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Hepatobiliary & Pancreatic Diseases International

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Original Article/Liver

Acute onset of autoimmune hepatitis in children and adolescents

Vratislav Smolka a,∗, Oksana Tkachyk a, Jiri Ehrmann b, Eva Karaskova a, Martin Zapalka a,
Jana Volejnikova a
a
Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 185/6, Olomouc 779 00,
Czech Republic
b
Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova
185/6, Olomouc 779 00, Czech Republic

a r t i c l e i n f o a b s t r a c t

Article history: Background: Autoimmune hepatitis (AIH) is a rare progressive liver disease, which manifests as acute
Received 5 March 2019 hepatitis in 40%-50% of pediatric cases. This refers predominantly to spontaneous exacerbations of previ-
Accepted 15 August 2019
ously unrecognized subclinical AIH with laboratory and histological signs of chronic hepatitis, or to acute
Available online xxx
exacerbations of known chronic disease. Only a few of these patients fulfill criteria for acute liver failure
Key words: (ALF).
Acute liver failure Methods: Forty children diagnosed with AIH in our center between 20 0 0 and 2018 were included in this
Autoimmune hepatitis study. All of them fulfilled revised diagnostic criteria of the International Autoimmune Hepatitis Group
Children (IAIHG) for probable or confirmed AIH, and other etiologies of liver diseases were excluded. Patients were
Onset divided into two groups: acute AIH (A-AIH) or chronic AIH (C-AIH).
Results: Acute onset of AIH occurred in 19/40 children (48%). Six of them fulfilled the criteria of ALF
with coagulopathy and encephalopathy. Five of 6 children with ALF suffered from exacerbation of previ-
ously undiagnosed chronic AIH, among which 4 children were histologically confirmed as micronodular
cirrhosis. The remaining one patient had fulminant AIH with centrilobular necrosis, but no histological
signs of previous chronic liver damage. We observed significantly lower levels of albumin, higher levels
of aminotransferases, bilirubin, INR, IgG, higher IAIHG score and more severe histological findings in A-
AIH than in C-AIH. No differences in patient age and presence of autoantibodies were observed between
A-AIH and C-AIH. All children, including those with ALF and cirrhosis, were treated with corticosteroids,
and are alive and achieved AIH remission. Liver transplant was not indicated in any patient.
Conclusion: Rapid and accurate diagnosis of A-AIH may be difficult. However, timely start of immunosup-
pressive therapy improves prognosis and decreases number of indicated liver transplantations in children
with AIH.
© 2019 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier
B.V. All rights reserved.

Introduction
Autoimmune hepatitis (AIH) is a severe chronic inflammatory
liver disease, predominant in females. It is characterized by hy-
pergammaglobulinemia, presence of specific autoantibodies and a
good response to immunosuppressive treatment. The cause of AIH
is still not entirely elucidated. Initial presentation of AIH is highly
variable, in 40%-50% of children AIH clinically and biochemically
resembles acute hepatitis of other (mostly viral) etiologies [1].
Acute manifestation of AIH can also occur as a spontaneous exacer-
bation of previously undiagnosed AIH with clinical and histological
signs of chronic hepatitis. Only very few patients with acute AIH
onset fulfill criteria of acute liver failure (ALF) with coagulopathy
and encephalopathy without histological changes of chronic liver
disease. Fulminant course of AIH occurs in approximately 6% of
children with diagnosed and treated ALF [2]. In clinical practice,
timely recognition of autoimmune ALF improves prognosis of pa-
tients. The present study aimed to report the presentation of chil-
dren with AIH at the time of diagnosis and their response to im-
munosuppression.
Methods
Patients

∗
Corresponding author. Forty children diagnosed with AIH between 20 0 0 and 2018
E-mail address: vratislav.smolka@fnol.cz (V. Smolka). were included in this study. AIH diagnosis was established

https://doi.org/10.1016/j.hbpd.2019.08.004
1499-3872/© 2019 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.

Please cite this article as: V. Smolka, O. Tkachyk and J. Ehrmann et al., Acute onset of autoimmune hepatitis in children and adolescents,
Hepatobiliary & Pancreatic Diseases International, https://doi.org/10.1016/j.hbpd.2019.08.004
JID: HBPD
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2 V. Smolka, O. Tkachyk and J. Ehrmann et al. / Hepatobiliary & Pancreatic Diseases International xxx (xxxx) xxx
according to the revised International Autoimmune Hepatitis
Group (IAIHG) criteria for probable (10–15 points) or confirmed
(>15 points) AIH [3] and had to be concluded before the start of
immunosuppressive treatment in all cases. Hepatitis A, B, C, cy-
tomegalovirus (CMV) and Epstein-Barr virus (EBV) infections were
serologically excluded in all patients. Herpes simplex virus (HSV)
status was not routinely examined in immunocompetent children
older than 6 years. Clinical and biochemical examinations did
not confirm autosomal recessive metabolic disorders connected
with chronic liver damage, such as Wilson disease and alpha-
1-antitrypsin deficiency. Toxic and alcoholic liver damage were
excluded anamnestically. At the time of diagnosis, we obtained
anamnestic and clinical data and laboratory results. The follow-
ing autoantibodies were examined: antinuclear antibodies (ANA),
smooth muscle antibodies (SMA), antimitochondrial antibodies
(AMA), liver/kidney microsome antibodies (anti-LKM), liver cytosol
antibodies (LC1), antineutrophil cytoplasmic antibodies (ANCA) and
soluble liver antigen antibodies (SLA). For ANA and SMA, titers
1:20 and above were considered positive; SLA, anti-LKM and LC1
were examined using the LIVER 7 DOT qualitative EIA immun-
odot assay and evaluated semi-quantitatively (positive/weak posi-
tive/borderline/negative) by visual comparison with a reference dot
(cut-off). AIH was classified as type 1 (AIH-1) in cases with ANA or
SMA seropositivity, or as type 2 (AIH-2) in LKM-1 or LC1 positivity.
Abdominal ultrasonography was performed in all patients.
Magnetic resonance cholangiopancreatography (MRCP) was indi-
cated at the time of diagnosis only in children with gamma-
glutamyltransferase (GGT) level exceeding the upper reference
limit more than two fold (i.e., GGT over 81.6 IU/L) to exclude
the association of AIH with primary sclerosing cholangitis (PSC)
– an overlap syndrome. Diagnostic percutaneous non-targeted
liver biopsy was done in all except one patient within 4 weeks
since acute manifestation of hepatitis or after 6 months in silent
chronic hepatitis. Histology examined activity of portal inflamma-
tion, severity of lobular damage and grade of fibrosis according to
Knodell et al. [4]. In one patient with ALF, histological finding was
evaluated based on proposed specific criteria for autoimmune ALF
(AI-ALF) [5].
Definitions
According to the onset of AIH, patients were classified as acute
AIH (A-AIH) or chronic AIH (C-AIH). Biochemical and clinical find-
ings in A-AIH strongly resembled acute viral hepatitis: alanine
aminotransferase levels (ALT) were more than 10 times higher than
the upper reference limit (i.e., >350 IU/L) and total bilirubin ex-
ceeded 22 μmol/L with conjugated bilirubin fraction over 50% of
total bilirubin. C-AIH was characterized by non-specific or even
lacking symptoms prior to diagnosis and by elevated aminotrans-
ferase levels. Within the A-AIH group, we identified patients with
ALF and histological findings of acute liver disease and patients ful-
filling the ALF definition in originally unknown, but subsequently
histologically confirmed, chronic liver disease. ALF was defined by
biochemical markers of liver damage, presence of coagulopathy re-
sistant to vitamin K and hepatic encephalopathy in children with-
out previous liver disease. International normalized ratio (INR) cut-
off was ≥1.5 in patients with hepatic encephalopathy and ≥2.0
without the presence of hepatic encephalopathy [2].
Treatment
Patients were treated by corticosteroids, either in monotherapy
(prednisone 2 mg/kg/day; maximum 60 mg/day) or in combination
with azathioprine (1–2 mg/kg/day). After 4 to 6 weeks of initial
treatment, the dose of prednisone was tapered (decrease by 5 mg
after each 10 days) to a maintenance dose of 0.1–0.2 mg/kg/day.
Please cite this article as: V. Smolka, O. Tkachyk and J. Ehrmann et al., Acute onset of autoimmune hepatitis in children and adolescents,
Hepatobiliary & Pancreatic Diseases International, https://doi.org/10.1016/j.hbpd.2019.08.004
[m5G;August 29, 2019;19:31]
Azathioprine was administered continuously for 3 to 5 years de-
pending on clinical condition and biochemical results of the indi-
vidual patients. Therapy response was evaluated 6 weeks after the
start of immunosuppression [6]. Disease remission was defined as
normalization of aminotransferase levels and decrease of IgG. Con-
trol liver biopsy was not performed within one year after treat-
ment initiation in any patient.
Statistical analysis
Data were analyzed by “R” freeware (R Foundation for Statisti-
cal Computing, Vienna, Austria, 2017). To compare characteristics
of two groups, we used Pearson Chi-square test (or Fisher test) for
categorical variables and Student’s t-test (or Wilcoxon two-sample
test) for continuous variables. A P value of <0.05 was considered
statistically significant.
Results
A total of 40 patients with age range of 2–17 years were in-
cluded in our cohort, females accounted for 65% (26 patients). Di-
agnostic criteria of confirmed AIH were met in 26 children and cri-
teria of probable AIH in 14 children. According to the autoantibody
profile, 32 children had AIH-1 and 8 had AIH-2. Personal or family
history of another autoimmune disease was positive in 10 children
(25%): four patients had celiac disease (including 2 patients with
A-AIH), two had immune thrombocytopenia and one had type 1
diabetes mellitus. One patient’s brother was followed with autoim-
mune sclerosing cholangitis, two other patient’s mothers with au-
toimmune thyroiditis and one patient’s mother with Crohn disease.
Abdominal ultrasonography revealed ascites in 7 patients with A-
AIH and acalculous cholecystitis in 4 patients with A-AIH. Hepatic
copper concentration did not exceed 250 μg/g dry weight in any
patient. MRCP at diagnosis was performed in 18 patients, always
with normal finding on biliary ducts; overlap syndrome was not
diagnosed in any of our patients during the follow-up.
A-AIH was diagnosed in 19 children (48%). All except one of
these patients were initially admitted to infectious diseases depart-
ment due to suspicion of acute viral hepatitis, which was, however,
swiftly excluded. The most common signs and symptoms included
fatigue, loss of appetite, abdominal pain, vomiting, icterus and hep-
atomegaly. Fourteen of 19 children with A-AIH (74%) underwent
febrile viral infection of respiratory or gastrointestinal tract within
one month before the hepatitis onset. Patients with A-AIH had sig-
nificantly higher levels of aminotransferases, bilirubin, IgG and INR,
and they had lower serum albumin levels than patients with C-
AIH. A-AIH group had higher scores according to the IAIHG diag-
nostic criteria than the C-AIH group (Table 1).
A total of six patients with A-AIH fulfilled the criteria for
ALF. Five patients with A-AIH (26%) were classified as ALF follow-
ing originally unknown chronic liver disease. Micronodular cirrho-
sis was histologically confirmed in 4 of these patients (Table 2).
Another one patient fulfilled criteria of ALF with coagulopathy,
hepatic encephalopathy and histological findings (see the follow-
ing case). All of these patients developed hepatic encephalopathy
within 28 days after the first clinical symptoms.
A 2-year-old male with history of preceding upper respira-
tory tract infection was admitted due to fatigue, fever and ab-
dominal pain to a regional pediatric department. He was subse-
quently transferred to our tertiary center ICU with deteriorating
level of consciousness and developed systemic inflammatory re-
sponse syndrome (SIRS). The laboratory examination showed signs
of acute hepatitis (ALT 1447 IU/L; AST 2741 IU/L) with conjugated
hyperbilirubinemia (total bilirubin 163 μmol/L, conjugated bilirubin
134 μmol/L) and coagulopathy (INR 2.01). His IgG level was ele-
vated for age (14.2 g/L) and serum ANA antibodies were positive.
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V. Smolka, O. Tkachyk and J. Ehrmann et al. / Hepatobiliary & Pancreatic Diseases International xxx (xxxx) xxx 3

Table 1 None of the 40 patients with AIH suffered from complica-

Comparison of basic clinical and laboratory characteristics at the time of
tions of portal hypertension. Among patients who underwent liver
diagnosis in patients with A-AIH and C-AIH.
biopsy, histological finding of micronodular cirrhosis was found in
Characteristics A-AIH (n = 19) C-AIH (n = 21) P value 13 children (33%), including 8 children (42%) with A-AIH. Signifi-
Female sex 12 (63%) 14 (67%) 1.000 cantly higher grade of portal and lobular inflammation and fibrosis
Age (yr) 10.8 ± 3.9 10.4 ± 4.5 0.732 was observed in patients with A-AIH than C-AIH patients (Table 1).
Diagnostic criteria A 7-year-old female patient, the only one liver biopsy was
IAIHG score 17.2 ± 2.9 15.3 ± 2.3 0.014
not performed in, fulfilled diagnostic criteria for probable AIH-2
AIH-1 16 (84%) 16 (76%) 0.698
AIH-2 3 (16%) 5 (24%) with presence of anti-LKM antibodies. She underwent viral respi-
Bilirubin (μmol/L) 99.5 ± 87.4 16.7 ± 10.2 <0.001 ratory infection three weeks before admission. Disease onset re-
ALT (U/L) 1158.8 ± 541.0 452.9 ± 441.0 <0.001 sembled acute hepatitis (ALT 1929 IU/L; AST 2035 IU/L; bilirubin
AST (U/L) 1205.9 ± 647.0 300.0 ± 265.0 <0.001
223 μmol/L) with coagulopathy (INR 1.54) and grade I encephalopa-
INR 1.6 ± 0.4 1.2 ± 0.2 <0.001
IgG (g/L) 28.1 ± 11.2 18.7 ± 7.5 0.003 thy. Plasma ammonia level was normal. On admission, she had
GGT (U/L) 120.0 ± 84.0 90.0 ± 60.0 0.235 leukopenia (3.2 × 109 /L) and lymphocytopenia (0.58 × 109 /L) but
Albumin (g/L) 37.9 ± 8.7 44.0 ± 5.2 0.002 normal IgG level (9.5 g/L). MRCP showed acalculous cholecystitis
Histology grade and normal finding on biliary ducts. Aminotransferase levels de-
Portal inflammation 3.2 ± 0.7 1.8 ± 0.6 <0.001
creased within 2 weeks of corticosteroid therapy, but the patient
Lobular damage 2.1 ± 0.9 1.3 ± 0.7 0.001
Fibrosis 3.1 ± 1.4 1.9 ± 1.1 0.011 developed aplastic anemia. She was transferred to Department of
Autoantibodies (%, positive) Hematology, where she achieved AIH remission on immunosupres-
ANA 14 (74%) 11 (52%) 0.288 sive therapy. However, there was no bone marrow response af-
SMA 11 (58%) 8 (38%) 0.350
ter 6 months of therapy, therefore she proceeded to allogeneic
Anti-LKM-1 3 (16%) 3 (14%) 1.000
LC1 1 (5%) 2 (10%) 1.000
hematopoietic stem cell transplant from unrelated donor.
SLA 2 (11%) 2 (10%) 1.000 Thirty-three patients were treated by corticosteroid monother-
pANCA 6 (32%) 4 (19%) 0.473 apy, including 17 patients with A-AIH. Combined treatment was
Data were expressed as number (percentage) or mean ± SD. A-AIH: acute used in 2 children with A-AIH. Disease remission was achieved
autoimmune hepatitis; C-AIH: chronic autoimmune hepatitis; IAIHG: In- within 6 weeks in all patients with A-AIH and C-AIH, includ-
ternational Autoimmune Hepatitis Group; ALT: alanine aminotransferase; ing those with cirrhosis. No complications of cirrhosis were ob-
AST: aspartate aminotransferase; GGT: gamma-glutamyltransferase; INR: served, no surgical procedures including liver transplantation were
international normalized ratio; IgG: immunoglobulin G; ANA: antinuclear
required and all patients with cirrhosis are alive and followed with
antibodies; SMA: smooth muscle antibodies; anti-LKM: liver/kidney micro-
some antibodies; LC1: liver cytosol antibodies; SLA: soluble liver antigen a stable liver condition.
antibodies; ANCA: antineutrophil cytoplasmic antibodies.
Discussion

The patient had grade 2 encephalopathy with slow alpha and theta
activity on electroencephalography (EEG). Abdominal ultrasound
revealed acalculous cholecystitis. Histology detected lymphoplas-
macytic periportal inflammation, massive hepatic necrosis (MHN)
including centrilobular necrosis and presence of cholestasis with-
out involvement of biliary ducts. These findings corresponded to
the MHN5 pattern, which is typical for AI-ALF in adult patients [5].
Immunophenotyping of liver tissue demonstrated histiocytic acti-
vation with high positivity of CD3+ T-lymphocytes. After diagnosis
of probable AIH and exclusion of different etiology leading to ALF,
treatment with corticosteroids was administered, which led to the
achievement of remission.
Contrarily, in 21 patients with silent C-AIH, no preceding febrile
infections were reported. Elevated aminotransferase levels were
found incidentally during examinations indicated either due to
non-specific complaints, e.g. weight loss/failure to thrive, tiredness,
abdominal pain or headache, or even due to unrelated indications.
AIH is a rare disease with variable clinical, laboratory and histo-
logical manifestations. The onset of acute AIH involves either acute
exacerbation of previously unrecognized chronic liver condition, or
acute liver disease without chronical changes on histology. Strin-
gent clinical, biochemical and duration criteria for A-AIH diagnosis
in children and adolescents are still lacking. In our cohort, approx-
imately one half of the patients presented with acute disease on-
set resembling initial signs and symptoms of viral hepatitis; this
is in accordance with published data [1]. The majority of our pa-
tients underwent respiratory or gastrointestinal viral infection. In
such cases, even clinically insignificant infections may have trig-
gered the acute exacerbation of previously silent chronic liver dis-
ease and led to severe liver dysfunction.
Only one of our A-AIH patients had AI-ALF with ANA seroposi-
tivity (AIH-1). However, previous studies of larger pediatric cohorts
with AI-ALF reported predominance of AIH-2 [7,8]. AI-ALF is diffi-
cult to diagnose and can be easily missed due to its rarity. Not all

Table 2
Characteristics of patients with acute liver failure (ALF) following chronic liver disease.

Characteristics Case 1 Case 2 Case 3 Case 4 Case 5

Sex Female Female Female Male Male

Age (yr) 14 11 11 9 13
INR 2.07 2.19 1.82 1.79 1.60
Bilirubin (total/conjugated,μmol/L) 67/48 140/46 56/30 29/17 86/65
ALT (U/L) 380.6 548.2 1205.9 1423.5 1664.1
AST (U/L) 557.6 711.8 1280.0 1185.3 1670.0
IgG (g/L) 44.6 46.3 30.4 34.9 29.6
Antibodies detected ANA, ANCA ANA, ANCA ANA, SMA SMA, SLA ANA , ANCA , f-actin
Histology Micronodular Micronodular Micronodular Micronodular Portal inflammation (grade III)
cirrhosis cirrhosis cirrhosis cirrhosis Lobular damage (grade III)
Fibrosis (grade I)
Encephalopathy grade 2 1 1 1 1

ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibodies; SMA: smooth muscle antibodies; SLA: soluble liver antigen antibodies.

Please cite this article as: V. Smolka, O. Tkachyk and J. Ehrmann et al., Acute onset of autoimmune hepatitis in children and adolescents,
Hepatobiliary & Pancreatic Diseases International, https://doi.org/10.1016/j.hbpd.2019.08.004
JID: HBPD
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diagnostic criteria are necessarily met in fulminant AIH and con-
trariwise, some of the criteria may be fulfilled in other causes of
ALF; e.g., autoantibodies specific for both AIH types were present
in 20% children with ALF of different etiology [9]. Probability of
AIH increases with the number of detected autoantibodies [10].
Analogously, IgG levels may be normal in patients with AI-ALF
[8,11] and increased in other causes of ALF [12].
Histology in children with AI-ALF is non-specific and does
not help to differentiate between AI-ALF and other ALF. MHN4-
MHN5 pattern is not more frequent in AI-ALF than in ALF of dif-
ferent etiology [7]. In adult patients, presence of lymphoid fol-
licles, a plasma cell-enriched inflammatory infiltrate and central
perivenulitis was seen in addition to massive hepatic necrosis [4].
In our patient with concurrent A-AIH and aplastic anemia, clin-
ical and biochemical data suggested an autoimmune etiology and
possible diagnosis of hepatitis-associated aplastic anemia (HAA).
Lymphocytopenia at diagnosis could have indicated the risk of lat-
ter hematologic complication. In contrast with published findings
in HAA [13], speckled ANA pattern was missing and liver histology
was not performed in our patient. Successful treatment of hepati-
tis may not prevent the development of aplastic anemia and sub-
sequent need for hematopoietic stem cell transplant [14].
In contrast with previous studies of adult patients [11,15,16], no
differences regarding age and autoantibody profile were observed
between A-AIH and C-AIH groups in our pediatric cohort. Differ-
ent proportions of ANA-positivity in A-AIH vs. C-AIH in adults were
reported [15,17]. Significantly higher IgG levels in patients with A-
AIH reflect an increased inflammatory activity and greater extent
of fibrous changes. All evaluated histological markers were inferior
in our patients with A-AIH. Liver cirrhosis was found in approxi-
mately one third of children at the time of AIH diagnosis, more fre-
quently in patients with A-AIH. Significantly higher IAIHG score in
A-AIH patients might testify a more aggressive and longer course
of disease prior to diagnosis. In a multicentric study reporting mild
disease onset in the majority of patients, 20% of children had cir-
rhosis at the time of diagnosis [18], which is similar to our data.
Trend to higher proportion of AIH-1 within the A-AIH group is also
in accordance with literature [8].
Six of our patients with A-AIH (32%) fulfilled the criteria for
ALF. If definition of Asian Pacific Association for the Study of Liver
for acute-on-chronic liver failure (ACLF) [19] was applied, three of
these patients would not fulfill the ALF criteria due to their biliru-
binemia under 85 μmol/L. However, this definition was tailored to
adult patients and it can underestimate the ACLF occurrence in
children. In a pediatric study of ACLF in developing countries, Wil-
son disease and AIH were the most prevalent causes of chronic
liver damage and hepatitis E and A infections served as ACLF trig-
gers in endemic regions [20]. ACLF is associated with multiorgan
failure and mortality, where high Sequential Organ Failure Assess-
ment (SOFA) score and INR are negative predictors of outcome
[21]. However, it is still unclear how to evaluate pediatric patients
with previously undiagnosed chronic liver condition, who fulfill di-
agnostic criteria for ALF during the first acute manifestation [22].
Final conclusion is based upon histological finding, however, liver
biopsy at acute phase may confer high-risk of severe complications
and thus is frequently postponed.
Prognosis of A-AIH is mainly determined by timely start of im-
munosuppression, which reduces the need for urgent liver trans-
plantation and improves outcomes in children with AI-ALF [11].
Different etiology of liver disease must be strictly excluded prior
to corticosteroid therapy, otherwise the administration of steroids
may lead to increased morbidity and mortality [23]. Superior treat-
ment response is associated with lower grade of encephalopathy
[24]. All of our patients with A-AIH and C-AIH responded to corti-
costeroids and achieved initial disease remission regardless of their
histology result.
Please cite this article as: V. Smolka, O. Tkachyk and J. Ehrmann et al., Acute onset of autoimmune hepatitis in children and adolescents,
Hepatobiliary & Pancreatic Diseases International, https://doi.org/10.1016/j.hbpd.2019.08.004
[m5G;August 29, 2019;19:31]
This study has several limitations. First is the retrospective na-
ture of the study, which included patients diagnosed within a long-
time span. The number of patients is relatively small and they
were recruited from a single-center. IAIHG score was used for pa-
tient enrollment at the beginning of study; however, if validated
simplified diagnostic criteria [24] were used, number of diagnosed
AI-ALF cases may have been higher, as was shown both in children
and adult patients [24,25].
In conclusion, up to one half of pediatric AIH cases mani-
fest as acute hepatitis and their diagnosis may be difficult - pre-
dominantly in patients with fulminant disease course, where not
all of the diagnostic criteria are necessarily met. Without timely
diagnosis and immunosuppressive treatment, A-AIH can rapidly
evolve into severe hepatic dysfunction with necessity of urgent
liver transplantation. According to the published data, AI-ALF is
more common than originally assumed. In children over 1 year of
age fulfilling the ALF definition, AI-ALF diagnosis has to be consid-
ered after exclusion of hepatotropic infections and Wilson disease
[7].
CRediT authorship contribution statement
Vratislav Smolka: Data curation, Writing - original draft, For-
mal analysis, Writing - original draft. Oksana Tkachyk: Data cu-
ration, Writing - original draft. Jiri Ehrmann: Methodology, Writ-
ing - original draft. Eva Karaskova: Data curation, Writing - origi-
nal draft. Martin Zapalka: Formal analysis, Writing - original draft.
Jana Volejnikova: Writing - original draft, Formal analysis, Writing
- original draft.
Acknowledgement
We thank Dr. Pavla Kourilova for statistical analysis.
Funding
This work was supported by grants from the European Re-
gional Development Fund - Project ENOCH (CZ.02.1.01/0.0/0.0/
16_019/0 0 0 0868) and the Ministry of Health, Czech Republic –
conceptual development of research organization (MH DRO; grant
FNOL, 0098892).
Ethical approval
This study was approved by the Ethics Committee of the
Palacky University and University Hospital Olomouc.
Competing interest
No benefits in any form have been received or will be received
from a commercial party related directly or indirectly to the sub-
ject of this article.
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