’Original article

Serological markers of autoimmunity in children with

hepatitis A: relation to acute and fulminant
presentation
Tawhida Y. Abdel-Ghaffara,b, Mostafa M. Sirad, Ahmad M. Sirad, Tahany A. Salemd, Ahmed A. El-Sharawye
and Suzan El Naghia,c

Objectives Hepatitis A virus (HAV) infection tends to be a self-limiting disease without serious sequelae, but fulminant hepatitis,
with a high mortality, develops in 0.1–0.2% of the cases. Sometimes, HAV infection precipitates autoimmune hepatitis (AIH). We
aimed to assess the frequency and clinical significance of serologic markers of autoimmunity during hepatitis A infection with an
acute or fulminant presentation compared with those in AIH.
Methods The study included 126 children: 46 with HAV infection (33 with acute and 13 with fulminant presentation), 53 with
AIH, and 27 healthy controls. In all, we measured autoantibodies titer (antinuclear antibody, antismooth muscle antibody, and liver
kidney microsomal antibody-1) and serum gammaglobulins.
Results Autoantibodies were detected in the majority of HAV (63.1%) and AIH (79.2%) groups, but in none of the controls.
Gammaglobulins were significantly higher in the HAV group (1.93 ± 0.57 g/dl) than in the controls (1.32 ± 0.29 g/dl), but lower than
that in the AIH group (2.93 ± 1.2 g/dl) (P < 0.0001 for all). In the HAV group, gammaglobulins were significantly higher in those with
fulminant (2.21 ± 0.46 g/dl) than in those with acute presentation (1.82 ± 0.57 g/dl) (P = 0.019), but comparable with that in AIH
(P = 0.095). Gammaglobulins correlated significantly with disease severity in both HAV and AIH groups.
Conclusion Hypergammaglobulinemia and a high occurrence of autoantibodies are encountered in HAV infection. This may
support the immunological basis of its pathogenesis. Moreover, the higher gammaglobulins in fulminant HAV, with an insignificant
difference from that in AIH, suggest that a more aggressive immunological reaction is related to this presentation. Eur J
Gastroenterol Hepatol 27:1161–1169
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Introduction limiting disease without serious sequelae, but fulminant

Hepatitis A virus (HAV) is a major etiologic agent of acute
hepatitis and it poses a considerable health problem
worldwide. It is a single-strand RNA virus of the family
Picornaviridae and is transmitted almost always by the
fecal–oral route [1]. The expression of clinical symptoms
varies markedly with age. Approximately 50% of children
with hepatitis A younger than 6 years of age are asymp-
tomatic, with most of the remaining having mild symp-
toms. Less than 5% of children younger than 4 years of
age and less than 10% of children between 4 and 6 years
of age with hepatitis A develop jaundice. Starting from
6 years of age to adulthood, more than 75% develop the
characteristic illness [2]. Hepatitis A tends to be a self-
European Journal of Gastroenterology & Hepatology 2015, 27:1161–1169
Keywords: autoantibodies, autoimmune hepatitis, fulminant hepatitis,
hepatitis A virus, hypergammaglobulinemia
a
b
Yassin Abdel-Ghaffar Charity Center for Liver Disease and Research,
Department of Pediatrics, Faculty of Medicine, Ain Shams University, cPediatric
Department, National Hepatology and Tropical Medicine Research Institute, Cairo,
Departments of dPediatric Hepatology and eClinical Pathology, National Liver
Institute, Menofiya University, Menofiya, Egypt
Correspondence to Mostafa M. Sira, MD, Department of Pediatric Hepatology,
National Liver Institute, Menofiya University, 32511 Shebin El-koom,
Menofiya, Egypt
Tel: + 20 482 222 740; fax: + 20 482 234 586; e-mail: msira@liver-eg.org
Received 23 February 2015 Accepted 8 May 2015
hepatitis develops in 0.1–0.2% of the cases [3].
Approximately 1.4 million clinical cases are reported
worldwide annually and occur most probably in children,
in whom the disease tends to be asymptomatic or mildly
symptomatic. Unlike hepatitis B and C, hepatitis A is not a
cause of chronic liver disease [4].
The humoral immune response plays a pivotal role in
the diagnosis of HAV infection. Although anti-HAV
immunoglobulin M (IgM) and IgG are usually present at
the onset of symptoms, IgM has been used as the primary
marker of acute infection [5]. In addition, a mild increase
in the gammaglobulin level is a common feature [6].
In patients with hepatitis A, the occasional absence of
anti-HAV IgM [7,8], together with the presence of auto-
antibodies [1] and hypergammaglobulinemia [6], both of
which are features of autoimmune hepatitis (AIH) [9],
make it sometimes difficult to distinguish between both
conditions. Moreover, the etiology of fulminant hepatitis,
a possible presentation of both conditions, may pose a
diagnostic challenge especially in seronegative AIH cases
in whom liver biopsy would be difficult [10].
The development of AIH after HAV infection, albeit
rare, has been reported. Such reports have described that
HAV infection seemed to trigger the development of AIH
[11]. AIH is a chronic and progressive disease character-
ized by histological interface hepatitis, hypergammaglo-
bulinemia, circulating autoantibodies, and a favorable

0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000000413 1161

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

1162 European Journal of Gastroenterology & Hepatology
response to immunosuppressive drugs [12]. In AIH, the
timely diagnosis with early immunosuppressive therapy is
life-saving [13]. Serologic features that may support the
diagnosis of AIH can occur with variable frequency in
other liver disorders [9].
The aim of the current study was to assess the frequency
and clinical significance of serologic markers of auto-
immunity during HAV infection in children and their
relation to disease severity compared with those in AIH.
Patients and methods
Study population
This prospective case–control study included 126 children.
They were divided into three groups. Group 1 included 46
children with HAV infection (33 with acute and 13 with
fulminant presentation), group 2 included 53 children with
AIH, and group 3 included 27 apparently healthy children
serving as controls. Patients were recruited from the
Pediatric Hepatology department, National Liver Institute,
Menofiya University, and Yassin Abdel-Ghaffar Charity
Center for Liver Diseases and Research (YAGCCLD). A
signed informed consent was obtained from the parents
of the patients and controls before enrollment in the
study. The study was approved by the Research Ethics
Committee of both National Liver Institute, Menofiya
University, and YAGCCLD.
Etiological diagnosis and group allocation
Acute HAV infection was defined by the clinical picture of
acute hepatitis and confirmed by the presence of anti-HAV
IgM antibodies. Patients with associated other hepatitis
viral infections or other liver disease were excluded from
the study. None of them showed a history of any auto-
immune disorder in the patient or first-degree relatives and
history of any liver disease. Fulminant hepatitis A was
defined by the acute onset of liver disease, caused by HAV,
with no known evidence of chronic liver disease, together
with coagulopathy [prothrombin time (PT) ≥ 20 s or
international normalized ratio (INR) ≥ 2.0] that is not
corrected by parenteral vitamin K and/or hepatic ence-
phalopathy (must be present if the PT is 15–19.9 s or the
INR is 1.5–1.9, but not if the PT is ≥ 20 s or INR is ≥ 2.0)
[14]. AIH was defined according to the simplified AIH
score [13]. Patients with associated liver disease or other
immunologic disorders were excluded from the study.
Serum autoantibodies and protein electrophoresis
All patients and controls were tested for serum auto-
antibodies and gammaglobulins at presentation. Antinuclear
antibody (ANA), antismooth muscle antibody (ASMA),
liver kidney microsomal antibody-1 (LKM1), and anti-
mitochondrial antibody (AMA) were tested by an indirect
immunofluorescence technique using a Fluoro-Kit Combo
Pak (DiaSorin, Stillwater, Minnesota, USA). Protein electro-
phoresis was performed using the Titan III Cellulose Acetate
Plate and scanned using Helena QuickScan 2000 (both from
Helena Laboratories, Beaumont, Texas, USA).
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
October 2015 • Volume 27 • Number 10
Serum viral markers, ultrasonography, and liver biopsy
Hepatitis B surface antigen (HBsAg), antihepatitis B core
IgM, and IgG types were tested using an enzyme-linked
immunosorbent assay (ELISA) kit (Sorin Biomedica Co,
Saluggia, Italy). Anti-HAV IgM was performed by ELISA
(Diapro Diagnostic Bioprobes, Sesto San Giovanni, Italy).
Hepatitis C virus antibody (anti-HCV) was tested by fourth-
generation ELISA (Innogenetics, Ghent, Belgium). Real-time
polymerase chain reaction for HCV-RNA was performed
using COBAS Ampliprep/COBAS TaqMan (Roche
Molecular Systems Inc., Branchburg, New Jersey, USA).
Ultrasonography (US) was performed using 2–5 MHz curved
linear and 4–8 MHz linear transducers (Xario XG; Toshiba,
Tokyo Japan). Liver biopsy was performed for AIH patients
only using a US-guided true-cut needle. Hepatic necroin-
flammatory activity and liver fibrosis were evaluated
according to the Ishak score [15]. Pathological criteria for
AIH disease were defined as typical or compatible [13].
Statistical analysis
Values were expressed as mean ± SD or number (percen-
tage) of individuals with a condition. For quantitative data,
statistical significance was tested by either an independent-
samples t-test or by the nonparametric Mann–Whitney
U-test according to the nature of the data. For qualitative
data, significance was tested using the χ2-test or Fisher’s
exact test. Correlation was tested using Spearman’s test. A
stepwise multiple regression analysis was also carried out
to examine independent factors associated with gamma-
globulins. The final model was determined using Pin less
than 0.05 and Pout less than 0.10. Standardized coefficient
(β), 95% confidence interval, and P values of each factor
are presented. The diagnostic value of serum gammaglo-
bulins was assessed by calculating the area under the
receiver-operating characteristic curves. The diagnostic
performance was measured as sensitivity, specificity, and
accuracy. The cut-off values for optimal clinical perfor-
mance were determined from the receiver-operating char-
acteristic curves. Results were considered significant if the
P-value was up to 0.05. Statistical analysis was carried out
using SPSS, version 13 (SPSS Inc., Chicago, Illinois, USA).
Results
Study population’s characteristics
The study included 46 children with HAV infection and 53
children with AIH. A group of 27 apparently healthy children
were included as controls (there were 13 females and 14 males
between 1.5 and 15 years of age). The patients (n = 99) and
controls were age (9.6 ± 4.06 vs. 9.7 ± 4.23 years) and sex
(male/female were 46/53 vs. 14/13) matched (P = 0.138 and
0.619, respectively). There was a significant difference between
the HAV and AIH groups in the age at presentation and sex
predilection, where AIH patients were older and more likely to
be females. Of the HAV group, 13 (28.3%) children presented
with fulminant hepatitis, whereas 33 (71.7%) presented with a
picture of acute hepatitis. Five (9.4%) patients in the AIH group
had an acute presentation. Serum albumin, alanine transami-
nase to aspartate transaminase (AST) ratio, and platelet counts
were significantly lower in AIH patients than in acute HAV, but
comparable with that in fulminant HAV. Alkaline phosphatase
Autoimmunity in children with hepatitis A Abdel-Ghaffar et al. www.eurojgh.com 1163

Table 1. Demographic, clinical, ultrasonographic, and laboratory data of the studied patients
HAV (n = 46) Acute HAV (n = 33) Fulminant HAV (n = 13) AIH (n = 53) P-value1 P-value2

Age (years) 6.13 ± 3.8 6.09 ± 3.95 6.89 ± 3.48 9.39 ± 3.76 0.0001 0.039
Male [n (%)] 29 (63) 19 (57.6) 10 (76.9) 17 (32.1) 0.02 0.003
Jaundice [n (%)] 41 (89.1) 28 (84.8) 13 (100) 39 (73.6) 0.221 0.037
Encephalopathy [n (%)] 11 (23.9) 0.0 11 (84.6) 2 (3.8) 0.521 < 0.0001
Hematemesis [n (%)] 0.0 0.0 0.0 3 (5.7) 0.282 0.38
Disease presentation [n (%)]
Acute 33 (71.7) – – 5 (9.4)
Fulminant 13 (28.3) – – 0.0
Chronic 0.0 – – 48 (90.6)
Liver US [n (%)] 0.005 0.076
Enlarged 32 (69.6) 23 (69.7) 9 (69.2) 19 (35.8)
Shrunken 0.0 0.0 0.0 5 (9.4)
Splenomegaly US [n (%)] 28 (60.9) 16 (48.5) 12 (92.3) 46 (86.8) 0.0001 0.585
Ascites US [n (%)] 17 (37.9) 9 (27.3) 8 (61.5) 6 (11.3) 0.002 0.0002
Minimal 12 (26.1) 9 (27.3) 3 (23.1) 1 (1.9)
Mild 4 (8.7) 0.0 4 (30.8) 3 (5.7)
Moderate 0.0 0.0 0.0 2 (3.8)
Marked 1 (2.2) 0.0 1 (7.7) 0.0
Total bilirubin (mg/dl) 10.38 ± 9.29 8.11 ± 7.78 15.83 ± 10.64 5.15 ± 3.96 0.221 < 0.0001
Direct bilirubin (mg/dl) 6.69 ± 6.07 5.24 ± 5.13 10.15 ± 6.93 3.33 ± 3.04 0.15 0.0001
Alanine aminotransferase (U/l) 890.02 ± 743.11 852.73 ± 718.04 984.69 ± 826.05 249.89 ± 274.67 < 0.0001 0.001
Aspartate aminotransferase (U/l) 758.36 ± 762.45 647.16 ± 677.12 1023.54 ± 910.36 272.58 ± 300.23 0.003 0.001
ALT/AST ratio 1.48 ± 1.18 1.67 ± 1.34 1.02 ± 0.35 0.98 ± 0.41 0.005 0.60
Total proteins (g/dl) 6.73 ± 0.93 6.86 ± 0.86 6.41 ± 1.04 7.14 ± 1.22 0.394 0.076
Albumin (g/dl) 3.33 ± 0.67 3.53 ± 0.64 2.84 ± 0.49 3.02 ± 0.58 0.001 0.214
Alkaline phosphatase (U/l) 302.9 ± 171.91 325.74 ± 184.96 253.62 ± 132.96 217.29 ± 153.72 0.001 0.207
γ-Glutamyl transpeptidase (U/l) 154.74 ± 127.23 153.92 ± 113.68 156.38 ± 155.97 84.06 ± 88.14 0.0002 0.141
Prothrombin time (s) 19.91 ± 12.71 14.42 ± 4.59 32.98 ± 16.28 15.64 ± 4.04 0.013 < 0.0001
Hemoglobin (g/dl) 10.79 ± 1.79 10.82 ± 1.65 10.74 ± 2.19 10.36 ± 1.41 0.058 0.827
White blood cells (×103/mm3) 8.93 ± 4.37 8.1 ± 2.73 10.89 ± 6.63 6.99 ± 3.22 0.094 0.068
Platelets (×103/mm3) 306.09 ± 166.21 332.61 ± 174.46 242.85 ± 129.39 187.06 ± 107.56 < 0.0001 0.149

AIH, autoimmune hepatitis; ALT, alanine transaminase; AST, aspartate transaminase; HAV, hepatitis A virus; US, ultrasonography.
P-value1 represents acute HAV versus AIH.
P-value2 represents fulminant HAV versus AIH.

and γ-glutamyl transpeptidase levels in the AIH group were
comparable with that in fulminant HAV, but significantly
lower than that in acute HAV (Table 1). On comparing the
basic demographic and laboratory data between HAV patients
with different presentations, it was found that the mean serum
albumin was significantly lower, whereas the frequency of
splenomegaly and ascites by US and the mean total and direct
bilirubin were significantly higher in those with fulminant than
in those with acute HAV infection. Ascites detected in those
with acute presentation was of the minimal type in all (n = 9)
patients. There was no significant difference in the other para-
meters studied (Table 2).
Occurrence of autoantibodies in the groups studied
Autoantibodies were present in the majority of patients in this
study (63.1% of HAV and 79.2% of AIH patients). ASMA
was the most common type of autoantibody found in the sera
of children whether they had HAV infection (60.9%) or AIH
(71.7%), with no significant difference between the two
groups. However, the frequency of ANA was significantly
higher in AIH (26.4%) patients compared with the HAV
patients (4.3%) (P = 0.002). LKM1 autoantibody positivity
was found only in one AIH patient and in none of the HAV
patients. AMA was negative in all patients. A total of 20.8%
of AIH cases were seronegative for the autoantibodies tested
(ASMA, ANA, and LKM1) (Table 3).
Most of the HAV patients (23/28) had low titer (1/20) of
ASMA, with only two patients exceeding the 1/40 titer (1/80
and 1/160) (Table 3), and there was no significant difference in
autoantibody titers in different HAV presentations (Table 2).
Most of the AIH patients (29/38) also had a low ASMA titer
(1/20), with only two patients also having a titer exceeding
1/40 (1/80 and 1/320). There was no significant difference
between the two groups in this respect. The titer of ANA
attained in HAV patients did not exceed 1/40 (1/20 and 1/40)
while most ANA positive AIH patients had a titer of 1/20
(9/14), four had a titer of 1/40 and one 1/80. ASMA and/or
ANA (type-I AIH) were positive in 41 (77.4%) children and
LKM1 (type-II AIH) was positive in only one (1.9%) child.
None of the controls was positive for autoantibodies (Table 3).
Gammaglobulin levels in the studied groups
Gammaglobulins were significantly higher in the AIH group
than in the HAV and control groups. The levels in HAV group
were significantly higher than those in the control group
(P < 0.0001 for all; Fig. 1a). On comparing HAV patients with
different presentations, gammaglobulins were significantly
higher in those with fulminant than in those with acute pre-
sentation (P = 0.019; Fig. 1b). Furthermore, in the AIH group,
patients with acute presentation (n = 5) had significantly higher
serum gammaglobulins than those with a chronic presentation
(P = 0.048; Fig. 1c). The gammaglobulins were comparable in
children with fulminant HAV and those with AIH, with no
statistically significant difference (Fig. 1d).
Correlation of gammaglobulins in both HAV and AIH
groups with age and laboratory data, in addition to
histopathological parameters in AIH
In both HAV and AIH groups, gammaglobulins showed
a significant direct correlation with AST and PT and a

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1164 European Journal of Gastroenterology & Hepatology October 2015 • Volume 27 • Number 10

Table 2. Comparison between acute and fulminant hepatitis A regression analysis was carried out. As a result, albumin in
Fulminant HAV
both groups, PT in the HAV group, and AST in the AIH
Acute HAV (n = 33) (n = 13) P-value group were finally included in the model as independent
variables associated with gammaglobulins. Other variables
Age (years) 6.09 ± 3.95 6.89 ± 3.48 0.321
Male [n (%)] 19 (57.6) 10 (76.9) 0.221
were excluded from the model (Table 5).
Jaundice [n (%)] 28 (84.8) 13 (100) 0.301
Hepatomegaly US 23 (69.7) 9 (69.2) 0.975 Clinical performance of gammaglobulins
[n (%)]
Splenomegaly US 16 (48.5) 12 (92.3) 0.006 Gammaglobulins at a cut-off value of greater than 2.015 g/
[n (%)]
Ascites US [n (%)] 9 (27.3) 8 (61.5) 0.002
dl discriminate between HAV and AIH patients with
Minimal 9 (27.3) 3 (23.1) 73.6% sensitivity and 63% specificity (Fig. 2a), and at a
Mild 0.0 4 (30.8) cut-off value of greater than 2.1 g/dl discriminate between
Marked 0.0 1 (7.7)
Total bilirubin (mg/dl) 8.11 ± 7.78 15.83 ± 10.64 0.007
acute HAV and acute AIH with 100% sensitivity and
Direct bilirubin (mg/dl) 5.24 ± 5.13 10.15 ± 6.93 0.014 75.8% specificity (Fig. 2b).
Alanine 852.73 ± 718.04 984.69 ± 826.05 0.788
aminotransferase
(U/l) Discussion
Aspartate 647.16 ± 677.12 1023.54 ± 910.36 0.161
aminotransferase Autoantibodies and hypergammaglobulinemia are the
(U/l) serological hallmark of AIH; yet, they can be found in
ALT/AST ratio 1.67 ± 1.34 1.02 ± 0.35 0.12
Total proteins (g/dl) 6.86 ± 0.86 6.41 ± 1.04 0.202 other non-AIH conditions. There is considerable evidence
Albumin (g/dl) 3.53 ± 0.64 2.84 ± 0.49 0.001 favoring HAV as one of the etiological factors for AIH.
Alkaline phosphatase 325.74 ± 184.96 253.62 ± 132.96 0.251 This includes individual case reports of persistent hepatic
(U/l)
γ-Glutamyl 153.92 ± 113.68 156.38 ± 155.97 0.475
inflammation, with serological and histological features of
transpeptidase (U/l) AIH following proven infection with HAV, and the
Prothrombin time (s) 14.42 ± 4.59 32.98 ± 16.28 < 0.0001 development of autoantibodies to hepatic constituents
Hemoglobin (g/dl) 10.82 ± 1.65 10.74 ± 2.19 0.562
White blood cells 8.1 ± 2.73 10.89 ± 6.63 0.382
during and after HAV infection [16]. The aim of this study
(×103/mm3) was to assess the frequency of autoantibodies and hyper-
Platelets (×103/mm3) 332.61 ± 174.46 242.85 ± 129.39 0.068 gammaglobulinemia in children with HAV infection
Autoantibodies [n (%)] 20 (60.6) 9 (69.2) 0.585 compared with their frequency in AIH and their relation to
ASMA (total) 20 (60.6) 8 (61.5) 0.952
1/20 15 (45.5) 8 (61.5) the clinical presentation and the severity of liver disease
1/40 3 (9.1) 0.0 as well.
1/80 1 (3.0) 0.0 In our study, the autoantibodies were present in the
1/160 1 (3.0) 0.0
ANA (total) 1 (3.0) 1 (7.7) 0.49
majority of both HAV (63.1%) and AIH (79.2%) groups.
1/20 0.0 1 (7.7) Most of the AIH patients (77.4%) were of type-I and only
1/40 1 (3.0) 0.0 one patient (1.9%) was of type-II. It was reported that
ALT, alanine transaminase; ANA, antinuclear antibody; ASMA, antismooth muscle
type-I AIH represented 80% of the cases of AIH [17]. In
antibody; AST, aspartate transaminase; HAV, hepatitis A virus; US, ultrasonography. the group of HAV patients in this study, the autoantibody
pattern was similar to that of type-I AIH, where most were
either ASMA (60.9%) or ANA (4.3%) positive and none
Table 3. Occurrence and titer of autoantibodies in the studied groups
was LKM1 positive. All the patients were negative for
AMA. Moon et al. [1] reported that in adult patients with
Controls acute HAV, 8% were positive for ASMA, whereas only
Autoantibody HAV (n = 46) AIH (n = 53) (n = 27) P-value‡
5.4% were ANA positive. Furthermore, Lopez et al. [18]
ASMA reported that in children with HAV, 47.3% were ASMA
Total 28 (60.9) 38 (71.7) 0.0 0.254
positive (titers 1/40 and 1/80), whereas ANA and LKM1
1/20 23 (50) 29 (54.7)
1/40 3 (6.5) 7 (13.2) were negative in all cases. Moreover, Roy et al. [19]
1/80 1 (2.2) 1 (1.9) reported that 94.4% of children with prolonged HAV
1/160 1 (2.2) 0.0 infection were positive for ASMA and also had hyper-
1/320 0.0 1 (1.9)
ANA gammaglobulinemia. In addition, Seo et al. [20] reported
Total 2 (4.3) 14 (26.4) 0.0 0.002 that ANA was detected in 179/442 (42.4%) of adult
1/20 1 (2.2) 9 (17) patients with acute hepatitis A. This not uncommon; the
1/40 1 (2.2) 4 (7.5)
1/80 0.0 1 (1.9)
presence of autoantibodies in HAV infection may com-
AMA 0.0 0.0 0.0 NA plicate its diagnosis. An autoantibody titer of 1 : 40 is
LKM1 significant in adults, whereas in children titers of 1 : 20 for
1/80 0.0 1 (1.9) 0.0 0.349
Total positive cases 29 (63.1) 42 (79.2) 0.0 0.074
ANA and ASMA, and 1 : 10 for anti-LKM1 are clinically
Total negative cases 17 (37) 11 (20.8) 27 (100) relevant because autoantibody reactivity is infrequent in
healthy children [21].
AIH, autoimmune hepatitis; AMA, antimitochondrial antibody; ANA, antinuclear anti- Under some circumstances, HAV patients may be
body; ASMA, antismooth muscle antibody; HAV, hepatitis A virus; NA, not applicable.
‡
P-value represents HAV versus AIH. negative for anti-HAV IgM because of immunosuppressive
use [7], early testing in the course of the disease [8], or
negative correlation with serum albumin, whereas there inadequate or delayed anti-HAV IgM response after
was no significant correlation with the other parameters known exposure to HAV [22], thus making the differ-
studied (Table 4). Subsequently, a stepwise multiple entiation from AIH with acute presentation a major

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Autoimmunity in children with hepatitis A Abdel-Ghaffar et al. www.eurojgh.com 1165

(a) (b)
P < 0.0001
8 4
P < 0.0001 P = 0.019

6 3
γ globulins (g/dl)

P < 0.0001
4 2 1.82 ± 0.57 2.21 ± 0.46

2.93 ± 1.2

1.93 ± 0.57 1.32 ± 0.29

2 1

0 0
AIH HAV Controls Acute HAV Fulminant HAV

(c) (d)
8 8
P = 0.048 P = 0.095

6 6
γ globulins (g/dl)

4 4
3.88 ± 1.11
2.83 ± 1.17 2.93 ± 1.2
2 2 2.21 ± 0.46

0 0
Acute AIH Chronic AIH AIH Fulminant HAV
Fig. 1. Gammaglobulins in the groups studied. Box-and-whiskers plot for serum gammaglobulins. The top and bottom of each box are the 75th and 25th
percentiles. The line through the box is the median and the error bars are the maximum and minimum. The horizontal bar represents the significance between
the designated groups. The number indicated on the box represents mean ± SD. (a) The value of gammaglobulins in the studied groups. (b) The value of
gammaglobulins in HAV-infected patients with acute and fulminant presentation. (c) The value of gammaglobulins in AIH patients with acute and chronic
presentation. (d) The value of gammaglobulins in patients with AIH and fulminant HAV. The dotted line in (a) represents the upper limit of normal. AIH,
autoimmune hepatitis; HAV, hepatitis A virus.

problem, especially in those with autoantibody-negative also reported by Dehghani et al. [23]. In addition, Joshi
AIH. The current study showed that 20.8% of the children and Khettry [24] reported that some AIH patients, at their
in the AIH group were seronegative for the conventional initial presentation, may be negative for serum auto-
serological markers (ASMA, ANA, and LKM1). This was antibodies, whereas others may persistently remain
autoantibody-negative. Autoantibody-negative AIH may
be associated with an autoantibody outside the conven-
Table 4. Correlation of gammaglobulins in both AIH and HAV groups
with age and laboratory data, in addition to histopathological
tional battery; it may have a signature autoantibody that is
parameters in AIH still undiscovered or its characteristic autoantibodies may
have been suppressed or have a delayed expression [25].
HAV (n = 46) AIH (n = 53)
The reason why autoantibodies are produced in indi-
Parameter r P-value r P-value viduals with viral hepatitis is a matter of investigation. A
Age (years) 0.166 0.269 0.262 0.06 frequently offered explanation is that the release of intra-
Total bilirubin (mg/dl) 0.268 0.078 − 0.039 0.784 cellular antigens at the time of hepatocellular injury trig-
Direct bilirubin (mg/dl) 0.279 0.067 − 0.023 0.87 gers an immune response in the form of autoantibody
Albumin (g/dl) − 0.381 0.011 − 0.335 0.015
Alanine aminotransferase (U/l) 0.217 0.148 0.234 0.091 production [26]. ANA are most commonly directed at
Aspartate aminotransferase (U/l) 0.305 0.044 0.372 0.006 DNA and histones. ASMA react with a variety of cytos-
ALT/AST ratio − 0.136 0.379 − 0.262 0.058 keletal components including F-actin, myosin, desmin,
Alkaline phosphatase (U/l) − 0.165 0.303 0.155 0.278
γ-Glutamyl transpeptidase (U/l) − 0.082 0.619 − 0.026 0.856 vimentin, and tubulin. LKM1 is directed for the cyto-
Prothrombin time (s) 0.321 0.034 0.437 0.001 chrome isoform P450IID6 [27].
Hemoglobin (g/dl) − 0.150 0.332 − 0.07 0.616 ANA and ASMA are commonly found in patients
White blood cells (×103/mm3) − 0.009 0.955 − 0.204 0.144
Platelets (×103/mm3) − 0.127 0.411 − 0.178 0.181
with chronic hepatitis B virus and chronic HCV [28].
Fibrosis stage – – 0.234 0.126 Moreover, LKM1 is found in up to 10% of HCV-infected
Activity grade – – 0.164 0.311 patients, but it is invariably absent in patients with
AIH, autoimmune hepatitis; ALT, alanine transaminase; AST, aspartate transami- viral hepatitis A, B, and D, suggesting that a particular
nase; HAV, hepatitis A virus. viral agent is associated with a specific autoantibody [26].

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1166 European Journal of Gastroenterology & Hepatology October 2015 • Volume 27 • Number 10

Table 5. Multiple regression analysis of gammaglobulins in both HAV and AIH groups with age and laboratory data, in addition to histopathological
parameters in AIH
HAV (n = 46) AIH (n = 53)

95% CI 95% CI

Parameter β P-value Lower Upper β P-value Lower Upper

Age (years) NI NI
Total biirubin (mg/dl) NI NI
Direct bilirubin (mg/dl) NI NI
Albumin (g/dl) − 0.597 0.001 − 0.801 − 0.227 − 0.377 0.0001 − 1.171 − 0.402
Alanine aminotransferase (U/l) NI NI
Aspartate aminotransferase (U/l) NI 0.295 0.013 0.0003 0.002
ALT/AST ratio NI NI
Alkaline phosphatase (U/l) NI NI
γ-Glutamyl transpeptidase (U/l) NI NI
Prothrombin time (s) 0.324 0.028 0.002 0.034 NI
Hemoglobin (g/dl) NI NI
White blood cells (×103/mm3) NI NI
Platelets (×103/mm3) NI NI
Fibrosis stage – NI
Activity grade – NI

AIH, autoimmune hepatitis; ALT, alanine transaminase; AST, aspartate transaminase; β, regression coefficient; CI, confidence interval; HAV, hepatitis A virus; NI, not
included.

(a) (b)
AIH versus HAV Acute AIH versus acute HAV
100 100

2.1 g/dl

80 80

2.015 g/dl
60 60
Sensitivity

40 40

20 AUROC: 77% 20 AUROC: 94.5%

Sensitivity: 73.6% Sensitivity: 100%
Specificity: 63% Specificity: 75.8%
Accuracy: 68% Accuracy: 78.9%
0 0
0 20 40 60 80 100 0 20 40 60 80 100
100−Specificity 100−Specificity
Fig. 2. Receiver-operating characteristic (ROC) curves of gammaglobulins. (a) AIH versus HAV. (b) Acute AIH patients versus acute HAV-infected patients.
The arrows indicate the cut-off values. AIH, autoimmune hepatitis; AUROC, area under receiver-operating characteristic; HAV, hepatitis A virus.

This can be explained by the extensive cross-reactivity
between highly homologous regions of HCV and
P450IID6, the molecular target of LKM1, as reported by
Kerkar et al. [29].
Furthermore, viral infection converts the normal func-
tions of a cell to optimize viral replication and virion
production. One striking observation of this conversion is
the reconfiguration and reorganization of cellular actin
[30]. This may render the cellular actin antigenic with the
production of antiactin autoantibodies [18]. Additional
evidence indicated that HAV can elicit immune reactions
against viral antigens expressed on cell surfaces of infected
patients [31].
Genetic predisposition may represent another link
between HAV and AIH. In AIH, genetic susceptibility
coinduces with the loss of self-tolerance and subsequently
the development of the disease. The genes most strictly
involved in AIH are located within the human leukocyte
antigen class II region, with particular respect to the allelic
variants of DRB1, of which DRB1*0301 was reported.
The same allelic variant was reported in association with
persistent HAV infection, which highlights a possible role
of HAV in the pathogenesis of AIH [32].
In the current study, there was no significant difference
between acute and fulminant presentation of HAV infection
in the titer of ASMA and ANA. It was reported that

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Autoimmunity in children with hepatitis A Abdel-Ghaffar et al.
autoantibodies in AIH cannot be used to reliably monitor
disease behavior [33]. The same may apply for HAV
infection.
In AIH patients with acute presentation, the diagnosis is
sometimes rendered difficult both because of the severity of
hepatic insult at presentation, making histological eva-
luation extremely difficult, and because of the presence of
centrilobular zone 3 necrosis. In such cases, this can sug-
gest an acute viral or toxic injury that can later transform
into the classical pattern of interface hepatitis as the dis-
ease evolves [33]. In addition, the immunoparesis com-
monly seen in the critically ill patient in whom both
autoantibodies and/or increased IgG concentrations may
be absent [34] is another confounding factor in diagnosis.
In the present study, there was hypergammaglobuline-
mia in the HAV group, with a mean level of 1.93 ± 0.57 g/
dl, which was significantly higher than that in the controls,
but lower than the level in AIH. It was reported that, in
acute HAV infection, there is an elevation in nonvirus-
specific serum IgM as a common feature in addition to a
mild increase in total immunoglobulins [6], suggesting that
there is a development of autoimmune reactions that may
trigger AIH [35]. Therefore, the finding of hypergamma-
globulinemia in patients with HAV warrants follow-up to
rule out the induction of AIH [11]. In the current study, we
found that gammaglobulins at a cut-off value of 2.1 g/dl
could discriminate AIH with acute presentation from acute
HAV with 100% sensitivity and 75.8% specificity.
Muratori et al. [36] reported that the optimal cut-off point
of gammaglobulins was 1.91 g g/dl (sensitivity 76.5%,
specificity 93.5%) for differentiation between AIH and
acute viral hepatitis.
The mechanism of hypergammaglobulinemia in viral
infections is unclear. One explanation is that viruses lead
to antigen-specific induction of T and B lymphocytes [37].
However, these usually protective responses are often
accompanied by the appearance of autoantibodies to self-
antigens of the host [38].
In this work, gammaglobulin levels in both HAV and
AIH patients showed a significant correlation with disease
severity. Fallatah and Akbar [39] reported that AIH
patients with advanced disease stage had significantly
higher levels of serum IgG.
In the present work, the gammaglobulin level in HAV
patients with fulminant presentation was significantly
higher than in those with acute presentation, whereas it
was comparable with those of AIH (P =0.095). These
findings can suggest a more aggressive autoimmunity as a
contributing factor for the development of the fulminant
presentation during HAV infection.
It could be suggested, in part, that genetic variations of
HAV might influence both the replication of the virus and
the cellular immune response of the human host, and in
large part that vigorous clearance of HAV-infected hepa-
tocytes by the immune response might be the cause of
fulminant disease [3]. Many early trials using adreno-
corticotrophic hormone and/or corticosteroids in treating
fulminant hepatitis have yielded conflicting results, but
none was specifically been conducted in children.
Although some studies reported no value of steroids [40–
45], other investigators [46,47] reported that the intro-
duction of high-dose corticosteroids in the early stage of
acute liver failure was effective in suppressing the
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www.eurojgh.com 1167
destruction of hepatocytes and ameliorating the course of
the disease and it may be life-saving. In addition, it was
found that most adult patients with fulminant hepatitis B
who were treated with early corticosteroids (with or
without antiviral drugs), but none of those who were
treated with delayed corticosteroids (with or without
antiviral drugs), survived [48].
This work showed that 9.4% of AIH patients had an
acute presentation clinically indistinguishable from acute
hepatitis A, whereas the remaining 90.6% had a chronic
presentation. However, 71.7% of patients with hepatitis A
had an acute presentation, whereas the remaining 28.3%
had a fulminant presentation. Ajmera et al. [49] reported
that HAV infection usually follows an innocuous course,
remaining subclinical in most children, while appearing as
acute self-limited hepatitis in adults. Less than 1% of acute
HAV cases result in acute liver failure. The high prevalence
of fulminant cases in this work could be attributed to the
fact that both centers conducting the study are tertiary
centers where severe and fulminant cases are referred. No
single viral factor has been associated with the develop-
ment of fulminant disease. Similarly, a heterogeneous
presentation of AIH has been described. Some patients
may present with an acute pattern that clinically resembles
acute hepatitis [50]. Others may present with fulminant
hepatitis [51].
Ascites, despite being a marker of chronicity in liver
disease [52], could occur in acute conditions including HAV.
In the current study, ascites was found in 11.3% of AIH
patients, whereas it was found in 37.9% of patients with
HAV infection. It is unusual to find ascites clinically in acute
hepatitis. Ascites in this study was detected by US, and not
clinically, during the routine workup performed for those
patients. In accordance with our results, several reports have
shown that acute HAV may also cause ascites [53,54]. In
addition, Yoo et al. [55] reported the presence of spleno-
megaly and pelvic fluid collection in the majority of patients
with acute HAV infection. It was reported that ascites in
acute hepatitis may be because of hemodynamic changes
associating acute hepatitis in the form of increased hepatic
venous pressure gradient leading to portal hypertension [56].
Another contributing factor toward the occurrence of portal
hypertension in acute conditions is the increased portal
venous blood flow resulting in increased cardiac output, a
hemodynamic disorder that is common in fulminant hepa-
titis [57]. As detected by US, splenomegaly was found in
60.9% of the patients in the HAV group, and yet the fre-
quency was significantly higher in the AIH group (86.8%).
In conclusion, although hypergammaglobulinemia and
autoantibodies are still considered the key points in the
diagnosis of AIH, they are not specific as their occurrence,
even at high levels, was found in acute hepatitis A, impli-
cating that an immunological basis may be involved in the
pathogenesis of HAV infection.
Acknowledgements
This study was funded by the National Liver Institute,
Menofiya University, Egypt, in collaboration with the
Yassin Abdel-Ghaffar Charity Center for Liver Disease
and Research, Cairo, Egypt, without any particular role in
the study design, recruitment of individuals, data analysis,
or the writing of the report.
1168 European Journal of Gastroenterology & Hepatology
Conflicts of interest
There are no conflicts of interest.
References
1 Moon HW, Noh JK, Hur M, Yun YM, Lee CH, Kwon SY. High prevalence
of autoantibodies in hepatitis A infection: the impact on laboratory
profiles. J Clin Pathol 2009; 62:786–788.
2 Franco E, Meleleo C, Serino L, Sorbara D, Zaratti L. Hepatitis A: epi-
demiology and prevention in developing countries. World J Hepatol
2012; 4:68–73.
3 Fujiwara K, Kojima H, Yasui S, Okitsu K, Yonemitsu Y, Omata M,
Yokosuka O. Hepatitis A viral load in relation to severity of the infection.
J Med Virol 2011; 83:201–207.
4 Di Giammarino L, Dienstag JL. Hepatitis A – the price of progress.
N Engl J Med 2005; 353:944–946.
5 Sarin SK, Kumar M. Viral hepatitis A. In: Monga SPS, editor.
Molecular pathology of liver diseases. New York, Dordrecht, Heidelberg,
London: Springer Science + Business Media, LLC; 2011. pp.
527–552.
6 Di Giammarino L, Dienstag JL. Hepatitis A. In: Rodés J, Benhamou J,
Blei AT, Reichen J, Rizzetto M, editors. Textbook of hepatology from
basic science to clinical practice, 3rd ed. Massachusetts, Oxford,
Victoria: Blackwell Publishing Ltd; 2007. pp. 857–865.
7 Chakvetadze C, Mallet V, Gaussec L, Hannoun L, Pol S. Acute hepatitis
A virus infection without IgM antibodies to hepatitis A virus. Ann Intern
Med 2011; 154:507–508.
8 Hirata R, Hoshino Y, Sakai H, Marumo F, Sato C. Patients with hepatitis
A with negative IgM-HA antibody at early stages. Am J Gastroenterol
1995; 90:1168–1169.
9 Al-Obeidy ES, Al-Khalidi NM. A comparison of the prevalence of auto-
antibodies in individuals with chronic hepatitis C and those with auto-
immune hepatitis. Iraq J Gastroenterol 2006; 1:49–54.
10 Fujiwara K, Yasui S, Tawada A, Fukuda Y, Nakano M, Yokosuka O.
Diagnostic value and utility of the simplified International Autoimmune
Hepatitis Group criteria in acute-onset autoimmune hepatitis. Liver Int
2011; 31:1013–1020.
11 Tabak F, Ozdemir F, Tabak O, Erer B, Tahan V, Ozaras R. Autoimmune
hepatitis induced by the prolonged hepatitis A virus infection. Ann
Hepatol 2008; 7:177–179.
12 Mehendiratta V, Mitroo P, Bombonati A, Navarro VJ, Rossi S, Rubin R,
Herrine SK. Serologic markers do not predict histologic severity or
response to treatment in patients with autoimmune hepatitis. Clin
Gastroenterol Hepatol 2009; 7:98–103.
13 Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al.
International Autoimmune Hepatitis Group. Simplified criteria for the
diagnosis of autoimmune hepatitis. Hepatology 2008; 48:169–176.
14 Whitington PF, Alonso EM, Squires RH. Acute liver failure. In: Kelly D,
editor. Diseases of the liver and biliary system in children, 3rd ed.
Oxford, UK: Blackwell Publishing; 2008. pp. 169–188.
15 Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, et al.
Histological grading and staging of chronic hepatitis. J Hepatol 1995;
22:696–699.
16 Singh G, Palaniappan S, Rotimi O, Hamlin PJ. Autoimmune hepatitis
triggered by hepatitis A. Gut 2007; 56:304.
17 Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an
autoimmune liver disease: immunological aspects and clinical overview.
Autoimmune Dis 2012; 2012:312817.
18 Lopez SI, Seia J, Roy A, Cuarterolo M, Canero V, Maria C, et al. Anti-
actin antibodies in acute viral hepatitis A in children. Acta Gastroenterol
Latinoam 1998; 28:261–264.
19 Roy A, Velazco MC, Ciocca M, Campos G, Zelasko M. Antiactin anti-
bodies in prolonged viral type a hepatitis (Hav) in chilhood. Pediatr Res
1997; 42:924–924.
20 Seo YS, Lee KG, Jung ES, An H, Kim JH, Yeon JE, et al. Clinical
significance of the detection of antinuclear antibodies in patients with
acute hepatitis A. Gut Liver 2011; 5:340–347.
21 Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G,
Vergani D, Vierling JM. American Association for the Study of Liver
Diseases. Diagnosis and management of autoimmune hepatitis.
Hepatology 2010; 51:2193–2213.
22 Nainan OV, Xia G, Vaughan G, Margolis HS. Diagnosis of hepatitis a
virus infection: a molecular approach. Clin Microbiol Rev 2006;
19:63–79.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
October 2015 • Volume 27 • Number 10
23 Dehghani SM, Haghighat M, Imanieh MH, Honar N, Negarestani AM,
Malekpour A, et al. Autoimmune hepatitis in children: experiences in a
tertiary center. Iran J Pediatr 2013; 23:302–308.
24 Joshi M, Khettry U. Approach to diagnosis of auto-immune hepatitis.
Indian J Pathol Microbiol 2009; 52:297–303.
25 Czaja AJ. Autoantibody-negative autoimmune hepatitis. Dig Dis Sci
2012; 57:610–624.
26 Bogdanos DP, Mieli-Vergani G, Vergani D. Non-organ-specific auto-
antibodies in hepatitis C virus infection: do they matter? Clin Infect Dis
2005; 40:508–510.
27 Zeman MV, Hirschfield GM. Autoantibodies and liver disease: uses
and abuses. Can J Gastroenterol 2010; 24:225–231.
28 Daschakraborty S, Aggarwal A, Aggarwal R. Non-organ-specific auto-
antibodies in Indian patients with chronic liver disease. Indian J
Gastroenterol 2012; 31:237–242.
29 Kerkar N, Choudhuri K, Ma Y, Mahmoud A, Bogdanos DP, Muratori L,
et al. Cytochrome P4502D6(193-212): a new immunodominant epitope
and target of virus/self cross-reactivity in liver kidney microsomal auto-
antibody type 1-positive liver disease. J Immunol 2003; 170:1481–1489.
30 Taylor MP, Koyuncu OO, Enquist LW. Subversion of the actin
cytoskeleton during viral infection. Nat Rev Microbiol 2011; 9:427–439.
31 Fainboim L, Canero Velasco MC, Marcos CY, Ciocca M, Roy A,
Theiler G, et al. Protracted, but not acute, hepatitis A virus infection is
strongly associated with HLA-DRB*1301, a marker for pediatric auto-
immune hepatitis. Hepatology 2001; 33:1512–1517.
32 Francque S, Vonghia L, Ramon A, Michielsen P. Epidemiology and
treatment of autoimmune hepatitis. Hepat Med 2012; 4:1–10.
33 Czaja AJ. Difficult treatment decisions in autoimmune hepatitis. World J
Gastroenterol 2010; 16:934–947.
34 Yeoman AD, Westbrook RH, Al-Chalabi T, Carey I, Heaton ND,
Portmann BC, Heneghan MA. Diagnostic value and utility of the sim-
plified International Autoimmune Hepatitis Group (IAIHG) criteria in acute
and chronic liver disease. Hepatology 2009; 50:538–545.
35 Manangeeswaran M, Jacques J, Tami C, Konduru K, Amharref N,
Perrella O, et al. Binding of hepatitis A virus to its cellular receptor 1
inhibits T-regulatory cell functions in humans. Gastroenterology 2012;
142:1516.e3–1525.e3.
36 Muratori P, Muratori L, Stroffolini T, Pappas G, Terlizzi P, Ferrari R, et al.
Prevalence of non-organ specific autoantibodies in HCV-infected sub-
jects in the general population. Clin Exp Immunol 2003; 131:118–121.
37 Jellison ER, Guay HM, Szomolanyi-Tsuda E, Welsh RM. Dynamics and
magnitude of virus-induced polyclonal B cell activation mediated by
BCR-independent presentation of viral antigen. Eur J Immunol 2007;
37:119–128.
38 Ludewig B, Krebs P, Metters H, Tatzel J, Tureci O, Sahin U. Molecular
characterization of virus-induced autoantibody responses. J Exp Med
2004; 200:637–646.
39 Fallatah HI, Akbar HO. Elevated serum immunoglobulin G levels in
patients with chronic liver disease in comparison to patients with auto-
immune hepatitis. Libyan J Med 2010; 5. doi: 10.3402/ljm.v5i0.4857.
40 Evans AS, Sprinz H, Nelson RS. Adrenal hormone therapy in viral
hepatitis. III. The effect of ACTH and cortisone in severe and
fulminant cases. Ann Intern Med 1953; 38:1148–1159.
41 Naglo O, Rydenstam B, Silverstolpe L. ACTH-treatment of acute viral
hepatitis. Acta Med Scand 1959; 165:167–171.
42 Sborov VM, Giges B, Plough IC, Mandel W. ACTH therapy in acute viral
hepatitis. J Lab Clin Med 1954; 43:48–57.
43 Ducci H, Katz R. Treatment of acute hepatitis with cortisone and anti-
biotics. Gastroenterology 1955; 29:381–390.
44 Deritis F, Giusti G, Mallucci L, Piazza M. Negative results of prednisone
therapy in viral hepatitis. Lancet 1964; 1:533–534.
45 Vakil BJ, Iyer SN, Shah SC, Gadgil RK, Wagholikar UN. A controlled trial
of prednisolone in the treatment of infective hepatitis. J Indian Med
Assoc 1965; 45:357–362.
46 Huber TE, Wiley AT. Cortisone in the treatment of infectious hepatitis.
Ann Intern Med 1955; 42:1011–1025.
47 Fujiwara K, Yasui S, Yonemitsu Y, Mikata R, Arai M, Kanda T, et al.
Efficacy of high-dose corticosteroid in the early stage of viral acute liver
failure. Hepatol Res 2014; 44:491–501.
48 Fujiwara K, Yasui S, Yonemitsu Y, Fukai K, Arai M, Imazeki F, et al.
Efficacy of combination therapy of antiviral and immunosuppressive
drugs for the treatment of severe acute exacerbation of chronic
hepatitis B. J Gastroenterol 2008; 43:711–719.
49 Ajmera V, Xia G, Vaughan G, Forbi JC, Ganova-Raeva LM,
Khudyakov Y, et al. What factors determine the severity of hepatitis
A-related acute liver failure? J Viral Hepat 2011; 18:e167–e174.
Autoimmunity in children with hepatitis A Abdel-Ghaffar et al. www.eurojgh.com 1169

50 Yachha SK, Goel A, Khanna V, Poddar U, Srivastava A, Singh U.
Ascitic form of sporadic acute viral hepatitis in children: a distinct
entity for recognition. J Pediatr Gastroenterol Nutr 2010; 50:
184–187.
51 Czaja AJ. Acute and acute severe (fulminant) autoimmune hepatitis. Dig
Dis Sci 2013; 58:897–914.
52 Pinto RB, Schneider AC, da Silveira TR. Cirrhosis in children and ado-
lescents: an overview. World J Hepatol 2015; 7:392–405.
53 Erdem E, Urganci N, Ceylan Y, Kara N, Ozcelik G, Gulec SG. Hepatitis A
with pleural effusion, ascites and acalculous cholecystitis. Iran J Pediatr
2010; 20:479–482.
54 Vaidya P, Kadam C. Hepatitis A: an unusual presentation. Indian Pediatr
2003; 40:910–911.
55 Yoo SM, Lee HY, Song IS, Lee JB, Kim GH, Byun JS. Acute hepatitis A:
correlation of CT findings with clinical phase. Hepatogastroenterology
2010; 57:1208–1214.
56 Valla D, Flejou JF, Lebrec D, Bernuau J, Rueff B, Salzmann JL,
Benhamou JP. Portal hypertension and ascites in acute hepatitis: clin-
ical, hemodynamic and histological correlations. Hepatology 1989;
10:482–487.
57 Navasa M, Garcia-Pagan JC, Bosch J, Riera JR, Banares R, Mas A,
et al. Portal hypertension in acute liver failure. Gut 1992; 33:965–968.

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.