Journal of Pediatric Gastroenterology and Nutrition

49:158–164 # 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

Invited Review

Autoimmune Hepatitis
Giorgina Mieli-Vergani, ySolange Heller, zPaloma Jara, §Diego Vergani,
jjMei-Hwei Chang, ôTomoo Fujisawa, #Regino P. González-Peralta, Deirdre Kelly,
yyNeelam Mohan, zzUzma Shah, and §§Karen F. Murray
King’s College London School of Medicine at King’s College Hospital, London, UK, {Gastroenterology and Nutrition Department,
Hospital Infantil de México Federico Gómez, México D.F. Mexico, {Pediatric Hepatology and Transplantation Service,
Pediatric University Hospital La Paz, Madrid, Spain, §Institute of Liver Studies, King’s College Hospital, London, UK,
jjDepartment of Pediatrics, National Taiwan University Hospital, Taipei, ôChildren’s Center for Health and Development,
Yokohama East Hospital, Yokohama City, Japan, #Pediatric Hepatology and Liver Transplantation, Division of Pediatric
Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine, Gainesville, Liver Unit,
Birmingham Children’s Hospital NHS Trust and University of Birmingham, Birmingham, UK, {{Pediatric Gastroenterology,
Hepatology and Pediatric Liver Transplantation, Department of Pediatrics, Centre of Child Health, Sir Ganga Ram Hospital,
New Delhi, India, {{MassGeneral Hospital for Children, Boston, MA, and §§Hepatobiliary Program,
Seattle Children’s Hospital, Seattle, WA

ABSTRACT
Autoimmune hepatitis is characterized by inflammatory liver sporine and mycophenolate mofetil. Long-term treatment is
histology, circulating nonorgan-specific autoantibodies, and usually required, with only some 20% of AIH type 1 patients
increased levels of immunoglobulin G, in the absence of a able to discontinue therapy successfully. In childhood, scleros-
known etiology. Two types of juvenile autoimmune hepatitis ing cholangitis with strong autoimmune features, including
(AIH) are recognized according to seropositivity for smooth interface hepatitis and serological features identical to AIH
muscle and/or anti-nuclear antibody (AIH type 1) or liver type 1, is as prevalent as AIH, but it affects boys and girls
kidney microsomal antibody (AIH type 2). There is a female equally. Differential diagnosis relies on cholangiographic
predominance in both. AIH type 2 presents more acutely, at a studies. In autoimmune sclerosing cholangitis liver parenchy-
younger age and commonly with immunoglobulin A deficiency, mal damage responds satisfactorily to immunosuppressive
whereas duration of symptoms before diagnosis, clinical signs, treatment, whereas bile duct disease tends to progress. In
family history of autoimmunity, presence of associated auto- this article we review the state of the art of diagnosis, monitor-
immune disorders, response to treatment, and long-term prog- ing, and treatment for children with AIH. JPGN 49:158–164,
nosis are similar in the 2 groups. Immunosuppressive treatment 2009. Key Words: Autoimmune hepatitis—hepatitis—
with steroids and azathioprine, which should be instituted Immunosuppression—Liver disease—Pediatrics. # 2009 by
promptly to avoid progression to cirrhosis, induces remission European Society for Pediatric Gastroenterology, Hepatology,
in 80% of cases. Relapses are common, often due to non- and Nutrition and North American Society for Pediatric
adherence. Drugs effective in refractory cases include cyclo- Gastroenterology, Hepatology, and Nutrition

Autoimmune hepatitis (AIH) is a progressive inflam- absence of a known etiology (1) (Fig. 1). Laboratory and
matory liver disorder affecting mainly females, charac- histological features of AIH are at times associated with
terized serologically by high levels of transaminases and bile duct disease typical of primary sclerosing cholangi-
immunoglobulin G (IgG), and presence of autoanti- tis. This overlap syndrome is referred to as autoimmune
bodies, and histologically by interface hepatitis, in the sclerosing cholangitis (ASC) (2).
AIH is divided into 2 types according to the autoanti-
body profile: type 1 is positive for anti-nuclear (ANA)
Received October 14, 2008; accepted January 6, 2009. and/or anti-smooth muscle (SMA) antibody, type 2 is
Address correspondence and reprint requests to Karen F. Murray, positive for anti-liver kidney microsomal antibody type 1
MD, Professor of Pediatrics, Director, Hepatobiliary Program, Seattle
Children’s, 4800 Sand Point Way, NE, PO Box 5371/W7830, Seattle, (anti-LKM-1). AIH responds satisfactorily to immuno-
WA 98105, USA (e-mail: [email protected]). suppressive treatment. If left untreated, it generally pro-
The authors report no conflicts of interest. gresses rapidly to cirrhosis and liver failure.
158

Copyright © 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.
 AUTOIMMUNE HEPATITIS 159

Discussion of the possible pathogenic mechanisms

leading to AIH that may in the future be manipulated
to prevent the disease is beyond the scope of the current
review, which concentrates on diagnosis and manage-
ment.

DIAGNOSTIC CRITERIA
Diagnosis of AIH is based on a series of positive and
negative criteria (5,6) (Table 1). Liver biopsy is necessary
to establish the diagnosis; the typical histological picture
including a dense mononuclear and plasma cell infiltra-
tion of the portal areas, which expands into the liver
lobule; destruction of the hepatocytes at the periphery of
the lobule with erosion of the limiting plate (‘‘interface
hepatitis’’); and connective tissue collapse resulting from
hepatocyte death and expanding from the portal area into
the lobule (‘‘bridging collapse’’); and hepatic regenera-
tion with ‘‘rosette’’ formation. In addition to the typical
histology, other positive criteria include elevated serum
transaminase and IgG levels, and presence of ANA,
SMA, or anti-LKM-1. The diagnosis of AIH has been
advanced by the criteria developed by the International
Autoimmune Hepatitis Group (IAIHG) (5,6), in which
negative criteria such as evidence of infection with
FIG. 1. Flowchart for treatment decision making in children with
hepatitis B or C virus or Wilson disease and alcohol,
autoimmune liver disease. among others, are taken into account in addition to the
positive criteria mentioned above. The International
Most patients are diagnosed before the age of 18 years Autoimmune Hepatitis Group has provided a useful
and 75% are girls, the peak incidence of the disease being scoring system for the diagnosis of AIH for research
before puberty. The epidemiology of childhood AIH is purposes. A simplified scoring system, easier to use in
unknown, but type 1 AIH accounts for two thirds of the clinical practice and on the basis of autoantibodies, IgG,
cases and presents usually during adolescence, whereas histology, and exclusion of viral hepatitis has been
type 2 AIH presents at a younger age and also during published recently (7). A limitation of all of these scoring
infancy. Immunoglobulin G is usually raised at presen-
tation in both types, although 15% of children with AIH TABLE 1. Criteria for the diagnosis of autoimmune hepatitis
type 1 and 25% of those with AIH type 2 have normal in childhood
levels (3). Immunoglobulin A deficiency is common in
AIH type 2 (3). Severity of disease is similar in the Elevated transaminases
Positive autoantibodies ANA and/or SMA
2 types. Anti-LKM-1–positive patients, however, have a (titer 1:20) ¼ type 1 AIH
higher tendency to present as acute liver failure. Both Anti-LKM1 (titer 1:10)
types are often associated with autoimmune disorders ¼ type 2 AIH
(about 20%) and a family history of autoimmune disease Anti-LC1 ¼ type 2 AIH
(40%) (3). Type 2 AIH can be part of the autoimmune Anti-SLA ¼ present in type 1
or 2 AIH or in isolation
polyendocrinopathy-candidiasis-ectodermal dystrophy Elevated immunoglobulin G
syndrome, an autosomal recessive genetic disorder in Liver biopsy Interface hepatitis
which the liver disease is reportedly present in some 20% Multilobular collapse
of cases (4). Exclusion of viral hepatitis
Exclusion of Wilson disease
The main issues related to AIH are identification of Normal cholangiogram
etiopathogenic factors that may lead to its prevention; (nuclear magnetic resonance
interpretation of liver autoimmune serology and diag- or retrograde cholangiography)
nostic criteria in children; treatment, including type of
AIH ¼ autoimmune hepatitis, ANA ¼ antinuclear antibody, anti-
drugs, length and criteria for stopping it, alternative drugs LKM-1 ¼ anti-liver/kidney microsomal antibody type 1, anti-
for refractory cases; and management of posttransplant LC1 ¼ anti-liver cytosol type 1 antibody, anti-SLA ¼ anti-soluble liver
recurrent, and de novo autoimmune hepatitis. antigen antibody, SMA ¼ anti-smooth muscle antibody.

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

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 160 MIELI-VERGANI ET AL.

TABLE 2. Methods, associations, and reactants for autoantibodies in autoimmune liver disease
Conventional method Molecularly based
Autoantibody of detection assays Disease association Molecular target(s)

ANA IIF N/A AIH-1; ASC Multiple targets, particularly chromatin

SMA IIF ELISA AIH-1; ASC Microfilaments (actin?), intermediate
filaments (vimentin, etc)

Anti-LKM-1 IIF ELISA, IB, RIA AIH-2; HCV infection (5%) Cytochrome P450 2D6
Anti-LC1 IIF, DID, CIE ELISA, RIA AIH-2 Formiminotransferase cyclodeaminase
Anti-SLA Inhibition ELISA ELISA, IB, RIA AIH-1; AIH-2 and AIH tRNP(Ser)Sec
negative for other reactivities
Atypical pANCA IIF N/A AIH-1; ASC Unidentified antigen(s) at nuclear periphery
(pANNA)

AMA IIF ELISA, IB, RIA Primary biliary cirrhosis E2 subunits of 2-oxo-acid dehydrogenase
complexes, particularly PDC-E2

AIH ¼ autoimmune hepatitis, AMA ¼ anti-mitochondrial antibody, ANA ¼ anti-nuclear antibody, anti-LC1 ¼ anti-liver cytosol type 1 antibody, anti-
LKM-1 ¼ anti-liver/kidney microsomal antibody type 1, anti-SLA ¼ anti-soluble liver antigen antibody, ASC ¼ autoimmune sclerosing cholangitis,
CIE ¼ counterimmunoelectrophoresis, DID ¼ double dimension immunodiffusion, ELISA ¼ enzyme-linked immunosorbent assay, HCV ¼ hepatitis C
virus, IB ¼ immunoblot, IIF ¼ indirect immunofluorescence, N/A ¼ not available, pANCA ¼ perinuclear anti-neutrophil cytoplasmic antibody,
pANNA ¼ perinuclear anti-neutrophil antibody, RIA ¼ radioimmunoprecipitation assay, SMA ¼ anti-smooth muscle antibody.

Anti-LKM-1 and AMA both stain renal tubules and are frequently confused (1).

systems, however, is that they have been produced for guidelines have been given by the IAIHG serology
adult patients and need to be adapted to children. committee (8). An important concept is that significant
A key diagnostic criterion for all scoring systems is the titers of diagnostic autoantibodies differ in adult and
detection of ANA, SMA, and anti-LKM-1 (Table 2). pediatric patients. Because healthy adults may show
Autoantibody detection not only assists in the diagnosis reactivity at the conventional starting serum dilution of
but also allows differentiation of AIH types. Autoanti- 1/10, the arbitrary dilution of 1/40 has been considered
bodies to nuclei and SMA that characterize type 1 AIH clinically significant by the IAIHG. In contrast, autoanti-
and anti-LKM-1 that defines type 2 AIH are practically body reactivity in healthy children is infrequent, so that
mutually exclusive; in those rare instances in which they titers of 1/20 for ANA and SMA and 1/10 for anti-LKM-1
are present simultaneously, the clinical course is similar are clinically relevant. In this context, it is important to
to that of AIH type 2 (8). note that the use of commercially available tissue
It is important to note that positivity for autoantibodies samples for the detection of autoantibodies is not recom-
is not sufficient for the diagnosis of AIH because they can mended because these sections, fixed for achieving long
be present, usually at low titer, in other liver disorders shelf life, are of variable quality, hindering the recog-
such as viral hepatitides (9,10), Wilson disease (11), and nition of diagnostic autoantibodies at low titer. It is
nonalcoholic steatohepatitis (12). advisable for the laboratory to report any level of posi-
The technique that should be used for routine testing of tivity from 1/10 in children and 1/40 in adults, and for the
autoantibodies relevant to AIH is indirect immunofluor- attending physician to interpret the result within the
escence on a freshly prepared rodent substrate (8). This clinical context.
substrate should include kidney, liver, and stomach tissue On a freshly prepared rodent substrate, ANA is readily
to allow the detection of ANA, SMA, anti-LKM-1, as detectable as a nuclear staining in kidney, stomach, and
well as anti-liver cytosol type 1 (anti-LC-1), a second liver. In the liver, the ANA pattern may be detected as
antibody defining type 2 AIH, and anti-mitochondrial homogeneous, or coarsely or finely speckled. In most but
antibody (AMA), the serological hallmark of primary not all cases of AIH the pattern is homogeneous. To
biliary cirrhosis, which is only rarely associated with AIH obtain a much clearer and more reliable definition of the
in childhood. Recognition and interpretation of the nuclear pattern, human epithelial type 2 cells that have
immunofluorescence patterns is not always straightfor- prominent nuclei are used. Human epithelial type 2 cells,
ward because it is operator dependent. Moreover, the however, should not be used for screening purposes,
relative rarity of AIH occasionally leads to errors in because nuclear reactivity to these cells is frequent at
autoantibody reporting, particularly for those less fre- low serum dilution in the normal population (13), includ-
quently encountered such as anti-LKM-1, whose pattern ing in healthy children (14).
is often confused with AMA. Problems in laboratory Smooth muscle antibody is detected on kidney,
reporting and clinical interpretation of results are not only stomach, and liver, where it stains the walls of the
dependent on insufficient standardization of the tests but arteries. On the renal substrate, it is possible to visualize
also on a degree of unfamiliarity of some clinicians with the V (vessels), G (glomeruli), and T (tubules) patterns.
the disease spectrum of AIH. In regard to standardization, The VG and VGT patterns are more specific for AIH than

J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

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 AUTOIMMUNE HEPATITIS 161

the V pattern. The VGT pattern corresponds to the ‘‘F In pediatrics, primary sclerosing cholangitis is often
actin’’ or microfilament (MF) pattern observed using associated with florid autoimmune features, including
cultured fibroblasts as substrate. Neither the VGT nor elevated titers of autoantibodies, in particular ANA and
the anti-MF patterns are, however, entirely specific for SMA, elevated IgG, and interface hepatitis (2). Because
the diagnosis of AIH type 1 and some 20% of SMA these features are shared in common with AIH and are
positive AIH type 1 patients do not have the anti-MF/ often not accompanied by elevated alkaline phosphatase
VGT pattern. The absence, therefore, of anti-actin SMA or g-glutamyl transpeptidase levels at disease onset, the
does not exclude the diagnosis of AIH (15). diagnosis of sclerosing cholangitis relies on cholangio-
Anti-LKM-1 stains brightly the liver cell cytoplasm graphic studies. In the absence of cholangiographic studies
and the P3 portion of the renal tubules, but does not stain at presentation many of these children are diagnosed and
gastric parietal cells. Anti-LKM-1 is often confused with treated as AIH, although the diagnosis of sclerosing cho-
AMA because both autoantibodies stain liver and kidney. langitis may become apparent during follow-up. This
However, in contrast to anti-LKM-1, AMA also stains the condition, referred to as ASC, is as prevalent as AIH
gastric parietal cells. The identification of the molecular type 1 in childhood, but in contrast to AIH it affects boys
targets of anti-LKM-1, such as cytochrome P4502D6 and girls equally (2). Autoimmune sclerosing cholangitis
(CYP2D6), and of AMA, such as enzymes of the responds satisfactorily to immunosuppression, at least in
2-oxo-acid dehydrogenase complexes, has led to the esta- regard to the parenchymal inflammation, if treatment is
blishment of immunoassays on the basis of the use of the started early. Current IAIHG criteria do not allow distinc-
recombinant or purified antigens. Commercially avail- tion between AIH and ASC.
able enzyme-linked immunosorbent assays are accurate
for the detection of anti-LKM-1, at least in the context of TREATMENT
AIH type 2, and reasonably accurate for the detection of
AMA. Therefore, if a doubt remains after examination by Definition of Remission/Relapse
immunofluorescence, this can be resolved by the use of
molecularly based immunoassays. Remission is defined as complete clinical recovery,
Other autoantibodies less commonly tested but of normal transaminase and IgG levels, negative or extremely
diagnostic importance include those to liver cytosol type low titer autoantibodies, and histological resolution of
1 (LC-1), antineutrophil cytoplasm (ANCA), and soluble inflammation. The histological response lags behind the
liver antigen (SLA). Anti-LC-1, which can be present on biochemical response (22–24) and clinical/biochemical
its own, but frequently occurs in association with anti- remission does not necessarily reflect histological resolu-
LKM-1, is an additional marker for AIH type 2 and tion. After a mean duration of 4 years of treatment,
targets formimino-transferase cyclodeaminase (16). Anti- improvement of the intensity of portal inflammation is
neutrophil cytoplasmic antibody can also be positive in observed in up to 95% of cases and is accompanied by an
autoimmune hepatitis. There are 3 types of ANCA, namely improvement of the fibrosis scores (22). Relapse is charac-
cytoplasmic, perinuclear, and atypical perinuclear, the terized by increase of serum aminotransferase levels after
target of which is a peripheral nuclear and not cytoplasmic remission has been achieved. Relapse during treatment is
perinuclear antigen (hence the suggested name of periph- common, occurring in about 40% of patients and requiring
eral anti-nuclear neutrophil antibody [pANNA]). The type a temporary increase in the steroid dose. An important role
found in AIH type 1 is pANNA, which is also found in in relapse is played by nonadherence, which is common,
inflammatory bowel disease and sclerosing cholangitis, particularly in adolescents (25). In more aggressive cases,
whereas it is virtually absent in AIH type 2. Anti-SLA that the risk of relapse is higher if steroids are administered on
was originally described as the hallmark of a type 3 of an alternate-day schedule, which is often instituted
AIH (17) is also found in 50% of patients with AIH type 1 because it may have a less negative effect on the child’s
and type 2, where it defines a more severe course (18). growth. Small daily doses are more effective in maintain-
The molecular target of anti-SLA is UGA transfer RNA ing disease control and minimize the need for high-dose
suppressor-associated antigenic protein (tRNP(Ser)Sec) steroid pulses during relapses (with the consequent
(19,20). Molecularly based diagnostic assays have become more severe adverse effects) and do not affect final height
available, but their full evaluation is still under way (26).
(Table 2).
After assessment of all of the specificities described When to Treat
above, there is a small proportion of patients with AIH
without detectable autoantibodies. This condition, which AIH should be suspected and sought in all children
responds to immunosuppression like the seropositive with evidence of liver disease after exclusion of infec-
form, represents seronegative AIH (5,6,21), a rare form tious and metabolic etiologies. AIH is exquisitely respon-
of AIH in adults, whose prevalence and clinical charac- sive to immunosuppression and treatment should be
teristics remain to be defined in children. initiated promptly to avoid progression of disease. The

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 162 MIELI-VERGANI ET AL.

goal of treatment is to reduce or eliminate liver inflam- Alternative Treatment

mation, induce remission, improve symptoms, and pro-
long survival (27,28). The rapidity and degree of the Induction of remission has been obtained in treatment-
response depends on the disease severity at presentation. naı̈ve children using cyclosporine A alone for 6 months,
Although cirrhosis is found between 44% and 80% of followed by the addition of prednisone and azathioprine.
children at the time of diagnosis (3,29,30), mortality is One month later the cyclosporine is discontinued (36,37).
low and most children remain clinically stable, with a Cyclosporine is used at the dose of 4 mg  kg1  day1 in
good quality of life on long-term treatment. 3 divided doses, increased if necessary every 2 to 3 days
to achieve a whole blood concentration of 250  50 ng/
mL for 3 months. If there is clinical and biochemical
How to Treat
response in the first months, then cyclosporine is reduced
With the exception of a fulminant presentation with to achieve a concentration of 200  50 ng/mL for the
encephalopathy, AIH responds satisfactorily to immuno- following 3 months, before discontinuing it. Whether this
suppressive treatment whatever the degree of liver impair- mode of induction has any advantage over the standard
ment, with a reported remission rate around 80% (Fig. 1). treatment has yet to be evaluated in controlled studies.
Tacrolimus is a more potent immunosuppressive agent
than cyclosporine, but it also has significant toxicity.
Standard Treatment
There is limited evidence supporting its role in the treat-
Conventional treatment of AIH consists of predniso- ment of AIH apart from anecdotal reports in adults.
lone (or prednisone) 2 mg  kg1  day1 (maximum 40–
60 mg/day), which is gradually decreased over a period of Treatment of Refractory Cases
4 to 8 weeks in parallel to the decline of transaminase
levels, to a maintenance dose of 2.5 to 5 mg/day (31–33). Mycophenolate mofetil is the prodrug of mycopheno-
In most patients an 80% decrease of the aminotransferase lic acid. Its effect on purine synthesis leads to decreased
levels is achieved in the first 2 months, but their complete T and B lymphocyte proliferation. In patients (up to 10%)
normalization may take several months (31,34). During in whom standard immunosuppression is unable to
the first 6 to 8 weeks of treatment, liver function tests induce stable remission, or who are intolerant to azathio-
should be checked weekly to allow frequent dose adjust- prine, mycophenolate mofetil at a dose of 20 mg/kg twice
ments, avoiding severe steroid adverse effects. The tim- daily, together with prednisolone, is successfully used
ing for the addition of azathioprine as a steroid-sparing (38). If there is a persistent absence of response or if there
agent varies according to the protocols used in different is intolerance of mycophenolate mofetil (headache, diar-
centers. In some, azathioprine is added only in the rhea, nausea, dizziness, hair loss, and neutropenia), then
presence of serious steroid adverse effects, or if the the use of calcineurin inhibitors should be considered.
transaminase levels stop decreasing on steroid treatment Tacrolimus may also be useful in combination with
alone, at a starting dose of 0.5 mg  kg1  day1, which prednisolone as second-line therapy.
in the absence of signs of toxicity is increased up to
a maximum of 2.0 to 2.5 mg  kg1  day1 until bio- Other Treatments
chemical control is achieved. In other centers azathio-
prine is added at a dose of 0.5 to 2 mg  kg1  day1 after No data are available on the effectiveness of budeso-
a few weeks of steroid treatment, when the serum ami- nide or ursodeoxycholic acid (UDCA) in childhood AIH.
notransferase levels begin to decrease. Whatever the
protocol, 85% of the patients eventually require the Treatment of Autoimmune Sclerosing Cholangitis
addition of azathioprine. Some centers use a combination
of steroids and azathioprine from the beginning, but Autoimmune sclerosing cholangitis responds to the
caution is recommended because azathioprine can be same immunosuppressive treatment described above for
hepatotoxic, particularly in severely jaundiced patients. AIH. However, although steroids and azathioprine are
Measurement of thiopurine methyltransferase activity beneficial in abating the parenchymal inflammatory
level before initiating azathioprine therapy has been lesions, they appear to be less effective in controlling
advocated to predict azathioprine metabolism and toxi- the bile duct disease. UDCA is usually added to steroids
city (34). Measurement of the azathioprine metabolites and azathioprine for the treatment of ASC, but whether it
6-thioguanine and 6-methylmercaptopurine has been is helpful in arresting the progression of the bile duct
reported to help in identifying drug toxicity and non- disease remains to be established. In adults with primary
adherence and in achieving a level of 6-thioguanine sclerosing cholangitis high-dose UDCA has been reported
considered therapeutic for inflammatory bowel disease as more beneficial than standard doses (39), but a random-
(35), although an ideal therapeutic level for AIH has not ized double-blind controlled study presented as a late-
been determined. breaking abstract by the Mayo Clinic group at the 50th

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 AUTOIMMUNE HEPATITIS 163

American Association for the Study of Liver Disease Additionally, a form of graft dysfunction called de novo
meeting (October 31–November 4, 2008, San Francisco) AIH, associated with positive autoantibodies, high IgG,
shows that high-dose UDCA has a negative long-term histological features of interface hepatitis, and respon-
effect. It is prudent, therefore, to use doses not higher than siveness to the standard treatment of AIH (but not to
15 mg  kg1  day1. ASC is often associated with inflam- antirejection regimens), has been described in 6% to 10%
matory bowel disease, which should be investigated even of children receiving transplantation for nonautoimmune
in the absence of symptoms and appropriately treated. disorders (42,43).

Duration of Treatment and Prognosis

SUMMARY
The optimal duration of immunosuppressive treatment
AIH is a progressive inflammatory liver disorder
of AIH is unknown. Treatment withdrawal is successful
affecting mainly girls. It is divided in 2 types according
only if there is histological resolution of inflammation.
to autoantibody positivity: SMA/ANA characterize AIH
Hence, cessation of treatment should considered if a liver
type 1 and anti-LKM1 antibodies AIH type 2. Even low
biopsy shows minimal or no inflammatory changes after
titers of autoantibodies are diagnostic in pediatric age.
1 to 2 years of normal liver function tests, normal IgG
Liver biopsy is required to establish the diagnosis. A
levels, and negative or low titer autoantibodies. However,
juvenile form of sclerosing cholangitis has strong auto-
it is advisable not to attempt to withdraw treatment within
immune features and resembles AIH type 1, differen-
3 years of diagnosis or during or immediately before
tiation between the 2 conditions being possible only
puberty, when relapses are more common. It has been
by cholangiography.
reported that 20% of patients with AIH type 1 can
Treatment should be instituted as soon as possible to
successfully and permanently stop treatment, whereas
avoid progression of disease and consists of prednisolone
this is rarely achieved in AIH type 2 (3). Long-term
(or prednisone), to which azathioprine is added. Steroids
treatment is required for the majority of patients and
should be weaned as tolerated over 6 to 12 months to the
parents and patients should be counseled accordingly. In
lowest dose able to maintain remission. Discontinuation
the pediatric setting, an important role in monitoring the
of therapy could be considered after 1 to 2 years of
response to treatment is the measurement of autoantibody
complete remission if a liver biopsy shows no evidence
titers and IgG levels, the fluctuation of which correlates
of inflammation.
with disease activity (40). In particular, for patients with
high IgG levels, their decrease is a reliable, objective, and
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J Pediatr Gastroenterol Nutr, Vol. 49, No. 2, August 2009

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