Journal of Autoimmunity 46 (2013) 7e16

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

Autoimmune hepatitis: Contrasts and comparisons in children and

adults e A comprehensive review
Annarosa Floreani a, *, Rodrigo Liberal b, Diego Vergani b, Giorgina Mieli-Vergani b
a
b

Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy

Paediatric Liver Centre and Institute of Liver Studies, Kings College London School of Medicine at 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:
Received 29 July 2013
Received in revised form
13 August 2013
Accepted 14 August 2013

This review concentrates on autoimmune hepatitis (AIH), a liver disorder affecting both children and
adults, characterized by inammatory liver histology, elevated transaminase levels, circulating nonorgan-specic autoantibodies, and increased levels of immunoglobulin G, in the absence of a known
aetiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or
antinuclear antibody dene AIH type 1, while antibodies to liver-kidney microsome type 1 and/or liver
cytosol type 1 dene AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a
paediatric disease, though it does occasionally affects young adults. There is a female predominance in
both types. AIH is particularly aggressive in children/adolescents, progressing rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission
and long-term survival. In childhood/adolescence, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH,
but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In
autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease progresses in 50% of cases, leading to a worse prognosis
and higher transplantation requirement; it has a higher recurrence rate after transplant than AIH. AIH
can arise de novo in patients transplanted for non-autoimmune liver disease. Post transplant de novo AIH
affects children and adults and responds well to the same treatment schedule used for classical AIH, but
not to that used for acute rejection.
2013 Elsevier Ltd. All rights reserved.

Keywords:
Autoimmune hepatitis
Autoimmune sclerosing cholangitis
De novo autoimmune hepatitis post liver
transplant
Corticosteroids
Azathioprine
Mycophenolate mofetil

1. Autoimmune liver disease in children

1.1. Autoimmune hepatitis (AIH)
AIH is a progressive inammatory liver disorder characterized
serologically by high levels of transaminases and immunoglobulin
G (IgG), and presence of autoantibodies, and histologically by
interface hepatitis (Fig. 1), in the absence of a known aetiology [1].
In children and adolescents, AIH often presents acutely and has a
more aggressive course than in middle-age and elderly patients.
Usually it responds satisfactorily to immunosuppressive treatment,
which should be started as soon as the diagnosis is made, as if left
untreated, AIH progresses rapidly to cirrhosis and liver failure.
Three fourth of patients are girls.
* Corresponding author. Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
Tel.: 39 0498212894; fax: 39 0498760820.
E-mail address: annarosa.oreani@unipd.it (A. Floreani).
0896-8411/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jaut.2013.08.004

The epidemiology of childhood AIH is unknown, but AIH type

1 [anti-nuclear antibody (ANA) and/or anti-smooth muscle
antibody (SMA) positive] accounts for two thirds of the cases and
presents often around puberty [2], whereas AIH type 2 [positive
for anti-liver kidney microsomal antibody (anti-LKM1) and/or
anti liver cytosol type 1 antibody (anti-LC1) [3]] tends to present
at a younger age and also during infancy. IgG is usually raised at
presentation in both types, though 15% of children with AIH type
1 and 25% of those with AIH type 2 have normal levels. IgA
deciency is common in AIH type 2 [2]. Severity of disease is
similar in the two types, but anti-LKM1-positive children have
higher levels of bilirubin and transaminases at presentation than
those who are ANA/SMA-positive and present signicantly more
frequently with fulminant hepatic failure (Table 1) [2]. Excluding
children with the fulminant presentation, a severely impaired
hepatic synthetic function (i.e. prolonged prothrombin time and
hypoalbuminaemia) is more common in AIH type 1 than in AIH
type 2. The severity of interface hepatitis at diagnosis is similar in
both types, but cirrhosis on initial biopsy is more frequent in AIH

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

Fig. 1. Autoimmune hepatitis: Portal and periportal lymphocyte and plasma cell
inltrate extending to and disrupting the parenchymal limiting plate (interface hepatitis) (haematoxylin & eosin, original magnication 100). (Figure kindly provided by
Dr. Alex Knisely).

type 1 than in AIH type 2, suggesting a more chronic course of

disease in the former. Progression to cirrhosis during treatment is
more frequent in AIH type 1.
In both types of AIH, a more severe disease course and a higher
tendency to relapse are associated with the possession of antibodies to soluble liver antigen (SLA), which are present in
approximately half of the patients with either type of AIH at
diagnosis (Table 1) [4]. In both types, about 20% of patients have
associated autoimmune disordersdincluding thyroiditis, vitiligo,
type 1 diabetes, inammatory bowel disease, and nephrotic

Table 1
Clinical, immunological and histological features at presentation of autoimmune
hepatitis type 1 (AIH-1), autoimmune hepatitis type 2 (AIH-2) and autoimmune
sclerosing cholangitis (ASC) among patients referred to the Kings College Hospital
tertiary Paediatric Liver Centre [2,5].

Median age in years

Females (%)
Mode of presentation (%)
Acute hepatitis
Acute liver failure
Insidious onset
Complication of chronic liver disease
Associated immune diseases (%)
Inammatory bowel disease (%)
Family history of autoimmune disease (%)
Abnormal cholangiogram (%)
ANA/SMA (%)
Anti LKM1 (%)
pANNA (%)
Anti SLA (%)a
Increased IgG level (%)
Partial IgA deciency (%)
Low C4 level (%)
Increased frequency of HLA DR*0301
Increased frequency of HLA DR*0701
Increased frequency of HLA DR*1301
Interface hepatitis (%)
Biliary features (%)
Cirrhosis (%)

AIH-1

AIH-2

ASC

11
75

7
75

12
55

47
3
38
12
22
20
43
0
100
0
45
58
84
9
89
Yes
No
No
66
28
69

40
25
25
10
20
12
40
0
25
100
11
58
75
45
83
Nob
Yes
No
72
6
38

37
0
37
26
48
44
37
100
96
4
74
41
89
5
70
No
No
Yes
35
31
15

ANA, anti-nuclear antibodies; SMA, anti-smooth muscle antibody; LKM1, liver

kidney microsomal type 1 antibody; pANNA, peripheral anti-nuclear neutrophil
antibody; SLA, soluble liver antigen; IgG, immunoglobulin G; IgA, immunoglobulin
A; C4, C4 component of complement; HLA, human leukocyte antigen.
a
Measured by radioligand assay.
b
Increased in HLA DR*0701 negative patients.
From Best Pract Res Clin Gastroenterol 2011; 25:783e795.

syndromedand about 40% have a family history of autoimmune

disease (Table 1) [2].
There are three clinical patterns of AIH presentation in paediatric
age [2]: (a) In w40% of patients, the presentation is indistinguishable
from that of an acute viral hepatitis (non-specic symptoms of malaise, nausea/vomiting, anorexia, and abdominal pain, followed by
jaundice, dark urine, and pale stools). Some children, particularly
those who are anti-LKM1-positive, develop acute hepatic failure with
grade II to IV hepatic encephalopathy within 2e8 weeks from onset of
symptoms. (b) In 25e40% of patients, the onset is insidious, with an
illness characterized by progressive fatigue, relapsing jaundice,
headache, anorexia, amenorrhoea, and weight loss, lasting for several
months and even years before diagnosis. (c) In w10% of patients, there
is no history of jaundice, and the diagnosis follows presentation with
complications of portal hypertension, such as splenomegaly, haematemesis from oesophageal varices, bleeding diathesis, chronic
diarrhoea, and weight loss. The mode of presentation of AIH in
childhood is therefore variable, and the disease should be suspected
and excluded in all children presenting with symptoms and signs of
liver disease not ascribable to more common pathologies. The course
of the disease can be uctuating, with ares and spontaneous remissions, a pattern that may result in delayed referral and diagnosis.
The majority of children, however, on physical examination have
clinical signs of an underlying chronic liver disease, including cutaneous stigmata (spider naevi, palmar erythaema, leukonychia, striae),
rm liver and splenomegaly. At ultrasound, the liver parenchyma of
these patients is often nodular and heterogeneous.
1.2. AIH/sclerosing cholangitis overlap (autoimmune sclerosing
cholangitis, ASC)
In paediatrics, sclerosing cholangitis is often associated with
orid autoimmune features, including elevated titres of autoantibodies, in particular ANA and SMA; elevated IgG; and interface
hepatitis (Table 1) [5]. This AIH/sclerosing cholangitis overlap
syndrome, called autoimmune sclerosing cholangitis (ASC) has the
same prevalence as AIH type 1 in childhood, as shown in a prospective study conducted over a period of 16 years [5]. In this study,
all children with serological (i.e. positive autoantibodies, high IgG
levels) and histological (i.e. interface hepatitis) features of autoimmune liver disease underwent a cholangiogram at the time of
presentation. Approximately 50% of the patients enrolled in this
prospective study had alterations of the bile ducts characteristic of
sclerosing cholangitis and were diagnosed as having ASC. A quarter
of the children with ASC, despite abnormal cholangiograms, had no
histological features suggesting bile duct involvement, and the
diagnosis of sclerosing cholangitis was only possible because of the
cholangiographic studies. Virtually all ASC patients were seropositive for ANA and/or SMA. ASC was diagnosed in a similar proportion of boys and girls.
The mode of presentation of ASC was similar to that of AIH-1.
Inammatory bowel disease, mostly asymptomatic or paucisymptomatic, was present in 45% of children with ASC compared
to 20% of those with typical AIH, and 90% of children with ASC
had greatly increased serum IgG levels. At the time of presentation, standard liver function tests did not help in discriminating
between AIH and ASC, although the alkaline phosphatase/aspartate aminotransferase ratio was signicantly higher in ASC.
Atypical perinuclear anti-neutrophil cytoplasmic antibody (atypical pANCA, also termed pANNA) was present in 74% of patients
with ASC compared with 45% of patients with AIH-1 and 11% of
those with AIH-2. Clinical, laboratory, and histological features of
type 1 and 2 AIH and ASC are compared in Table 1. Evolution from
AIH to ASC has been documented, suggesting that AIH and ASC are
likely to be part of the same pathogenic process [5].

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

1.3. Genetic predisposition

In northern Europe, AIH type 1, similarly to what observed in
adult AIH, is associated with the possession of the human leucocyteantigen (HLA) DRB1*03 [2,6]. In contrast to adult patients,
possession of DRB1*04 does not predispose to AIH in childhood,
and can even exert a protective role [2]. AIH-2 is associated with
possession of DRB1*07 and DRB1*03 [7]. In South America,
possession of the HLA DRB1*1301 allele, which predisposes to
paediatric AIH-1 in that population, is also associated with persistent infection with the endemic hepatitis A virus [8,9]. Paediatric
patients with AIH, whether anti-LKM1 or ANA/SMA-positive, have
isolated partial deciency of the HLA class III complement
component C4, which is genetically determined [10].
AIH-2 can be part of the autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy.
(APECED) syndrome, an autosomal-recessive monogenic disorder [11,12] in which the liver disease is reportedly present in some
20% of cases [13].
In the UK, susceptibility to ASC is conferred by the possession of
HLA DRB1*1301 [14].
1.4. Diagnosis
Diagnosis of AIH is based on a series of positive and negative
criteria developed by the International Autoimmune Hepatitis
Group (IAIHG) for adult patients [15,16]. The IAIHG scoring system
was devised mainly for research purposes to allow ready comparison between series from different centres, but has also been used
clinically, including in paediatric series [2,17]. More recently the
IAIHG have published a simplied scoring system based on autoantibodies, IgG, histology, and exclusion of viral hepatitis that is
better suited to clinical application [18]. However, neither scoring
system is readily applicable to the juvenile form of the disease,
where diagnostically relevant autoantibodies often have titres
lower than the cut-off value considered positive in adults. In
addition, neither system can distinguish between AIH and ASC [19],
which can only be differentiated if a cholangiogram is performed at
presentation.
1.5. Treatment
Remission is dened as clinical recovery, normal transaminase
and IgG levels, negative or very low titre autoantibodies by
immunouorescence (1:20 for ANA and SMA; 1:10 for antiLKM-1) and histological resolution of inammation. The histological response lags behind the biochemical response [20] and clinical/biochemical remission does not necessarily reect histological
resolution. After a mean duration of 4 years of treatment,
improvement of the intensity of portal inammation is observed in
up to 95% of AIH cases and is accompanied by an improvement of
brosis scores [20]. Relapse is characterized by an increase of serum
aminotransferase levels after remission has been achieved. Relapse
during treatment is common, occurring in about 40% of patients
and requiring a temporary increase in the steroid dose [2]. An
important role in relapse is played by non-adherence, particularly
in adolescents [21]. In more aggressive cases, the risk of relapse is
higher if steroids are administered on an alternate-day schedule,
which is often instituted in the belief that it has a less negative
effect on the childs growth. Small daily doses are more effective in
maintaining disease control and minimize the need for high-dose
steroid pulses during relapses (with consequent more severe side
effects) and do not affect nal height [22].
Both AIH and ASC respond to immunosuppression and treatment should be initiated promptly to avoid progression of disease.

The goal of treatment is to reduce or eliminate liver inammation,

to induce remission, improve symptoms, and prolong survival [23].
The rapidity and degree of the response depends on the disease
severity at presentation. In AIH, though cirrhosis is found in between 44% and 80% of children at the time at diagnosis [2,24],
development of end-stage liver disease requiring liver transplantation is rare, most children remaining clinically stable, with a
good quality of life on long-term treatment. The prognosis is worse
in ASC, where bile duct disease progresses despite treatment in
some 50% of cases [5,25] (Table 2).
With the exception of a fulminant presentation with encephalopathy, where liver transplant is usually required, AIH and ASC
responds satisfactorily to immunosuppressive treatment whatever
the degree of liver impairment, with a reported remission rate
exceeding 80% [2,5,26,27].
1.6. AIH e standard treatment
Conventional treatment of AIH in childhood consists of prednisolone (or prednisone) 2 mg/kg/day (maximum 60 mg/day),
which is gradually decreased over a period of 4e8 weeks, in parallel
to the decline of transaminase levels, to a maintenance dose of 2.5e
5 mg/day, depending on the childs age and weight [23,28]. In most
patients an 80% decrease of the aminotransferase levels is achieved
in the rst two months, but their complete normalization may take
several months [2]. During the rst 6e8 weeks of treatment, liver
function tests should be checked often to allow weekly dose adjustments, avoiding severe steroid side effects. At Kings College
Paediatric Liver Centre, azathioprine is added as a steroid sparing
agent if the transaminase levels stop decreasing on steroid treatment alone or in the presence of early serious steroid side effects
(e.g. psychosis), at a starting dose of 0.5 mg/kg/day, which in the
absence of signs of toxicity is increased up to a maximum of 2.0e
2.5 mg/kg/day until biochemical control is achieved. The timing for
the addition of azathioprine varies in different centres: in some it is
added in all cases at a dose of 0.5e2 mg/kg/day after a few weeks of
steroid treatment, while other centres use a combination of steroids and azathioprine from the beginning, but caution is recommended because azathioprine can be hepatotoxic, particularly in
severely jaundiced patients. Whatever the protocol, 85% of the
patients eventually require the addition of azathioprine.
Though measurement of thiopurine methyltransferase activity
level before initiating azathioprine therapy is often advocated to
predict azathioprine metabolism and toxicity, only patients with
near-zero erythrocyte concentrations of thiopurine methyltransferase activity are at risk for myelosuppression during
azathioprine treatment [29], and determination of the enzyme
activity is warranted only when there is pre- or intra-treatment
cytopaenia, or the need of higher than conventional doses [30].
Measurement of the azathioprine metabolites 6-thioguanine and
6-methylmercaptopurine has been reported to help in identifying

Table 2
Response to treatment and outcome in patients with autoimmune hepatitis type 1
(AIH-1), autoimmune hepatitis type 2 (AIH-2) and autoimmune sclerosing cholangitis (ASC) treated at the Kings College Hospital tertiary Paediatric Liver Centre
[2,25].

Remission rate (%)

Median time to remission (months)
Relapse rate (%)
Cessation of treatment (%)
Liver transplant rate (%)
Disease recurrence post transplant (%)

AIH-1

AIH-2

ASC

97
6
42
19
6
0

87
9
46
0
13
0

89
2
45
5
23
67

From Best Pract Res Clin Gastroenterol 2011; 25:783-795

10

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

drug toxicity and non-adherence and in achieving a level of 6thioguanine considered therapeutic for inammatory bowel disease [31], though an ideal therapeutic level for AIH has not been
determined.
1.7. Alternative treatment
Induction of remission has been obtained in treatment nave
children using cyclosporine A alone for 6 months, followed by the
addition of prednisone and azathioprine. One month later the
cyclosporine was discontinued [26,27]. Whether this mode of induction has any advantage over the standard treatment has yet to
be evaluated in controlled studies. Budesonide is an attractive
alternative to predniso(lo)ne, as it has a hepatic rst-pass clearance
of >90% of oral dose and less side effects, though it cannot be used
in cirrhotic patients, who represent a large proportion of AIH cases.
In a large European study, where a combination of budesonide and
azathioprine was compared to medium-dose prednisone and
azathioprine [32], the results among the paediatric cohort were
disappointing, with a similarly low remission rate of 15.8% for
budesonide and 14.8% for prednisone after 6 months of treatment
and of 50% and 41.7% respectively after 12 months of treatment
[33]. Nevertheless, budesonide could be a valid alternative in
selected non-cirrhotic patients who are at risk of adverse effects
from steroids.
1.8. Treatment of refractory cases
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid
that affects purine synthesis, has been successfully used in children
(up to 10%) resistant to standard immunosuppression or intolerant
to azathioprine in association with predniso(lo)ne [34]. In the
presence of persistent absence of response or of intolerance for
MMF (headache, diarrhoea, nausea, dizziness, hair loss, and neutropenia), calcineurin inhibitors should be considered. In our
centre, Tacrolimus, in combination with prednisolone, has been
successful in inducing remission in difcult-to-treat patients.
1.9. Autoimmune sclerosing cholangitis
ASC responds to the same immunosuppressive treatment
described above for AIH if treatment is started early, with resolution
of liver test abnormalities within a few months in most patients
(Table 2), but its medium- to long-term prognosis is worse than that
of AIH because of progression of bile duct disease despite treatment
in some 50% of patients [5]. Ursodeoxycholic acid (UDCA) is usually
added to steroids and azathioprine for the treatment of ASC, but
whether it is helpful in arresting the progression of the bile duct
disease remains to be established. In adults with primary sclerosing
cholangitis high-dose UDCA was reported as more benecial than
standard doses [35], but a randomized double-blind controlled study
from the Mayo Clinic shows that high-dose UDCA has a negative
long-term effect [36]. It is prudent, therefore, to use doses not higher
than 15e20 mg/kg/day. ASC is often associated with inammatory
bowel disease which should be investigated even in the absence of
symptoms and appropriately treated. Flares up of the liver disease
often follow ares up of the intestinal disease.
1.10. Duration of treatment and prognosis
The optimal duration of immunosuppressive treatment for AIH
is unknown. Treatment withdrawal is successful only if there is
histological resolution of inammation. Hence, cessation of treatment should considered if a liver biopsy shows minimal or no inammatory changes after 1e2 years of normal liver function tests,

normal IgG levels and negative or low titre autoantibodies. In our

centre, treatment withdrawal is not attempted within 3 years of
diagnosis or during or immediately before puberty, when relapses
are more common. Twenty percent of juvenile patients with AIH
type 1 can successfully and permanently stop treatment, while this
is rarely achieved in AIH type 2 [2]. Long-term treatment, therefore,
is required for the majority of patients, and parents and patients
should be counselled accordingly. In the paediatric setting, an
important role in monitoring the response to treatment both in AIH
and ASC is the measurement of IgG levels and autoantibody titres,
the uctuation of which correlates with disease activity [37]. In
particular, for patients with high IgG levels, their decrease is a
reliable, objective and inexpensive measure of disease control.
The prognosis of those children with AIH who respond to
immunosuppressive treatment is generally good, with most patients surviving long-term with excellent quality of life on low dose
medication. Development of end-stage liver disease requiring liver
transplantation despite treatment, however, has been reported 8e
14 years after diagnosis in 8.5% of children with AIH [2]. The medium- to long-term prognosis of children with ASC is worse than
that of children with AIH because of progression of bile duct disease
in w50% of them [5,25].
1.11. Liver transplantation
Liver transplantation is indicated in patients who present with
fulminant hepatic failure (with encephalopathy) and those who
develop end-stage liver disease despite treatment. Approximately
10% of children with AIH and 20% of those with ASC require liver
transplantation Table 2. After transplantation, recurrent AIH has
been described in about 20% of cases [38] and recurrent ASC in
about 70% [25]. Diagnosis of recurrence is based on biochemical
abnormalities, presence of autoantibodies, interface hepatitis on
liver histology, steroid dependence, and, for ASC, presence of
cholangiopathy. Recurrence may appear even years after transplantation, and consequently maintenance of steroid-based
immunosuppression at a higher dose than that used for patients
not transplanted for autoimmune liver diseases is generally
recommended.
AIH can arise de novo after liver transplantation in children who
have not been transplanted for autoimmune liver disease. Characteristic of this condition is a histological picture of interface hepatitis and multilobular collapse associated with increased IgG levels
and positive autoantibodies [39], and responds to prednisolone and
azathioprine (or MMF) using the same schedule for classical AIH,
concomitant with reduction of the calcineurin inhibitor dose.
Difcult-to treat patients respond to rapamycin Ref. [40]. De novo
AIH after liver grafting has been reported also in adult transplant
recipients [38,41,42].
2. Autoimmune hepatitis in adults
AIH is an immune-mediated liver condition which affects predominantly females (70e80% of patients are women). The median
age at diagnosis is 40 years in men and 50 years in women [43].
Prevalence and incidence data on AIH are still limited, but an
estimated prevalence ranging between 50 and 200 cases per
million has been reported in Western Europe and North America
among the Caucasian population [44]. These gures are likely to be
an underestimate, however, especially considering that AIH results
in a variety of clinical presentations including fulminant hepatitis,
chronic liver disease and overlap syndromes with primary biliary
cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Moreover,
the clinical diagnosis may be difcult, thus other forms of chronic

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

liver disease must be ruled out, including AIH-like disorders triggered by several drugs [45].
According to the antibody prole, AIH is classied as type 1 in
the presence of positive smooth muscle antibody (SMA) and nuclear antibody (ANA), and type 2 in the presence of LKM antibody.
Type 1 AIH affects adults and children, while type 2 AIH is mainly a
disease of children and adolescents.
2.1. Treatment
The goals of treatment include: 1) the induction of remission; 2)
the maintenance of remission; 3) the prevention of progression to
cirrhosis and its complications.
The third goal, namely the progression to cirrhosis is possible
only in approximately 30e40% of cases, because at presentation at
least one third of patients present histological cirrhosis [46,47].
According to the AASLD guidelines treatment is indicated for patients with established diagnosis of AIH, elevation of aminotrasferase activities (ALT, AST), elevation of serum immunoglobulin
G, and histological evidence of interface hepatitis or necroinammatory activity [23]. Standard therapy includes prednisone or
prednisolone in monotherapy alone or in combination with
azathioprine. Monotherapy starts with 60 mg of steroid with
reduction by 10 mg/week to maintenance of 20 mg for at least 6
months, and further reduction until lowest dose in 2.5 mg decrements. Combination therapy with low-dose prednisolone (20e
30 mg/day) with 1 mg/kg azathioprine permits to reduce steroidrelated side-effects in the induction phase. Although recommendations of experts for treatment have been extensively published,
including monitoring of liver function tests and drug side-effects
[44,48], treatment of AIH remains still a challenge for a hepatologist, especially because every patient requires a personalized
therapy. The open questions that are still unclear include: i) the
outcome of therapy; ii) the possibility to discontinue treatment; iii)
the alternative or new therapies which can offer a better control of
liver disease.
2.2. Treatment outcomes
The outcomes of therapy include: remission, relapse, treatment
failure, and stabilization. Remission is dened as a complete
normalization of all inammatory parameters including histology.
Remission can be obtained in 65e75% of patients after 24 months of
standard therapy [49]. Relapse is dened as a are in aminotransferase levels and the re-occurrence of clinical symptoms either under treatment, following the minimum dose of maintenance
therapy, or after withdrawal. Relapse occurs in 50% of patients
within 6 months of treatment withdrawal and in 80% after 3 years,
and is associated with progression to cirrhosis in 38% of cases and
liver failure in 14% [47]. Treatment failure is dened as a progression
of clinical, serological and histological parameters during standard
therapy. In case of treatment failure diagnosis should be reconsidered to exclude an overlap syndrome with PSC or PBC or
different aetiologies. Moreover, there is an indication for second-line
therapies and eventually, in the presence of end-stage liver disease,
consideration of liver transplantation. Stabilization is the achievement of a partial remission. These patients should be reconsidered
for an alternative treatment including liver transplantation.
2.3. Discontinuing treatment
This point has not been completely claried so far. In fact, while
the British literature in the 80s recommended treatment for ever
[50], the American guidelines consider discontinuing treatment as
a possibility during the course of the disease. AASLD

11

recommendations propose the withdrawal of therapy for patients

who achieved a complete response after 2 years of treatment, and
in absence of histological cirrhosis [23]. It is not clear, however, if
remission includes also the disappearance of non organ-specic
autoantibodies. If remission includes negativity of the autoimmune prole together with the normalization of liver function tests
and the absence of necro-inammatory abnormalities in liver histology, only a small percentage of adult patients can withdraw
treatment (less than 5% of cases).
2.4. Alternative and new treatments
2.4.1. Budesonide
Budesonide is a synthetic steroid with high rst-pass metabolism in the liver rstly used in inammatory bowel diseases for
limiting the systemic side-effects of standard treatment with steroids. Budesonide has been employed in 3 pilot studies including a
small number of patients with AIH (Table 3). The rst study, by
Danielson et al. [51] included nave patients with AIH, the second
one, by Czaja et al. [52] enrolled patients previously treated with
azathioprine and steroids who failed to reach a satisfactory
remission. The third study by Wiegand et al. [53] enrolled 12 previously untreated patients. The study by Czaja et al. [52] showed an
unsatisfactory result with budesonide, while the conclusions of the
other two studies raised some interesting considerations. First of
all, the study by Danielson et al. [51] demonstrated a good tolerability of budesonide in the short term. Secondly, Wiegand et al. [53]
performed a kinetic analysis of budesonide and found that in the
presence of cirrhosis and high inammatory activity the area under
the curve of budesonide was increased. This nding demonstrates
that in the presence of porto-systemic shunts, portal hypertension
limits the effects of rst pass metabolism, indicating that budesonide is contraindicated in patients with cirrhosis due to the poor
drug metabolism and the risk of systemic toxicity.
In a large prospective multicentre phase II study 207 patients
were randomized to budesonide (3 mg three times daily) or
prednisone (40 mg/day with tapering course) plus azathioprine
(1e2 mg/kg daily). The complete response rate, dened as
biochemical remission without steroid side effects at the end of a 6month treatment period, was signicantly higher in the budesonide group than in the prednisone group 84% vs 18%, p < 0.0001)
[32]. Biochemical remission was superior in the same group of
treatment (60% vs 39%, p 0.0012); moreover, side-effects at 12
months were signicantly lower in the budesonide than in the
steroid group (26% vs 45%). However, the remission rates at 6 and
12 months for both the budesonide and the prednisone arms were
lower than that reported using the standard treatment with
prednisone and azathioprine [1].
In summary, budesonide may have a potential role in AIH in
combination with azathioprine in patients without cirrhosis and
portal hypertension. There are no sufcient data to recommend
budesonide in monotherapy for adult patients with AIH.
2.4.2. Mycophenolate mofetil (MMF)
MMF is a pro-drug that is converted in the liver to its active
metabolite mycophenolic acid which is a selective inhibitor of
Table 3
Pilot studies involving budesonide in adult patients with AIH.
Author

Year

No patients

Follow-up (months)

Responders

Danielson [51]
Czaja [52]
Wiegand [53]

1994
2000
2005

13
10
12a

9
2e12
3

100%
30%
58%

Combination treatment.

12

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

inosine monophosphate dehydrogenase, which blocks the ratelimiting enzymatic step in de novo purine synthesis. MMF is
extensively used as a transplant immunosuppressant and has been
used as second-line agent in sporadic patients with AIH who did
not obtain a biochemical response with standard treatment. Table 4
summarizes the published studies employing MMF in adult patients with AIH [54e62]. The majority of these studies are retrospective and conducted in patients who failed to reach a clinical/
biochemical remission after standard immunosuppressive therapy
or were intolerant to azathioprine. The results should be evaluated
with caution. Indeed, only a small number of patients has been
treated with MMF, the studies are mainly retrospective, the rate of
remission ranges between 39 and 100% with a median of 60%. The
reported side-effects of MMF include nausea, vomiting, diarrhoea,
and pancreatitis. In our own experience (unpublished data) two
young female patients with AIH refractory to a standard immunosuppressive therapy reached remission within 6 months from
starting MMF at a dosage of 1000 mg twice a day associated to a low
dose of prednisolone. In summary, new trials including MMF in the
treatment of AIH are warranted, but this agent appears to be
effective as second-line agent in difcult-to treat AIH.
2.4.3. Cyclosporine A (CyA)
CyA is a calcineurin inhibitor extracted from the tolypocladium
inatum and cylindrocarpum lucidum. It acts on calcium dependent
signalling and inhibits T cell function via the interleukin 2 gene [63].
Table 5summarizes the results of the most important studies. The
experience is limited to two pilot studies including a small number
of patients [64,65]. The data are, however, encouraging; thus CyA
might be considered an alternative therapy to steroids in patients
who do not achieve a complete remission. However, side-effects are
a serious problem and include: hypertension, renal failure, hyperlipidaemia, hirsutism, infection, and malignancy.
2.4.4. Tacrolimus
Tacrolimus is a macrolide lactone antibiotic which acts as a
potent immunosuppressive agent on CD4 T-helper cells. There are
no controlled trials on the use of tacrolimus in AIH. The main
ndings in pilot studies are summarized in Table 6 [66e69].
Although the reported results are encouraging, more extensive
studies are warranted before tacrolimus can be recommended as a
safe and useful agent in AIH.
2.4.5. Anti-TNF-alpha agents
Anti-TNF-alpha agents, such as iniximab, etanercept and adalimumab are commonly used for the treatment of immunemediated diseases including rheumatoid arthritis, psoriasis and
inammatory bowel disease. TNF-alpha is a pro-inammatory
Table 4
Studies involving MMF in adult patients with AIH resistant or intolerant to standard
therapy.
Author

Year

No.
patients

Follow-up
(months)

Remission

Histology

Richardson [54]
Devlin Ref. [55]
Brunt [56]
Chatur [57]
Czaja [58]

2000
2004
2004
2005
2005

7
5
1
13
8

46
24
48
27
19

5
5
1
8
5

Inductivo-Yu [59]
Hlivko [60]
Hennes [61]
Wolf [62]

2007
2008
2008
2009

15
29
36
16

41
NA
15
23.1

10
16
14
12

Improvement
N.T.
Improvement
N.T.
No prevention
for brosis/
progression
Improvement
N.T.
N.T.
N.T.

NA not available; NT not tested.

(71%)
(100%)
(62%)
(63%)

(67%)
(55%)
(39%)
(75%)

Table 5
Case studies involving CyA in adult patients with AIH.
Author

Year

No
patients

Follow-up
(months)

Responders

Dose

Malekzadeh [64]
Fernandes [65]

2001
1999

19
5

6
3

79%
80%

2e5 mg/kg
2e3 mg/kg

cytokine known to be implicated in the pathogenesis of AIH [70].

Additionally, genetic polymorphisms in the TNF promoter region
have been identied in patients with AIH type 1 and associated
with a poorer response to corticosteroid therapy and a higher frequency of progression to cirrhosis [71,72]. Over the last decade,
some anecdotal reports have suggested that iniximab is effective
in the treatment of difcult-to-treat cases of AIH [73,74]. Very
recently, Weiler-Normann et al. reported the rst series of AIH
patients treated with iniximab in a single centre [75]. This retrospective study included 11 AIH patients who did not achieve
remission with a standard immunosuppressive regimen upon
diagnosis, and who also failed to respond to other alternative
treatments, including cyclosporine, tacrolimus and cyclophosphamide. Patients were given infusions of iniximab at a dose of 5 mg/
kg at weeks 0, 2 and 6, and then every 4e8 weeks depending on
response. Throughout the course of iniximab treatment, all patients but one were also on prednisolone (at a dose ranging from 5
to 15 mg/day). After 3 infusions of iniximab, all patients showed a
decrease in the levels of transaminases and of IgG; normalisation of
transaminases and IgG levels was observed in 8 and 6 patients
respectively. Of the 5 patients in whom a liver biopsy was performed after treatment, all showed reduction of inammation, as
expressed by a modied histological activity index [75]. However,
despite these encouraging results, recent experience also cautions
against its use in AIH since iniximab therapy has been associated
with the induction of severe de novo AIH in some patients treated
for other diseases [76]. Moreover, the use of anti-TNF-alpha agents
is known to be associated with the development of severe infections [77]. In this respect, the series referred to above reported
that 6 of the 11 patients developed an infection while on iniximab
therapy, which led in one case to the discontinuation of the drug
[75]. For all the above reasons, while more studies are warranted to
evaluate the efcacy and tolerability of iniximab in AIH, this type
of treatment should be considered in well dened cases and
administered only in specialised centres.
2.4.6. Rituximab
Rituximab is a chimeric monoclonal antibody to CD20, a surface
marker expressed on B cells, from early pre-B to memory B lymphocytes. Treatment with rituximab leads to B cell depletion
through both complement- and antibody-dependent cellular
cytotoxicity [78]. Initially developed for the treatment of B-cell
lymphoma, rituximab has since proven effective for the treatment
of autoimmune diseases such as rheumatoid arthritis, systemic
lupus erythematosus or autoimmune haemolytic anaemia [79],
suggesting it might also be effective in patients with AIH. A case

Table 6
Case studies involving tacrolimus in adult patients with AIH.
Author

Year

No.
patients

Follow-up
(months)

Responders

Dose

Van Thiel [67]

Aqel [68]
Larsen [69]
Heneghan [66]

1995
2004
2007
2002

21
11
9a
7a

12
N.A.
18
N.A.

75%
90%
100%
6/7

0.075 mg/kg
0.5e2 mg/kg
2e4 mg/kg
N.A.

In combination with steroids.

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

report of a patient with AIH, who developed EpsteineBarr virusassociated lymphoproliferative disease secondary to azathioprine,
rst described that institution of a treatment regimen which
included rituximab resulted not only in the remission of the lymphoma, but also in the normalisation of liver function tests [80]. A
later report of a patient with concurrent diagnoses of B cell lymphoma and steroid resistant AIH/PBC overlap syndrome showed
that a total of a 12-week treatment with rituximab resulted in
clinical, biochemical and histological remission of the liver disease
[81]. Rituximab has also been reported as an effective treatment of
AIH in patients with concomitant idiopatic thrombocytopaenic
purpura [82], cryoglobulinaemic glomerulonephritis [83], or Evans
syndrome [84]. In a phase 1 study, 6 patients with isolated AIH
refractory to standard treatment, were treated with rituximab
(1000 mg at days 1 and 15) [85]. All patients were maintained on
stable doses of prednisolone plus azathioprine for at least 1 month
before and 3 months after rituximab infusions, after which steroids
were tapered. All patients achieved biochemical remission by week
12, and the treatment was well tolerated with no serious adverse
event being reported during the 72-week follow-up [85]. Although
these results are promising and the toxicity prole is favourable,
controlled clinical trials are needed before rituximab can be recommended as an alternative treatment in AIH.
2.5. The future of AIH treatment
2.5.1. Regulatory T cell therapy
There is a wealth of data indicating that CD4posCD25high regulatory T cells (Tregs) are both numerically and functionally
decient in AIH patients [86,87], supporting the idea that an
immune regulatory defect accounts for the un-restrained immune attack targeted to the liver. Since, in health, Tregs effectively dampen auto-aggression, adoptive Treg cell transfer for
autoimmune conditions is a promising candidate for immune

13

intervention aimed at reconstituting self-tolerance. Until

recently, this approach has been hampered by the reluctance of
Tregs to expand to any great extent in vitro and by their propensity to apoptosis [88]. However, the observation that corticosteroid therapy can partially restore Treg number and function
in AIH highlights the previously unrecognised resilience of this
population [89], suggesting that appropriate conditions in vitro
could promote functional recovery. Indeed, following polyclonal
T-cell stimulation in vitro, Tregs from AIH patients, like those
from healthy controls, can be expanded from circulating
CD4CD25 Tregs, and also generated de novo from nonregulatory CD4 T-cells [90].
Several studies have demonstrated that autoantigen-specic
Tregs suppress more prociently than their non-antigen-specic
counterparts. Because in AIH-2 the key autoantigenic target
(CYP2D6) and its specic antigenic regions (CYP2D6217-260 and
CYP2D6305-348) are well dened [91], AIH-2 represents an ideal
model for attempting reconstitution of self-tolerance. In support of
this, antigen-specic Tregs from patients with AIH-2 more potently
suppress CD4 and CD8 T-cell responses than polyclonal expanded
Tregs [92]. Interestingly, co-culture of CYP2D6-exposed Tregs with
semi-mature dendritic cells loaded with the same peptide, promotes particularly effective suppression of autoreactive T-cells [92].
It is envisaged that adoptive transfer of autologous antigen-specic
Tregs could become a tailored, highly effective mode of treatment
for AIH in the future.
2.6. Overlap syndromes
Overlap syndromes are characterized by the coexistence of
clinical, biochemical or serological features of AIH and PBC or PSC
[93]. Features of the two conditions may be present simultaneously
but sometimes those of AIH develop acutely and change the overall
pattern of the liver disease. The clinical denition of the overlap

Table 7
Comparison of clinical characteristics between adults and children with autoimmune hepatitis [2,5,23,46].

Median age at presentation

Mode of presentation
Acute liver failure
Acute hepatitis
Insidious onset
Chronic liver disease
Associated autoimmune diseases
Most common associated immune-mediated
disease
Family history of autoimmune diseases
Overlap syndromes
Initial treatment regimen

Maintenance treatment regimen

Response to treatment
Remission rate
Relapse rate
Liver transplant rate
Recurrence after liver transplantation

Adults

Children

40e50 years

7e11 years

9e20%
30e40%
20e25%
25e30%
10e40%
Autoimmune thyroiditis

3e25%
37e47%
25e38%
10e26%
20e48%
Inammatory bowel disease

30%
PBC-AIH reported in 9% of patients
AIH-PSC reported in 10% of patients
Prednis(ol)one 60 mg/day OR Prednis(ol)one
30e60 mg/day
in combination with azathioprine
1e2 mg/kg/day

37e43%
ASC reported in 50% of patients

Prednis(ol)one 10 mg/week reduction until

20 mg/day,
followed by 5 mg/week reduction until
10 mg/day
and by 2.5 mg/week reduction to reach
maintenance (5 mg/day)
Azathioprine 1e2 mg/kg/day if in
combination with
prednis(ol)one or 2 mg/kg/day if alone
80%
40%
10%
12e42%

Prednis(ol)one 2 mg/kg/daily (up to 60 mg/daily)

decreased weekly if transaminase levels decrease.
Azathioprine (1e2 mg/kg/day) added if transaminase
levels plateau or increase. In the absence of jaundice,
azathioprine can be started at the same time as prednisolone
Prednis(ol)one tapered over 6e8 weeks to
0.1e0.2 mg/kg/day or 5 mg/day Azathioprine
1e2 mg/kg/day if added initially

87e97%
42e46%
6e23%
30%

14

A. Floreani et al. / Journal of Autoimmunity 46 (2013) 7e16

syndromes is often difcult, and guidelines for treatment have not

been validated so far.
2.6.1. AIH/PBC
Chazouillres et al. [94] performed a retrospective study
comparing treatment regimens and outcomes in 12 patients with
AIH/PBC overlap over a median of 7.5 years. One group (5 patients) was treated with UDCA monotherapy and the other (6
patients) with corticosteroids alone. Three patients treated with
UDCA alone experienced increase in brosis and marked histological activity; the remaining two patients had stability or
decrease in brosis with mild activity. None of the 6 patients
under corticosteroids in monotherapy had a complete biochemical normalization. Thus 9 patients were switched to UDCA plus
steroids (4 patients) or to UDCA steroids azathioprine (5
patient). A further patient with consecutive PBC and AIH was
sequentially treated with UDCA, UDCA steroids, and
UDCA steroids azathioprine. Of the 6 patients treated with
UDCA combination therapy (steroids azathioprine) four
showed a favourable response. In summary, UDCA alone is ineffective in patients with AIH/PBC overlap syndrome, and liver
brosis progression can be observed in patients under UDCA plus
immunosuppression.
Another study from the Majo Clinic, reported a similar response
to UDCA in patients with AIH/PBC and in patients with PBC without
features of AIH [95]. Favourable response to combination therapy
with UDCA plus immunosuppression have been reported by other
centres [96,97].
2.6.2. AIH/PSC
Adults with AIH/PSC might have a benecial effect on
biochemical prole with an immunosuppressive therapy associated
to UDCA [98]. Indeed subjects with signicant elevation of transaminases are more likely to achieve a biochemical improvement
with steroids compared to patients with classical PSC [99]. In
general, patients with AIH/PSC are younger at presentation than
patients with classical PSC and have higher levels of transaminases
and gamma-globulins [97]. In a prospective study, 7 patients with
AIH/PSC overlap syndrome, treated with UDCA, prednisolone and
azathioprine demonstrated a signicant reduction in serum AST
over 5 years (p < 0.05) although changes in ALT, ALP and IgG failed
to reach a statistical signicance [97]. A good response in regard to
aminotransferase levels has been also reported by Olsson et al. in a
Swedish study including 16 patients with AIH/PSC overlap treated
with steroids and azathioprine [100].
3. Concluding remarks
AIH is an important cause of liver disease both in children and
adults, having a particularly aggressive course in young patients. If
diagnosed and treated early, AIH has an excellent prognosis, with
only a minority of patients who achieve remission with immunosuppression requiring liver transplantation. As its mode of presentation is variable, AIH should be suspected in all cases of liver
disease in which common aetiologies are excluded, so that appropriate treatment can be started promptly (Table 7). Tasks for the
future include a better understanding of the pathogenesis of AIH
and the establishment of novel, less toxic and more specic treatments aimed at arresting liver autoaggression and reinstating
tolerance to self.
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