Clin Liver Dis 6 (2002) 623 – 634

Autoimmune hepatitis in children

Giorgina Mieli-Vergani, MD, PhD, FRCP, FRCPCHa,*,
Diego Vergani, MD, PhD, FRCPath, FRCP b
a
Paediatric Liver Service, King’s College Hospital, Denmark Hill, London SE5 9RS, UK
b
Institute of Hepatology, University College London, 69 – 75 Chenies Mews, London WCIE 6HX, UK

There are three liver diseases in childhood in which the liver damage is likely
to arise from an autoimmune attack. These diseases are autoimmune hepatitis
(AIH), autoimmune sclerosing cholangitis (ASC) overlap syndrome, and de novo
autoimmune hepatitis after liver transplantation (post LT AIH). The prevalence of
these three conditions in a tertiary pediatric liver center is shown in Table 1.

Autoimmune hepatitis

Clinical features
Two types of AIH have been proposed based on seropositivity for anti-
nuclear antibodies and/or smooth muscle antibodies (ANA/SMA) or antibodies
to liver/kidney microsome type 1 (LKM1). Pediatric series [1], including our
own [2], report a similarly severe disease in patients who are positive for ANA/
SMA or LKM1.
In our retrospective review of 52 children with AIH who were seen between
1973 and 1993, 32 had ANA and/or SMA, and 20 had LKM1 [2]. All other
known causes of liver disease were excluded. Only one child, who was LKM1
positive and presented with acute liver failure, had evidence of exposure to
hepatitis C virus (HCV) infection. This patient had received plasma transfusions
abroad before referral, and antibodies to HCV (anti-HCV) were present by
second-generation assay.
Girls (75%) predominated in both groups [2]. Although patients with LKM1
presented at a younger age (median age, 7.4 vs 10.5 years), the duration of
symptoms before diagnosis and frequency of hepatosplenomegaly were similar in
each population. No significant difference was noted in the frequency of

* Corresponding author.
E-mail address: giorgina.vergani@kcl.ac.uk (G. Mieli-Vergani).

1089-3261/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 1 0 8 9 - 3 2 6 1 ( 0 2 ) 0 0 0 2 0 - X
624 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634

Table 1
Frequency and types of autoimmune liver disease in children
Disease category Prevalence in tertiary referral center
Autoimmune hepatitis 1.2%
Autoimmune sclerosing cholangitis 1.1%
De novo autoimmune hepatitis after transplant 4% of transplanted children

associated autoimmune disorders and family history of autoimmune disease

between the groups. Associated autoimmune disorders included nephrotic syn-
drome, thyroiditis, Behcßet’s disease, ulcerative colitis, insulin-dependent diabetes,
and urticaria pigmentosa in the children with ANA/SMA and thyroiditis, vitiligo,
hypoparathyroidism, and Addison’s disease in the children with LKM1.
Three clinical patterns of disease were observed [2]. Pattern 1: in 50% of
patients with ANA/SMA and 65% of patients with LKM1, the presentation was
indistinguishable from that of an acute viral hepatitis. Nonspecific symptoms of
malaise, nausea/vomiting, anorexia, and abdominal pain followed by jaundice,
dark urine, and pale stools typified this pattern. Six children, including five with
LKM1, developed acute hepatic failure with grade II-IV hepatic encephalopathy
developing from 2 weeks to 2 months after onset of symptoms (median interval,
1 month). In the remaining children, the duration of disease before diagnosis
ranged from 10 days to 5 months (median interval, 1.8 months). Pattern 2: 25%
of children with LKM1 and 38% with ANA/SMA had an insidious onset with an
illness characterized by progressive fatigue, relapsing jaundice, headache,
anorexia, and weight loss, lasting from 6 months to 2 years before diagnosis
(median interval, 9 months). Pattern 3: in six children, including two with
LKM1, there was no history of jaundice, and the diagnosis followed presentation
with complications of chronic liver disease, including hematemesis from esopha-
geal varices, bleeding diathesis, chronic diarrhea, weight loss, and vomiting.
Clearly, the mode of presentation of AIH in childhood is variable, and the disease
should be suspected and excluded in all children presenting with symptoms and
signs of prolonged or severe acute liver disease.

Laboratory features
Children with LKM1 had higher median levels of serum bilirubin and
aspartate aminotransferase (AST) than children with ANA/SMA [2]. These
differences were not, however, significant when the six patients with acute
hepatic failure were excluded. Severe impairment of hepatic synthetic function,
as reflected in a prolonged prothrombin time and hypoalbuminemia, tended to
be more common in patients with ANA/SMA than in those with LKM1 (53%
vs 30%).
Most patients (80%) had increased levels of immunoglobulin G (IgG), but ten,
including five with LKM1, had normal serum IgG levels for age [2]. Three of
these latter patients had presented with acute hepatic failure. These findings
indicate that a normal serum IgG value in children, albeit a rare finding, does not
 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634 625

exclude the diagnosis of AIH. As reported in another study [3], a partial serum
immunoglobulin A (IgA) deficiency was more common in children with LKM1
than those with ANA/SMA (45% vs 9%).
The frequency of human leukocyte antigen (HLA) DR3 was significantly
higher in patients with ANA/SMA than in control subjects [2]. This difference
was not seen in patients with LKM1, and the finding suggested that the two
groups had different immunopathic mechanisms. Future studies must confirm this
hypothesis in larger numbers of children.

Histologic features
The severity of portal tract inflammation, lobular activity, and interface
hepatitis at diagnosis was similar in both groups [2]. Cirrhosis on initial biopsy
evaluation was more frequent in patients with ANA/SMA than in those with
LKM1 (69% vs 38%). Notably, 57% of children who had cirrhosis at diagnosis
presented with a clinical picture reminiscent of a prolonged acute viral hepatitis.
Multiacinar or panacinar collapse suggestive of an acute liver injury was present
in eight children, including five with LKM1. Six of these had acute liver failure,
and the degree of fibrosis and the presence of cirrhosis could not be ascertained.
Consequently, it was not possible to determine if the acute presentation
represented a sudden deterioration of an underlying unrecognized chronic process
or a new liver injury.
Progression to cirrhosis was noted in four of seven children with ANA/SMA
and two of five children with LKM1 during biopsy intervals of 17 to 56 months
[2]. Overall, 74% of patients with ANA/SMA and 44% of patients with LKM1
showed evidence of cirrhosis on initial or follow-up histologic assessment. This
finding indicated that apart from the greater tendency to present as acute liver
failure, the disease associated with LKM1 was of similar severity to that asso-
ciated with ANA/SMA.

Treatment
Autoimmune hepatitis responds well to immunosuppression unless it presents
as acute liver failure. In the latter circumstance, urgent liver transplantation is
usually required. Prednisolone 2 mg/kg/d (maximum dose, 60 mg/d), is the
typical initial treatment. The dose is gradually decreased over 4 to 8 weeks if
there is a progressive improvement of the serum aminotransferase level. The
patient is then maintained on the minimal dose of prednisolone necessary to keep
the serum aminotransferase level normal (usual maintenance dose, 2.5 to 5 mg/d,
depending on age).
During the first 6 to 8 weeks of therapy, liver indices are checked weekly to
allow a constant fine-tuning of the treatment and avoidance of severe cortico-
steroid-related side effects. Failure to achieve a progressive improvement in the
liver tests or inability to reduce the dose of prednisolone justifies the addition of
azathioprine (0.5 mg/kg/d) to the schedule. In the absence of toxicity, the dose of
626 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634

azathioprine is increased to a maximum of 2 mg/kg/d until biochemical control

is achieved. Azathioprine is not recommended as first-line treatment because of
its hepatotoxicity, particularly in severely jaundiced patients.
In most children, an 80% decrease in the initial serum aminotransferase
abnormality is achieved within 6 weeks. Complete resolution of the liver test
abnormality, however, may take several months. In our own series, normalization
of the serum aminotransferase level occurred at a median of 0.5 years (range, 0.2
to 7 years) in children with ANA/SMA and 0.8 years (range, 0.02 to 3.2 years) in
children with LKM1 [2].
Relapse while on treatment affects 40% of children and requires a temporary
increase in the dose of prednisolone. The risk of relapse is greater if prednisolone
is administered on alternate days. The alternate day schedule is often instituted
because of the unsubstantiated belief that it has less effect on growth. A small
daily dose schedule of prednisolone is actually preferred, because it is more
effective in maintaining disease control. This latter approach also minimizes the
need for high-dose corticosteroid pulses during relapse and avoids more severe
side effects.
Discontinuation of treatment should be considered after 1 year of normal liver
tests and demonstration of minimal or no inflammatory changes in liver biopsy
tissue. Treatment should not be weaned just before or during puberty because
relapse is more common during this period. In our experience, treatment was
successfully withdrawn in six of 13 children who fulfilled these remission
criteria. All six patients had ANA/SMA. Treatment withdrawal was accomplished
after a median treatment duration of 3.2 years (range, 1 to 11 years), and
remission was sustained in all six for 9 to 13 years. The remaining seven children
relapsed between 1 and 15 months after drug withdrawal (median interval,
2 months). Three of these patients had ANA/SMA, and four had LKM1. All
responded to reintroduction of the original treatment schedule. These observa-
tions indicate that most children with AIH, particularly those with LKM1, require
life-long immunosuppressive therapy.
Despite the efficacy of current treatment, severe hepatic decompensation may
develop even after many years of apparent good biochemical control. Indeed,
four of our patients who responded satisfactorily to immunosuppressive treatment
ultimately required liver transplantation 8 to 14 years after diagnosis. Overall, in
our experience, 46 of the 47 patients treated with immunosuppression are alive at
last follow-up between 0.3 and 19 years after diagnosis (median interval, 5 years),
including five after liver transplantation.
Sustained remission of AIH has been reported in adult patients maintained
long term on azathioprine alone [4]. The authors have attempted to discontinue
prednisolone while continuing therapy with azathioprine in five children.
Although this strategy was successful in the two patients with ANA/SMA, all
three children with LKM1 relapsed and required reinstitution of the cortico-
steroid regimen.
An investigational strategy administering cyclosporin A for 6 months as the
initial drug and then low-dose prednisone in combination with azathioprine as the
 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634 627

maintenance schedule induced remission in 25 of 32 children with AIH [5]. The

side effects associated with short-term cyclosporin treatment were mild despite
relatively high blood concentrations of the drug, and corticosteroid-induced side
effects were avoided. A disadvantage of the investigational protocol was that all
patients were eventually treated with prednisone and azathioprine. While using
the conventional treatment schedule described above, the authors have shown
that one third of children can be maintained in remission with very low-dose
corticosteroids alone. Longer follow-up is clearly needed to establish the safety of
the cyclosporin regimen.
Mycophenolate mofetil (MMF) has been successfully used in adult patients
with type 1 AIH who have been either intolerant of or nonresponsive to azathio-
prine [6]. MMF is an inhibitor of purine nucleotide synthesis and has a mechanism
of action similar to that of azathioprine [7]. It is neither hepatotoxic nor nephro-
toxic, and its main side effects are diarrhea, vomiting, and bone marrow suppres-
sion. In our experience, the drug was able to resolve laboratory abnormalities in
five of 12 children who did not tolerate or respond to azathioprine. In four other
children, it reduced serum aminotransferase levels to a degree that allowed a
decrease in the dose of prednisolone. Only three patients did not respond to MMF,
and the side effects were minor except for severe nausea and dizziness in one of
these three children.
Children who present with acute hepatic failure pose a particularly difficult
therapeutic problem. Although they may benefit from conventional immuno-
suppressive therapy [8,9], only one of the six children with acute liver failure in
our own series responded to such therapy and survived without liver trans-
plantation. Of the four children with LKM1, one died before a donor organ could
be found, and two died soon after liver transplantation. Although encouraging
results have been reported using cyclosporin A in children with LKM1 who
present with fulminant hepatitis [8,10], these results must be confirmed in a
larger number of patients.

ASC overlap syndrome

Clinical, laboratory, and histologic features

An overlapping syndrome between AIH and sclerosing cholangitis has been
anecdotally reported in children [11 –13] and in adults [14 –16]. A retrospective
study from our institution has shown that 40% of patients with sclerosing
cholangitis have clinical, biochemical, immunologic, and histologic features that
are indistinguishable from those of AIH [12]. In both AIH and sclerosing
cholangitis, the serum IgG level is commonly increased, and nonorgan specific
ANA and/or SMA are frequently present. Both diseases also commonly have
portal tract inflammation and interface hepatitis. Indeed, most of the reported
cases of overlap were originally diagnosed as AIH [14 –17]. Typically, the
overlap with sclerosing cholangitis was not recognized until years later when
628 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634

biliary features on follow-up liver biopsy examination justified the performance

of cholangiography. The sequence of diagnoses was then interpreted as an
evolution from AIH to sclerosing cholangitis when in fact the concurrence
of these diseases had not been excluded by cholangiographic studies performed
at presentation.
In a prospective study over a 16-year period, the authors have found that 27 of
55 children who presented with clinical and/or laboratory evidence of AIH had
evidence of sclerosing cholangitis when assessed by liver biopsy examination,
cholangiography, sigmoidoscopy, and rectal biopsy at presentation [18]. Bile duct
abnormalities on cholangiography were both intra- and extrahepatic in two thirds
of patients and intrahepatic in one third. The cholangiographic changes justified
the diagnosis of ASC in these individuals.
Of the 27 patients with ASC, 26 were seropositive for ANA and/or SMA, and
one for LKM1 [18]. Fifty-five percent were girls, and the mode of presentation
was similar to that of 28 patients with typical AIH. Symptoms were those of acute
hepatitis or chronic liver dysfunction. In some instances, symptoms were absent,
and the diagnosis was revealed after the incidental discovery of abnormal liver
tests. Inflammatory bowel disease was present in 44% of children who underwent
cholangiography, compared with 20% of those with typical AIH, and more than
75% of children with ASC had greatly increased serum IgG levels. Perinuclear
antineutrophil cytoplasmic antibodies (pANCA) were present in 74% of indi-
viduals with ASC compared with 36% of patients with typical AIH. Laboratory
features at presentation in patients with ASC and typical AIH are summarized
in Table 2.
A partial concordance was noted between the histologic and radiologic
findings, and six patients had histologic features more compatible with AIH
than with sclerosing cholangitis [18]. Interestingly, all patients fulfilled the
criteria for the diagnosis of ‘‘definite’’ or ‘‘probable’’ AIH established by the

Table 2
Laboratory features at presentation of autoimmune sclerosing cholangitis and autoimmune hepatitis
Autoimmune Autoimmune
sclerosing cholangitis a hepatitis a
Laboratory findings (n = 27) (n = 28) P
Bilirubin (nL, < 20 mmol/L) 20 (40 – 178) 35 (4 – 360) 0.04
AST (nL, < 50 IU/L) 102 (18 – 1215) 333 (24 – 4830) 0.002
Albumin (nL, > 35 g/L) 39 (27 – 54) 35 (25 – 47) 0.05
INR (nL, < 1.2) 1.1 (0.9 – 1.6) 1.2 (0.9 – 2.5) 0.006
Alkaline phosphatase (nL, 303 (104 – 1710) 356 (131 – 878) NS
< 350 IU/L)
GGT (nL, < 50 IU/L) 129 (13 – 948) 76 (29 – 383) NS
All phos/AST ratio>3 (%) 59 14 0.0005
Abbreviations: AST, serum aspartate aminotransferase level; INR, international normalized
prothrombin ratio; GGT, serum gammaglutamyl transpeptidase level; Alk phos, serum alkaline
phosphatase level; NS, not statistically significant.
a
Numbers in parentheses are ranges.
 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634 629

International Autoimmune Hepatitis Group [19]. Indeed, the diagnosis of scle-

rosing cholangitis was possible only because of the cholangiographic studies. The
similarities and differences among type 1 AIH, type 2 AIH, and ASC are
summarized in Table 3.

Treatment
Children with ASC respond to the same immunosuppressive treatment as
described earlier for typical AIH [18]. The liver test abnormalities resolve in
almost 90% of our patients within a median of 2 months after beginning
treatment. This good response is in contrast to the outcome in adults with
primary sclerosing cholangitis (PSC) who have no beneficial effects from
corticosteroids [20,21]. The PSC in adults, however, is usually diagnosed at an
advanced stage and may be caused by various etiologies. Although disappointing
results with immunosuppressive agents have been reported in a small number of
children with sclerosing cholangitis associated with autoimmune features, these
children may have had a more advanced disease than those recruited into our
prospective study [13].

Table 3
Comparison between autoimmune hepatitis and autoimmune sclerosing cholangitis
Clinical features at presentation Type 1 AIH Type 2 AIH ASC
Median age (yr) 11 7 12
Females (%) 75 75 55
Mode of presentation (%)
Acute hepatitis 47 40 37
Acute liver failure 3 25 0
Insidious onset 38 25 37
Complication of chronic liver disease 12 10 26
Associated immune diseases (%) 22 20 48
Inflammatory bowel disease (%) 20 12 44
Family history autoimmune disease (%) 43 40 37
Abnormal cholangiogram (%) 0 0 100
ANA/SMA (%) 100 25 96
LKM1 (%) 0 100 4
ANCA (%) 45 11 74
Increased serum IgG level (%) 84 75 89
Serum IgA deficiency (%) 9 45 5
Low C4 level (%) 89 83 70
Increased frequency of HLA DR3 Yes No No
Interface hepatitis (%) 66 72 35
Biliary features (%) 28 6 31
Cirrhosis (%) 69 38 15
Remission after immunosuppressive treatment (%) 97 87 89
Abbreviations: AIH, autoimmune hepatitis; ASC, autoimmune sclerosing cholangitis; ANA,
antinuclear antibodies; SMA, antismooth muscle antibody; LKM1, anti-liver-kidney microsomal
type 1 antibody; ANCA, antineutrophil cytoplasmic antibody; IgG, immunoglobulin G; IgA,
immunoglobulin A; C4, C4 component of complement; HLA, human leukocyte antigen.
630 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634

Ursodeoxycholic acid (UDCA) was added to our treatment schedule in 1992

after preliminary reports noted its value in treating adult PSC [22,23]. The small
number of patients and the relatively short follow-up period do not let us
determine whether treatment with UDCA from onset is successful in arresting
the progression of ASC. In adults with well-established PSC, UDCA treatment
has been disappointing, possibly because of its advanced stage at the time of
diagnosis [24].
Follow-up liver biopsy assessments in our series have shown no progression to
cirrhosis; although one patient did develop a vanishing bile duct syndrome.
Follow-up endoscopic retrograde cholangiograms have shown static bile duct
disease in half of our patients with ASC and progression of the bile duct
abnormalities in the other half. Interestingly, one of the children with AIH who
was followed prospectively developed sclerosing cholangitis 8 years after pres-
entation despite treatment with corticosteroids and no biliary changes on several
follow-up liver biopsy specimens. This experience suggests that AIH and ASC are
part of the same pathogenic process and that prednisolone and azathioprine may
not be as effective in controlling the bile duct component of the disease.
The medium term prognosis of ASC is good [18]. All patients in our series
were alive after a median follow-up of 7 years. Four patients with ASC, however,
required liver transplantation after 2 to 11 years of observation (median follow-up
interval, 7 years). In contrast, liver transplantation has not been required by any
of the 28 children with typical AIH who have been followed for this same time.

Pathophysiology
It is unclear if the juvenile autoimmune form of sclerosing cholangitis and
AIH are two distinct entities or different aspects of the same condition. Like AIH,
liver-specific autoantibodies, including antibodies to liver-specific lipoprotein,
asialoglycoprotein receptor, alcohol dehydrogenase, and soluble liver antigen are
found in ASC [25 – 27]. HLA DR3, DR13, and DR15 occur as commonly in
patients with ASC as in healthy control subjects; however, HLA DR4 occurs less
often. This HLA profile has been associated with susceptibility to sclerosing
cholangitis in adults [28], and a shared genetic predisposition between AIH and
PSC may facilitate the expression of a hybrid syndrome.

De novo autoimmune hepatitis after liver transplantation

Clinical, laboratory, and histologic features

Late graft dysfunction not caused by recognized causes, such as rejection,
infection, or vascular, and/or biliary complications, may occur after liver
transplantation. The authors have recently observed and reported a particular
type of graft dysfunction associated with autoimmune features in seven of
180 children (4%) transplanted at our institution between 1991 and 1996 [29].
 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634 631

These children developed an unexplained but characteristic form of graft dys-

function during a median postoperative period of 24 months (postoperative range,
6 to 45 months). Five of the seven children were boys; the median age at pres-
entation was 10.3 years (age range, 2 to 19.4 years), and none had been trans-
planted for autoimmune liver disease. The indications for transplantation were
extrahepatic biliary atresia (four patients), Alagille’s syndrome (one patient),
drug-induced acute liver failure (one patient), and a1-antitrypsin deficiency (one
patient). At the time of graft dysfunction, four children were receiving triple drug
immunosuppressive therapy with cyclosporin A, azathioprine, and prednisolone,
and three children were being treated with tacrolimus. Common causes of graft
dysfunction, such as infectious and surgical complications, had been excluded,
and liver biopsy examination showed portal and interface hepatitis with lympho-
cytes and plasma cells, bridging necrosis, and perivenular (zone 3) necrosis in the
absence of changes typical of acute or chronic rejection. All patients had
increased serum levels of IgG and ANA, SMA, or atypical liver/kidney micro-
somal antibodies. In the latter instance, the proximal renal tubules disclosed
immunofluorescence similar to the staining pattern of LKM1, but the hepatocytes
did not.
After this report [29], autoimmune phenomena and liver disease mimicking
AIH after liver transplantation have been described in adults and children [30 – 33].
The graft dysfunction has been responsive to therapy with corticosteroids and
azathioprine but not to increased doses of cyclosporin A or tacrolimus [30 – 33].

Treatment
In our study, all patients but one responded to the conventional treatment reg-
imen for AIH based on prednisolone (2 mg/kg/d) and azathioprine (1.5 mg/kg/d)
[29]. Antirejection therapy with cyclosporin A or tacrolimus was not changed
during the treatment interval. Serum aminotransferase abnormalities resolved
within a median treatment period of 32 days (range, 7 to 316 days). The one
child who did not respond had a history of poor compliance with therapy. One
responder relapsed because of poor compliance; however, remission was again
achieved after retreatment. All six responders remained in remission on a reduced
dose of prednisolone (5 to 10 mg/d) and azathioprine (1.5 mg/kg/d) during a me-
dian follow-up interval of 283 days (range, 108 to 730 days). Similar satisfactory
results have been reported by other authors using prednisolone and azathioprine
[31 – 34], whereas the condition has worsened in the absence of such treatment
[35,36]. These findings underscore the importance of prompt recognition of the
condition and institution of appropriate treatment.

Pathophysiology
It remains to be established whether the liver damage observed in these
patients is a form of rejection or the result of an ‘‘autoimmune’’ injury possibly
triggered by drugs or viral infection. Further characterization of the target
632 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634

specificity of intrahepatic lymphocytes may provide information regarding its

pathogenesis. The administration of cyclosporin or tacrolimus to rodents after
bone marrow transplantation can result in a ‘‘paradoxic’’ autoimmune syndrome
in which the immunosuppressive drugs interfere with maturation of T cells and
favor the emergence of autoaggressive T cell clones [34,37,38]. This experience
in animals may partly explain the development of this disorder in immuno-
suppressed children after liver transplantation.
The manifestations of the autoimmune condition in rodents vary in different
strains and depend on genetic factors possibly encoded by the major histo-
compatibility complex (MHC) [34]. Analysis of the HLA phenotypes of the
recipients and donors in our study did not show an association among the
development of autoimmune features, the possession of either HLA DR3 or DR4,
or the degree of donor/recipient HLA mismatch [29]. Five of the seven patients,
however, had received livers from donors with HLA markers known to be
associated with susceptibility to AIH, including two with DR4, one with DR3,
and two DR3 and DR4 [39].

Summary
AIH, ASC, and de novo AIH after liver transplantation are childhood liver
diseases of an autoimmune nature. The mode of presentation of AIH in childhood
is variable, and the disease should be suspected and excluded in all children
presenting with symptoms and signs of prolonged or severe acute liver disease.
Although corticosteroids are effective in all types of childhood AIH, patients with
LKM1 have a higher frequency of acute hepatic failure and relapse after
corticosteroid withdrawal than do patients with ANA/SMA. ASC occurs com-
monly in the absence of inflammatory bowel disease, requires cholangiography
for diagnosis, and improves during corticosteroid therapy. The development of
AIH de novo in children who undergo liver transplantation for nonautoimmune
liver disease may reflect interference with the maturation of T cells by immuno-
suppressive drugs.

References
[1] Maggiore G, Veber F, Bernard O, et al: Autoimmune hepatitis associated with anti-actin anti-
bodies in children and adolescents. J Pediatr Gastroenterol Nutr 1993;17:376 – 81.
[2] Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year expe-
rience. Hepatology 1997;25:541 – 7.
[3] Homberg J-C, Abuaf N, Bernard O, et al. Chronic active hepatitis associated with antiliver/
kidney microsome antibody type 1: a second type of ‘‘autoimmune’’ hepatitis. Hepatology 1987;
7:1333 – 9.
[4] Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in
autoimmune hepatitis. N Engl J Med 1995;333:958 – 63.
[5] Alvarez F, Ciocca M, Canero-Velasco C, et al. Short-term cyclosporine induces a remission of
autoimmune hepatitis in children. J Hepatol 1999;30:222 – 7.
 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634 633

[6] Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in
autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol 2000;33:
371 – 5.
[7] Dhawan A, Mieli-Vergani G. Mycophenolate mofetil—a new treatment for autoimmune hepa-
titis? J Hepatol 2000;33:480 – 1.
[8] Debray D, Maggiore G, Girardet JP, et al. Efficacy of cyclosporin A in children with type 2
autoimmune hepatitis. J Pediatr 1999;135:111 – 4.
[9] Maggiore G, Bernard O, Hadchouel M, et al. Life-saving immunosuppressive treatment in severe
autoimmune chronic active hepatitis. J Pediatr Gastroenterol Nutr 1985;4:655 – 8.
[10] Debray D, Maggiore G, Bernard O. Cyclosporin treatment of autoimmune hepatitis in children.
[abstract] J Pediatr Gastroenterol Nutr 1995;20:470.
[11] Debray D, Pariente D, Urvoas E, et al. Sclerosing cholangitis in children. J Pediatr 1994;124:
49 – 56.
[12] el-Shabrawi M, Wilkinson ML, Portmann B, et al. Primary sclerosing cholangitis in childhood.
Gastroenterology 1987;92:1226 – 35.
[13] Wilschanski M, Chait P, Wade JA, et al. Primary sclerosing cholangitis in 32 children: clinical,
laboratory, and radiographic features, with survival analysis. Hepatology 1995;22:1415 – 22.
[14] Gohlke F, Lohse AW, Dienes HP, et al. Evidence for an overlap syndrome of autoimmune
hepatitis and primary sclerosing cholangitis. J Hepatol 1996;24:699 – 705.
[15] McNair AN, Moloney M, Portmann BC, et al. Autoimmune hepatitis overlapping with primary
sclerosing cholangitis in five cases. Am J Gastroenterol 1998;93:777 – 84.
[16] Rabinovitz M, Demetris AJ, Bou-Abboud CF, et al. Simultaneous occurrence of primary scle-
rosing cholangitis and autoimmune chronic active hepatitis in a patient with ulcerative colitis.
Dig Dis Sci 1992;37:1606 – 11.
[17] Sisto A, Feldman P, Garel L, et al. Primary sclerosing cholangitis in children: study of five cases
and review of the literature. Pediatrics 1987;80:918 – 23.
[18] Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing cholangitis overlap
syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544 – 53.
[19] Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review
of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929 – 38.
[20] Czaja AJ. Frequency and nature of the variant syndromes of autoimmune liver disease. Hepa-
tology 1998;28:360 – 5.
[21] Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995;332:924 – 33.
[22] Beuers U, Spengler U, Kruis W, et al. Ursodeoxycholic acid for treatment of primary sclerosing
cholangitis: a placebo-controlled trial. Hepatology 1992;16:707 – 14.
[23] Lebovics E, Salama M, Elhosseiny A. Resolution of radiographic abnormalities with ursodeoxy-
cholic acid therapy of primary sclerosing cholangitis. Gastroenterology 1992;102:2143 – 7.
[24] Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-
Ursodeoxycholic Acid Study Group. N Engl J Med 1997;336:691 – 5.
[25] Ma Y, Okamoto M, Thomas MG, Bogdanos DP, et al. Antibodies to conformational epitopes of
soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002;35:
658 – 64.
[26] Ma Y, Gaken J, McFarlane BM, et al. Alcohol dehydrogenase: a target of humoral autoimmune
response in liver disease. Gastroenterology 1997;112:483 – 92.
[27] Mieli-Vergani G, Lobo-Yeo A, McFarlane BM, et al. Different immune mechanisms leading
to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of
childhood. Hepatology 1989;9:198 – 203.
[28] Donaldson PT, Manns MP. Immunogenetics of liver disease. In: Bircher J, Benhamou J-P,
McIntyre N, et al, editors. Oxford textbook of clinical hepatology. Oxford: Oxford University
Press; 1999. p. 173 – 88.
[29] Kerkar N, Hadzic N, Davies ET, et al. De-novo autoimmune hepatitis after liver transplantation.
Lancet 1998;351:409 – 13.
[30] Andries S, Casamaiou L, Sempoux C, et al. Posttransplant immune hepatitis in pediatric liver trans-
634 G. Mieli-Vergani, D. Vergani / Clin Liver Dis 6 (2002) 623–634

plant recipients: incidence and maintenance therapy with azathioprine. Transplantation 2001;72:
267 – 72.
[31] Duclos-Vallee JC, Johanet C, Bach JF, et al. Autoantibodies associated with acute rejection after
liver transplantation for type-2 autoimmune hepatitis. J Hepatol 2000;33:163 – 6.
[32] Heneghan MA, Portmann BC, Norris SM, et al. Graft dysfunction mimicking autoimmune
hepatitis following liver transplantation in adults. Hepatology 2001;34:464 – 70.
[33] Hernandez HM, Kovarik P, Whitington PF, et al. Autoimmune hepatitis as a late complication of
liver transplantation. J Pediatr Gastroenterol Nutr 2001;32:131 – 6.
[34] Bucy RP, Xu XY, Li J, et al. Cyclosporin A-induced autoimmune disease in mice. J Immunol
1993;151:1039 – 50.
[35] Conti FDB, Levillayer H, Gruska J, et al. Autoantibodies after liver transplantation: a marker of
allograft disease [abstract] J Hepatol 1997;26(suppl):150.
[36] Hernandez Albujar A, Alvarez E, Salcedo M, et al: Autoimmune mediated liver disease after
liver transplantation [abstract]. J Hepatol 1997;26(suppl):152.
[37] Cooper MH, Hartmann GG, Starzl TE, et al. The induction of pseudo-graft-versus-host disease
following syngeneic bone marrow transplantation using FK 506. Transplant Proc 1991;23:
3234 – 5.
[38] Hess AD, Fischer AC, Horwitz LR, et al. Cyclosporine-induced autoimmunity: critical role of
autoregulation in the prevention of major histocompatibility class II-dependent autoregression.
Transplant Proc 1993;25:2811 – 3.
[39] Donaldson PT, Doherty DG, Hayllar KM, et al. Susceptibility to autoimmune chronic active
hepatitis: human leukocyte antigens DR4 and A1 – B8-DR3 are independent risk factors.
Hepatology 1991;13:701 – 6.