Screening of celiac disease in children and adolescents with type 1 diabetes mellitus Текст научной статьи по специальности «Клиническая медицина»

X|YK) JOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN

Озык, Макала / Оригинальная Статья / Original Article

DOI: 10.23950/1812-2892-JCMK-00755

Screening of celiac disease in children and adolescents with type 1 diabetes mellitus_

Hasret Ayyildiz Civan1, Esra Papatya £akir2

'Department of Gastroenterology, Hepatology and

Nutrition, Bakirköy Dr. Sadi Konuk Training and

Research Hospital, Istanbul, Turkey

Department of Pediatric Endocrinology, Bakirköy Dr.

Sadi Konuk Training and Research Hospital, Istanbul,

Turkey

© ®

This work is licensed under a Creative Commons Attribution 4.0 International License

Received: 2020-03-22 Accepted: 2020-03-23 UDC: 618.1

J Clin Med Kaz 2020; 2(56):21-26

Corresponding Author: Hasret Ayyildiz Civan, Bakirkoy Dr. Sadi Konuk Egitim ve Ara^tirma Hastanesi, Istanbul, Turkey. Tel.: +905057479765 E-mail: hasretayyildiz@yahoo.com

Abstract

Background and aim: Celiac disease is the most frequent autoimmune disease in Type 1 diabetes mellitus. We aimed to determine the celiac disease prevalence in patients with type 1 diabetes mellitus, additionally to evaluate the clinical, serological and molecular characteristics of type 1 diabetes mellitus and celiac disease which have a common genetic predisposition.

Material and methods: A total number of 76 type 1 diabetes mellitus patients aged between 1-18 years, were evaluated retrospectively. Serologic screening for celiac disease was performed via anti-tissue transglutaminase and anti-endomysial antibodies. Presence of human leukocyte antigens (HLA) (DQ2 and DQ8) documented as well. Patients with positive tissue transglutaminase and endomysial antibodies underwent endoscopic biopsy. Histopathological analysis were performed according to the modified Marsh classification. Patients' demographic characteristics, anthropometric measurements, physical examination, laboratory findings, age at type 1 diabetes mellitus and celiac disease onset, and celiac disease prevalence were evaluated. In addition all findings were compared between type 1 diabetes mellitus patients and newly diagnosed celiac disease patients.

Results: Serum tissue transglutaminase was positive in 14,5% (n=11) of all patients and serum endomysial antibodies was positive in 13,2% (n=10). The overall prevalence of celiac disease in type 1 diabetes mellitus was confirmed as 10.5% (n=8) by histopathological examination in present study. Of the celiac disease patients 37.5% were asymptomatic. In addition, 6 were anti-tissue transglutaminase and 7 were endomysial antibodies positive. Moreover, 60.3% (n=41) were HLADQ2 and 58.8% (n=40) were HLA-DQ8 positive. Selective IgA deficiency was described in 3 cases. In one of them HLA-DQ2/HLA-DQ8 was found positive and celiac disease diagnosis was confirmed by biopsy. HLA-DQ8 ratio was found significantly higher in patients with celiac disease than the type 1 diabetes mellitus patients. In addition, HLA-DQ2/DQ8 positivity was observed in 62.5% (n=5) of celiac disease patients.

Conclusion: Our findings have demonstrated the increasing prevalence of celiac disease in children with type 1 diabetes mellitus. Particularly the higher risk of asymptomatic celiac disease in type 1 diabetes mellitus patients, revealed the diagnostic value of serological screening. Furthermore, increased HLA-DQ2 and HLA-DQ8 positivity, which are more prominent in case of selective IgA deficiency, clearly demonstrates the requirement of routine total IgA and HLA analysis in serological screening.

Key words: type 1 diabetes mellitus, celiac disease, serological screening, human leukocyte antigens

1 ТИПТ1 ЦАНТ ДИАБЕТ БАР БАЛАЛАР МЕН ЖАСвСШРШДЕРДЕ ЦЕЛИАКИЯ АУРУЫН АНЬЩТАУ Х.А. Циван1, Э.П. Чакир2

'Гастроэнтерология, гепатология жэне тамацтану бeлiмi, Доктор Сади Конук атындагы Бакыркей гылыми клиникасы, Ысмтамб^л, ТYркия *Балалар эндокринологиясы бeлiмi, Доктор Сади Конук атындагы Бакыркей гылыми клиникасы, Ыстамб^л, ТYркия

Т¥ЖЫРЫМДАМА

Максаты: целиакия ауруы - 1 титт кант диабетшдеп ец кеп таралган аутоиммундык ауру. Бедщ зертгеу1мЬдщ максаты 1 титт кант диабет бар наукастарда целиакия ауруыныц таралуын аныктау, сонымен катар жалпы генетикалык бешмдтИ бар 1 титт кант диабет мен целиакия ауруыныц клиникалык, серологиялык жэне молекулалык сипаттамаларын багалау болды.

Материалдар мен эдютер: Зерттеуге 1 жастан 18 жаска дейiнгi 1 типт кант диабетiмен ауыратын 76 наукас енгiзiлдi. Целиакия ауруына серологиялык скрининг трансглутаминазга карсы антиденелер мен эндомизияга карсы антиденелердi колдана отырып ЖYрriзiл-дi. Адамныц лейкоциттiк антигендерЫщ ^А) (DQ2 жэне DQ8) болуы да зертханалык зерттеулермен расталады. Эндоскопиялык биопсия трансглутаминазга карсы антиденелер мен эндомизияга карсы антиденелер Yшiн оц нэтижелерi бар пациенттерде жасалды. Гистопатологи-ялык талдау Марштыц модификацияланган жiктелуiне сэйкес ЖYргiзiлдi. Демографиялык сипаттама, антропометриялык керсетиштер, физи-калык тексеру, зертханалык мэлiметтер, 1 типтi кант диабетi жэне целиакия ауруыныц басталу кезiндегi жас, сондай-ак целиакия ауруыныц таралуы багаланды. Сонымен катар, барлык нэтижелер 1 типт кант диабетi бар наукастар мен жацадан диагноз койылган целиакия ауруы бар емделушiлер арасында салыстырылды.

Нэтижелер: Трансглутаминазга карсы антиденелерге арналган кан сарысуыныц нэтижесi барлык пациенттердщ 14,5% -ында (п = 11) оц, ал кан сарысуыныц эндомизияга антиденелер Yшiн тестi 13,2% (п = 10) оц болды. Осы зерттеуде 1 типтi кант диабетшдеп целиакия ауруыныц жалпы таралуы гистопатологиялык зерттеу аркылы 10,5% (п = 8) ретЫде расталды. Целиакия ауруы бар пациенттердщ 37,5% -ы симптомсыз болды. Сонымен катар, 6 наукаста трансглутаминазга карсы антиденелер, ал 7 емделушлде эндомизияга карсы антиденелер бар. Сонымен катар, 60,3% (п = 41) HLADQ2 жэне 58,8% (п = 40) HLA-DQ8-оц болды. 3 жагдайда окшауланган 1дА типiндегi жетюпеушллк сипатталды. Олардыц бiреуiнде HLA-DQ2 / HLA-DQ8 оц болды, ал целиакия ауруы диагнозы биопсиямен расталды. HLA-DQ8 коэффициент целиакия ауруы бар наукастарда 1 типтi кант диабетмен ауыратындарга караганда едэуiр жогары болды. Сонымен катар, HLA-DQ2 / DQ8-позитивтiлiгi целиакия ауруы бар пациенттердiц 62,5% -ында (п = 5) байкалды.

Корытынды: Бiздiц нэтижелерiмiз 1 типт кант диабетiмен ауыратын балаларда целиакия ауруыныц кец таралгандьнын керсеттi. Атап айтканда, 1 типтi кант диабет бар пациенттерде симптомсыз целиакия ауруыныц жогары каупi серологиялык скринингтiц диагностикалык мацыздыльнын керсеттi. Сонымен катар, окшауланган 1дА типтi жетiспеушiлiк жагдайында айкын болатын HLA-DQ2 жэне HLA-DQ8 пози-тивтiлiгiнiц жогарылауы серологиялык скринингте 1дА жэне HLA жиынтыктарын стандартты талдау кажеттлИн айкын керсетедi.

Негiзгi сездер: 1 типтi кант диабетi, целиакия ауруы, серологиялык скрининг, адамныц лейкоцитпк антигендерi

ВЫЯВЛЕНИЕ ЦЕЛИАКИИ У ДЕТЕЙ И ПОДРОСТКОВ С САХАРНЫМ ДИАБЕТОМ 1 ТИПА Х.А. Циван1, Э.П. Чакир2

'Отделение гастроэнтерологии, гепатологии и питания, Научно-исследовательская клиника Бакыркёй имени доктора Сади Конук, Стамбул, Турция Ютделение педиатрической эндокринологии, Научно-исследовательская клиника Бакыркёй имени доктора Сади Конук, Стамбул, Турция

РЕЗЮМЕ

Цель: Целиакия является наиболее частым аутоиммунным заболеванием при сахарном диабете 1 типа. Целью нашего исследования стало определение распространенности целиакии у пациентов с сахарным диабетом 1 типа, а также оценка клинических, серологических и молекулярных характеристик сахарного диабета 1 типа и целиакии, которые имеют общую генетическую предрасположенность.

Материалы и методы: Всего 76 больных сахарным диабетом 1 типа в возрасте от 1 до 18 лет были включены в исследование. Серологический скрининг на целиакию проведен с помощью антител против трансглутаминазы и антител к эндомизию. Наличие человеческих лейкоцитарных антигенов ^А) (DQ2 и DQ8) также подтверждено результатами лабораторных исследований. Пациентам с положительными результатами на антитела против трансглутаминазы и антитела к эндомизию проведена эндоскопическая биопсия. Гистопатологический анализ проведен по модифицированной классификации Марша. Оценены демографические характеристики, антропометрические показатели, физикальное обследование, лабораторные данные, возраст при появлении сахарного диабета 1 типа и целиакии, а также распространенность целиакии. Кроме того, все результаты были сопоставлены между больными сахарным диабетом 1 типа и пациентами с впервые диагностированной целиакией.

Результаты: Анализ сыворотки крови на антитела против трансглутаминазы был положительный у 14,5% (п=11) всех пациентов, а анализ сыворотки крови на антитела к эндомизию был положительным у 13,2% (п=10). В настоящей работе общая распространенность целиакии при сахарном диабете 1 типа была подтверждена гистопатологическим исследованием как 10,5% (п=8). 37,5% пациентов с целиакией были бессимптомными. Кроме того, положительный результат был у 6 пациентов на антитела против трансглутаминазы и у 7 пациентов на антитела к эндомизию. Более того, 60,3% (п=41) были HLADQ2 и 58,8% (п=40) HLA-DQ8-положительными. В 3 случаях описана изолированная недостаточность 1дА-типа. В одном из них HLA-DQ2/HLA-DQ8 оказался положительным, а диагноз целиакии был подтвержден биопсией. Отношение HLA-DQ8 было значительно выше у пациентов с целиакией, чем у пациентов с сахарным диабетом 1 типа. Кроме того, HLA-DQ2/DQ8-позитивность наблюдалась у 62,5% (п=5) пациентов с целиакией.

Заключение: Наши результаты показали растущую распространенность целиакии у детей с сахарным диабетом 1 типа. В частности, более высокий риск возникновения бессимптомной целиакии у больных сахарным диабетом 1 типа выявил диагностическую ценность серологического скрининга. Кроме того, повышенная позитивность HLA-DQ2 и HLA-DQ8, которая более выражена в случае изолированной недостаточности 1дА-типа, ясно демонстрирует необходимость проведения стандартного анализа общего 1дА и HLA при серологическом скрининге.

Ключевые слова: сахарный диабет 1 типа, целиакия, серологический скрининг, человеческий лейкоцитарный антиген

Introduction

Type 1 diabetes mellitus (T1DM) is an immune mediated disease characterized by insulin deficiency or insufficiency as a result of the destruction of insulin-producing beta cells in the islets of langerhans. Childhood T1DM has increased rapidly in recent years and accounting for the approximately 2-3% of the general population [1]. T1DM was significantly associated with autoimmune diseases such as thyroid disease, celiac disease (CD) and Addison's disease [2]. CD is the most frequent autoimmune disorder coexisting with T1DM [3].

CD is a chronic immune-mediated disease characterized by inflammation and villous atrophy in the small intestine. CD-patients suffer from lifelong intolerance to the gluten contained in cereals particularly in wheat [4]. The CD prevalence in children and adolescents with T1DM varies between 1.6 and 16.4% in worldwide [5,6].

Whether the initial diagnosis is T1DM or CD; both diseases have been numerously documented to exhibit strong comorbidity with each other [7]. Supportively, both diseases were significantly associated with the 'major histocompatibility complex class II antigen DQ2' encoded by common alleles [4]. Along with the accompanying pathology in T1DM, the lack of symptoms that indicate gluten-sensitive enteropathy in approximately half of CD patients further complicates clinical management [8,9].

Therefore, in order to prevent malabsorption in asymptomatic CD-patients, all T1DM patients should be screened for early diagnosis of CD. Although CD-associated antibodies such as tissue transglutaminase-IgA (TGA), antiendomysial-IgA (EMA) manifest high sensitivity in serologic screening, duodenal biopsy is the gold standard method especially in patients with negative serology [1,10]. Thus, we aimed to

determine the CD prevalence in TIDM-patients, additionally to compare the clinical, serological and molecular characteristics of patients with T1DM and CD.

Material and methods

This study was performed with the Institutional Review Board protocol approval date 18/02/2019 and number 201929 in Istanbul Training and Research Hospital, Department of Gastroenterology, Hepatology and Nutrition, 01 January 2017 -30 June 2018. A total number of 76 T1DM-patients aged between 1-18 years, were evaluated retrospectively. During application, height and weight percentiles of cases, as well as the body mass index (BMI) for patients over two years of age were determined.

Serologic screening for CH was performed using anti tissue transglutaminase antibodies (tTGAb) via enzyme-linked immunosorbent assay (ELISA). All patients also screened for anti-endomysial antibodies by the immunofluorescence method using human umbilical cord and fluorescein isothiocyanate conjugated anti human-IgA (INOVA, San Diego, Calif., USA). In case of serum IgA deficiency, total serum IgA levels were measured by nephelometry. Presence of HLA antigens (DQ2 and DQ8) determined via polymerase chain reaction (PCR) technique through genomic DNA isolated from the all patients' peripheral blood. Patients with positive tTGA and EmA underwent endoscopic biopsy from distal duodenum. Histopathological analysis were performed according to the modified Marsh classification [11]. All CD-confirmed patients were referred for a gluten-free diet and followed.

In addition, cell blood count analysis was performed on patients' venous blood samples. Haematological parameters were analysed using a haematology analyser (Cell-Dyne 3700, Abbott, Abbott Park, IL, USA). Biochemical analysis performed from serum samples by electro-chemiluminescence immunoassay on Beckman Coulter Unicel DXI 800 analyzer. Serum glycosylated hemoglobin (HbA1c) level <7% determined as well metabolic control, between 7-9% as moderate metabolic control and 9% as poor metabolic control.

Patients' demographic characteristics, age at T1DM and CH onset, anthropometric measurements, physical examination, imaging and laboratory findings, were evaluated. In addition all findings were compared between T1DM-patients and newly diagnosed CH-patients.

Statistical analysis

All the data were analysed with SPSS (Statistical Package for the Social Sciences) software for Windows (v21.0; IBM, Armonk, NY, USA). Individual and aggregate data were summarized using descriptive statistics including mean, standard deviations, medians (min-max), frequency distributions and percentages. Normality of data distribution was verified by Kolmogorov-Smirnov test. Comparison of the variables with normal distribution was made with Student t-test. The variables which were not normally distributed, the Mann Whitney and Kruskal Wallis tests were conducted to compare between groups. Evaluation of categorical variables was performed by Chi-Square test. P-Values of <0.05 were considered statistically significant.

Results

The 76 T1DM-patients included in this study were 45 (59,2%) female, 31 (40,8%) male, and the mean age of symptom onset was 139,16±46,99 months (Ranged=40-120) in our sample group. Additionally, the mean age of total participants

was 95,67±52,85 months (Ranged: 0-215) at the time of DM diagnosis. Six of the cases (7.9%) were screened due to the CD history in family members, and one of these patients was diagnosed with CD. The overall prevalence of CD in T1DM was confirmed as 10.5% (n=8) by histopathological examination in present study. The mean age of CD-patients was 109,20±56,10 months (Ranged: 78-188) at the time of CD diagnosis (Table 1). The most common symptom reported in our patients was abdominal pain with a ratio of 32,9% (n=25) followed by constipation (25.0%), and diarrhea (11,8%) respectively. The 46.1% (n=35) of the all patients and 37.5% (n=3) of the CD patients were asymptomatic (Table 2).

Table 1

Comparison of the data according to the age at disease onset and gender.

n (%) Age (Months) (Mean±SD) P-value

Male 31 (%40,8) 142,90±50,40 0,485

Female 45 (%59,2) 136,58±44,88

Mean Age at Application 76 (%100) 139,16±46,99

Mean Age at DM Diagnosis 76 (%100) 95,67±52,85

Mean Age at CD Diagnosis 8 (%10,5) 109,20±56,10

SD=Standard Deviation. * = p<0.05 statistically significant.

Distribution of symptoms during application.

Symptoms n %

Abdominal pain 25 %32,9

Constipation 9 %25,0

Diarrhea 19 %11,8

Puffiness 9 %11,8

Asymptomatic 35 %46,1

According to the evaluation of anthropometric measurements obtained from all cases; mean height was 146,20±20,47 cm, mean weight was 44,09±18,39 kg, and mean BMI was 19,08±4,75 (Ranged=12,0-38,0). In addition, laboratory outcomes are represented in Table 3. There were no statistically significant differences found between the CD and T1DM groups according to the age, BMI and laboratory findings (p>0,05) (Table 3). Additionally, vitamin D deficiency was detected in 88,2% (n=67) of patients, folic acid deficiency in 1.3% (n=1) and vitamin B12 deficiency in 9.2% (n=7). Iron-deficiency anemia detected in 1 patient and selective IgA deficiency was detected in 3 (3,9%) patients. Only 2.7% of patients (n=2) had normal levels of glycosylated hemoglobin; well-controlled HbA1c was 10,5%, moderate controlled HbA1c was 40,8% and poorly controlled HbA1c was 48,7%.

In addition, anti-tTGA was positive in 14,5% (n=11), anti-transglutaminaz IgG (anti-tTGG) in 17,1% (n=13), anti-EMA in 13,2% (n=10) and antiendomisyum IgG (anti-EMG) in 7,9% (n=6) of all patients. Of the CD patients, 6 were anti-tTGA and 7 were EMA positive.

The distribution of patients according to the tissue groups analysis (n=68); 60.3% (n=41) were HLADQ2 and 58.8% (n=40) were HLA-DQ8 positive. Moreover, rates of HLA-DQ8, anti-tTGA, anti-tTGG, anti-EMA and anti-EMG were found significantly higher in patients with CD than the T1DM patients (Table 4).

Table 3

Comparison of clinical features and laboratory outcomes between CD and DM patients.

DM Group (Mean±SD) CD Group (Mean±SD) P-value

Age 140,56±47,04 127,25±47,95 0,515

BMI 19,29±4,80 16,83±3,76 0,146

HbA1c(%) 9,10±2,06 9,61±2,33 0,542

Hemoglobin (g/dL) 13,45±1,17 12,88±1,04 0,115

MCV (fL) 80,74±7,07 82,32±6,57 0,747

Iron (ug/dL) 81,01±33,51 63,96±39,51 0,189

Vitamin B12 (pg/mL) 460,96±231,47 400,53±170,53 0,602

Folate (mg/L) 11,22±3,51 13,56±5,69 0,291

Vitamin D (ng/ml) 17,50±8,22 22,33±10,51 0,233

Total IgA (mg/dL) 150,45±66,94 165,31±82,75 0,564

Table 4

Results of serological screening in DM and CD patients.

Clinical Variables DM Group CD Group P-value

TG IgA (mg/dL) - 8,08±33,86 171,46±127,28 0,000*

(Mean±SD)

TG IgG (mg/dL) - 6,86±14,35 46,20±37,63 0,001*

(Mean±SD)

EMA-IgA Negative 65 (%95,6) 1 (%12,5) 0,000*

n (%) Positive 3 (%4,4) 7 (%87,5)

EMA-IgG Negative 67 (%98,5) 3 (%37,5) 0,000*

n (%) Positive 1 (%1,5) 5 (%62,5)

HLADQ2 Negative 25 (%41,0) 2 (%28,6) 0,420

n (%) Positive 36 (%59,0) 5 (%71,4)

HLADQ8 Negative 28 (%45,9) 0 (%0,0) 0,019*

n (%) Positive 33 (%54,1) 7 (%100,0)

*= p<0.05 statistically significant.

Clinical characteristics of celiac patients are presented in Table 5. Selective IgA deficiency was described in 1 CD-case. Anti-tTGA and EMA negativity was observed in a CD-patient due to the selective IgA deficiency, then HLA-DQ2/ HLA-DQ8 was found positive in this patient. In addition, HLA-DQ2/DQ8 positivity was observed in 62.5% (n=5) of CH patients. HLA-DQ8 was found to be positive in all CD patients

I Clinical characteristics of CD patients.

except a single patient with missing data. While a high rate of vitamin D deficiency was detected in the CD-cases (75%), B12 deficiency was detected in only one CD-case. All patients with positive laboratory findings for CD underwent duodenal biopsy by gastroscopy and after histopathological evaluation; 2 were identified as Marsh Type 2, 2 were Marsh Type 3b and 2 were Marsh Type 3c.

No Gender Age TG IgA TG IgG Total IgA EMA IgA EMA IgG HLADQ2 HLADQ8 Vit. D Vit B12 Folate MARSH

1 Female 104 + + N + + + + 23,0 426 19,3 Type 1

2 Male 118 + + N + + 13,4 493 9,3 Type3C

3 Male 86 + - N + - + + 38,8 549 6,3 Type 2

4 Female 48 + + N + + + + 10,7 649 14,4 Type3C

5 Female 188 + + N + + - + 21,0 243 19,4 Type3B

6 Male 149 - + L - + + + 36,2 443 7,9 Type 1

7 Male 183 + + N + + + + 22,9 244 11,2 Type 3B

8 Female 142 - + N + - - + 12,7 157 20,7 Type 2

*N: Normal, L: Low

Discussion

The risk of CD is significantly associated with female gender, young age and DM diagnosis especially at early ages [3]. In addition, patients mostly diagnosed with T1DM (75-80%) before the onset of CD. Classic CD disease often diagnose aged between 2 to 3 years, while the mean age of T1DM comorbid CD is about 8 years at diagnosis [12]. Rami et al. reported a mean

age of T1DM diagnosis as 6.5 ± 4.1 years and CD diagnosis as 10.0 ± 5.4 years in 98 children [13]. Similarly, Deja et al. reported a mean age of 7.39 years for T1DM and 8.43 years for CD diagnosis in 27 children. Researchers also documented no statistically significant differences according to the gender[14]. In accordance with these data, the mean age at diagnosis of DM was 95,67±52,85 months and CD was 109,20±56,10 months

Journal of Clinical Medicine of Kazakhstan: Volume 2, Number 56, Issue 2020

in our study. Additionally, there was no significant differences found according to the gender.

In recent years it has been reported that the prevalence of CD in patients with T1DM has increased in worldwide and ranged from 4.4% to 11.1% in studies both with children and adults[12]. The CD prevalence in T1DM ranging from 4.4 to 6.4% in European countries and 10.5-11.1% in South America and India [15]. Ergur et al. documented a CD prevalence of 7,8% in 38 children with T1DM[16]. Supportively, the overall prevalence of CD in T1DM was found as 10.5% in present study.

The clinical presentation of the CD in TIDM is generally silent. Joshi et al. found positive TGA in 11 of 71 screened children, and 5 were (7,04%) diagnosed with CD histopathologically. The researchers reported that the majority of CD-positive patients (64%) were asymptomatic and frequently reported symptoms were puffiness, abdominal pain, and diarrhea. Moreover, researchers reported 45.5% vitamin D deficiency and 54.5% iron deficiency anemia in CD patients [17]. Tsouka et al. revealed 41-undiagnosed CD patients as a result of 771 serologically screened children with T1DM between 2005 and 2011 years. In same study 21 of 41 patients were asymptomatic and 10 of them had vitamin D deficiency [18]. Similarly in our study the 46.1% of the all patients and 37.5% of the CD patients were asymptomatic. The most common symptom reported in our patients was abdominal pain with a ratio of 32,9% followed by constipation (25.0%), and diarrhea (11,8%) respectively. There were no statistically significant differences found between the CD and T1DM groups according to the age, BMI and laboratory findings. Vitamin D deficiency was detected in 88,2% of all patients, folic acid deficiency in 1.3% and vitamin B12 deficiency in 9.2%. Iron-deficiency anemia detected in only 1 patient and a high rate of vitamin D deficiency was detected in the CD-cases (75%).

Although histopathological evaluation for CD diagnosis in T1DM patients is the gold standard, serological screening via TGA and EMA is highly valuable particularly in detecting asymptomatic patients. As a result of serologic screening in 268 patients with T1DM, Ozdemir et al. reported 8 EMA positive, 13 TGA positive patients and normal IgA levels in all patients. Researchers confirmed CD diagnosis in 5 (1.9%) patients. They revealed positive EMA and TGA in all of these 5 patients, additionally reported 100%, 100% sensitivity, and 95%, 86% specificity for these two tests respectively [19]. Yildirmaz et al. reported 16 (7.3%) TGA positive cases in 218 T1DM patients and CD diagnosis confirmed in 11 (5%) of these TGA positive cases. As a result of histopathological evaluation; 3 were identified as Marsh Type 2, 1 were Marsh Type 3a, 4 were Marsh Type 3b and 3 were Marsh Type 3c in same study [20]. Bolad et

al. documented 10,1% TG and 7,2% EMA positivity in a study comparing 69 T1DM patients with healthy controls. Researchers also noted significantly higher TGA-G titres than healthy controls [21]. Singh et al. detected positive CD serology in 43 (34.1%) of 126 T1DM patients. The CD diagnosis confirmed in 17 patients (13.5%) by histopathological examination [22]. Supportively in present study, anti-tTGA was positive in 14,5%, and anti-EMA was positive in 13,2% of all patients. Of the CD patients, 6 were anti-tTGA and 7 were EMA positive. According to the histopathological evaluation of CD patients; 2 were identified as Marsh Type 2, 2 were Marsh Type 3b and 2 were Marsh Type 3c.

HLA plays a prominent role in the genetic predisposition to celiac disease, supportively there is a strong association between HLA-DQ2/DQ8 and CD. This relationship is so strong that CD is rarely found in individuals with HLA-DQ2 and HLA-DQ8 negative. HLA-DQ2 is responsible for the prevalence of CD in T1DM[23]. Ghawil et al. detected 75% HLADQ2, 21% HLA-DQ2 / HLA-DQ8 and 4% HLA-DQ8 in 24 CD patients with T1DM (n=218) [24]. Dezsofi et al. defined DQ2 / DQ8 heterozygosity as a risk factor for both CD and T1DM in a study consisted of 80 children with T1DM, 100 children with CD, and 47 children with CD+T1DM. Researchers stated that homozygous HLA-DQ8 genotype in T1DM patients and HLA-DQ2 / DQ8 heterozygosity in CD+T1DM patients were significantly higher than CD- patients and healthy controls [25]. In addition, HLA-DQ8 was the most frequently detected genotype in a study conducted by Ergur et al. among CD patients [16]. In accordance with these data, HLADQ2 was positive in 60.3% and HLA-DQ8 was positive in 58.8% of all patients in our study. HLA-DQ8 ratio was significantly higher in patients diagnosed with CD than the T1DM patients. Moreover, HLA-DQ2/DQ8 positivity was observed in 62.5% (n=5) of CD patients. Additionally, HLA-DQ8 was found to be positive in all CD patients except a single patient with missing data. Furthermore, HLA-DQ2/HLA-DQ8 was found positive in a patient with selective IgA deficiency.

In conclusion, our findings have demonstrated the increasing prevalence of CD in children with T1DM. Particularly the higher risk of asymptomatic CD in T1DM patients, revealed the diagnostic value of serological screening. Furthermore, increased HLA-DQ2 and HLA-DQ8 positivity, which are more prominent in case of selective IgA deficiency, clearly demonstrates the requirement of routine total IgA and HLA analysis in serological screening.

Disclosures: There is no conflict of interest for all authors.

References

1. Volta U, Tovoli F, Caio G. Clinical and immunological features of celiac disease in patients with type 1 diabetes mellitus. Expert review of gastroenterology & hepatology. 2011; 5(4):479-87. https://doi.org/10.1586/egh.11.38

2. Triolo TM, Armstrong TK, McFann K, Yu L, Rewers MJ, Klingensmith GJ, Eisenbarth GS, Barker JM. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes care. 2011; 34(5):1211-3. https://doi.org/10.2337/dc10-1756

3. Pham-Short A, Donaghue KC, Ambler G, Phelan H, Twigg S, Craig ME. Screening for celiac disease in type 1 diabetes: a systematic review. Pediatrics. 2015; 136(1):e170-6. https://doi.org/10.1542/peds.2014-2883

4. Mahmud FH, Murray JA, Kudva YC, Zinsmeister AR, Dierkhising RA, Lahr BD, Dyck PJ, Kyle RA, El-Youssef M, Burgart LJ, Van Dyke CT. Celiac disease in type 1 diabetes mellitus in a North American community: prevalence, serologic screening, and clinical features. InMayo Clinic Proceedings. 2005; 80(11):1429-1434). Elsevier. https://doi.org/10.4065/80.11.1429

5. Elfström P, Sundström J, Ludvigsson JF. Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes. Alimentary pharmacology & therapeutics. 2014; 40(10):1123-32. https://doi.org/10.1111/apt.12973

6. Ludvigsson JF, Ludvigsson J, Ekbom A, Montgomery SM. Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. Diabetes Care. 2006; 29:2483-8. https://doi.org/10.2337/dc06-0794

7. Valerio G, Maiuri L, Troncone R et al. Severe clinical onset of diabetes and increate prevalence of other autoimmune diseases in children with celiac disease diagnosed before diabetes mellitus. Diabetologica. 2002; 45 (12):1719-1722. https://doi.org/10.1007/s00125-002-0923-5

8. Leeds JS, Hopper AD, Hadjivassiliou M, Tesfaye S, Sanders DS. High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease. Diabetes care. 2011; 34(10):2158-63. https://doi.org/10.2337/dc11-0149

9. Holmes GK. Coeliac disease and Type 1 diabetes mellitus-the case for screening. Diabetic Medicine. 2001; 18(3):169-77. https://doi. org/10.1046/j.1464-5491.2001.00498.x

10. Pham-Short A, Donaghue KC, Ambler G, Phelan H, Twigg S, Craig ME. Screening for celiac disease in type 1 diabetes: a systematic review. Pediatrics. 2015; 136(1):e170-6. https://doi.org/10.1542/peds.2014-2883

11. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. European journal of gastroenterology & hepatology. 1999; 11(10):1185-94. https://doi.org/10.1097/00042737-199910000-00019

12. Camarca ME, Mozzillo E, Nugnes R, Zito E, Falco M, Fattorusso V, Mobilia S, Buono P, Valerio G, Troncone R, Franzese A. Celiac disease in type 1 diabetes mellitus. Italian journal of pediatrics. 2012; 38(1):10. https://doi.org/10.1186/1824-7288-38-10

13. Rami B, Sumnik Z, Schober E, Waldhör T, Battelino T, Bratanic N, Kürti K, Lebl J, Limbert C, Madacsy L, Odink RJ. Screening detected celiac disease in children with type 1 diabetes mellitus: effect on the clinical course (a case control study). Journal of pediatric gastroenterology and nutrition. 2005; 41(3):317-21. https://doi.org/10.1097/01.mpg.0000174846.67797.87

14. Deja G, Myrda A, Jarosz-Chobot P, Siekiera U. The assessment of autoimmunological status and prevalence of different forms of celiac disease among children with type 1 diabetes mellitus and celiac disease. Mediators of inflammation. 2008. https://doi. org/10.1155/2008/285989

15. Akirov A, Pinhas-Hamiel O. Co-occurrence of type 1 diabetes mellitus and celiac disease. World journal of diabetes. 2015; 6(5):707. https://doi.org/10.4239/wjd.v6.i5.707

16. Ergür AT, ÖQal G, Berberoglu M, Adiyaman P, §iklar Z, Aycan Z, Evliyaoglu O, Kansu A, Girgin N, Ensari A. Celiac Disease and Autoimmune Thyroid Disease in Children with Type 1 Diabetes Mellitus: Clinical and HLA- Genotyping Results. Journal of clinical research in pediatric endocrinology. 2010; 2(4):151. https://doi.org/10.4274/jcrpe.v2i4.151

17. Joshi R, Madvariya M. Prevalence and clinical profile of celiac disease in children with type 1 diabetes mellitus. Indian journal of endocrinology and metabolism. 2015; 19(6):797. https://doi.org/10.4103/2230-8210.167555

18. Tsouka A, Mahmud FH, Marcon MA. Celiac disease alone and associated with type 1 diabetes mellitus. Journal of pediatric gastroenterology and nutrition. 2015; 61(3):297-302. https://doi.org/10.1097/MPG.0000000000000789

19. Özdemir H, Kutlu T, Özdemir M, Isguven P, Erkan T, Cokugras FC, Dervisoglu S. Prevalence of celiac disease in children with type 1 diabetes mellitus and the accuracy of serological tests. Medicine. 2018; 7(4):882-5. https://doi.org/10.5455/medscience.2018.07.8901

20. Yildirmaz S, Altay D, Esen I, Dogan Y. Prevalence of Celiac Disease in Children With Type 1 Diabetes Mellitus in Southeast Region of Turkey. International Journal of Clinical Pediatrics. 2016; 5(2):32-5. https://doi.org/10.14740/ijcp239w

21. Bolad A, Farouk A, Lutfi MF, Nemeiri M. Association between diabetes mellitus type 1 and celiac disease: case-control study among Sudanese patients 2009-2011. Sudan Journal of Medical Sciences. 2012; 7(2):105-10.

22. Singh P, Seth A, Kumar P, Sajjan S. Coexistence of celiac disease & type 1 diabetes mellitus in children. The Indian journal of medical research. 2017; 145(1):28. https://doi.org/10.4103/ijmr.IJMR_199_15

23. Akirov A, Pinhas-Hamiel O. Co-occurrence of type 1 diabetes mellitus and celiac disease. World journal of diabetes. 2015; 6(5):707. https://doi.org/10.4239/wjd.v6.i5.707

24. Ghawil M, Miotti V, Tonutti E, Tenore A, Hadeed I, Sindici C, Visentini D, Morgham A, Abusrewil S. HLA-DQ types of celiac disease in Libyan children with type 1 diabetes mellitus. European journal of gastroenterology & hepatology. 2012; 24(1):59-63. https://doi. org/10.1097/MEG.0b0 13e32834d09d4

25. Dezsofi A, Szebeni B, Hermann CS, Kapitany A, Veres G, Sipka S, Körner A, Madacsy L, Korponay-Szabo I, Rajczy K, Arato A. Frequencies of genetic polymorphisms of TLR4 and CD14 and of HLA-DQ genotypes in children with celiac disease, type 1 diabetes mellitus, or both. Journal of pediatric gastroenterology and nutrition. 2008; 47(3):283-7. https://doi.org/10.1097/ MPG.0b013e31816de885

How to cite this article: Hasret Ayyildiz Civan, Esra Papatya Cakir. Screening of celiac disease in children and adolescents with type 1 diabetes mellitus. J Clin Med Kaz. 2020; 2(56):21-26