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ORIGINAL ARTICLE
Characteristics and outcome of autoimmune liver disease in Asianchildren
Way S. Lee • Su H. Lum • Chooi B. Lim • Sze Y. Chong • Kim M. Khoh •
Ruey T. Ng • Kai M. Teo • Christopher C. M. Boey • Jayalakshmi Pailoor
Received: 30 March 2014 / Accepted: 23 June 2014
� Asian Pacific Association for the Study of the Liver 2014
Abstract
Background Little is known about autoimmune liver
disease (AILD) in Asian children. We studied the clinical
features and predictors of outcome in childhood AILD in
an Asian population.
Methods Retrospective review of AILD [autoimmune
hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing
cholangitis (PSC) and autoimmune sclerosing cholangitis
(ASC)] seen at two pediatric liver units in Malaysia.
Results At presentation, 17 (56 %) of the 32 children [19
females, 59 %; median (range) age 7.7 (1.8–15.5) years]
with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9)
had liver cirrhosis. At final review [median (range) dura-
tion of follow-up 4.8 (0.4–12) years], 24 patients (75 %)
survived with a native liver. Twenty-one (66 %) were in
remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on
prednisolone and/or azathioprine, one on cyclosporine and
another on mycophenolate mofetil. Three (AIH1 = 3)
were in partial remission. Of the two who underwent liver
transplantation (LT; 6.5 %; both ASC), one died of pri-
mary graft failure after LT. Six patients (19 %) died
without LT (acute liver failure, n = 1; end-stage liver
disease, n = 5). The overall survival rate (native liver and
survival post-LT) was 78 %. A delay in seeking treatment
adversely affected the final outcome [survival with native
liver vs. LT or death (duration between onset of disease
and treatment; median ± standard error) = 2.5 ± 2.9 -
months vs. 24.0 ± 13.3 months; p = 0.012].
Conclusions Although remission was achieved in the
majority of patients with prednisolone and/or azathioprine
therapy, delay in seeking diagnosis and treatment adversely
affects the outcome of childhood AILD in Malaysia.
Keywords Autoimmune liver disease � Asian children �Outcome
Introduction
Autoimmune liver disease (AILD) is an umbrella term for a
group of diseases characterized by unresolving inflamma-
tion of the liver of unknown cause and includes conditions
such as autoimmune hepatitis type 1 and 2 (AIH1, AIH2),
primary sclerosing cholangitis (PSC) and autoimmune
sclerosing cholangitis (ASC) [1–3]. The hallmark of these
diseases is the combination of inflammatory liver histol-
ogy, circulating non organ-specific autoantibodies and
raised immunoglobulin G (IgG) in the absence of a known
cause [3], which is believed to be the outcome of a com-
plex interplay between immune dysregulation and envi-
ronmental triggers in genetically susceptible hosts [4].
AILD occurs in both adults and children. Based on
limited epidemiological studies, the incidence of AIH1
among individuals of Caucasian origin in Europe and
W. S. Lee (&) � S. H. Lum � R. T. Ng �K. M. Teo � C. C. M. Boey
Department of Paediatrics, University Malaya Medical Center,
59100 Kuala Lumpur, Malaysia
e-mail: [email protected]
W. S. Lee
University Malaya Paediatric and Child Health Research Group,
University Malaya, Kuala Lumpur, Malaysia
C. B. Lim � S. Y. Chong � K. M. Khoh
Paediatric Unit, Selayang Hospital, Batu Caves, Selangor,
Malaysia
J. Pailoor
Department of Pathology, University Malaya Medical Center,
Kuala Lumpur, Malaysia
123
Hepatol Int
DOI 10.1007/s12072-014-9558-0
North America ranges from 0.1–1.9/100,000/year [5, 6].
The incidence is considerably lower in Asia [7].
Before the widespread use of immunosuppressive ther-
apy, as many as 40 % of patients with severe disease died
within 6 months of diagnosis [8, 9]. Prednisolone and
azathioprine have been shown to improve survival and are
now established as standard immunosuppressive therapy
[10]. The available evidence indicates that these agents are
as efficacious in children as in adults, although there are as
yet no randomized, controlled, treatment trials in children
[3]. However, even with the use immunosuppressive ther-
apy, between 3–18 % of children with AILD would
eventually require liver transplantation (LT) [3, 11–13].
The clinical phenotype and outcome of AIH varies with
ethnic background [14–16]. Adults of Hispanic origin have
the highest prevalence of cirrhosis [15], while Asians have
poorer survival outcomes that may require the use of
alternative or more aggressive therapy [16].
Most of the current knowledge about the clinical fea-
tures and outcome of childhood AILD is based on studies
from Caucasian children [1, 2, 6, 11–13, 17, 18]. Little is
known about this condition in non-Caucasian [19] or Asian
children [20]. This present observational study attempts to
bridge this knowledge gap by describing the characteristics
and outcome of children with AILD encountered consec-
utively at two pediatric hepatology centers in Malaysia.
Patients and methods
The University of Malaya Medical Center (UMMC), Kuala
Lumpur, and Selayang Hospital (SH), Selangor, are referral
centers for pediatric liver diseases in Malaysia. SH is the
only liver transplant center in Malaysia. This is a retro-
spective review of all children who were consecutively
diagnosed to have AILD at these two centers from January
1999 to December 2012. The present study was approved
by the institutional ethics review committees of both cen-
ters (UMMC 1017.13 and NMRR-13-971-17741).
Data collection
The following information was collected from a review of
patient medical records: demographic data, presenting
clinical features, biochemical parameters, histological and
radiological findings, treatment response and outcome. All
liver biopsies were reassessed by a single pathologist.
Diagnostic criteria
Diagnosis of AIH was made according to the diagnostic
criteria defined by International Autoimmune Hepatitis
Group [3, 21]: (1) a raised IgG level and presence of organ-
specific and non-organ-specific autoantibodies; (2) pre-
sence of interface hepatitis and portal plasma cell infiltra-
tion on liver histology; (3) the absence of other liver
diseases of known etiology [21]. AIH was classified into
two subtypes according to seropositivity for autoantibod-
ies: patients with the presence of antinuclear antibodies
(ANA, titer C 1:20) and/or antismooth muscle antibodies
(anti-SMA, titer C 1:20) were classified as having AIH1
and those with the presence of liver-kidney-microsomal
type 1 antibody (LKM1, titer C 1:10) as having AIH2 [3].
All the antibodies were detected using the immunofluo-
rescence method (Innova Biosciences, Cambridge, UK).
The diagnosis of PSC was made in patients who had a
cholestatic biochemical profile with demonstration of
characteristic multifocal stricturing and dilatation of
intrahepatic and/or extrahepatic bile ducts on cholangiog-
raphy in the absence of a secondary cause of sclerosing
cholangitis [22]. Secondary causes of sclerosing cholangi-
tis, which include cholangiocarcinoma, choledocholithiasis
and intrahepatic metastases, were excluded by hepatic
imaging studies such as CT scan of the abdomen. The
diagnosis of Langerhans cell histiocytosis was established
by the presence of pancytopenia, typical histology of the
affected tissue/organ and imaging study of the hepatobil-
iary system. ASC was diagnosed in patients who had fea-
tures of PSC as well as positive ANA and/or anti-SMA,
elevated IgG and liver biopsy abnormalities consistent with
AIH [2].
Serological tests for viral hepatitis A, B, C and E,
cytomegalovirus as well as Epstein-Barr virus excluded the
presence of these infections. Wilson disease was excluded
by ophthalmologic examination for Kayser-Fleischer rings
together with measurements of ceruloplasmin, serum cop-
per and urinary copper before and after penicillamine
challenge. Alpha-1-antitrypsin deficiency was excluded by
the absence of characteristic clinical features and deter-
mination of plasma levels of alpha-1-antitrypsin level and
phenotype.
Pattern of presentation
Patients were deemed to have an acute hepatitis pattern if
they had presenting features of fever, jaundice, vomiting,
abdominal pain and diarrhea indistinguishable from clini-
cal features of acute viral hepatitis [13]. Criteria for acute
liver failure were the presence of evidence of acute liver
injury with coagulopathy unresponsive to vitamin K pro-
thrombin time [(PT) C 15 s or international normalized
ratio (INR) C 1.5 with encephalopathy or PT C 20 s or
INR C 2.0 without encephalopathy] in the absence of any
known pre-existing chronic liver disease [23].
Hepatol Int
123
Histology
Liver biopsy was performed at initial referral in most
patients. Histopathology was re-evaluated by a single
pathologist. The number of portal tracts available for
review was noted. The presence of interface hepatitis,
lymphoplasmacytic infiltrate and rosette formation was
recorded [3, 13]. Biliary features, including ductular
transformation, biliary epithelial damage and sclerosing
lesions, were graded as absent, mild, moderate or severe
[2].
Cholangiography
Cholangiography was performed by means of either mag-
netic resonance cholangiopancreatography (MRCP) or
endoscopic retrograde cholangiopancreatography (ERCP).
Cholangiography was performed in patients who developed
features of cholestasis such as raised conjugated bilirubin
and/or gamma glutamyltranspeptidase during the course of
monitoring their disease.
Treatment
In both centers, prednisolone with or without azathioprine
was the first-line therapy for patients with AIH [3]. Aza-
thioprine, started at an initial dose of 0.5 mg/kg body
weight and gradually increased to 2 mg/kg body weight,
was added when maintenance of remission could not be
sustained without steroid toxicity [3]. Pre-treatment testing
of thiopurine methyltransferase (TPMT) levels could not
be performed as this test was not available. Patients with
inadequate response to first-line therapy were given sec-
ond-line therapy consisting of mycophenolate mofetil
(MMF) or cyclosporine (CsA) [3]. CsA was started at a
dose of 5 mg/kg/day, with a targeted therapeutic (trough)
level of 150–250 ng/ml [11]. The initial dose of MMF was
20 mg/kg/day, increasing to a maximum of 40 mg/kg/day
[24]. Levels of MMF were not monitored. Prior to 2010,
high-dose ursodeoxycholic acid (UDC, up to 30 mg/kg/
day) was also administered in addition to immunosup-
pression as the standard therapy for PSC and ASC [3].
Subsequent to emerging evidence about the possible dele-
terious effect of UDC in patients with PSC in 2009 [25],
this practice was gradually abandoned in both centers.
Response to treatment and remission were defined as
normalization of liver enzymes. Partial remission referred
to improvement in liver enzymes without normalization
[3]. Relapse was defined as the presence of elevation of
liver enzymes in isolation or in combination with histo-
logical evidence of disease activity when this was available
[3]. Patients who remained in continuous remission for
2 years together with a documented normalization of IgG
levels were offered discontinuation of therapy. Treatment
was restarted in patients who relapsed after discontinuation
of treatment [3].
Assessment of prognostic indicators
For classification of the final outcome, patients were
divided into two groups. Group 1 comprised patients who
survived without LT (either in full or partial remission
with or without immunosuppressive therapy). Group 2
consisted of patients who died as a result of the disease
without LT or those who survived with a LT. The fol-
lowing clinical and laboratory parameters were compared
between the groups: gender and age at onset of disease,
interval between the onset of first symptoms and diag-
nosis as well as biochemical and hematological param-
eters at diagnosis.
Statistical analysis
Data were managed with IBM SPSS statistical package
version 21.0.0 for Windows. Dichotomous measures were
compared by means of the @2 test. If the minimum
expected frequency requirements for the @2 test were not
met, the Fisher exact test was used instead. The Mann-
Whitney U test was used for continuous variables. Multi-
variate logistic regression was used to weigh the parame-
ters found to be significant in the univariate analysis.
Statistical significance was set at a p \ 0.05.
Results
A total of 32 children who were referred to the two centers
during the study period fulfilled the diagnostic criteria for
AIH 1 and 2, PSC and ASC (UMMC, n = 25; SH, n = 7).
Of these, 18 (56 %) children had AIH1, 5 (16 %) had
AIH2, and 9 (28 %) had ASC. No cases of PSC were
encountered.
There were patients from all major ethnic groups in
Malaysia (Malays, n = 14; Chinese, n = 10; Indians,
n = 7; native Sabahan, n = 1; Table 1), with a female
preponderance (n = 19, 59 %). The median age at pre-
sentation was 7.7 years (range 1.8–15.5 years).
Clinical features at onset of the disease
The median duration between the onset of the first symp-
tom and referral was 2.0 months (range 2 days–8 years).
The two most common modes of presentation were acute
hepatitis (n = 13, 41 %) and insidious onset of symptoms
Hepatol Int
123
(n = 11, 34 %), which included jaundice (n = 10),
abdominal pain (n = 3), anorexia (n = 2), pruritus (n = 2)
and loss of weight (n = 1). Four children (13 %) were
diagnosed during the course of evaluation and follow-up
for other problems. Three (9 %) were under monitoring for
other autoimmune diseases while one was being investi-
gated for poor weight gain. Two patients with AIH1 pre-
sented with acute liver failure (6 %).
Presenting symptoms at the onset of disease were fever
(n = 8, 25 %), weight loss (n = 6, 19 %) and anorexia
(n = 6, 19 %). Two thirds of the patients had jaundice and
liver enlargement (n = 21, 66 % each). Common signs at
the onset of disease were splenomegaly (n = 12, 44 %),
stigmata of chronic liver disease (n = 7, 22 %), pruritus
(n = 5, 16 %) and ascites (n = 4, 13 %). One child had
encephalopathy at presentation.
A total of 17 patients (53 %) had evidence of cirrhosis at
diagnosis. A diagnosis of cirrhosis was based on clinical
manifestations (n = 4, all had bleeding esophageal vari-
ces), imaging studies (n = 7), liver biopsy (n = 12) or any
combination of the three.
Associated autoimmune and other disorders
One quarter of the children (n = 8, 25 %) had an associ-
ated autoimmune disorder (Table 1). Three patients each
had SLE and inflammatory bowel disease [IBD; UC = 2,
Crohn’s disease (CD) = 1]. The onset of AILD preceded
the onset of other autoimmune disorders in four children,
while in the remaining four patients the autoimmune con-
ditions preceded the onset of AILD.
Two children had pre-existing medical conditions not
related to AILD. One boy had a right pelvi-ureteric junc-
tion obstruction requiring surgical re-implantation of the
ureter, while another girl had a germinoma of the brain,
requiring surgical removal and chemotherapy. The latter
patient was in clinical remission of the tumor at the time of
the diagnosis of AIH1.
Family history
Three patients (9 %) had a first-degree relative and another
a second-degree relative with other autoimmune
Table 1 Demographic, clinical characteristics and laboratory data of 32 Malaysian children with autoimmune liver disease
AIH1 AIH2 ASC All
Number of patients (%) 18 (56) 5 (16) 9 (28) 32 (100)
Female (%) 12 (67) 4 (80) 3 (33) 19 (59)
Age at diagnosis [median, in years (range)] 7.7 (1.8–15.5) 8.7 (1.8–11.0) 5.9 (3.0–15.0) 7.7 (1.8–15.5)
Duration of symptoms [median, in months (range)] 2.0 (0.07–48.0) 0.9 (0.8–8.4) 24 (0.4–96.0) 2.0 (0.07–96.0)
Pattern of presentation
Acute hepatitis (%) 8 4 1 13 (41)
Insidious onset (%) 5 1 6 11 (34)
Complications of chronic liver disease (%) 4 0 0 4 (13)
Incidental findings (%) 2 0 2 4 (13)
Acute liver failure (%) 2 0 0 2 (6)
Associated autoimmune disorders (%) 4 (22) 1 (20) 3 (33) 8 (25)
Systemic lupus erythematosus 2 0 1 3
Inflammatory bowel diseasea 1 0 2 3
Autoimmune thyroiditis 1 0 0 1
Type 1 diabetes mellitus 0 1 0 1
Family history of autoimmune disorders (%) 3 (16) 0 (0) 1 (14) 4 (14)
Antinuclear antibody Positive 15 3 9 27
Negative 3 2 0 5
Antismooth muscle antibody Positive 10 1 1 12
Negative 6 3 6 15
Antiliver, kidney, microsomal antibody Positive 0 5 0 5
Negative 18 0 8 26
Evidence of cirrhosis at presentation 8 (44) 3 (60) 6 (67) 17 (53)
AIH1 autoimmune hepatitis type 1, AIH2 autoimmune hepatitis type 2, ASC autoimmune sclerosing cholangitisa One patient has Crohn’s disease and two have ulcerative colitis
Hepatol Int
123
conditions. A girl with AIH1 and SLE had a sister with
SLE. The father of a girl with AIH1 also had AIH1 himself.
A girl with AIH1 and autoimmune thyroiditis had several
female family members with autoimmune thyroiditis. The
grandfather of a boy with ASC had autoimmune thyroiditis.
Laboratory features at presentation
Nine children (28 %) in the present study had normal
serum bilirubin levels (B 17 lmol/l) at initial presentation.
Of these, five patients with no pre-existing disease were
found to have raised liver enzyme levels during routine
screening for health insurance, while four were found to
have raised liver enzyme levels during monitoring of the
pre-existing conditions (other autoimmune conditions,
n = 3; poor weight gain, n = 1). The median alanine
transferase level was 331 IU/l (range 53–4158 IU/l).
Fourteen children (44 %) had an INR level C 1.5, with two
(6 %) having an INR C 2.0.
Antibodies
Of the 18 patients with AIH1, 15 were positive for ANA
(titer ranged from 1:40 to 1:5,120; Table 1). The three
patients who were negative for ANA were positive for anti-
SMA. All five patients with AIH2 were positive for LKM1
antibody. Three of the five patients with AIH2 were also
positive for ANA antibody. LKM1 antibody was negative
in all 18 patients with AIH1. All nine patients with ASC
were positive for ANA and negative for LKM1 antibody.
Histology
Liver biopsies of 29 patients were available for review.
Overall, the liver architecture was normal in 12 (41 %)
cases. In 11 (38 %) cases, a few portal tracts showed
fibrosis. In the remaining six (21 %) cases, there were
features of cirrhosis, four of which showed on-going
inflammation at the portal tracts with interface hepatitis.
Portal inflammation was noted in 25 (86 %) cases and was
mild in 9, moderate in 9 cases and severe in the remaining
7 cases. Interface hepatitis was noted in 17 (59 %) cases
and involved all the portal tracts in 10 cases. The inflam-
matory cell infiltrate included lymphocytes, plasma cells,
neutrophils and eosinophils. Severe fatty change was noted
in one case. Cholangitis was noted in one case. Mild bile
duct proliferation was present in eight cases.
Cholangiography
Fifteen patients (47 %) underwent either MRCP (n = 14)
or ERCP (n = 1). Of the seven children with ASC who had
a cholangiographic study, six had features suggestive
sclerosing cholangitis. Diagnosis of ASC was confirmed
histologically in the remaining three children who either
had a normal MRCP study (n = 2) or did not undergo
cholangiography (n = 1). All three had histological fea-
tures of small duct disease.
Treatment and outcome
The final status of all patients was ascertained (median
duration of follow-up: 4.8 years; range 0.4–12 years;
Table 3). Of these, 24 patients (75 %) were still alive with
their native liver (Table 3). All but one patient were started
on therapy with steroids after diagnosis.
Remission (n = 20; 66 %)
Twenty-one patients (66 %; Table 2) were in full remission
(AIH1, n = 13; AIH2, n = 4; ASC, n = 3): (1) two
patients with AIH1 were on prednisolone monotherapy; (2)
11 patients with AIH1 and three with AIH2 were on
prednisolone followed by the addition of azathioprine; (3)
one patient with AIH2 was on CsA after failure to respond
to azathioprine and MMF; (4) four patients with ASC were
given UDC in addition to prednisolone and azathioprine.
None of the patients were able to discontinue drug therapy.
Nine (43 %) of the 21 patients had at least one episode of
Table 2 Treatment and outcome of 32 Malaysian children with
autoimmune liver disease
AIH1
n (%)
AIH2
n (%)
ASC
n (%)
All
n (%)
Number of patients 18 (56) 5 (16) 9 (28) 32 (100)
Alive, in remission 13 4 3 20 (66)
Prednisolone monotherapy 2 0 0 2
Prednisolone ? azathioprine 11 3 3 17
MMF 0 0 1 1
MMF then CsA 0 1 0 1
Alive, in partial remission 3 0 0 3 (9)
MMF then CsA 1 0 0 1
Non-adherence to therapy 2 0 0 2
Alive after liver transplant 0 0 1 1 (3)
Died after liver transplant 0 0 1 1 (3)
Died without liver transplant 2 1 3 6 (19)
Fulminant failure 1 0 0 1
Disease complication 1 0 0 1
Progressive disease 0 1 1 2
Refused continual therapy 0 0 1 1
Refused initial therapy 0 0 1 1
AIH1 autoimmune hepatitis type 1, AIH2 autoimmune hepatitis type 2,
ASC autoimmune sclerosing cholangitis, CsA cyclosporin, MMF myco-
phenolate mofetil
Hepatol Int
123
relapse (median number of episodes = 2; range 1–10
episodes).
Partial remission (n = 3; 9 %)
One patient who had liver cirrhosis and portal hypertension
was initially started on prednisolone and azathioprine.
Therapy was subsequently changed to MMF. A repeat
biopsy 3 years later showed persistent inflammatory
activity with worsening of liver cirrhosis. Partial remission
was achieved when CsA was started.
The remaining two patients who were in partial remis-
sion were non-compliant to treatment. The treatment of an
11-year-old who had 3 years of therapy was discontinued
by his parents. He had liver cirrhosis and was in partial
remission. Another boy with AIH1 responded to initial
immunosuppressive therapy (prednisolone and azathio-
prine) although he did not achieve full remission with
normalization of liver enzymes. He was treated for a total
of 3 years but refused further treatment.
Liver transplant (n = 2; 6 %)
Two patients with ASC underwent LT. The indication for
LT in one child was unacceptable quality of life with
intense pruritus. This 7-year-old boy died because of pri-
mary non-function of the liver graft. The second child, an
8-year-old girl, underwent LT for advanced liver disease
and was alive 3 years post-LT.
Deaths (n = 7; 22 %)
A total of seven patients died, six without LT and one after
LT.
Of the six patients (19 %) who died without LT, three
(AIH1, n = 2; ASC, n = 1) died after adequate immuno-
suppressive therapy but without LT (Table 2). The first was
a 6-year-old girl with AIH1 who presented with acute liver
failure after a 2 week history of jaundice. The INR was 2.7
on admission. She did not respond to methylprednisolone
therapy and succumbed without LT. The second was a girl
who with both AIH1 and SLE, who was in remission with
prednisolone monotherapy but subsequently died of a
ruptured appendicitis at another hospital. The third was a
child with ASC who was first diagnosed at 8 years of age.
She was treated with prednisolone, azathioprine and UDC.
Following numerous relapses, she succumbed to progres-
sive disease at 15 years of age without LT.
Another three patients (ASC, n = 2; AIH1, n = 1) died
without therapy or as a result of insufficient therapy. The
first was a 5-year-old boy with ASC who responded ini-
tially to prednisolone and azathioprine. Due to non-
compliance with therapy, the child succumbed 5 years after
the initial diagnosis. The second was a 3-year-old boy with
ASC who had experienced intermittent jaundice for
2 years. The family of this child who had signs of advanced
cirrhosis at diagnosis refused treatment and the child suc-
cumbed without therapy. The third was a girl with AIH2
who was first diagnosed at 3 years of age. She did not
continue follow-up and returned at 10 years of age with
advanced liver cirrhosis. She was given intravenous
methylprednisolone but succumbed while undergoing
assessment for LT.
Final outcome
At final review, 75 % (n = 24) of patients were alive with
their native liver, 20 % (n = 6) died without LT, 3 %
(n = 1) were alive after LT while 3 % died after LT. The
overall survival (both native liver and after LT) was 78 %.
Prognostic indicators
Univariate analysis was conducted to determine predictors
of favorable (group 1; survival with native liver in either
full or partial clinical remission; n = 24) or unfavorable
outcome (group 2; LT or death as a result of end stage liver
disease; n = 8) (Table 3). Patients in group 1 had a sig-
nificantly shorter duration between the onset of first
symptoms and seeking treatment compared to those in
group 2 [median duration (month) ± standard error =
2.5 ± 2.9 vs. 24.0 ± 13.3; p = 0.012; Table 3].
Comparison with studies from Caucasian populations
A search of the literature was made to ascertain the sub-
types, characteristics and outcomes of childhood AILD
(Table 4). Of the nine studies identified, one study that was
based on a therapeutic trial on CsA on AIH did not provide
sufficient clinical details and was excluded from analysis
[11]. Seven of the eight studies selected were from Cau-
casian children, while the remaining one was from Iranian
children. Overall, the presenting features and outcome of
childhood AILD in the present study are fairly similar to
those described in the Caucasian children. Generally, there
is a female preponderance (49–96 %). The median age at
diagnosis ranged from 7.1 years (present study) to
12.9 years (Cleveland, OH, USA) [17]. Acute liver failure
was an an uncommon mode of presentation (0–11.5 %).
The survival rate with native liver ranged from 75 %
(present study) to 100 % (Denmark) [18], while the overall
survival (native liver and LT) ranged from 78 % (present
study) to 100 % (Denmark) [18].
Hepatol Int
123
Discussion
The present study is the first of its kind on childhood AILD
in Asian children. The current knowledge on childhood
AILD is based largely on studies from Caucasian popula-
tions [1, 2, 6, 11–13, 17, 18]. There are only a few reports
of AILD from non-Caucasian children. Rafeey et al. [19]
described 60 Iranian children with AIH. However, no
detailed description on outcome was available, and no
cases of ASC or PSC were included [19]. A study by Yeh
et al. [20] on nine Taiwanese children with AIH did not
distinguish between AIH 1 and AIH 2, nor did it include
cases of ASC or PSC.
The characteristics of childhood AILD from this Asian
population are similar to what has been reported in Cau-
casian children [1, 2, 6, 11–13, 17, 18, 26, 27]. There is a
female preponderance (59 % female). However, the med-
ian age at first diagnosis (7.1 years) was somewhat younger
than that in similar studies (Table 4). Acute liver failure
was uncommon [1, 12, 13, 17]. The proportion of patients
who had liver cirrhosis (56 % in the present study) at initial
diagnosis was also similar to those observed by others [12,
17].
AILD may be associated with other autoimmune con-
ditions [3, 26]. Studies based predominantly on Caucasian
populations have noted a strong association of AILD and
IBD. In particular, PSC is strongly associated with UC [6].
In contrast, diseases such as SLE are rarely encountered in
children with AILD in these populations.
In adult and pediatric patients with SLE, AIH is an
uncommon association [28]. Of the 361 reported cases of
childhood AILD in Caucasian children in the literature [2,
3, 6, 12, 13, 17, 18], only three cases (0.09 %) of SLE were
noted. However, in one study, AIH was seen in up to 10 %
of Caucasian children with SLE [28].
There appears to be a different pattern in studies of
children from Asian populations where SLE is more
commonly encountered among children with AILD. In a
study from Taiwan [20], 6 (67 %) of the 9 children with
AIH had SLE, whereas 3 (10 %) of the 32 cases of
childhood AILD had SLE.
Several genes confer susceptibility to AIH [26]. In
European and North American populations, the strongest
associations are found within the HLA-DRB1 locus,
including the alleles encoding the HLA-DR3 (DRB1*0301)
and DR4 (DRB1*0401) [26]. The HLA-DR2 (DQB1*0501
and DQB1*0601) locus has been reported to be consis-
tently associated with SLE in both Caucasian and Asian
populations [29, 30]. Further genetic studies in patients
with AILD and SLE are necessary to identify genes that
Table 3 Assessment of
prognostic factors in childhood
autoimmune liver disease
All numerical values are
expressed in median ± standard
errora The duration of the onset of
the first symptom and diagnosis
Parameters All n = 32 Group 1 (alive
with native liver)
n = 24
Group 2 (died or
with LT)
n = 8
p
Sex
Males 12 9 3 0.656
Females 20 15 5
Age at diagnosis (years) 7.7 ± 0.7 8.2 ± 0.8 6.1 ± 1.2 0.322
Presence of comorbidity
Yes 10 9 1 0.193
No 22 15 7
Duration to diagnosis (months)a 3.4 ± 4.2 2.5 ± 2.9 24.0 ± 13.3 0.012
Jaundice at diagnosis
Yes 18 13 5 0.504
No 22 15 7
Signs of cirrhosis at diagnosis
Yes 17 11 6 0.154
No 15 13 2
Albumin (g/l) 33 ± 1 33 ± 1 33 ± 3 0.499
Total bilirubin (lmol/l) 74 ± 22 83 ± 22 73 ± 57 0.580
Alanine transferase (IU/l) 369 ± 171 419 ± 216 301 ± 208 0.349
Aspartate transferase (IU/l) 434 ± 177 793 ± 198 230 ± 399 0.423
Alkaline phosphatase (IU/l) 435 ± 34 397 ± 43 488 ± 42 0.227
Gamma glutamyltranspeptidase (IU/l) 176 ± 31 176 ± 39 193 ± 49 0.970
International normalized ratio (INR) 1.4 ± 0.1 1.3 ± 0.1 1.5 ± 0.3 0.163
Hepatol Int
123
Ta
ble
4D
emo
gra
ph
y,
clin
ical
feat
ure
san
do
utc
om
eo
fch
ild
ho
od
auto
imm
un
eli
ver
dis
ease
inse
lect
edse
ries
Stu
dy
Lo
nd
on
,
UK
Lo
nd
on
,
UK
aM
elb
ou
rne,
Au
stra
lia
Bir
min
gh
am,
UK
Cle
vel
and
,U
SA
Den
mar
kb
Uta
h,
US
AIr
anK
ual
aL
um
pu
r,
Mal
aysi
a(p
rese
nt
stu
dy
)
Yea
r(r
efer
ence
)1
99
7(1
)2
00
1(2
)2
00
1(1
2)
20
10
(13
)2
01
0(1
7)
20
12
(18
)2
01
3(6
)2
00
7(1
9)
20
14
Cen
ter
Ref
erra
l
cen
ter
Ref
erra
l
cen
ter
Ref
erra
lce
nte
rR
efer
ral
cen
ter
Ref
erra
lce
nte
rP
op
ula
tio
n-
bas
ed
Po
pu
lati
on
-
bas
ed
Ref
erra
lce
nte
rR
efer
ral
cen
ter
Nu
mb
ero
fp
atie
nts
52
27
30
10
13
33
38
55
43
2
Nat
ure
of
dis
ease
AIH
on
lyA
SC
on
lyA
IHo
nly
AIH
and
AS
CA
IHA
IHan
dA
SC
AIH
,A
SC
,
PS
C
AIH
on
lyA
IH,
AS
C
Eth
nic
ity
Eu
rop
ean
-
Cau
caso
id
Eu
rop
ean
-
Cau
caso
id
Eu
rop
ean
-Cau
caso
idE
uro
pea
n-
Cau
caso
id
Eu
rop
ean
-
Cau
caso
idan
d
Bla
ck
Eu
rop
ean
-
Cau
caso
id
Eu
rop
ean
-
Cau
caso
id
Iran
ian
Asi
an
Fem
ale
(%)
39
(75
)1
5(5
5)
22
(73
)6
0(6
0)
25
(76
)1
6(4
9)
43
(51
)5
2(9
6)
19
(59
)
Ag
eat
dia
gn
osi
s
(med
ian
,y
ears
)
10
.5fo
r
AIH
1
7.4
for
AIH
2
11
.89
.4(m
ean
)1
1.5
12
.9N
ot
stat
ed8
.47
.1
AIH
1(%
)3
2(6
2)
–1
8(6
0)
67
(67
)3
0(9
1)
29
(88
)4
4(5
2)c
40
(67
)1
8(5
6)
AIH
2(%
)2
0(3
8)
–3
(10
)1
8(1
8)
3(9
)2
(6)
14
(23
)5
(16
)
AS
C/A
ISC
(%)
–2
7(1
00
)–
16
(16
)–
6(1
8)b
12
(14
)–
9(2
8)
Oth
ers
(%)
4(1
3)
wer
en
egat
ive
for
AN
A/S
MA
/LK
M
2(6
)w
ere
neg
ativ
e
for
auto
anti
bo
dy
PS
C=
29
(34
)
AL
Fat
pre
sen
tati
on
(%)
6(1
1.5
)0
(0)
1(3
)7
(7)
2(6
)0
(0)
4(7
)2
(6)
Fo
llo
w-u
p(m
edia
n,
ran
ge
iny
ears
)
5(0
.3–
19
)6
(2–
16
)M
ean
:1
0.0
±7
.81
0.1
(2.6
–2
0)
6.1
(0.9
–2
8.7
)4
.5(1
.1–
11
.9)
Mea
n:
5.9
(0.4
–1
7.8
)
Ran
ge:
1–
20
mo
nth
s
4.8
(0.2
–1
2)
Ou
tco
me
Ali
ve
wit
hn
ativ
eli
ver
(%)
40
(77
%)
23
(85
%)
27
(89
%)
83
(82
%)
22
5y
:6
6%
10
y:
58
%
33
(10
0%
)5
-yea
r
surv
ival
rate
:
PS
C:
78
%
AS
C:
90
%
AIH
:8
7%
54
(96
%)
24
(75
%)
Die
d,
no
LT
(%)
3(6
)0
(0)
2(7
)0
(0)
2(6
)0
(0)
2(4
)6
(19
)
Ali
ve
po
st-L
T(%
)6
(12
)4
(15
)1
(3)
15
(15
)5
(15
)0
(0)
0(0
)1
(3)
Die
d,
po
st-L
T(%
)3
(6)
0(0
)0
(0)
3(3
)4
(12
)0
(0)
0(0
)1
(3)
Hepatol Int
123
confer susceptibility to both diseases of patients, particu-
larly in Asian populations.
The incidence of AIH1 among adult Caucasian popu-
lations in Europe and North America ranges from 0.1–1.9/
100,000/year [4, 5]. Estimates from Asia are much lower,
with AIH having an estimated incidence of between 0.08
and 0.15 cases/100,000/year in Japan [31] and 0.52/
100,000/year in Taiwan [32].
The incidence of AILD among Asian children is
unknown. In the present study, 32 cases of AILD were
reported from two referral centers in Malaysia over a
14-year period (2.3 cases/year). The population of Malay-
sia aged 14 years and below in 1999 and 2010 were
7,885,600 and 7,827,900, respectively (nearest available
population census figures corresponding to the period of
the present study), giving an average of 7,856,750 between
1999 and 2010 [33]. Thus, the estimated incidence of
childhood AILD in Malaysia is 0.03 case/100,000 children/
year, while the estimated incidence of childhood AIH
(AIH1 and 2) is 0.02 cases/100,000 children/year. How-
ever, it should be pointed out that the present study was
hospital based and may be limited by referral bias, as only
the more severe cases may have been referred. This present
figure is most likely an underestimation of the true inci-
dence of childhood AILD in Malaysia. Nevertheless, sim-
ilar to studies in adult populations, AILD appears to be
much more uncommon in Asian children than in the
Caucasian children.
Evidence from adult populations suggests that ethnicity
may affect the outcome of AIH [14–16]. It has been shown
that adult Hispanics with AIH had the highest prevalence
of cirrhosis [15] and Asians had poorer survival outcomes
[16]. There are no studies on the effect of ethnicity on the
outcome of childhood AIH or AILD, as these conditions
are much rarer in children than in the adults. Furthermore,
the ability to make comparisons on the outcome of child-
hood AILD between various populations is hindered by
wide variation among available studies in the literature
with regard to inclusion criteria, the nature of cases
reported, the referral patterns of the respective centers and
the study population, i.e., whether it was community based
or based on a clinical population at a referral center.
The outcome of the present study is comparable to those
reported by other referral centers (Table 4). The transplant-
free survival rate was 75 %. This was adversely affected by
several factors. An advanced stage of disease at initial
presentation may have adversely affected the outcome of
three patients, whereas adverse social and family situations
adversely affected the adherence of therapy in another two
patients. In addition, the lack of access to timely LT in
those with end-stage liver failure also adversely affected
the outcome [34]. Only two patients underwent LT, while
another six patients died without LT.Ta
ble
4co
nti
nu
ed
Stu
dy
Lo
nd
on
,
UK
Lo
nd
on
,
UK
aM
elb
ou
rne,
Au
stra
lia
Bir
min
gh
am,
UK
Cle
vel
and
,U
SA
Den
mar
kb
Uta
h,
US
AIr
anK
ual
aL
um
pu
r,
Mal
aysi
a(p
rese
nt
stu
dy
)
Ov
eral
lsu
rviv
al(%
;
nat
ive
liv
eran
dL
T)
46
(88
)2
7(1
00
)2
8(9
2)
98
(97
)5
y:
88
%
10
y:
80
%
33
(10
0)
52
(96
)2
5(7
8)
AS
Cau
toim
mu
ne
scle
rosi
ng
cho
lan
git
is,
PS
Cp
rim
ary
scle
rosi
ng
cho
lan
git
is,
LT
liv
ertr
ansp
lan
t,A
NA
anti
nu
clea
ran
tib
od
y,
SM
Aan
tism
oo
thm
usc
lean
tib
od
y,
LK
Man
tili
ver
,k
idn
ey
mic
roso
mal
anti
bo
dy
aO
nly
23
case
sw
ith
AS
Co
fth
eto
tal
51
chil
dre
nw
ere
incl
ud
edfo
rco
mp
aris
on
.T
he
rem
ain
ing
28
chil
dre
nin
the
ori
gin
alca
ses
had
AIH
1an
d2
bIn
this
stu
dy
,A
ISC
sw
ere
des
crib
edas
asso
ciat
edau
toim
mu
ne
dis
ord
ers
cA
IH1
and
AIH
2co
mb
ined
.A
IH1
:au
toim
mu
ne
hep
atit
isty
pe
1,
AIH
2:
auto
imm
un
eh
epat
itis
typ
e2
,A
LF
acu
teli
ver
fail
ure
Hepatol Int
123
In the present study, a delay in diagnosis after the onset
of disease was found to be the only significant factor that
adversely affected the final outcome. Unlike the study by
Radhakrishnan et al. [17], who noted that the presence of
liver cirrhosis at initial diagnosis adversely affected the
outcome of children with AIH, the presence of liver cir-
rhosis at initial presentation did not adversely affect the
outcome in the present study.
UDC was previously used routinely in patients with PSC
[25]. However, after the discovery that the use of high-dose
UDC may have possible deleterious effects on the outcome
of PSC, its use in patients with PSC or in patients with
AILD who also have features of cholangitis has largely
been abandoned [25].
We acknowledge the following limitations in the present
study. First, the estimated disease prevalence based on
cases referred to pediatric liver centers in Malaysia is
almost certainly an underestimate. Second, patients with
AIH negative for ANA, SMA or anti-LKM 1 may have
been missed and labeled as having cryptogenic chronic
hepatitis because of limitations in diagnostic testing [3]. It
is well known that some patients with AIH are negative for
the conventional autoantibodies, such as ANA, SMA and
anti-LKM 1 [3]. Tests for other uncommon autoantibodies
that are used in the diagnosis of AIH, such as LKM 3,
antisoluble liver antigen/liver-pancreas (anti-SLA/LP),
antiliver cytosol 1 (anti-LC1), antipyruvate dehydrogenase
subunit E2 (anti-PDH-E2) or perinuclear antineutrophil
cytoplasmic antibodies (pANCA), were not available for
patients in the present study [3].
In conclusion, childhood AILD is an uncommon con-
dition among Asian children and is likely to be less com-
mon than in Caucasian populations. SLE is an important
associated autoimmune condition and should be routinely
excluded in Asian children with AILD. A delay in referral
for diagnosis and treatment has been identified as a factor
adversely affecting the outcome of childhood AILD in
Malaysia. Despite some adverse social factors and poor
adherence to therapy, the transplant-free survival of chil-
dren with AILD in Malaysia is comparable to that reported
by referral centers with predominantly Caucasian patient
populations. These findings suggest that more aggressive
immunosuppressive therapy is not indicated in Asian
children with AILD.
Acknowledgements
Compliance with ethical requirements and Conflict of inter-est The authors declare that no human subjects or animals were
involved in the conduct of the present research and that it was not a
clinical trial. The present study was approved by the institutional
ethics review committees of both centers (UMMC 1017.13 and
NMRR-13-971-17741). Way Seah Lee, Su Han Lum, Chooi Bee Lim,
Sze Yee Chong, Kim Mun Khoh, Ruey Terng Ng, Kai Ming Teo,
Chiong Meng Boey and Jayalakshmi Pailoor declare that they have no
conflict of interest. None of the authors received any external funding
in relation to the preparation of this work.
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