Journal of Autoimmunity xxx (2016) 1e14

Contents lists available at ScienceDirect

Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

Review article

Cutting edge issues in autoimmune hepatitis

Rodrigo Liberal a, Edward L. Krawitt b, c, John M. Vierling d, Michael P. Manns e,
Giorgina Mieli-Vergani a, f, Diego Vergani a, *
a
Institute of Liver Studies, Kings College Hospital, London, UK
b
Department of Medicine, Dartmouth College, Hanover, NH, USA
c
Department of Medicine, University of Vermont, Burlington, VT, USA
d
Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Lukes Medical Center, Houston, TX, USA
e
Hannover Medical School, Hannover, Germany
f
Paediatric Liver, GI & Nutrition Centre, Kings College Hospital, London, UK

a r t i c l e i n f o a b s t r a c t

Article history: Autoimmune hepatitis (AIH) is a severe liver disease affecting all age groups worldwide. Novel basic and
Received 28 April 2016 clinical aspects of AIH, addressed at a Monothematic Conference in London in September 2015, are
Received in revised form highlighted in this review. The diagnosis of AIH relies upon detection of characteristic autoantibodies,
6 July 2016
hypergammaglobulinemia, and interface hepatitis on liver histology. The International Autoimmune
Accepted 10 July 2016
Available online xxx
Hepatitis Group (IAIHG) has devised diagnostic scoring systems to help in comparative studies and
clinical practice. AIH arises in a genetically predisposed host, when yet unknown triggers e such an
encounter with a pathogen e lead to a T cell-mediated immune response targeting liver autoantigens.
Keywords:
Autoimmune hepatitis
This immune response is inadequately controlled because regulatory mechanisms are impaired. The
Pathogenesis mainstay of treatment for AIH is immunosuppression, which should be instituted as soon as the diag-
Immunosuppression nosis is made. Standard treatment regimens include relatively high doses of predniso(lo)ne, which are
International Autoimmune Hepatitis Group tapered gradually as azathioprine is introduced. Recent guidelines have described newer treatment
regimens and have tightened the goal of therapy to complete normalization of biochemical, serological
and histological parameters. Mycophenolate mofetil, calcineurin inhibitors, mTOR inhibitors and bio-
logical agents are potential salvage therapies, but should be reserved for selected non-responsive pa-
tients and administered only in experienced centers. Liver transplantation is a life-saving option for those
patients who progress to end-stage liver disease. Further dissection of cellular and molecular pathways
involved in AIH pathogenesis is likely to lead to the discovery of novel, tailored and better tolerated
therapies.
2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Potential triggers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Effector immune mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.4. Regulatory immune mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.5. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Presentation and natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Corresponding author. Institute of Liver Studies, Kings College Hospital,

Denmark Hill, London SE5 9RS, UK.
E-mail address: diego.vergani@kcl.ac.uk (D. Vergani).

http://dx.doi.org/10.1016/j.jaut.2016.07.005
0896-8411/ 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: R. Liberal, et al., Cutting edge issues in autoimmune hepatitis, Journal of Autoimmunity (2016), http://
dx.doi.org/10.1016/j.jaut.2016.07.005
2 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14

4.2. Diagnosis and scoring systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.3. Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Standard treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Alternative treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.3. Liver transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Special presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Variant syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Acute severe to fulminant AIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. Drug induced AIH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.4. AIH and pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Grant support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction unrestrained because of the failure of immunoregulatory mecha-

nisms, is thought to initiate and perpetuate the liver damage [14].
In 1965, about a decade after the concept of immune tolerance Sixteen years after the American Association for the Study of the
had been established, Ian Mackay and colleagues proposed the Liver (AASLD) convened a Single Topic Conference on clinical as-
term autoimmune hepatitis, now widely accepted by the hepatol- pects of AIH, Atlanta 1999 [15], a Monothematic Conference dedi-
ogy community, for a form of chronic liver disease characterized by cated to AIH took place in London in September 2015. This 2-day
hyperglobulinemia and a mixed histological inltrate of plasma conference, jointly sponsored by the European Association for the
cells and lymphocytes that had been recognized already in the Study of the Liver (EASL) and the AASLD, covered both pathogenic
1950s by Jan Go sta Waldenstro m [1,2]. The presence of lupus ery- and clinical aspects of the disease. This review summarizes the
thematosus cells and the detection of anti-nuclear antibody (ANA) topics discussed, highlighting recent breakthroughs in our under-
seropositivity, previously had led to the adoption of the term standing of the pathogenesis of AIH and linking them to advances
lupoid hepatitis and the idea that the condition stemmed from a in clinical practice.
loss of immunological tolerance [3]. The positive impact of gluco-
corticosteroid therapy, initially recognized in the 1950s, resulted in 2. Epidemiology
the publication of three controlled clinical trials which incontro-
vertibly showed the life-saving value of corticosteroids [4e6]. The AIH most commonly affects females, with a male:female ratio of
recognition that chronic active autoimmune hepatitis, as it was 1:4 [16]. Although the peak incidences of the disease are in
then known, constituted a distinct clinical entity, led to the sys- adolescence and at 30e45 years of age, AIH can affect children and
tematic evaluation of its clinical symptoms, laboratory features, and adults of all ages [16]. The exact incidence and prevalence of AIH are
molecular immunopathology [7]. During two working meetings unknown because most studies were conducted before the intro-
held in the early 1990s, the International Autoimmune Hepatitis duction of standardized criteria developed by the IAIHG [9]. Re-
Group (IAIHG) formally endorsed the term autoimmune hepatitis, ported prevalences varies from 11.6 cases per 100,000 inhabitants
as originally suggested in 1965 [8], as the most appropriate and over the age of 14 in Spain [17], to 24.5 per 100.000 in New Zealand
least redundant name, noting that the disease frequently presents and 35.9 cases per 100,000 in Alaskan natives [18,19]. Reported
acutely, often has a uctuating course, characterized by sponta- mean annual incidences are 1.9 cases per 100,000 inhabitants in the
neous remission, and periods of inactivity [9,10]. The IAIHG con- Norwegian population [20], and 3 cases per 100,000 inhabitants in
tinues to monitor developments in the eld and was responsible for the United Kingdom [21]. More recently, a nationwide registry-
devising an AIH scoring system, which was subsequently revised based cohort study from Denmark reported an incidence rate of
[9,10]. More recently, a simplied system, designed for use in in- 1.68 cases per 100,000 people and demonstrated that the incidence
dividual patients in clinical practice, was proposed which has of the disease increased during 1994e2012 [22]. A recent study
gained wide acceptance [11]. including all pediatric centres in Canada and using the IAIHG
Two types of AIH are recognized, based on the serological standardized criteria reported an annual incidence of AIH of 0.23
autoantibody prole: AIH type 1 (AIH-1) is dened by positivity for cases per 100,000 children [23]. AIH is thought to be less frequent
ANA and/or anti-smooth muscle antibody (SMA), whereas AIH type in Asia; in Japan the incidence and prevalence are estimated to be
2 (AIH-2) is characterized by the presence of anti-liver kidney 1.5 and 15.0 cases per 100,000 people respectively [24]. Epidemi-
microsomal type 1 antibody (anti-LKM-1) or anti-liver cytosol type ological studies are detailed in Table 1.
1 antibody (anti-LC-1). Besides the presence of autoantibodies, AIH
is associated with elevated transaminase and immunoglobulin G 3. Pathogenesis
(IgG) levels, and histologically, with interface hepatitis. In symp-
tomatic cases, immunosuppressive therapy, which remains the 3.1. Genetics
mainstay of treatment, should be instituted as soon as the diagnosis
is made to avoid progression of disease and, generally, the response AIH is a complex trait disease: at variance with single gene
is good. If left untreated, AIH usually progresses to liver failure disorders, where a single mutation is responsible for a complete
requiring transplantation [12,13]. The etiology of AIH is unknown, phenotype, the inheritance of AIH involves both genetic and envi-
though both genetic and environmental factors are likely to be ronmental factors whose interaction either increase or reduce the
involved. An immune response targeting liver autoantigens, risk of the disease [25]. Susceptibility to AIH is strongly inuenced

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 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14 3

Table 1 reinforcing the previously acknowledged HLA association [29].

Epidemiology of autoimmune hepatitis. HLA alleles have also been linked to clinical manifestations,
Location Year Incidence Prevalence Reference response to treatment and prognosis of the disease. For example,
(per 100.000 (per 100.000 DRB1*0301 positive AIH-1 patients are more likely to be male, to
inhabitants) inhabitants) present with high IgG levels, to deteriorate despite corticosteroid
Norway 1998 1.9 16.9 [20] treatment and to progress more frequently to liver transplantation
Alaska 2002 n/a 35.9 [19] [30e32].
Spain 2004 0.83a 11.6a [17]
Susceptibility to, and severity of, AIH-2 have been linked to al-
United 2007 3.0 n/a [21]
Kingdom leles encoding the DR3 (DRB1*0301) and DR7 (DRB1*0701) mole-
New Zealand 2010 2.0 24.5 [18] cules in the United Kingdom and Brazil [33,34]. Allelic variation
Denmark 2014 1.68 23.9 [22] within HLA-DRB1 has been associated to differences in the auto-
Canada 2015 0.23b n/a [23]
antibody seropositivity proles of AIH-2 patients [35]. Since the
Japan 2015 1.5 15.0 [24]
specic residues conferring susceptibility vary geographically, it is
n/a, non applicable. possible that the T-cell mediated immune responses characteristic
a
In individuals over 14 years of age.
b of AIH are initiated by a range of antigenic peptides, which vary
Pediatric patients only.
geographically alongside the HLA molecules presenting them
[32,36]. The reported HLA associations are summarized in Table 2.
by the large and highly polymorphic human leukocyte antigen There are also reports of polymorphisms outside the HLA locus
(HLA) region, which contains several genes related to the adaptive inuencing susceptibility to AIH. For example, polymorphisms
immune system. Indeed, AIH has been long linked with variations located within the CTLA-4, TNF-a gene promoter and Fas genes have
in the HLA locus on the short arm of chromosome 6, with the been suggested, albeit inconsistently, to confer susceptibility to
strongest associations found within the genes encoding the HLA AIH-1 [12]. Similarly, the GWAS mentioned above reported that
class II DRB1 alleles. Initial candidate-gene studies have shown that AIH-1 is associated not only with polymorphisms within the HLA
the alleles encoding the HLA-DR3 (DRB1*0301) and DR4 region, but also with variants of CARD10 and SH2B3 genes [29], the
(DRB1*0401) molecules confer susceptibility to AIH-1 in European latter being also linked to primary biliary cholangitis (PBC) and
and North American populations [26], whereas the alleles primary sclerosing cholangitis (PSC) susceptibility [37]; an associ-
DRB1*0405 and DRB1*0404 are linked to AIH susceptibility in Japan, ation with single-nucleotide polymorphisms described in other
Argentina and Mexico [27]. Besides imparting risk, there are also immune-mediated diseases was also observed.
variants that may protect from disease, as shown in a meta-analysis The occurrence of an AIH-like picture in patients with rare
reporting that in Latin America DRB1*1302 and DQB1*0301 are monogenic disorders, such as autoimmune polyendocrinopathy-
protective alleles [28]. candidiasis-ectodermal dystrophy (APECED) or immunodysregu-
More recently, the rst AIH genome wide association study lation polyendocrinopathy enteropathy X-linked (IPEX) syndromes
(GWAS), conducted in Dutch adult AIH-1 patients and replicated in e caused by mutations in AIRE-1 and FOXP3 genes respectively e as
a German cohort, identied DRB1*0301 and DRB1*0401 as primary well as in patients with CTLA-4 or GATA-2 mutations, further sup-
and secondary susceptibility genotypes, respectively, thus ports the role of non-HLA genes in the pathogenesis of AIH [38,39].

Table 2
HLA associations in autoimmune hepatitis.

HLA locus Allele association AIH-1 AIH-2

HLA-B B8 LD with DRB1*0301

Severe disease course
Relapse after drug withdrawal
More frequent requirement for LT
HLA-C Cw7 Susceptibility in United Kingdom (LD with DRB1*0301)
HLA-DRB1 DRB1*0301 Susceptibility in Europe and North America Second most frequent susceptibility allele in
Younger age at onset, higher rate of treatment failure, relapse after children
drug withdrawal, and requirement for LT than DR4 Associated with seropositivity for both
More frequently linked to anti-SLA/LP anti-LKM-1 and anti-LC-1
DRB1*0401 Susceptibility in Europe and North America
Later age at onset than DR3
Higher frequency in women
Low frequency of progression to hepatic failure and death
Higher frequency of ANA positivity
DRB1*0404 Susceptibility in Mexico
DRB1*0405 Susceptibility in Japan and Argentina
DRB1*0701 Susceptibility in Europe and in Brazil
Predominant amongst patients
positive for only anti-LKM-1
Aggressive disease course and worse prognosis
DRB1*1301 Susceptibility in South America and in DR3/DR4-negative Early age onset in Brazil
North American patients
DRB1*1501 Protection in United Kingdom
HLA-DQ DQB1*0201 Susceptibility in United Kingdom and South America Susceptibility in Europe and in North America
(LD with DRB1*0301 and DRB1*0701)
DQB1*0301 Protection in South America
DQB1*0601 Susceptibility in Brazil (LD with DRB1*1301)

HLA, human leukocyte antigen; AIH, autoimmune hepatitis; LD, linkage desiquilibrium; LT, liver transplantation; anti-SLA/LP, anti-soluble liver antigen/liver pancreas; anti-
LKM-1, anti-liver microsomal antibody type 1 antibodies; anti-LC-1, anti-liver cytosol type 1 antibodies; ANA, anti-nuclear antibodies.

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4 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14
Interestingly, in all these conditions patients have an impairment of
regulatory T-cells, a feature that characterizes AIH and is likely to be
involved in its pathogenesis.
3.2. Potential triggers
In patients with increased genetic susceptibility to AIH, there are
a number of mechanisms by which the immune response could be
aberrantly directed towards liver-derived antigenic sequences. One
model e molecular mimicry e proposes that immune responses to
exogenous pathogens cross-react with self-components with
structural homology. The strongest support for this model derives
from the observation that the hepatitis C virus (HCV) shares high
amino-acid sequence homology with the auto-antigenic target of
anti-LKM-1 autoantibodies, cytochrome P4502D6 (CYP2D6) [40,41]
and some 10% of HCV patients are seropositive for anti-LKM-1
[42,43]. Other potential viral triggers for AIH include hepatitis B
virus, hepatitis E virus, cytomegalovirus and herpes simplex virus
[14].
Non-viral environmental triggers have also been proposed, such
as the antibiotics nitrofurantoin and minocycline, as well as statins,
and the anti-TNF agents adalimumab and iniximab [44]. However,
in contrast to classical AIH, drug-induced liver injury (DILI) with
features of AIH usually does not require long-term immunosup-
pressive treatment and should be considered independently [44].
Another potential explanation for autoreactivity is the exposure
of hidden auto-antigenic epitopes during hepatocellular injury. In
one study, patients with hepatocellular carcinoma or liver cirrhosis
spontaneously developed autoantibodies to cryptic a-fetoprotein
epitopes [45]. Despite the above described evidence, a universal
trigger for AIH has not yet been discovered.
3.3. Effector immune mechanisms
The histological picture of AIH, characterized by a dense
mononuclear cell inltrate eroding the limiting plate and invading
the parenchyma (known as interface hepatitis), rst suggested that
auto-aggressive cellular immunity might be involved in its causa-
tion. Whatever the trigger, a powerful stimulus must be promoting
the formation of the massive inammatory cell inltration present
at diagnosis [32]. There are different possible pathways that an
autoimmune attack can follow to inict damage on the hepatocyte
(Fig. 1). The autoimmune attack is thought to be initiated by the
presentation of an autoantigen to a nave CD4 effector T-cell.
Antigen presentation in the presence of interferon-g (IFN-g) and
interleukin (IL)-12 leads to T helper (Th)1-cell differentiation and
consequent production of IFN-g, which causes the up-regulation of
MHC class I and the aberrant expression of MHC class II by hepa-
tocytes, leading to further CD4 T-cell activation and antigen pre-
sentation to CD8 T-cells, and thus to the perpetuation of liver
damage [14]. IFN-g also promotes cytotoxicity by CD8-T cells,
augments monocyte differentiation, promotes macrophage and
immature dendritic cell (DC) activation and contributes to
enhanced natural killer (NK)-cell killing [32].
IL-4 is important for the generation of Th2-cells which promote
humoral immunity [32]. There is evidence indicating autoantibody
contribution to hepatocyte damage, by antibody-mediated cellular
cytotoxicity and possibly complement activation. Indeed, several
autoantibodies have been reported to contribute to liver damage in
AIH. The titres of anti-liver-specic membrane lipoprotein (LSP)
antibody, as well as antibodies to the LSP components ASGPR and
alcohol dehydrogenase (ADH) correlate with biochemical and his-
tological indices of disease severity [46,47]. The role of these au-
toantibodies in the autoimmune liver attack has been suggested by
the nding that hepatocytes, isolated from patients with AIH, are
Please cite this article in press as: R. Liberal, et al., Cutting edge issues in autoimmune hepatitis, Journal of Autoimmunity (2016), http://
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Liver
cell NK
IL-17 IL-1
TNF-
M P
IFN- CD8
Th17 Th1
IL-2 B cell
IL-12
IL-10
IL-4
TGF- IL-13
Th2
IL-6 Th0
IL-4
APC
Treg
Fig. 1. Mechanisms of liver damage. Liver damage is initiated by the presentation of a
self-antigenic peptide within a major histocompatability molecule (MHC) by profes-
sional antigen presenting cells (APCs). The presence of appropriate co-stimulation
alongside exposure to various cytokines drives the differentiation of uncommitted
CD4 helper T-cells (Th0). Exposure to IL-12 leads to the differentiation intof Th1 cells
secreting IFNg, which activates monocytes and cytotoxic CD8 T-cells, and promotes
NK-cell killing. IFNg also increases MHC class I and induces class II expression by
hepatocytes, further exacerbating inammation. Exposure to IL-4 leads to Th2 differ-
entiation. Th2 cells secrete IL-4, IL10 and IL-13, cytokines that enable B-cell maturation
into plasma cells with the consequent production of autoantibodies. Autoantibodies
are in turn involved in antibody-mediated cellular cytotoxicity and complement acti-
vation. The role of Th17 is under investigation.
coated with immunoglobulins and are susceptible to cytotoxicity
when exposed to autologous Fc receptor bearing mononuclear cells
[48,49]. More recently, anti-SLA antibodies, targeting the UGA
suppressor tRNP-associated antigenic protein (tRNP(ser)sec) [50],
were found in 50% of AIH-1 and AIH-2 patients, dening a disease
course more severe compared to seronegative patients [51]. In AIH-
2, the evidence that anti-LKM-1 antibodies are involved in liver
damage stems from studies showing that CYP2D6 is also expressed
on the surface of hepatocytes, and therefore may be susceptible to
recognition by anti-LKM-1 antibodies [52].
The role of Th17-cells in AIH is incompletely understood. There
is, however, evidence that they contribute to the cholangiopathy
characteristic of PBC [53], implying that Th17-cells are involved in
cholestatic forms of liver injury. In support of this, it has been
demonstrated that circulating Th17-cells are more prevalent in the
pediatric AIH/PSC overlap syndrome compared to pediatric AIH
[54]. Th17 cells are also elevated in the circulation and the liver of
patients with AIH. Moreover, IL-17 production by Th17-cells has
been shown to induce hepatocytes to produce IL-6, which further
enhances Th17-cell activation [55].
3.4. Regulatory immune mechanisms
Imbalance between regulatory and effector mechanisms results
in the breakdown of immune tolerance and development of auto-
immune disease. CD4posCD25highFOXP3pos regulatory T-cells
(Tregs) play a crucial role in the maintenance of immune homeo-
stasis by restraining effector cell proliferation and function [56].
Treg impairment has been widely associated with both murine
 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14 5

Table 3
Selected mouse models of autoimmune hepatitis.

Model Strategy Characteristics Reference

Experimental autoimmune Repeated immunization with liver Persistent liver damage [65]
hepatitis homogenate and adjuvant Perivascular liver inltration
Con-A induced hepatitis Administration of Con-A Nonspecic T-cell activation [64]
Cytokine storm
Acute liver damage
TF-OVA transgenic OVA expression under control of Acute liver injury [66]
hepatocyte TF promoter Transient hepatitis
OT-1 cell administration
Human CYP2D6 Human CYP2D6 delivered by adenovirus construct Persistent cellular inltration [67]
targeted to the liver of WT or humanized mice and brosis
High titer autoantibodies
CYP2D6 DNA vaccine Injection of plasmids encoding CYP2D6 and IL-12 CD4-mediated liver damage [70,71]
Transient autoantibodies
Variable transaminase levels
PD-1 decient Neonatal thymectomy in PD-1 decient mice CD4 and CD8 inltrate [72]
Fatal hepatitis
CYP2D6/FTCD vaccine Injection of plasmids encoding CYP2D6/FTCD Autoantibodies [69]
Interface hepatitis and brosis

Con-A, concanavalin-A; CYP2D6, cytochrome P4502D6; FTCD, formiminotransferase cyclodeaminase; OVA, ovalbumin; PD-1, programmed death-1; TF, transferrin; WT, wild-
type.

and human autoimmune conditions [56]. Studies performed in the
1970s and 80s described defects in suppressor cells in patients
with AIH. Since then lower frequencies of Tregs, initially identied
as CD4posCD25pos and CD4posCD25high cells, were reported in pe-
diatric patients with AIH and associated with reduced levels of
FOXP3, and impaired ability to control adaptive and innate immune
responses [57,58]. Of note, in these investigations circulating Treg
frequencies were shown to increase during remission without,
however, reaching the levels seen in health [57]. Subsequent re-
ports have challenged these earlier observations and showed that
the number of CD4posCD25highCD127negFOXP3pos cells was similar
in adult AIH patients and controls and higher in patients with active
disease compared to those at remission [59,60].
Recently, one study has re-examined the phenotypic and func-
tional Treg properties of patients with juvenile-onset AIH and
found that circulating CD4posCD25posCD127neg Tregs are decreased
in AIH compared to health, their frequency being inversely corre-
lated with parameters of disease activity and not affected by the
immunosuppressive treatment [61]. These bona de Tregs produce
less IL-10 and are impaired in their ability to suppress CD4 target
cells, a feature that in healthy subjects, but not in patients, is
dependent on IL-10 secretion. Notably, decreased IL-10 production
by Tregs in AIH is linked to defective responsiveness to IL-2 and
pSTAT-5 up-regulation [61].
The reasons for Treg impairment in AIH remain unclear. There is
evidence showing that Tregs, and also Th17 effector cells, in AIH are
defective in the expression of CD39, an ectonucleotidase that ini-
tiates an ATP/ADP hydrolysis cascade culminating with the gener-
ation of immunosuppressive adenosine [62,63]. CD39pos Tregs from
AIH patients are therefore defective in their ectoenzymatic activity
and inhibition of Th17-cell function. Of note, in AIH but not in
healthy individuals, CD39pos Tregs undergo a marked increase in
the production of IFN-g and IL-17 upon challenge with pro-
inammatory stimuli. This suggests that in AIH Tregs are more
prone to be skewed into effector cells, therefore contributing to the
maintenance of the effector lymphocyte pool and to the perpetu-
ation of autoimmune liver damage [62].
3.5. Animal models
The Con-A induced hepatitis model has been a useful tool to
identify key cell populations and cytokines involved in hepatocel-
lular injury. However, it is merely a model of acute injury mediated
by cytokine storm when strong activation of the immune system
occurs, and it does not accurately reect the chronic disease seen in
human AIH [64]. In fact, animal models faithfully reecting all the
characteristics of AIH e which include a well-dened initiating
event followed by chronic inammation leading to brosis e are
lacking, although there are several candidates [64e72] (Table 3).
Transgenic models which express antigen under the control of
liver-specic promoters feature prominently. Tolerance to these
antigens is generally broken by the adoptive transfer of adjuvant
and/or antigen-specic T-cells. The TF-OVA transgenic mouse, in
which OVA expression is driven by the hepatocyte transferrin
promoter, is an example. In this model, OVA-specic OT-1 cells are
administered to produce acute, transient hepatitis [66]. Although
transgenic models have benets e i.e. the initiating antigen is well
dened and conned to the liver e liver injury is usually transient.
One exception to this is the human CYP2D6 model, in which human
CYP2D6 is delivered to the liver via an Adenovirus construct. Both
wild-type and humanized CYP2D6 mice have been used to produce
chronic persistent hepatitis [67,68]. Interestingly, a recent study has
shown that inducing non-alcoholic fatty liver disease with a high-
fat diet potentiated the severity of liver injury in the CYP2D6
mouse model [73].
Recently, Yuksel et al. developed a model based on the HLA-DR3
transgenic mouse on the non-obese diabetic background by im-
munization with a DNA plasmid coding for human CYP2D6/for-
miminotransferase cyclodeaminase (FTCD) fusion protein (the
target antigen of anti-LC1) [69]. Immunization with CYP2D6/FTCD
fusion protein leads to increased transaminase levels, development
of autoantibodies, interface hepatitis and brosis [69].
Murine studies have also been used to investigate the role of
Tregs in AIH. In one study e using a mouse model generated by
DNA vaccination against CYP2D6 e the immunoregulatory
impairment associated with AIH was attributed to defects in the
peripheral tolerance compartment, low thymic expression of the
autoantigen being necessary, but not sufcient, to induce the dis-
ease [70,71]. Diseased mice had a lower frequency of
CD4posCD25posFoxp3pos Tregs compared to other strains [71].
Another model was generated using mice decient for the inhibi-
tory molecule PD-1 [72]. In these mice, neonatal thymectomy
prevents Treg thymic development, leading to fatal AIH character-
ized by elevated titers of ANA, lobular necrosis and marked inl-
tration of CD4pos and CD8pos T-cells. Adoptive transfer of Tregs
successfully prevented the induction of the disease [72].

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4. Clinical features
4.1. Presentation and natural history
Although AIH in most patients has an insidious onset with
symptoms of chronic liver disease, some 20e30% of patients pre-
sent with an acute icteric hepatitis [16]. Presentation as acute liver
failure (ALF) is rare, but has important therapeutic implications
[74]. On the other side of the spectrum, some patients are diag-
nosed after incidental discovery of abnormal liver function tests
[75]. Occasionally, AIH presents with complications of portal hy-
pertension, such as hypersplenism or gastrointestinal bleeding [16].
An acute presentation is more frequent in children than in adults,
while an insidious onset is more frequently observed in adults [76].
Longstanding subclinical disease can be often elicited through
clinical history and investigations, even in patients presenting
acutely, with about one third of cases having histological evidence
of cirrhosis at the time of diagnosis [77].
Some 20% of AIH patients have concomitant autoimmune dis-
eases or will develop them during follow-up, the most common
being thyroiditis, diabetes, inammatory bowel disease and rheu-
matoid arthritis [12]. A family history of autoimmune disorders is
reported in up to 40% of AIH patients [78].
Without treatment, the reported 5- and 10-year survival rates
are 50% and 10% respectively [4e6]. Because of the use of cortico-
steroid treatment, the 10-year survival rate has risen to approxi-
mately 90% [16]. However, these data are based on different patient
cohorts and no comparative prospective studies are available.
The complications associated with AIH are similar to those of
other progressive liver diseases. Chronic hepatitis can evolve to
cirrhosis and ultimately to hepatocellular carcinoma (HCC) despite
the use of immunosuppressive therapy. HCC is relatively rare in AIH
[77]. Yeoman et al. reported, during a 16-year follow-up period, 15
cases of HCC, all with underlying cirrhosis, among 243 patients
with AIH [79]; thus, surveillance for HCC is warranted [16].
4.2. Diagnosis and scoring systems
There is no single diagnostic test for AIH; therefore diagnosis is
based upon several indicative clinical, serological, biochemical and
histological ndings. The presence of other causes of liver disease
must also be excluded [16].
The IAIHG has established and revised a set of diagnostic criteria
for AIH [9,10] to be used mainly for research purposes (Table 4). This
score comprises clinical, laboratory and histological parameters,
including response to treatment [10]. Although too cumbersome
for general bedside use, the system is clinically useful when eval-
uating patients with few or atypical features of AIH [13].
In an attempt to devise a less complicated and more practical
diagnostic tool, the IAIHG has proposed in 2008 a simplied scoring
system (Table 5) to be used in clinical practice [11]. The system,
which only uses four parameters (hypergammaglobulinemia, au-
toantibodies, histology and exclusion of viral hepatitis) [11], has
since received external validation [13]. In the United States, how-
ever, where solid phase immunoassays are used for autoantibody
detection and titres are not available, these scoring systems need to

Table 4
International autoimmune hepatitis group revised diagnostic scoring system.

Parameter Feature Score

Sex Female 2
ALP: AST (or ALT) ratio >3 2
1.5e3 0
<1.5 2
Serum globulins or IgG (times above normal) >2.0 3
1.5e2.0 2
1.0e1.5 1
<1.0 0
ANA, SMA or anti-LKM-1 titres >1:80 3
1:80 2
1:40 1
<1:40 0
AMA Positive 4
Viral markers of active infection Positive 3
Negative 3
Hepatotoxic drug history Yes 4
No 2
Average alcohol <25 g/day 2
>60 g/day 2
Histological features Interface hepatitis 3
Plasma cells 1
Rosettes 1
None of the above 5
Biliary changesa 3
Atypical changesb 3
Immune diseases Thyroiditis, colitis, other 2
HLA DR3 or DR4 1
Seropositivity for other autoantibodies Anti-SLA/LP, actin, ASGPR, pANNA 2
Response to therapy Remission 2
Relapse 3

Pre-treatment score >15: denite AIH; 10e15: probable AIH; Post-treatment score >17: denite AIH; 12e17: probable AIH.
ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; IgG, immunoglobulin G; ANA, anti-nuclear antibody;
SMA, anti-smooth muscle antibody; anti-LKM-1, anti-liver kidney microsomal type 1 antibodies; AMA, anti-mitochondrial antibodies; SLA/LP,
soluble liver antigen/liver pancreas; ASGPR, asialoglycoprotein receptor; p-ANNA, peripheral anti-nuclear neutrophil antibody; HLA, human
leukocyte antigen.
a
Including granulomatous cholangitis, concentric periductal brosis, ductopenia, marginal bile duct proliferation and cholangiolitis.
b
Any other prominent feature suggesting a different aetiology.
Adapted from Alvarez F, Berg PA et al. J Hepatol 1999; 31: 929:938.

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 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14 7

Table 5 methods for autoantibody detection, acknowledging the central

Simplied criteria for the diagnosis of autoimmune hepatitis. role played by autoantibodies in the diagnosis of AIH [81]. The
Variable Cut-off Points document recommends that rst line screening should consist of
ANA or SMA 1:40 1
indirect immunouorescence on fresh, multi-organ rodent sec-
ANA or SMA 1:80 2a tions (usually rat liver, kidney and stomach) to enable the
or anti-LKM-1 1:40 simultaneous screening of a range of autoantibodies relevant to
or SLA Positive liver disease: ANA, SMA, anti-LKM-1, anti-LC-1 and anti-
IgG > upper limite of normal 1
mitochondrial antibodies (AMA) [81]. If only rodent kidney tis-
>1.10 times upper limit of normal 2
Liver histology Compatible with AIH 1 sue is used, AMA may be confused with anti-LKM-1. The identi-
Typical of AIH 2 cation of the molecular targets of anti-LKM-1 and AMA (Table 6)
Absence of viral hepatitis Yes 2 has led to the establishment of immuno-assays based on the use
Score 6: probable AIH; 7: denite AIH. of the recombinant or puried autoantigens [82]. Regarding ANA
ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; anti-LKM-1, anti- detection, as there are no ANA molecular targets specic for AIH,
liver kidney microsomal antibody type 1; SLA, soluble liver antigen; IgG, immuno- immunouorescence remains the preferred method [83]; how-
globulin G; AIH, autoimmune hepatitis.
a ever, in North America, where immunouorescence for autoanti-
Addition of points achieved for all autoantibodies cannot exceed a maximum of
2 points. body testing is not always available, solid phase assays are used
Adapted from Hennes EM, Zeniya M et al. Hepatology 2008; 48: 169-176. instead [80], though their performance should be validated as
recommended by a position paper of the American College of
Rheumatology [83].
be adapted [80]. When conventional diagnostic autoantibodies are absent, the
positivity for other reactivities may aid the diagnosis [16]. For
4.3. Autoantibodies example, perinuclear anti-nuclear neutrophil antibody (p-ANNA) is
an additional marker of AIH-1 [81]. The positivity for anti-soluble
The detection of antibodies against components of the nuclei, liver antigen (SLA) antibodies is specic for AIH, can be present in
smooth muscle and liver kidney microsome is a crucial step in the both AIH-1 and AIH-2 and is associated with a more severe clinical
diagnostic work-up of patients with suspected AIH, and has been course and worse prognosis [51]. Occasionally, anti-SLA are the
incorporated in all scoring systems [10,11]. only antibodies present and they should be tested in all cases of
Besides aiding the diagnosis, the autoantibody prole is used to suspected AIH. Importantly, anti-SLA are detectable by ELISA or
dene two types of AIH; AIH-1, characterized by positivity for ANA radio-immuno-assays, but not by immunouorescence [82,84].
and/or SMA, and AIH-2, characterized by the presence of anti-LKM- Anti-LKM-3 antibodies, directed to family 1 of UDP-glycuronosyl
1 and/or anti-LC-1 [16]. transferases (UGT1), are a further marker for AIH-2 [85,86], and
The IAIHG has published a consensus statement detailing the may also be the only serological maker for AIH.

Table 6
Autoantibodies and their antigens in autoimmune liver diseases.

Autoantibody Target antigen(s) Liver disease Value in AIH Conventional method Molecular based
of detection assays

ANA Chromatin, AIH Diagnostic of AIH-1 IIF N/A

histones, PBC
centromeres, PSC
Cyclin A, Drug-induced
ribonuclueoproteins Chronic hepatitis C
Chronic hepatitis B
NAFLD
SMA Microlaments Same as ANA Diagnostic of AIH-1 IIF N/A
(lamentous actin)
Intermediate laments
(vimentin, desmin)
Anti-LKM-1 Cytochrome P4502D6 AIH-2 Diagnostic of AIH-2 IIF ELISA, IB, RIA
Chronic hepatitis C
Anti-LC-1 Forminino-transferase cyclodeaminase AIH-2 Diagnostic of AIH-2 IIF, DID, CIE ELISA, RIA
Chronic hepatitis C Prognosis of severe disease
SLA/LP O-Phosphoseryl-tRNA: AIHRarely chronic Diagnostic of AIH Inhibition ELISA, IB, RIA
selenocysteinyl-tRNA synthase (SepSecS) hepatitis C Prognostic of severe ELISA
disease, relapse and
treatment dependence
Anti-LKM-3 UDP-glucuronosyl-transferase AIH-2 Diagnostic of AIH-2 IIF ELISA
family 1 A (UGT1A) Chronic hepatitis D
pANNA Nuclear lamina AIH Point towards IIF N/A
proteins PSC/ASC diagnosis of AIH
AMA E2 subunits of 2-oxoacid PBC Against diagnosis of IIF ELISA, IB, RIA
dehydrogenase AIH
complexes, particularly
PDC-E2

ANA, anti-nuclear antibodies; SMA, anti-smooth muscle antibodies; anti-LKM-1, anti-liver kidney microsomal antibody type 1; anti-LC-1, anti-liver cytosol antibody type 1;
SLA/LP, soluble liver antigen/liver pancreas; pANNA, peripheral anti-nuclear neutrophil antibodies; AMA, anti mitochondrial antibodies; AIH, autoimmune hepatitis; PBC,
primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ASC, autoimmune sclerosing cholangitis; NAFLD, non-alcoholic fatty liver disease; IIF, indirect immunouo-
rescence; DID, double-dimension immunodiffusion; CIE, counter-immune-electrophoresis; ELISA, enzyme-linked immunosorbent assay; IB, immunoblot; LIA, line-immuno-
assay; RIA, radio-immuno-precipitation assay; N/A, not applicable.

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8 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14

4.4. Histology
Liver histology is essential to conrm the diagnosis of AIH, as
highlighted in all diagnostic scoring systems [10,11]. Hepatitis at
the portal-parenchymal interface, known as interface hepatitis
(Fig. 2), is characteristic, but not exclusive, of AIH [87]. In addition,
there are other non-specic features that may point to the diag-
nosis of AIH, such as multilobular collapse in cases presenting
acutely, emperipolesis and hepatocyte rosetting [88]. Interestingly,
a recent study suggests that the latter two characteristics are
stronger indicators of AIH than interface hepatitis or plasma-cell
rich inltrate [89]. In some patients, however, such ndings may
be absent [90]. Histology is also the gold standard for evaluating the
extent of brosis and it helps in identifying overlap syndromes as
well as the possible presence of concomitant diseases, such as
alcoholic and non-alcoholic fatty liver disease [91]. Moreover, the
information provided by histology is important in terms of man-
agement, as the presence of orid inammation and bridging/
multiacinar necrosis warrants prompt treatment; while in the
presence of inactive cirrhosis or mild portal inammation treat-
ment can be withheld, especially in patients prone to steroid side
effects [16].
In contrast to patients with an insidious course, those present-
ing with ALF show histological damage predominantly in the
Fig. 2. Interface hepatitis. Liver biopsy histology of a patient with autoimmune
hepatitis typically reveals a dense portal and periportal mononuclear cell inltrate,
including several plasma cells.
centrilobular area [74]. Several patients presenting with fulminant
hepatic failure have massive necrosis and multilobular collapse
[77]. In one study including pediatric patients presenting with ALF
histology did not allow to distinguish autoimmune ALF from
indeterminate ALF [92]. In addition, in the setting of coagulopathy,
liver biopsy should be performed by the transjugular route, which
is not without risk. If transjugular biopsy is technically not avail-
able, the absence of histology should not preclude initiation of
treatment, though liver biopsy should be performed as soon as
coagulation indices permit.
5. Treatment
5.1. Standard treatment
The goal of AIH treatment is to induce and maintain complete
suppression of the inammatory activity, thus preventing pro-
gression to cirrhosis and liver decompensation [16,93]. In contrast
to previous guidelines [94] e where remission was dened by
achievement of transaminase levels below twice the upper limit of
normal e, current guidelines require normal levels of trans-
aminases, bilirubin and IgG [16,93]. A retrospective single-center
analysis shows that when the old denition was used over 70% of
patients achieved remission, whereas when the new denition was
used only 26% did so [95]. In this study, 54% of patients fullling the
old criteria for remission had histologically progressive disease;
while when the new denition was applied, only 4% showed his-
tological deterioration, underscoring the importance of achieving
normal biochemical and serological indices in order to prevent
progression of disease [95].
The induction regimen usually consists of high dose pre-
dniso(lo)ne with or without azathioprine (Table 7). When used as
monotherapy, the starting dose of steroids is 60 mg/day in adults
and 1e2 mg/kg/day (up to 60 mg/day) in children [16]. Regarding
combination therapy, there are differences between AASLD and
EASL guidelines: while AASLD recommends starting either a xed
dose of 50 mg/day or 1e2 mg/kg/day of azathioprine at the same
time as steroids [16], EASL recommends 1e2 mg/kg/day of azathi-
oprine to be started only 2 weeks after the introduction of steroids
[93]. In addition, and since budesonide has meanwhile become
approved in 27 European and non-European countries [13], EASL
guidelines suggest that remission can also be induced by replacing
prednisolone with budesonide (starting dose of 9 mg/day), partic-
ularly in patients in whom the occurrence of steroid-specic side
effects are expected [93]. Data supporting the use of budesonide
come from a relatively recent multi-center, randomized controlled

Table 7
Therapeutic options for induction of remission in patients with autoimmune hepatitis according to AASLD and EASL guidelines.

Week Monotherapy Combination therapy (AASLD) [16] Combination therapy (EASL) [93]
(AASLD) [16]

Prednisone Prednisone Azathioprine Prednisoloneaor budesonideb (mg/day) Azathioprinea

(mg/day) (mg/day) (mg/day or mg/Kg/day) (mg/day)

1 60 30 50 or 1-2 60 9 0
2 40 20 50 or 1-2 50 9 0
3 30 15 50 or 1-2 40 6 50
4 30 15 50 or 1-2 30 6 50
5 20 10 50 or 1-2 25 6 100
6 20 10 50 or 1-2 20 6 100
78 20 10 50 or 1-2 15 6 100
89 20 10 50 or 1-2 12.5 6 100
From week 10 20 and below 10 50 or 1-2 10 and below 6 and below 100
a
Considering an adult patient weighing 60 Kg; Initial prednisolone dose of 1 mg/kg body weight; Azathioprine dose of 1e2 mg/kg body weight.
b
Alternative to Prednisolone for non-cirrhotic adult patients.
Adapted from Ref. [16,93].

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prospective trial conducted in a well-characterized cohort of non-
cirrhotic AIH patients, in which treatment with azathioprine plus
budesonide 9 mg/day was compared with azathioprine plus
prednisolone 40 mg/day (tapered to 10 mg/day) [96]. Steroid-
specic side effects were less frequent in patients on budesonide
compared to those on prednisone (28% vs 53%). Complete remis-
sion, meaning normal ALT as well as lack of predened steroid-
specic side effects, was achieved in 60% of the budesonide arm
vs only 39% of those in the prednisolone arm [96]. However, it
should be stressed that this rate of remission is lower than that
observed when a higher starting dose of prednisolone is used,
though it is difcult to compare different studies in different co-
horts of patients, in particular if they are not prospective and use
different endpoints, such as less than twice the upper limit of
normal for ALT levels and not normalization of ALT and IgG levels
according to recent guidelines. The European trial shows that
budesonide at the dose employed offers no benet over predni-
sone, apart from less weight gain, in children and adolescents
[97,98], a group of patients in whom higher remission (dened as
normalization of transaminase and IgG levels) rates have been re-
ported with standard prednisolone and azathioprine treatment
[99]. In addition, budesonide cannot be used in the presence of
cirrhosis, excluding at least one third of AIH patients who have
cirrhosis at diagnosis [100].
Once remission is achieved, it can be maintained with azathio-
prine monotherapy or a combination of steroids with azathioprine.
A systematic review of randomized controlled trials in adult pa-
tients showed that maintenance therapy with prednisolone mon-
otherapy was inferior to azathioprine alone or in combination with
prednisolone [101]. The European budesonide trial mentioned
above, in which patients on the prednisolone arm were switched at
6 months to open-label budesonide, shows that budesonide (plus
azathioprine) not only maintained remission but also reduced the
frequency of steroid-specic side effects, suggesting that more than
a rst-line induction-agent budesonide may play a role as a
maintenance drug in non-cirrhotic patients who experience steroid
side effects [96].
Although maintenance of remission after treatment withdrawal
is possible in some patients, a recent multicentre retrospective
study including 131 patients in whom treatment was discontinued
after achieving biochemical remission shows that over 80%
relapsed within 3 years, reinforcing the notion that the majority of
patients requires long-term, if not life-long, maintenance therapy
[102]. It is cautious not to attempt immunosuppression withdrawal
within two years of diagnosis [16]. During withdrawal attempts, it
is essential to monitor liver function tests closely, as relapse may be
severe and even fatal. Patients who have successfully stopped
immunosuppression should undergo long-term follow-up, because
relapse can occur as long as 10 years later [103].
5.2. Alternative treatment
In patients who are intolerant to standard treatment or who fail
to achieve remission, alternative therapies have been proposed. If
prednisolone is not tolerated, budesonide is an adequate alterna-
tive in absence of cirrhosis [93]. In case of azathioprine intolerance
or known thiopurine methyltransferase (TPMT) deciency, steroids
in monotherapy or in combination with mycophenolate mofetil
(MMF) or 6-mercaptopurine (6-MP) have been tried with success
[80]. MMF is a purine antagonist not dependent on the activity of
TMTP. Azathioprine non-responders usually do not respond satis-
factorily to MMF, while reported remission rates in patients that
respond, but are intolerant to azathioprine, are 60e80% [104,105].
Although less frequently used, 6-MP seems to be effective in AIH
patients [106,107], its safety having been shown in the setting of
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9
inammatory bowel disease [108].
For patients who fail to achieve remission on standard immu-
nosuppression [109], proposed alternative therapies are based on
scarce published data, mainly in the form of case reports or small
case-series. Before alternative therapies are contemplated, how-
ever, patients who fail to respond to standard regimens should be
tried on higher doses of steroids (up to 100 mg/day) and/or
azathioprine (up to 150 mg/day) [16,93]. Since budesonide has a
mode of action similar to other steroids, it is unlikely that it will be
effective in non-responders, and therefore should not be used for
these patients [13]. Similarly, MMF has been reported to be inef-
fective in azathioprine non-responders [104], although there are
studies showing that it does induce remission in some patients in
this category [110], particularly within the pediatric population
[111].
Calcineurin inhibitors, cyclosporine and tacrolimus, have been
used as a rescue treatment for difcult-to-treat cases of AIH [109].
Small case-series have reported the efcacy of low dose tacrolimus
(usually with a 2e5 ng/ml trough level target) [109,112]. A recent
study reporting the combined experience of two large European
centers, Birmingham and Hamburg, shows that out of 16 patients
switched to tacrolimus due to non-response to standard therapy,
the majority achieved improved biochemical and immunological
proles, though only 29% and 50% reached normal transaminase
and IgG levels respectively within one year of therapy [113]. Despite
the acknowledged risk of nephrotoxicity, all patients showed stable
renal function. Of 9 patients on long-term tacrolimus treatment,
only one progressed to end-stage liver disease requiring trans-
plantation, and the other 8 had signicant biochemical improve-
ment on a reduced dose of steroids [113]. Despite these
encouraging results, the experience is limited: this coupled to the
toxicity prole, should limit the use of tacrolimus to carefully
selected cases followed up in experienced centers.
Anti-TNF-a agents, such as iniximab, are commonly used to
treat immune-mediated diseases such as rheumatoid arthritis,
psoriasis and inammatory bowel disease. A recent paper reports
that inixmab is effective in the treatment of AIH patients not
responding to other therapies [114]: iniximab led to a decrease in
transaminase and IgG levels in 11 out of 12 refractory AIH adult
patients, although in 7 treatment was complicated by infections
[114]. Anecdotal evidence also suggests some benet in the use of
sirolimus and everolimus e inhibitors of the mammalian target of
rapamycin e as well as of rituximab e an anti B-cell monoclonal
antibody e in the management of patients who fail to respond to
other therapies [115e117].
5.3. Liver transplantation
Liver transplantation (LT) is indicated for AIH patients with end-
stage chronic liver disease, those with HCC who meet transplant
criteria, and those who present with ALF unresponsive to steroids
[96,118]. Overall, AIH accounts for some 3% and 5% of pediatric and
adult LTs performed in Europe and the United States [16].
LT for AIH has a very successful outcome, with reported 1- and
5-year graft survival rates of 84% and 75% respectively, and 5- and
10-year patient survival rates of 80e90% and 75% respectively [119].
Despite the overall good outcome and the use of immunosup-
pression to prevent rejection, AIH may recur post-LT [120]. The
reported recurrence rate is highly variable, ranging from 12% to
46%, depending on the diagnostic criteria used, the length of
follow-up, and the performance of per-protocol biopsies [118]. The
severity of necroinammatory activity in the native liver and high
IgG levels at the time of LT, as well as the presence of inammatory
bowel disease are the best predictors of recurrence [121,122].
Recurrent AIH is responsive to the reintroduction (or to an increase
10 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14
in the dose) of corticosteroids and azathioprine. Only in rare cases
recurrent AIH leads to graft failure despite aggressive immuno-
suppression [118].
Interestingly, AIH can also arise de novo following LT for non-
autoimmune liver diseases [120]. This form of graft dysfunction,
known as de novo AIH, is characterized by biochemical, serological
and histological features identical to those of classical AIH [123].
Treatment with steroids with or without azathioprine or MMF is
successful in most cases, leading to excellent graft and patient
survival [124].
6. Special presentations
6.1. Variant syndromes
AIH, PBC and PSC are generally viewed as distinct autoimmune
liver diseases. There is, however, a group of patients presenting
with clinical, biochemical, serological and/or histological features
of both a cholestatic liver disease and AIH, either simultaneously or
consecutively. These variant conditions are often designated as
overlap syndromes, and comprise PBC with features of AIH (PBC/
AIH overlap) and AIH with biliary features suggestive of PSC (AIH/
PSC overlap). There is debate as to whether these syndromes
represent distinct entities or are variants of the main autoimmune
liver disease. The IAIHG advocates that patients with overlapping
features should not be categorized as separate diagnostic entities,
but instead considered to be part of the classical diseases [125].
Due to its low frequency and lack of standardized diagnostic
criteria, the prevalence of PBC/AIH overlap syndrome is difcult to
establish; it is estimated that it accounts for 2e20% of AIH patients
and up to 10% of those with PBC [126,127]. The diagnosis of this
condition remains a challenge and there is no validated scoring
system, but in most reports, PBC/AIH overlap syndrome has been
dened using the Paris criteria proposed by Chazouille res et al.,
where the diagnosis of overlap requires the presence of at least 2 of
the 3 key criteria for the diagnosis of each component of the overlap
[126]. The PBC criteria comprise: 1) ALP 2 the upper limit of
normal (ULN) or GGT  5 ULN; 2) presence of AMA, and 3) histo-
logical evidence of orid bile duct lesions. The AIH criteria include:
1) ALT  5 ULN, 2) IgG 2 ULN (or IgG  1.5 ULN, Chazouille res
personal communication) or presence of SMA, and 3) liver biopsy
with moderate or severe periportal or periseptal inammation
[126]. These criteria have been incorporated in the EASL guidelines
for the management of cholestatic liver diseases published in 2009,
where it is, however, stressed that histological evidence of interface
hepatitis is essential for making the diagnosis of overlap [128].
Compared to PBC alone, patients with PBC/AIH overlap appear to
have a more aggressive course, a worse response to ursodeoxycolic
acid (UDCA), and a more rapid progression in terms of brosis
[126,129]. When compared to AIH, the outcome does not differ
signicantly. Since no controlled studies are available, treatment is
largely empiric [125]. According to EASL guidelines, patients with
PBC/AIH overlap should receive combined therapy with UDCA and
immunosuppressants; alternatively, patients with dominant AIH
phenotype should be started on immunosuppressants only, and
have UDCA added in case of insufcient response [93].
Besides PBC/AIH overlap, it is now well recognized that a vari-
able proportion of patients with cholangiographically conrmed
PSC also have features of AIH [130]. AIH/PSC overlap is character-
ized by hypergammaglobulinemia, autoantibody seropositivity,
and interface hepatitis e all features typical of classical AIH e in
conjunction with cholestatic biochemical alterations, histological
bile duct injury, frequent concurrence of inammatory bowel dis-
ease, and poor response to therapy [125].
In children, overlapping features of AIH and PSC are much more
Please cite this article in press as: R. Liberal, et al., Cutting edge issues in autoimmune hepatitis, Journal of Autoimmunity (2016), http://
dx.doi.org/10.1016/j.jaut.2016.07.005
common than in adults and the term autoimmune sclerosing
cholangitis (ASC) has been coined [131]. Interestingly, 50% of chil-
dren with clinical and histological evidence of AIH have cholan-
giographic changes characteristic of sclerosing cholangitis,
including some 25% that despite abnormal cholangiograms, have
no histological features suggesting bile duct involvement.
Compared to AIH, children with ASC more commonly have con-
current inammatory bowel disease, and more often progress to
end-stage liver disease requiring LT [131]. Whether childhood ASC
and adult PSC belong to the same disease spectrum remains un-
dened, although a retrospective study has shown that a high
proportion of adults initially diagnosed as having AIH were found
to have sclerosing cholangitis on cholangiography at follow up
[132].
6.2. Acute severe to fulminant AIH
Although AIH typically manifests as a chronic liver disease, it is
estimated that up to 20% of patients have an acute presentation,
which can be associated with the development of acute liver failure
(ALF) [133e136]. Diagnosis of AIH in this setting is difcult, as the
classical autoimmune manifestations may be absent, the published
scoring systems not being readily applicable to this cohort of pa-
tients [10,11]. The management of patients with AIH presenting
acutely with severe hepatitis or liver failure is challenging.
Although some of these patients do respond to corticosteroids, for
the majority of those with ALF LT remains the only available rescue
treatment. It is therefore of utmost importance to identify early
those patients with a higher likelihood to respond to steroids.
Although one recent study did not nd differences in prognostic
scores between steroid responders and failures [137], others have
reported that a model for end-stage liver disease (MELD) score of
28 on admission, absence of massive necrosis on histology, and
initial stabilization or improvement of bilirubin levels and INR
within 4 days of therapy were associated with a higher response
rate to steroids [136,138]. If no improvement is observed during the
rst few days of treatment, continuing corticosteroid therapy may
be a futile exercise, and may result in serious adverse events, such
as sepsis. Even if therapy with corticosteroids is maintained,
assessment for LT should occur simultaneously [16,93].
6.3. Drug induced AIH
Drug induced liver disease (DILI) is a complex disorder affecting
susceptible individuals exposed to therapeutic doses of certain
drugs [139,140]. Although remaining a diagnosis of exclusion, it
should be considered in the differential diagnosis of AIH. Several
drugs have been implicated as triggers of AIH; more recently, a new
entity called drug-induced AIH (DI-AIH) has been recognized [44].
DI-AIH shares with AIH clinical, serological and immunological
features; however, cirrhosis at baseline is never present in DI-AIH,
while it is not uncommon in AIH [44]. Differentiating DILI from DI-
AIH and AIH triggered by drugs has management implications,
since DI-AIH does not require long-term immunosuppression. A
recent study proposed a model in which histological features such
as portal inammation, portal plasma cells, intra-acinar lympho-
cytes and eosinophils, rosette formation, and canalicular chole-
stasis could predict whether DILI or AIH was present [141]. In
addition, withdrawal of steroids with no recurrence also helps in
identifying those patients with DI-AIH [44].
6.4. AIH and pregnancy
Since its rst description, fertility and pregnancy issues have
been a concern for a disease that affects mainly females [1].
 R. Liberal et al. / Journal of Autoimmunity xxx (2016) 1e14
Successful pregnancies have been reported in AIH patients. Worse
pregnancy outcomes e i.e. high incidence of AIH exacerbations and
serious maternal adverse events e have been associated with
positivity for anti-SLA, absence of immunosuppressive drug ther-
apy during pregnancy and the occurrence of a are in the year
before conception [142,143], underscoring the need of stable
immunosuppression before and throughout pregnancy. Though
azathioprine is listed as category D drug by the Food and Drug
Administration, its use in pregnancy appears to be safe, while MMF
is contra-indicated [16,93]. Of note, most disease ares occur in the
post-partum period, even in patients whose condition improved
during pregnancy [143]; thus, it is recommended to increase pre-
emptively the dose of immunosuppression shortly before the ex-
pected date of delivery, and to closely monitor disease activity in
the weeks following delivery [144].
7. Conclusion
Over the last 60 years, we have witnessed great progresses in
the understanding of AIH. A recent genome-wide association study
has conrmed the original reports implicating a key predisposing
role for genes encoded in the HLA region. Autoantigens targeted by
autoantibodies characteristic of AIH have been identied and
cloned, allowing a more focused investigation of the interplay be-
tween effector and regulatory immune mechanisms. Animal
models have been instrumental in the identication of cell pop-
ulations and cytokines involved in liver damage, though a model
faithfully mirroring the human disease is still lacking. Over the
years the IAIHG has strived to produce a reliable AIH diagnostic
scoring system applicable to clinical practice, which has also led to
the identication of diverse clinical phenotypes, including overlap
syndromes, acute severe presentations and drug-induced AIH.
Despite these advances there are still areas of unmet needs that
should be addressed in the future. For example, genetic associa-
tions outside the HLA locus, as well as the early events responsible
for loss of liver tolerance are still to be uncovered. With emerging
laboratory techniques and a fruitful cooperation between research
groups, it is hoped that in the near future novel diagnostic and
prognostic biomarkers, as well as a better understanding of AIH
pathogenesis, will lead to the development of more specic and
effective therapies.
Grant support
None.
Disclosures
JMV: Novartis, global advisory board; Roche-Genentech,
research grant funding, scientic advisory board; TaiwanJ,
research grant funding; BioIncept, consultant; MM: received
research funding and trial support from Falk Pharma GmbH, Frei-
burg, Germany; RL, ELK, GMV and DV: none.
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Please cite this article in press as: R. Liberal, et al., Cutting edge issues in autoimmune hepatitis, Journal of Autoimmunity (2016), http://
dx.doi.org/10.1016/j.jaut.2016.07.005