INTRODUCTION — Type 1 diabetes mellitus (T1DM), one of the most common chronic diseases in childhood, is caused by insulin deficiency resulting from the destruction of insulin-producing pancreatic beta cells. (See "Pathogenesis of type 1 diabetes mellitus".)

Children and adolescents with T1DM are at increased risk for developing other autoimmune diseases, most commonly autoimmune thyroiditis and celiac disease. One study from the United Kingdom reported that almost one-quarter of patients with T1DM younger than 21 years old have one or more other organ-specific antibodies [1]. As with autoimmunity in general, females are at greater risk for multiple autoantibodies. These associated autoimmune diseases are presented here.

Other issues in this population are discussed separately:

●(See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents".)

●(See "Overview of the management of type 1 diabetes mellitus in children and adolescents".)

●(See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus".)

●(See "Complications and screening in children and adolescents with type 1 diabetes mellitus".)

●(See "Diabetic ketoacidosis in children: Treatment and complications".)

HUMAN LEUKOCYTE ANTIGEN (HLA) GENOTYPE — In general, associated endocrinopathies are more common in patients with T1DM expressing human leukocyte antigen (HLA)-DR3 [2]. These individuals have a longer period of dormancy before developing diabetes, presumably because of a slower pace and/or later onset of beta cell destruction, and are more likely to have positive anti-islet cell antibodies compared with patients expressing HLA-DR4, who are younger at diagnosis, have positive anti-insulin antibodies, and are less likely to develop other autoimmune endocrinopathies.

AUTOIMMUNE THYROIDITIS

Epidemiology — Up to 20 percent of patients with T1DM have positive antithyroid antibodies (antithyroid peroxidase [anti-TPO] and/or antithyroglobulin [anti-TG]) [3-7]. Patients with circulating antibodies may be euthyroid or they may develop autoimmune hypothyroidism, with a prevalence of approximately 2 to 5 percent in patients with T1DM [3-5,7-9]. In one study, 9.4 percent of patients required levothyroxine therapy and 6.1 percent with positive antibodies remained euthyroid after a median diabetes duration of 3.9 years (0.2 to 12.4 years) [5]. Rarely, children with T1DM may be hyperthyroid, with a reported prevalence of approximately 1 percent, which is higher than in the general population [10,11]. Children with T1DM and hyperthyroidism are more likely to have a history of diabetic ketoacidosis, hypoglycemia, and high blood pressure [11].

The prevalence of autoimmune thyroiditis is higher in girls with diabetes compared with boys, and it increases with age [12,13]. This was illustrated in an observational study that looked for evidence of autoimmune thyroiditis in 659 children with T1DM, with a median age at initial screening of 10.9 years (range 0.1 to 24 years) and a duration of diabetes of 1.2 years [5]. Anti-TPO and anti-TG were present in 15.4 and 14.4 percent of patients. Girls were more likely than boys to have anti-TPO (19.9 versus 11.6 percent) and anti-TG (18.6 versus 11 percent) antibodies.

Children with antibodies to glutamic acid decarboxylase and zinc-transporter 8 appear to have a higher risk of developing anti-thyroid antibodies [1,12-16]. Specific human leukocyte antigen (HLA) subtypes (eg, HLA-DQB1*0302) have also been associated with greater risk of developing autoimmune thyroid disease [4,17]. One study reported that DR3-DQ2/DRB1*04:01-DQ8 is a susceptibility genotype for T1DM with autoimmune thyroiditis, while the DRB1*11:01-DQA1*05:05-DQB1*03:01 and DRB1*15:01-DQA1*01:02-DQB1*06:02 genotypes are protective [18]. DQB1*05:01 may also be protective [16].

Subclinical hypothyroidism is defined biochemically as a normal serum free thyroxine (T4) concentration in the presence of an elevated serum thyrotropin (thyroid-stimulating hormone [TSH]) concentration. Subclinical hypothyroidism in patients with T1DM can be associated with an increased risk of symptomatic hypoglycemia [19] and reduced linear growth [20]. (See "Subclinical hypothyroidism in nonpregnant adults".)

Thyroid screening — Because of the high prevalence of thyroiditis and its potential clinical impact, all children with T1DM should be screened regularly for thyroid disease by measuring TSH (table 1) [21]. (See "Acquired hypothyroidism in childhood and adolescence".)

●Thyrotropin, also known as TSH, is the most useful screening test. In general, TSH should be tested soon after the diagnosis of T1DM, when the patient is clinically stable; ie, after glycemic control has been established [21]. This is because at least 20 percent of patients will have transient abnormalities of thyroid function when T1DM is first diagnosed, which resolve as diabetes is treated [22,23]. However, thyroid laboratory studies should be performed more promptly (within a few days of resolution of initial diabetes symptoms) in newly diagnosed children with clinical suspicion of thyroid disease because of thyroid enlargement or symptoms of hypo- or hyperthyroidism.

•If the TSH level is abnormal, free T4 is measured.

•If the TSH level is normal, patients should have a repeat measurement every one to two years or sooner if the patient has clinical symptoms that might be attributable to thyroid dysfunction, such as an abnormal growth rate or unexplained glycemic excursions, or if thyromegaly is detected [21].

●Patients with elevated TSH levels should be treated with thyroid hormone replacement therapy. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

●The American Diabetes Association suggests that anti-TPO and anti-TG antibodies be measured at diagnosis [21]. An alternative strategy is to measure these antibodies only if abnormalities of thyroid function are detected. In patients with autoimmune thyroid disease, anti-TPO antibodies are more likely to be positive than anti-TG antibodies [24].

●If Graves disease is suspected, levels of thyrotropin receptor-binding antibodies or thyroid-stimulating immunoglobulins should be measured, depending on which of these tests is offered by the local laboratory. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Diagnostic evaluation'.)

●If the initial antibody screening is positive, the patient should be monitored closely by screening with TSH annually and if any symptoms of hyper- or hypothyroidism develop. Repeat antibody testing is not needed.

CELIAC DISEASE

Epidemiology — Approximately 5 percent of patients with T1DM will develop celiac disease (gluten-sensitive enteropathy), diagnosed by a positive small bowel biopsy sample, and 5 to 10 percent have anti-endomysial antibodies [25-27] or tissue transglutaminase antibodies [7,28,29]. Most cases of celiac disease (up to 79 percent in one study) are diagnosed within five years of diabetes onset [30].

These prevalence rates appear to be the same in the United States, Europe, Canada, and Asia, although one study from Sweden has reported a higher prevalence rate of 9 percent [31]. In the Swedish study, 62 percent of those diagnosed with celiac disease following onset of T1DM had positive celiac-specific antibodies within 24 months of diagnosis of T1DM. One study also reported a higher five-year cumulative incidence of celiac disease in Finland compared with neighboring Estonia (0.77 versus 0.27 percent) [32].

Risk factors for celiac disease include female gender, younger age of onset and longer duration of T1DM, and the presence of thyroid disease [7,33-35]. The study cited above suggests that early life sequential infections may increase the risk of celiac disease [32]. The genetic susceptibility to celiac disease and T1DM has been attributed to specific shared alleles [36]. The human leukocyte antigen (HLA)-DR3-DQ2 and DR4-DQ8 haplotypes are associated with increased risk for these disorders [1], whereas the DQB1*06:02 and DRB1*04 alleles are protective [37,38].

Only a minority of children with T1DM and celiac disease present with gastrointestinal symptoms of food intolerance, food avoidance, gastrointestinal discomfort, and diarrhea. More common initial findings include unpredictable blood glucose measurements, recurrent episodes of hypoglycemia, poor glycemic control, and growth failure because of erratic intestinal absorption of nutrients [39-44]. In addition, bone mineralization may be reduced [45]. High-density lipoprotein cholesterol levels are lower in children with T1DM and celiac disease at diagnosis than in those without celiac disease and increase following implementation of the gluten-free diet [46].

Whether a gluten-free diet improves glycemic control in patients who have diabetes and celiac disease is unclear. Only a few small studies have investigated the effect of a strict gluten-free diet on patients with T1DM and silent celiac disease [47-49]. Some studies have shown that the gluten-free diet was associated with a trend toward an increased body mass index and improved bone health, without any change in insulin requirements [47,48]. Other studies have reported greater glycemic excursions and a higher insulin requirement but unchanged hemoglobin A1c levels [50,51], as well as a reduction in severe hypoglycemic episodes [50]. Some have reported an imbalance in macronutrients [52], while others have reported unchanged folate and hemoglobin levels. In one small study, a gluten-free diet did not seem to alter risks for chronic complications of diabetes during adulthood [53]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Autoimmune disease'.)

Celiac screening — Because of the prevalence of celiac disease and its potential clinical impact on patients with T1DM, all children with T1DM should be screened for celiac disease (table 1) [21]. Screening for celiac disease with antibody levels is relevant only when the child is being exposed to dietary gluten and is of no relevance for those on a gluten-free diet. (See "Diagnosis of celiac disease in children" and "Diagnosis of celiac disease in children", section on 'Patients already on a gluten-free diet'.)

Screening and diagnosis of celiac disease in children with T1DM and other high-risk groups are summarized in the algorithm (algorithm 1).

●Children with T1DM should be screened for celiac disease by measuring immunoglobulin A antibodies to tissue transglutaminase (tTG-IgA) soon after the diagnosis of T1DM [21]. Because these tests are based upon IgA antibodies, a quantitative serum IgA level should also be obtained during the screening process to ensure that levels are not falsely low due to IgA deficiency. In patients with IgA deficiency, screening may be performed by measuring immunoglobulin G (IgG)-deamidated gliadin peptides or IgG-tTG. Testing for HLA DQ2/DQ8 to determine genetic susceptibility to celiac disease generally is not a suitable method to screen for celiac disease, because a majority of individuals with T1DM carry these risk alleles [54].

●If the screening test is positive (tTG >3 times the upper limit of normal [ULN]), the patient should be referred to a gastroenterologist for confirmatory small bowel biopsy.

•If the small bowel biopsy is consistent with celiac disease, the patient should be placed on a gluten-free diet. The diagnosis is confirmed by resolution of symptoms on a gluten-free diet and a decrease in antibody titers. Nutritional counseling should be provided by a registered dietitian who has experience in caring for patients with both diabetes and celiac disease. Because gluten-free dietary substitutes are often high in carbohydrate content, identifying gluten-free products with acceptable carbohydrate content is essential for successful management of these patients. (See "Management of celiac disease in children".)

Implementation of a gluten-free diet is associated with a decrease in gastrointestinal symptoms and episodes of severe hypoglycemia and an increase in insulin requirement [50]. Interestingly, the development of celiac disease in children with T1DM is reported to have minimal impact on quality of life in these children [55]. Checking antibody levels in children with T1DM and celiac disease who are on a gluten-free diet may be useful to assess adherence to this diet.

•Some asymptomatic children and their families will reject a gluten-free diet. In this case, monitoring for symptoms, 25-hydroxyvitamin D levels, and adequate bone mineralization is particularly important.

●For patients and families who are reluctant to proceed with a small bowel biopsy, guidance depends upon the tTG-IgA antibody titer:

•For selected patients with very high levels of tTG-IgA (>10 times the ULN), it is reasonable to make a provisional diagnosis of celiac disease without intestinal biopsy. The diagnosis is confirmed if the tTG antibody titer normalizes after instituting a gluten-free diet. This approach is suggested as an option for patients without T1DM who wish to avoid intestinal biopsy [56] and is also supported by one study in patients with T1DM [57]. (See "Diagnosis of celiac disease in children", section on 'Is biopsy necessary for all patients?'.)

•Patients with intermediate tTG-IgA titers (3 to 10 times the ULN) or those who have gastrointestinal symptoms should be strongly encouraged to proceed with intestinal biopsy rather than empirically beginning a gluten-free diet. This is because the dietary restrictions required to manage both T1DM and celiac disease represent a substantial lifelong burden. HLA typing provides little additional diagnostic value because virtually all patients with positive tTG antibodies will have celiac-associated HLA haplotypes [56,58].

●If the screening test is borderline positive (tTG-IgA 1 to 3 times the ULN) and the patient is asymptomatic, it is reasonable to measure a second celiac-specific antibody, such as anti-endomysial antibodies or deamidated gliadin peptide, to help categorize the risk and decide whether to proceed to intestinal biopsy or close monitoring (algorithm 1).

●If the screening test is negative, patients should be rescreened for celiac disease within two years of diagnosis and then again after five years [21]. More frequent screening and repeat screening after five years of diagnosis is appropriate for children who develop symptoms suggestive of celiac disease (gastrointestinal symptoms, poor growth, weight loss, or increased occurrence of hypoglycemia) or for those who have a first-degree relative with celiac disease. Repeat testing for IgA levels is not necessary. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)

A threefold higher risk of disordered eating behavior has been reported in patients with T1DM and celiac disease compared with those with T1DM alone or celiac disease alone, particularly when the patient is older, female, or overweight [59]. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Eating disorders'.)

OTHER DISEASES — Other autoimmune disorders associated with T1DM include:

●Addison's disease – Less than 1 percent of children with T1DM have autoimmune adrenalitis. In one report, approximately 2 percent of children with type 1 disease had circulating antibodies to steroid 21-hydroxylase [60]. This condition is associated with decreased insulin requirement and increased frequency of hypoglycemia. (See "Pathogenesis of autoimmune adrenal insufficiency", section on 'Humoral immunity'.)

●Autoimmune polyglandular syndrome type 2 (APS 2) – Autoimmune adrenal insufficiency is present with other autoimmune endocrine disorders in APS 1 and 2 (table 2). Although T1DM can be seen in either syndrome, it is more commonly seen as a component of APS 2. The DR3-DQ2/DRB1*04:04-DQ8 genotype has been associated with APS 2 [18]. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Autoimmune adrenalitis'.)

●IPEX – This syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is characterized by severe immune deficiency and late onset of endocrinopathy and enteropathy. It is caused by mutations in the FOXP3 gene, leading to abnormal T regulatory cell function. The condition commonly manifests in the first few months of life and is characterized by diarrhea, dermatitis, and T1DM. IPEX-like syndromes have also been identified related to loss-of-function mutations in CD25, STAT5b, and ITCH and gain-of-function mutations in STAT1 [61]. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

●Autoimmune gastritis – A higher risk of autoimmune gastritis has been reported in T1DM, characterized by antibodies that target the gastric H⁺/K⁺ -ATPase (ATPA) pump [1]. This disorder is associated with DR3-DQ2, DRB1*0404 (in males) and the DR3-DQ2/DR4-DQ8 genotype.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in children".)

SUMMARY AND RECOMMENDATIONS — Individuals with type 1 diabetes mellitus (T1DM) have increased risks for autoimmune thyroiditis and celiac disease compared with the general population.

●Thyroiditis

•Approximately 2 to 5 percent of patients with T1DM have autoimmune hypothyroidism. In addition, 20 percent of patients with T1DM have circulating antibodies to thyroid peroxidase (anti-TPO) and thyroglobulin (anti-TG). Subclinical hypothyroidism has been associated with an increased risk for hypoglycemia and reduced linear growth. (See 'Autoimmune thyroiditis' above.)

•In all children and adolescents with T1DM, we suggest screening for autoimmune thyroiditis (Grade 2B). We typically measure thyroid-stimulating hormone (TSH) and antithyroid antibodies. This testing should be performed after metabolic control has been established, usually several weeks after the diagnosis of T1DM. (See 'Thyroid screening' above.)

•If TSH is normal, it is repeated every one to two years or obtained whenever thyroid disease is suspected (table 1). If it is high, a free thyroxine (T4) level is measured and thyroid hormone replacement therapy initiated. If antibody screening is positive, there is no need to repeat the antibody testing. TSH is sufficient for screening.

●Celiac disease

•Approximately 5 percent of patients with T1DM have celiac disease. These patients do not usually present with gastrointestinal symptoms but more commonly are asymptomatic or have episodes of hypoglycemia or poor growth. Decreased bone mineral accrual is a major concern for children with untreated celiac disease. (See 'Celiac disease' above.)

•In children and adolescents with T1DM, we suggest screening for celiac disease (Grade 2C). The initial screening can be done by measuring immunoglobulin A antibodies to tissue transglutaminase (tTG-IgA) soon after the diagnosis of T1DM. Further steps for patients with positive screening results are outlined in the algorithm (algorithm 1). (See 'Celiac screening' above.)

•If the screening test is negative, patients should be rescreened for celiac disease within two years after diagnosis of T1DM and again after five years or whenever the patient exhibits symptoms suggestive of celiac disease (table 1). More frequent screening should be considered in those with a first-degree relative with celiac disease. A positive result requires referral to a gastroenterologist for a small bowel biopsy.

•If the child has celiac disease, nutritional counseling should be provided by a registered dietitian who has experience in caring for patients with both diabetes and celiac disease.