV, HDV infections Compatible with type 1 or 2 AIH,
Prognostic for severe disease,
histopathologic activity and
relapse after withdrawal of
immunosuppression

NOTE. New autoantigens being investigated in AIH include a-actinin, a ubiquitous cytoskeletal cross-linking protein within the family of filamentous actin (F-
actin)214; phosphoenolpyruvate carboxykinase 2215; ribosomal P216; nucleosome217; programmed cell death-1218; and interleukin-4 receptor.219 APECED,
autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; ASGPR, anti-asialoglycoprotein receptor antibody; HDV, hepatitis D virus; IBD, inflammatory
bowel disease; LC-1, anti-liver cytosol type 1 antibody; NAFLD, nonalcoholic fatty liver disease; pANCA, perinuclear neutrophil cytoplasmic antibody; tRNA,
transfer RNA; UDP, uridine diphosphate; UGT, uridine diphosphate glucuronosyltransferase.

The performances of RDC and SDC have been Autoantibodies as Biomarkers of

compared.17,26–29 In a large retrospective study, the Autoimmune Hepatitis
specificities of the RDC and SDC were 97.9% and 97%,
respectively.27 Scoring of 185 adult AIH patients at pre-
Serum autoantibodies play important roles in the clas-
sentation26 indicated probable AIH in 9% by using RDC
sification and diagnosis of AIH (Tables 1 and 2).1,2,32 The
versus 15% by using SDC. The concordance of RDC and
autoantigenic targets of the autoantibodies used in the
SDC scores was 79%. In 39 patients (21%) with discor-
diagnosis of AIH have been identified (Table 2).1,33 Clini-
dant scores, 5 who scored definite by using RDC scored
cians should test for both SMA and anti–F-actin because
probable by using SDC. In 12 patients, SDC scores were
they are complementary and prognostic.34 If ANA, SMA,
non-diagnostic because of low g-globulin and IgG levels
and anti-LKM1 are negative, perinuclear antineutrophil
and autoantibody titers <1:80. By using RDC, 6 of the 12
cytoplasmic antibodies, anti-SLA/LP, liver cytosol type 1
scored as definite and the other 6 as probable. When 8 of
antibody, and anti–LKM-3 (Table 2) should be tested. A
the 12 were treated with steroids, 5 (62%) responded.
minority express only these autoantibodies.33 If all auto-
The RDC and SDC have been validated in China,30 but the
antibodies are absent but the RDC score is compatible with
RDC were superior, primarily because they include
a diagnosis of AIH, an empiric trial of steroid is appropriate.
associated immunologic diseases.29 These results indi-
The RDC score should be recalculated on the basis of the
cate that all patients with SDC scores of probable or non-
response and autoantibodies retested.35 Occasionally pa-
diagnostic should be reassessed by using RDC.
tients without detectable autoantibodies before therapy
Neither the RDC nor the SDC have been validated for
express them after being immunosuppressed.1,17,35
the diagnosis of AIH in patients with putative PBC or PSC
The performance of autoantibody testing in AIH has
OS.12,31 Thus, use of RDC and SDC for the diagnosis of
been studied and underscores the fact that ANA and
AIH OS is arbitrary and problematic.12

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November 2015 Autoimmune Hepatitis and Overlap Syndromes 2091

Table 3. Revised and Simplified Diagnostic Criteria for AIH

RDC SDC

Female sex þ2 Autoantibodies:

ANA or SMA
1:40 þ1
Alk Phos/AST or (ALT) ratio >3 –2
1:80 þ2
<1.5 þ2 LKM-1
1:40 þ2
Anti-SLA Positive þ2
g-Globulin or IgG  ULN >2 þ3
1.5–2.0 þ2 Immunoglobulin level
1.0–1.5 þ1 IgG or >ULN þ1
<1.0 0 g-Globulin >1.1  ULN þ2
ANA, SMA, LKM-1 titers >1:80 þ3 Histologic features:
1:80 þ2 Compatible with AIH þ1
1:40 þ1 Typical of AIHa þ2
<1:40 0
Absence of viral hepatitis:
AMA positive –4 Yes þ2
No 0
Viral markers Positive –3
Negative þ3 Pretreatment aggregate score
Definite diagnosis:
7
Drugs Yes –4 Probable diagnosis:
6
No þ1
Alcohol <25 g/d þ2
>60 g/d –2
HLA DR3 or DR4 þ1
Concurrent immunologic disease
Thyroiditis, colitis, etc þ2
Other markers
Anti-SLA, F-actin, pANCA þ2
Histologic features
Interface hepatitis þ3
Plasma cells þ1
Rosettes þ1
None of above –5
Biliary changes –3
Other features –3
Treatment response
Complete þ2
Relapse þ3
Pretreatment aggregate score
Definite diagnosis: >15
Probable diagnosis: 10–15
Post-treatment aggregate score
Definite diagnosis: >17
Probable diagnosis: 12–17

Alk Phos, alkaline phosphatase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; F-actin, anti-actin antibody; LKM-1, liver-kidney-microsomal-1
antibody; pANCA, perinuclear neutrophil cytoplasmic antibody; SLA, soluble liver antigen; SMA, anti-smooth muscle antibody; ULN, upper limit of normal.
a
Typical histologic features are those contained in the RDC, principally interface hepatitis.

SMA are frequently detected in other diseases.36,37
Among the multiple autoantigens detected by ANA
testing, Sp100 and gp210 are highly specific for PBC.38
Sensitivities for ANA (32%), SMA (16%), or LKM1 (1%)
were poor in a comparison of autoantibody tests in 265
adults with AIH and 342 patients with other chronic
liver diseases. Diagnostic accuracy of autoantibody
testing ranged from 56% to 61%. A majority of AIH
patients (51%) had multiple autoantibodies, compared
with only 8% of patients with other liver diseases.
Concurrent presence of ANA and SMA increased diag-
nostic sensitivity for AIH to 43% and specificity to
99%. The positive predictive value for AIH was 97% for
the presence of both ANA and SMA, and the diagnostic
accuracy was 74%. Autoantibodies should be inter-
preted by using RDC and SDC (Table 3). Anti-SLA/LP
autoantibodies are specific for the disease AIH,
whereas the other autoantibodies are not.2,4,5,39 The
autoantigenic epitopes of SLA/LP share aa sequences
with the asialoglycoprotein receptor, an autoantigen
expressed by periportal hepatocytes.2,4,5,39 Anti-LKM1
autoantibodies recognize autoantigenic epitopes in
CYP2D6, which shares amino acid sequences with HCV
proteins.2,4,5,39
Specific autoantibodies are prognostic in AIH.40
Severity and progression have been associated with

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2092 John M. Vierling Clinical Gastroenterology and Hepatology Vol. 13, No. 12

Figure 1. Algorithm for diagnosis and treatment of AIH. RDC13 and SDC.14 *Clinical trials in United States proved that AZA
at 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 AZA dosages of 1–2 mg/kg/d also were safe and effective when combined with pre-
dnisone to induce remission in AIH. Thus, both are evidence-based induction regimens.1 MA, mycophenolic acid; TID, 3
times daily.

anti-SLA/LP, Ro/SSA (Ro52), anti–F-actin, liver cytosol
type 1 antibody, asialoglycoprotein receptor, chromatin,
cyclic citrullinated peptide, and uridine glucuronosyl-
tranferase.40,41 In type 1 AIH the combination of anti-
SLA/LP and Ro/SSA portends a poor prognosis41 and
also has been associated with adverse outcomes during
pregnancy.42
Role of Liver Biopsy in the Diagnosis of
Autoimmune Hepatitis
Liver biopsy is required for the diagnosis of acute or
chronic AIH (Figure 2). Surrogate serum tests for hepatic
inflammation and fibrosis, transient elastography, and
magnetic resonance elastography are inappropriate for
the diagnosis of AIH. Interface hepatitis is the primary
histologic feature of AIH (Figure 2, Table 4).18,43 It is not
pathognomic, however, because it also occurs in chronic
HBV (with or without hepatitis D virus), HCV, and HEV
infections, WD, DILI, and PBC.24,44–47 Central zonal ne-
crosis and/or perivenulitis of the central veins (Figure 2)
is another feature of acute and chronic AIH and may
occur in the absence of interface hepatitis.48,49
The need for a liver biopsy to diagnose AIH has been
challenged.50 However, SDC scores were probable in
77% and nondiagnostic in 22% diagnosed without liver
biopsy. Thus, RDC scoring by using histologic features

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November 2015
Table 4. Criteria for Remission in Revised AASLD 2010 AIH Practice Guideline
2010 Practice Guideline
Goals 1. Prevent progression and need for OLT
2. Minimize adverse events of immunosuppression
Biochemical Normalize:
remission 1. ALT (<19 U/L women; <30 U/L men)
2. g-Globulin and IgG levels
Histologic remission Eliminate:
1. Interface hepatitis
2. Portal inflammatory infiltrates
Fibrosis Prevent:
1. Progression to cirrhosis
2. Progression of existing cirrhosis to decompensation
or increasing Child-Turcotte-Pugh and Model for
End-Stage Liver Disease scores
Immunosuppression 1. Use combinations of immunosuppressive drugs to minimize
adverse events caused by any single drug
2. Use alternative therapies as needed to achieve remission
NOTE. Developed from references 1 and 7.
would be required to diagnose the 22% with non-
diagnostic SDC scores.
Cholestatic Variant or Overlap
Syndromes
The coexistence of AIH and features of cholestatic
liver diseases has been designated as either cholestatic
variant syndrome (CVS) or OS. The term OS implies the
coexistence of AIH and either PBC or PSC.11 The term
CVS51 indicates coexistence of AIH and cholestatic fea-
tures resembling either PBC or PSC. Importantly, the
term CVS prompts investigation of causes of cholestasis
other than PBC or PSC, including biliary obstruction,
granulomatous or other infiltrative diseases, cholestatic
viral hepatitis, and cholestatic DILI.
There are 5 postulated explanations for AIH-PBC or
AIH-PSC CVS or OS: (1) sequential or concurrent occur-
rence of 2 distinct and independent AILDs, (2) a distinct
pathologic entity that differs from each of the individual
AILDs, (3) a clinicopathologic midpoint in a continuum
ranging from pure AIH to pure cholestatic AILDs, (4) one
of several heterogeneous expressions of AIH, or (5) a
primary AILD with 1 or more features of another AILD.
The consensus among experts reviewing the evidence for
OS favored the fifth explanation.12 The first explanation
(defining AIH OS as the coexistence of AIH and either
PBC or PSC) currently cannot be proved or refuted. Only
future discovery of biomarkers for the specific immu-
nopathogenic mechanisms of AIH, PBC, and PSC can
settle this issue.
The reported prevalence of CVS/OS varies, and the
accuracy of diagnoses is suspect because of the inap-
propriate use of diagnostic scoring systems validated
only for AIH.11,31,51,52 The IAIHG’s critical review of OS
concluded that current diagnostic criteria were arbitrary,
lacked discriminate power, and misused the RDC and
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Autoimmune Hepatitis and Overlap Syndromes 2093
2002 Practice Medline
1. Reduce mortality and symptoms
2. Minimize adverse events of immunosuppression
Reduce:
AST/ALT to 1.5–2  upper limit of normal
1. Eliminate interface hepatitis
2. Confine inflammatory infiltrates to portal tracts
Reduce rate of:
1. Progression to cirrhosis
2. Worsening of existing cirrhosis
Minimize doses of standard immunosuppressive
drugs to minimize serious adverse events
SDC to diagnose AIH.12 The IAIHG recommended that
patients with suspected CVS/OS be classified on the basis
of their primary disease as AIH, PBC, or PSC (including
small duct variant).12 Therapy of primary disease should
determine therapy.11,51
Despite imprecise definitions, clinicians encounter
patients with AIH CVS/OS that requires diagnostic eval-
uation and therapy.11,31,51 Because ANA and SMA auto-
antibodies are detected in the majority of patients with
antimitochondrial antibody (AMA)–positive PBC and are
the only autoantibodies in AMA–negative PBC, their
presence must not be misinterpreted as evidence of AIH-
PBC CVS/OS.31 Interface hepatitis is part of the histo-
pathologic progression of PBC; thus, its presence does
indicate AIH-PBC CVS/OS.53,54 Because steroids55 and
cyclosporine (CSA)56 have therapeutic efficacy in PBC,
response should not be construed as evidence of AIH-
PBC CVS/OS. In contrast, azathioprine (AZA) is ineffec-
tive in PBC.57 However, overall responses to immuno-
suppressive therapy are inferior in patients with AIH and
cholestasis.11,31,51
Autoimmune Hepatitis–Primary Biliary Cirrhosis
Cholestatic Variant or Overlap Syndromes
Criteria for the diagnosis of AIH-PBC CVS/OS have not
been independently validated.12 In the absence of an
independent way to diagnose coexistent AIH and PBC, it
is difficult to interpret a report showing that the Paris
criteria for AIH-PBC CVS/OS58 had a diagnostic sensi-
tivity of 92% and specificity of 97%.59 In accord with the
IAIHG’s conclusions,12 both the RDC and SDC had low
sensitivities and specificities. The Paris and other criteria
are tautological; they were derived from analyses of
patients arbitrarily diagnosed as having AIH-PBC
CVS/OS. By using these criteria, the frequency of AIH-
PBC CVS/OS ranged from 7% to 13%.11 Conversely, a
2094 John M. Vierling Clinical Gastroenterology and Hepatology Vol. 13, No. 12

Figure 2. Histopathologic features of AIH. (A) Lymphoplasmacytic portal inflammation and interface hepatitis (arrows) in
chronic AIH (original magnification, 100). (B) Central zonal necrosis and perivenulitis of central vein in acute AIH (original
magnification, 200). (C) Hepatocyte regeneration forming rosettes (arrows) in chronic AIH (original magnification, 200). (D)
Plasma cells in inflammatory infiltrate in chronic AIH (original magnification, 400). Note pale staining of Golgi adjacent to
nuclei. (E) Emperipolesis of hepatocyte in AIH (original magnification, 400). Note lymphocyte within cytoplasm (arrow),
displaced nucleus, and early evidence of apoptosis. Central zonal pathology is prominent in AIH patients presenting with ALF
or acute hepatitis.18,43 The National Institutes of Health Acute Liver Failure Study Group proposed that diagnostic criteria for
AIH in ALF patients include liver biopsy evidence of multilobular necrosis, lymphoplasmacytic inflammatory infiltrates,
lymphoid follicles, and central zonal necrosis with perivenulitis of the central vein.18 In ALF a transjugular liver biopsy is
required because of coagulopathy.18,43 RDC includes scores for interface hepatitis, plasma cells, and rosettes (Table 3). CD8 T
cells (cytotoxic T lymphocytes) mediate emperipolesis in AIH.222 Clinicians should interpret features of a biopsy in the context
of all clinical, biochemical, and serologic features by using either RDC or SDC (Table 3). If a pathology report lacks necessary
details for RDC or SDC scoring, the pathologist should be consulted. Experienced pathologists can categorize a biopsy as
typical, compatible, or incompatible with AIH.43 (A) and (B) Modified from reference 3 and reproduced with permission. (C)
Modified from reference 223 and reproduced with permission. (E) Modified from reference 222 and reproduced with
permission.

retrospective, long-term follow-up of 1476 PBC patients
documented the occurrence of AIH in only 8 (0.54%).60
Among 16 Japanese patients with putative AIH-PBC
CVS/OS, PBC preceded the diagnosis of AIH in 6 pa-
tients, whereas 10 were diagnosed concurrently.61 A
multicenter comparison of features in consecutive pa-
tients with AIH (n ¼ 48), AIH-PBC CVS/OS (n ¼ 15), or
PBC (n ¼ 52) reported that AIH-PBC CVS/OS patients
were significantly younger (median age, 44 vs 59 years
for PBC patients), and they presented with jaundice in
20% and pruritus in 20%.62 AIH-PBC CVS/OS patients
had significantly higher AST/ALT and g-globulin levels
than PBC patients, whereas alkaline phosphatase, g-glutamyl
transpeptidase, and IgM levels were significantly higher
than those in AIH patients. Liver biopsies showed inter-
face hepatitis in 86% and lymphocytic cholangitis in 93%
of patients with AIH-PBC CVS/OS.
Outcomes of 26 patients with AIH-PBC CVS/OS were
worse than those of 109 PBC patients63 because of
significantly higher rates of portal hypertension (P ¼ .01),
esophageal varices (P < .01), gastrointestinal bleeding
(P ¼ .02), ascites (P < .01), and death or OLT (P < .05).
Thirty-one of 71 AIH-PBC CVS/OS patients (43.6%) had
extrahepatic immunologic diseases,64 including
autoimmune thyroid diseases in 18%, Sjögren syndrome
in 8%, celiac disease in 4%, psoriasis in 4%, rheumatoid
arthritis in 4%, vitiligo in 3%, and systemic lupus ery-
thematosus in 3%. Each of the following occurred in single
patients (1.4%): autoimmune hemolytic anemia, multiple
sclerosis, membranous glomerulonephritis, sarcoidosis,
systemic sclerosis, antiphospholipid syndrome, and tem-
poral arteritis. Multiple extrahepatic immunologic dis-
eases were common; 56% had 2 diseases, 32% had 3, and
11% had 4. These findings indicate that AIH-PBC CVS/OS
patients are highly susceptible to a variety of autoimmune
and immunologic diseases. A high frequency of HLA-DR7
in AIH-PBC OS has been considered evidence of immu-
nogenetic susceptibility to CVS/OS.65 Evidence of a
significantly increased prevalence of AIH-PBC CVS/OS in
Hispanic compared with non-Hispanic PBC patients (31%
vs 13%, P ¼ .002) also suggested genetic predisposition.66
Quantitative comparison of plasma cells expressing
IgG or IgM in liver biopsies has been proposed as a
diagnostic aid in AIH-PBC CVS/OS because hepatic
plasma cells predominantly express IgG in AIH and IgM
in PBC.67,68 In one study, results in AIH-PBC CVS/OS
patients were inconsistent with low specificity and
sensitivity.67 In another study, the ratio of IgG to IgM

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November 2015
plasma cells of <1 distinguished PBC from AIH-PBC CVS/
OS where the ratio was >1.68
Autoimmune Hepatitis–Primary Sclerosing
Cholangitis Cholestatic Variant or
Overlap Syndromes
On the basis of criteria deemed arbitrary by the
IAIHG, the frequency of AIH-PSC CVS/OS ranged from
6% to 11%.11,31 AIH and PSC can be diagnosed concur-
rently, or a diagnosis of AIH can either precede or follow
the diagnosis of PSC. RDC scoring of 211 PSC patients
found scores of definite in only 1.4% and probable in
6%.69 AIH-PSC CVS/OS patients had higher serum glob-
ulins (P ¼ .01), IgG levels (P ¼ .001), autoantibody titers
(P < .001), and histologic scores (P < .001) than patients
with PSC alone. Magnetic resonance cholangiography in
24 of 118 AIH patients (20%) with cholestatic liver tests
showed features consistent with AIH-PSC CVS/OS in 12
of 24 (50%), which extrapolates to a prevalence of
w10% among the 118 AIH patients.70 Comparison of 24
cholestatic AIH and 94 non-cholestatic AIH patients
showed that cholestatic patients had lower AST levels
(P ¼ .012) and higher IgM levels (P ¼ .002), and some
had ulcerative colitis. Comparison of 7 of 41 PSC patients
(17%) diagnosed with AIH-PSC CVS/OS and 34 “classic”
PSC patients showed that CVS/OS patients were signifi-
cantly younger (mean age, 21.4  5.0 vs 32.3  10 years;
P < .01) and had higher ALT (357  26.5 vs 83.7  60.7
U/L, P < .005) and IgG levels (25.6  4.7 vs 12.9  6.0
mg/dL, P < .0001).71 During a mean follow-up of 93
months, OLT was required in 1 of 7 CVS/OS and 6 of 34
classic PSC patients. Deaths or malignancies occurred
exclusively in classic PSC patients. Another retrospective
study showed 10 patients with AIH-PSC CVS/OS had
better survival than 12 patients with AIH-PBC OS
(90% vs 50%, P ¼ .045).72
Atypical Cholestatic Variant or
Overlap Syndromes
Atypical AIH CVS/OS include AMA–negative PBC,
small duct PSC, autoimmune sclerosing cholangitis,
IgG4–secondary sclerosing cholangitis, and IgG4-
associated AIH.31,73–75 IgG4-associated AIH was detec-
ted in 2 of 60 patients with type 1 AIH (3.3%) on the
basis of high serum IgG4 and/or increased quantities of
IgG4 plasma cells in portal tracts.76
Drug-induced Liver Injury and
Autoimmune Hepatitis
DILI must be considered in the differential diagnosis
of AIH77–82 and has been implicated as the cause of
w9%–10% cases of classic type 1 AIH.81 DILI may (1)
cause a syndrome mimicking clinical, biochemical, and
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Autoimmune Hepatitis and Overlap Syndromes 2095
serologic features of AIH that will subside after drug
discontinuation; (2) “trigger” autoimmune responses to
hepatobiliary antigens resulting in classic AIH; or (3)
unmask subclinical AIH.20,81,82 Prescription drugs and
complementary and alternative medications have been
associated with AIH (Table 5). Curiously, DILI-associated
AIH is most often type 1, although type 2 would be
predicted as the result of drug metabolism by CYP iso-
forms and uridine glucuronosyltransferases. Clinicians
must inquire specifically about complementary and
alternative medications because patients may not regard
them as drugs.20,81,82 Use of standardized case defini-
tions for DILI-related AIH may aid in identification of
cases.83 Any drug or complementary and alternative
medication suspected of causing DILI should be reported
to national agencies.
Chronic Liver Diseases and Suspicion of
Concomitant Autoimmune Hepatitis
Patients with AIH may have comorbid liver diseases,
and chronic liver diseases may have features suggestive
of AIH.3 For example, patients with nonalcoholic steato-
hepatitis may have autoantibodies and portal inflamma-
tion,84,85 whereas patients with AIH may also be infected
with HBV or HCV. In 25 patients with chronic HCV (n ¼
20, 80%) or chronic HBV (n ¼ 5, 20%) infections,
probable AIH scores were found in 18 (72%) by using
RDC and in 12 (48%) by using SDC.44 None scored as
definite. The hypothesis that severe interface hepatitis in
92 HCV-infected patients was due to concomitant AIH
proved to be false,86 and no occult HCV infections were
Table 5. Drugs and Complementary and Alternative
Medications Reported to Cause AIH
Complementary-alternative
Prescription drugs medications
Minocycline Melatonin
Nitrofurantoin Dai-taiko (da chai hu tang)
Propylthiouracil Glucosamine chondroitin sulfate
Diclofenac Korean combination herbal
Tienilic acid Green tea extract
Alpha-methyldopa
Stains
Pemoline
Ornidazole
Infliximab
Adalimumab
Ramelton
Natalizumab
Clometazine
Synthetic estrogen
Liraglutide
NOTE. Currently, minocycline (especially prolonged courses for acne vulgaris)
and nitrofurantoin for chronic suppression of urinary tract infections account for
90% of DILI-related AIH.81,82,220,221
2096 John M. Vierling
identified in AIH patients.87 Interferon treatment of HCV
infections can cause a flare of AIH in patients with con-
current HCV and AIH.1,21
Chronic HEV infection can occur in immunosup-
pressed post-transplant patients.88,89 The prevalence of
anti-HEV antibodies was significantly increased in AIH
patients (16 of 208, 7.7%) compared with healthy adult
controls (11 of 537, 2%), patients with rheumatoid
arthritis (4 of 114, 3.5%), or those with HCV-HBV in-
fections (2 of 109, 1.8%).45 HEV-specific proliferative
T-cell responses verified that 100% of the positive AIH
patients had had prior HEV infection, suggesting that
acute HEV infection may trigger AIH. Only one immu-
nosuppressed AIH patient had active HEV infection
(detectable HEV RNA), which cleared spontaneously af-
ter reducing the dose of immunosuppression. AIH pa-
tients with poor responses to immunosuppression
should be tested for active HEV infection by using HEV
RNA polymerase chain reaction.
Autoimmune Hepatitis Presenting
as Acute Liver Failure or Severe
Acute Hepatitis
AIH rarely causes ALF,18–20 and presentation as se-
vere acute hepatitis is uncommon.20 Clinicopathologic
features of 28 AIH patients with ALF or severe acute
hepatitis90 included positive ANA (100%; 29% with low
titer of 1:40) and elevated IgG (75%). Histologic find-
ings included lobular hepatitis, multilobular necrosis,
central zonal necrosis, and perivenulitis.
Presentation of Autoimmune Hepatitis
as an Extrahepatic Immunologic Disease
Signs or symptoms of extrahepatic autoimmune or
immune-mediated inflammatory diseases may be pre-
senting complaints of patients with AIH1,91 and include
hyperthyroidism, thyroiditis, hypothyroidism, mixed
connective tissue disease, autoimmune hemolytic ane-
mia, idiopathic thrombocytopenic purpura, polymyositis,
uveitis, sicca syndrome, systemic lupus erythematosus,
vitiligo, celiac sprue, diabetes mellitus, rheumatoid
arthritis, and ulcerative colitis. Patients with established
connective tissue diseases may have delayed onset of
AIH.92
Hepatocellular Carcinoma in
Autoimmune Hepatitis
Cirrhosis, regardless of etiology, is a risk factor for
HCC,93,94 and the reported frequency in cirrhotic AIH
patients varied from 1% to 9%.95 Estimates of incidence
ranged from 0.3% to 1.9%/year.95,96 The ratio of the
observed rate of HCC in AIH to an age-adjusted expected
rate in Sweden was 23.3 (95% confidence interval,
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Clinical Gastroenterology and Hepatology Vol. 13, No. 12
7.5–54.3).96 Significant risk factors for HCC in AIH were
cirrhosis for
10 years, portal hypertensive complica-
tions, chronic hepatic inflammation, and immunosup-
pression for
3 years. A Japanese national survey
identified HCC in 5.1% of AIH patients, with mean age at
diagnosis of 69 years, mean duration of AIH of 8 years,
cirrhosis in 78%, and a female-to-male ratio of 5.7:1.97
This survey also indicated that HCC can occur in non-
cirrhotic AIH. A prospective, single-center study detec-
ted HCC in 15 of 243 (6.2%) type 1 AIH patients (1090
cases per 100,000 patient follow-up years), with an
incidence of 1.1%/year in cirrhotic patients.98 The fre-
quency of HCC was unexpectedly comparable for female
(6.1%) and male patients (6.4%). Significant HCC risk
factors included cirrhosis at presentation (9.3% vs 3.4%,
P ¼ .048) and variceal bleeding (20% vs 5.3%, P ¼ .003).
The median time to diagnosis of HCC was 102.5 months
in cirrhotic patients (range, 12–195 months). Patients
diagnosed by using surveillance imaging had signifi-
cantly higher median survival than patients with symp-
tomatic presentations, 19 months (range, 6–36 months)
vs 2 months (range, 0–14 months; P ¼ .042). The inci-
dence of HCC in cirrhotic patients with AIH merits ul-
trasound surveillance imaging every 6 months to
enhance survival.93,94,98
Management of Autoimmune Hepatitis
Practice Guideline and Revised Definition
of Remission
The primary goal of therapy in AIH is to achieve
remission.1,3,6 The 2010 PG redefined remission1
(Table 4) to require (1) normal levels of AST, ALT
(optimally <19 U/L in women and 30 U/L in men),
total bilirubin, g-globulin, or IgG and (2) absence of in-
flammatory activity on liver biopsy. Secondary goals of
therapy are (1) prevention of progression of fibrosis to
cirrhosis and (2) reversion of cirrhosis to a lower stage of
fibrosis, an outcome which has been documented.99,100
By using the 2002 PG criteria (Table 4), w80% of
patients met criteria for remission within 3 years of
immunosuppression, and w20% of jaundiced patients
required alternative therapies or OLT.101 No prospective
studies have assessed outcomes by using 2010 PG remis-
sion criteria; however, a retrospective report confirmed
the expectation of improved outcomes.102 By using 2002
PG criteria, 119 of 163 adult Italians (73%) achieved
remission, but histology progressed during remission in 36
of 66 patients (54.5%) with elevated AST/ALT levels. Only
42 of 163 patients (26%) achieved 2010 PG criteria for
remission. AIH progressed in only 1 of 23 patients (4%)
during mean follow-up of 8.33 years, confirming that
normalization of biochemical and histologic features pre-
vents progression. The IAIHG has proposed an interna-
tional database for a combined retrospective-prospective
study of the utility of the 2010 PG criteria.
November 2015
Induction and Maintenance
Immunosuppression
Three induction regimens have been demonstrated to
be safe and efficacious in adults with AIH (Figure 1).1,15
Before induction, patients should have normal vitamin D
levels103 and baseline bone mineral densitometry to
detect osteopenia.
Combination of prednisone or prednisolone and
azathioprine. Although steroid dosing is identical, AZA
dosing differs in the United States and Europe (Figure 1).
In the United States, the AZA dose is 50 mg/d, regardless
of body weight. In Europe, the AZA dose is 1–2 mg/kg/d.
For a 70-kg patient, low-dose AZA in Europe is w40%
higher than in the United States. A rising prevalence of
obesity makes under-dosing of AZA increasingly more
likely in the United States. Thus, AZA doses should be
incrementally increased to 2 mg/kg/d. Steroid is con-
traindicated by brittle diabetes mellitus, uncontrolled
hypertension, prior steroid intolerance, severe osteope-
nia, and psychosis. AZA is contraindicated by thiopurine
methyltransferase (TPMT) deficiency, leukopenia, or
thrombocytopenia.
Combination of budesonide and azathioprine. The
combination of budesonide and AZA in non-cirrhotic pa-
tients15 takes advantage of the avid first-pass extraction
of budesonide by the liver,21,104 dramatically reducing the
risk of systemic steroid toxicity.105 Budesonide is con-
traindicated in cirrhosis because portal systemic shunting
and abnormal hepatic metabolism prevent complete he-
patic first-pass extraction, reduce therapeutic efficacy,
and cause systemic steroid side effects.106 Budesonide
should never be used as monotherapy.107
A European multicenter, randomized controlled trial
showed that a combination of budesonide and AZA
induced remission more rapidly and effectively than
combination of prednisone and AZA in noncirrhotic pa-
tients with AIH.15 The first 6 months of the study were a
prospective, double-blind, randomized controlled, phase
2b comparison of AZA 1–2 mg/kg/d plus either bude-
sonide 3 mg 3 times a day or prednisone 40 mg/d
(tapered to 10 mg/d). After 6 months, all patients
switched to open-label budesonide and AZA. A composite
primary end point of normalization of AST/ALT levels
and absence of predefined steroid-specific side effects
after 6 months was used. Significantly more patients in
the budesonide group achieved the composite primary
end point within 6 months than in the prednisone group,
47% vs 18.4% (P < .001). After 6 months, 60% of pa-
tients in the budesonide group had normal AST/ALT
levels compared with 38.8% of patients in the predni-
sone group. Steroid-specific side effects were signifi-
cantly less frequent in patients on budesonide (28%)
than in patients on prednisone (53%). After switching to
open-label budesonide and AZA, the frequency of
steroid-specific side effects in the prednisone group fell
to 26.4%. Combination budesonide and AZA therapy is
safe and effective for induction and maintenance of
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Autoimmune Hepatitis and Overlap Syndromes 2097
remission in non-cirrhotic patients with AIH studied for
12 months.
Steroid monotherapy. Initiation with high-dose ste-
roid monotherapy (Figure 2) can identify a therapeutic
response within 4 weeks in the presence or absence of
cirrhosis.1 It is the regimen of choice for pregnant pa-
tients and those with cytopenias (eg, cirrhotic patients
with portal hypertension and hypersplenism), TPMT
deficiency, or malignancy. AZA can be combined with the
steroid after a minimum of 4 weeks to optimize immu-
nosuppression. Steroid doses can be tapered after addi-
tion of AZA to minimize risks of postmenopausal
osteoporosis, obesity, diabetes mellitus, hypertension,
emotional lability, and acne.
Maintenance regimens. A systematic review of ran-
domized controlled trials showed equivalent results for
induction by using prednisone alone or combination of
prednisone and AZA.108 A combination of prednisone
and AZA was superior for maintaining remission. How-
ever, the frequency of drug-induced complications is
higher in cirrhotic patients (25%) than in non-cirrhotic
patients (8%)1 treated with a combination of steroid
and AZA. Maintenance with AZA monotherapy was as
effective as continuation of low-dose steroid and AZA.108
In cirrhotic patients with portal hypertensive hyper-
splenism and cytopenias who cannot use AZA, alternative
therapies can be added after steroid induction (Figure 1).
Outcomes of maintenance therapy by using combination
of budesonide and AZA longer than 12 months have not
been reported.
AIH may “burn out”, resulting in normal AST/ALT and
g-globulin levels and biopsies showing “inactive”
cirrhosis or mild portal inflammation without interface
hepatitis. The 2010 PG recommended observation for
these patients.1
Extrahepatic malignancies, especially non-melanoma
skin cancers, are more frequent in immunosuppressed
patients with AIH than in the general population.95,96
Immunosuppressed patients should avoid excessive sun
exposure, use UVA/UVB sunscreen lotions, and have
annual skin examinations.
Steroid Treatment of Autoimmune Hepatitis
Presenting as Acute Liver Failure or Severe
Acute Hepatitis
Empiric steroids are often started in ALF patients
before results of autoantibodies or transjugular liver
biopsy are available.109,110 In 28 AIH patients with ALF
or severe acute hepatitis, only 17 of 28 responded to
steroids.90 In another series of 9 patients treated with
steroids, 4 recovered without OLT, and in the 5 non-
responders, 2 died and 3 required OLT.111 Indicators of
steroid response included decreased bilirubin and pro-
thrombin time international normalized ratio within 72
hours.112 No patient with a Model for End-Stage Liver
Disease score
28 responded to steroids.110,113 Because
2098 John M. Vierling Clinical Gastroenterology and Hepatology Vol. 13, No. 12

bacterial and fungal infections are absolute contraindi- A retrospective study in 7 academic and 14 regional
cations for OLT, the risks of infections with steroids must centers in the Netherlands reported relapse in 117 of
be weighed against the fact that steroids benefit only a 131 patients (89%),122 which included flares during
minority of patients.109,110 weaning in 49% and after withdrawal in 51%. The pro-
portion requiring retreatment rose progressively from
59% during the first year after withdrawal to 73% after
Thiopurine Methyltransferase and
2 years and 81% after 3 years. Risk factors for relapse
Azathioprine Metabolites
included use of combination steroid and AZA therapy,
coexistent autoimmune diseases, and younger age at
AZA is converted non-enzymatically to 6-mercaptopurine
withdrawal. After relapse, all later attempts to discon-
(6-MP), and enzymatic metabolism of 6-MP governs
tinue immunosuppression failed. In contrast, publica-
the immunosuppressive effect. Hypoxanthine phos-
tions from 1972 to 2014 reported successful long-term
phoribosyltransferase generates immunosuppressive 6-
withdrawal in 19%–40% of patients.121 Factors associ-
thioguanine nucleotide (6-TGN). In contrast, TPMT and
ated with sustained withdrawal were complete normal-
xanthine oxidase enzymatically convert 6-MP to 6-thiouric
ization of biochemical tests and histology. Sustained
acid and 6-methylmercaptopurine nucleotide (6-MMP),
withdrawal required biochemical remission of >12–24
respectively. Levels of 6-TGN and 6-MMP metabolites are
months, and histologic remission often lagged behind
similar in AIH patients with active disease or those in
biochemical remission by
8 months.121 Patients who
remission, indicating little impact of hepatic impairment
developed cirrhosis during therapy were particularly
on metabolism.114 Levels of 6-TGN and 6-MMP correlated
prone to relapse.
with the AZA dosage in native Alaskans and other non-
whites with AIH and normal TPMT activity.115 Leuko-
penia was not a surrogate for TPMT activity, because
Management of Autoimmune Hepatitis
patients with leukopenia on AZA predominantly had
in Pregnancy
normal TPMT activity.115
Testing for TPMT deficiency before AZA treatment of
Pregnancy affects AIH, and AIH impacts outcomes for
AIH is unnecessary, because severe TPMT deficiency
both mother and fetus.42 Thus, all pregnancies in women
occurs in 0.3%–0.5% of the general population and does
with AIH are high risk. Clinicians must discuss contra-
not invariably cause AZA-induced bone marrow
ception, family planning, and the need to report un-
toxicity.116–118 Advanced fibrosis and cirrhosis are better
planned pregnancies. In one study of women with AIH,
predictors of AZA toxicity than TPMT genotype or ac-
48% did not consult a physician before pregnancy.124
tivity.118 Heterozygotes with modestly decreased TPMT
Patients who did consult a physician reported being
activity tolerate doses of AZA of 50–150 mg/d. TMPT
advised to avoid pregnancy or to consider abortion.
testing should be done in cirrhotic patients with
Pregnancy induces maternal immunosuppression to
cytopenias.
protect the chimeric fetus. Thus, women with AIH may
Immunosuppressive 6-TGN levels are indicators
tolerate lower doses or even withdrawal of immuno-
of patient adherence and useful for individualizing
suppressive medications.125 In one study, more than
AZA doses.119 In a minority of nonresponders to AZA,
50% of unsupervised women stopped immunosuppres-
6-MP is preferentially metabolized by xanthine oxidase
sion during pregnancy and/or while breastfeeding.124
to non-immunosuppressive 6-thiouric acid. Allopurinol
Inappropriate reductions or cessation of immunosup-
inhibition of xanthine oxidase can redirect 6-MP
pression during pregnancy can result in flares in 33%–
metabolism to produce immunosuppressive 6-TGN.120
86%.125–127 Similarly, lower immunosuppressive doses
Thus, TPMT testing is required before categorizing
sufficient during pregnancy were usually inadequate
a patient as a nonresponder in need of alternative
post partum, resulting in flares in 30%–52%.42,124,127
immunosuppression.
In 2 reports, between 41% and 68% of pregnant
women had cirrhosis with increased risks of portal hy-
Remission and Withdrawal of pertensive complications because of the increased blood
Immunosuppressive Therapy volume and hyperdynamic circulation of preg-
nancy.126,127 Pregnant cirrhotic women should have
After documenting a sustained remission by endoscopic screening for gastroesophageal varices and
biochemical tests and liver biopsy, all adults are potential continue abdominal ultrasound surveillance for HCC.
candidates for a single trial of withdrawal of immuno- Maternal complications occurred in 11% in 1 retro-
suppressive therapy.1,121 Unfortunately, only a minority spective study and included flares resulting in decom-
of patients achieve permanent withdrawal.122 With- pensation, maternal death, or need for OLT during
drawal after a relapse is contraindicated because the pregnancy or within 1 year post partum.126 Cirrhosis
number of failed attempts significantly increased risks of was a significant risk factor for decompensation during
progression to cirrhosis (38% vs 4%) and death because pregnancy or within 3 months after delivery.126 Adverse
of liver failure or need for OLT (20% vs 0%).123 fetal outcomes included reduced live birth rates because

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November 2015
of fetal loss to prematurity, increased need for neonatal
intensive care, and congenital malformations.42,126,127
Use of AZA at conception and during pregnancy
appeared to be safe; overall, immunosuppressive therapy
was not a risk factor for decreased live birth rates,
elective abortions, miscarriages, or prematurity.42,124,127
In one series, however, AZA was discontinued in favor of
steroid monotherapy in 80%, and 20% discontinued all
immunosuppression during pregnancy.127 Budesonide
monotherapy should not be used in the absence of data
on safety and efficacy in pregnancy and the risk of flares
in AIH patients treated with budesonide alone.107 In
women taking AZA, both mothers and neonates had
immunosuppressive 6-TGN metabolites in serum at
birth. None of the neonates had 6-MMP metabolites.128
To prevent postpartum flares of AIH, clinicians should
preemptively increase the doses of immunosuppressive
drugs or add back AZA and frequently monitor AST/ALT
levels. Onset of de novo AIH can also occur 4 months
post partum, presumably because of reconstitution of
immunocompetence in a susceptible woman.129
Treatment of Overlap Syndromes
Patients with putative AIH-PBC or AIH-PSC OS
or cholestasis often have had ursodeoxycholic acid
(UDCA) added to their immunosuppressive regi-
mens.12,31,51,72,130,131 UDCA has not been studied in a
randomized controlled trial in such patients.31,51 Simi-
larly, patients with classic PBC or PSC and features of
AIH have been treated with empiric immunosuppression,
despite absence of proof of efficacy.12,31,51 Evidence that
classic PBC responds to steroids55 or CSA56 but not
AZA54,57 complicates interpretation of efficacy. Current
knowledge of therapy for OS is based on small case series
of patients arbitrarily treated with immunosuppression
and/or UDCA. No randomized controlled trials have been
performed.
Treatment of autoimmune hepatitis–primary biliar
cirrhosis overlap. Among 16 patients from Japan, diag-
nosis of PBC preceded features of AIH in 6 (38%); AIH
and PBC were diagnosed concurrently in the other 10
(62%).61 AST/ALT and alkaline phosphatase levels
normalized in 13 of 16 by using combination of immu-
nosuppression and UDCA. The 3 patients treated with
either steroid or UDCA as monotherapy progressed to
decompensated cirrhosis or liver-related deaths after 5,
12, or 14 years.
Five centers retrospectively reported clinical and
histologic features and treatment responses in 115
consecutive patients with AIH (n ¼ 48), AIH-PBC OS
(n ¼ 15), and PBC (n ¼ 52).62 Six of 11 OS patients
(55%) responded to either UDCA monotherapy or
immunosuppressive drugs. All 7 patients treated with
combination therapy responded, 5 to a combination of
steroids-AZA-UDCA. When steroids were added to UDCA
in 20 of 28 Japanese PBC patients with suspected OS,132
15 of the 20 (75%) responded. Factors predictive of
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Autoimmune Hepatitis and Overlap Syndromes 2099
steroid failure were high levels of alkaline phosphatase,
gp210-specific ANA, and absence of SMA. The outcomes
of steroid responders were superior to those of the 5
nonresponders and 8 ineligible for steroid treatment.
Among 12 Turkish patients with AIH-PBC OS, 3 were
treated with UDCA alone and 9 with immunosuppression
and UDCA.72 Six of the 12 patients progressed to liver
failure.
Treatment of autoimmune hepatitis–primary sclerosing
cholangitis. Although the safety and efficacy of immu-
nosuppressive treatment are established in AIH, no
effective therapy exists for PSC. Whereas immunosup-
pression is rational for the AIH component of AIH-PSC OS
use of empiric UDCA is controversial. In PSC patients,
UDCA doses of 13–15 mg/kg/d were ineffective, doses of
20 mg/kg/d showed promise in a small randomized
controlled trial, doses of 17–23 mg/kg/d showed a trend
toward benefit but did not reach statistical significance,
and high doses of 30–35 mg/kg/d were deleterious.75
The efficacy of combination therapy with immunosup-
pression and varying doses of UDCA in AIH-PSC OS
ranged from 20% to 100% and varied inversely with
severity of cholestasis.11,51,72 In selected patients,
empiric CSA, mycophenolate mofetil (MMF), and bude-
sonide were beneficial.11,31
Alternative immunosuppression for autoimmune
hepatitis overlap syndromes. Two retrospective studies
reported the effect of MMF for treatment of AIH OS. By
using the 2002 PG definition of remission, 5 of 16 pa-
tients (31%) with AIH, AIH-PBC, or AIH-PSC OS treated
with MMF had biochemical remission, 7 (44%) had
partial remission, 2 (12.5%) had incomplete responses,
and 2 (12.5%) had no response.133 The choice of MMF
was based on AZA intolerance, nonresponse to steroid
and AZA, or physician preference. The Dutch Autoim-
mune Hepatitis Group cohort assessed the efficacy of
MMF in patients with AIH OS with AZA intolerance or
nonresponse.134 MMF induced remissions in 57% of
nonresponders to AZA and in 63% of patients intolerant
of AZA. MMF caused adverse events in 33% and required
discontinuation in 13%. Decompensated cirrhosis, OLT,
and death occurred exclusively among AIH non-
responders to AZA. In a retrospective report combining
data from 5 centers, 2 patients with AIH-PBC overlap
responded to a combination of CSA and UDCA.62
Autoimmune hepatitis–immunoglobulin G4 variant. The
AIH-IgG4 variant was identified in 2 of 60 patients
(3.3%) with type 1 AIH.76 Steroid therapy normalized
both ALT and histology and decreased serum IgG4
levels. One of the 2 patients developed IgG4-associated
secondary sclerosing cholangitis 5 years later.
Serum IgG4 levels may not be diagnostic. Normal serum
levels do not exclude the diagnosis, which requires
quantification of plasma cells expressing IgG4 in liver
tissue.76
Autoimmune hepatitis–immunoglobulin G4 secondary
sclerosing cholangitis overlap syndrome. Accurate diag-
nosis of this subset of OS patients is essential because of
excellent responses to steroid therapy.75,135–137 The
2100 John M. Vierling
efficacy of combination of steroids and UDCA remains
undefined.11,75
Alternative Immunosuppressive Therapies
Alternative immunosuppressive therapies are
appropriate for AIH patients who fail to achieve re-
mission by using conventional immunosuppression
or those who cannot tolerate steroids or AZA
(Figure 1).21,74,105,108,130,138–152 Application of the strin-
gent 2010 PG criteria for remission will increase the
number of AIH patients requiring alternative thera-
pies.102 The choice of alternatives is empiric, because
none of the alternative therapies has been studied in
randomized controlled trials.
Before resorting to alternative therapies, non-
responders to conventional immunosuppression
should be treated with intensified conventional therapy
by using either prednisone 60 mg/d or prednisone 30
mg/d and AZA 150 mg/d.1 Patients unresponsive to
AZA should have TPMT testing to detect lack of
adherence and possible need for allopurinol. Because
AZA is the prodrug of 6-MP, 6-MP may be more effec-
tive than AZA and should be tried before resorting to
alternative therapies. Neither UDCA nor budesonide
was effective in AIH patients refractory to or intolerant
of standard immunosuppression.153,154 Enthusiasm for
methotrexate as an alternative therapy for AIH155,156
or AIH-PBC OS157 waned after reports of AIH induced
by methotrexate158,159 and methotrexate hepatotoxic-
ity in patients with inflammatory bowel disease or
arthritis.158,160
Mycophenolate mofetil or mycophenolic acid. My-
cophenolate mofetil (MMF) is the prodrug of mycophe-
nolic acid. Both MMF and mycophenolic acid are
alternatives for the antiproliferative effects of AZA;
however, MMF and mycophenolic acid more selectively
target B and T cells than AZA.161 MMF treatment led to
sustained remissions in 8 of 9 patients (88%) with AZA
intolerance but in none of 12 nonresponders to AZA.161
MMF treatment of 29 AIH patients (12 with AZA intol-
erance or nonresponse to prednisone and AZA and 17
with or without initial therapy with prednisone) was
associated with adverse events requiring discontinuation
in 10 of the 29 (34%).162 However, 16 of the remaining
19 (84%) achieved 2002 PG criteria for remission. In a
small study, 5 of 8 patients (62%) treated with MMF as
initial therapy or after adverse steroid events achieved
remission based on 2002 PG criteria,163 but none
normalized AST/ALT or achieved histologic resolution.
The Dutch Autoimmune Hepatitis Group achieved
remission in only 13% of AZA nonresponders compared
with 67% in those with AZA intolerance (P ¼ .008).134 A
multicenter Canadian consortium reported that 7 of 11
patients (64%) treated with MMF for AZA nonresponse
or intolerance had sustained normalization of AST/
ALT.164 Another study reported that ALT levels and
histologic inflammatory and fibrosis scores decreased
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Clinical Gastroenterology and Hepatology Vol. 13, No. 12
significantly in 15 patients treated with MMF (mono-
therapy or combined with prednisone) after AZA
nonresponse or intolerance.165 Overall, patients who
failed to respond to AZA were unlikely to achieve 2010
PG criteria for remission after switching to MMF or
mycophenolic acid. In contrast, MMF and mycophenolic
acid appear to be effective for patients intolerant of AZA.
Calcineurin inhibitors. The calcineurin inhibitors
(CNIs), tacrolimus (TAC) and cyclosporine (CSA), were
endorsed as alternative therapies by the 2010
PG.1,130,143,144 Both TAC and CSA inhibit the calcineurin-
dependent production of the nuclear factor for activated
T cells (NFAT) required for production of the T-cell
mitogen interleukin-2 and other growth factors required
for proliferation and maturation of CD4 and CD8 effector
T cells.
Tacrolimus. TAC has been a successful alternative
therapy in AIH patients with suboptimal responses to
steroid and AZA and those with drug intoler-
ance.139,145–147,166–169 In a case series, 21 adults treated
with TAC had 80% reductions in ALT levels after 3
months and low median serum trough levels of 0.5 ng/
dL.170 TAC caused mild rises in blood urea nitrogen
(12–18 mg/dL) and serum creatinine (0.9–1.3 mg/dL)
and modest decreases in leukocytes and platelets. Low-
dose TAC (1 mg/d) therapy in 11 steroid-refractory
adults significantly reduced the median ALT (77 U/L to
21 U/L at end of follow-up; P ¼ .005) and achieved
histologic remission without major adverse events.171 A
single center reported that TAC treatment normalized
AST/ALT in 12 of 13 patients (92%) with advanced
histology (5 with cirrhosis, 8 with multilobular necrosis
or bridging fibrosis).172 TAC was discontinued in 1 pa-
tient for hemolytic uremic syndrome and in another for
squamous cell carcinoma. A retrospective Canadian
report identified only 3 patients treated with TAC mon-
otherapy and 2 treated with TAC and MMF.164 A single
patient (20%) had a biochemical response. In 9 steroid-
refractory patients, TAC treatment for a median of 18
months significantly decreased mean ALT levels (154 U/
L to 47 U/L, P ¼ .007) and mean IgG levels (16 g/L to
14.5 g/L, P ¼ .032).173 Biopsies showed significant de-
creases in hepatic inflammatory activity (P ¼ .016) and
Ishak fibrosis score (P ¼ .049). TAC permitted significant
reductions of prednisolone doses to a mean of 7.5 mg/
d (range, 5–12.5 mg/d) from pretreatment doses of
20–80 mg (P ¼ .004).
Cyclosporine. CSA appears to be safe and effica-
cious as an alternative therapy for AIH. In 1 report, CSA
therapy (3 mg/kg/d) normalized or nearly normalized
ALT within 10 weeks in 5 of 6 adults with type 1 AIH
(1 with possible AIH-PSC OS) who had failed treatment
with steroids or steroids and AZA.174 Biochemical re-
missions were sustained for up to 1 year. Liver biopsies
performed in 3 of the 5 responders showed histologic
improvement. Adverse events occurred in 33%. Another
study of 5 adult AIH patients who were nonrespon-
ders to steroids and AZA showed that low-dose CSA
November 2015
normalized AST/ALT in 4 (80%) within 3 months.175
CSA monotherapy maintained remission in 2 patients.
Low-dose CSA was well-tolerated without renal insuffi-
ciency. CSA therapy in 8 patients with AIH, 2 with
autoimmune cholangitis and 2 with giant cell hepatitis,
induced remission in all 12 in a median of 4.5 weeks
(range, 2–12 weeks).176 CSA sustained remission during
a median follow-up of 6.5 years (range, 1.5–15 years); 3
patients with severe hepatic impairment required a
combination of CSA and standard immunosuppression.
CSA was well-tolerated with only 1 transient elevation of
serum creatinine. An open-label study of low-dose CSA
for 26 weeks in 19 AIH patients (9 treatment-naive, 10
nonresponders) showed significant decreases in mean
ALT levels (454.8 U/L to 78.5 U/L, P < .001) and
improved histology (hepatic activity index, 15.2 to 7.14;
P < .005).177 Serum creatinine levels were stable.
Sirolimus and everolimus. Sirolimus (SIR) and ever-
olimus (EVR) inhibit the mammalian target of rapamycin,
blocking mammalian target of rapamycin activation
caused by mitogenic interleukin-2 binding to its T-cell
receptor (CD25).178,179 Thus, mammalian target of rapa-
mycin inhibition prevents proliferation and maturation of
CD4 and CD8 effector T cells.1,130,143,144 Because CNIs
decrease interleukin-2 production and SIR/EVR block
interleukin-2 effects, combination therapy is a rational, yet
untested, option. In contrast to CNI nephrotoxicity, SIR or
EVR protects renal function. SIR treatment of 5 adults
with steroid-refractory AIH resulted in sustained
normalization of ALT in 2 (40%), reduction of ALT by
>50% in 4 (80%), and allowed significant reductions in
steroid dosage (P < .05).178 In 7 adult nonresponders to
steroids, AZA, MMF, or CNIs, EVR induced sustained
biochemical remission in 4 (57%), whereas liver biopsies
showed either no progression in 2 or improvement in
2.179 SIR and EVR treatments were successful in recurrent
AIH or interferon-induced AIH after OLT.180,181
Rituximab. Rituximab (RIT), a monoclonal antibody
against CD20 expressed on mature B cells, is used ther-
apeutically to deplete B cells in patients with B-cell
lymphomas or antibody-mediated autoimmune dis-
eases.149 Efficacy in AIH was discovered by chance in 2
adult patients with AIH who were treated with RIT for
idiopathic thrombocytopenia purpura or B-cell lym-
phoma.182,183 Subsequently, RIT successfully induced
remission in a woman with refractory AIH complicated
by autoimmune hemolytic anemia and idiopathic
thrombocytopenic purpura consistent with Evans syn-
drome184 and an elderly woman with steroid-refractory
AIH.185 An open-label, single-center pilot study of RIT
in 6 adult nonresponders to steroid and AZA showed
significant decreases in mean levels of AST (90.0 vs 31.3
U/L, P ¼ .03) and IgG (16.4 g/L vs 11.5 g/L, P ¼ .056).149
Repeat liver biopsies in 4 patients showed improved
inflammation. No serious adverse events occurred. Lim-
itations of RIT for AIH include need for intravenous
infusion, risk of reducing protective antibody titers to
pathogens, and high cost.
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Autoimmune Hepatitis and Overlap Syndromes 2101
Infliximab. Infliximab, a monoclonal antibody against
tumor necrosis factor alpha, has been used successfully
in refractory AIH.186,187 In a single-center, off-label study
of 11 AIH patients who failed standard immunosup-
pression, infliximab therapy significantly decreased
mean AST levels (475 U/L to 43 U/L) and mean IgG
levels (24.8 mg/dL to 17.4 mg/dL).186 Reports that
either infliximab188–191 or adalimumab150,192 can cause
DILI resembling AIH are disturbing. Whether infliximab
causes de novo AIH remains controversial.193
Need for Randomized Controlled Trials of
Alternative Immunosuppression
None of the alternative therapies have been studies in
multicenter, randomized controlled trials, despite de-
cades of empiric use. Impediments to randomized
controlled trials include high costs with little prospect of
funding, differing opinions about which alternative
therapies should be studied and whether they should be
added to standard immunosuppression or used as a
substitute, and the prospect that patients randomized to
a control group will exit the study to obtain off-label
empiric therapy.
Orthotopic Liver Transplantation
AIH is the indication for OLT in approximately 4% of
adults in the United States and Europe.16,194
OLT for AIH has achieved excellent 5-year and 10-
year survivals of >70% for adults with AIH.16,194,195 In
Europe, the 5-year survival of 827 AIH patients after OLT
of 73% (95% confidence interval, 67%–77%) was com-
parable to that of 6424 patients transplanted for alco-
holic cirrhosis (74%; 95% confidence interval,
72%–76%) but significantly inferior to that in 1588 pa-
tients transplanted for PBC (83%; 95% confidence in-
terval, 80%–85%).194 Infections after OLT were a
significant factor for increased mortality of AIH patients
compared with PBC (hazard ratio, 1.8; P ¼ .002). Five-
year survivals after OLT for AIH varied inversely with
age, 78% (95% confidence interval, 70%–86%) for ages
18–34 vs 61% (95% confidence interval, 51%–70%) for
age >50 years.
AIH recurs in donor allografts, despite the absence of
intentional HLA matching between donor and recipient
in OLT.16,196,197 Because autoreactive T cells are
restricted to recognition of autoantigens presented by
self-HLA molecules,198,199 putative recurrent AIH may be
a different disease involving distinct pathogenic mecha-
nisms.198 HLA restriction may not be absolute after OLT.
For example, in recurrent HCV infection after OLT, HLA-
restricted recipient T cells paradoxically engage specific
HCV antigens expressed by mismatched donor HLA on
hepatocytes.200
On the basis of arbitrary diagnostic criteria for
recurrent AIH,16,196,197 reported rates varied from 12%
2102 John M. Vierling
Figure 3. Future strategies for therapy and prevention of AIH.
Novel strategies for immunosuppression: Block co-
stimulation of T cells required for proliferation and effector
cell functions (belatacept); inhibit pyrimidine synthesis
required for T- and B-cell proliferation (leflunomide); lyse
activated effector T cells expressing CD3 (otelixizumab,
teplizumab), CD4 (MTRX1011A or CD52 (alemtuzumab); in-
hibition of promoter genes involved in pathogenesis by using
small interfering RNA. Prevention of effector cell trafficking to
portal tracts: Sequester activated T cells in lymphoid tissues
and thymus (fingolimod); prevent effector T-cell trans-
endothelial migration from portal veins to portal tracts (leflu-
nomide and inhibitors of chemokine receptors expressed on
T cells). Antifibrotics to prevent cirrhosis: Block collagen
cross-linking (simtuzamab); inhibit hepatic fibrogenesis (fuz-
heng huayu). Autoantigen-specific immunoregulation: Inhibit
hepatic autoantigen-specific effector functions of CD4 T cells
in AIH by ex vivo induction of autologous autoantigen-
specific T-regulatory cells and infusion to achieve immuno-
regulation. Restoration of tolerance to hepatic autoantigens:
No specific strategies applicable to AIH have been proposed.
Theoretically, elimination of autoreactive T and B cells, fol-
lowed by inhibition of co-stimulation for newly generated T
cells and block of their chemokine receptors could lead to
clonal anergy and/or exhaustion. Tolerogenic vaccination for
prevention: Identification of primary hepatic autoantigen(s) for
type 1 AIH and those because of epitope spreading in both
types 1 and type 2 diseases could be exploited for tolero-
genic vaccination in susceptible persons with family histories
of autoimmunity and associated HLA haplotypes.
to 50% after 8–10 years, with a median time to diagnosis
of 2 years.201–204 After corrections for biases, the true
weighted recurrence rate appears to be 22%,205 and the
rate of AIH recurrence was similar for TAC or CSA
immunosuppression.
Remission of recurrent AIH usually occurs after
resumption of steroids and optimization of calcineurin
inhibitor doses.206,207 In refractory patients, remission
may require AZA208 or SIR.180 Refractory AIH infre-
quently progresses to cirrhosis or allograft failure, and
retransplantation is rare. However, AIH may recur in a
second allograft.209
De novo autoimmune hepatitis after trans-
plantation. AIH is unique among AILDs because of de
novo occurrence in allografts after OLT for other disease
indications such as HCV infection or alcohol, WD, PBC,
PSC, and ALF.1,16,210–212 De novo AIH after OLT should be
considered in the differential diagnosis of patients with
abnormal AST/ALT levels and interface hepatitis.213
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Clinical Gastroenterology and Hepatology Vol. 13, No. 12
Successful treatments have been reported by using
intensified dosing or reintroduction of steroids and
optimizing dosages of calcineurin or mammalian target
of rapamycin inhibitors.16,196,197 Refractory patients may
benefit from the addition of AZA (1–2 mg/kg/d) or MMF.
SIR has been used to treat recurrent AIH in children,
suggesting that it might be effective in de novo AIH in
adults.180
Future Therapies
The incomplete understanding of the immunopatho-
genesis of AIH continues to impede identification of
specific therapies.5 This is especially true for type 1 AIH
because neither B-cell nor T-cell autoantigenic epitopes
have been identified. Figure 3 summarizes future thera-
peutic and preventative strategies.
Key Points
After exclusion of liver diseases with clinical,
biochemical, and histologic features similar to those of
AIH, IAIHG diagnostic criteria can aid in determining the
probability of a diagnosis of type 1 or 2 AIH (Table 3).
AIH with cholestatic features of either PBC or PSC occurs
in a minority of patients; however, it is premature to
conclude that this represents the concomitant presence
of 2 distinct AILDs. The AASLD 2010 PG redefined the
goal of immunosuppressive therapy to be complete
normalization of ALT and elimination of hepatic inflam-
mation (Table 4). To achieve this more stringent goal will
require increased use of alternative immunosuppressive
therapies, none of which have been studied in appro-
priately powered, randomized controlled trials. The
weight of available evidence favors use of calcineurin
inhibition with CSA or TAC, but only by clinicians expe-
rienced with these drugs. Studies of immunopathogenic
mechanisms in AIH may result in discovery of novel
diagnostic and prognostic biomarkers and innovative
therapeutic strategies.
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Correspondence
Address correspondence to: John M. Vierling, MD, 6620 Main Street, Suite
1425, Houston, Texas 77030. e-mail: vierling@bcm.edu; fax: (713) 610-2479.
Acknowledgments
The author thanks Donna M. Vierling, MD for assistance in research of the
literature and critique of the manuscript.
Conflicts of interest
Dr Vierling is co-author of “Immunosuppression in Liver Transplantation” in
UptoDate. He was a principal investigator in clinical trials of antiviral agents for
HCV infection sponsored by Roche, the maker of mycophenolate mofetil, and
Novartis, the maker of mycophenolic acid, and everolimus. He was principal
investigator in a clinical trial of Fuzheng Huayu (Chinese herbal antifibrotic
compound) in chronic HCV infection.