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

AUTREV-01716; No of Pages 17 Autoimmunity Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

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Kakleas Kostas a, Soldatou Alexandra a, Karachaliou Feneli b, Karavanaki Kyriaki a,⁎ a

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Article history: Received 28 April 2015 Accepted 6 May 2015 Available online xxxx

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Keywords: Associated autoimmune diseases T1DM Children Polyglandular autoimmune syndromes

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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 diseases. 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 as well as suggested screening and follow-up strategies for early detection and management are also discussed. © 2015 Published by Elsevier B.V.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Diagnosis and classification of autoimmune diabetes mellitus . . . . . . . . . . . . . 1.1.1. Pathogenesis of autoimmunity in diabetes . . . . . . . . . . . . . . . . . . 1.1.2. T1DM and pancreatic autoimmunity . . . . . . . . . . . . . . . . . . . . 1.1.3. GADA and neurological syndromes . . . . . . . . . . . . . . . . . . . . . 1.1.4. Autoimmune polyendocrine syndromes . . . . . . . . . . . . . . . . . . . 1.1.5. Familial autoimmune diseases . . . . . . . . . . . . . . . . . . . . . . . Additional autoimmune diseases in children and adolescents with T1DM . . . . . . . . . . . 2.1. T1DM and thyroid autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Screening for autoimmune thyroid disease in T1DM patients . . . . . . . . . 2.1.2. Autoimmune thyroiditis and thyroid cancer . . . . . . . . . . . . . . . . . 2.2. T1DM and gastric autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Thyrogastric autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . 2.3. T1DM and coeliac disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Etiopathogenesis of CD in T1DM patients . . . . . . . . . . . . . . . . . . 2.3.2. The key environmental trigger in T1DM: the role of viruses and/or wheat gluten 2.3.3. Diagnosis of CD in T1DM . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.4. Screening for CD in T1DM patients . . . . . . . . . . . . . . . . . . . . . 2.3.5. Association of CD with thyroid autoimmunity . . . . . . . . . . . . . . . . 2.4. T1DM and adrenal autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. T1DM and vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. T1DM and non-organ-specific autoimmune diseases . . . . . . . . . . . . . . . . . 2.7. T1DM and multiple autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . .

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Diabetic Clinic, 2nd Department of Pediatrics, University of Athens, “P&A Kyriakou” Children's Hospital, Athens, Greece Department of Endocrinology—Growth and Development, “P. & A. Kyriakou” Children's Hospital, Athens, Greece

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Associated autoimmunity in children and adolescents with type 1 diabetes mellitus (T1DM)

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⁎ Corresponding author at: Diabetic Clinic, Second University Department of Pediatrics, “P. & A. Kyriakou” Children's Hospital, Goudi 11527, Athens, Greece. Tel.: +30 210 77 26 488; fax: +30 210 777 43 83. E-mail address: [email protected] (K. Kyriaki).

http://dx.doi.org/10.1016/j.autrev.2015.05.002 1568-9972/© 2015 Published by Elsevier B.V.

Please cite this article as: Kostas K, et al, Associated autoimmunity in children and adolescents with type 1 diabetes mellitus (T1DM), Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.05.002

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3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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The term “autoimmune diabetes mellitus” encompasses disorders with heterogeneous epidemiology, etiopathogenesis, diagnostic criteria and management, distinct from type 2 diabetes (T2DM).

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1. Type 1 diabetes is a condition with pancreatic β-cell destruction leading to insulin deficiency. There are two forms of T1DM: a. Type 1A or immune based diabetes Type 1A diabetes (T1A) results from cellular-mediated autoimmune destruction of β-cells in the pancreas; abnormal activation of T-cells leads to insulitis and production of antibodies against β-cells (humoral B cell response), which may constitute useful markers of immune destruction [9]. However, recent studies showed that, for unknown reasons, β-cell proliferation precedes insulitis in genetically susceptible individuals [10]. Some argue whether T1A is a solely T-cell mediated disease, as the degree of insulitis is discrete, it affects few islets and is present in 1/3 of cases of overt T1A diabetes. The failure of immunosuppressant medication and the slow progression of T1A are also in favor of this hypothesis. It has been suggested that T1A is more likely to be due to inflammatory disease, with clinical characteristics arising from β-cell loss. Although there is no evidence that the presence of autoantibodies is associated with the pathogenetic mechanism of T1A diabetes, the presence and persistence of multiple autoantibodies increase the risk for progression to clinical disease. In non-diabetic individuals islet autoantibodies are strong predictors for the later development of T1A. Currently measurements

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2. Fulminant T1DM. Fulminant T1DΜ is defined as a subtype of type 1 diabetes, with a remarkably acute onset, attributed to direct destruction of pancreatic β-cells by viruses [16]. It has been described in Japan and other East Asian countries, based on the following criteria [17]: a. Presence of ketoacidosis soon after the onset of hyperglycaemia, plasma glucose levels N/288 mg/dl and HbA1c levels b 8.5%, fasting c-peptide level b 0.3 and postprandial b0.5 ng/ml at the onset of disease. b. Presence of common-cold-like and gastrointestinal symptoms before onset, pregnancy and increased serum pancreatic enzyme levels. c. Early development of microvascular complications [18]. 3. Latent autoimmune diabetes in adults (LADA). Latent autoimmune diabetes in adults (LADA) is characterized by a unique combination of insulin resistance and autoimmunity [19] defined by: 1. GADΑ antibody positivity, 2. Age at onset N35 years, and 3. Insulin dependence at diagnosis (at least 6 months). Thus patients with LADA have pancreatic autoantibodies, fasting and stimulated c-peptide levels lower than those observed in patients with T2DM and insulin secretion intermediate between patients with T1DM and T2DM. A decline in both insulin and stimulated c-peptide secretion is expected only a few years after diagnosis.

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Type 1 diabetes mellitus (T1DM) is an autoimmune disease, caused by the destruction of insulin producing pancreatic β-cells [1]. The autoimmune nature of T1DM has been proven with the detection of autoantibodies against pancreatic islet cells and their infiltration by T-cells, B-cells and macrophages as well as the presence of cellular immunity abnormalities [2,3]. Potential triggers of the autoimmune process include genetic and environmental factors [4]. Furthermore autoimmunity may involve other organs resulting in organ specific autoimmune disease, or several organs and tissues resulting in non-organ-specific autoimmune disease, e.g. rheumatoid arthritis. The most frequent organspecific autoimmune diseases associated with T1DM in childhood are autoimmune thyroid disease, coeliac disease and autoimmune gastric disease. Organ-specific autoimmune diseases may be part of an autoimmune polyendocrine syndrome (APS), defined as a functional disorder of two or more glands. Among the three different types of APS, type 1 is characterized by the presence of Addison's disease, mucocutaneous candidiasis and autoimmune hypoparathyroidism, but can also present with T1DM, Grave's disease, hypogonadism, vitiligo or pernicious anemia [5,6]. APS type 2 can present with Addison's disease, autoimmune thyroiditis, T1DM, hypogonadism, vitiligo, myasthenia gravis and alopecia. APS type 3A is associated with T1DM and autoimmune thyroiditis, but also with growth hormone deficiency and other abnormalities, whereas in APS type 3C T1DM is associated with psoriasis and coeliac disease [7, 8]. The main aim of this review is to explore the presence of associated autoimmunity in children and adolescents with T1DM, to focus on the predictive factors for its development and to review the management plan regarding each type of autoimmune disease.

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of pancreatic glucamic acid decarboxylase (GADA) and tyrosine phosphatase (IA2A) autoantibodies are recommended for initial confirmation of suspected diagnosis of T1A [9]. Genetic susceptibility to T1A has been linked to HLA DR and DQ genotypes and T1A genes expressed in the pancreatic β-cells. Environmental factors have also been implicated, such as viruses (Enterovirus, Cytomegalovirus, Mumps virus and Ljungan virus) [11], nutrition (early onset of cow's milk-based formulas) [12], or low vitamin D levels [13]. b. T1B, or idiopathic diabetes T1B (idiopathic) is a type of diabetes with no autoimmune markers, in which the reason for β-cell destruction is unknown [14]. T1B mainly occurs in Asian or African people, who have varying degrees of insulin deficiency between episodes of ketoacidosis [15].

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Based on the titre of GADΑ, patients with LADA are classified in two 156 different groups of with characteristic clinical, immune and genetic 157 features. 158 159

a. LADA-type 1: The presence of a high titre of GADΑ antibodies in combination with islet cell antibodies (ICA) in patients with LADA is characteristic of insulin deficiency with the clinical features of T1DM. These patients have more profound autoimmunity and dependency on insulin, higher levels of HbA1c, lower BMI, fewer diabetes-related complications and signs of metabolic syndrome than single antibody-positive or antibody negativepatients and are more likely to present with an additional autoimmune condition [20]. b. LADA-type 2: LADA-type 2 is characterized by single antibody positivity, low titre of GADΑ antibodies and the clinical and metabolic phenotype of T2DM [21]. It is associated with insulin resistance [22], with 50% of insulin secretory failure occuring within the first 4 years.


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AICD. On the other hand naïve/effector cells become more sensitive to 238 AICD with proliferation. This pattern of homeostasis results in the phys- 239 iological resolution of inflammation [36]. 240

4. Double diabetes or 1.5 diabetes. Double diabetes (DD) is characterized by the presence of hyperglycaemia in children and adolescents with a combination of markers of type 1 and type 2 diabetes [23]. The presence of GADA, IA2A and endogenous insulin autoantibodies (IAA) typically define DD in patients with T2DM. In children the diagnosis of DD includes the presence of clinical features of T2DM (obesity and insulin resistance), some features of type 1 diabetes, family history for type 1 and type 2 diabetes and islet cell antibody positivity [23]. 5. Type 2 diabetes Although beta cell dysfunction is considered the leading mechanism of overt T2DM, the main cause of the disease remains largely unknown [24]. According to recent data, immune factors may be involved in the pathogenesis of insulin resistance and T2DM [25]. In conclusion, current classifications of diabetes include subtypes with features of both type 1 and type 2 diabetes. Thus some argue that all the subtypes of diabetes share a common origin with differences in the tempo.

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1.1.1. Pathogenesis of autoimmunity in diabetes In type 1 diabetes autoimmunity erupts early and the autoimmune process lasts for years. The eruption of the autoimmune process is determined by genetic polymorphism [26] and triggered by environmental factors [27] and especially infectious agents [28]. There are two hypotheses regarding the initiation and pathogenesis of autoimmunity in diabetes. According to the “effector hypothesis”, autoimmunity is caused by aberrant T cell clones that are reactive against self-antigens. The opposite, “suppressor hypothesis” [29,30], states that autoimmunity erupts from defective suppression of T cells against self antigens by T regulatory (Treg) cells [31]. Autoimmune insulitis may start at a very early age, even prenatally. Pancreatic β-cell mass increases in utero and in the neonatal period due to high insulin requirements and the ample provision of nutrients through the placenta and lactation respectively. Weaning results in reduction of β-cell mass by apoptosis, leading to physiological cycles of immune sensitisation against them. In most individuals this anti-islet reactivity stops, while those, in whom it continues, eventually become diabetic. The presence of autoantibodies in the umbilical cord blood of individuals that do not develop autoimmune insulitis supports this theory [32]. It is unclear at which point autoimmune insulitis cannot be reversed and perpetuates itself. Indeed the pancreatic lymph nodes provide a fertile field for the pathogenic clones to evolve and amplify, similarly to the cervical lymphoid trunk for thyroiditis [33]. In addition B-cells stimulate and promote the inflammatory process either through the presentation of new antigens after cell injury (bystander activation or molecular mimicry) or precipitation of self-injury and promotion of the autoimmune reaction. There is controversy in the literature regarding the sensitivity of effector T cells to activation-induced cell death (AICD) or to regulatory T cells (Treg) [34]. Furthermore true sensitivity to negative regulation of both Treg and effector T cells is controlled by multiple sensitizing and protecting signals under different environments. Treg cells directly kill cytotoxic cells, reduce the activity of antigen presenting cells, inhibit the production/proliferation of pathogenic T cells and alter the environment through secretion of anti-inflammatory cytokines. Depressed suppressive ability of Treg cells might be ascribed to their reduced absolute or relative number, although accurate enumeration is difficult due to phenotypic variation and migration [35]. Naturally occurring Treg cells are activated at the site of inflammation where IL-2 and other inflammatory cytokines allow them to thrive and expand. Subsequently T cell receptors (TCR) promote their proliferation and differentiation specific to the antigen presented to them [36]. In addition proliferation of Treg cells reduces their susceptibility to

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1.1.2. T1DM and pancreatic autoimmunity Islet cell antibodies (ICA) were the first auto-antibodies found in patients with T1DM in 1974 [37]. Since then, other antibodies against the pancreas have been discovered, such as 65-decarboxylase of glutamic acid (GADA—Glutamic Acid Decarboxylase), tyrosine phosphatase (IA2A) and endogenous insulin (IAA-Insulin) auto-antibodies. ICA are exclusively IgG and react against the cytoplasm of a- and βpancreatic cells. They are found in 70% of patients with newlydiagnosed T1DM and their first degree relatives [38]. If ICA are detected in the serum of the siblings of monozygotic twins suffering from T1DM, it is expected that they will develop diabetes in the following five years [39]. However the prognostic value of ICA in the general population is not as significant, since only a small percentage of individuals with ICA positivity will eventually develop T1DM [40]. IAA are usually detected at T1DM diagnosis, before the exogenous administration of insulin and disappear within a short period after [41]. They are produced against insulin or pro-insulin. IAA in combination with other auto-antibodies can play an important role in T1DM prognosis, especially in children less than 5 years old, where they are commonly present [42]. GADA are detected in 70–80% of patients with T1DM, long before the clinical manifestations of the disease and remain positive for a long time after. They target glutamic acid decarboxylase (GAD), a protein with a molecular weight of 64,000 Da, which participates in the synthesis of γ-aminobutyrate in pancreatic cells. GAD enzyme is also located in the brain, the stomach and the thyroid gland in the form of two isomers, GAD65 and GAD67. GAD-65 is the antigenic target for T1DM [43]. Loss of immune-tolerance on GAD65 coincides with the onset of insulitis and the detection of GADA [44,45]. These findings indicate a significant involvement of GAD antigen in the triggering of the autoimmune process in patients with T1DM. IA2 (insulinoma-antigen 2) antibodies against the extra-cellular part of beta-cells tyrosine phosphatase are detected in 50–75% of newly diagnosed T1DM patients and in 2.5% of the general population [46]. The role of IA2 is possibly regulatory on insulin secretion. Studies have shown that there is a genetic predisposition to the presence of pancreatic autoantibodies. Haplotype HLA DQA1*0501DQB1*0201 (associated with DR3) and haplotype HLA DQA1*0301DQB1*0302 (associated with DR4) have been linked to GADA and ΙΑ2Α positivity respectively [47]. The presence of GADA is positively related to female gender and to the age at diabetes onset (higher titres are found in newly diagnosed T1DM adolescents) [19]. GADA levels decrease slower compared to ICA and IA2A levels, which decrease fast after the diagnosis of the disease [48–50]. Pancreatic autoantibodies in T1DM can help discriminate between T1DM and T2DM, diagnose acute onset diabetic ketoacidosis in obese patients and non-ketotic diabetes in lean individuals, as well as determine the prognosis of T1DM [51]. Pancreatic autoantibody positivity at an early age has been associated with rapid progression to clinical diabetes [52–55]. Moreover, the higher number of pancreatic autoantibodies and the lower age at detection in asymptomatic individuals increases the risk for developing T1DM at a younger age [56,57]. In a recent study 70% of people with N/2 positive autoantibodies developed T1DM in the next 10 years, compared to only 10% of those with one positive autoantibody [58]. Furthermore antibody persistence is also preferentially associated with rapid progression to clinical onset of T1DM in asymptomatic patients [59,60]. Among pancreatic auto-antibodies, IA2A is considered the best predictive marker for T1DM development; in a study 59% of people with positive IA2A and 84% of those with IA2A positivity and HLA DQ2/DQ8 haplotype developed diabetes within the next 5 years [61]. In another

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1. Autoimmune polyendocrine syndrome type 1 (APS-1). The diagnosis of APS-1 requires the presence of two of the following conditions: Addison's disease, hypoparathyroidism and mucocutaneous candidiasis, and is confirmed by AIRE gene mutation analysis. Other conditions associated with APS-1 are autoimmune hepatitis, primary hypothyroidism, vitiligo, pernicious anemia and type 1 diabetes. APS-I is caused by a single gene abnormality at the autoimmune regulator gene (AIRE) in chromosome 21, inherited in an autosomal recessive fashion [105–107], and affects children at the age of 3–5 years or in early adolescence. The onset of the disease is usually in infancy, with the development of mucocutaneous candidiasis. Screening for antiislet cell antibodies, 21-hydroxylase antibodies, antiparietal cell antibodies (APCA), transglutaminase antibodies (tTG-IgA) and vitamin B12 deficiency is indicated in patients with APS-1.

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1.1.4. Autoimmune polyendocrine syndromes Autoimmune polyendocrine syndromes (APS), also called polyglandular autoimmune syndromes (PGAS), are a heterogeneous group of rare diseases characterized by autoimmunity against more than one endocrine organs, although non-endocrine organs may also be affected. The term APS was first coined by Schmidt et al. in 1926, when a patient with autoimmune thyroiditis and non-tuberculous adrenal insufficiency was described. The first classification was created by Neufeld et al. in 1980 [103]. Current classification of three types of APS is based on the clinical picture, the genetic background and the age of occurrence. A prominent component of the two major autoimmune polyendocrine syndromes (type 1–type 2/APS-1 and APS-2) is Addison's disease. They both have a genetic basis; type 2 syndrome occurs in multiple generations and type 1 syndrome in siblings [104].

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More studies are needed to elucidate whether the presence of GADA in patients with T1DM is directly related to the development of seizures and epilepsy (through the impairment of GABA production) or they reflect the underlying autoimmune process that is directed toward multiple targets. Although not completely unraveled, there is evidence that the presence of GADA can play an important role in the development of diverse neurological conditions, probably related to the generous distribution of gabaminergic neurons in the CNS. Other neurological conditions associated with the presence of GADA are the stiff-man syndrome (SMS), cerebellar ataxia, limbic encephalitis, schizophrenia and memory disorders. Indeed, GADA are found in 60– 80% of patients suffering from SMS, a disease characterized by muscle stiffness and painful muscle spasms [91,92]. The presence of GADA has also been associated with cerebellar ataxia, which can present with truncal ataxia, dysarthria and nystagmus, and limbic encephalitis (LE), which can cause notoriously difficult to treat drug-resistant seizures. Gabaminergic neurotransmission in the hippocampus is essential for memory functions. GADA are associated with memory disturbances encountered in schizophrenia, SMS and LE. The presence of GADA might be secondary to paraneoplastic neurological disorders in patients suffering from thymoma or other solid tumors [93]. It is suggested that the immune response to the aberrant expression of GAD by the tumor can result in the neurological manifestations [94]. Finally, olfactory dysfunction may be the link between CNS, psychiatric and autoimmune disorders [95–100], probably related to the close anatomical connection of olfactory receptors to the limbic system. Indeed, olfactory abnormalities are observed in patients with neurocognitive and psychiatric disorders [101]. Recently it was found that a single nucleotide polymorphism in the olfactory receptor gene (OR14J1 C allele) is associated with T1DM [102]. Furthermore olfactory receptor plays an important role in the pathogenesis of diabetes microvascular complications [102]. However more research is needed to completely elucidate the role of olfaction in the pathogenesis of autoimmune and neurological disorders.

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1.1.3. GADA and neurological syndromes Gamma-aminobutyric acid (GABA) is an abundant amino acid widely distributed in the CNS, where it plays an inhibitory role. The presence of autoantibodies against GAD (GADA) decreases the conversion of glutamic acid to GABA, resulting in an imbalance between inhibitory and excitatory amino acids and a generalized excitability of the CNS. The long-term persistence of high titres of GADA in patients with T1DM has been associated with the eventual development of diabetic peripheral or autonomic neuropathy [74]. It was speculated that senescent neurons release GAD, which triggers and maintains the autoimmune response. Subsequent data supported the association of GADA with functional abnormalities of both the central and peripheral nervous systems. In a cohort of adolescents and young adults with recent onset disease without clinical or subclinical neuropathy, patients with high titres of GADA were found to have poorer diabetic control and poorer performance on functional neurological testing, despite adjustment for HbA1C levels [75]. The association of GADA with diabetic neuropathy seems unique to T1DM; multiple studies have failed to reveal an association of GADA with diabetic neuropathy in the context of T2DM [76–79]. Recent data indicate an association between T1DM and epilepsy. The correlation of the presence of GADA and seizures in diabetic patients remains questionable; some studies showed a positive [80–82] and others no association [83–86]. Furthermore, glycaemic control abnormalities might contribute to the development of seizures. Hyperglycaemia is associated with frontal lobe epilepsy and occipital focal seizures [87,88] and hypoglycaemia with generalized tonic–clonic seizures [89,90].

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study the combination of GADA and IA2A was the best predictor for future development of diabetes [62]. The combination of IA2A, GADA and ICA has a 72% predictive value, 13% annual incidence and 87% accumulative relative risk for the development of T1DM and is preferred in clinical practice [63]. Recently it was shown that high titres of IAA and IA2A auto-antibodies belonging to subclasses IgG2, IgG3 and IgG4 are associated with a higher risk of developing T1DM [64]. Pancreatic autoantibodies can be used as markers of the progression of the disease in patients already diagnosed with T1DM. The presence of GADA one month after diagnosis is predictive of the quality of glycaemic control a year later, whereas the presence of GADA and IAA is predictive of residual b-cell function 12 months after the diagnosis of diabetes [65]. In addition the presence of GADA after diabetes diagnosis is associated with slower progression toward b-cell failure, compared to the presence of ICA or multiple autoantibodies against the pancreas [66]. A recently discovered autoantibody in patients with T1DM is that against ZnT8 [67]. ZnT8 is a member of the SlC30A8 gene family and is involved in islet cell endocrine hormone release [68]. In particular ZnT8 concentrates Zn in insulin secretory granules. ZnT8 antibody (ZnT8A) was found positive in 68–72% of patients with newly diagnosed T1DM [69,70]. Among young patients with newly-onset T1DM who were negative for ICA, GADA, IA-2A, and IAA, 26% were positive for ZnT8A; thus ZnT8A has a specificity of 99% and a sensitivity of 72% in terms of T1DM diagnosis [69,70]. The levels of ZnT8A decrease rapidly over time and are associated with the presence of IA2A antibodies [70]. The presence of ZnT8A is associated with an older age at diabetes diagnosis, the metabolic status at diagnosis and also the DR13-DQB1*0604 haplotype [71]. In addition in patients with T1DM the presence of GADA and ZnT8A increases the risk for future development of autoimmune thyroiditis [72]. Athough ZnT8A is not yet routinely used in the diagnosis and prognosis of T1DM, it could become an important marker for screening for T1DM and future outlook. Thus it is suggested that patients with newly diagnosed T1DM are initially tested for the presence of GADA and IA2A [73]. If GADA and IA2A are negative, then testing for ICA and IAA autoantibodies should be pursued for the confirmation of T1DM and the prediction of the course of the disease [73]. In the future it will be important to incorporate ZnT8A for screening and prognosis of T1DM.

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Autoimmune thyroiditis (AIT) is the most common autoimmune disease, encountered in children with T1DM [126,127]. Its prevalence in patients with T1DM is two to four times more frequent than in the general population and its usual clinical presentation is autoimmune thyroiditis (Hashimoto thyroiditis, HT) and less frequently Grave's disease. Indeed, the prevalence of thyroid antibody positivity in the general pediatric population ranges from 2.9% to 4.6% [128–130], whereas in children and adolescents with T1DM it ranges from 12.1% to 23.4% [7,

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1.1.5. Familial autoimmune diseases “Familial autoimmunity” occurs when members of a nuclear family present diverse autoimmune diseases [118]. Autoimmune thyroid disease, followed by systemic lupus erythematosus (SLE) and rheumatoid arthritis are the most frequent familial autoimmune diseases [119]. Although environmental factors may have an effect, shared genetic factors are the most likely cause for the aggregation of autoimmune diseases in families. The relative risk for familial autoimmunity in T1DM probands was 1.5. The most common autoimmune diseases among family members of a patient with T1DM are autoimmune thyroid disease, followed by coeliac disease, psoriasis, vitiligo and Addison's disease [120–123]. First degree relatives of a patient with T1DM are more likely to have autoimmune thyroid disease, multiple sclerosis, rheumatoid arthritis or SLE [124,125].

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131,132]. Likewise, anti-thyroid antibodies are detected in 6.6%–14% of the general adult population [133–135] and in 20%–40% of adult patients with T1DM [136–138]. AIT is characterized by the production of autoantibodies against the thyroid gland, T-lymphocytic infiltration of the gland, and subsequent development of various degrees of thyroid dysfunction [139]. Antibodies are directed against specific thyroid gland proteins, thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO). Thyroglobulin is a glucoprotein with molecular weight of 660,000 Da. It is a basic constituent of colloid and contains tyrosyl residues, which play a major role in the iodination and formation of thyroid hormones. Thyroid peroxidase is a glucosylated transmembrane protein which is located in the apical part of follicular thyroid cells and is responsible for the iodination of tyrosine and production of thyroid hormones T4 and T3. Thyroid peroxidase can also be found in eosinophils, reticular cells and salivary gland cells. The role of anti-TPO in the inflammatory process against the thyroid gland is important, as they were found to activate complement, whereas anti-TG seem to play no pathogenic role in the inflammatory process [140,141]. These antibodies are detected only in 17–25% of patients at T1DM diagnosis; in the majority of cases they present during the course of diabetes [142,143] 2.5–3 years after T1DM diagnosis [139,142,144]. In patients with T1DM the presence of HLA DQA1*0301, DQB1*0301, and DQB1*0201 haplotypes has been linked with the development of hyperthyroidism, whereas the presence of HLA DQA1*0501 with hypothyroidism [145]. The presence of DQB1*05 appears to protect against the development of AIT [146]. There is a strong association between thyroid antibody positivity and female gender [139,147–149]. De Block et al. [147] reported that female adolescents with T1DM are three times more prone to develop positive anti-TPO, compared to males. Indeed, in animal models and patients with T1DM estradiol has been found to accelerate the progression of autoimmune disease by interfering in the T helper type 2 cell (Th2) pathway, while androgens had a protective effect [150–152]. Furthermore in T1DM patients the prevalence of thyroid autoantibodies increases with increasing age and diabetes duration [127, 131,132,136,153–156]. In these studies the highest prevalence of thyroid auto-antibody positivity was observed around puberty (14–15 years) and after 3.5–4 years of diabetes duration. This observation suggests that autoimmune disease is the final stage of a process that begins with auto-recognition, progresses through autoimmunity with the appearance of autoantibodies and eventually ends in the destruction of the target organ and the clinical manifestation of the disease [157]. The fact that puberty is associated with the highest prevalence of autoantibodies can be explained by the effect of female hormones on the development and progression of the autoimmune process. Although the majority of patients with positive antithyroid antibodies have normal thyroid function, autoimmune thyroiditis may present either as hypothyroidism (Hashimoto thyroiditis) or hyperthyroidism (Grave's disease). Hypothyroidism may be subclinical (elevated TSH and normal free T4 levels) or clinical (elevated TSH and low free T4 levels). The prevalence of clinical hypothyroidism in patients with T1DM ranges between 4 and 18% [158–161] and is higher than in the general population (5–10%) [159,160,162]; the prevalence of subclinical hypothyroidism in patients with T1DM reaches 40–55% [127,132]. Clinical hypothyroidism is diagnosed in 10% of children with thyroid antibody positivity, while ultrasound changes, i.e. thyroid enlargement, disturbances in the echostructure and/or nodular lesions, are observed in 50% of them [163]. TSH levels have been found to be proportionally associated with double thyroid antibody positivity [132]. The simultaneous presence of anti-TPO and anti-TG might result in more intense immune stimulation and thyroid gland dysfunction. However it is not completely elucidated whether autoantibodies are directly involved in the pathophysiologic mechanism of thyroid gland destruction or reflect

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2. Autoimmune polyendocrine syndrome type 2 (APS-2). APS-2 is the most common autoimmune polyendocrine syndrome and includes Addison's disease, IgA deficiency, Graves disease (thyrotoxicosis), primary hypothyroidism, hypogonadism, hypopituitarism, T1DM, Parkinson's disease, myasthenia gravis, celiac disease, vitiligo, alopecia, pernicious anemia, stiff-man syndrome and autoimmune thyroiditis. Thus apart from the mandatory presence of autoimmune adrenal insufficiency, APS-type 2 can be associated with malabsorption, hepatitis, asplenia and alopecia [108]. It presents in the first decade of life, reaching its peak prevalence at 25–40 years of age and affecting females preferentially [109,110]. APS-2 is usually associated with class II HLA alleles (immune response genes), particularly DQ2 and DQ8. Several of the APS-2 diseases have been associated with HLA-DR3 or HLA-DR4 [111]. Patients with APS-2 should be periodically screened for autoantibodies associated with diabetes (IA2, IAA and GADA), thyroid disease (i.e.anti-TG and anti-TPO), Addison's disease (21-hydroxylase), celiac disease (tissue transglutaminase) and autoimmune hepatitis (cytochrome P450 enzymes). 3. Autoimmune polyendocrine syndrome type 3 (APS-3). APS-3 involves the same array of endocrine gland autoimmune disease as type 2, but usually without adrenal insufficiency. There are three sub-types: a) autoimmune thyroiditis with T1DM, b) autoimmune thyroiditis with pernicious anemia, and c) autoimmune thyroiditis with vitiligo and/or alopecia and/or other organ specific or systemic autoimmune diseases (coeliac disease, hypogonadism, myasthenia gravis, sarcoidosis, rheumatoid arthritis, Sjogren syndrome) [112– 114]. Similar to APS-2, APS-3 exhibits polygenic inheritance and is associated with HLA class II haplotypes [115,116]. 4. Autoimmune polyendocrine syndrome type 4 (APS-4). If the autoimmune endocrine gland disorder does not fulfill the criteria of APS 1–3, the disease may be categorized as APS type 4 [117]. The prevalence of T1DM is 4–18% in APS-type 1, 60% in APS-type 2 and 14.5% in APS-type 3 [114]. Although clinical manifestations of APS usually present in the third decade of life, the first signs can present in childhood. Therefore every pediatrician needs to be aware of the manifestations of APS, especially in association with T1DM.

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patients with Hashimoto's thyroiditis (HT) ranges between 1 and 30% [182]. In a Greek study of 228 children with HT, the prevalence of thyroid cancer was 1.3% [183]. In a study by Karavanaki K et al. [184], among 144 children and adolescents with T1DM, 17.36% developed thyroid autoimmunity, while one patient with multiple autoimmunity (T1DM, thyroid and celiac autoimmunity) developed papillary thyroid carcinoma [185]. This wide variation in the prevalence of thyroid cancer in HT patients may be attributed to geographic and ethnic diversity, as well as patient selection differences among studies. The role of lymphocytic infiltration in cancer pathogenesis is controversial. Lymphocytic infiltration in HT has been reported to have a protective role [186], or no effect on thyroid cancer development [187]. However other studies highlighted an increased prevalence of thyroid cancer among patients with HT (26–30%), suggesting that HT may be a premalignant state of papillary carcinoma [187,188]. According to Guarino et al. [189], inflammatory-immune cells, with either pro- or anti-tumorigenic activity, infiltrate thyroid cancer. Thus lymphocytic infiltration seems to confer protection against cancer progression. On the other hand, the presence of innate immunity cells (macrophages and mast cells) enhances tumor progression. The oncogenes activated in thyroid carcinomas (i.e.RET/PTC, RAS and BRAF) can activate cytokine activity and further enhance tumor progression by stimulating angiogenesis and by inducing subversion of the anti-tumoral immune response [190]. Thus patients with HT should be carefully followed-up for the development of specific clinical and sonographic findings consistent with malignancy needing further investigation [191].

2.2. T1DM and gastric autoimmunity In the context of T1DM autoimmune nature, antibodies can also be directed against the gastric mucosa. In particular in children with T1DM autoantibodies target the specific protein H+/K+ ATPase (proton pump), that is located at the apical surface of parietal cells of the stomach [192], and participates in the exchange of hydrogen and potassium ions between the cytoplasm of parietal cells and the gastric tube. These autoantibodies are called Parietal Cell Auto-antibodies (APCA). In adult patients with T1DM the prevalence rate of APCA is 3–30% [193,194], while in T1DM children and adolescents 5.3–7.5% [156,195, 196]. In contrast, APCA prevalence in non-diabetic children and adolescents aged 0–15 years is 0.3–1.98% [156,197] and in adults in the third decade of life 2.5% [127]. The presence of a specific HLA haplotype (HLADQA1*0501DQB1*0301) in patients with T1DM increases the risk of gastric autoimmunity [156]. This genotype is also associated with the presence of GADA and anti-TPO antibodies [156]. There is a controversy in the literature regarding the effect of other factors, such as age, gender or diabetes duration in the development of APCA. The presence of APCA has been associated with older age of T1DM patients, longer diabetes duration [154,156,194] and female gender [197,198]. However other studies found no association between the presence of gastric autoimmunity and the above parameters [148,153, 192,196,199]. An association has also been reported between APCA and GADA antibodies [197]. GAD is responsible for the conversion of glutamic acid to gamma-aminobutyric acid, is found at the submucosa and mucosal basic membrane of the stomach and promotes acid production by parietal cells of the stomach through the production of GABA [200–202]. The autoimmune response against the pancreas might be generalized toward common antigens, located in other tissues, explaining the coexistence of GADA and APCA in diabetic patients [203]. The presence of APCA positivity in T1DM patients is associated with various clinical gastrointestinal manifestations. Patients with T1DM and positive APCA are at higher risk for autoimmune gastritis, which is frequently associated with iron deficiency anemia, and/or pernicious anemia [204].

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2.1.1. Screening for autoimmune thyroid disease in T1DM patients Regarding the screening for AIT in children with T1DM, there is wide variation in the recommendations from different Diabetes Societies. According to the recommendations of the American Diabetes Association (ADA) and the International Society for Paediatric and Adolescent Diabetes (ISPAD), thyroid function and thyroid auto-antibodies should be assessed at diabetes diagnosis [179,180]. If normal, patients should be screened every 2 years, unless they develop symptoms of autoimmune thyroiditis. The Australasian Paediatric Endocrine Group (APEG) recommends measurement of thyroid antibodies every 2–3 years and assessment of TSH levels every year, rather than biennially [181]. Thyroid antibodies are not usually present on T1DM diagnosis, but they develop later in the course of diabetes [127,142]. For this reason serological screening and thyroid function testing is suggested on T1DM diagnosis and then annually in case of negative or every six months in case of positive anti-TPO and anti-TG antibodies [8]. In the presence of thyroid antibody positivity or goiter, a thyroid ultrasound should be performed, at least once a year [179,180].

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thyroid tissue destruction by thyroid-infiltrating T cells [155]. Although still controversial, anti-TPO seem to be more specific markers for thyroid gland function than anti-TG [132,164]. Due to frequent screening of T1DM patients for TSH and antibodies, clinical findings of overt hypothyroidism, such as painless goiter, fatigue, cold intolerance, bradycardia, increased weight gain, lethargy or decreased linear growth, are rare. The treatment of hypothyroidism is based on replacement therapy with levo-thyroxine. Subclinical hypothyroidism in T1DM patients, in particular in those with TSH N/10 μIU/ L may be associated with symptomatic hypoglycaemia and decreased linear growth [165–167]. Hypoglycaemia results in decreased insulin requirements and inhibited absorption into the circulation, which in turn leads to increased insulin dosage and unpredictable cumulative insulin secretion [7]. On the other hand, no effect of subclinical hypothyroidism on growth, BMI and glycaemic control in patients with T1DM was reported in other studies [127,132,168,169]. Nevertheless, since subclinical hypothyroidism may be associated with an adverse lipid profile, early treatment of subclinical hypothyroidism in patients with T1DM reduces the future risk for hyperlipidaemia and atherosclerotic heart disease [170]. Finally, levothyroxine treatment in euthyroid T1DM patients with thyroid antibody positivity reduces thyroid volume, prevents the development of goiter and hypothyroidism by decreasing TSH levels and thyroid antigen expression, leading to a decline in thyroid antibody concentration and reduction of thyroid lymphocytic infiltration [171], but seems to have no effect on thyroid function and serum autoantibody level [172]. The prevalence of hyperthyroidism due to Grave's disease or the hyperthyroid phase of Hashimoto thyroiditis (Hashitoxicosis) among T1DM patients is lower (1.5–4%) than hypothyroidism [158,173,174], but still higher than in the general population. Hyperthyroidism should be suspected when patients with T1DM have difficulty maintaining glycaemic control, lose weight despite normal appetite, suffer from palpitations, heat intolerance, thyroid enlargement or show typical eye signs [7]. Thyroid function tests reveal suppressed TSH level, elevated levels of T4 and T3 and — in Grave's disease — positive TSH receptor antibodies. Hyperthyroidism results in increased needs for glucose due to increased metabolism [169]. This in turn results in stimulation of gluconeogenesis and glucogenolysis, reduced insulin sensitivity, increased glucose absorption and lipolysis, leading to deterioration of metabolic control [175,176]. Thyrostatic drugs (such as carbimazole and methimazole) or radioiodine and propranolol are used for the treatment of hyperthyroidism and associated tachycardia, respectively [177, 178].

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2.1.2. Autoimmune thyroiditis and thyroid cancer The association of autoimmune thyroiditis with the development of thyroid cancer is still unclear. The prevalence of thyroid cancer among


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2.3. T1DM and coeliac disease

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Coeliac disease (CD) is an autoimmune disease, found in 0.2–5.5% of children in the general population, with the lowest incidence in Germany and the highest in Algeria [241]. In children with T1DM the prevalence of CD is higher and fluctuates between 1 and 16% [242– 245]. A high prevalence of CD (3.8–10%) has also been observed in the first degree relatives of patients with T1DM [246–248]. Common allele genes that belong to HLA II area of chromosome 6 are linked to the development of CD and T1DM [249]. Although not a usual clinical practice, it has been suggested that all patients with T1DM and HLA haplotype DQA1*0501-DQB1*0201 should be screened for the development of coeliac disease [250–252]. The time relationship between T1DM and CD diagnoses varies. Thus CD may precede, coincide or follow the diagnosis of T1DM. In some studies coeliac disease precedes the diagnosis of diabetes, subclinically (silent CD) [253,254]. In particular CD can be present 5 years before the diagnosis of T1DM in individuals less than 20 years of age [254–256]. On the other hand there are studies that

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2.2.1. Thyrogastric autoimmunity The coexistence of autoimmune thyroid disease with gastric autoimmunity is called “thyrogastric autoimmunity” [196,230]. In other studies the term “thyrogastric autoimmunity” or disease has been used to define the presence of thyroid autoantibodies and/or overt AIT in patients with pernicious anemia (PA), which, in turn, was considered synonymous with atrophic body gastritis [231]. Thyrogastric autoimmunity has been reported in both adult [230,232] and pediatric T1DM patients [195,196]. A possible explanation for the coexistence of thyroid and gastric autoimmunity can be found in the shared genetic background, located on chromosome 4 [233,234]. Patients with GADA antibodies are more prone to have anti-TPO and APCA [198,230,235–238]. In fact the persistence of GADA antibodies for more than 5 years in patients with T1DM has been considered a marker for the future development of thyrogastric autoimmunity [156]. The association of GAD-65 and thyrogastric antibodies in patients with T1DM may be explained by the hypothesis that the pancreas, thyroid gland, and stomach share common antigens [202,239]. Once a T cell response to GAD has been primed in the pancreas, the resulting activated T cells initiate damage of other neuroendocrine tissues containing the same or similar enzyme(s) [203]. Moreover, APCA and thyroid antibody positivity have a common genetic background, such as the presence of HLADQA1*0501-DQB1*0301 genotype [220,240]. In addition the presence of H. pylori has been implicated in the pathogenesis of gastric autoimmunity through the mechanism of molecular mimicry [198,240]. Thus, patients with T1DM, and in particular those with thyroid and/or pancreatic autoimmunity (persistence of GADA), should have periodic autoantibody screening for the early diagnosis and follow-up of gastric autoimmunity.

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patients with thyroid autoimmunity and/or the persistence of GADA antibodies for more than 5 years after T1DM diagnosis should be investigated every 2 years for APCA status, as they are at increased risk to develop gastric autoimmunity [196,203,221]. The identification of specific markers to predict the development and progress of gastric atrophy might circumvent the need for gastroscopy and gastric biopsy in the diagnosis and management of autoimmune gastritis in the future. Loss of gastric acid secretion leads to hypergastrinemia; thus gastrin levels can be used instead of gastric biopsy to predict gastric mucosa atrophy [228]. Serum ghrelin, produced by the endocrine cells of the gastric mucosa, reportedly has a very high sensitivity and specificity (97.3% and 100%, respectively) for the detection of gastric atrophy compared to gastrin [229]. However ghrelin is not routinely used in clinical practice and more evidence is required in order to decide not to perform gastric biopsy in T1DM patients with APCA positivity.

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The destruction of parietal cells of the stomach by APCA autoantibodies leads to autoimmune gastritis, characterized by hypo- or achlorydria, hypergastrinemia and low pepsinogen I concentration [200,204]. Chronic hypergastrinemia induces hyperplasia of enterochromafin-like (ECL) cells in the oxyntic mucosa (hypertrophic gastritis) [202,204], which may progress toward dysplasia (atrophic gastritis) and gastric carcinoid tumors [154,204]. The destruction of parietal cells is associated with an endoscopic picture of atrophic gastritis. Actually the titre of APCA correlates with the severity of corpus atrophy and is inversely proportional to the concentration of parietal cells [147]. Parietal cells produce hydrochloric acid and also intrinsic factor, that is responsible for vitamin B12 absorption [197,205]. APCA are detected in 60–85% of patients with autoimmune gastritis, while intrinsic factor antibodies are detected in 30– 50% of them [154,197]. Furthermore inadequate hydrochloric acid production reduces iron absorption from the stomach, whereas insufficient intrinsic factor production results in abnormal vitamin B12 absorption by the small intestine, and the development of pernicious anemia [206]. Actually anemia has been reported in 28.3% of patients with autoimmune thyroid disease and other associated autoimmune diseases (atrophic gastritis or celiac disease) [207]. Atrophic gastritis was found in 50–95% of adolescents or adults with T1DM and positive APCA antibodies [197,198,208–210]. In a study of T1DM children and adolescents, 40% of patients with APCA positivity were found to have atrophic gastritis, while the majority had hypertrophic gastritis [196]. This suggests that it takes time for the lesions to develop and lead to atrophic changes in the stomach [196]. Other clinical manifestations in patients with T1DM and positive APCA include hypochlorydria or achlorydria in 25–70% [196,211,212], pernicious anemia in 1–25% [213,214] and raised gastrin levels in 27– 50% [215]. The role of Helicobacter pylori in the pathogenesis of autoimmune gastritis in patients with T1DM and APCA positivity has not yet been elucidated. H. pylori mainly causes antral gastritis (type B gastritis), whereas autoimmune gastritis is usually limited to the fundus of stomach (type A gastritis) [216,217]. However in patients with T1DM and positive APCA, H. pylori has been isolated from biopsies [196]. A potential explanation involves the mechanism of molecular mimicry since H. pylori and H+/K+ ATPase share common antigens [218–220]. On the other hand patients with positive APCA that are negative for H. pylori eventually developed autoimmune gastritis [221]. A “hit and run” hypothesis for H. pylori none-the-less remains possible, where the infection starts in the antrum, and subsequently progresses to corpus atrophy and loss of acid secretion [222]. However more research is needed to clarify the role of H. pylori in the development of gastric autoimmunity. APCA antibodies are not only excellent markers to detect autoimmune gastritis, but also can predict atrophy of the corpus of the stomach and subsequent hematologic manifestations [223,224]. APCA levels rise progressively over time, reach a peak and then decline, following progressive gastric mucosal destruction and loss of target antigen stimulation [225]. Atrophic gastritis may lead to the development of gastric malignant tumors (carcinoid and adenocarcinoma), related to intestinal metaplasia and ECL cell hyperplasia or dysplasia in 1–10% of patients later in life [226]. There are no consensus guidelines on the follow-up of patients with APCA positivity. As gastric autoimmunity is usually asymptomatic [227], it has been suggested that patients with APCA positivity should be annually investigated with complete blood count, ferritin, vitamin B12 and gastrin levels [227]. Should elevated APCA levels and hypergastrinemia be detected, gastroscopy with multiple biopsies should be performed [203]. We suggest that all T1DM children and adolescents should be screened for APCA status at diagnosis and, if negative, every 4 years; clinical indications should prompt screening, since gastric autoimmunity can occur at any age, although it is positively associated with diabetes duration [196,203,221]. On the other hand, APCA negative

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2.3.2. The key environmental trigger in T1DM: the role of viruses and/or wheat gluten It has been suggested that wheat gluten is an important environmental trigger of T1DM. CD and T1DM are highly comorbid; the prevalence of CD is estimated 20 times higher in T1DM patients than in the general population [263]. Due to linkage disequilibrium between CD and T1DM susceptibility genes, there is higher probability for a single individual to inherit both genes, than each gene independently [264]. HLA-DR alleles can predispose to T1DM and CD, particularly when combined with HLA-DQ alleles [265]. However the actual gene(s) that cause susceptibility to CD may be different from those that confer susceptibility to T1DM. Studies in animals have shown that not only the presence, but also the amount and time of introduction of gluten in the diet can affect the future risk for diabetes [266,267]. Gluten can cause small intestinal enteropathy in animals; the inflammatory response can spread to mesenteric lymph nodes and then to the pancreas [268]. As in humans, pancreatic β-cells are attacked mainly by Th1 lymphocytes [269,270]. Introduction of gluten in infants less than 3 months of age can increase their risk for developing T1DM [271], attributed to the absence of oral tolerance in this age group [272]. On the other side patients with T1DM have increased intestinal permeability and immunological activity [273–277], as well as increased CD3+ T-cell reactivity against gluten compared to healthy controls [278,279]. Other dietary components, such as nitrates [280,281] or cow's milk proteins [282] could also influence the development of T1DM. Viruses may be the most important trigger in some T1DM patients and wheat protein in others, or viruses might instead serve to accelerate the disease process. Inversely exposure to viral, bacterial or helminth pathogens and vitamin D3 might provide some protection against T1DM [283,284]. Thus multiple gene–environment interactions probably ultimately determine susceptibility to T1DM [285,286].

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2.3.1. Etiopathogenesis of CD in T1DM patients There are two theories explaining the time relationship between T1DM and CD. The first theory suggests that as T1DM is an autoimmune disorder, deranged immune function can be generalized and expand toward other tissues and against gliadin in genetically predisposed individuals [259,260]. In the second theory, CD is associated with immunologic stimulation and polyclonic activation of B-cells, leading to other immune disorders. The intestinal mucosa abnormalities that are prominent in CD may result in the absorption of foreign antigens and the development of an abnormal immune reaction against them in genetically predisposed individuals [258,261]. This theory is supported by the discovery of the Glb1 protein in wheat, which is antigenic in diabetic mice and is associated with immune system aggressiveness against the pancreas. Furthermore a percentage of T-cells implicated in insulitis has intestinal origin; patients with CD, submitted to strict gluten free diet, have a lower possibility to develop autoantibodies against other organs [261,262].

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CD, whereas anti-tTG-IgA antibodies have 88–98% sensitivity and 98% specificity [293–296]. Although EMA antibodies are considered the best serological marker for CD diagnosis, their detection by immunofluorescence has several disadvantages. This method is laborious to perform and may show false negative results in children younger than 2 years and in patients with partial alterations in the intestinal mucosa. In addition the interpretation of the results depends on the experience of the technician [297,298]. However recent studies have shown that EMA are sensitive even in younger children [299]. On the other hand anti-tTG-IgA antibodies are determined using ELISA technique, which is easier to interpret, albeit with reportedly low positive predictive value, particularly in low-risk populations and false positivity in patients with hepatic disease [256,300]. Another impediment in the serological diagnosis of CD is the fact that EMA and anti-tTG are IgA antibodies and patients with CD have ten times higher prevalence of IgA deficiency compared to the general population [301]. Therefore, if IgA levels in patients tested for CD are low, IgG EMA or anti-tTG-IgG levels should be determined [302]. The use of auto-antibodies is important for CD, as most cases are asymptomatic. Coeliac disease can be divided into silent, potential, latent and active disease [303]. Silent CD is defined as the presence of positive CD antibodies along with an HLA celiac predisposing genotype (DQ2 and/or DQ8) accompanied by small intestinal histological abnormalities, but without signs or symptoms consistent with CD. Potential CD is defined as the presence of positive CD antibodies along with an HLA coeliac predisposing genotype (DQ2 and/or DQ8), but without any histological abnormalities in the small intestine. Latent CD, by definition, occurs in a child with HLA coeliac predisposing genotype, who has had a documented gluten dependent enteropathy at some point in the past, but whose enteropathy later resolved even after gluten reintroduction into the diet; the child may or may not have symptoms or coeliac-specific antibodies. Active CD is characterized by the presence of malabsorption symptoms that begin after introduction of gluten in the diet [303]. In the majority of children with T1DM, CD is diagnosed in the phase of silent or potential CD prior to clinical symptoms. In a study of children with T1DM and positive anti-tTG-IgA, it was found that the majority (55.6%) had no or very mild symptoms of CD [304]. According to relevant data in children with T1DM, CD is mainly diagnosed during screening and rarely after the development of gastrointestinal symptoms [259, 305,306]. Moreover most adults with T1DM had the silent form of CD. The importance of antibody screening for coeliac disease is also supported by studies that found positive histological findings of small intestinal villous atrophy, in 50–60% of asymptomatic diabetic patients with positive anti-tTG IgA and in 44–100% of those with positive EMA [289, 305–308]. The presence of anti-tTG IgA in T1DM patients is positively associated with younger age and female gender [304,309]. Regarding the presence of EMA IgA, some studies have found a positive association with younger age at diabetes onset and younger age [310,311]. Screening for CD, in particular in T1DM patients with silent or potential disease, is recommended because CD is associated with growth failure, pubertal abnormalities, weight loss, osteopenia, osteoporosis, anemia and neurological disorders [258,312,313]. In addition prompt diagnosis and treatment of CD with gluten free diet (GFD) improves glycaemic control in patients with T1DM, whereas poor adherence to GFD diet has been associated with unexplained hypoglycaemia [296, 314]. However, recent studies revealed that GFD in patients with T1DM has some disadvantages [315]. Compliance with strict GFD is lower in patients with T1DM and CD, compared to patients with CD alone [316]. GFD diet could result in increased weight gain and raised BMI in patients with T1DM, due to its high saturated fat and high glycaemic index carbohydrate, and low protein and fiber content [315]. This could in turn increase the long term risk of cardiovascular complications in T1DM patients [317] and affect glycaemic control. However the effect

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support the initial presence of T1DM and the subsequent development of CD [257,258].

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2.3.3. Diagnosis of CD in T1DM The diagnosis of CD is based on the detection of specific autoantibodies and confirmed by small intestine biopsy. The two major antibodies found in CD are the antiendomysial antibodies (EMA) which are IgG and IgA antibodies, and IgA anti-tissue transglutaminase antibodies (anti-tTG-IgA). EMA are positive in 0.5–11% of patients with T1DM [155,287–289] compared to 0–3% of the general population [289,290]. Anti-tTG-IgA antibodies are positive in 4–12% of children with T1DM [184,291,292]. At present the determination of anti-gliadin antibodies is not recommended for the diagnosis of CD, because they have less sensitivity and specificity compared to EMA and anti-tTG-IgA antibodies [293]. EMA antibodies have 68–10% sensitivity and 100% specificity for


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2.3.5. Association of CD with thyroid autoimmunity The evidence regarding the potential association between CD and 1006 thyroid autoimmunity is contradictory [324–327]. Some studies found 1007 a weak or no association between these conditions, with the prevalence 1008 of CD in patients with AIT ranging between 1 and 4.8% [328–332].

More than half a century ago autoimmune adrenal disease or Addison's disease (AD) and T1DM were described as part of the Autoimmune Polyendocrine syndrome type II (APS-II) [343]. Patients with APS II may also suffer from autoimmune thyroid disease, vitiligo, gonadal failure, chronic atrophic gastritis and alopecia [344,345]. The prevalence of AD in adult patients with T1DM has been found to be 0.8–1.9% [346,347]. On the contrary the presence of T1DM in patients with AD has been reported to be 10–18% [347]. In childhood diabetes, two previous studies [6,184] reported no patient with adrenocortical antibodies (ACA) positivity among 144 and 461 children and adolescents with T1DM respectively. The presence of autoantibodies against the adrenal cortex ACA is characteristic of autoimmune adrenal disease. ACA are directed against 21-hydroxylase, a microsomal cytochrome P450-enzyme that converts 17-α-progesterone and progesterone into 11-deoxycortisol and 11deoxycorticosterone [348,349]. The prevalence of ACA antibodies in adult T1DM patients has been found to be 0–4% [145,350,351]. The prevalence of ACA is increased in patients with T1DM and co-existent autoimmune thyroid disease and it was found that approximately 70% of the T1DM population with positive ACA was also affected by thyroid autoimmunity [350,352]. The coexistence of autoimmune adrenal disease and T1DM is due to the common genetic background. The presence of ACA increases by 5% in patients who are heterozygotes for DQ8/DQ2, and in particular in those with hypo-types DRB1*0404/DQ8 and DRB1*0301/DQ2 [352– 355]. Notably, patients with T1DM and AD have an estimated 75– 100% chance of having a first degree relative with AD [356,357]. There are conflicting reports on the factors affecting the development of ACA positivity in T1DM patients. Some studies report a positive association between ACA positivity and female sex or longer diabetes duration [358–360], while others found no association of ACA positivity with the above parameters or age at T1DM diagnosis [350,355]. Patients with T1DM that eventually develop AD, usually present with atypical findings, such as frequent episodes of hypoglycaemia, fatigue, nausea, salt craving and weight loss [346–348,361]. Other symptoms consistent with AD are postural hypotension and hyperpigmentation of the skin and mucosae. Hypoglycaemia and decreased insulin requirements can be explained by the increased sensitivity of insulin target tissues due to low or absent cortisol levels [347,361]. Recurrent unexplained hypoglycaemia should raise the possibility of Addison's disease in all patients with T1DM. Classical Addisonian crisis is very rare in T1DM patients. According to different studies, 30–40% of T1DM patients with ACA positivity eventually develop clinical manifestations of AD, the mean time between ACA positivity and symptom development being 2–5 years [362,363]. Currently there are no recommendations regarding the follow-up of patients with T1DM and possible adrenal autoimmunity. Routine testing of patients with T1DM for ACA is not recommended, as the possibility and timing of the development of adrenal gland autoimmune disease in these patients cannot be predicted. Therefore we recommend testing

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2.3.4. Screening for CD in T1DM patients Regarding the screening strategy for the diagnosis of CD in patients with T1DM, there is no consensus in the guidelines issued by the American Diabetes Association (ADA), the International Society for Pediatric and Adolescent Diabetes (ISPAD), the North American Society for Pediatric Gastroenterology and Hepatology (NASPGHAN), and the National Institutes of Health (NIH) [179,321–323]. The ADA 2014 guidelines recommend screening of children with T1DM by measuring antitTG-IgA or EMA antibodies soon after first diagnosis, following documentation of normal total serum IgA levels. Thereafter screening should be performed in children with a positive family history of CD, atypical or typical symptoms and signs of CD (such as growth failure, failure to gain weight, weight loss, diarrhea, flatulence, abdominal pain), or signs of malabsorption or in children with frequent unexplained hypoglycemia or deterioration in glycemic control [323]. ISPAD guidelines recommend that screening for CD with EMA or anti-tTG-IgA should be carried out at the time of diabetes diagnosis, annually for the first five years and every two years thereafter. More frequent assessment is indicated if there are clinical symptoms suggestive of CD or there is a first-degree relative with CD [179]. All guidelines suggest that children with repetitively positive CD antibodies should be referred to a pediatric gastroenterologist for biopsy and upon confirmation of the diagnosis to start GFD and receive support from a pediatric dietician with relative experience. A significantly different recommendation was issued recently by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) [324]. According to this guideline it is not necessary to submit children to intestinal biopsy if CD diagnosis is supported by compatible symptoms, the presence of specific antibodies, especially high anti-tTG-IgA antibody levels (10 times the upper normal limit for a standard curve-based calculation) and specific HLA haplotypes. Antibody decline and clinical response to a GFD confirm the diagnosis. Gluten challenge and repetitive biopsies are necessary only in selected patients due to diagnostic uncertainty or high index of suspicion despite negative serology. A recent study revealed that the specificity of serological testing in combination with symptomatology for CD is high, and the application of the new proposed ESPGHAN diagnostic criteria in clinical practice could save intestinal biopsy in 28% of suspected cases [325]. However the assessment includes both EMA and anti-tTG-ΙgA antibodies and HLA-DQ screening, which are expensive and sometimes not readily available. According to ISPAD guidelines [179], serological screening for CD in children with T1DM is suggested on T1DM diagnosis, yearly during the first 5 years of diabetes and subsequently every 2 years. More frequent screening is suggested in the presence of clinical symptoms and signs of the disease, or in the presence of a positive family history of confirmed CD diagnosed in first degree relatives.

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Inversely other authors found a significant association between CD and AIT. Positive anti-tTG antibodies were found in 6–7.8% of patients with AIT [333,334] and positive anti-TPO in 10.5–14.6% in patients with CD [335–337]. Furthermore children with coeliac disease were found to have threefold risk to develop thyroid autoimmunity [338]. This association has been attributed to a common genetic background between CD and AIT [258,339,340] or to environmental factors that affect self-tolerance and promote development of autoimmunity according to the “fertile field” hypothesis [341]. Ventura et al. showed that patients with CD had high prevalence of gluten dependent thyroid autoantibodies, which disappeared during treatment with GFD [342]. The above findings justify periodic screening of thyroid function in patients with T1DM and CD as well as screening for CD in patients with AIT.

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of GFD in diabetic patients with CD on optimizing glycaemic control is controversial [318–320]. Finally, gluten free foods have a reduced content of micronutrients, such as vitamins B and D, calcium, iron, magnesium and zinc. For all the aforementioned reasons it is important to manage the GFD diet of CD patients by dieticians specialized in pediatric CD. In case of poor adherence to GFD, CD may lead to the development of intestinal malignancies, especially lymphoma, in adult life [296]. The link between chronic inflammation and cancer is well established and has been attributed to chronic T-lymphocyte activation [188,190]. Other intestinal chronic inflammatory diseases (Crohn's disease and ulcerative rectocolitis) have also been associated with adenocarcinoma of the colon [190].

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2.6. T1DM and non-organ-specific autoimmune diseases

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Apart from the above mentioned organ-specific autoimmune diseases, other non-organ-specific or systemic autoimmune diseases, such as juvenile idiopathic rheumatoid arthritis (JIA), Sjogren syndrome, psoriasis, and sarcoidosis, and other diseases, such as gastric carcinoid tumor and malabsorption due to exocrine pancreatic insufficiency [368] may also develop in T1DM patients. Indeed, Pohjankoski H et al. reported that 21.4% of 355 families with a patient with JIA had members with T1DM, coeliac disease, multiple sclerosis or chronic arthritis [369]. Among parents 15.2% had T1DM, coeliac disease or multiple sclerosis, while 10.7% had chronic arthritis. Available research data corroborate with these findings; the prevalences of rheumatoid or psoriatic arthritis, spondyloarthropathy and pediatric T1DM (in siblings) have been found increased in families affected by JIA. However, the prevalence of coeliac disease does not seem to differ from the general population. In children with T1DM, JIA is the most frequently encountered nonorgan-specific autoimmune disease. Pohjankoski H et al. report that the occurrence of patients with both JIA and T1DM increased over 3 decades, while 22% of them had a third autoimmune disease and 16% serious psychiatric problems [369]. There are very limited previous studies on the coexistence of T1DM with JIA in childhood [370–372]. In a study of children with T1DM, the prevalence of JIA was 8/461 (1.73%); JIA usually developed 3–5 years before the appearance of T1DM, while only in 1 female patient it was observed 2 years after T1DM diagnosis [7]. The majority of the JIA cases seem to precede the diagnosis of T1DM raising the suspicion that T1DM is a consequence of steroid therapy for JIA, while steroid therapy impaired glycaemic control in patients with T1DM and JIR [7]. There are also reports on the development of T1DM after the administration of etanercept [372]. However Ben-Skowronek et al. [7] suggest that, irrespective of the biological treatment, JIA may develop first, followed by T1DM. Thus careful follow-up of patients with JIA for T1DM and other autoimmune diseases is necessary, especially in the context of the selected therapeutic regimen for JIA. Recent data suggest that obesity may be implicated in the association between diabetes and non-organ specific autoimmune diseases [373]. Obesity has been proposed to be a risk factor for T1DM [374] as hyperinsulinemia results in β-cells stress, which accelerates apoptosis and immunogenicity (overload hypothesis). Furthermore increased levels of leptin might have a role in immune mediated β-cell destruction [375,376]. In addition obesity has been associated with the development of other autoimmune conditions, such as rheumatoid or psoriatic arthritis and Hashimoto thyroiditis [377–381], potentially through the harmful action of adipokines. Further studies will need to overcome previous limitations such as small number of patients, possible confounding factors or inadequate measurement of body fat [373].

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3. Conclusions

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T1DM is an autoimmune disease caused by autoimmune destruction of pancreatic β-cells. Autoimmune diabetes encompasses a wide range of autoimmune disorders distinct from T2DM, or it is possible that various subtypes of diabetes share a common origin with differences in the tempo of expression. The eruption of the autoimmune process is determined by genetic and environmental factors, such as viruses and wheat protein. Children and adolescents with T1DM are at higher risk of developing additional autoimmune diseases in the context of APS types 1–3 and familial autoimmunity, with autoimmune thyroiditis being the most prevalent. Early diagnosis and treatment of co-existing autoimmune conditions can result in better metabolic control and lipid metabolism, as well as optimum linear growth. Thus periodic testing of these children is necessary for the prompt identification of auto-antibodies against different organs. All children and adolescents with T1DM should be investigated for the presence of thyroid, gastric and coeliac autoimmunity at the time of diabetes diagnosis. Thereafter all T1DM patients should be screened yearly for thyroid antibody positivity. Children should be screened for CD-specific antibodies yearly before and bienially after the age of 10 years. They should also be screened biennially until and annually after the age of 10 years for gastric autoimmunity. Adrenal autoimmunity should be screened for after the age of 18 years in patients with T1DM, especially in those with a family history of Addison's disease. Regardless of previous negative testing, patients with signs and symptoms indicative of CD, autoimmune gastritis or Addison's disease, or other rare autoimmune diseases, should be investigated for the respective autoantibodies, especially in the presence of a relevant family history, as associated autoimmunity may develop anytime during the course of diabetes.

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Finally another rare associated autoimmune disease in patients with T1DM is vitiligo. Its reported prevalence in the general population is 0.5%, while in T1DM patiens it is ten to twenty times more frequent [8]. A genetic predisposition to both T1DM and vitiligo has been suggested, based on an ATXN2 gene deficiency-mediated predisposition to lipid and glucose metabolism pathology [364]. In half of the T1DM patients it presents before adulthood [365]. In children with T1DM, the prevalence of vitiligo has been reported to be 6% [366]. Most of the patients have antibodies against melaninocytes [365,367]. Vitiligo is also associated with thyroid autoimmunity [8] and has been reported in 0.2% of children with T1DM. However there are no studies on the prevalence of vitiligo in children with T1DM and autoimmune thyroiditis.

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Multiple autoimmunity is defined as the coexistence of more than two autoimmune diseases in the context of APS. There are very limited data — mainly case reports — on the prevalence of multiple autoimmunity in adults. Masood et al. [115] reported a case of T1DM patient with 5 autoimmune diseases (T1DM, autoimmune hemolytic anemia, systemic lupus erythematosus, vitiligo, and psoriasis). In children and adolescents with T1DM the studies on multiple autoimmunity are also scarce [7,184,185,371,380]. In a case report by Nagy KH et al. [370], childhood T1DM has been associated with Hashimoto's thyroiditis and juvenile rheumatoid arthritis. Furthermore in a study of 461 children with T1DM, 25.6% had one and 16/461 (3.47%) had two additional autoimmune diseases (T1DM, thyroid autoimmunity, celiac disease, JIR, psoriasis or vitiligo) [7]. In a study by Karavanaki K et al. [184] of 144 children and adolescents with T1DM, 23.6% had one and 3.8% two additional autoimmune diseases (i.e. T1DM, autoimmune thyroiditis, coeliac or gastric disease). Moreover one patient had psoriasis and one multiple sclerosis (unpublished data). It is noteworthy that Ramagopalan SV et al. [116] reported that families with multiple cases of MS were no more likely to report autoimmune diseases than families with single MS cases. As the development of one or more additional autoimmune diseases is common in clinical practice among patients with T1DM, patients with T1DM should be examined for symptoms and signs of additional autoimmune diseases, especially in light of relevant positive family history. Appropriate testing for early diagnosis and treatment of the specific coexistent autoimmune disease should follow.

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for ACA of T1DM patients over 18 years of age only in the presence of clinical indications of autoimmune adrenal disease or family history of 1075 AD in first degree relatives every five years.

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• T1DM is an autoimmune disorder, caused by the destruction of 1192 pancreatic β-cells. Autoimmune diabetes encompasses a wide range 1193 of autoimmune disorders distinct from T2DM, or it is possible that 1194



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[1] Castano L, Eisenbarth GS. Type 1 diabetes: a chronic autoimmune disease of human, mouse and rat. Annu Rev Immunol 1990;8:647–79. [2] Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994;331(21):1. [3] Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358(9277):221–9. [4] Krolewski AS, Warram JH, Rand LI, Kahn CR. Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications. N Engl J Med 1987;317(22): 1390–9. [5] Cutolo M. Autoimmune polyendocrine syndromes. Autoimmun Rev Feb 2014; 13(2):85–9. [6] Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol 2010;6(5):270–7. [7] Ben-Skowronek I, Michalczyk A, Piekarski R, Wysocka-Łukasik B, Banecka B. Type III Polyglandular Autoimmune Syndromes in children with type 1 diabetes mellitus. Ann Agric Environ Med 2013;20(1):140–6. [8] Van den Driessche A, Eenkhoorn V, Van Gaal L, De Block C. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. Neth J Med Dec 2009; 67(11):376–87. [9] Winter WE, Schatz DA. Autoimmune markers in diabetes. Clin Chem 2011;57: 168–75. [10] Rowe PA, Campbell-Thompson ML, Schatz DA, Atkinson MA. The pancreas in human type 1 diabetes. Sem Immunopathol 2011;33:29–43. [11] Oikarinen M, Tauriainen S, Honkanen T, Oikarinen S, Vuori K, Kaukinen K, et al. Detection of enteroviruses in the intestine of type 1 diabetes patients. Clin Exp Immunol 2007;151:71–5. [12] Knip M, Virtanen SM, Seppa K, Ilonen J, Savilathi E, Vaarala O, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 2010; 363:1900–8. [13] Forlenza GP, Rewers M. The epidemic of type 1 diabetes: what is it telling us? Curr Opin Endocrinol Diabetes Obes 2011;18:248–51. [14] Diagnosis and classification of diabetes mellitus. Diabetes Care 2009;32(Suppl. 1): S62–7. [15] Abiru N, Kawasaki E, Eguch K. Current knowledge of Japanese type 1 diabetic syndrome. Diabetes Metab Res Rev 2002;18:357–66. [16] Kobayashi T, Nishida Y, Tanaka S, Aida K. Pathological changes in the pancreas of fulminant type 1 diabetes and slowly progressive insulin-dependent diabetes mellitus (SPIDDM): innate immunity in fulminant type 1 diabetes and SPIDDM. Diabetes Metab Res Rev 2011;27:965–70. [17] Imagawa A, Hanafusa T. Fulminant type 1 diabetes—an important subtype in East Asia. Diabetes Metab Res Rev 2011;27:959–64. [18] Shibasaki S, Imagawa A, Hanafusa T. Fulminant type 1 diabetes mellitus: a new class of type 1 diabetes. Adv Exp Med Biol 2012;771:20–3. [19] Redondo MJ. LADA: time for a new definition. Diabetes 2013;62:339–40. [20] Zampetti S, Capizzi M, Spoletini M, Campagna G, Leto GCipolloni L, et al. GADA titer-related risk for organ-specific autoimmunity in LADA subjects subdivided according to gender (NIRAD study 6). J Clin Endocrinol Metab 2012;97:3759–65.

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References

T

1222

C

1220 1221

•

E

1218 1219

R

1216 1217

F

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•

1206 1207

R

1204 1205

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[21] Lohman T, Kellner K, Verlohren HJ, Krug J, Syeindorf J, Scherbaum WA, et al. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia 2001;44:1005–10. [22] Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP, Ronandsson O, Colman PG, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 2005;48:2206–12. [23] Pozzilli P, Buzzetti R. A new expression of diabetes: double diabetes. Trends Endocrinol Metab 2007;18:52–7. [24] Ashcroft FM, Rorsman P. Diabetes mellitus and the beta cell: the last ten years. Cell 2012;148:1160–71. [25] Velloso LA, Eizirik DL, Cnop M. Type 2 diabetes mellitus—an autoimmune disease? Nat Rev Endocrinol 2013;9(12):750–5. [26] Awdeh ZL, Yunis EJ, Audeh MJ, Fici D, Pugliese A, Larsen CE, et al. A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease. J Autoimmun 2006;27:174–81. [27] Borchers AT, Uibo R, Gershwin ME. The geoepidemiology of type 1 diabetes. Autoimmun Rev 2010;9:355–65. [28] Bach JF. Infections and autoimmune diseases. J Autoimmun 2005;25:74–80 [Suppl.]. [29] Cohen IR, Young DB. Autoimmunity, microbial immunity and the immunological homunculus. Immunol Today 1991;12:105–10. [30] Poletaev AB, Stepanyuk VL, Gershwin ME. Integrating immunity: the immunculus and self-reactivity. J Autoimmun 2008;30:68–73. [31] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64. [32] Stanley HM, Norris JM, Barriga K, Hoffman M, Yu L, Miao D, et al. Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? Diabetes Care 2004;27:497–502. [33] Pearl-Yafe M, Iskovich S, Kaminitz A, Stein J, Yaniv I, Askenasy N. Does physiological beta cell turnover initiate autoimmune diabetes in the regional lymph nodes? Autoimmun Rev 2006;5:338–43. [34] D'Alise AM, Auyeung V, Feuerer M, Nishio J, Fontenot J, Benoist C, et al. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc Natl Acad Sci U S A 2008;105:19857–62. [35] Yarkoni S, Kaminitz A, Sagiv Y, Askenasy N. Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice. Diabetologia 2010;53:356–68. [36] Yolcu ES, Ash S, Kaminitz A, Sagiv Y, Askenasy N, Yarkoni S. Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression. Immunol Cell Biol 2008;86: 650–8. [37] Bottazzo GF, Floriu-Christensen A, Doniach D. Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiency. Lancet 1974;2(7892): 1279–83. [38] Bottazzo GF, Dean BM, Gorsuch AN, Cudworth AG, Doniach D. Complement-fixing islet-cell antibodies in type 1 diabetes mellitus: possible monitors of active beta cell damage. Lancet 1980;1(8170):668–72. [39] Johnson C, Millward M, Hoskins P, Bottazzo GF, Pyke DA. Islet cell antibodies as predictors of the later development of type 1 (insulin dependent) diabetes mellitus: a study in identical twins. Diabetologia 1989;32(6):382–6. [40] Bingley PJ, Bonifacio S, Shattock M, Gilmor HA, Sawtel PA, Dunger DB, et al. Can islet cell antibodies predict insulin-dependent diabetes in the general population? Diabetes Care 1993;16(1):45–50. [41] Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK, et al. Insulin antibodies in insulin-dependent diabetes before insulin treatment. Science 1983; 222(4630):1337–9. [42] Bingley PJ, Bonifacio R, Gale EAM. Can we really predict IDDM? Diabetes 1993; 42(2):213–28. [43] Pipi E, Marketou M, Tsirogianni A. Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus. World J Diabetes 2014;5(4):505–10. [44] Kaufman DL, Clare-Salzler MC, Tian J, Forsthuber T, Ting GS, Robinson P, et al. Spontaneous loss of T-cell tolerance of glutamine acid decarboxylase in murine insulindependent diabetes. Nature 1993;366(6450):69–72. [45] Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt O. Immune response to glutamic acid decarboxylase toleranve correlates with insulinitis in non-obese diabetic mice. Nature 1993;366(6450):72–5. [46] Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in type 1 (insulindependent) diabetes. Diabetologia 1999;42:3–14. [47] Lowe RM, Graham J, Sund G, Kockum I, Landin-Olsson M, Schaefer JB, et al. The length of the CTLA-4 microsatellite (AT)N-repeat affects the risk for type 1 diabetes. Autoimmunity 2000;32(3):173–80. [48] Ronkainen MS, Savola K, Knip M. Antibodies to GAD65 epitopes at diagnosis and over the first 10 years of clinical type 1 diabetes mellitus. Scand J Immunol Mar 2004;59(3):334–40. [49] Borg H, Marcus C, Sjoblad S, Fernlund P, Sundkvist G. Islet cell antibody frequency differs from that of glutamic acid decarboxylase antibodies/IA2 antibodies after diagnosis of diabetes. Acta Paediatr 2000;89(1):46–51. [50] Decochez K, Tits J, Coolens J-L, Van Gaal L, Krzentowski G, Winnock F, et al. High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age: the Belgian Diabetes Registry. Diabetes Care 2000;23(6):838–44. [51] Han S, Donelan W, Wang H, Reeves W, Yang LJ. Novel autoantigens in type 1 diabetes. Am J Transl Res May 24 2013;5(4):379–92.

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various subtypes of diabetes share a common origin with differences in the tempo of expression. Potential triggers of the autoimmune process include genetic and environmental factors, such as viruses and possibly dietary components (e.g.wheat gluten, cow's milk proteins, nitrates/nitrites). Children and adolescents with T1DM are at increased risk of developing other autoimmune conditions, which may involve other organs, resulting in organ specific autoimmune disease, or several organs and tissues resulting in non-organ-specific autoimmune diseases e.g. rheumatoid arthritis. Among the organ-specific autoimmune diseases the most frequently encountered are autoimmune thyroid disease, followed by celiac, gastric disease and other rare autoimmune diseases. These associated autoimmune conditions may be isolated or in the context of autoimmune polyglandular syndromes (APS) — types 1–3 and familial autoimmunity. Early diagnosis and treatment of coexisting autoimmune conditions in T1DM children can result in better growth, lipid and glycemic control. All children with T1DM will have to be investigated at diabetes diagnosis for the presence of additional autoimmune diseases, especially in light of relevant positive family history. The long term follow-up is dependent on national guidelines. Inversely any child with T1DM with signs or symptoms of associated autoimmune conditions or with suboptimal growth and glycemic control after optimal management, should be investigated for associated autoimmunity, despite negative previous serology.

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[79] Myhill P, Davis WA, Bruce DG, Mackay IR, Zimmet P, Davis TM. Chronic complications and mortality in community-based patients with latent autoimmune diabetes in adults: the Fremantle Diabetes Study. Diabet Med Oct 2008; 25(10):1245–50. [80] Mancardi MM, Striano P, Giannattasio A, Baglietto MG, Errichiello L, Zara F, et al. Type 1 diabetes and epilepsy: more than a casual association? Epilepsia 2010; 51:320–1. [81] Saiz A, Blanco Y, Sabater L, Gonza'lez F, Bataller L, Casamitjana R, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008;131:2553–63. [82] Olson JA, Olson DM, Sandborg C, Alexander S, Buckingham B. Type 1 diabetes mellitus and epilepsia partialis continua in a 6-year-old boy with elevated antiGAD65 antibodies. Pediatrics 2002;109(3):E50. [83] Falip M, Miró J, Carreño M, Jaraba S, Becerra JL, Cayuela N, et al. Hypoglycemic seizures and epilepsy in type I diabetes mellitus. J Neurol Sci Nov 15 2014;346(1–2): 307–9. [84] Kwan P, Sills GJ, Kelly K, Butler E, Brodie MJ. Glutamic acid decarboxylase autoantibodies in controlled and uncontrolled epilepsy: a pilot study. Epilepsy Res 2000;42(2–3):191–5. [85] McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, et al. Serum antibodies in epilepsy and seizure-associated disorders. Neurology 2005;65(11):1730–6. [86] Errichiello L, Perruolo G, Pascarella A, Formisano P, Minetti C, Striano S, et al. Autoantibodies to glutamic acid decarboxylase (GAD) in focal and generalized epilepsy: a study on 233 patients. J Neuroimmunol 2009;211(1-2):120–3. [87] Wang CP, Hsieh PF, Chen CC, Lin WY, Hu WH, Yang DY, et al. Hyperglycemia with occipital seizures: images and visual evoked potentials. Epilepsia 2005;46(7): 1140–4. [88] Cokar O, Aydin B, Ozer F. Non-ketotic hyperglycaemia presenting as epilepsia partialis continua. Seizure 2004;13(4):264–9. [89] Manford M, Fuller GN, Wade JP. “Silent diabetes”: non-ketotic hyperglycaemia presenting as aphasic status epilepticus. J Neurol Neurosurg Psychiatry 1995;59(1): 99–100. [90] Caraballo RH, Sakr D, Mozzi M, Guerrero A, Adi JN, Cersosimo RO, et al. Symptomatic occipital lobe epilepsy following neonatal hypoglycaemia. Pediatr Neurol 2004; 31(1):24–9. [91] Walikonis JE, Lennon VA. Radioimmunoassay for glutamic acid decarboxylase [GAD65] autoantibodies as a diagnostic aid for stiffman syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin Proc 1998;73(12): 1161–6. [92] Dinkel K, Meinck HM, Jury KM, Karges W, Richter W. Inhibition of gammaaminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol Aug 1998;44(2):194–201. [93] McHugh JC, Murray B, Renganathan R, Connolly S, Lynch T. GAD antibody positive paraneoplastic stiff person syndrome in a patient with renal cell carcinoma. Mov Disord 2007;22(9):1343–6. [94] Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008;131(Pt 10):2553-1263. [95] Marine N, Boriana A. Olfactory markers of depression and Alzheimer's disease. Neurosci Biobehav Rev Sep 2014;45:262–70. [96] Takeda A, Baba T, Kikuchi A, Hasegawa T, Sugeno N, Konno M, et al. Olfactory dysfunction and dementia in Parkinson's disease. J Parkinsons Dis 2014;4(2):181–7. [97] Kivity S, Ortega-Hernandez OD, Shoenfeld Y. Olfaction—a window to the mind. Isr Med Assoc J Apr 2009;11(4):238–43. [98] Strous RD, Shoenfeld Y. To smell the immune system: olfaction, autoimmunity and brain involvement. Autoimmun Rev Nov 2006;6(1):54–60. [99] Bechter K. Updating the mild encephalitis hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry Apr 5 2013;42:71–91. [100] Katzav A, Ben-Ziv T, Blank M, Pick CG, Shoenfeld Y, Chapman J. Antibody-specific behavioral effects: intracerebroventricular injection of antiphospholipid antibodies induces hyperactive behavior while anti-ribosomal-P antibodies induces depression and smell deficits in mice. J Neuroimmunol Jul 15 2014;272(1–2):10–5. [101] Moscavitch SD, Szyper-Kravitz M, Shoenfeld Y. Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: the olfactory and immune system interrelationship. Clin Immunol Mar 2009;130(3): 235–43. [102] Jahromi MM. Haplotype specific alteration of diabetes MHC risk by olfactory receptor gene polymorphism. Autoimmun Rev Dec 2012;12(2):270–4. [103] Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann 1980;9(4):154–62. [104] Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab 2006;91:1210–7. [105] Shaikh SB, Haji IM, Doddamani P, Rahman M. A study of autoimmune polyglandular syndrome (APS) in patients with type1 diabetes mellitus (T1DM) followed up at a teritiary care hospital. J Clin Diagn Res Feb 2014;8(2):70–2. [106] Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet 1997;17(4):393–8. [107] Finnish–German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997;17(4):399–403. [108] Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome type 2: the tip of an iceberg? Clin Exp Immunol 2004;137(2):225–33. [109] Dosi RV, Tandon N. A study on prevalence of thyroid auto-immunity in diabetes mellitus. J Indian Med Assoc 2010;108(6):349–50. [110] Turkoglu Z, Kavala M, Kolcak O, Zindanci I, Can B. Autoimmune polyglandular syndrome—3C in a child. Dermatol Online J 2010;16(3):8.

N

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O

R

R

E

C

T

[52] Vermeulen I, Weets I, Costa O, Asanghanwa M, Verhaeghen K, Decochez K, et al. An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age. Diabetologia Feb 2012;55(2):413–20. [53] Barker JM, Barriga KJ, Yu L, Miao D, Erlich HA, Norris JM, et al. Prediction of autoantibody positivity and progression to type 1 diabetes: diabetes autoimmunity study in the young (DAISY). J Clin Endocrinol Metab 2004;89(8):3896–902. [54] Truyen I, De Grijse J, Weets I, Kauffman L, Pipeleers L, Nanos N, et al. Identification of prediabetes in first-degree relatives at intermediate risk of type I diabetes. Clin Exp Immunol 2007;149(2):243–50. [55] Savola K, Läärä E, Vähäsalo P, Kulmala P, Akerblom HK, Knip M, et al. Dynamic pattern of disease-associated autoantibodies in siblings of children with type 1 diabetes. Diabetes 2001;50(11):2625–32. [56] Hummel M, Bonifacio E, Schmid S, Walter M, Knopff A, Ziegler AG. Brief communication: early appearance of islet autoantibodies predicts childhood type 1 diabetes in offspring of diabetic parents. Ann Intern Med Jun 1 2004;140(11):882–6. [57] Krischer JP, Cuthbertson DD, Yu L, Orban T, Maclaren N, Jackson R, et al. Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes. J Clin Endocrinol Metab Jan 2003;88(1):103–8. [58] Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA Jun 19 2013;309(23):2473–9. [59] Ziegler AG, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 1999;48:460–8. [60] Achenbach P, Bonifacio E, Koczwara K, Ziegler A. Natural history of type 1 diabetes. Diabetes 2005;53(Suppl. 2):S25–31. [61] Decochez K, De Leeuw IH, Keymeulen B, Mathieu C, Rottiers R, Weets I, et al. IA-2 autoantibodies predict impending type I diabetes in siblings of patients. Diabetologia Dec 2002;45(12):1658–66. [62] Ota T, Takamura T, Nagai Y, Bando Y, Usuda R. Significance of IA-2 antibody in Japanese type 1 diabetes: its association with GAD antibody. Diabetes Res Clin Pract Jan 2005;67(1):63–9. [63] Betterle C, Spadaccino AC, Presotto F, Zanchetta R, Pedini B, Lai M, et al. The number of markers of pancreatic autoimmunity is proportional to the risk for type 1 diabetes mellitus in Italian and English patients with organ-specific autoimmune diseases. Ann N Y Acad Sci Apr 2002;958:276–80. [64] Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes Feb 2004;53(2):384–92. [65] Mortensen HB, Swift PG, Holl RW, Hougaard P, Hansen L, Bjoerndalen H, et al. Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of age, ketoacidosis, HLA status, and autoantibodies on residual betacell function and glycemic control 12 months after diagnosis. Pediatr Diabetes Jun 2010;11(4):218–26. [66] Borg H, Gottsäter A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes Jun 2002;51(6):1754–62. [67] Wenzlau JM, Moua O, Sarkar SA, Yu L, Rewers M, Eisenbarth GS, et al. SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Ann NY Acad Sci 2008;1150:256–9. [68] Schweiger M, Steffl M, Amselgruber WM. The zinc transporter ZnT8 (slc30A8) is expressed exclusively in beta cells in porcine islets. Histochem Cell Biol Dec 2013;140(6):677–84. [69] Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 2007;104(43):17040–5. [70] Petruzelkova L, Ananieva-Jordanova R, Vcelakova J, Vesely Z, Stechova K, Lebl J, et al. The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of Type 1 diabetes mellitus. Diabet Med Feb 2014;31(2):165–71. [71] Salonen KM, Ryhänen S, Härkönen T, Ilonen J, Knip M, Finnish Pediatric Diabetes Register. Autoantibodies against zinc transporter 8 are related to age, metabolic state and HLA DR genotype in children with newly diagnosed type 1 diabetes. Diabetes Metab Res Rev Nov 2013;29(8):646–54. [72] Rogowicz-Frontczak A, Zozuliłska-Ziołkiewicz D, Litwinowicz M, Niedźwiecki P, Wyka K, Wierusz-Wysocka B. Are zinc transporter type 8 antibodies a marker of autoimmune thyroiditis in non-obese adults with new-onset diabetes? Eur J Endocrinol Mar 14 2014;170(4):651–8. [73] Winter WE, Schatz DA. Autoimmune markers in diabetes. Clin Chem 2011;57: 168–75. [74] Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ. Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. J Clin Invest 1992;89(1):283–92. [75] Hoeldtke RD, Bryner KD, Hobbs GR, Horvath GG, Riggs JE, Christie I, et al. Antibodies to glutamic acid decarboxylase and peripheral nerve function in type 1 diabetes. J Clin Endocrinol Metab 2000;85(9):3297–308. [76] Morano S, Tiberti C, Cristina G, Sensi M, Cipriani R, Guidobaldi L, et al. Autoimmune markers and neurological complications in non-insulin-dependent diabetes mellitus. Hum Immunol Sep 1999;60(9):848–54. [77] Arikan E, Sabuncu T, Ozer EM, Hatemi H. The clinical characteristics of latent autoimmune diabetes in adults and its relation with chronic complications in metabolically poor controlled Turkish patients with Type 2 diabetes mellitus. J Diabetes Complications Sep–Oct 2005;19(5):254–8. [78] Isomaa B, Almgren P, Henricsson M, Taskinen MR, Tuomi IT, Groop L, et al. Chronic complications in patients with slowly progressing autoimmune type 1 diabetes (LADA). Diabetes Care 1999;22(8):1347–53.

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[140] Blanchin S, Estienne V, Durand-Gorde JM, Carayon P, Ruf J. Complement activation by direct C4 binding to thyroperoxidase in Hashimoto's thyroiditis. Endocrinology 2003;144(12):5422–9. [141] Bernet V. Autoimmune thyroid disease. In: Rich RR, editor. Clinical immunology. London: Mosby; 1998. [142] Kordonouri O, Hartmann R, Deiss D, Wilms M, Gruters-Kieslich A. Natural course of autoimmune thyroiditis in type 1 diabetes: association with gender, age, diabetes duration, and puberty. Arch Dis Child Apr 2005;90(4):411–4. [143] Triolo TM, Armstrong TK, McFann K, Yu L, Rewers MG, Klingensmith GJ, et al. Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 2011;34(5):1211–3. [144] Severinski S, Banac S, Severinski NS, Ahel V, Cvijović K. Epidemiology and clinical characteristics of thyroid dysfunction in children and adolescents with type 1 diabetes. Coll Antropol Mar 2009;33(1):273–9. [145] Barker JM, Yu J, Yu L, Wang J, Miao D, Bao F, et al. Autoantibody ‘subspecificity’ in type 1 diabetes. Diabetes Care 2005;28(4):850–5. [146] Sumnik Z, Drevinek P, Snajderova M, Kolouskova S, Sedlakova P, Pechova M, et al. HLA-DQ polymorphisms modify the risk of thyroid autoimmunity in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2003;16(6):851–8. [147] De Block CE, Silveira LFG, MacColl GS, Bouloux PMG. The hypothalamic–pituitary– gonadal axis: immune function and autoimmunity. J Endocrinol 2003;176(3): 293–304. [148] Landin-Olsson M, Karlsson A, Dahlquist G, Blom L, Lernmark A, Sundkvist G. Islet cell and other organ-specific autoantibodies in all children developing type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children. Diabetologia 1989;32(6):387–95. [149] Verge CF, Howard NJ, Rowley MJ, Mackay IR, Zimmet PG, Egan M, et al. Antiglutamate decarboxylase and other antibodies at the onset of childhood IDDM: a population-based study. Diabetologia 1994;37(11):1113–20. [150] Ahmed SA, Talal N. Sex hormones and the immune system—part 2. Animal data. Baillieres Clin Rheumatol 1990;4(1):13–31. [151] Fox HS. Androgen treatment prevents diabetes in non-obese diabetic mice. J Exp Med 1992;175(5):1409–12. [152] Talal N. Autoimmunity and the immunological network. Arthritis Rheum 1978;21: 853. [153] Landin-Olsson M, Karlsson FA, Lernmark A, Sundkvist G. Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the diabetes incidence study in Sweden. Diabetes 1992;41(8):1022–7. [154] Kokkonen J, Kiuttu J, Mustonen A, Rasanen O. Organ-specific antibodies in healthy and diabetic children and young adults. Acta Paediatr Scand 1982;71(2):223–6. [155] Prazny M, Skrha J, Limanova Z, Vanickova Z, Hilgertova J, Prazna J, et al. Screening for associated autoimmunity in type 1 diabetes mellitus with respect to diabetes control. Physiol Res 2005;54(1):41–8. [156] De Block CE, de Leeuw IH, Vertommen JJ, Rooman RP, Du Caju MV, Van Campehout CM, et al. Beta-cell, thyroid, gastric, adrenal and coeliac autoimmunity and HLA-DQ types in type 1 diabetes. Clin Exp Immunol 2001;126(2):236–41. [157] Talal N. Lessons from autoimmunity. Ann N Y Acad Sci Aug 12 1993;690:19–23. [158] Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH T4 and thyroid antibodies in the United States population 988 to 199: National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metabol 2002;87(2):489–99. [159] Kim EY, Shin CH, Yang SW. Polymorphisms of HLA class II predispose children and adolescents with type 1 diabetes mellitus to autoimmune thyroid disease. Autoimmunity 2003;36(3):177–81. [160] Kota SK, Meher LK, Jammula S, Kota SK, Modi KD. Clinical profile of coexisting conditions in type 1 diabetes mellitus patients. Diabetes Metab Syndr Apr–Jun 2012; 6(2):70–6. [161] Glastras SJ, Craig ME, Verge CF, Chan AK, Cusumano JM, Donaghue KC. The role of autoimmunity at diagnosis of type 1 diabetes in the development of thyroid and celiac disease and microvascular complications. Diabetes Care 2005; 28(9):2170–5. [162] Riley WJ, Maclaren NK, Lezotte DC, Spillar RP, Rosenbloom AL. Thyroid autoimmunity in insulin-dependent diabetes mellitus: the case for routine screening. J Pediatr Sep 1981;99(3):350–4. [163] Czerniawska E, Szalecki M, Piatkowska E, Młynarski W, Bodalski J, Lewiński A. Prevalence of thyroid antibodies (TPO, and ATG) at the onset of type 1 diabetes mellitus in children treated in two diabetes centers in Lotz and Kielce. Med Wieku Rozwoj Apr–Jun 2003;7(2):223–8. [164] Padberg S, Heller K, Usadel KH, Schumm-Draeger PM. One year prophylactic treatment of euthyroid Hashimoto's thyroiditis patients with levothyroxine: is there a benefit? Thyroid 2001;11(3):249–55. [165] Mohn A, Di Michele S, Di Luzio R, Tumini S, Chiarelli F. The effect of subclinical hypothyroidism on metabolic control in children and adolescents with type 1 diabetes mellitus. Diabet Med 2002;19(1):70–3. [166] Chase HP, Garg SK, Cockerham RS, Wilcox WD, Walravens PA. Thyroid hormone replacement and growth of children with subclinical hypothyroidism and diabetes. Diabet Med 1990;7(4):299–303. [167] Hage M, Zantout MS, Azar ST. Thyroid disorders and diabetes mellitus. J Thyroid Res 2011;10(4061):1–7. [168] Mouradian M, Abourizk N. Diabetes mellitus and thyroid disease. Diabetes Care 1983;6(5):512–20. [169] Sinclair D. Analytical aspects of thyroid antibodies estimation. Autoimmunity 2008; 41(1):46–54. [170] Denzer C, Karges B, Näke A, Rosenbauer J, Schober E, Schwab KO, et al. Subclinical hypothyroidism and dyslipidemia in children and adolescents with type 1 diabetes mellitus. Eur J Endocrinol Mar 15 2013;168(4):601–8.

E

T

[111] Rottembourg D, Deal C, Lambert M, Mallone R, Carel JC, Lacroix A, et al. 21Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison's disease. J Autoimmun 2010;35:309–15. [112] Pohjankoski H, Kautiainen H, Kotaniemi K, Korppi M, Savolainen A. Diabetes, coeliac disease, multiple sclerosis and chronic arthritis in first-degree relatives of patients with juvenile idiopathic arthritis. Acta Paediatr Jul 2012;101(7):767–71. [113] Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009;161(1): 11–20. [114] Flesch BK, Matheis N, Alt T, Weinstock C, Bux J, Kahaly GJ. HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III. J Clin Endocrinol Metab Jan 2014;99(1):E177–82. [115] Masood S, Sajid S, Jafferani A, Tabassum S, Ansar S. Multiple autoimmune syndromes associated with psoriasis: a rare clinical presentation. Oman Med J Mar 2014;29(2):130–1. [116] Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M, Yee IM, et al. Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol Jul 2007;6(7):604–10. [117] Schneller C, Finkel L, Wise M, Hageman JR, Littlejohn E. Autoimmune polyendocrine syndrome: a case-based review. Pediatr Ann 2013;42:203–8. [118] Anaya JM, Corena R, Castiblanco J, Rojas-Villarraga A, Shoenfeld Y. The kaleidoscope of autoimmunity: multiple autoimmune syndromes and familial autoimmunity. Expert Rev Clin Immunol 2007;3:623–35. [119] Cardenas-Roldan J, Rojas-Villarraga A, Anaya JM. How do autoimmune diseases cluster in families? A systematic review and meta-analysis. BMC Med 2013;11: 73–95. [120] Wagner AM, Santana A, Hernndez M, Wiebe JC, Novoa J, Mauricio D. Predictors of associated autoimmune diseases in families with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes Metab Res Rev 2011;27:493–8. [121] Hemminki K, Li X, Sundquist J, Sundquist K. Familial association between type 1 diabetes and other autoimmune and related diseases. Diabetologia 2009;52:1820–8. [122] Lebenthal Y, Yackobovitch-Gavan M, de Vries L, Phillip M, Lazar L. Coexistent autoimmunity in familial type 1 diabetes: increased susceptibility in sib-pairs? Horm Res Paediatr 2011;75:284–90. [123] Petaros P, Martelossi S, Tommasini A, Torre G, Caradonna M, Ventura A. Prevalence of autoimmune disorders in relatives of patients with celiac disease. Dig Dis Sci 2002;47:1427–31. [124] Deretzi G, Kountouras J, Koutlas E, Zavos C, Polyzos S, Rudolf J, et al. Familial prevalence of autoimmune disorders in multiple sclerosis in Northern Greece. Mult Scler 2010;16:1091–101. [125] Alonso A, Hernan MA, Ascherio A. Allergy, family history of autoimmunediseases, and the risk of multiple sclerosis. Acta Neurol Scand 2008;117:15–20. [126] Prina Cerai LM, Weber G, Meschi F, Mora S, Bognetti E, Siragusa Y, et al. Prevalence of thyroid autoantibodies and thyroid autoimmune disease in diabetic children and adolescents. Diabetes Care 1994;17(7):782–3. [127] Kordonouri O, Klinghammer A, Lang EB, Gruters-Keslich A, Grabert M, Holl RW. Thyroid autoimmunity in children and adolescents with type 1 diabetes. Diabetes Care 2002;25(8):1346–50. [128] Kabelitz M, Liesenkotter KP, Stach B, Willgerodt H, Stablein W, Singendonk W, et al. The prevalence of anti-thyroid peroxidase antibodies and autoimmune thyroiditis in children and adolescents in an iodine replete area. Eur J Endocrinol 2003; 148(3):301–7. [129] Loviselli A, Velluzzi F, Mossa P, Cambosu MA, Secci G, Atzeni F, et al. The Sardinian Autoimmunity Study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: relationship to goiter prevalence and thyroid function. Thyroid 2001;11(9):849–57. [130] Kaloumenou L, Duntas L, Alevizaki M, Mastorakos G, Mantzou E, Antoniou A, et al. Thyroid volume, prevalence of subclinical hypothyroidism and autoimmunity in children and adolescents. J Greek Paediatr Soc 2007;70(5):107–14. [131] Holl RW, Bohm B, Loos U, Grabert M, Heinze E, Homoki J. Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Horm Res 1999;52(3): 113–8. [132] Kakleas K, Paschali E, Kefalas N, Fotinou A, Kanariou M, Karayianni C, et al. Factors for thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Ups J Med Sci 2009;114(4):214–20. [133] Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43(1):55–68. [134] Zamrazil V, Pohunkova D, Vavrejnova V, Nemec J, Vana S. Prevalence of thyroid diseases in two samples of Czech population. A preliminary study. Endocrinol Exp 1989;23(2):97–104. [135] Doufas AG, Mastorakos G, Chatziioannou S, Tseleni-Balafouta S, Piperingos G, Boukis MA, et al. The predominant form of non-toxic goiter in Greece is now autoimmune thyroiditis. Eur J Endocrinol 1999;140(6):505–11. [136] Shiau MY, Tsai ST, Hwang J, Wu CY, Chang YH. Relationship between autoantibodies against glutamic acid decarboxylase, thyroglobulin/thyroid microsome and DNA topoisomerase II in the clinical manifestation of patients with type 1 diabetes mellitus in Taiwan. Eur J Endocrinol 2000;142(6):577–85. [137] Maugendre D, Guilhem I, Karacatsanis C, Poirier JY, Leguerrier AM, Lorcy Y, et al. Anti-TPO antibodies and screening of thyroid dysfunction in type 1 diabetic patients. Ann Endocrinol (Paris) 2000;61(6):524–30. [138] Rattarasarn C, Diosdado MA, Ortego J, Leelawattana R, Soonthornpun S, Setasuban W, et al. Thyroid autoantibodies in Thai type 1 diabetic patients: clinical significance and their relationship with glutamic acid decarboxylase antibodies. Diabetes Res Clin Pract 2000;49(2–3):107–11. [139] Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996; 335(2):99–107.

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[201] Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. New Engl JMed 1997;337(20): 1441–8. [202] Tsai LH, Taniyama K, Tanaka C. Gamma-aminobutyric acid stimulates acid secretion from the isolated guinea pig stomach. Am J Physiol 1987;253(5 PT1):G601–6. [203] Esteban M, Baxter AG. Polyspecificity of autoimmune responses in type 1 (autoimmune) diabetes. Clin Exp Immunol 2001;126(2):184–6. [204] De Block CE, De Leeuw IH, Van Gaal LF. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. Clin Endocrinol Metab Feb 2008;93(2):363–71. [205] Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable hematologic presentation of autoimmune gastritis: age-related progression fromiron deficiency to cobalamin depletion. Blood 2006;107(4):1673–9. [206] Strober W, Neurath MF. Immunologic diseases of the gastrointestinal tract. In: Rich RR, editor. Clinical immunology. London: Mosby; 1998. p. 1408–23. [207] Sibilla R, Santaguida MG, Virili C, Gargano L, Nardo S, Della Guardia M, et al. Chronic unexplained anaemia in isolated autoimmune thyroid disease or associated with autoimmune related disorders. Clin Endocrinol 2008;68(4):640–5. [208] Presotto F, Betterle C. Insulin-dependent diabetes mellitus: a constellation of autoimmune diseases. J Ped End Metab 1997;10(5):455–69. [209] Karlsson FA, Burman P, Loof L, Olsson M, Scheynius A, Mardh S. Enzyme-linked immunosorbent assay of H+, K+-ATPase, the parietal cell antigen. Clin Exp Immunol 1987;70(3):604–10. [210] De Block CF, De Leeuw Ivo H, Pelckmans Paul A, Callens Dirk, Máday Emöke, Van Gaal Luc F. Delayed gastric emptying and gastric autoimmunity in type 1 diabetes. Diabetes Care May 2002;25(5):912–7. [211] Kokkonen J. Parietal cell antibodies and gastric secretion in children with diabetes mellitus. Acta Paediatr Scand 1980;69(4):485–9. [212] Hanukoglu A, Mizrachi A, Dalal I, Admoni O, Rakover Y, Bistritzer J, et al. Extrapancreatic autoimmune manifestations in type 1 diabetes patients and their first-degree relatives: a multicenter study. Diabetes Care 2003;26(4):1235–40. [213] Trudeau WL, McGuigan JE. Relations between serum gastrin levels and rates of gastric hydrochloric acid secretion. N Engl J Med 1971;284(8):408–12. [214] Sipponen P, Valle J, Varis K, Kekki M, Ihamaki T, Siurala M. Fasting levels of serum gastrin in different functional and morphologic states of the antrofundal mucosa. An analysis of 860 subjects. Scand J Gastroenterol 1990;25(5):513–9. [215] De Block CE, de Leeuw IH, Bogers JJ, Pelckmans PA, Ieven MM, Van Marck EA, et al. Autoimmune gastropathy in type 1 diabetic patients with parietal cell antibodies: histological and clinical findings. Diabetes Care 2003;26(1):82–8. [216] Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic gastritispathogenesis, pathology and management. Nat Rev Gastroenterol Hepatol 2013;10(9):529–41. [217] Strickland RG, Mackay IR. A reappraisal of the nature and significance of chronic atrophic gastritis. Am J Dig Dis 1973;18(5):426–40. [218] Telaranta-Keerie A, Kara R, Paloheimo L, Harkonen M, Sipponen P. Prevalence of undiagnosed advanced atrophic corpus gastritis in Finland: an observational study among 4256 volunteers without specific complaints. Scand J Gastroenterol 2010;45(9):1036–41. [219] Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, et al. Molecular mimicry between Helicobacter pylori antigens and H+, K+-adenosine triphosphatase in human gastric autoimmunity. J Exp Med 2003;198(8):1147–56. [220] Veijola LI, Oksanen AM, Sipponen PI, Rautelin HI. Association of autoimmune type atrophic corpus gastritis with Helicobacter pylori infection. World J Gastroenterol 2010;16(1):83–8. [221] Saito M, Morioka M, Wakasa K, Izumiyama K, Mori A, Irie T, et al. In Japanese patients with type a gastritis with pernicious anemia the condition is very poorly associated with Helicobacter pylori infection. J Infect Chemother 2013;19(2):208–10. [222] Toh BH. Diagnosis and classification of autoimmune gastritis. Autoimmun Rev April–May 2014;13(4–5):459–62. [223] Carmel R. Reassessment of the relative prevalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race. Clin Exp Immunol 1992;89(1):74–7. [224] Alonso N, Granada ML, Soldevila B, Salinas I, Joaquin C, Reverter JL, et al. Serum autoimmune gastritis markers, pepsinogen i and parietal cell antibodies, in patients with type 1 diabetes mellitus: a 5-year prospective study. J Endocrinol Invest 2011;34(5):340–4. [225] Tozzoli R, Kodermaz G, Perosa AR, Tampoia M, Zucano A, Antico A, et al. Autoantibodies to parietal cells as predictors of atrophic body gastritis: a five-year prospective study in patients with autoimmune thyroid diseases. Autoimmun Rev 2010; 10(2):80–3. [226] Solcia E, Fiocca R, Villani L, Gianatti A, Cornaggia M, Chiaravalli A, et al. Morphology and pathogenesis of endocrine hyperplasias, precarcinoid lesions, and carcinoids arising in chronic atrophic gastritis. Scand J Gastroenterol Suppl 1991;180:146–59. [227] Muhsen K, Barak M, Henig C, Alpert G, Ornoy A, Cohen D. Is the association between Helicobacter pylori infection and anemia age dependent? Helicobacter Oct 2010;15(5):467–72. [228] Korstanje A, van Eeden S, Offerhaus JA, Waltman FL, Hartog G, Roelandse FW, et al. Comparison between serology and histology in the diagnosis of advanced gastric body atrophy: a study in a Dutch primary community. J Clin Gastroenterol 2008; 42(1):18–22. [229] Checchi S, Montanaro A, Pasqui L, Ciuoli C, Cevenini G, Sestini F, et al. Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies. J Clin Endocrinol Metab 2007;92(11):4346–51. [230] De Block CE, De Leeuw IH, Decochez K, Winnock F, Van Autreve J, Van Campenhout CM, et al. The presence of thyrogastric antibodies in first degree relatives of type 1 diabetic patients is associated with age and proband antibody status. J Clin Endocrinol Metab Sep 2001;86(9):4358–63.

N

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R

R

E

C

T

[171] Kordonouri O, Hartmann R, Riebel T, Liesenkoetter KP. Early treatment with Lthyroxine in children and adolescents with type 1 diabetes, positive thyroid antibodies, and thyroid gland enlargement. Pediatr Diabetes Aug 2007;8(4): 180–4. [172] Karges B, Muche R, Knerr I, Ertelt W, Wiesel T, Hub R, et al. Levothyroxine in euthyroid autoimmune thyroiditis and type 1 diabetes: a randomized, controlled trial. J Clin Endocrinol Metab May 2007;92(5):1647–52. [173] Umpierrez GE, Latif KA, Murphy MB, Lambeth HC, Stentz F, Bush A, et al. Thyroid dysfunction in patients with type 1 diabetes: a longitudinal study. Diabetes Care Apr 2003;26(4):1181–5. [174] Leong KS, Wallymahmed M, Wilding J, MacFarlane I. Clinical presentation of thyroid dysfunction and Addison's disease in young adults with type 1 diabetes. Postgrad Med J Aug 1999;75(886):467–70. [175] Chidakel A, Mentuccia D, Celi FS. Peripheral metabolism of thyroid hormon and glucose homeostasis. Thyroid 2005;15(8):899–903. [176] Mitrou P, Raptis SA, Dimitriadis G. Insulin action in hyperthyroidism: a focus on muscle and adipose tissue. Endocr Rev 2010;31(5):663–79. [177] Glinoer D, Cooper DS. The propylthiouracil dilemma. Curr Opin Endocrinol Diabetes Obes Oct 2012;19(5):402–7. [178] Karras S, Memi E, Kintiraki E, Krassas GE. Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts. J Pediatr Endocrinol Metab 2012; 25(7–8):623–30. [179] Kordonouri O, Maguire AM, Knip M, Schober E, Lorini R, Holl RW, et al. ISPAD clinical consensus guidelines2009 compendium. Other associated conditions in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes 2009; 10(Suppl. 12):204–10. [180] Standards of medical care in diabetes—2014. Diabetes Care 2014;37(supplement 1):S14–80. [181] Barker JM. Clinical review: type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. J Clin Endocrinol Metab Apr 2006;91(4): 1210–7. [182] Carson HJ, Castelli MJ, Gattuso P. Incidence of neoplasia in Hashimoto's thyroiditis: a fine-needle aspiration study. Diagn Cytopathol Feb 1996;14(1):38–42. [183] Scarpa V, Kousta E, Tertipi A, Vakaki M, Fotinou A, Petrou V, et al. Treatment with thyroxine reduces thyroid volume in euthyroid children and adolescents with chronic autoimmune thyroiditis. Horm Res Paediatr 2010;73(1):61–7. [184] Karavanaki K, Kakleas K, Paschali E, Kefalas N, Konstantopoulos I, Petrou V, et al. Screening for associated autoimmunity in children and adolescents with type 1 diabetes mellitus (T1DM). Horm Res 2009;71(4):201–6. [185] Karavanaki K, Karayianni C, Vassiliou I, Tzanela M, Sdogou T, Kakleas K, et al. Multiple autoimmunity, type 1 diabetes (T1DM), autoimmune thyroiditis and thyroid cancer: is there an association? A case report and literature review. J Pediatr Endocrinol Metab Sep 2014;27(9–10):1011–6. [186] Shi L, Li Y, Guan H, Li C, Shi L, Shan Z, et al. Usefulness of serum thyrotropin for risk prediction of differentiated thyroid cancers does not apply to microcarcinomas: results of 1,870 Chinese patients with thyroid nodules. Endocr J 2012;59(11): 973–80. [187] Pisello F, Geraci G, Lo Nigro C, Li Volsi F, Modica G, Sciumè C. Neck node dissection in thyroid cancer. A review G Chir Mar 2010;31(3):112–8. [188] Malamut G, El Machhour R, Montcuquet N, Martin-Lannerée S, Dusanter-Fourt I, Verkarre V, et al. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest Jun 2010;120(6):2131–43. [189] Guarino V, Castellone MD, Avilla E, Melillo RM. Thyroid cancer and inflammation. Mol Cell Endocrinol May 28 2010;321(1):94–102. [190] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet Feb 17 2001;357(9255):539–45. [191] Corrias A, Cassio A, Weber G, Mussa A, Wasniewska M, Rapa A, et al. Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med Jun 2008;162(6):526–31. [192] Alonso N, Granada ML, Salinas I, Lucas AM, Reverter JL, Junca J, et al. Serum pepsinogen I: an early marker of pernicious anemia in patients with type 1 diabetes. J Clin Endocrinol Metab 2005;90(9):5254–8. [193] Magzoub MM, Abdel-Hameed AA, Bottazzo GF. Prevalence of islet cell and thyrogastric autoantibodies in Sudanese patients with type 1 diabetes. Diabet Med 1994;11(2):188–92. [194] Bright GM, Blizzard RM, Kaiser DL, Clarke WL. Organ-specific autoantibodies in children with common endocrine diseases. J Pediatr 1982;100(1):8–14. [195] Frohlich-Reiterer EE, Huber J, Katz H, Suppan E, Obermayer-Pietsch B, Deutschmann A, et al. Do children and adolescents with type 1 diabetes mellitus have a higher frequency of parietal cell antibodies than healthy controls? J PGN 2011;52(5):558–62. [196] Kakleas K, Kostaki M, Critselis E, Karayianni C, Giannaki M, Anyfantakis K, et al. Gastric autoimmunity in children and adolescents with type 1 diabetes: a prospective study. Horm Res Paediatr 2012;77(2):121–6. [197] De Block CE, De Leeuw IH, Van Gaal LF, the Belgian Diabetes Registry. High prevalence of manifestations of gastric autoimmunity in parietal cell antibody-positive type 1 diabetic patients. J Clin Endocrinol Metab 1999;84(11):4062–7. [198] Riley WJ, Toskes PP, Maclaren NK, Silverstein JH. Predictive value of gastric parietal cell autoantibodies as a marker for gastric and hematologic abnormalities associated with insulin-dependent diabetes. Diabetes 1982;31(12):1051–5. [199] Ramachandran A, Rosenbloom AL, Mohan V, Snehalatha C, Viswanathan M, Riley WJ, et al. Autoimmunity in South Indian patients with IDDM. Diabetes Care 1986; 9(4):435–6. [200] Gilon P, Tappaz M, Remade C. Localization of GAD-like immuno-reactivity in the pancreas and stomach of the rat and mouse. Histochemistry 1991;96(4):355–65.

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[260] Hummel M, Bonifacio E, Stern M, Dittler J, Schimmel A, Ziegler AG. Development of coeliac disease-associated antibodies in offspring of parents with type 1 diabetes. Diabetologia 2000;43(8):1005–11. [261] MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, et al. A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Gib1, linked to islet damage. J Biol Chem 2003;278(1):54–63. [262] Toscano V, Conti FG, Anastasi E, Mariani P, Tiberti C, Poggi M, et al. Importance of gluten in the induction of endocrine autoantibodies and organ disfunction in adolescent coeliac patients. Am J Gastroenterol 2000;95(7):1742–8. [263] Barera G, Bonfati R, Viscardi M, Bazzigaluppi E, Calori G, Meschi F, et al. Occurence of coeliac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics 2002;109(5):833–8. [264] Lie BA, Sollid LM, Ascher H, Ek J, Akselsen HE, Ronningen KS, et al. A gene telomeric of the HLA class I region is involved in predisposition to both type 1 diabetes and coeliac disease. Tissue Antigens 1999;54:162–8. [265] Bratanic N, Schweiger DS, Mendez A, Bratina N, Battelino T, Vidan-Jeras B. An influence of HLA-A, B, DR, DQ, and MICA on the occurrence of celiac disease in patients with type 1 diabetes. Tissue Antigens 2010;76:208–15. [266] Funda DP, Kaas A, Bock T, Tlaskalova-Hogenova H, Buschard K. Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev 1999;15:323–7. [267] Wang G-S, Gruber H, Smyth P, Puilido O, Rosenberg L, Duguid W, et al. Hydrolysed casein diet protects BB rats from developing diabetes by promoting islet neogenesis. J Autoimmun 2000;15:407–16. [268] Graham S, Courtois P, Malaisse WJ, Rozing J, Scott FW, AMcI Mowat. Enteropathy precedes type 1 diabetes in the BB rat. Gut 2004;53:1437–44. [269] Flohe SB, Wasmuth HE, Kerad JB, Beales PE, Pozzilli P, Elliott RB, et al. A wheat based, diabetes promoting diet induces a Th-1 type cytokine bias in the gut of NOD mice. Cytokine 2003;21:149–54. [270] Ott PA, Herzog BA, Quast S, Hofsetter H, Boehm BO, Tary-Lehmann M. Islet-cell antigen reactive T cells show different expansion rates and Th1/Th2 differentiation in type 1 diabetic patients and healthy controls. Clin Immunol 2005;115: 102–14. [271] Ziegler A-G, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003;290: 1721–8. [272] Prescott SL, Smith P, Tang M, Palmer DJ, Sinn J, Huntley SJ, et al. The importance of early complementary feeding in the development of oral tolerance: concerns and controversies. Pediatr Allergy Immunol 2008;19:375–80. [273] Bosi E, Molteni L, Radaelli MG, Folini L, Fermo I, Bazzigaluppi E, et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 2006; 49:2824–7. [274] Kuitunen M, Saukkonen T, Ilonen J, Akerblom HK, Savilahti E. Intestinal permeability to mannitol and lactulose in children with type 1 diabetes with the HLADQB1* 02 allele. Autoimmunity 2002;35:365–8. [275] Secondulfo M, Iafusco D, Carratu R, deMagistris L, Sapone A, Generoso M, et al. Ultrastructural mucosal alterations and increased intestinal permeability in nonceliac, type 1 diabetic patients. Dig Liver Dis 2004;36:35–45. [276] Savilahti E, Ormala T, Saukkonen T, Sandini-Pohjavuori U, Kantele JM, Arato A, et al. Jejuna of patients with insulin-dependent diabetes mellitus (IDDM) show signs of immune activation. Clin Exp Immunol 1999;116:70–7. [277] Westerholm-Ormio M, Vaarala O, Pihkala P, Ilonen J, Savilahti E. Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. Diabetes 2003;52:2287–95. [278] Klemetti P, Savilahti E, Ilonen J, Akerblom HK, Vaarala O. T-cell reactivity to wheat gluten in patients with insulin-dependent diabetes mellitus. Scand J Immunol 1998;47:48–53. [279] Mojibian M, Chakir H, Lefebvre DE, Crookshank JA, Sonier B, Keeley E, et al. Diabetes-specific HLA-DR restricted proinflammatory T cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes. Diabetes 2009;58:1789–96. [280] Helgason T, Jonasson MR. Evidence for a food additive as a cause of ketosis-prone diabetes. Lancet 1981;316:716–20. [281] Helgason T, Ewen SWB, Ross IS, Stowers JM. Diabetes produced in mice by smoked/ cured mutton. Lancet 1982;320:1017–22. [282] Virtanen SM, Laara E, Hypponen E, Reijonen H, Rasanen L, Aro A, et al. Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case–control study of siblings of children with diabetes. Childhood diabetes in Finland study group. Diabetes 2000;49:912–7. [283] Littorin B, Blom P, Scholin A, Arnqvist HJ, Blohme G, Bolinder J, et al. Lower levels of plasma 25-hydroxyvitamin D among adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS). Diabetologia 2006;49:2847–52. [284] Cooke A. Review series on helminths, immune modulation and the hygiene hypothesis: how might infection modulate the onset of type 1 diabetes? Immunology 2008;126:12–7. [285] Borchers AT, Uibo R, Gershwin ME. The geoepidemiology of type 1 diabetes. Autoimmun Rev 2010;9:A355–65. [286] Shapira Y, Agmon-Levin N, Shoenfeld Y. Defining and analyzing geoepidemiology and human autoimmunity. J Autoimmun 2010;34:J168–77. [287] Carlsson AK, Axelsson IE, Borulf SK, Bredberg AC, Lindberg BA, Sjoberg KG, et al. Prevalence of IgA-antiendomysium and IgA-antigliadin autoantibodies at diagnosis of insulin-dependent diabetes mellitus in Swedish children and adolescents. Pediatrics 1999;103(6 Pt1):1248–52. [288] Doolan A, Donaghue K, Fairchild J, Wong M, Williams AJ. Use of HLA typing in diagnosing coeliac disease in patients with type 1 diabetes. Diabetes Care 2005;28(4): 806–9.

E

T

[231] Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, Delle Fave G, et al. Atrophic body gastritis in patients with autoimmune thyroid disease. Arch Intern Med 1999;159(15):1726–30. [232] De Block CE, De Leeuw IH, Rooman RP, Winnock F, Du Caju MV, Van Gaal LF. Gastric parietal cell antibodies are associated with glutamic acid decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 haplotype in Type 1 diabetes mellitus. Belgian Diabetes Registry. Diabet Med Aug 2000;17(8):618–22. [233] Becker KG. Comparative genetics of type 1 diabetes and autoimmune disease: common loci, common pathways? Diabetes Jul 1999;48(7):1353–8. [234] Silveira PA, Baxter AG, Cain WE, van Driel IR. A major linkage region on distal chromosome 4 confers susceptibility to mouse autoimmune gastritis. J Immunol May 1 1999;162(9):5106–11. [235] Maclaren NK, Riley WJ. Thyroid, gastric, and adrenal autoimmunities associated with insulin-dependent diabetes mellitus. Diabetes Care Sep–Oct 1985;8(Suppl. 1):34–8. [236] Kawasaki E, Takino H, Yano M, Uotani S, Matsumoto K, Takao Y, et al. Autoantibodies to glutamic acid decarboxylase in patients with IDDM and autoimmune thyroid disease. Diabetes 1994;43(1):80–6. [237] Martino GV, Tappaz ML, Braghi S, Dozio N, Canal N, Pozza G, et al. Autoantibodies to glutamic acid decarboxylase (GAD) detected by an immuno-trapping enzyme activity assay: relation to insulin-dependent diabetes mellitus. J Autoimmunity 1991;4(6):915–23. [238] Yokota I, Matsuda J, Naito E, Ito M, Shima K, Kuroda Y. Comparison of GAD and ICA512/IA-2 antibodies at and after onset of IDDM. Diabetes Care 1998;21(1): 49–52. [239] Ahrén B. GABA inhibits thyroid hormone secretion in the mouse. Thyroidology Dec 1989;1(3):105–8. [240] Sterzl I, Hrdá P, Matucha P, Cerovská J, Zamrazil V. Anti-Helicobacter pylori, antithyroid peroxidase, anti-thyroglobulin and anti-gastric parietal cells antibodies in Czech population. Physiol Res 2008;57(Suppl. 1):S135–41. [241] Newton KP, Singer SA. Celiac disease in children and adolescents: special considerations. Semin Immunopathol Jul 2012;34(4):479–96. [242] Holmes GK. Coeliac disease and type 1 diabetes mellitus—the case for screening. Diabet Med 2001;18(3):169–77. [243] Hansen D, Brock-Jacobsen B, Lund E, Bjorn C, Hansen LP, Nielsen C, et al. Clinical benefit of a gluten-free diet in type 1 diabetic children with screening-detected celiac disease: a population-based screening study with 2 years' follow-up. Diabetes Care 2006;29(11):2452–6. [244] Liu E, Li M, Bao F, Miao D, Rewers MJ, Eisenbarth GS, et al. Need for quantitative assessment of transglutaminase autoantibodies for celiac disease in screeningidentified children. J Pediatr 2005;146(4):494–9. [245] Salardi S, Volta U, Zucchini S, Fiorini E, Maltoni G, Vaira B, et al. Prevalence of celiac disease in children with type 1 diabetes mellitus increased in the mid-1990s: an 18-year longitudinal study based on anti-endomysial antibodies. J Pediatr Gastroenterol Nutr 2008;46(5):612–4. [246] Acerini CL, Ahmed ML, Ross KM, Sullivan PB, Bird G, Dunger DB. Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet. Diabet Med Jan 1998;15(1):38–44. [247] Sumnik Z, Kolouskova S, Malcova H, Vavrinec J, Venhacova J, Lebl J, et al. High prevalence of coeliac disease in siblings of children with type 1 diabetes. Eur J Pediatr Jan 2005;164(1):9–12. [248] Murray JA. Celiac disease in patients with an affected member, type 1 diabetes, iron-deficiency, or osteoporosis? Gastroenterology Apr 2005;128(4 Suppl. 1): S52–6. [249] Faas S, Schork NJ. Genetic analysis of NIDDM. The study of quantitatiretraits. Diabetes 1996;45(1):1–14. [250] Sumnik Z, Kolouskova S, Cinek O, Kotalova S, Vavrinec J, Snajderova M. HLADQA1*05-DQB1*0201 positivity predisposes to coeliac disease in Czech diabetic children. Acta Paediatr 2000;89(12):1426–30. [251] Arato A, Korner A, Veres G, Dezsofi A, Ujpal I, Madacsy L. Frequency of coeliac disease in Hungarian children with type 1 diabetes mellitus. Eur J Pediatr 2003; 162(1):1–5. [252] Martin-Villa JM, Lopez-Suarez JC, Perez-Blas M, Martinez-Laso J, Ferre-Lopez S, Garcia-Torre C, et al. Coeliac- and enteropathy-associated autoantibodies in Spanish insulin-dependent diabetes mellitus patients and their relation to HLA antigens. J Diabetes Complications 2001;15:38–43. [253] Ascher H. Coeliac disease and type 1 diabetes: an affair still with much hidden behind the veil. Acta Paediatr 2001;90(11):1217–25. [254] 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(11):2483–8. [255] Larsson K, Carlsson A, Cederwall E, Jonsson B, Neiderud J, Jonsson B, et al. Annual screening detects coeliac disease in children with type 1 diabetes. Pediatr Diabetes 2008;9(4 Pt 2):354–9. [256] Peretti N, Bienvenu F, Bouvet C, Fabien N, Tixier F, Thivolet C, et al. The temporal relationship between the onset of type 1 diabetes and coeliac disease: a study based on immunoglobulin A antitransglutaminase screening. Pediatrics 2004; 113(5):418–22. [257] Not T, Tomasini A, Torini G, Buratti E, Pocecco M, Tortul C, et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with type 1 diabetes mellitus. Diabetologia 2001;44(2):151–5. [258] Pocecco M, Ventura A. Coeliac disease and insulin-dependent diabetes mellitus: a causal association? Acta Paediatr 1995;84(12):1432–3. [259] Lorini R, Scaramuzza A, Vitali L, d'Annunzio G, Avanzini MA, De Giacomo C, et al. Clinical aspects of coeliac in children with insulin dependent diabetes mellitus. J Pediatr Endocrinol Metab 1996;9(Suppl. 1):101–11.

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[318] Nóvoa Medina Y, López-Capapé M, Lara Orejas E, Alonso Blanco M, Camarero Salces C, Barrio Castellanos R. Impact of diagnosis of celiac disease on metabolic control of type 1 diabetes. An Pediatr (Barc) 2008;68(1):13–7. [319] Saadah OI, Zacharin M, O'Callaghan A, Oliver MR, Catto-Smith AG. Effect of glutenfree diet and adherence on growth and diabetic control in diabetics with coeliac disease. Arch Dis Child 2004;89(9):871–6. [320] Kaukinen K, Salmi J, Lahtela J, Siljamäki-Ojansuu U, Koivisto AM, Oksa H, et al. No effect of gluten-free diet on the metabolic control of type 1 diabetes in patients with diabetes and celiac disease. Retrospective and controlled prospective survey. Diabetes Care 1999;22(10):1747–8. [321] Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40(1):1–19. [322] NIH consensus development conference on celiac disease. NIH Consens State Sci Statements 2004;21(1):1–23. [323] Standards of medical care in diabetes—2014. Diabetes Care 2014;37(supplement 1):S14–80. [324] Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. ESPGHAN Working Group on Coeliac Disease Diagnosis, ESPGHAN Gastroenterology Committee, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatric Gastroenterol Nutr 2012;54:136–60. [325] Nevoral J, Kotalova R, Hradsky O, Valtrova V, Zarubova K, Lastovicka J, et al. Symptom positivity is essential for omitting biopsy in children with suspected celiac disease according to the new ESPGHAN guidelines. Eur J Pediatr Nov 2013;15. [326] Sumnik Z, Cinek O, Bratanic N, Lebl J, Rozsai B, Limbert C, et al. Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and coeliac disease: a multicentre study. J Pediatr Endocrinol Metabol 2006;19(4):517–22. [327] Li Voon Chong JS, Leong KS, Wallymahmed M, Sturgess R, MacFarlane IA. Is coeliac disease more prevalent in young adults with coexisting type 1 diabetes mellitus and autoimmune thyroid disease compared with those with type 1 diabetes mellitus alone? Diabet Med 2002;19(4):334–7. [328] Kaukinen K, Collin P, Mykkanen AH, Partanen J, Maki M, Salmi J. Coeliac disease and autoimmune endocrinologic disorders. Dig Dis Sci 1999;44(7):1428–43. [329] Kaspers S, Kordonouri O, Schober E, Grabert M, Hauffa BP, Holl RW. Anthropometry, metabolic control and thyroid autoimmunity in type 1 diabetes with celiac disease: a multicenter study. J Pediatr 2004;145(6):790–5. [330] Wiebolt J, Achterbergh R, den Boer A, van der Leij S, Marsch E, Suelmann B, et al. Clustering of additional autoimmunity behaves differently in Hashimoto's patients compared with Graves' patients. Eur J Endocrinol May 2011;164(5):789–94. [331] Berti I, Trevisiol C, Tommasini A, Citta A, Neri E, Geatti O, et al. Usefulness of screening program for celiac disease in autoimmune thyroiditis. Dig Dis Sci 2000;45(2): 403–6. [332] Hadithi M, Meijer JW, Willekens F, Kerckhaert JA, Heijmans R, Pena AS, et al. Coeliac disease in Dutch patients with Hashimoto's thyroiditis and vice versa. Wo r l d Journal of Gastroenterology 2007;13(11):1715–22. [333] Chong CL, Biswas M, Benton A, Jones MK, Kingham JG. Prospective screening for coeliac disease in patients with Graves' hyperthyroidism using anti-gliadin and tissue transglutaminase antibodies. Clin Endocrinol (Oxf) 2005;62(3):303–6. [334] Sari S, Yesilkaya E, Egritas O, Bideci A, Dalgic B. Prevalence of celiac disease in Turkish children with autoimmune thyroiditis. Dig Dis Sci 2009;54(4):830–2. [335] Larizza D, Calcaterra V, De Giacomo C, De Silvestri A, Asti M, Badulli C, et al. Celiac disease in children with autoimmune thyroid disease. J Pediatr 2001;139(5): 738–40. [336] Meloni A, Mandas C, Jores RD, Congia M. Prevalence of autoimmune thyroiditis in children with celiac disease and effect of gluten withdrawal. J Pediatr 2009; 155(1):51–5. [337] Oderda G, Rapa A, Zavallone A, Strigini L, Bona G. Thyroid autoimmunity in childhood celiac disease. J Pediatr Gastroenterol Nutr 2002;35(5):704–5. [338] Marwaha RK, Garg MK, Tandon N, Kanwar R, Narang A, Sastry A, et al. Glutamic acid decarboxylase (anti-GAD) & tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity. Indian J Med Res Jan 2013;137(1):82–6. [339] van der Pals M, Ivarsson A, Norström F, Högberg L, Svensson J, Carlsson A. Prevalence of thyroid autoimmunity in children with celiac disease compared to healthy 12-year olds. Autoimmune Dis 2014;2014:417356. [340] Ide A, Eisenbarth GS. Genetic susceptibility in type 1 diabetes and its associated autoimmune disorders. Rev Endocrinol Metab Dis 2003;4(3):243–53. [341] Von Herrath MG, Fujinami RS, Witton JL. Microorganisms and autoimmunity: making the barren field fertile? Nat Rev Microbiol 2003;1(2):151–7. [342] Ventura A, Neri E, Ughi C, Leopaldi A, Città A, Not T. Gluten-dependent diabetesrelated and thyroid-related autoantibodies in patients with celiac disease. J Pediatr 2000;137(2):263–5. [343] Farloni A, Laureti S, Santeusanio F. Autoantibodies in autoimmune polyendocrine syndrome type II. Endocrin Metab Clin North Am 2002;31(2):369–89. [344] Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004;350(20):2068–79. [345] Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol 2009;161(1): 11–20. [346] Leong KS, Wallymahmed M, Wilding J, MacFarlane I. Clinical presentation of thyroid dysfunction and Addison's disease in young adults with type 1 diabetes. Postgrad Med J 1999;75(886):467–70. [347] Armstrong L, Bell PM. Lesson of the Week: Addison's disease presenting as reduced insulin requirement in insulin dependent diabetes. BMJ 1996; 312(7046):1601–2.

N

C

O

R

R

E

C

T

[289] de Graaff LC, Smit JW, Radder JK. Prevalence and clinical significance of organspecific autoantibodies in type 1 diabetes mellitus. Neth J Med Jul–Aug 2007; 65(7):235–47. [290] Mansour AA, Najeeb AA. Coeliac disease in Iraqi type 1 diabetic patients. Arab J Gastroenterol Jun 2011;12(2):103–5. [291] Kanungo A, Shtauvere-Brameus A, Samal KC, Sanjeevi CB. Autoantibodies to tissue transglutaminase in patients from eastern India with malnutrition-modulated diabetes mellitus, insulin-dependent diabetes mellitus, and non-insulin-dependent diabetes mellitus. Ann N Y Acad Sci 2002;958:232–4. [292] Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. J Autoimmun 1999;13(1):143–8. [293] Reddick BK, Crowell K, Fu B. Clinical inquiries: what blood tests help diagnose celiac disease? J Fam Pract Dec 2006;55(12):1088 [1090, 1093]. [294] Contreas G, Valletta E, Ulmi D, Cantoni S, Pinelli L. Screening of coeliac disease in north Italian children with type 1 diabetes: limited usefulness of HLA-DQ typing. Acta Paediatr May 2004;93(5):628–32. [295] Chan KN, Philips AD, Mirakian R, Walter-Smith JA. Endomysial antibody screening in children. J Pediatr Gastroenterol Nutr 1994;18(3):316–20. [296] Spiekerkoetter U, Seissler J, Wendel U. General screening for celiac disease is advisable in children with type 1 diabetes. Horm Metab Res Apr 2002;34(4):192–5. [297] Hopper AD, Cross SS, Hurlstone DP, McAlindon ME, Lobo AJ, Hadjivassiliou M, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. BMJ 2007;334(7596):729. [298] Abrams JA, Diamond B, Rotterdam H, Green PH. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci 2004; 49(4):546–50. [299] Misak Z, Hojsak I, Jadresin O, Kekez AJ, Abdovic S, Kolacek S. Diagnosis of coeliac disease in children younger than 2 years. J Pediatr Gastroenterol Nutr 2013; 56(2):201–5. [300] Villalta D, Crovatto M, Stella S, Tonutti E, Tozzoli R, Bizzaro N. False positive reactions for IgA and IgG anti-tissue transglutaminase antibodies in liver cirrhosis are common and method-dependent. Clin Chim Acta 2005;356(1–2):102–9. [301] Ludvigsson JF, Neovius M, Hammarström L. Association between IgA deficiency & other autoimmune conditions: a population-based matched cohort study. J Clin Immunol May 2014;34(4):444–51. [302] Wang N, Truedsson L, Elvin K, Andersson BA, Rönnelid J, Mincheva-Nilsson L, et al. Serological assessment for celiac disease in IgA deficient adults. PLoS One Apr 7 2014;9(4):e93180. [303] Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54(1): 136–60. [304] Kakleas K, Karayianni C, Critselis E, Papathanasiou A, Petrou V, Fotinou A, et al. The prevalence and risk factors for coeliac disease among children and adolescents with type 1 diabetes mellitus. Diabetes Res Clin Pract Nov 2010;90(2):202–8. [305] Kordonouri O, Dieterich W, Schuppan D, Weber G, Muller C, Sarioglu N, et al. Autoantibodies to tissue transglutaminase are sensitive serological parameters for detecting silent coeliac disease in patients with type 1 diabetes mellitus. Diabetes UK Diabet Med 2002;17(6):441–4. [306] Sategna-Guidetti C, Grosso S, Pulitano R, Benaduce E, Dani F, Carta Q. Coeliac disease and insulin-dependent diabetes mellitus. Screening in an adult population. Dig Dis Sci 1994;39(8):1633–7. [307] Sakly W, Bienvenu F, Peretti N, Lachaux A, Morel S, Bouvier R, et al. IgA antitransglutaminase antibodies as a tool for screening atypical forms of coeliac disease in a French at-risk paediatric population. Eur J Gastroenterol Hepatol 2005; 17(2):235–9. [308] Buysschaert M, Tomasi JP, Hermans MP. Prospective screening for biopsy proven coeliac disease, autoimmunity and malabsorption markers in Belgian subjects with Type 1 diabetes. Diabet Med 2005;22(7):889–92. [309] Cerruti F, Bruno G, Chiarelli F, Lorini R, Meschi F, Sacchetti C. Younger age at onset and sex predict coeliac disease in children and adolescents with type 1 diabetes. Diabetes Care 2004;27(6):1294–8. [310] Shahbazkhani B, Faezi T, Akbari MR, Mohamadnejad M, Sotoudeh M, Rajab A, et al. Coeliac disease in Iranian type I diabetic patients. Dig Liver Dis 2004;36(3):191–4. [311] Schober E, Bittmann B, Granditsch G, et al. Screening by anti-endomysium antibody for coeliac disease in diabetic children and adolescents in Austria. Pediatr Gastroenterol Nutr 2000;30(4):391–6. [312] Freemark M, Levitsky LL. Screening for celiac disease in children with type 1 diabetes: two views of the controversy. Diabetes Care Jun 2003;26(6):1932–9. [313] Rubio-Tapia A, Kyle RA, Kaplan EL, Johnson DR, Page W, Erdtmann F, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 2009;137(1):88–93. [314] Saukkonen T, Vaisanen S, Akerblom HK, Savilahti E, Childhood Diabetes in Finland Study Group. Coeliac disease in children and adolescents with type 1 diabetes: a study of growth, glycaemic control, and experiences of families. Acta Paediatr 2002;91(3):297–302. [315] Scaramuzza AE, Mantegazza C, Bosetti A, Zuccotti GV. Type 1 diabetes and celiac disease: the effects of gluten free diet on metabolic control. World J Diabetes Aug 15 2013;4(4):130–4. [316] Errichiello S, Esposito O, Di Mase R, Camarca ME, Natale C, Limongelli MG, et al. Celiac disease: predictors of compliance with a gluten-free diet in adolescents and young adults. J Pediatr Gastroenterol Nutr 2010;50(1):54–60. [317] Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, et al. Body-mass index and mortality among 1.46 million white adults. N Engl J Med 2010;363(23):2211–9.

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[365] Taïeb A, Picardo M. Clinical practice. Vitiligo. N Engl J Med Jan 8 2009;360(2): 160–9. [366] Montagnani A, Tosti A, Patrizi A, Salardi S, Cacciari E. Diabetes mellitus and skin diseases in childhood. Dermatologica 1985;170(2):65–8. [367] Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001;34(1):65–77. [368] Bahceci M, Tuzcu A, Pasa S, Ayyildiz O, Tuzcu S. Polyglandular autoimmune syndrome type III accompanied by common variable immunodeficiency. Cynecol Endocrinol 2004;19(1):47–50. [369] See comment in PubMed Commons belowPohjankoski H, Kautiainen H, Korppi M, Savolainen A. Simultaneous juvenile idiopathic arthritis and diabetes mellitus type 1 — a Finnish nationwide study. J Rheumatol Feb 2012;39(2):377–81 [See comment in PubMed Commons below]. [370] Nagy KH, Lukacs K, Sipos P, Hermann R, Madacsy L, Soltesz G. Type 1 diabetes associated with Hashimoto's thyroiditis and juvenile rheumatoid arthritis: a case report with clinical and genetic investigations. Pediatr Diabetes Dec 2010;11(8): 579–82. [371] Nolfi-Donegan D, Viswanathan A, Chefitz D, Moorthy L. Case report of a child with recently diagnosed diabetes mellitus type 1 and subsequent systemic arthritis. Internet J Pediatr Neonatol 2012 [ISSN: 1528-8374.9 (access:10.08.2012)]. [372] Tack CJ, Kleijwegt FS, Van Riel PL, Roep BO. Development of type 1 diabetes in a patient treated with anti-TNF-alpha therapy for active rheumatoid arthritis. Diabetologia 2009;52(7):1442–4. [373] Versini M, Jeandel PY, Rosenthal E, Shoenfeld Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun Rev Sep 2014;13(9):981–1000. [374] Verbeeten KC, Elks CE, Daneman D, Ong KK. Association between childhood obesity and subsequent Type 1 diabetes: a systematic review and meta-analysis. Diabet Med Jan 2011;28(1):10–8. [375] Pang TT, Chimen M, Goble E, Dixon N, Benbow A, Eldershaw SE, et al. Inhibition of islet immunoreactivity by adiponectin is attenuated in human type 1 diabetes. J Clin Endocrinol Metab Mar 2013;98(3):E418–28. [376] Procaccini C, Pucino V, Mantzoros CS, Matarese G. Leptin in autoimmune diseases. Metabolism Jan 2015;64(1):92–104. [377] Symmons DP, Bankhead CR, Harrison BJ, Brennan P, Barrett EM, Scott DG, et al. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case–control study in Norfolk, England. Arthritis Rheum Nov 1997;40(11):1955–61. [378] Feldt-Rasmussen U. Thyroid and leptin. Thyroid May 2007;17(5):413–9. [379] Kumar S, Han J, Li T, Qureshi AA. Obesity, waist circumference, weight change and the risk of psoriasis in US women. J Eur Acad Dermatol Venereol Oct 2013;27(10): 1293–8. [380] Love TJ, Zhu Y, Zhang Y, Wall-Burns L, Ogdie A, Gelfand JM, et al. Obesity and the risk of psoriatic arthritis: a population-based study. Ann Rheum Dis Aug 2012; 71(8):1273–7. [381] Araujo J, Brandao LA, Guimarães RL, Santos S, Falcão EA, Milanese M, et al. Prevalance of autoimmune thyroid dysfunction in young Brazillian patients with type 1 diabetes. Pediatr Diabetes 2008;9(4 pt1):272–6.

N C O

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[348] Falorni A, Laureti S, Nikoshkov A, Picchio ML, Hallengren B, Vandewalle CN, et al. 21-Hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry. Clin Exp Immunol 1997;107(2):341–6. [349] Peterson P, Salmi H, Hyoty H, Miettinen A, Ilonen J, Reijonen H, et al. Steroid 21hydroxylase autoantibodies in insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. Clin Immunol Immunopathol 1997;82(1): 37–42. [350] Fichna M, Fichna P, Gryczyńska M, Walkowiak J, Zurawek M, Sowiński J. Screening for associated autoimmune disorders in Polish patients with Addison's disease. Endocrine Apr 2010;37(2):349–60. [351] Brewer KW, Parziale VS. Eisenbarth GS Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency. N Engl J Med 1997;337(3):202. [352] Marks SD, Girgis R, Couch R. Screening for adrenal antibodies in children with type 1 diabetes and autoimmune thyroid disease. Diabetes Care 2003;26(11):3187–8. [353] Yu L, Brewer KW, Gates S, Wu A, Wang T, Babu SR, et al. Eisenbarth.DRB1-04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease. J Clin Endocrinol Metabol 1999;84(1):328–35 [Vol.]. [354] Myhre AG, Undlien DE, Lovas K, Uhlving S, Nedrebo BG, Kristian JF, et al. Autoimmune adrenocortical failure in Norway: autoantibodies and HLA class II associations related to clinical features. J Clin Endocrinol Metab 2002;87(2):618–23. [355] Barker JM, Ide A, Hostetler C, Yu L, Miao D, Fain PR, et al. Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison's disease in a high risk population. J Clin Endocrinol Metab 2005; 90(1):128–34. [356] McAulay V, Frier BM. Addison's disease in type 1 diabetes presenting with recurrent hypoglycaemia. Postgrad Med J 2000;76(894):230–2. [357] Pearce S, Leech N. Toward precise forecasting of autoimmune endocrinopathy. J Clin Endocrinol Metabol 2004;89(2):544–7. [358] Jaeger C, Hatziagelaki E, Petzoldt R, Bretzel RG. Comparative analysis of organspecific autoantibodies and coeliac disease-associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects. Diabetes Care 2001;24(1):27–32. [359] de Graaff LC, Martín-Martorell P, Baan J, Ballieux B, Smit JW, Radder JK. Long-term follow-up of organ-specific antibodies and related organ dysfunction in type 1 diabetes mellitus. Neth J Med Feb 2011;69(2):66–71. [360] Neufeld M, Maclaren NK, Riley WJ, Lezotte D, McLoughlin JV, Silverstein J, et al. Islet cell and other organ-specific antibodies in U.S. Caucasians and Blacks with insulindependent diabetes mellitus. Diabetes 1980;29(8):589–92. [361] Betterle C, Zanette F, Pedini B, Pressoto F, Rapp LB, Monciotti CM, et al. Clinical and subclinical organ-specific autoimmune manifestations in type 1 (insulin-dependent) diabetic patients and their first-degree relatives. Diabetologia 1984;26(6): 431–6. [362] Betterle C, Scalici C, Presotto F, Pedini B, Moro L, Rigon F, et al. The natural history of adrenal function in autoimmune patients with adrenal autoantibodies. J Endocrinol 1988;117(3):467–75. [363] Betterle C, Coco G, Zanchetta R. Adrenal cortex autoantibodies in subjects with normal adrenal function. Best Pract Res Clin Endocrinol Metab 2005;19(1):85–99. [364] Auburger G, Gispert S, Lahut S, Omür O, Damrath E, Heck M, et al. 12q24 locus association with type 1 diabetes: SH2B3 or ATXN2? World J Diabetes Jun 15 2014; 5(3):316–27.

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Vitamin D Deficiency and Glycemic Status in Children and Adolescents with Type 1 Diabetes Mellitus.

Association between magnesium concentration and HbA1c in children and adolescents with type 1 diabetes mellitus.

Increased Usage of Insulin Pump Functions Not Associated With Improved HbA1c in Children and Adolescents With Type 1 Diabetes Mellitus.

[Insulin-induced edema in adolescents with type 1 diabetes mellitus].

Analysis of insulin pump settings in children and adolescents with type 1 diabetes mellitus.

Initiating insulin therapy in children and adolescents with type 1 diabetes mellitus.

Evaluation of corneal endothelium in children and adolescents with type 1 diabetes mellitus.

Thyroid autoimmunity in children and adolescents with newly diagnosed type 1 diabetes mellitus.

Glycemic Control in Kenyan Children and Adolescents with Type 1 Diabetes Mellitus.

Association of PTPN22 gene polymorphism with type 1 diabetes mellitus in Chinese children and adolescents.

Preliminary study: Evaluation of melatonin secretion in children and adolescents with type 1 diabetes mellitus.

Periodontal Diseases and Dental Caries in Children with Type 1 Diabetes Mellitus.

Thyroid autoimmunity and function among Ugandan children and adolescents with type-1 diabetes mellitus.

Type 2 diabetes mellitus in children and adolescents.

Psychological characteristics of Korean children and adolescents with type 1 diabetes mellitus.

Growth status of children and adolescents with type 1 diabetes mellitus.

Bone status of Indian children and adolescents with type 1 diabetes mellitus.

Autoimmune tolerance and type 1 (insulin-dependent) diabetes mellitus.

Autoimmune hepatitis related autoantibodies in children with type 1 diabetes.

Genetic analysis of autoimmune type 1 diabetes mellitus in mice.

Pulmonary function in children with type 1 diabetes mellitus.

Heart rate variability in children with type 1 diabetes mellitus.

Metabolic profiling of type 1 diabetes mellitus in children and adolescents: a case-control study.

Celiac Disease Alone and Associated With Type 1 Diabetes Mellitus.