Kostas Kakleas

Screening for Associated Autoimmunity in Children and Adolescents with Type 1 Diabetes Mellitus (T1DM)

Background/Aims: Type 1 diabetes (T1DM) is associated with autoimmune thyroid, celiac, autoimmune gastric and Addison’s disease. Our aim was to investigate the prevalence of associated autoantibodies in relation to the demographic and β-cell autoantibody status (anti-GAD). Methods: Antibodies against thyroid peroxidase (anti-TPO), thyroglobulin (anti-Tg), tissue transglutaminase (anti-tTG IgA), parietal cells (APCA) and adrenal tissue (AAA) were measured in 144 children with T1DM with a mean ± SD age of 12.3 ± 4.6 years and a diabetes duration of 4.6 ± 3.8 years. Results: The prevalence of antibody positivity among our patients was: anti-GAD 53.2%, anti-thyroid (anti-TPO 17.4%, anti-Tg 11.1%); anti-tTG IgA 7.6%, APCA 4.0%, and AAA 0%. Among the children with positive anti-thyroid antibodies, 60% developed autoimmune thyroiditis, while among those anti-tTG IgA positive, 62.5% developed biopsy-confirmed celiac disease. Female gender was more frequent among anti-tTG IgA-positive patients (OR 4.47, p = 0.068), while increasing age was associated with anti-Tg positivity (OR 22.9, p = 0.041). The presence of anti-thyroid antibodies was associated with the presence of anti-GAD (OR 1.45, p = 0.01) and parietal cell antibodies (OR 4.98, p = 0.09). Conclusion: Among T1DM patients, the prevalence rates of anti-thyroid and parietal cell antibodies increased with age and diabetes duration. As the presence of anti-GAD was associated with gastric and thyroid autoimmunity, it could serve as marker for the development of additional autoimmunity in adolescents with diabetes.

Factors for thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus.

Abstract Introduction. Type 1 diabetes mellitus (T1DM) is associated with an autoimmune reaction to thyroid antigens including thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg). Aims. We determined in children with T1DM the relationship of positive anti-thyroid antibodies to potential risk factors, including, age, gender, duration of diabetes, and glutamic acid decarboxylase antibodies (anti-GAD). Materials and methods. We studied 144 children and adolescents with T1DM. Their age was 12.3 ± 4.6 (mean ± SD) years, and duration of diabetes was 4.6 ± 3.8 years. Anti-thyroid antibodies were determined using a luminescence method and anti-GAD using an enzyme-linked immunosorbent assay. Results. The prevalence rates of anti-thyroid antibodies among the children with T1DM in our study were: anti-TPO (17.4%), anti-Tg (11.1%), and of both anti-thyroid antibodies (10.4%). The presence of serum anti-thyroid antibodies was positively associated with age (16.6 years in those with positive tests versus 12.0 years in those with negative tests, P = 0.027), duration of diabetes (7.4 versus 4.3 years, P = 0.031), and serum TSH (Thyroid-stimulating hormone) levels (4.8 versus 2.3 μIU/mL, P = 0.002). The presence of both anti-thyroid antibodies was associated with female sex (boys: 4/75 (5.3%), girls: 11/69 (15.9%), chi-square = 6.44, P = 0.04). Subclinical autoimmune thyroiditis (SAIT) was present in 55.5% of the patients with thyroid antibody-positivity and was positively associated with age (16.6 versus 12.0 years, P = 0.001) and diabetes duration (7.6 versus 4.2 years, P = 0.001). Multiple logistic regression analysis revealed that the development of anti-thyroid antibodies was predicted by: 1) the presence of anti-GAD (odds ratio (OR) 1.45, 95% confidence interval (CI) 1.09–1.92), 2) the presence of a second anti-thyroid antibody (OR 134.4, 95% CI 7.7–2350.3), and 3) older age (OR 22.9, 95% CI 1.13–463.2). Conclusions. Thyroid autoimmunity was associated with female gender, increasing age, long diabetes duration, the persistence of anti-GAD, and with TSH elevation, indicating subclinical hypothyroidism.

Psychological stress as a factor potentially contributing to the pathogenesis of Type 1 diabetes mellitus

Diabetes mellitus Type 1 (T1D) is an autoimmune disorder attributed to both genetic and environmental factors. The aim of this study was to identify certain stressful conditions potentially associated with the pathogenesis and/or expression of T1D. The study group included 107 children with diabetes (CD) and 153 controls of comparable age and gender distribution at diagnosis of T1D (10.73±3.62 yr vs 9.59 ±3.42 yr, respectively). The parents of both groups completed a questionnaire on socioeconomic status and stressful life events or adverse situations at home and school. Results: Lower social class was more prevalent among the mothers of CD (p=0.002) in comparison with the controls. Stressful life events (parental death, divorce, parental job loss), problems at home (parental abuse, parental dispute) and at school (poor performance) were more frequently observed in the CD group than in the controls (parental death: p=0.05, job loss: p=0.05, parental abuse: p=0.002, quarrels between parents: p=0.05, and among siblings p=0.002, poor school performance: p=0.037). A stepwise logistic regression analysis indicated that lower maternal social class [odds ratio (OR): 3.86, 95% confidence interval (CI): 1.37,10.9], parental dispute or divorce (OR: 2.78, 95%CI: 0.97,7.95), body mass index (OR: 0.87, 95%CI: 0.78,0.97), increasing age (OR: 1.14, 95%CI: 1.02,1.27) were the factors potentially influencing the occurrence of T1D, while the 2-yr period prior to diabetes occurrence emerged as the most important one (OR: 2.49, 95%CI: 1.14,5.42). Conclusion: Children with diabetes seem to experience certain stressful conditions with significantly increased frequency compared to controls, especially during the 2 yr preceding the diagnosis of T1D, with a higher clustering in those of lower social class. The resultant stress possibly contributes to the development of T1D in genetically susceptible individuals.

Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM).

Type 1 diabetes (T1DM) is an autoimmune disease with aberrant immune responses to specific β-cell autoantigens, resulting in insulin deficiency. Children and adolescents with T1DM may also develop organ-specific multiple autoimmunity in the context of APS (autoimmune polyendocrine syndrome) type 1, 2 or 3. The most frequently encountered associated autoimmune disorders in T1DM are autoimmune thyroid, followed by celiac, autoimmune gastric disease and other rare autoimmune conditions. There are limited previous studies on the prevalence of associated autoimmunity, especially multiple, in children with T1DM. The present review reports on the classification of autoimmune diabetes, and on the prevalence, pathogenesis, predictive factors and clinical presentation of pancreatic autoimmunity and of all associated autoimmune disorders in children with T1DM. The impact of associated autoimmunity on diabetes control and general health is also discussed, along with suggestions regarding screening strategies and follow-up for early detection and management of the autoimmunity.

The prevalence and risk factors for coeliac disease among children and adolescents with type 1 diabetes mellitus

AIMS Our aim was to determine in children with T1DM the prevalence of positive antibodies against tissue transglutaminase (anti-tTG IgA) as indices of coeliac disease (CD), as well as its clinical presentation, its determinants and its association with thyroid (anti-TG, anti-TPO) and pancreatic b-cell autoimmunity (anti-GAD). METHODS The study included 105 children and adolescents with T1DM, aged (mean±SD) 12.44±4.76 years, with a T1DM duration of 4.41±3.70 years. RESULTS Fifty of our patients (47.6%) were positive for anti-GAD, 9/105 (8.6%) for anti-tTG IgA and 21/105(20%) for anti-thyroid antibodies. The anti-tTG IgA (+) children, in comparison with the rest of the study population, were of younger age (9.31 vs. 12.74 years, p=0.038), shorter diabetes duration (2.16 vs. 4.62 years, p=0.056) and had mild growth impairment (height SDS: -0.55 vs. +0.20, p=0.055). Univariate logistic regression analysis revealed that the presence of anti-tTG IgA (+) was associated with younger age and shorter T1DM duration. Only 5/9 (55.6%) children with high titres of anti-tTG IgA developed mild gastrointestinal symptoms or growth retardation and had histological findings typical of CD. CONCLUSIONS The prevalence of anti-tTG IgA positivity among T1DM children was 8.6% and its occurrence was associated with younger age and short diabetes duration. Since CD presents in T1DM patients asymptomatically or with non-specific symptoms, periodic autoantibody screening is necessary for its early diagnosis.

Plasma high sensitivity C-reactive protein and its relationship with cytokine levels in children with newly diagnosed type 1 diabetes and ketoacidosis

BACKGROUND High-sensitivity C-reactive protein (hs-CRP) and pro-inflammatory cytokines have been suggested as sensitive markers of endothelial dysfunction. Our aim was to monitor plasma hs-CRP levels at different time-points and in different degrees of ketoacidosis severity, its association with cytokine levels and its role as a marker of severe ketoacidosis complications. PATIENTS AND METHODS We studied in 38 newly diagnosed children with type 1 diabetes and ketoacidosis, aged 7.7 ± 3.1 years, hs-CRP, white blood cell count (WBC), and plasma levels of cytokines IL-1β (interleukin-1β), IL-2, IL-6, IL-8, IL-10, TNF-α (tumor necrosis factor-α) prior to and during DKA management. RESULTS On admission, the levels of WBC, PMN, IL-6 and IL-10 were elevated, but were all reduced within 120 h after ketoacidosis management. In the group with moderate/severe ketoacidosis, but not in mild ketoacidosis, hs-CRP levels were significantly reduced at 24h (p=0.021), WBC and IL-6 at 120 h (p=0.003), while IL-10 was prematurely reduced at 6-8h (p=0.008). Moreover hs-CRP was significantly associated with WBC (p=0.023) and IL-6 (p=0.028) on admission, with IL-6 (p=0.002) and IL-8 (p=0.014) at 24h and with IL-10 (p=0.027) at 120 h. The above were not observed in the group with mild ketoacidosis. CONCLUSIONS In the children with moderate/severe diabetic ketoacidosis of our study, increased levels of hs-CRP and IL-6 were observed, together with leukocytosis and neutrophilia, without the presence of infection. As hs-CRP was found to be strongly associated with the inflammatory IL-6, the prolonged elevation of hs-CRP levels in children with severe ketoacidosis could serve as a marker for the development of its severe complications.

QT interval prolongation in association with impaired circadian variation of blood pressure and heart rate in adolescents with Type 1 diabetes.

Aims  The aim of our study was to assess diurnal blood pressure (BP) and heart rate variability and their possible relationship to the duration of the QT interval in adolescents with Type 1 diabetes.

Gastric Autoimmunity in Children and Adolescents with Type 1 Diabetes: A Prospective Study

Background/Aims: Type 1 diabetes (T1DM) is associated with gastric autoimmunity, which is characterized by the presence of parietal cell antibodies (APCA). We investigated gastric autoimmunity prevalence in T1DM children, its manifestations, determinants and association with thyroid gland (anti-Tg, anti-TPO) and pancreatic β-cell autoimmunity (anti-GAD) at baseline and 4 years later. Methods: The initial cohort (D1) included 97 children with T1DM. At follow-up after 4 years (D2), 84.5% of participants were evaluated. We assessed APCA, anti-Tg, anti-TPO, and anti-GAD presence, as well as symptoms of gastritis. APCA-positive patients were evaluated with gastrin, B12, ferritin levels and were submitted to gastroscopy. Results: Thyroid antibody positivity was increased among the APCA-positive patients. Four years later, among initially APCA-positive patients, 2/6 became APCA negative, while 4/6 developed high titers of APCA. On gastroscopy, 2 patients had chronic hypertrophic gastritis and one Helicobacter pylori gastritis. Conclusions: Gastric autoimmunity was associated with thyroid autoimmunity and anti-GAD persistence. After 4 years, the majority of APCA-positive patients developed high titers of APCA and mild symptoms of gastritis. Thus, patients with T1DM, and in particular those with thyroid and/or pancreatic autoimmunity, should have periodic autoantibody screening for the early diagnosis and follow-up of gastric autoimmunity.

Prevalence of allergic symptoms among children with diabetes mellitus type 1 of different socioeconomic status

Abstract:  The aim of the study was to assess the possible associations between allergies and type 1 diabetes mellitus (DM1), stratified by social class. We studied 127 children with DM1 with a median age of 10.8 yr and 150 controls of comparable age and sex distribution. The parents completed questionnaires on their education and occupation and on their children’s history of allergic symptoms, breast‐feeding, viral infections, and measles–mumps–rubella (MMR) vaccination. Lower family’s social class was more frequently encountered among the DM1 families than in the controls (OR = 0.56, 95% CI: 0.35–0.92). The occurrence of any allergic symptoms among children with DM1 (35.45%) was not significantly different from the controls (38.78%), neither in the total group (OR = 0.87, 95% CI: 0.52–1.45) nor in the stratified analysis by social class. Similar findings were observed regarding the different types of allergic symptoms. In the univariate analysis, breast‐feeding, the experience of viral infections, and MMR vaccination were found to be protective of DM1 presentation in both upper and lower social classes. In the multiple logistic regression analysis, the experience of more than 2 infections/yr (OR = 0.12, 95% CI: 0.04–0.34), the origin from middle and upper social classes (OR = 0.42, 95% CI: 0.22–0.80) and breast‐feeding (OR = 0.58, 95% CI: 0.31–1.07) were protective of DM1 occurrence. In children with DM1, the presence of allergic symptoms was not associated with the development of DM1. Among the environmental factors, the origin from middle or upper social classes, breast‐feeding, the experience of viral infections, and MMR vaccination were found to have a protective effect on DM1 presentation.

Multiple autoimmunity, type 1 diabetes (T1DM), autoimmune thyroiditis and thyroid cancer: is there an association? A case report and literature review.

Abstract Type 1 diabetes mellitus (T1DM) is characterized by selective autoimmune destruction of pancreatic b-cells, resulting in insulin deficiency. Associated autoimmune disorders, such as celiac disease, autoimmune thyroiditis, and gastritis, can coexist in patients with T1DM. These disorders are characterized by the presence of antibodies against tissue transglutaminase (anti-tTG-IgA), thyroglobulin, and thyroid peroxidase (anti-TG, anti-TPO), as well as antibodies against gastric parietal cells. Children with T1DM may also develop organ-specific multiple autoimmunity, with the coexistence of one or more autoimmune disorders. Furthermore, there is a lot of controversy regarding the role of thyroid autoimmunity in the pathogenesis of thyroid cancer. We present a child with T1DM and multiple autoimmunity including autoimmune Hashimoto’s thyroiditis (HT), who developed thyroid cancer. The literature on the prevalence of associated autoimmunity in children with T1DM and the prevalence, pathogenesis, and timely diagnosis of thyroid cancer among patients with HT is also reviewed.