J Pediatr Endocrinol Metab 2019; aop
Case Report
Tiago Jeronimo Dos Santos*, Caroline Gouvêa Buff Passone, Marina Ybarra,
Simone Sakura Ito, Milena Gurgel Teles, Thais Della Manna and Durval Damiani
Pitfalls in the diagnosis of insulin autoimmune
syndrome (Hirata’s disease) in a hypoglycemic
child: a case report and review of the literature
https://doi.org/10.1515/jpem-2018-0441
Received October 17, 2018; accepted January 29, 2019
Abstract
Background: Insulin autoimmune syndrome (IAS) is a
rare cause of hyperinsulinemic hypoglycemia (HH) not
addressed as a potential differential diagnosis in current
pediatric guidelines. We present a case of IAS in a child
with no previous history of autoimmune disease, no pre-
vious intake of triggering medications and absence of
genetic predisposition.
Case presentation: A 6-year-old boy presented with recur-
rent HH (blood glucose of 26  mg/dL [1.4  mmol/L] and
insulin of 686 μU/mL). Abdominal imaging was normal.
After multiple therapeutic failures, we hypothesized
misuse of exogenous insulin and factitious hypoglycemia.
Council of Guardianship had the child separated from his
mother, but insulin levels remained high. A chromatogra-
phy test was then performed which showed high titers of
endogenous insulin autoantibody (IAA) with early disso-
ciation from the insulin molecule. The human l­eukocyte
antigen (HLA) test showed a DRB1 *13:01/*08:02 geno-
type. The patient was advised to control food intake and
physical activity routines. During a 5-year follow-up,
*Corresponding author: Dr. Tiago Jeronimo Dos Santos, MD, MPH,
Pediatric Endocrinology Unit, Instituto da Criança, Hospital das
Clínicas, Faculdade de Medicina, Universidade de São Paulo,
Av. Dr. Enéas Carvalho de Aguiar, 647 – 7°, Andar, CEP 05403-000,
São Paulo/SP, Brazil, E-mail: tiagojer@gmail.com.
https://orcid.org/0000-0001-9682-0289
Caroline Gouvêa Buff Passone, Marina Ybarra, Simone Sakura Ito,
Thais Della Manna and Durval Damiani: Pediatric Endocrinology
Unit, Instituto da Criança, Hospital das Clínicas, Faculdade de
Medicina, Universidade de São Paulo, São Paulo/SP, Brazil
Milena Gurgel Teles: Unidade de Diabetes/Unidade de Genética
(LIM/25), Disciplina de Endocrinologia, Faculdade de Medicina,
Universidade de São Paulo (USP), São Paulo/SP, Brazil; and
Diabetes Center, Fleury Institute, São Paulo/SP, Brazil
hypoglycemic episodes were sparse, despite high insulin
levels.
Conclusions: Misdiagnosis of IAS with factitious hypogly-
cemia may happen if IAS is not considered as a differential
diagnosis, leading to potential traumatic consequences.
Further efforts should be made to increase awareness of
IAS as a differential diagnosis of hypoglycemia and to
include it in pediatric guidelines.
Keywords: hyperinsulinemia; hypoglycemia; insulin anti-
body; insulin autoimmune syndrome.
Background
Insulin autoimmune syndrome (IAS) – Hirata’s disease
– is a rare cause of hyperinsulinemic hypoglycemia (HH)
in children, with an uncertain prevalence [1]. Most of the
described cases were associated with either concomi-
tant autoimmune conditions or assumption of previous
use of drugs containing sulfur/sulfhydryl groups [2]. A
wide range of clinical manifestations were described,
though the hallmarks for the diagnosis are: (i) develop-
ment of a spontaneous non-ketotic HH state; (ii) marked
high titers of insulin levels (insulin/C-peptide molar
ratio >1); (iii) presence of positive insulin autoantibody
(IAA); and (iv) never being previously exposed to insulin
therapy [1, 2].
The episodes of hypoglycemia are triggered when the
steady bound of the endogenous antibody and the native
insulin molecule, during the pre-prandial state, dissoci-
ates at the immediate postprandial state [2]. Current pedi-
atric guidelines do not include IAS as a possible cause of
hypoglycemia, although it is mentioned in current adult
guidelines [3, 4]. Some pediatric cases reported a facti-
tious cause as a differential diagnosis, but most of them
had an underlying condition [1, 5–14].
We report a case of IAS with no previous history of
autoimmune disease, no previous intake of triggering
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2      Dos Santos et al.: Insulin autoimmune syndrome in childhood

medications and absence of genetic predisposition, and
review the existing literature on IAS in the pediatric age.
We also propose a flowchart approach to hypoglycemia
in children that could be adopted in current pediatric
guidelines.
Case presentation
A 6-year-old Brazilian boy, with combined European,
Native and African ancestry, presented with symptomatic
hypoglycemia. He was born preterm at 34  weeks, with a
birth weight of 3040 g (97th percentile) and an Apgar score
of 7 and 8 at 1 and 5 min of life, respectively. At the first
48  h of life, the patient presented hypoglycemia, which
was promptly resolved with oral glucose. His mother had
type 2 diabetes mellitus, with outset during the gesta-
tional period, on irregular use of oral antidiabetics and
insulin therapy. No other familial carbohydrate disorders
were revealed. At 7 months of age, the patient presented
with seizures and was started on anticonvulsants (phe-
nobarbital and carbamazepine) with good control of the
seizures and proper patterns of neuropsychological devel-
opment. At the age of 5, one episode of seizure occurred
and was associated with HH (blood glucose: 12  mg/
dL [1.16  mmol/L] and insulin: 34.7 μU/mL); he was then
referred for a broader evaluation in our clinic.
On physical examination, no midline defects or dys-
morphic features were observed; he had proportional
limbs and trunk, normal penis size with descended testes,
no pubertal signs and no signs of acanthosis nigricans.
His height was 117 cm (0.27 standard deviation [SD]) and
his weight was 28 kg (1.83 SD), with a body mass index
of 20.5 kg/m2 (2.20 SD). Laboratory i­nvestigation at a full
hypoglycemic episode showed serum glucose of 26 mg/dL
(1.4 mmol/L), insulin of 686 μU/mL (chemiluminescence
immunoassay), C-peptide of 0.5 ng/mL, ammonia of
39  μmol/L (normal range [NR]: 16–60), lactate of
8.8 mg/dL (NR: 9–22), blood gas with pH of 7.33 and bicar-
bonate of 20.4 mmol/L, insulin-like growth factor 1 (IGF-1)
of 155 ng/mL (NR: 58–338) and cortisol of 12.3 μg/dL (NR:
5–25), with normal transaminases. Beta-hydroxybutyrate
and free-fat acid were unavailable. Abdominal and hypo-
thalamus-pituitary magnetic resonances were normal.
As our hypothesis at that moment was HH, he was
started on oral diazoxide (maximum dosage 20 mg/kg per
day), and owing to the recurrence, we also prescribed sub-
cutaneous octreotide and glucagon, and oral hydrochloro-
thiazide, with no effective control. Given the unexpected
high insulin level, we suspected of misuse of exogenous
insulin and admitted him for further evaluation. During
admission, we asked for Council of Guardianship to sepa-
rate the child from his mother, hypothesizing she would
be giving the insulin to her boy. Blood samples across hos-
pitalization, however, continued with similar results. The
extended oral glucose tolerance test (OGTT) evidenced an
extremely high insulin level, and not suppressed C-peptide
level (Table 1). Proinsulin measure was unavailable in our
lab. Yet we measured insulin secretagogues, including sul-
fonylurea, which were negative. The IAA was higher than
500 IU/mL (expected value: less than 1.1 IU/mL, radioim-
munoassay, RSR Insulin Ab RIA Assay kit, UK) in multiple
blood samples during different phases of hypoglycemia, as
well as during fasting, few hours after a meal or after an
extended OGTT. The very high insulin antibody titers led
us to suspect of IAS. Next, we carried out a gel-filtration

Table 1: Extended oral glucose tolerance test (OGTT) responses after 1.75 g/kg performed in three different occasions: A, at the first week of
hospitalization; B, at the third week of hospitalization; C, 2 months after discharged.

A.   0  30′  60′  90′  120′  180′

Glycemia, mg/dL (mmol/L)  33 (1.8)  91 (5.0)  79 (4.4)  55 (3.0)  65 (3.6)  21 (1.2)

C-peptide, ng/mL   1.5  –  1.5  1.3  1.3  1.2
Insulin, μIU/mL   >1000  –  >1000  >1000  >1000  >1000

B.   0  60′  90′  120′  150′  180′

Glycemia, mg/dL (mmol/L)   89 (4.9)  71 (3.9)  112 (6.2)  84 (4.7)  75 (4.2)  74 (4.1)
C-peptide, ng/mL   –  3.1  5.2  3.7  2.0  1.8
Insulin, μIU/mL   –  550  781  652  514  407

C.   0  60′  120′  180′  240′  300′  360′

Glycemia, mg/dL (mmol/L)  94 (5.2)  121 (6.7)  100 (5.5)  104 (5.8)  108 (5.9)  77 (4.3)  100 (5.5)
C-peptide, ng/mL   2.1  4.4  3.4  –  3.6  1.6  1.8
Insulin, μIU/mL   214  350  300  306  291  176  172

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 Dos Santos et al.: Insulin autoimmune syndrome in childhood      3
chromatography (GFC) test (Sigma Aldrich, Saint Louis,
MO, USA), which revealed the presence of endogenous
insulin antibody (Figure 1). Lastly, we performed a human
leukocyte antigen (HLA) test, which showed a DRB1
*13:01/*08:02 genotype. Screening for viral infections was
negative, and for other autoimmune conditions were as the
following: anti-tyrosine phosphatase antibody (IA2) (RSR
Limited, Llanishen, Cardiff, UK) <94 U/mL (NR: <125 U/mL),
anti-glutamic acid decarboxylase (GAD) (RSR Limited,
Llanishen, Cardiff, UK) <25 U/mL (NR: <25 U/mL), anti-
endomysium antibody (Immco Diagnostics, The Hague,
The Netherlands) <1/10, thyroid stimulating hormone
receptor antibody (TRAb) (Roche Diagnostics GmbH, Man-
nheim, Germany) <0.3 (NR: <1.75 U/L), anti-thyroperoxidase
antibody (Beckman Coulter, Brea, CA, USA) of 3 U/L (NR:
<9  U/L), anti-thyroglobulin antibody (Beckman Coulter,
Brea, CA, USA) <4 U/L (NR: <4 U/L).
With these results, the hypothesis of factitious hypo-
glycemia was rejected and so the patient was reunited
with his mother. He was advised to eat every 3  h prefer-
ably low glycemic index food and vigorous physical activi-
ties were contraindicated. These recommendations led
to fewer symptomatic hypoglycemic episodes. At the age
of 11, he maintained a high insulin level (149 μU/mL),
normal blood sugar (88 mg/dL [4.9 mmol/L]) and normal
C-­peptide level (2.4 ng/mL). We did not perform another
IAA test since then. No other symptomatic or proven HH
episodes have occurred so far.
60
Normal ins – 142
Patient ins – 201
40
Insulin, mUI/mL
20
0 We were able to rule out a likely association between
5 10 15 20
Tube
Figure 1: Gel-filtration chromatography study (Superdex Peptide
0.9 × 30 cm) in one single sample depicts that the patient’s “insulin
molecule” elutes early (tube 11) due to its higher molecular weight
(insulin molecule and insulin antibody in cluster) compared with a
normal insulin molecule (tube 14).
Serum glucose in sample: 63 mg/dL (3.5 mmol/L).
Ethics statement was obtained by one relative at the
first visit, as recommended by the Institutional Review
Board of our hospital.
Discussion
The present case report demonstrates the importance of
having spontaneous endogenous IAA as a differential
diagnosis of hypoglycemia in children and the poten-
tial hazardous consequences of not having it. After HH
treatment failure and imaging workup showing no insu-
linoma, our impression was that the boy was receiving
surreptitious insulin from his mother, as she had access to
insulin due to her diabetes condition. We, therefore, rec-
ommended keeping him separated from her. The absence
of decrease in insulin levels and improvement in his clini-
cal status with such a drastic measure, along with the
demonstration of endogenous IAA, allowed us to initiate
a proper management.
HH demands prompt detection and treatment to avoid
brain sequelae [3, 15]. IAS is not often described in children
and, most of the time, it overlaps with other autoimmune
conditions, especially with type 1 diabetes, but it can also
be triggered by infections or by the use of medications
containing sulfhydryl group [2, 8, 9]. Table 2 summarizes
a review of the literature on IAS among children. Since
1973, when the first case was described in Japan, the clini-
cal manifestations, age of onset, biochemical and genetic
profiles, workup and follow-up have been very heteroge-
neous, what may prevent a standardized approach.
From our case report, we highlight three key clinical
aspects that can be present in the diagnosis of IAS. Firstly,
high insulin levels can be found in a patient without signs
of insulin resistance and only occasional hypoglycemic
episodes. Secondly, in a child who (supposedly) had
never received insulin, it is possible to have high insulin
levels presented not simultaneously with hypoglycemic
symptoms, but concomitantly with the positivity of IAA.
And lastly, decision-making may be tough to exclude the
hypothesis of the previous inadvertent misuse of insulin
as etiology.
previous exposure to exogenous insulin molecule
and the onset of the disease, known as “Hirata-like
disease”, because (i) the t1/2 of the available exogenous
insulin on plasma cannot exceed more than 24  h and
(ii) the mother and patient were split apart for more
than 24  h during admission and insulin levels did not
decrease [9]. On follow-up, the patient did not require
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 Table 2: Review of previous reported cases with regard to IAS by country in the pediatric age.

Country   Year of   Ethnic   Sex   Age of onset   Underlying disease   Insulin on plasma   Anti-insulin antibody   HLA haplotype   Treatment and
(reference) publication background and method and method Evolution

Japan   (a) 1973   (a) NR   (a) Female   (a) 3 days   (a) Hypo­glycemia due   (a) 4143 μU/mL (free   (a) 1.82 BI/FI (bound   (a) NR   (a) Multiple artificial
(a. Nakagawa) to the presence insulin: 3.7 μU/ insulin/free feeding plus
of the antibody mL) by direct insulin – normal 1-month course
produced in two antibody value: 0.00) of prednisolone
her mother’s methods: with Sephadex therapy
body against immuno-reactive chromatography
endogenous insulin (IRI)
insulin and
transferred
to the patient
trans­placen­
tally, despite no
previous history of
insulin injection of
her or her mother
(b. Uchigata) (b) 1993 (b) Japanese (b) Two cases (b) Authors (b) No previous (b) serum IRI (>1000 (b) High titer of (b) HLA- (b) NR
were mention the history of pmol/L) antibody bound DRB1*0406/
female range of age receiving to human insulin DQA1*0301/
4      Dos Santos et al.: Insulin autoimmune syndrome in childhood

and one between 0 and methimazole nor (>30% [1251] DQB1*0302

was male 19 years, alpha-mercapto- insulin binding)
propionyl-glycine
Brazil (Alves)   2013   NR   Female   7 years   Non-ketotic fasting   5.6 μIU/mL   6.2% (normal, <2.4%)  HLA-   Spontaneous
hypoglycemia DRB1*1104 resolution of the
during treatment hypoglycemia,
for pneumonia with within 30 days, with
ceftriaxone and normalization of serum
oxacillin anti-insulin titers,
although therapy with
hydrocortisone was
started (bronchospasm
and a severe
urticarial allergic
reaction). Patient
died of multiple
organ dysfunctions
secondary to sepsis

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 Table 2 (continued)

Country   Year of   Ethnic   Sex   Age of onset   Underlying disease   Insulin on plasma   Anti-insulin antibody   HLA haplotype   Treatment and
(reference) publication background and method and method Evolution

Turkey (Savas-   2014   NR   Female   16 years   No history of chronic   379 mIU/mL (direct   41.8% (normal range:   NR   Controlled by a low-
Erdeve) disease or medication chemiluminescent 0–7%) carbohydrate diet, but
use technology) mildly symptomatic
hypoglycemia
occurred in the case of
noncompliance with
the diet
Australia   2016   African   Male   9 years   Type 1 diabetes   NR   High IA titer (>18 U,   HLA DR4 status   A combination of
(Sharwood) and Kawasaki normal <0.7) by 125I- was negative immune-suppressive
disease, treated (A14) human insulin therapies, including
with intravenous immunoprecipitation glucocorticoids,
immunoglobulin assay mycophenolate, high-
Anti-insulin receptor dose immunoglobulin
antibody negative and rituximab,
besides regular use
of therapeutic plasma
exchange
Argentina   2013   Caucasian   Male   12 years   Type 1 diabetes   NR   Binding rate: 48.2%   NR   After 10 years of
(Trabucchi) since 18 months, (cut-off value = 3.28%) evolution, the patient
with severe signs of by surface plasmon continued with regular
lipodystrophy in the resonance (SPR) metabolic control and
insulin injection sites technology lipodystrophy
USA   (a) 1979   (a) NR   (a) Male   (a) First symptoms   (a) No evidence   (a) 2
 54 μU/mL to   (a) 3.46 BI/FI (bound   (a) NR   (a) Appropriate
(a. Goldman) during the of exogenous >1000 μU/mL insulin/free glucagon response
neonatal insulin, though insulin – normal to hypoglycemia
period; a differential value: 0.00)
diagnosis at diagnosis between with Sephadex
25 months old factitious and chromatography
autoimmune
hypoglycemia
remained
(b. Gomez Cruz) (b) 2012 (b) African (b) Male (b) 16 years (b) Graves’ disease (b) 1184.5 pmol/L (b) At >50 U/mL (b) NR (b) Persistent
American and started on (reference range: (reference range: hypoglycemia was
methimazole 21.5–200.9 <0.4 U/mL managed with
4 weeks later pmol/L) prednisone and
diazoxide during
6 months when
antibodies

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Dos Santos et al.: Insulin autoimmune syndrome in childhood      5
 Table 2 (continued)

Country   Year of   Ethnic   Sex   Age of onset   Underlying disease   Insulin on plasma   Anti-insulin antibody   HLA haplotype   Treatment and
(reference) publication background and method and method Evolution

 levels decreased
to normal levels
(0.01 nmol/L)
South Korea   2013   Korean   Female   15 years   Graves’ disease and   238.2 μU/mL   Anti-insulin antibody   DRB1*04:06.   Treated with
(Lee) was being treated titer of >100 U/mL corticosteroid for
with methimazole (normal, <5 U/mL) 2 months. The
insulin antibody
titer decreased
dramatically, and
she did not have
any episode of
hypoglycemia since
then
Italy (Meschi)   1991   NR   Male   5 years   Recurrence of   6138–10,722 pM   62%–87%, insulin   NR   Several hypoglycemic
hypoglycemic (normal below binding at 1:80 serum episodes (some
symptoms and high 25 pM) dilution cases with loss of
titers of Insulin RIA (normal: below 5% for consciousness)
6      Dos Santos et al.: Insulin autoimmune syndrome in childhood

antibodies during undiluted serum) Treatment with

Spain (Rovira)   1982  
10 years prednisolone was
followed by a decrease
in antibody titer that
lasted for 2 years
NR   Male   4 years   The child had never   NR   NR   NR   After 17 months,
received insulin during which the
injections child remained
Presence of ketone asymptomatic, insulin
bodies in the urine antibodies could not
be detected in his
plasma

IAS, insulin autoimmune syndrome; HLA, human leucocyte antigen; NR, not reported: RIA, radioimmunoassay.

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 Dos Santos et al.: Insulin autoimmune syndrome in childhood      7
any course of corticosteroids or immunosuppressant,
neither plasma exchange. The number of hypoglycemic
episodes decreased as the immunoreactivity of insulin
downturned.
Variations in the genetic background and the pres-
ence of a polyclonal (instead of a monoclonal) pattern of
anti-insulin antibody were described in East-Asian and
Caucasian patients [1, 8, 10, 16]. In our patient, the HLA
profile was different from most of the previously pub-
lished cases, including a Brazilian one [8]. Our patient
did not have tested the protein profile pattern of the anti-
insulin antibody, so we cannot rule out monoclonality.
In an effort to increase the likelihood of diagnosing
IAS, we suggest that every child who presents with sympto-
matic hypoglycemia, elevated insulin value and who is not
receiving any trigger medication (e.g. containing sulfhydryl
groups), neither suffering from an acute illness, nor an auto-
immune disease, should have the IAA quantified. If IAA is
positive, an interference or a false-negative assay should be
excluded, by means of the GFC test, which is considered the
gold standard method for the detection of immunoglobulin-
bound macro-analyses [17]. We find appropriate to perform
a GFC test because higher titers of insulin level with anti-
insulin antibodies may interfere and mislead pancreatic
assays [2]. Whilst Sharwood et  al. proposed an algorithm
for the investigation of unexplained glycemic instability
and frequent and/or severe hypoglycemia in type 1 diabe-
tes patients [13], we propose a flowchart approach to assess
hypoglycemia in childhood, regardless of the clinical back-
ground (Supplementary Material, Figure 1 and Ref. [18]).
The novelty of this case is that the extremely high
insulin level and the mother history of diabetes led us to
hypothesize misuse of exogenous insulin before consid-
ering IAS. Therefore, we suggest that current guidelines
should advise that non-diabetic and non-acutely ill indi-
viduals with an unexplained cause of hypoglycemia be
tested for endogenous insulin antibody.
Learning points
1. IAS should be considered as a differential diagnosis
in patients with HH refractory to treatment.
2. The diagnosis of “Hirata-like disease” can be excluded
if insulin levels do not decrease after mother and
patient are separated after more than 24 h, since the
t1/2 of the available exogenous insulin on plasma can-
not exceed more than 24 h.
3. In a child who (supposedly) had never received
insulin, it is possible to have high insulin levels pre-
sented not simultaneously with hypoglycemic symp-
toms, but concomitantly with the positivity of IAA.
What’s new?
1. We present a case of IAS in a child with no previous
history of autoimmune disease, no previous intake
of triggering medications and absence of genetic
predisposition.
2. The unusual approach to explain an unexpected high
insulin value by means of searching for false posi-
tives, interfering types of insulin assays and presence
of endogenous insulin antibody.
3. The proposal of a flowchart for recognizing uncom-
mon cases of hypoglycemia among children.
Acknowledgments: The authors want to acknowledge
Leandra Steinmetz, MD, MSc, Hilton Kuperman, MD, PhD,
Hamilton Menezes, MD, Louise Cominato, MD, MSc, and
Ruth Rocha Franco, MD, MSc, all medical staff at the Chil-
dren’s Institute – University of São Paulo, for their assis-
tance in the case and contribution to solve the diagnosis
during grand rounds. Our recognitions to Roberta Sal-
vodelli, MD, PhD, and Débora Athaíde Menezes, MD, for
their contribution with patient care, and previous poster
presentation in medical meetings, respectively. Also to
Prince Kevin Danieles for proofreading this manuscript
and Andraea Von Hulst, RN, PhD, and Luiz Fernando
Ybarra, MD, MBA, PhD, for proofreading and reviewing
this manuscript. Our special acknowledgments to Fleury
Laboratory team, particularly to Claudia Maria Ferrer and
Teresinha Tamie Tachibana, for their availability to accept
to perform a non-routine experiment like the chromatog-
raphy test.
Author contributions: All the authors have accepted
responsibility for the entire content of this submitted
manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s)
played no role in the study design; in the collection,
analysis, and interpretation of data; in the writing of
the report; or in the decision to submit the report for
publication.
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Supplementary Material: The online version of this article offers
supplementary material (https://doi.org/10.1515/jpem-2018-0441).
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