ArticlePDF Available

Increasing Co-occurrence of Additional Autoimmune Disorders at Diabetes Type 1 Onset Among Children and Adolescents Diagnosed in Years 2010–2018—Single-Center Study

Frontiers
Frontiers in Endocrinology
Authors:

Abstract and Figures

Objectives: The prevalence of type 1 diabetes mellitus (T1D) in children is growing, but its relation to other autoimmune disorders that coexist since the onset of diabetes is not recognized. The objective of this study was to assess the incidence of T1D and the prevalence of autoimmune illnesses additionally coexisting since the diabetes mellitus onset in children during a period of 9 years' observation. Methods: In this retrospective study, the incidence rate (IR) of the T1D was calculated as the total number of all cases that were newly diagnosed per 100,000 population people between 0 and 18 years of age. The selected age groups (0–4, 5–9, 10–14, and 15–18 years) were examined, respectively. The studied group included 493 children (264 [53.55%] boys) between 0 and 18 years old newly diagnosed with T1D in one of the Polish centers in the years 2010–2018. Other autoimmune illnesses diagnoses were obtained from medical records taken from the first hospital treatment, when T1D was recognized. Results: The annual standardized IR of T1D increased from 19.2/100,000 in year 2010 to 31.7/100,000 in 2018 (1.7-fold over 9 years' observation), with an increase in the incidence rate ratio (IRR) by 4% per year. The highest growth in IR was recorded in 5- to 9-year-olds (from 19.61 in 2010 to 43.45 in 2018). In 61 (12.4%) of the studied group, at least one additional autoimmune disease was diagnosed. The prevalence doubled from 10.4% in the year 2010 to 20.8% in the year 2018. Autoimmune thyroid illnesses were found in 37 children (7.5%); their incidence increased from 6.3% to almost 2-fold, 12.5%, in 2018. In 26 children (5.3%), celiac disease was recognized; the prevalence increased from 4.2 to 9.8% in the study period. The prevalence of additional autoimmune thyroid disease was higher in glutamic acid decarboxylase–positive antibodies (χ2 = 3.4, p = 0.04) patients, the oldest age group (15–18 years) (χ2 =7.1, p = 0.06), and in girls (χ2 =7.1, p = 0.007). Conclusions:The standardized IR of T1D in children increased 1.7-fold over the 9-year observation period, and IRR increased 4% per year. Additional autoimmunity represents a significant comorbidity in patients with new-onset T1D. The number of children diagnosed with additional autoimmune diseases that accompany T1D is rapidly growing in all age groups throughout recent years.
Content may be subject to copyright.
ORIGINAL RESEARCH
published: 06 August 2020
doi: 10.3389/fendo.2020.00476
Frontiers in Endocrinology | www.frontiersin.org 1August 2020 | Volume 11 | Article 476
Edited by:
Aneta Monika Gawlik,
Medical University of Silesia, Poland
Reviewed by:
Maurizio Delvecchio,
Giovanni XXIII Children’s Hospital, Italy
George Paltoglou,
National and Kapodistrian University
of Athens, Greece
*Correspondence:
Barbara Głowi ´
nska-Olszewska
barbara.glowinska-olszewska
@umb.edu.pl
Specialty section:
This article was submitted to
Pediatric Endocrinology,
a section of the journal
Frontiers in Endocrinology
Received: 04 April 2020
Accepted: 17 June 2020
Published: 06 August 2020
Citation:
Głowi ´
nska-Olszewska B,
Szabłowski M, Panas P, ˙
Zoł ¸adek K,
Jamiołkowska-Sztabkowska M,
Milewska AJ, Kadłubiska A,
Polkowska A, Łuczy ´
nski W and
Bossowski A (2020) Increasing
Co-occurrence of Additional
Autoimmune Disorders at Diabetes
Type 1 Onset Among Children and
Adolescents Diagnosed in Years
2010–2018—Single-Center Study.
Front. Endocrinol. 11:476.
doi: 10.3389/fendo.2020.00476
Increasing Co-occurrence of
Additional Autoimmune Disorders at
Diabetes Type 1 Onset Among
Children and Adolescents Diagnosed
in Years 2010–2018—Single-Center
Study
Barbara Głowi ´
nska-Olszewska 1
*, Maciej Szabłowski1, Patrycja Panas 1, Karolina ˙
Zoł ¸adek 1,
Milena Jamiołkowska-Sztabkowska 1, 2, Anna Justyna Milewska 3, Anna Kadłubiska 1,
Agnieszka Polkowska 1, Włodzimierz Łuczy ´
nski 1,4 and Artur Bossowski 1
1Department of Pediatrics, Endocrinology, Diabetology With Cardiology Division, Medical University of Bialystok, Białystok,
Poland, 2Department of Pediatrics, Rheumatology, Immunology and Metabolic Bone Diseases, Medical University of
Bialystok, Białystok, Poland, 3Department of Statistics and Medical Informatics, Medical University of Bialystok, Białystok,
Poland, 4Department of Medical Simulations, Medical University of Bialystok, Białystok, Poland
Objectives: The prevalence of type 1 diabetes mellitus (T1D) in children is growing, but
its relation to other autoimmune disorders that coexist since the onset of diabetes is
not recognized. The objective of this study was to assess the incidence of T1D and the
prevalence of autoimmune illnesses additionally coexisting since the diabetes mellitus
onset in children during a period of 9 years’ observation.
Methods: In this retrospective study, the incidence rate (IR) of the T1D was calculated
as the total number of all cases that were newly diagnosed per 100,000 population
people between 0 and 18 years of age. The selected age groups (0–4, 5–9, 10–14, and
15–18 years) were examined, respectively. The studied group included 493 children (264
[53.55%] boys) between 0 and 18 years old newly diagnosed with T1D in one of the Polish
centers in the years 2010–2018. Other autoimmune illnesses diagnoses were obtained
from medical records taken from the first hospital treatment, when T1D was recognized.
Results: The annual standardized IR of T1D increased from 19.2/100,000 in year 2010
to 31.7/100,000 in 2018 (1.7-fold over 9 years’ observation), with an increase in the
incidence rate ratio (IRR) by 4% per year. The highest growth in IR was recorded in 5- to
9-year-olds (from 19.61 in 2010 to 43.45 in 2018). In 61 (12.4%) of the studied group,
at least one additional autoimmune disease was diagnosed. The prevalence doubled
from 10.4% in the year 2010 to 20.8% in the year 2018. Autoimmune thyroid illnesses
were found in 37 children (7.5%); their incidence increased from 6.3% to almost 2-fold,
12.5%, in 2018. In 26 children (5.3%), celiac disease was recognized; the prevalence
increased from 4.2 to 9.8% in the study period. The prevalence of additional autoimmune
thyroid disease was higher in glutamic acid decarboxylase–positive antibodies (χ2=3.4,
p=0.04) patients, the oldest age group (15–18 years) (χ2=7.1, p=0.06), and in girls
(χ2=7.1, p=0.007).
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
Conclusions: The standardized IR of T1D in children increased 1.7-fold over the
9-year observation period, and IRR increased 4% per year. Additional autoimmunity
represents a significant comorbidity in patients with new-onset T1D. The number of
children diagnosed with additional autoimmune diseases that accompany T1D is rapidly
growing in all age groups throughout recent years.
Keywords: diabetes type 1, autoimmune thyroid diseases, celiac disease, children, epidemiology
INTRODUCTION
The prevalence of type 1 diabetes mellitus (T1D) has received
much attention lately, and the rapid increase in the number
of patients should not be disregarded. According to the ninth
edition of IDF Diabetes Atlas 2019 (1), it is estimated that
1,110,100 young people younger than 20 years have T1D
worldwide. Type 1 diabetes incidence in children increases by 2–
5% annually worldwide, according to large epidemiologic studies
(2), and it depends on the geographic region; for example,
in Asian countries, the incidence rates (IRs) are usually very
low (3), whereas the rates in some European countries, for
example, Finland, are indisputably high (4). In European cases,
the incidence among girls is currently the highest in the age group
between 5 and 9 years, whereas that of boys is highest in the
10- to 14-years age group (5). In years 2010–2014 in Poland,
incidence rate ratio (IRR) increased 1.5-fold (by 12.73% annually)
in children and adolescents aged 0–17 years (6).
It has been reported recently, among them in meta-
analysis, that frequency of autoimmune diseases (AD) in
general, has increased significantly over the last 30 years, with
thorough research of risk factors and environmental impacts
on susceptibility to AD (7,8). The global prevalence of AD in
pediatric age is 5%, and the most frequent autoimmunities are
represented by autoimmune thyroid diseases (AITDs) (9). The
incidence of autoimmune hypothyroidism in children is rated
at 1–2% with a dominance of female 4:1 (10). Even subclinical
course of the disease is known to result in many adverse effects
such as increased risk of congestive cardiac failure and coronary
heart disease events. What is more, subclinical hypothyroidism is
likely to cause cognitive impairment and non-specific symptoms,
for example, fatigue and mood changes (11). Hyperthyroidism
constitutes 15% of children’s thyroid disorders, and most of
the cases can be attributed to hyperthyroidism of autoimmune
origin, Graves disease (GD) (10).
It is now recognized that the prevalence of additional
autoimmunity is increasingly encountered in clinical practice
of pediatric diabetologists. Additional ADs (AADs) frequently
occur in the same individual over the course of T1D,
suggesting strong shared genetic susceptibility and pathological
mechanisms. Patients with T1D demonstrate an increased
exposure to other autoimmune disorders, for example, AITD
(Hashimoto thyroiditis and GD, 15–30%), Addison disease
(0.5%), autoimmune gastritis (5–10%), celiac disease (CD; 4–
9%), and vitiligo (2–10%) (12,13). Revealed high prevalence of
associated autoimmune conditions generated the need for early
screening of these diseases (14).
There is increasing knowledge about the prevalence of AAD
in the course of long-lasting T1D in children with T1D (15,16).
Notably, the association of T1D with other autoimmune illnesses
that coexist from the onset of diabetes and the actual trend of
this connection over the years are not fully recognized. We aimed
to estimate the prevalence of patients diagnosed with the most
common autoimmune disorders: AITD and CD at the diagnosis
of T1D and the changes in prevalence of these diseases during 9
years (2010–2018) observation. Second, we intended to search for
possible clinical factors connected with multiple autoimmunities
since T1D onset. We hypothesized that together with increasing
prevalence of diabetes type 1 in children over the years, the
number of patients diagnosed with AAD will also increase.
PATIENTS AND METHODS
The study was planned as a retrospective, hospital records–based
study including 493 children and adolescents (264 boys and 229
girls, aged 0–18 years), who were diagnosed for T1D between
2010 and 2018 at the Department of Pediatrics, Endocrinology,
Diabetology with Cardiology Division, Medical University of
Białystok, Poland. This is the only center for diabetic children
in the Podlasie Voivodeship Region (northeast part of Poland),
where all young patients with newly diagnosed T1D from the
region are treated. The IR of the T1D was calculated as the
total number of all cases that were newly diagnosed per 100,000
people between 0 and 18 years of age. General population
figure was obtained from the Central Statistical Office of Poland
(Polish: Glowny Urzad Statystyczny) (17). The selected age
groups (0–4, 5–9, 10–14, and 15–18 years) were examined
separately. Laboratory and anthropometric data were obtained
from electronic medical records, body mass index (BMI), and
standard-deviation-score (SDS) for BMI was calculated using
age- and sex-specific BMI growth charts according to local Polish
OLAF study (18).
The diagnosis of T1D was made on the basis of criteria
for diabetes type 1 recognition according to the International
Society for Pediatric and Adolescent Diabetes guidelines: history
of polyuria, polydipsia, and weight loss with an elevated random
plasma glucose of 11.1 mmol/L or fasting plasma glucose of
7 mmol/L (19). Diabetic autoimmunity was confirmed on the
basis of at least one positive titer of autoantibodies to islet
cells (ICAs), glutamic acid decarboxylase (GADA), and also the
protein tyrosine phosphatase (IA2). Analysis was performed in
the same laboratory for all the study period. The diagnosis date
referred to the date of the very first injection of insulin, according
to EURODIAB criteria (20), and our previous publications. The
Frontiers in Endocrinology | www.frontiersin.org 2August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
age of the patients was calculated in completed years on the day
of T1DM diagnosis (21,22).
Serologically screening tests for thyroid autoimmunity
included anti-thyroid peroxidase antibodies (aTPO) and
antithyroglobulin (aTg), and, in cases of hyperthyroidism
suspicion, anti-thyroid stimulating hormone (TSH) antibodies
(TR-Ab). Confirmation of thyroid autoimmunity was based on
the elevated titer of aTPO, aTg, or TR-Ab. Both hypothyroid
and hyperthyroid autoimmunity was taken into consideration.
Children were screened for the thyroid diseases using TSH
and free thyroxine (fT4) levels at the moment of diagnosing.
Furthermore, in each case of newly diagnosed T1D, according
to our local recommendations, thyroid ultrasound has been
performed since 2016. The clinical entities found in AITDs
are diverse and vary depending on whether it is in a state
of autoimmune hypothyroidism (HT, Hashimoto disease) or
hyperthyroidism (GD). Patients suffering from HT represented
clinical and biochemical characteristics of hypothyroidism
and demonstrated an elevated TSH with presence of elevated
anti-TPO and/or aTg autoantibodies. Graves disease was
diagnosed in children with large goiter, hyperthyroidism in
laboratory tests and positive thyrotropin receptor (TR-Ab)
antibodies, anti-TPO antibodies, and aTg antibodies. Subclinical
hypothyroidism, without confirmed autoimmunity, was not
taken into consideration into further analyses. The diagnosis of
AITDs was set on the basis of clinical, laboratory, and ultrasound
investigations and was always set with experienced pediatric
endocrinologist, and pharmacological treatment was introduced
if needed.
To diagnose celiac autoimmunity, anti-tissue
transglutaminase (anti-tTGA) antibodies were performed.
With titer of 10 IU/mL or with questionable results, anti-
endomysial (EMA) and anti-reticulin (ARA) antibodies were
also implemented. In this case, small intestine–associated
autoimmunity was recognized. The CD was diagnosed on the
basis of the revised criteria of CD diagnosis according to the
European Society Pediatric Gastroenterology, Hepatology, and
Nutrition criteria (21,23) and always consulted with experienced
gastroenterologist. Patients positively serologically tested for
tTGA, EMA, and ARA had a gastroscopy performed if needed
for diagnosis. Children recognized with the disease started
gluten-free diet since diabetes onset. We did not test our patients
for Addison disease because it is out of obligatory screening in
Poland. Yet, none of the children represented clinical symptoms
of this or any other ADs that may accompany T1D (gastritis,
vitiligo, etc.).
Laboratory Analyses
The analyses were performed with routine laboratory methods
in hospital laboratory on an ongoing basis. Fasting blood sample
for analysis was collected in the morning. Serum levels of TSH,
fT4, and triiodothyronine (fT3) were assessed with the use of
electrochemiluminescence “ECLIA with Cobas E411 analyzer
(Roche Diagnostics, Warsaw, Poland). Values within the norm
presented the range between 0.28 and 4.3 µIU/L for TSH,
between 1.1 and 1.7 ng/dL for fT4, and between 2.6 and 5.4 ng/dL
for fT3. Anti-TPO, aTg, and TR-Ab antibodies were analyzed in
all samples with the use of ECLIA with Modular Analytics E170
TABLE 1 | General characteristics of the study group.
Parameters at
diagnosis
No. of valid results % of valid results Median [interquartile range] Minimal value Maximal value
Age at diagnosis (years) 493 100.00 9.50 [5.50–12.50] 0.50 18.00
0–4 n=109
5–9 n=151
10–14 n=172
15–18 n=61
HbA1c (%) 369 75 10.70 [9.46–12.42] 6.00 21.0
pH 487 99 7.37 [7.28–7.41] 6.93 7.64
HCO3220 45 16.60 [8.50–20.95] 2.60 43.4
C-peptide (ng/mL) 295 60 0.47 [0.28–0.79] 0.00 1.1
GADA (U/mL)
[86.82%—positive]
433 88 63.20 [8.67–280.03] 0.27 5,775
IA2A (U/mL)
[86%—positive]
434 88 188.05 [8.16–777.51] 0.00 3,626
ICA (JDF U)
[64.91%—positive]
431 87 20.00 [10.00–40.00] 0.00 640
TPO (IU/mL) 474 96 5.00 [5.00–6.90] 5.00 600.00
ATG (IU/mL) 474 96 10.00 [10.00–10.00] 3.15 4,000.00
TTGA (UI/mL) 461 93 10.00 [10.00–10.00] 0.4 1,700
BMI 470 95 15.7 [14.2–18.1] 8.9 35.01
SDS-BMI 429 87 0.43 [1.08 to 0.29] 3.40 5.07
Gender (%), nBoys: 53.55%
n=264
Girls: 46.45%
n=229
Frontiers in Endocrinology | www.frontiersin.org 3August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
analyzer (Roche Diagnostics). The positive values for antithyroid
antibodies were >1.75 U/L for TR-Ab, >34 IU/mL for anti-
TPO-Abs, and >115 IU/mL for aTg-Abs. Tests for beta cells and
thyroid and celiac antibodies were performed after recovery from
ketoacidosis and the initiation of subcutaneous insulin therapy,
usually between the fifth and the seventh day of the child’s stay in
the ward (in our hospital, hospitalization usually lasts 8–10 and
is related to patient’s education).
The study was performed in accordance with the Guidelines
of Good Clinical Practice. The protocol was approved by the
Medical University in Białystok, Poland Bioethical Committee.
Parents/legal guardians and their children both provided their
written informed consent. The study adhered to ethical standards
including ethics committee approval and consent procedure.
Also, standard biosecurity and institutional safety procedures
were adhered to.
Statistical Analysis
The IR of the T1D was calculated as the total number of all cases
that were newly diagnosed per 100,000 population people at 0- to
FIGURE 1 | (A) T1D IR Directly Standardized in years 2010–2018 in all age groups (0–18 y.o.) A incidence rate directly standardized is the number of new cases
occurring in a specified population during a year, expressed as the number of cases per 100,000 population of Podlaskie Voivedeship aged 0–18 yrs, standardized to
the age-matched population of Poland from 2010. Slope =0.948, P=0.057. (B) T1D incidence rate (IR) in years 2010–2018 in certain age groups. A crude
incidence rate is the number of new cases occuring, in a specified population during a year, expressed as the number of cases per 100,000 population of Podlaskie.
Voivodeship in these age groups.
0–4 y.o. slope =0.561, p=0.566.
5–9 y.o slope =1.78, p=0.095.
10–14 y.o slope =1.82, p=0.127.
15–18 y.o slope =1.78, p=0.521.
Frontiers in Endocrinology | www.frontiersin.org 4August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
18-year age per year. A multifactorial Poisson regression model
was made to assess the IRR, depending on age and year. For
the needs of the model for age, dummy variable was created, in
which the 0- to 4-year age group is the base (reference) variable.
Model fit was assessed using the Pearson goodness-of-fit test.
One-way linear regression models were used in the time trend
analysis. For IRR by age group and year, exact Poisson 95%
confidence intervals (CIs) were calculated. The IRs were directly
standardized by age according to the population of Poland 2010.
The prevalence of T1D and additional AID was evaluated using
χ2or Fisher exact test when appropriate. A multiple logistic
regression analysis was used to recognize independent factors
and their influence on additional autoimmunity prevalence. The
odds ratios with 95% CIs were calculated. p-value lower than
0.05 was determined as statistically significant. The results are
presented as mean ±SD, or numbers (n), and percentages (%).
Statistically significant results were found at p<0.05. The data
were calculated using Stata/IC 12.1 package from StataCorp
LP, College Station, TX, USA and STATISTICA 13.0 software,
StatSoft Polska Sp. z o.o. Kraków, Poland.
RESULTS
We analyzed the data from total 493 pediatric patients (264
male and 229 female) aged 0 to 18 years [median (interquartile
range) of age at diagnosis 9.50 (5.50–12.50) years], diagnosed
successively between 2010 and 2018. During the study period,
23 children were diagnosed with other types of diabetes
(11 with maturity-onset diabetes of the young 2, six with
type 2, and six were insulin dependent, but autoantibody
negative—not included into the present analysis as T1D).
Two of our patients were diagnosed with AITD, and one,
CD before the diagnosis of T1D. The general characteristics
of the studied group are presented in Table 1. Mean IR
of T1D among children and adolescent patients during the
study period was 23.78/100,000 age-matched population. We
found that incidence of diabetes mellitus type 1 in Podlaskie
Voivodeship keeps rising. During the time of the study, the
age-standardized annual incidence increased from 19.2/100,000
in 2010 up to 31.7/100,000 in 2018 over 9 years, in total
1.7-fold in the observed period. Annual fluctuations, with
the lowest IR in 2016, were noticed. Time trend analysis
revealed increase in incidence ratio (slope 1.06, p=0.039),
although statistically insignificant when standardized for age
(p=0.057) (Figure 1A). The increase in the IRR was 4%
per year.
We divided the studied population into certain age groups
and assessed the IR one by one. We discovered the growth in
three of the age groups (from 8.22 to 21.08 in group 0–4 years
old; from 19.61 to 43.45 in group 5–9 years old; from 29.26
to 52.01 in group 10–14 years old) and decrease in the oldest
(15–18 years) age group of patients, from 20.16 to 10.95. The
overall upward trend in incidence of T1DM seems to come
from the increase in groups 5–9 years old and 10–14 years old,
in which the rise in IR was the greatest. The lowest mean IR
was found in group 15–18 years old (12.52/100,000), and the
TABLE 2 | Model of Poisson regression for IRR based on a group of 0–4 years old.
Age group (years) IRR (95% CI) P
0–4 Base
5–9 1.37 (1.06–1.75) 0.013
10–14 1.57 (1.23–1.99) 0.000
15–18 0.61 (0.44–0.83) 0.002
Year 1.04 (1.00–1.07) 0.021
Pearson goodness of fit =33.0039.
TABLE 3 | Age-standardized incidence rates (per 100,000 person-years) of type 1
diabetes according to gender.
IR (95% CI) age standardized
Year Girls Boys Total
2010 17.5 (9.8–24.4) 21.2 (13.2–29.2) 19.2 (13.7–24.6)
2011 24.2 (15.2–22.2) 21.3 (13.1–29.4) 22.7 (16.6–28.8)
2012 20.9 (12.5–29.3) 24.2 (15.4–33) 22.6 (16.5–28.7)
2013 21.3 (12.6–29.6) 25.5 (16.4–24.6) 23.5 (17.2–29.7)
2014 23.3 (14.2–32.2) 26.9 (17.4–36.4) 25.1 (15.6–31.7)
2015 19.9 (11.5–28.3) 24.7 (15.7–33.8) 22.4 (16.2–28.3)
2016 21.6 (12.9–30.2) 16.7 (9.2–24.3) 19.1 (13.20–24.8)
2017 29.6 (19.2–39.9) 25.9 (16.5–35.4) 27.7 (20.7–34.7)
2018 25.2 (15.9–34.6) 37.9 (26.7–49.2) 31.7 (24.4–39.1)
highest IR was noticed in group 10–14 years old (32.89/100,000).
In other age groups, it was, respectively, 20.95 in group 0–
4 years old and 28.78 in group 5–9 years old. In the time
trend analysis, we did not prove significant differences when
selected age groups were studied (Figure 1B). The Poisson
regression model adjusted for the year of diagnosis and age
group demonstrated the incidence risk ratio increasing 1.37 in
children aged 5–9 years, 1.57 for children aged 10–14 years,
and 0.61 for children aged 15–18 years. The year of diagnosis
increased the IRR 1.04 times (4%) (Table 2). The differences
in the standardized incidence ratios of diagnosed T1D cases
between male and female were not statistically different and are
presented in Table 3. In Supplementary Table 1, we included the
data of incidence ratios with 95% CI in separated age groups in
every studied year.
Next, we assessed the prevalence of additional autoimmunity
and AD in all new-onset cases of T1D in subsequent years
of analysis. In total, thyroid autoimmunity was recognized in
66 patients (13.39%), and AITD was recognized in 37 patients
(7.51%) during the study period. Celiac autoimmunity was
recognized in 38 patients (7.7%), whereas CD was found in 26
patients (5.3%). We found that general specific autoimmunity
(other than diabetic antibodies) at T1D diagnosis remained stable
during the study period (from 25% of patients in 2010 up to
23.6% in 2018; χ2=1.2 p=0.26). As for AADs (celiac and
AITD), their prevalence fluctuated during the study: it started
from 10.4% in 2010, next increased in years 2012–2014, and then
fell in years 2015–2017 to eventually finish at 20.83% in 2018. In
Frontiers in Endocrinology | www.frontiersin.org 5August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
FIGURE 2 | Prevalence of additional autoimmune diseases (autoimmune thyroid disease and celiac disease) in new-onset type 1 diabetes mellitus patients.
TABLE 4 | Other organ autoimmunity and autoimmune diseases among DMT1 patients aged 0–18 years diagnosed in years 2010–2018.
Annual distribution
Year Total 2010 2011 2012 2013 2014 2015 2016 2017 2018 χ2and
p-value total
χ2and p-value
2010 vs. 2018
T1D, n493 48 54 50 54 57 51 43 61 72
TAI, n
(%)
66
(13.5)
8
(16.6)
10
(18.5)
9
(18.0)
8
(14.8)
6
(10.5)
6
(11.8)
4
(9.3)
5
(8.2)
10
(13.8)
χ2=5.2
p=0.7
χ2=2.3 p=0.12
Y=1.6 p=0.19
Fi p=0.09
TTGA, n
(%)
38
(7.8)
5
(10.4)
7
(13.7)
1
(1.9)
3
(5.6)
6
(10.5)
3
(5.9)
2
(4.6)
4
(6.5)
7
(9.8)
χ2=7.8
p=0.45
χ2=0.4 p=0.50
Y=0.09 p=0.70
Fi p=0.30
AI, n
(%)
99
(20.1)
12
(25)
15
(27.7)
10
(18.8)
10
(18.5)
11
(19.3)
9
(17.6)
6
(13.9)
9
(14.7)
17
(23.6)
χ2=5.7
p=0.68
χ2=1.2 p=0.26
Y=0.7 p=0.37
Fi p=0.18
AITD, n
(%)
37
(7.5)
3
(6.25)
2
(3.7)
7
(13.2)
5
(9.3)
3
(5.3)
3
(5.9)
3
(7)
2
(3.3)
9
(12.5)
χ2=8.7
p=0.36
χ2=1.2 p=0.20
Y=0.6 p=0.40
Fi p=0.20
CD, n
(%)
26
(5.3)
2
(4.2)
1
(1.8)
1
(1.9)
1
(1.8)
6
(10.5)
2
(3.9)
2
(4.6)
4
(6.7)
7
(9.8)
χ2=10.4
p=0.2
χ2=1.3 p=0.20
Y=0.6 p=0.42
Fi p=0.21
AAD, n
(%)
61
(12.4)
5
(10.4)
3
(5.6)
8
(15.1)
6
(11.1)
8
(14.0)
5
(9.8)
5
(11.6)
6
(9.8)
15
(20.8)
χ2=8.5
p=0.38
χ2=2.7 p=0.09
Y=1.9 p=1.50
Fi p=0.07
n, no. of patients; X2- Chi-squared; Y, Yates correction; Fi, Fisher exact test; T1D, type 1 diabetes mellitus; TAI, thyroid-positive autoimmunity; TTGA, anti-tissue transglutaminase
antibodies positive; AI, autoimmunity (thyroid +celiac); AITD, autoimmune thyroid disease; CD, celiac disease; AAD, additional autoimmune disease (total).
the end, this gives a 2-fold increase in the percentage of patients
with AADs during the 9-year study period (Figure 2,Table 4).
In further analysis, considering the frequency of
autoimmunity in T1D age groups, we did not show statistically
significant differences (χ2=1.7, p=0.63). As for AITD, it
was similar; we found higher prevalence of these diseases in
the oldest age group, although it was not statistically significant
(χ2=7.1, p=0.06) (Figure 3). The detailed comparison of
the differences in mean age between additional autoimmunity
“positive” and “negative patients is presented in Table 5. We
Frontiers in Endocrinology | www.frontiersin.org 6August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
FIGURE 3 | Prevalence of autoimmune thyroid disease and celiac disease in new-onset T1D. Comparison between age groups.
TABLE 5 | Mean age at diagnosis of T1D in the groups of “positive” and
“negative” patients in terms of total autoimmunity, AITD, thyroid autoimmunity,
celiac disease, TTGA autoimmunity, and additional autoimmune disease.
Additional
autoimmunity
“positive” patients
Additional
autoimmunity
“negative” patients
p-value
Mean age
Autoimmunity 10.13 ±4.42 8.80 ±4.58 0.009
AITD 11.14 ±4.33 8.91 ±4.56 0.004
Thyroid autoimmunity 10.14 ±4.68 8.92 ±4.55 0.040
Celiac disease 10.69 ±3.52 8.98 ±4.62 0.064
TTGA autoimmunity 10.03 ±4.29 9.02 ±4.59 0.203
Additional autoimmune
disease
10.70 ±3.96 8.85 ±4.62 0.004
found that patients with additional autoimmmune problem,
especially thyroid disease, were significantly older. Thyroid
autoimmunity varied significantly between male (9.13%) and
female (18.5%) (χ2=9.2, p=0.002), as well as thyroid AD
(male 4.55%, female 10.92%, χ2=7.2, p=0.007) (Figure 4).
Such differences were not found for CD.
Finally, we analyzed the prevalence of AAD according to
the presence of GADA antibodies. We discovered that children
with positive anti-GAD antibodies were much more likely to
develop thyroid autoimmunity at diagnosis of T1D than patients
with negative anti-GAD, and this difference was observed
as statistically significant (p=0.024). We also obtained a
significant difference in frequency of AITD between both groups
(p=0.045). As presented in Figure 5, in GADA(+) patients,
8.54% had AITD, and 14.33% had thyroid autoimmunity at
diagnosis of T1D, whereas in GADA(–) patients, it was 3.42 and
6.9%, respectively, p<0.05 (Figure 5). We have also assessed the
possible relationship between the age of patients and the titers of
GADA, ICAs, IA2, and antithyroid antibodies without showing a
statistically significant difference (Student t-test; data not shown).
Furthermore, we performed a multiple logistic regression
analysis, which showed that female gender (p=0.01), year of
onset (p=0.01), and GADA positive (p=0.04) influenced the
presence of additional thyroid autoimmunity at diabetes type
1 onset. In this analysis, we did not confirm the independent
influence for the age at onset. As for AITD, the independent
influencing factors were female gender (p=0.03), GADA-
positive antibodies (p=0.01), and age at onset (p=0.01)
(Table 6).
Autoimmune hyperthyroidism was found in three of our
patients. Their cases were included into the AITD group. Four of
the children had developed both CD and AITD; they were treated
separately in the analyses. None of our patients represented
clinical symptoms of any other autoimmune disorder.
DISCUSSION
In our study, we presented high, in our opinion, overall
prevalence of AADs (thyroid and celiac) in children and
adolescents who newly received the diagnosis of T1D. Our
results showed increasing T1D IRs over the observed years,
accompanied with growing prevalence of other coexisting
ADs, with the 2-fold increase in AITD. To the best of our
knowledge, this work represents the first report considering the
epidemiological trends and distribution by demographic data
(gender and age) of the most common AAD—AITD and CD—
among newly diagnosed T1D pediatric patients. Therefore, we
believe that our study may provide new insight into the relation
of T1D and other autoimmunities in pediatric population.
Moreover, we reported significant association between specific
diabetic autoimmunity (GADA) and female preponderance with
increased prevalence of thyroid autoimmunity and AITD. Last
Frontiers in Endocrinology | www.frontiersin.org 7August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
FIGURE 4 | Prevalence of patients with thyroid autoimmunity and autoimmune thyroid disease at diabetes type 1 diagnosis.
FIGURE 5 | Prevalence of autoimmune thyroid disease and thyroid autoimmunity in patient with positive or negative GADA autoantibodies.
but not least, we observed a trend for increase of AAD at T1D
onset with the older age at diagnosis.
In our present results, we observed increasing T1D incidence
over the observed 2010–2018 years; the overall IRR amounted to
4% a year (1.7-fold), and we noticed the highest IR in children
aged 10–14 years. According to the latest data, incidence of T1D
is increasing irrespectively of the genetics characteristic for the
region and geographical location. Numerous research tried to
find demographic trends concerning age and gender (6,24). The
recent literature emphasizes the trend of increased prevalence
of T1D among all age groups of people (2527). Observed
worldwide IR of T1D incidence in children is increasing by 2–5%
annually. Nevertheless, IRs vary among regions of the world. In
Asia, the incidence of T1D is very low: China (Shanghai), 3.1 per
Frontiers in Endocrinology | www.frontiersin.org 8August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
TABLE 6 | Independent factors influencing additional thyroid autoimmunity and
thyroid disease at diabetes type 1 onset in a multiple logistic regression analysis.
OR 95% CI p-value
Additional thyroid autoimmunity
Gender 1.9 (1.1–3.4) 0.01
Year of onset 0.9 (0.7–1.0) 0.01
GADA antibodies 1.0 (1.0–1.0) 0.04
Age at onset 1.2 (0.9–1.6) 0.09
Autoimmune thyroid disease
Gender 1.9 (0.9–4.0) 0.03
Year of onset 1.0 (0.9–1.1) 0.4
GADA antibodies 2.1 (0.7–6.1) 0.01
Age at onset 1.6 (1.1–2.3) 0.01
CI, confidence interval; OR, odds ratio.
100,000 (28). Some research was made, looking for a possible link
between these differences in IR and HLA specific to Caucasians
and Asian populations (29,30). In Europe, newly diagnosed cases
of T1D are increasing by 3.4% per year (25). According to the
large nationwide studies, in Poland, incidence of T1D is also
increasing year after year (6). In the previous study considering
our region, the lowest IR was observed in the youngest group of
children aged (0–4 years), whereas the highest IR was identified
in older children (10–14 years) (21). American SEARCH for
Diabetes in Youth, a multicenter study of American population,
also confirmed this phenomenon (an incidence of 33.9/100,000
between 10 and 14 years old, regardless of ethnic group and
region of residence). The researchers link this to an increase
in insulin resistance during puberty and pathogenic impact of
infections (31).
One of the main findings of our study is the general increase
in prevalence of AAD at T1D onset. During the study period, the
percentage of patients diagnosed with CD and AITD doubled,
with the greatest rise between 2017 and 2018. Numerous studies
reported that incidence and prevalence of autoimmunity and
AID in diabetic patients increase with age and are more common
in females (32,33), what we also confirmed in our research.
Although statistically significant differences were noted only
regarding AITD and thyroid autoimmunity, for autoimmunity
connected to CD, we observed only percentage differences.
The frequency of AITD in a combined population of
Europe is calculated as 3% for hypothyroidism and 0.75% for
hyperthyroidism (34). Autoimmune thyroid disease affects as
much as up to 3% of the pediatric population, so it represents the
example of the most common ADs (9). In T1D, patients’ reported
weighted mean prevalence of hypothyroidism was 9.8%, whereas
in hyperthyroidism it was 1.3% according to one of the recent
meta-analyses (35), so it is significantly increased compared to
general population. What is more, we could speculate that if
prevalence of AITD increases during the disease (36), and we
noticed incidence >20% at diagnosis in 2018, the prevalence of
AITD in children diagnosed in 2018 may in the further course
of the disease exceed the peak value of 30% reported by some
studies (37).
The presence of thyroid antibodies among new-onset T1D
patients occurs to be a common phenomenon, which may be
significant for predicting the possible clinical manifestation of
AITD at the same time of setting the T1D diagnosis (37).
According to a previously conducted study (38), thyroid function
at T1D onset is largely affected by metabolic derangement,
and the assessment of thyroid antibodies may be valuable in
recognizing patients prone to developing hypothyroidism. Our
findings provide further evidence that the highest number of
patients diagnosed with AITD was observed among teenagers
(15–18 years). We also found a solid female predominance in
both thyroid autoimmunity and AITD at diagnosis of T1D. Our
results are consistent with existing studies that notice thyroid
autoimmunity more often in girls (33,39) and increase by 4.6%
in prevalence of hypothyroidism (including subclinical cases) for
every 10-year increase of age in T1D and with diabetes duration
(15). These findings correlate with overall trends of thyroid
autoimmunity incidence in other countries (39,40) and also in
Poland (41). Contrary to our findings, the meta-analysis based
on 14 studies shows that the risk of thyroid dysfunction is much
higher in children in comparison to adults (42).
Another very interesting finding of our study is the
correlation between GADA and thyroid autoimmunity. In our
study, we found vital correspondence between the presence
of GADA antibodies and both clinically manifested thyroid
AD and asymptomatic thyroid autoimmunity. Our results are
consistent with previously published data (39,43). Glutamic acid
decarboxylase antibodies are found in 70–80% of patients who
suffer from T1DM, long before the onset of clinical symptoms,
and they remain positive over a long time after. The GADA
presence is linked positively to gender (female) and older age
at the time of diabetes onset (44). The association between
GADA and TPOAb was previously observed. Glutamic acid
decarboxylase in patients with T1D not only could indicate
higher risk of more severe course of T1D but also could
be a marker that takes part in reflecting other endocrine
autoimmunity such as thyroid autoimmunity (39).
Deficiency of thyroid hormones, even subclinical, may
lead to serious complications. Because of their influence on
heart, vessels, and adipose tissue function, they play an
important role in atherosclerotic processes (45,46). Moreover, a
possible link was found between subclinical hypothyroidism and
cardiovascular risk factors and heart failure in adult patients (47).
Despite the fact that similar conclusions have not been confirmed
in pediatric patients yet, several studies have found some subtle
proatherogenic abnormalities in children with a slight increase in
TSH levels, showing improvement after levothyroxine treatment
(45). All the facts mentioned above together with the results of
our analyses confirm the need for screening and early treatment
for AITD among T1D patients.
Celiac disease perception by clinicians has changed
remarkably over past 50 years (48), and it became to be
known as chronic, food-induced autoimmune disorder that is
common and is diagnosed worldwide in patients of any age.
Celiac disease keeps increasing in general population over last
decades (49,50). Some studies suggest that accuracy in diagnosis
of CD (51) depends on the criteria used for selection of patients
for the biopsy (the percentage of patients diagnosed increased
Frontiers in Endocrinology | www.frontiersin.org 9August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
with the percentage of patients qualified for biopsy) (35). Celiac
disease, when untreated, could lead to malnutrition and also
extraintestinal manifestations of this disease: impaired bone
density and stunted growth in children, liver failure, or even
infertility (52,53). Celiac disease, except for the aforementioned
complications, may lead to increased risk of occurrence of
other disorders. A retrospective study reported that patients
who were on a gluten-free diet for a long time developed 50%
fewer number of ADs during the period up to about 15 years
of follow-up (54). Because of this, screening, possibly early
identification and diagnosis are undoubtedly vital. The strong
association of CD and AITDs was widely described in literature
(55,56). In patients with T1D, prevalence of CD is higher (4.7%)
than in general population (1.4%) (35). Similarly to these results,
prevalence of CD was increased among our patients, and the
growth trend over the years was also noted.
Nowadays, there is a great effort in research trying
to find the possible reasons for increased and multiple
autoimmunity in T1D young patients (35). One of the possible
explanations could be a common genetic background and
defective immunoregulation (44). As for a shared genetic
background, we can observe familial aggregation of ADs. It is
widely known that some haplotypes of HLA predispose to both
T1D and other ADs, i.e., HLA-DQ2, DQ4, and CD (57,58).
Also both T1D and AITD represent similar susceptibility gene
polymorphisms, with HLA and non-HLA variants, which may
cause such a clustering (59).
The TEDDY Study Group has already assessed a number
of environmental candidate triggers, which include probiotics,
infections, micronutrient, and microbiome, which could be
responsible for recent increase in AD incidence (60). Other
possible factors are altering the balance of gut microbiota due
to probiotic or antibiotics use (61,62) and epigenetic changes
induced by air pollutants (63).
The increase in incidence of ADs over the last decades is
accompanied by the outbreak of obesity. Complex interplay
between the metabolic and immune processes is not fully
understood, but may interact in developing various disorders
(64). However, there are researches describing a visible
correlation between obesity and greater prevalence or a worse
prognosis of numerous immune-mediated conditions. In our
study, the trend in annual changes of SDS-BMI was not
considered, unfortunately. Numerous researches have described
the properties of white adipose tissue as a crucial site in the
dissolvable mediators generation defined as “adipokines” that
in majority carry a proinflammatory activity. These adipokines
occur to be the link between immune system and adipose
tissue (65).
LIMITATIONS OF THE STUDY
The first and foremost limitation to our study is the retrospective
design, the improvement over the years in the diagnosis of many
conditions, and not testing specifically for other autoimmune
conditions. Second is the fact that data were sourced from
electronic medical records. Tests screening for ADs other than
those mentioned in the study were not performed because of
lack of specific guidelines and lack of symptoms manifested
by patients accounted for in the study. Controversial finding
of our study is that we noticed a lack of simultaneous
significant increase in prevalence of laboratory-recognized
autoimmunity. It may be caused by growth in the amount of
currently unknown factors triggering the development of AD
in patients with present autoimmunity. We must also admit
that, over the observed years, the diagnostic methods improved,
ultrasonography of the thyroid gland was introduced into routine
diagnostic method in all T1D patients, and diagnostic criteria
for CD changed as well. These factors may have influence on
this discrepancy. Further analysis of data gathered by us is
required in order to identify factors possibly responsible for the
observed phenomenon.
CONCLUSIONS
The IRR of T1D in children increased 4% a year, and the
standardized IR increased 1.7-fold over the 9-year observation
period. Additional autoimmunity represents a significant
comorbidity in patients with new-onset T1D. The number of
children diagnosed with AADs that accompany T1D is rapidly
growing in all age groups throughout recent years. The most
prone group of patients occurred in girls, older children, and
patients who tested positive for GADA antibodies. Thus, more
attention should be paid on subjects with other coexisting AD
since T1D onset, and we hope that our work will contribute to
greater emphasis on monitoring this problem. We believe that
getting the comprehensive knowledge on this epidemiological
problem with great clinical impact will help to establish better
interdisciplinary treatment approach.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Medical University Bioethical Committee (no
of approval: APK.002.112.2020). Written informed consent to
participate in this study was provided by the participants’ legal
guardian/next of kin.
AUTHOR CONTRIBUTIONS
BG-O made substantial contributions to study design and
conception, acquisition, analysis and interpretation of data, and
wrote the paper. PP and KZ partially gathered the data, analyzed
and interpreted it, and co-wrote the paper. MS prepared the
figures, partially gathered the data, analyzed and interpreted it,
and co-wrote the paper. MJ-S made substantial contributions
to study conception and design, acquisition, analysis, and
interpretation of data. AM performed and interpreted statistical
analyses. AK, AP, and were involved in the critical revision
for important intellectual content. AB was involved in the
design, conception, analysis, and revised the paper. All authors
Frontiers in Endocrinology | www.frontiersin.org 10 August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
contributed in discussions, read, and approved the final version
of the manuscript.
FUNDING
This research was supported by grants from Medical University
of Bialystok, Poland.
ACKNOWLEDGMENTS
The part of the data were presented during 45th Annual
Meeting of the International Society for Pediatric and Adolescent
Diabetes (ISPAD), October 30–November 2, 2019, Boston, USA.
Poster presentation: P107 Increasing coexistence of additional
autoimmune diseases at diabetes type 1 onset among children
and adolescents in Podlaskie Voivodeship (Poland) diagnosed in
years 2010–2018.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fendo.
2020.00476/full#supplementary-material
REFERENCES
1. Federation International Diabetes. IDF Diabetes Atlas, 9th ed. Brussels (2019).
Available online at: https://www.diabetesatlas.org (accessed March 2, 2020).
2. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology
of type 1 diabetes. Endocrinol Metab Clin North Am. (2010) 39:481–
97. doi: 10.1016/j.ecl.2010.05.011
3. Tajima N, Morimoto A. Epidemiology of childhood diabetesmellitus in Japan.
Pediatr Endocrinol Rev. (2012) 10(Suppl. 1):44–50.
4. Harjutsalo V, Sund R, Knip M, Groop P-H. Incidence of type 1 diabetes in
Finland. JAMA. (2013) 310:427. doi: 10.1001/jama.2013.8399
5. Tuomilehto J. The emerging global epidemic of type 1 diabetes. Curr Diab Rep.
(2013) 13:795–804. doi: 10.1007/s11892-013-0433-5
6. Szalecki M, Wysocka-Mincewicz M, Ramotowska A, Mazur A, Lisowicz
L, Ben-Skowronek I, et al. Epidemiology of type 1 diabetes in Polish
children: a multicentre cohort study. Diabetes Metab Res Rev. (2018)
34:e2962. doi: 10.1002/dmrr.2962
7. Lerner A, Jeremias P, Matthias T. The world incidence and prevalence
of autoimmune diseases is increasing. Int J Celiac Dis. (2015) 3:151–
5. doi: 10.12691/ijcd-3-4-8
8. Selmi C. Autoimmunity in 2010. Autoimmun Rev. (2011) 10:725–
32. doi: 10.1016/j.autrev.2011.06.004
9. Minelli R, Gaiani F, Kayali S, Di Mario F, Fornaroli F, Leandro G, et al. Thyroid
and celiac disease in pediatric age: a literature review. Acta Biomed. (2018)
89:11–6. doi: 10.23750/abm.v89i9-S.7872
10. Hanley P, Lord K, Bauer AJ. Thyroid disorders in children
and adolescents: a review. JAMA Pediatr. (2016) 170:1008–
19. doi: 10.1001/jamapediatrics.2016.0486
11. Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review.
JAMA. (2019) 322:153–60. doi: 10.1001/jama.2019.9052
12. van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes
and autoimmune poly-glandular syndrome: a clinical review. Neth J Med.
(2009) 67:376–87.
13. Kahaly GJ, Hansen MP. Type 1 diabetes associated autoimmunity.
Autoimmun Rev. (2016) 15:644–8. doi: 10.1016/j.autrev.2016.02.017
14. Mahmud FH, Elbarbary NS, Fröhlich-Reiterer E, Holl RW, Kordonouri
O, Knip M, et al. ISPAD clinical practice consensus guidelines 2018:
ocomplications and associated conditions in children and adolescents with
type 1 diabetes. Pediatr Diabetes. (2018) 19:275–86. doi: 10.1111/pedi.12740
15. Kordonouri O. Natural course of autoimmune thyroiditis in type 1 diabetes:
association with gender, age, diabetes duration, and puberty. Arch Dis Child.
(2005) 90:411–4. doi: 10.1136/adc.2004.056424
16. Klonowska B, Charemska D, Jabłonska J, Banach A, Kacka A, Szynkarczuk
E, et al. Carotid artery intima-media thickness (cIMT) in young type 1
diabetic patients in relation to comorbid additional autoimmune diseases
and microvascular complications. Pediatr Endocrinol Diabetes Metab. (2016)
22:92–104. doi: 10.18544/PEDM-22.03.0057
17. Statistics Poland (Główny Urzad Statystyczny - GUS) LOCAL DATA BANK.
Available online at: https://bdl.stat.gov.pl/BDL/start (accessed March 15,
2020).
18. OLAF Project. Children’s Memorial Health Institute. Available online at:
http://olaf.czd.pl/index.php?option=com_content&view=category&layout=
blog&id=28&Itemid=75 (accessed March 15, 2020).
19. Mayer-Davis EJ, Kahkoska AR, Jefferies C, Dabelea D,Balde N, Gong CX, et al.
ISPAD clinical practice consensus guidelines 2018: definition, epidemiology,
and classification of diabetes in children and adolescents. Pediatr Diabetes.
(2018) 19:7–19. doi: 10.1111/pedi.12773
20. Patterson CC, Dahlquist G, Soltész G, Green A. Variation and trends
in incidence of childhood diabetes in Europe. Lancet. (2000) 355:873–
6. doi: 10.1016/S0140-6736(99)07125-1
21. Peczynska J, Peczynska J, Jamiołkowska M, Polkowska A, Zasim A, Łuczynski
W, et al. Epidemiology of diabetes type 1 in children aged 0–14 in Podlasie
Province in years 2005–2012. Pediatr Endocrinol Diabetes Metab. (2016)
22:14–9. doi: 10.18544/PEDM-22.01.0045
22. Chobot A, Polanska J, Brandt A, Deja G, Glowinska-Olszewska B, Pilecki
O, et al. Updated 24-year trend of type 1 diabetes incidence in children in
Poland reveals a sinusoidal pattern and sustained increase. Diabet Med. (2017)
34:1252–8. doi: 10.1111/dme.13345
23. Husby S, Koletzko S, Korponay-Szabó I, Kurppa K, Mearin ML, Ribes-
Koninckx C, et al. European society paediatric gastroenterology, hepatology
and nutrition guidelines for diagnosing coeliac disease 2020. J Pediatr
Gastroenterol Nutr. (2020) 70:141–156. doi: 10.1097/MPG.00000000000
02497
24. Craig ME, Jefferies C, Dabelea D, Balde N, Seth A, Donaghue KC. Definition,
epidemiology, and classification of diabetes in children and adolescents.
Pediatr Diabetes. (2014) 15:4–17. doi: 10.1111/pedi.12186
25. Patterson CC, Harjutsalo V, Rosenbauer J, Neu A, Cinek O, Skrivarhaug
T, et al. Trends and cyclical variation in the incidence of childhood type
1 diabetes in 26 European centres in the 25 year period 1989–2013:
a multicentre prospective registration study. Diabetologia. (2019) 62:408–
17. doi: 10.1007/s00125-018-4763-3
26. Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers J, et al.
Prevalence of type 1 and type 2 diabetes among children and adolescents from
2001 to 2009. JAMA. (2014) 311:1778–86. doi: 10.1001/jama.2014.3201
27. You WP, Henneberg M. Type 1 diabetes prevalence increasing globally and
regionally: the role of natural selection and life expectancy at birth. BMJ Open
Diabetes Res Care. (2016) 4:1–7. doi: 10.1136/bmjdrc-2015-000161
28. Zhao Z, Sun C, Wang C, Li P, Wang W, Ye J, et al. Rapidly
rising incidence of childhood type 1 diabetes in Chinese population:
epidemiology in Shanghai during 1997–2011. Acta Diabetol. (2014) 51:947–
53. doi: 10.1007/s00592-014-0590-2
29. PARK Y. Why is type 1 diabetes uncommon in Asia? Ann NY Acad Sci. (2006)
1079:31–40. doi: 10.1196/annals.1375.005
30. Sugihara S. Genetic susceptibility of childhood type 1 diabetes mellitus in
Japan. Pediatr Endocrinol Rev. (2012) 10(Suppl. 1):62–71.
31. Mayer-Davis EJ, Bell RA, Dabelea D, D’Agostino R, Imperatore G, Lawrence
JM, et al. The many faces of diabetes in American youth: type 1 and
type 2 diabetes in five race and ethnic populations: the SEARCH for
diabetes in youth study. Diabetes Care. (2009) 32:S99. doi: 10.2337/
dc09-S201
Frontiers in Endocrinology | www.frontiersin.org 11 August 2020 | Volume 11 | Article 476
Głowi ´
nska-Olszewska et al. Autoimmune Comorbidities in T1D Children
32. Cerqueiro Bybrant M, Grahnquist L, Örtqvist E, Andersson C, Forsander
G, Elding Larsson H, et al. Tissue transglutaminase autoantibodies in
children with newly diagnosed type 1 diabetes are related to human
leukocyte antigen but not to islet autoantibodies: a Swedish nationwide
prospective population-based cohort study. Autoimmunity. (2018) 51:221–
7. doi: 10.1080/08916934.2018.1494160
33. Hughes JW, Bao YK, Salam M, Joshi P, Kilpatrick CR, Juneja K, et al. Late-
onset T1DM and older age predict risk of additional autoimmune disease.
Diabetes Care. (2019) 42:32–8. doi: 10.2337/dc18-1157
34. Garmendia Madariaga A, Santos Palacios S, Guillén-Grima F, Galofré JC. The
incidence and preva-lence of thyroid dysfunction in Europe: a meta-analysis.
J Clin Endocrinol Metab. (2014) 99:923–31. doi: 10.1210/jc.2013-2409
35. Nederstigt C, Uitbeijerse BS, Janssen LGM, Corssmit EPM, de Koning EJP,
Dekkers OM. Associated auto-immune disease in type 1 diabetes patients:
a systematic review and meta-analysis. Eur J Endocrinol. (2019) 180:135–
44. doi: 10.1530/EJE-18-0515
36. Orzan A, Novac C, Mihu M, Tirgoviste CI, Balgradean M. Type 1 diabetes and
thyroid autoimmunity in children. Maedica. (2016) 11:308–12.
37. Jonsdottir B, Larsson C, Carlsson A, Forsander G, Ivarsson SA, Lernmark A,
et al. Thyroid and islet autoantibodies predict autoimmune thyroid disease
at type 1 diabetes diagnosis. J Clin Endocrinol Metab. (2017) 102:1277–
85. doi: 10.1210/jc.2016-2335
38. Balsamo C, Zucchini S, Maltoni G, Rollo A, Martini AL, Mazzanti L, et al.
Relationships between thyroid function and autoimmunity with metabolic
derangement at the onset of type 1 diabetes: a cross-sectional and longitudinal
study. J Endocrinol Invest. (2015) 38:701–7. doi: 10.1007/s40618-015-0248-0
39. Jonsdottir B, Larsson C, Lundgren M, Ramelius A, Jönsson I, Larsson HE.
Childhood thyroid autoim-munity and relation to islet autoantibodies in
children at risk for type 1 diabetes in the diabetes prediction in skåne (DiPiS)
study. Autoimmunity. (2018) 51:228–37. doi: 10.1080/08916934.2018.1519027
40. Al-Khawari M, Shaltout A, Qabazard M, Al-Sane H, Elkum N. Prevalence of
thyroid autoantibodies in children, adolescents and young adults with type 1
diabetes in Kuwait. Med Princ Pract. (2015) 24:280–4. doi: 10.1159/000381547
41. Piatkowska E, Szalecki M. Autoimmune thyroiditis in children and
adolescents with type 1 diabetes. Pediatr Endocrinol Diabetes Metab.
(2011) 17:173–7.
42. Shun CB, Donaghue KC, Phelan H, Twigg SM, Craig ME. Thyroid
autoimmunity in type 1 diabetes: systematic review and meta-analysis. Diabet
Med. (2014) 31:126–35. doi: 10.1111/dme.12318
43. Jonsdottir B, Andersson C, Carlsson A, Delli A, Forsander G, Ludvigsson
J, et al. Thyroid autoimmunity in relation to islet autoantibodies and HLA-
DQ genotype in newly diagnosed type 1 diabetes in children and adolescents.
Diabetologia. (2013) 56:1735–42. doi: 10.1007/s00125-013-2934-9
44. Kakleas K, Soldatou A, Karachaliou F, Karavanaki K. Associated autoimmune
diseases in children and adolescents with type 1 diabetes mellitus (T1DM).
Autoimmun Rev. (2015) 14:781–97. doi: 10.1016/j.autrev.2015.05.002
45. Salerno M, Capalbo D, Cerbone M, De Luca F. Subclinical hypothyroidism
in childhood-current knowledge and open issues. Nat Rev Endocrinol. (2016)
12:734–46. doi: 10.1038/nrendo.2016.100
46. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin
Endocrinol Metab. (2003) 88:2438–44. doi: 10.1210/jc.2003-030398
47. Biondi B, Cooper DS. The clinical significance of subclinical thyroid
dysfunction. Endocr Rev. (2008) 29:76–131. doi: 10.1210/er.2006-0043
48. Popp A, Mäki M. Changing pattern of childhood celiac
disease epidemiology: contributing factors. Front Pediatr. (2019)
7:1–16. doi: 10.3389/fped.2019.00357
49. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. (2018) 391:70–
81. doi: 10.1016/S0140-6736(17)31796-8
50. Almallouhi E, King KS, Patel B, Wi C, Juhn YJ, Murray JA, et al. Increasing
incidence and altered presentation in a population-based study of pediatric
celiac disease in North America. J Pediatr Gastroenterol Nutr. (2017) 65:432–
7. doi: 10.1097/MPG.0000000000001532
51. Costa Gomes R, Cerqueira Maia J, Fernando Arrais R, André Nunes Jatobá
C, Auxiliadora Carvalho Rocha M, Edinilma Felinto Brito M, et al. The celiac
iceberg: from the clinical spectrum to serology and histopathology in children
and adolescents with type 1 diabetes mellitus and down syndrome. Scand J
Gastroenterol. (2016) 51:178–85. doi: 10.3109/00365521.2015.1079645
52. Tye-Din JA, Galipeau HJ, Agardh D. Celiac disease: a review of current
concepts in pathogenesis, prevention, and novel therapies. Front Pediatr.
(2018) 6:350. doi: 10.3389/fped.2018.00350
53. Laurikka P,Nurminen S, Kivelä L, Kurppa K. Extraintestinal manifestations of
celiac disease: early detection for better long-term outcomes. Nutrients. (2018)
10:1015. doi: 10.3390/nu10081015
54. Cosnes J, Cellier C, Viola S, Colombel JF, Michaud L, Sarles J, et al. Incidence
of autoimmune diseases in celiac disease: protective effect of the gluten-
free diet. Clin Gastroenterol Hepatol. (2008) 6:753–8. doi: 10.1016/j.cgh.2007.
12.022
55. Kurien M, Mollazadegan K, Sanders DS, Ludvigsson JF. Celiac disease
increases risk of thyroid disease in patients with type 1 diabetes: a
nationwide cohort study. Diabetes Care. (2016) 39:371–5. doi: 10.2337/dc
15-2117
56. Kahaly G, Frommer L, Schuppan D. Celiac disease and glandular
autoimmunity. Nutrients. (2018) 10:814. doi: 10.3390/nu10070814
57. Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, et al. One third of
HLA DQ2 homo-zygous patients with type 1 diabetes express celiac disease-
associated transglutaminase autoantibodies. J Autoimmun. (1999) 13:143–
8. doi: 10.1006/jaut.1999.0303
58. Ayesh BM, Zaqout EK, Yassin MM. HLA-DQ2 and -DQ8
haplotypes frequency and diagnostic utility in celiac disease
patients of gaza strip, Palestine. Autoimmun Highlights. (2017)
8:11. doi: 10.1007/s13317-017-0099-0
59. Anaya JM, Tobon GJ, Vega P, Castiblanco J. Autoimmune disease aggregation
in families with primary Sjögren’s syndrome. J Rheumatol. (2006) 33:2227–34.
60. Rewers M, Hyöty H, Lernmark Å, Hagopian W, She J-X, Schatz D, et al. The
environmental determinants of diabetes in the young (TEDDY) Study: 2018
update. Curr Diab Rep. (2018) 18:136. doi: 10.1007/s11892-018-1113-2
61. Calcinaro F, Dionisi S, Marinaro M, Candeloro P, Bonato V, Marzotti S,
et al. Oral probiotic administration induces interleukin-10 production and
prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse.
Diabetologia. (2005) 48:1565–75. doi: 10.1007/s00125-005-1831-2
62. Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes:
the complex interplay be-tween intestinal microbiota, gut permeability, and
mucosal immunity. Diabetes. (2008) 57:2555–62. doi: 10.2337/db08-0331
63. Zhao C, Xu Z, Wu G, Mao Y, Liu L, Dan Y, et al. Autoimmunity reviews
emerging role of air pollution in autoimmune diseases. Autoimmun Rev.
(2019) 18:607–14. doi: 10.1016/j.autrev.2018.12.010
64. La Cava A. Leptin in inflammation and autoimmunity. Cytokine. (2017)
98:51–8. doi: 10.1016/j.cyto.2016.10.011
65. Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune
diseases: not a passive bystander. Autoimmun Rev. (2014) 13:981–
1000. doi: 10.1016/j.autrev.2014.07.001
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2020 Głowi´
nska-Olszewska, Szabłowski, Panas, ˙
Zoła¸dek,
Jamiołkowska-Sztabkowska, Milewska, Kadłubiska, Polkowska, Łuczy´
nski and
Bossowski. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). The use, distribution or reproduction
in other forums is permitted, provided the original author(s) and the copyright
owner(s) are credited and that the original publication in this journal is cited, in
accordance with accepted academic practice. No use, distribution or reproduction is
permitted which does not comply with these terms.
Frontiers in Endocrinology | www.frontiersin.org 12 August 2020 | Volume 11 | Article 476
... Similar to the current study, Grasso and Chiarelli [13] found that thyroid disorders and celiac disease are the most common AIDs diagnosed in children and adolescents with T1DM, but it's also critical to take into account the onset of other conditions like juvenile idiopathic arthritis, multiple sclerosis, atrophic gastritis, inflammatory bowel diseases, and skin conditions like vitiligo and psoriasis. The literature revealed that the global prevalence of AIDs in children is about 5%, with the most frequent ones being autoimmune thyroid diseases, which are consistent with the current study's findings [14,15]. In the United States, Maahs et al. [16] documented a prevalence of one case per 300 children. ...
... In the United States, Maahs et al. [16] documented a prevalence of one case per 300 children. Nonetheless, research including 179 children with diabetes found that 2.8% of the cohort had another AID at the time of the T1DM diagnosis, and 15.6% of the group tested positive for additional autoantibodies (anti-transglutaminase, antithyroglobulin, or anti-thyroid peroxidase antibodies) [14]. ...
... Patients with T1DM had a 2% to 10% prevalence of vitiligo [14]. Vitiligo was discovered in five out of a cohort of 300 young T1DM patients, representing 1.6% of the overall population, as opposed to 0.7% of the general population [32]. ...
... The global prevalence of AIDs in children is about 5%, with the most frequent ones being autoimmune thyroid diseases and T1D [36,40], the latter of which has an estimated prevalence of 1 case per 300 children in the United States [2]. However, a study of 179 children with diabetes reported that 15.6% of the cohort was positive for additional autoantibodies (anti-thyroid peroxidase, anti-thyroglobulin, or antitransglutaminase antibodies) and 2.8% already had another AID at the time of the diagnosis of T1D [5]. ...
... HLA loci have been linked with different conditions, thus identifying overlaps may help to understand the onset of comorbidities ( Figure 1). For example, DBQ1, DR3-DQ2, [36,37] 0.09%-1% [38] Of note, the estimated prevalence reflects the characteristics of the population studied. Pediatric Diabetes and DR4-DQ8 are the primary determinants for T1D [1], but DR3-DQ2 also predisposes to CD, and the risk of having transglutaminase antibodies in homozygote T1D patients is estimated to be equal to 33% [44]. ...
... Another point of interest is the geographic prevalence of AIDs; since some countries report a higher prevalence for many of these conditions [36,49], which cannot be explained by the genetics alone. Indeed, migrant studies proved how the risk of developing AIDs may vary moving from a region with a lower prevalence to one with a higher one [50,51]. ...
Article
Full-text available
The incidence of autoimmune disorders (AIDs) has been dramatically increasing in both children and adults over the past few years, and type 1 diabetes (T1D) is one of the diseases that has seen the highest growth. It is well-known that the dysimmune process may spread to other systems, leading to the onset of one or more AIDs in the same individual; however, the relationship between AIDs is not often recognized. The most frequently diagnosed AIDs in children and adolescents with T1D are thyroid diseases and celiac disease, but it is also important to consider the onset of the other conditions, such as juvenile idiopathic arthritis, multiple sclerosis, atrophic gastritis, inflammatory bowel diseases, and skin disorders such as vitiligo and psoriasis. This review aims to explore the overlap of T1D and other AIDs, focusing on the less common and lesser-known diseases. A better knowledge of these comorbidities may facilitate the identification of patients at risk to treat them in the preclinical period, before the onset of complications.
... The lower proportion of children diagnosed with type 1 diabetes and positive for thyroid autoimmunity at or before diabetes diagnosis in our study may therefore be explained by the low median age of 5.9 years at the diagnosis of type 1 diabetes. Seroconversion at a young age is consistent with an increasing occurrence of coexisting autoimmune disorders in children newly diagnosed with type 1 diabetes (24). ...
Article
Purpose Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define pre-clinical autoimmune thyroid disease (AITD) which can progress to either clinical hypo- or hyperthyroidism. We determined the age at seroconversion in children genetically at risk for type 1 diabetes. Methods TPOAb and TgAb seropositivity were determined in 5066 healthy children with HLA DR3 or DR4 containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Children seropositive on the cross-sectional initial screen at 8-13 years of age had longitudinally collected samples (from 3.5 months of age) screened retrospectively and prospectively for thyroid autoantibodies to identify the age at seroconversion. First-appearing autoantibody was related to sex, HLA genotype, family history of AITD, and subsequent thyroid dysfunction and disease. Results The youngest appearance of TPOAb and TgAb was 10 and 15 months of age, respectively. Girls had higher incidence rates of both autoantibodies. Family history of AITD was associated with a higher risk of TPOAb hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.17, 3.08; and TgAb HR 2.55, 95% CI 1.91, 3.41. The risk of progressing to hypo- or hyperthyroidism was not different between TgAb and TPOAb, but children with both autoantibodies appearing at the same visit had a higher risk compared to TPOAb appearing first (HR 6.34, 95% CI 2.72, 14.76). Main conclusion Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypo- or hyperthyroidism.
... 86 which are the most frequent autoimmunity (15-30%), celiac disease (4-9%), autoimmune gastritis (5-10%), Addison's disease (0.5%), and vitiligo (2-10%). 7,8,9,10 Moreover, the incidence of these diseases is higher in children and adolescents with type 1 diabetes mellitus as opposed to well-healthy children. Thoroughly, these autoimmune diseases are discovered by the detection of specific autoantibodies in blood serum prior to the development of clinically overt disease. ...
Article
Full-text available
Background and objective: Type-1 diabetes mellitus is the most common chronic endocrine disorder of childhood and adolescence and is characterized by immune-mediated destruction of pancreatic cells, which has been proven to be correlated with and increase the risk of developing autoimmune thyroid disease, celiac disease, Addison’s disease, and further autoimmune diseases. The aim of this study is to evaluate the prevalence of autoimmune disease-related markers in type 1 diabetes mellitus in children and adolescents in Erbil city. Methods: One hundred children and adolescents with type 1 diabetes mellitus were enrolled in this cross-sectional study. Patients <1 year old were excluded from the study. Autoimmune thyroid antibodies (anti-thyroid peroxidase and anti-thyroglobulin) along with tissue transglutaminase (IgA and IgG) antibodies were measured with further evaluation by thyroid function test and endoscopy with biopsy (for positive serological autoantibodies level). Results: Elevated anti-thyroglobulin, anti-thyroid peroxidase, and tissue transglutaminase IgA and IgG antibodies were determined in 24.0%, 26%, 10%, and 8%, respectively. 50.0% of cases with positive anti-thyroid peroxidase antibodies had overt hypothyroidism; on the flip side, 3.8% had subclinical hypothyroidism. As well, the high level of thyroid autoantibodies was significantly correlated to the prevalence of overt hypothyroidism (P <0.001). Nine of the patients with positive tissue transglutaminase antibodies were verified to have biopsy-proven celiac disease. Conclusion: Children and adolescents with type 1 diabetes mellitus are at risk of developing positive antithyroid and celiac-related autoantibodies, so they are at risk of progressing to autoimmune thyroid and celiac diseases.
... Se han reportado la presencia de otras enfermedades autoinmunes en dichos pa-cientes, por ejemplo, enfermedades tiroideas autoinmunes (Tiroiditis de Hashimoto y Enfermedad de Graves, 15-30%), Enfermedad de Addison (0,5%), gastritis autoinmune (5-10%), enfermedad celíaca (4 -9%) y vitíligo (2-10%) [7][8] . En un estudio reciente se informó una asociación entre la positividad de GADA, sobre todo en mujeres, con una mayor prevalencia de autoinmunidad tiroidea asintomática y enfermedades tiroideas autoinmunes 9 . ...
Article
Full-text available
Combate de los Pozos 1881-CABA RESUMEN En la Diabetes tipo 1 (DM1) la pérdida de células β pancreáticas es consecuencia de un proceso de autoinmunidad que cursa con la presencia de autoanticuerpos anti-islotes pancreáticos (AAPs). Estos AAPs son marcadores útiles para la clasificación de la enfermedad. En un centro pediátrico de tercer nivel se analizó la frecuencia de presentación de GADA, IA-2A, ZnT8A e IAA en un grupo con reciente debut entre enero 2018 y agosto 2021 (n= 90). Además, se investigó la frecuencia de presentación y relación de los AAPs con la edad, sexo y tiempo de evolución en pacientes en seguimiento (n= 240). En el grupo de debut se obtuvo positividad de GADA, IA-2A, ZnT8A y IAA en 77,8; 60; 62 y 47,8% de los pacientes respectivamente, un 4% no presentó AAPs. El 95,6% de los pacientes presentaron al menos un AAPs positivo. La frecuencia de IAA en el grupo en debut fue mayor en menores de 5 años. En el grupo en seguimiento el 75,2% resultaron GADA positivo (85,7% en mujeres y 62,8% en varones) p<0,05. IA-2A y ZnT8A fueron positivos en 45 y 51.7% respectivamente. El 91% presentaron al menos un AAP positivo. En este grupo se evidenció una menor positividad en función del tiempo de evolución. Se pudo determinar la frecuencia de presentación de los AAPs en un grupo en debut y la relación con la edad, sexo y tiempo de evolución en pacientes en seguimiento. La determinación de APPs facilita la correcta clasificación y elección de la terapia adecuada. Palabras clave: Diabetes mellitus tipo 1; autoanticuerpos anti-islotes pancreáticos; autoinmunidad. Medicina Infantil 2023; XXX: 90-95. ABSTRACT In type 1 diabetes (DM1) the loss of pancreatic β-cells is a consequence of an autoimmune process that results in the presence of pancreatic anti-islet autoantibodies (PAAs). PAAs are useful markers for the classification of the disease. The frequency of presentation of GADA, IA-2A, ZnT8A, and IAA in a group with recent debut seen between January 2018 and August 2021 (n= 90) was analyzed in a tertiary pediatric center. In addition, we investigated the frequency of presentation and association of PAAs with age, sex, and time of evolution in patients in follow-up (n= 240). In the debut group, GADA, IA-2A, ZnT8A, and IAA positivity was found in 77.8, 60, 62, and 47.8% of patients, respectively; no PAAs were observed in 4% of the patients. Overall, 95.6% presented at least one positive PAA. The frequency of IAA in the debut group was higher in children younger than 5 years. In the follow-up group, 75.2% were GADA positive (85.7% of females and 62.8% of males) p<0.05. IA-2A and ZnT8A were positive in 45 and 51.7% respectively. Ninety-one percent presented with at least one positive PAA. In this group, a lower positivity was evidenced as a function of the time of evolution. The frequency of presentation of PAAs in a debut group and the relationship with age, sex, and time of evolution in patients in follow-up was demonstrated. The assessment of PAAs facilitates the correct classification and choice of adequate therapy.
Article
Background It is well recognized that type 1 diabetes mellitus (T1DM) and autoimmune diseases are related; however, exact frequency of autoimmune diseases in T1DM is still unknown. Objective To determine the frequency of autoimmune disorder associated with T1DM. Materials and Methods A cross-sectional study was performed at Baqai Institute of Diabetology and Endocrinology (BIDE), Baqai Medical University (BMU), Karachi. One hundred and fifty-one diagnosed patients of T1DM having age <35 years were selected by using consecutive sampling technique. Clinical evidence (sign and symptoms) supported by diagnostic tests (where indicated) were used to confirm autoimmune disorder in T1DM. Results Out of 151 T1DM patient, male patients were 80 (53.0%) and female patients were 71 (47.0%) with a mean age of 17.10 ± 5.74 years. Autoimmune disease was diagnosed in 43 (28.5%) T1DM patients. Most commonly reported autoimmune and other disorder associated with T1DM patient s was hypothyroidism diagnosed in 25 (16.6%) patients followed by celiac disease in 22 (14.6%) patients and Addison disease in four (2.6%) patients. Moreover, polycystic ovarian syndrome was found in 15 (21.1%) female patients. Conclusion The substantial linkage observed between T1DM and autoimmune diseases underscores the critical importance of timely diagnosis for both conditions.
Article
Full-text available
Background Coeliac disease (CD) is common in patients with type 1 diabetes (T1D), but prevalence varies globally due to differing screening protocols. There have been substantial changes in screening guidelines over the past two decades. Aim To evaluate CD prevalence in patients with T1D, focusing on screening studies using antitissue transglutaminase (anti‐tTG) antibody. Methods We searched PubMed, Web of Science, Embase and Scopus for studies published up to 11 December 2023 using keywords related to CD and diabetes. We used random‐effects models for overall prevalence and all subgroups, with heterogeneity assessed using Cochran's Q test and the I² statistic performed in STATA 18. Results We included 106 articles involving 65,102 T1D patients across 40 countries. The pooled CD seroprevalence and confirmed CD prevalence were 9% (95% confidence interval, CI, 8%–10%) and 6% (95% CI 5%–7%), respectively. The prevalence was higher in females and children. Denmark, Saudi Arabia and Libya exhibited the highest prevalence (11%), followed by India and Egypt (10%). Belgium, France, Germany, South Africa and the United States had the lowest prevalence (2%). High‐income countries showed significantly a lower CD prevalence than middle‐income countries (p = 0.03). Meta‐regression based on the Human Development Index (HDI) indicated that countries with higher HDI have lower seroprevalence and confirmed CD prevalence. Conclusion Approximately 1 in 16 patients globally and 1 in 12 patients in Asia and the Middle East with T1D has CD. We suggest that all patients with T1D should be screened for CD.
Article
Full-text available
Up until the 1960s and 1970s, diarrhea, malabsorption syndrome, and failure to thrive were the presenting symptoms and signs of celiac disease (CD) in young infants; however this disease was also at the same time reported to be disappearing. Indeed, clinical childhood CD was seen to transform into a milder form, resulting in an upward shift in age at diagnosis during the 1970s (and years later for many countries). This changing pattern of CD presentation then altered the epidemiology of the disease, with major differences between and within countries observed. An awareness of the changing clinical nature of CD and use of case-finding tools to detect even clinically silent CD became an important factor in this changing epidemiology. Countries report both low and high prevalence but it seems to be on the increase resulting in a population-based level of 1–2%. This paper discusses the potential causes and environmental factors behind these observed clinical changes, identifying new clues from different studies published at the time this transformation took place. For instance, it was found that breastfeeding postponed the diagnosis of the disease but did not altogether prevent it. Moreover, gluten introduction at a young age, specifically at the mean age of 2 months, seemed to also have a clear impact in inducing malabsorption syndrome and failure to thrive in young infants in addition to other factors such as gluten intake volume and type of cereal present in the weaning food. Further, the impact of cow's milk and its high osmolarity might have played an important role; humanized milk formulas were not yet invented. Future epidemiological studies on the contributing environmental factors to the shift in CD presentation are thus recommended for countries in which these changing clinical features are still being observed.
Article
Full-text available
Chronic autoimmune thyroid disease or Hashimoto thyroiditis (HT) and Graves-Basedow disease (GD) are the main autoimmune thyroid diseases in pediatric age. Both are characterized by the production of anti-thyroid antibodies, by an infiltration of autoreactive B and T lymphocytes into the thyroid parenchyma and by alterations in thyroid function (hyperthyroidism in GD, normal function or subclinical hypothyroid-ism in HT with possible evolution towards manifest hypothyroidism). Celiac disease (CD) is a systemic auto-immune disease caused by gluten ingestion in genetically predisposed subjects, its prevalence is around 1% in Western Countries. It presents with a pathognomonic enteropathy, a variety of clinical manifestations, posi-tivity for specific antibodies, positivity for typical haplotypes HLA DQ2/DQ8. The clinical manifestations may vary among four types: typical, atypical, silent and latent. Diagnosis can be made in presence of specific histopathologic findings in duodenal biopsies and antibodies positivity. Celiac disease is associated to various endocrine autoimmunities such as thyropathies, diabetes mellitus type 1, Addison disease, multiendocrine syndromes. The most frequent associated thyropaties are HT and GD. The present review aims to explore the associations between thyropathies and celiac disease in pediatric age. (www.actabiomedica.it)
Article
Full-text available
Background: The aim was to determine prevalence and age at seroconversion of thyroid autoimmunity in relation to islet autoantibodies, gender and HLA-DQ genotypes in children with increased risk for type 1 diabetes followed from birth. Methods: In 10-year-old children (n = 1874), blood samples were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase 65 (GADA), Zink transporter 8 (ZnT8R/W/QA), insulinoma-associated protein-2 (IA-2A), insulin (IAA) and HLA-DQ genotypes. Prospectively collected samples from 2 years of age were next analysed for TPOAb, and TGAb and, finally, in confirming samples at 11–16 years of age along with TSH and FT4. Frequencies were tested with Chi-square or Fischer’s exact tests, autoantibody levels with Wilcoxon and correlations between autoantibody levels with Spearman’s rank correlation test. Results: The prevalence of thyroid autoimmunity was 6.9%, overrepresented in girls (p
Article
Full-text available
Aims/hypothesis: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. Methods: Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. Results: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. Conclusions/interpretation: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.
Article
Full-text available
Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment.
Article
Full-text available
Objectives: This study explored the association between tissue transglutaminase autoantibody (tTGA), high-risk human leucocyte antigen (HLA) genotypes and islet autoantibodies in children with newly diagnosed type 1 diabetes (T1D). Patients and methods: Dried blood spots and serum samples were taken at diagnosis from children <18 years of age participating in Better Diabetes Diagnosis (BDD), a Swedish nationwide prospective cohort study of children newly diagnosed with T1D. We analyzed tTGA, high-risk HLA DQ2 and DQ8 (DQX is neither DQ2 nor DQ8) and islet auto-antibodies (GADA, IA-2A, IAA, and three variants of Zinc transporter; ZnT8W, ZnT8R, and ZnT8QA). Results: Out of 2705 children diagnosed with T1D, 85 (3.1%) had positive tTGA and 63 (2.3%) had borderline values. The prevalence of tTGA was higher in children with the HLA genotypes DQ2/2, DQ2/X or DQ2/8 compared to those with DQ8/8 or DQ8/X (p = .00001) and those with DQX/X (p ≤ .00001). No significant differences were found in relation to islet autoantibodies or age at diagnosis, but the presence of tTGA was more common in girls than in boys (p = .018). Conclusion: tTGA at T1D diagnosis (both positive and borderline values 5.4%) was higher in girls and in children homozygous for DQ2/2, followed by children heterozygous for DQ2. Only children with DQ2 and/or DQ8 had tTGA. HLA typing at the diagnosis of T1D can help to identify those without risk for CD.
Article
Objectives: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. Methods: Literature databases and other sources of information were searched for studies that could inform on ten formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. Results: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable an IgG based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10xULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10xULN at least 4 biopsies from the distal duodenum and at least one from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. Conclusions: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.
Article
Importance Subclinical hypothyroidism, defined as an elevated serum thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) level with normal levels of free thyroxine (FT4) affects up to 10% of the adult population. Observations Subclinical hypothyroidism is most often caused by autoimmune (Hashimoto) thyroiditis. However, serum thyrotropin levels rise as people without thyroid disease age; serum thyrotropin concentrations may surpass the upper limit of the traditional reference range of 4 to 5 mU/L among elderly patients. This phenomenon has likely led to an overestimation of the true prevalence of subclinical hypothyroidism in persons older than 70 years. In patients who have circulating thyroid peroxidase antibodies, there is a greater risk of progression from subclinical to overt hypothyroidism. Subclinical hypothyroidism may be associated with an increased risk of heart failure, coronary artery disease events, and mortality from coronary heart disease. In addition, middle-aged patients with subclinical hypothyroidism may have cognitive impairment, nonspecific symptoms such as fatigue, and altered mood. In the absence of large randomized trials showing benefit from levothyroxine therapy, the rationale for treatment is based on the potential for decreasing the risk of adverse cardiovascular events and the possibility of preventing progression to overt hypothyroidism. However, levothyroxine therapy may be associated with iatrogenic thyrotoxicosis, especially in elderly patients, and there is no evidence that it is beneficial in persons aged 65 years or older. Conclusions and Relevance Subclinical hypothyroidism is common and most individuals can be observed without treatment. Treatment might be indicated for patients with subclinical hypothyroidism and serum thyrotropin levels of 10 mU/L or higher or for young and middle-aged individuals with subclinical hypothyroidism and symptoms consistent with mild hypothyroidism.
Article
Introduction: The association between type 1 diabetes (T1D) and other auto-immune diseases is well-known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking. Methods: We searched Pubmed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo, and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalences using a random effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration. Results: 180 articles were eligible including a total of 293,889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8 percent (95%CI 7.5-12.3) of patients. Meta-regression showed that for every 10 years age-increase, hypothyroidism prevalence increased with 4.6 percent (95% CI 2.6-6.6, P <0.000, 54 studies). Weighted prevalence of celiac disease was 4.5 percent (95%CI 4.0-5.5, 87 studies). Gastric autoimmunity was found in 4.3 percent of patients (95%CI 1.6-8.2, 8 studies), vitiligo in 2.4 percent (95%CI 1.2-3.9, 14 studies) of patients. The prevalence of adrenal insufficiency was 0.2 percent (95%CI 0.0-0.4, 14 studies) and hyperthyroidism was found in 1.3 percent (95%CI 0.9-1.8, 45 studies) of type 1 diabetes patients. For all analyses, statistical heterogeneity between studies was moderate to high. Conclusions: The prevalence of antibody mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.
Article
Objective: Type 1 diabetes (T1DM) is associated with other autoimmune diseases (AIDs), which may have serious health consequences. The epidemiology of AIDs in T1DM is not well defined in adults with T1DM. In this cross-sectional cohort study, we sought to characterize the incident ages and prevalence of AIDs in adults with T1DM across a wide age spectrum. Research design and methods: A total of 1,212 adults seen at the Washington University Diabetes Center from 2011 to 2018 provided informed consent for the collection of their age, sex, race, and disease onset data. We performed paired association analyses based on age at onset of T1DM. Multivariate logistic regression was used to evaluate the independent effects of sex, race, T1DM age of onset, and T1DM duration on the prevalence of an additional AID. Results: Mean ± SD age of T1DM onset was 21.2 ± 14.4 years. AID incidence and prevalence increased with age. Female sex strongly predicted AID risk. The most prevalent T1DM-associated AIDs were thyroid disease, collagen vascular diseases, and pernicious anemia. T1DM age of onset and T1DM duration predicted AID risk. Patients with late-onset T1DM after 30 years of age had higher risks of developing additional AIDs compared with patients with younger T1DM onset. Conclusions: The prevalence of AIDs in patients with T1DM increases with age and female sex. Later onset of T1DM is an independent and significant risk factor for developing additional AIDs. Individuals who are diagnosed with T1DM at older ages, particularly women, should be monitored for other autoimmune conditions.