CASE REPORT

published: 31 July 2019

doi: 10.3389/fped.2019.00310

Overlap Syndrome Involving

Systemic Lupus Erythematosus and
Autoimmune Hepatitis in Children: A
Case Report and Literature Review
Wan-Tz Lai 1† , Wan-Hua Cho 2† , Hock-Liew Eng 3 , Ming-Hui Kuo 1 and Fu-Chen Huang 1*
1
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine,
Kaohsiung, Taiwan, 2 Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University
Edited by: College of Medicine, Kaohsiung, Taiwan, 3 Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital,
Pascal Lapierre, Chang Gung University College of Medicine, Kaohsiung, Taiwan
University of Montreal Hospital Centre
(CRCHUM), Canada
Reviewed by: Background: The diagnosis of overlap syndrome involving systemic lupus
Isabel Gonçalves Costa, erythematosus (SLE) and autoimmune hepatitis (AIH) is not easily established because
Hospital and University Center of
Coimbra, Portugal
of its similar clinical presentations and biochemical features to those of lupus hepatitis.
Tudor Lucian Pop, The term overlap syndrome is usually used in the context of overlap of autoimmune
Iuliu HaT, ieganu University of Medicine hepatitis with PSC (primary sclerosing cholangitis) or PBC (primary biliary cholangitis).
and Pharmacy, Romania
Victor Manuel Navas-López, Few cases of AIH complicated by SLE have been reported in the literature, and the
Hospital Materno-Infantil, Spain condition is even rarer in childhood.
*Correspondence:
Case presentation: Here we report the case of a 16-year-old girl with SLE who initially
Fu-Chen Huang
huang817@cgmh.org.tw presented with autoimmune (cholestatic) hepatitis. According to American Association
† These for the Study of Liver Diseases practice guidelines, the diagnosis was made based on
authors have contributed
equally to this work aggregated scores including female (+2); ALP:AST (or ALT) ratio <1.5(+2); elevated
serum IgG level(+3); ANA > 1:80 (+3); negative hepatitis viral markers and drug history
Specialty section:
(+3, +1); average alcohol intake <25 g/day (+2); and histological interface hepatitis
This article was submitted to
Pediatric Gastroenterology, features (+3). She then developed a malar rash, ANA positivity, anti-double-stranded
Hepatology and Nutrition, DNA (anti-dsDNA) antibodies, and a low complement level. She met 4 of 17 Systemic
a section of the journal
Frontiers in Pediatrics
Lupus International Collaborating Clinics classification criteria (1) for SLE. Our patient
Received: 13 November 2018
responded very well to corticosteroid at an initial dose of methylprednisolone 40 mg
Accepted: 09 July 2019 Q12H for 4 days tapering to 1 mg/kg/day according to liver function test results and
Published: 31 July 2019
bilirubin level. No relapse occurred during the 3-year follow-up course.
Citation:
Lai W-T, Cho W-H, Eng H-L, Kuo M-H Conclusions: Overlapping of SLE and AIH should be suspected when children with SLE
and Huang F-C (2019) Overlap have impaired liver function or AIH patients present with a malar or other skin rash. Liver
Syndrome Involving Systemic Lupus
Erythematosus and Autoimmune
biopsy plays an important role in establishing the differential diagnosis of SLE with liver
Hepatitis in Children: A Case Report impairment or overlap with AIH. The prompt diagnosis and adequate further treatment
and Literature Review. plans can improve disease outcomes.
Front. Pediatr. 7:310.
doi: 10.3389/fped.2019.00310 Keywords: overlap syndrome, childhood, systemic lupus erythematosus, autoimmune hepatitis, jaundice

Frontiers in Pediatrics | www.frontiersin.org 1 July 2019 | Volume 7 | Article 310

Lai et al. SLE Overlap Syndrome

BACKGROUND saturation, 100% on room air. Physically, she looked normal

at the time when the icteric sclera were observed. No
Systemic lupus erythematosus (SLE) is a systemic autoimmune lymphadenopathy or neck mass was palpated. The chest
disease characterized by multiple clinical features and expanded symmetrically and the breathing sounds were clear;
autoantibody series; its diagnostic criteria have been her heart sounds were regular without an audible murmur; the
modified over the past 40 years with discoveries regarding abdomen was soft and the bowel sounds were normal while mild
its pathophysiology and clinical nature (2) SLE affects the central dull pain was noted over the right upper quadrant. No cyanosis
nervous system, cardiovascular system, lungs, liver, kidneys, or pitting edema over the extremities was noted. Laboratory
joints, and skin (3). tests revealed no leukocytosis (white blood cell count, 5,400/µL)
Autoimmune hepatitis (AIH) presents as generally unresolved but anemia (hemoglobin, 10.5 g/dL). Elevated direct bilirubin
inflammation of the liver of unknown cause and it is (8.69 mg/dL), total bilirubin (11.6 mg/dL), AST (931 U/L),
characterized by autoantibodies, hypergammaglobulinemia, and ALT (507 U/L), hypoalbuminemia (2.8 g/dL), gamma-glutamyl
interface hepatitis on histological examination. The diagnosis of transpeptidase (GGT) (23 U/L), alkaline phosphatase (136 U/L),
AIH is based on characteristic clinical and laboratory findings, prolonged prothrombin time (PT; 14.8 s), and activate partial
abnormal serum globulin levels, the presence of one or more thromboplastin time (aPTT; 36 s) were also detected. Under the
characteristic autoantibodies, and histologic abnormalities (4, 5). impression of cholestatic hepatitis, she was admitted for further
AIH–SLE overlap syndrome has not been clearly observation and treatment.
distinguished from lupus hepatitis due to similarities in After admission, ursodeoxycholic acid (100 mg 1pc QID)
their clinical and biochemical features, and few cases of AIH was administered to treat the cholestatic hepatitis. The cause
complicated with SLE have been reported. Due to the rarity of the cholestatic hepatitis was considered: anti-hepatitis A
of the condition, its exact frequency is unclear (6). Here we virus immunoglobulin M (IgM), anti-hepatitis B core antigen
report a case of a patient who presented to our hospital with IgM, hepatitis B surface antigen (enzyme-linked immunosorbent
elevated liver enzymes followed by jaundice 1 month later and assay), anti-hepatitis C virus antibody (Ab), Epstein-Barr
was later found to have AIH and underlying SLE with no viral or virus/cytomegalovirus immunoglobulin G (IgG)/IgM, herpes
drug-related etiology. simplex virus for viral hepatitis were negative. Survey for
Wilson’s disease included serum ceruloplasmin (21.40 mg/dL)
and copper (101.9 µg) were within normal value. Abdominal
CASE PRESENTATION ultrasonography revealed a thick gallbladder wall (0.5 cm) with
pericholecystic fluid accumulation, which may be related to
A 16-year-old girl was admitted to our ward in October
hepatitis. The bilirubin level elevated despite of ursodeoxycholic
2015 complaining of an icteric scleral appearance for 1 week.
acid usage. A follow-up liver function test 3 days later revealed
Accompanying symptoms included intermittent dull abdominal
total bilirubin, 15 mg/dL (direct, 10.96 mg/dL); AST/ALT,
pain over the right upper abdomen and tea-colored urine.
1123/553 U/L; GGT, 23 U/L; and albumin, 3.0 g/dL. We also
Tracing back her history, elevated liver enzymes (aspartate
checked her serum iron level to rule out hemochromatosis; an
aminotransferase [AST], 397 U/L and alanine aminotransferase
elevated iron level (212 µg/dL) was found, while total iron
[ALT], 437 U/L) were noticed on the routine health examination
binding capacity (TIBC) and the serum lead concentration were
for junior high school students 1 month before presenting with
in the normal ranges. Tests for hemolysis, including direct
jaundice. She had no history of alcohol abuse, viral infections,
and indirect Coombs’ test, peripheral blood (PB) smear, red
or exposure to blood products. No fever, nausea or vomiting,
blood cell (RBC) fragility test, and reticulocyte results were
or clay-colored stool was observed during this period, and no
all negative, while a peripheral blood smear revealed rouleaux
specific medication was taken. She had no new dietary habits,
formation, indicating endothelial injury. Autoimmune disease
recent travel history, or contact with sick individuals. There was
was tentatively diagnosed by antinuclear antibody (ANA) titer
no known systemic or hereditary disease. A history of rash after
positivity (1:1,280), a high erythrocyte sedimentation rate (ESR;
taking an unspecified painkiller was mentioned.
92 mm/h), and low C3 and C4 levels (C3, 45.6 mg/dL; C4,
Upon arriving at our emergency department, her vital signs
2.68 mg/dL) as well as negative anti-mitochondrial and smooth
were as follows: body temperature, 36.5◦ C; pulse, 90/min;
muscle Ab test results.
respiratory rate, 20/min; blood pressure, 115/68 mmHg; and
A liver biopsy was performed to screen for AIH. However,
the patient developed a fever of 39.2◦ C after the liver biopsy
Abbreviations: SLE, systemic lupus erythematosus; AIH, autoimmune hepatitis; for which antibiotic therapy of cefazolin was administered.
ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine
aminotransferase; ANA, antinuclear antibody; anti-dsDNA, anti-double-stranded
A generalized maculopapular skin rash developed with
DNA; GGT, gamma-glutamyl transpeptidase; PT, prothrombin time; aPTT, itchiness at the upper extremities after the administration
activate partial thromboplastin time; IgM, immunoglobulin M; Ab, antibody; of acetaminophen. An allergy to acetaminophen was suspected,
IgG, immunoglobulin G; TIBC, total iron binding capacity; PB, peripheral blood; and the rash subsided spontaneously after its discontinuation.
RBC, red blood count; ESR, erythrocyte sedimentation rate; C3, Complement However, a bilateral reddish-purplish facial rash with a
component 3; C4, Complement component 4; SMA, anti-smooth muscle antibody;
anti-LKM1, antiliver kidney microsomal antibody type 1; anti-LC1, anti-liver
butterfly pattern developed 1 day later. This facial malar rash
cytosol type 1; PSC, primary sclerosing cholangitis; PBC, primary biliary persisted during the hospitalization period. Positive anti-ds
cholangitis; ASC, autoimmune sclerosing cholangitis. DNA Ab (242 WHO unit/mL) and IgG 4080 (mg/dL) were

Frontiers in Pediatrics | www.frontiersin.org 2 July 2019 | Volume 7 | Article 310

Lai et al. SLE Overlap Syndrome

reported, while anti-phospholipid Ab and anti-cardiolipin test results were completely normalized in 2 months. The
Ab test results were negative. The pathological report of the patient’s condition remained stable during the last 3 years of
liver biopsy showed features of lobular hepatitis with marked outpatient clinic follow-up without relapse. No renal or central
lymphoplasmacytic infiltration, bridging and confluent necrosis, nervous system involvement of the SLE was noticed. However,
and prominent interface activity, which were compatible with after a 3-year course of treatment, remission of the AIH was
AIH (Figure 1). Albumin was infused for 3 days to correct not achieved (ANA titer, 1:80). The liver function test results
the hypoalbuminemia (1.92 g/dL). Antibiotic therapy with remained in the normal range (AST, 14 U/L; ALT, 7 U/L).
ceftazidime was administered in response to the positive blood Other rheumatic laboratory workups showed a normal complete
culture of Acinetobacter and the fever episodes gradually blood cell count, elevated ESR (40 mm/h), anti-ds DNA Ab
subsided. As the patient met the type I AIH and SLE Systemic (<40.5 WHO unit/mL), normal complement levels (C3 120.0
Lupus Collaborating Clinics (SLICC) diagnostic criteria (1), and C4 15.5 mg/dL). Abdominal sonography showed no evidence
intravenous methylprednisolone 40 mg Q12H was administered of liver fibrosis or cirrhosis. Her maintenance medication
and then tapered according to the liver function test results included prednisolone 5 mg QOD, azathioprine 50 mg QOD, and
and bilirubin level, followed by oral prednisolone 50 mg/day. hydroxychloroquine 200 mg QOD.
Follow-up lab data after a 5-day-course of methylprednisolone
showed improved liver enzymes (AST, 160 U/L; ALT, 226 U/L); DISCUSSION
serum IgG (2,990 mg/dL); total bilirubin, 6.3 mg/dL (direct
bilirubin, 3.96 mg/dL); and anti-dsDNA Ab level (201.3 WHO Once a patient meets the newest SLICC criteria (1) for SLE and
unit/mL). She was discharged with satisfactory clinical remission. International Autoimmune Hepatitis Group scoring for AIH,
The steroid-sparing agent, hydroxychloroquine 200 mg QD AIH–SLE overlap syndrome should be considered. According to
was administered to treat SLE since the first pediatric rheumatic the American Association for the Study of Liver Diseases practice
outpatient clinic follow-up. Over 2 months, moon face developed guidelines, a revised original scoring system of the International
and her body weight increased from 55 to 66 kg, and another Autoimmune Hepatitis Group for the diagnosis of AIH was
steroid-sparing agent azathioprine 50 mg/day was administered established (5, 7). In our case, AIH was diagnosed based on the
after 6 weeks of steroid treatment in parallel with the decreasing aggregate scores including female sex (+2), ALP:AST (or ALT)
ESR and remission of the facial malar rash. The prednisolone ratio < 1.5 (136:931 or 136:507) (+2), elevated serum globulin
was gradually decreased to a maintenance dose of 5 mg/day or IgG (> 2.0×) (+3), ANA, SMA (anti-SM Ab) or liver kidney
in 3 months. An 80% reduction in transaminase levels was microsome type 1 > 1:80 (+3), negative hepatitis viral markers
achieved by 4 weeks of treatment, while the liver function (+3), negative drug history (+1), average alcohol intake <25

FIGURE 1 | Pathological findings of the liver biopsy showed marked lymphoplasmocytic infiltration (LPI), bridging necrosis (BN) and confluent necrosis (CN), and
prominent interface activity (IH), findings compatible with autoimmune hepatitis.

Frontiers in Pediatrics | www.frontiersin.org 3 July 2019 | Volume 7 | Article 310

Lai et al. SLE Overlap Syndrome

g/day (+2), and histological features of interface hepatitis (+3). nonalcoholic fatty liver disease, hepatic arteritis, and nodular
The pre-treatment aggregate score was 19 total points, which regenerative hyperplasia (20, 21). However, AIH is an
indicated a definite diagnosis, and 21 total points for the post- autoimmune disease with liver inflammation whose exact
treatment aggregate score (+2) because of complete treatment cause remains unclear.
response). According to serology, AIH is further subdivided into Lupus hepatitis and AIH–SLE overlap syndrome have not
2 types: type 1 positive for anti-nuclear antibody (ANA) and/or been clearly differentiated due to similarities in their clinical
antismooth muscle antibody (SMA), while AIH-2 is positive for and biochemical features; however, this is important since their
antiliver kidney microsomal antibody type 1 (anti-LKM1) and/or complications and therapies differ. Compared to hepatitis in the
anti-liver cytosol type 1 (anti-LC1) (8, 9). setting of SLE, AIH–SLE overlap syndrome has a more aggressive
Classification as having SLE by the SLICC criteria (1) requires histological pattern and untreated AIH has a poor prognosis
that a patient satisfy at least 4 of 17 criteria, including at least 1 (5-year survival rate, 50%; 10-year survival rate, 10%). High-dose
of the 11 clinical criteria and one of the six immunologic criteria, prednisone (1–2 mg/kg daily) is administered for up to 2 weeks to
or biopsy-proven lupus nephritis in the presence of antinuclear treat AIH-SLE overlap syndrome, while lupus hepatitis is treated
antibodies (ANA) or anti-double-stranded DNA (dsDNA) with non-steroidal anti-inflammatory drugs, corticosteroids, and
antibodies. Our patient met 4 criteria of the SLICC criteria immunomodulators (3, 22).
for SLE proposed in 2012 by the Systemic Lupus Collaborating Due to its numerous similarities with lupus hepatitis, AIH was
Clinics (1), including acute cutaneous lupus erythematosus, previously called lupoid hepatitis, while histological examination
positive ANA titer, positive anti-dsDNA Ab on 2 occasions, of the liver shows specific changes in AIH. In AIH, the typical
and low complement level (C3, C4, or CH50). Therefore, the histological feature of AIH is interface hepatitis, characterized
diagnosis of AIH–SLE overlap syndrome was established. by a dense inflammatory infiltrate composed of lymphocytes
The therapeutic management of SLE is highly individualized and plasma cells, which crosses the limiting plate and invades
and is based on clinical condition, including predominant disease the surrounding parenchyma (9). Other common histological
manifestations, disease activity and severity, organ involvement, finding include panlobular hepatitis with bridging necrosis
and previous treatment response. Among patients with SLE (9). Some features may also suggest the diagnosis of AIH is
with any degree and type of disease activity, administration emperipolesis and liver cell rosette formation (9, 18). These
of hydroxychloroquine or chloroquine was suggested, unless features appear in AIH but not lupus hepatitis. In contrast to
these agents are contraindicated (10, 11). The benefits of AIH, lupus hepatitis presents as lobular hepatitis, atrophy and
hydroxychloroquine or chloroquine in SLE include relief of necrosis of the central hepatic cells, fatty infiltration, and an
musculoskeletal manifestations, constitutional symptoms, and inflammatory infiltrate consisting mainly of lymphocytes. Lupus
mucocutaneous manifestations (10). Also, hydroxychloroquine is hepatitis patients frequently have a positive test for ribosomal
steroid-sparing agent. Additional therapy, such as non-steroidal P antibody (21, 23), and there appears to be an association of
anti-inflammatory drugs, or glucocorticoids, is based upon the antiribosomal P antibody and lupus hepatitis (24). In short, AIH
severity of disease and the combination of manifestations. has a more aggressive histological pattern than the majority of
Overlap syndrome was usually used in the context of cases of hepatitis in SLE (25). The liver biopsy in our case revealed
overlap of autoimmune hepatitis with primary sclerosing prominent interface activity, acute lobular hepatitis with bridging
cholangitis (PSC) or primary biliary cholangitis (PBC), also called and confluent necrosis, and an inflammatory infiltrate consisting
autoimmune sclerosing cholangitis (ASC). Although the case of lymphocytes and few plasma cells, which support the diagnosis
number is few, overlapping case of SLE and AIH has been of AIH.
occasionally diagnosed and reported (12, 13). Pediatric sclerosing AIH–SLE overlap syndrome reportedly responds rapidly
cholangitis also has autoimmune features similar to AIH type 1, to steroid therapy and has a generally good prognosis (6).
and the differential diagnosis depends on cholangiography (8). However, there have been no randomized controlled treatment
The co-occurrence of AIH and SLE is rare, especially in the trials in children with AIH, and very few reports have
pediatric population (3, 14). The reveal prevalence of overlapping documented the efficacy of regimens similar to those used
SLE and AIH still remained unknown. Balbi et al. (15) reported in adults (5). For children, prednisone is the preferred
in multicenter cohort study that AIH in pediatric SLE patients regimen and usually administered initially at a dose of 1–2
confirmed by biopsy was observed in 7/847 (0.8%) and all were mg/kg daily (maximum 60 mg daily), but tapering schedules
diagnosed during adolescence. The majority occurred before or vary. Moreover, the early administration of azathioprine (1–2
at SLE diagnosis [5/7 (71%)]. Irving et al. (16) reported incidence mg/kg daily) or 6-mercaptopurine (1.5 mg/kg daily) for
of AIH is 11.6% (42.1% of the patients with GIS involvement), all children without contraindications is also recommended
and the incidence of AIH was significantly higher in children because of the significant deleterious side effects of long-term
than adults (9.8 vs. 1.3%; p < 0.001). A case series and review intermediate- or high-dose corticosteroid therapy on linear
of the literature by Beisel et al summarized previous cases of growth, bone development, and physical appearance (5). In 2016,
overlap syndrome (17). All of the pediatric cases reported to date Czaja presented new treatment guidelines for AIH in which
including ours are summarized in Table 1. prednisone or a combination of prednisolone and azathioprine
SLE patients have a 25–50% chance of developing abnormal is the mainstay of therapy (4). Mieli-Vergani (8) reported
liver test function in their lifetime, and the most common in 2018 that the conventional treatment of AIH consists of
causes include hepatotoxic drug use, coincident viral hepatitis, prednisolone, and the timing for the addition of azathioprine

Frontiers in Pediatrics | www.frontiersin.org 4 July 2019 | Volume 7 | Article 310

Lai et al. SLE Overlap Syndrome

TABLE 1 | Summary of pediatric case reports in literature.

References Age Sex Clinical presentation Treatment Time of follow-up Outcomes

Mackay et al. (18) 16 F Failure to thrive, jaundice, non-erosive Cortisone Not reported Progression
arthritis, oral aphthous lesions
Usta et al. (3) 12 F Jaundice, hepatosplenomegaly, Prednisolone 3 years Stationary
polyarthralgia, malaise, arthritis, Hydroxychloroquine
butterfly-type facial erythema Chloroquine
Deen et al. (19) 13 M Articular involvement, cardiopulmonary Prednisolone Not reported Remission
involvement Azathioprine
Chloroquine
13 F Splenomegaly, articular involvement Prednisolone Not reported Remission
Azathioprine
Chloroquine
17 F Jaundice, ascites, cutaneous involvement, Prednisolone Not reported Remission
proteinuria > 0.5 g/day, cardiopulmonary Azathioprine
involvement Chloroquine
11 F Jaundice, cutaneous involvement, articular Prednisolone Not reported Remission
involvement, proteinuria > 0.5 g/day, Azathioprine
cardiopulmonary involvement Chloroquine
Lai et al. (2015) 16 F Jaundice, cholestatic hepatitis, malaise, Prednisolone 3 years Remission
butterfly-type facial erythema Azathioprine
Hydroxychloroquine
Battagliotti et al. (13) 16 F Jaundice, renal and articular involvement, Prednisolone 2 years Remission
butterfly-type facial erythema Mycophenolate mofetil

Revised from the Table 1 of Beisel et al. (17).

as a steroid-sparing agent varies according to the protocol with good response to immunosuppressive treatment and
used in the different centers. Approximately, 85% of the good prognosis of AIH. Since the case number is still few,
patients eventually require the addition of azathioprine despite further discussion should be done if more cases reported in
using which kind of protocol. Budesonide, mycophenolate the future.
mofetil, and calcineurin inhibitors can also be considered in
selected patients as frontline or salvage therapies. Our patient
responded very well to corticosteroid therapy (initial dose, CONCLUSION
1 mg/kg/day), and the initial intravenous methylprednisolone
40 mg Q12H for 4 days was soon tapered to oral prednisone For children with SLE and impaired liver function, screening
1 mg/kg/day. for AIH should be considered because these two can occur
Martínez Casas et al. (26) reported that adult patients with together as overlap syndrome. Vice versa, Overlapping
AIH-PBC had greater progression to cirrhosis (22.2 vs. 13.1%, of SLE and AIH should be suspected when AIH patients
p = 0.038), even in those who achieved partial or complete present with a malar or other skin rash. Liver biopsy plays
biochemical remission without relapse. Also these adult patients an important role in establishing the differential diagnosis
had greater indication of orthotopic liver transplantation (p = of SLE with liver impairment or overlap with AIH. The
0.009), but no differences in mortality. However, Rodrigues et al. prompt diagnosis and adjustment of further treatment
(27) reported statistically significant difference of prognosis and plans can improve disease outcomes and prevent liver
response to treatment was observed between the pediatric AIH disease progression.
and ASC groups.
According to previous studies of overlap syndrome, disease
relapse is common, and long-term low-dose prednisone or ETHICS STATEMENT
azathioprine therapy remains the treatment of choice after
multiple relapses (3). After previous relapse and retreatment, This patient and her parents provided all of the clinical
28% of patients can achieve a treatment-free state (28). Only and laboratory information and samples and agreed to the
a small minority of patients will progress to cirrhosis and case publication.
require liver transplantation. Despite the disease severity at
presentation, the response to corticosteroids with or without
azathioprine is generally excellent in children (3, 5). However, CONSENT TO PUBLISH
there seems to be a non–relapsing association in the case
reports of AIH-SLE overlapping in the recent years. Sönmez Written informed consent was obtained from the patient for
et al. (12) reported 8 pediatric SLE-AIH overlapping patients publication of this case report and any accompanying images.

Frontiers in Pediatrics | www.frontiersin.org 5 July 2019 | Volume 7 | Article 310

Lai et al. SLE Overlap Syndrome

AUTHOR CONTRIBUTIONS manuscript as submitted and agree to be accountable for all

aspects of the work.
W-TL and W-HC drafted the initial manuscript, designed the
study, interpreted the data, screened the literature, and approved
the final manuscript for submission. W-TL and W-HC are equal ACKNOWLEDGMENTS
contributors in this study. H-LE interpreted the specimen and
provided recommendations for this manuscript. M-HK provided We sincerely thank the patient and her parents for providing
recommendations for this manuscript. F-CH conceptualized the all of the clinical and laboratory information and samples.
study, reviewed and revised the manuscript, and approved the This study was partly supported by grants from Chang Gung
final manuscript for submission. All authors approved the final Memorial Hospital, Taiwan.

REFERENCES 17. Beisel C, Weiler-Normann C, Teufel A, Lohse AW. Association

of autoimmune hepatitis and systemic lupus erythematodes:a case
1. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. series and review of the literature. World J Gastroenterol. (2014)
Derivation and validation of the systemic lupus international collaborating 20:12662–7. doi: 10.3748/wjg.v20.i35.12662
clinics classification criteria for systemic lupus erythematosus. Arthritis 18. Mackay IR, Taft LI, Cowling DC. Lupoid hepatitis and the
Rheum. (2012) 64:2677–86. doi: 10.1002/art.34473 hepatic lesions of systemic lupus erythematosus. Lancet. (1959)
2. Yu C, Gershwin ME, Chang C. Diagnostic criteria for systemic 1:65–9. doi: 10.1016/S0140-6736(59)91136-5
lupus erythematosus:a critical review. J Autoimmune. (2014) 19. Deen MEJ, Porta G, Fiorot FJ, Campos LMA, Sallum AME, Silva CAA.
48–49:10–3. doi: 10.1016/j.jaut.2014.01.004 Autoimmune hepatitis and juvenile systemic lupus erythematosus. Lupus.
3. Usta Y, Gurakan F, Akcoren Z, Ozen S. An overlap syndrome involving (2009) 18:747–51. doi: 10.1177/0961203308100559
autoimmune hepatitis and systemic lupus erythematosus in childhood. World 20. van Hoek B. The spectrum of liver disease in systemic lupus erythematosus.
J Gastroenterol. (2007) 13:2764–7. doi: 10.3748/wjg.v13.i19.2764 Neth J Med. (1996) 48:244–53. doi: 10.1016/0300-2977(96)00003-4
4. Czaja AJ. Diagnosis and management of autoimmune hepatitis: current status 21. Matsumoto T, Kobayashi S, Shimizu H, Nakajima M, Watanabe S, Kitami
and future directions. Gut Liver. (2016) 10:177–203. doi: 10.5009/gnl15352 N, et al. The liver in collagen diseases: pathologic study of 160 cases with
5. Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, particular reference to hepatic arteritis, primary biliary cirrhosis, autoimmune
et al. Diagnosis and management of autoimmune hepatitis. Hepatology. (2010) hepatitis and nodular regenerative hyperplasia of the liver. Liver. (2000)
51:2193–213. doi: 10.1002/hep.23584 20:366–73. doi: 10.1034/j.1600-0676.2000.020005366.x
6. Tojo J, Ohira H, Abe K, Yokokawa J, Takiguchi J, Rai T, et al. Autoimmune 22. Kooy A, de Heide LJM, Engelkens HJH, Mulder AH, van Hagen M, Schalm
hepatitis accompanied by systemic lupus erythematosus. Intern Med. (2004) SW. Hepatitis in a patient with SLE: is it autoimmune hepatitis? Neth J Med.
43:258–62. doi: 10.2169/internalmedicine.43.258 (1996) 48:128–32. doi: 10.1016/0300-2977(95)00072-0
7. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, 23. Wallace DJ, Hahn BH. Gastrointestinal and Hepatic Manifestations. Dubois’
et al. International autoimmune hepatitis group report: review of criteria for lupus Erythematosus and Related Syndromes. Philadelphia, PA: Elsevier (2013).
diagnosis of autoimmune hepatitis. J Hepatol. (1999) 31:929–38. p. 422.
8. Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi 24. Ohira H, Takiguchi J, Rai T, Abe K, Yokokawa J, Sato Y, et al.
A, et al. Diagnosis and management of pediatric autoimmune liver disease: High frequency of anti-ribosomal P antibody in patients with systemic
ESPGHAN hepatology committee position statement. J Pediatr Gastroenterol lupus erythematosus-associated hepatitis. Hepatol Res. (2004) 28:137–
Nutr. (2018) 66:345–60. doi: 10.1097/MPG.0000000000001801 39. doi: 10.1016/j.hepres.2003.11.008
9. Sokollik C, McLin VA, Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani 25. Kaw R, Gota C, Bennett A, Barnes D, Calabrese L. Lupus-related hepatitis:
G. Juvenile autoimmune hepatitis: a comprehensive review. Journal of complication of lupus or autoimmune association? Case report and review of
Autoimmunity. (2018) 95:69–76. doi: 10.1016/j.jaut.2018.10.007 the literature. Dig Dis Sci. (2006) 51:813–8. doi: 10.1007/s10620-006-3212-1
10. Belmont HM. Treatment of systemic lupus erythematosus - 2013 update. Bull 26. Martínez Casas OY, Díaz Ramírez GS, Marín Zuluaga JI, Santos Ó, Muñoz
Hosp Jt Dis. (2013) 71:208–13. Maya O, Donado Gómez JH, et al. Autoimmune hepatitis — Primary
11. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta biliary cholangitis overlap syndrome. Long-term outcomes of a retrospective
MA. Clinical efficacy and side effects of antimalarials in systemic cohort in a university hospital. Gastroenterol Hepatol. (2018) 41:544–
lupus erythematosus: a systematic review. Ann Rheum Dis. (2010) 52. doi: 10.1016/j.gastre.2018.11.006
69:20. doi: 10.1136/ard.2008.101766 27. Rodrigues AT, Liu PM, Fagundes ED, Queiroz TC, de Souza Haueisen
12. Sönmez HE, Karhan AN, Batu ED, Bilginer Y, Gümüş E, Barbosa P, Silva SL, et al. Clinical characteristics and prognosis in children
Demir H, et al. Gastrointestinal system manifestations in and adolescents with autoimmune hepatitis and overlap syndrome. J
juvenile systemic lupus erythematosus. Clin Rheumatol. (2017) Pediatr Gastroenterol Nutr. (2016) 63:76–81. doi: 10.1097/MPG.0000000000
36:1521–6. doi: 10.1007/s10067-017-3571-3 001125
13. Battagliotti C, Rispolo Klubek D, Karakachoff M, Costaguta A. 28. Feldman M, Friedman L, Brandt L. Sleisenger and Fordtran’s Gastrointestinal
An overlap syndrome involving systemic lupus erythematosus and and Liver Disease:Pathophysiology, Diagnosis, Management, Expert Consult
autoimmune hepatitis in an adolescent girl. Arch Argent Pediatr. (2016) Premium Edition-Enhanced Online Features. Philadelphia, PA: Elsevier Health
114:e155–8. doi: 10.5546/aap.2016.eng.e155 Sciences (2010).
14. Matsumoto T, Yoshimine T, Shimouchi K, Shiotu H, Kuwabara N, Fukuda
Y, et al. The liver in systemic lupus erythematosus:pathologic analysis of Conflict of Interest Statement: The authors declare that the research was
52 cases and review of Japanese Autopsy Registry Data. Hum Pathol. (1992) conducted in the absence of any commercial or financial relationships that could
23:1151–8. doi: 10.1016/0046-8177(92)90033-Y be construed as a potential conflict of interest.
15. Balbi VA, Montenegro B, Pitta AC, Schmidt AR, Farhat SC, Coelho
LP, et al. Autoimmune hepatitis in 847 childhood-onset systemic lupus Copyright © 2019 Lai, Cho, Eng, Kuo and Huang. This is an open-access article
erythematosus population: a multicentric cohort study. Adv Rheumatol. distributed under the terms of the Creative Commons Attribution License (CC BY).
(2018) 58:43. doi: 10.1186/s42358-018-0043-7 The use, distribution or reproduction in other forums is permitted, provided the
16. Irving KS, Sen D, Tahir H, Pilkington C, Isenberg DA. A comparison of original author(s) and the copyright owner(s) are credited and that the original
autoimmune liver disease in juvenile and adult populations with systemic publication in this journal is cited, in accordance with accepted academic practice.
lupus erythematosus-a retrospective review of cases. Rheumatology. (2007) No use, distribution or reproduction is permitted which does not comply with these
46:1171–3. doi: 10.1093/rheumatology/kem108 terms.

Frontiers in Pediatrics | www.frontiersin.org 6 July 2019 | Volume 7 | Article 310