Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus

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".)

ROLE OF HUMAN LEUKOCYTE ANTIGEN GENOTYPE — In general, associated endocrinopathies are more common in patients with T1DM expressing human leukocyte antigen (HLA)-DR3. However, HLA genotyping is not performed in a clinical setting to determine the risk of future endocrinopathies. Instead, clinical care includes screening protocols for the more common endocrinopathies associated with T1DM.

AUTOIMMUNE THYROIDITIS

Epidemiology — Children with T1DM are predisposed to the following thyroid conditions:

●Positive antithyroid antibodies – Up to 25 percent have positive antithyroid antibodies (antithyroid peroxidase [TPO-Ab] and/or antithyroglobulin [Tg-Ab]) [2-7]. The prevalence is higher in females than males and increases with age and diabetes duration [4,8,9]. In one study, 15 percent of children with T1DM had antithyroid antibodies: TPO-Ab were found in 19.9 percent of girls and 11.6 percent of boys, and Tg-Ab were found in 18.6 of girls and 11 percent of boys [4]. Patients with antithyroid antibodies may remain euthyroid or develop compensated or overt hypothyroidism.

Children with antibodies to glutamic acid decarboxylase and zinc-transporter 8 appear to have a higher risk of developing antithyroid antibodies [1,8-12]. Specific human leukocyte antigen (HLA) subtypes (eg, HLA-DQB1*0302) have also been associated with greater risk of developing autoimmune thyroid disease [3,13]. 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 [14]. DQB1*05:01 may also be protective [12].

●Hypothyroidism – Autoimmune hypothyroidism develops before adulthood in up to 10 percent [4,15-17]. As an example, in one study, 9.4 percent of a pediatric cohort (or 61 percent of those with antithyroid antibodies) developed hypothyroidism after a median diabetes duration of 3.4 years [4]. Hypothyroidism is less common before adolescence; in a registry study of children <14 years, 3.2 percent had hypothyroidism and the highest rates were in females ≥10 years [16].

Other patients have subclinical hypothyroidism, defined as normal serum free thyroxine (fT4) concentration with elevated thyroid-stimulating hormone (TSH). One report suggested that subclinical hypothyroidism in patients with T1DM might be associated with an increased risk of symptomatic hypoglycemia [18] and reduced linear growth [19]. (See "Subclinical hypothyroidism in nonpregnant adults".)

Hyperthyroidism – Rarely, children with T1DM may be hyperthyroid, with a reported prevalence of approximately 0.2 to 1 percent, which is significantly higher than in the age-matched general population [4,20,21]. These cases represent Graves disease (caused by TSH receptor-stimulating antibodies) or Hashimoto thyroiditis (ie, the thyrotoxic phase of chronic autoimmune thyroiditis) [21]. Children with T1DM and hyperthyroidism are more likely to have a history of diabetic ketoacidosis, hypoglycemia, and high blood pressure [21]. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase'.)

Thyroid surveillance — All children with T1DM should have regular surveillance for thyroid disease by measuring TSH (table 1) [7,22]. Autoimmune thyroiditis is common in this population and can affect the clinical course. (See "Acquired hypothyroidism in childhood and adolescence".)

●TSH – Measure TSH (thyrotropin), followed by fT4 (or T4) if TSH is abnormal ("reflexive" testing) (algorithm 1).

Perform the first test soon after the diagnosis of T1DM, when the patient is clinically stable (ie, after glycemic control has been established) [7,22]. Testing should be performed more promptly for children with signs or symptoms suggesting thyroid disease, such as thyroid enlargement or symptoms of hypo- or hyperthyroidism. At least 20 percent of patients have transient abnormalities of thyroid function when T1DM is first diagnosed, which resolve as diabetes is treated [23,24].

If TSH is normal, repeat the test every one to two years, or annually if TPO-Ab or Tg-Ab are positive. Repeat if the patient develops clinical symptoms that might be attributable to thyroid dysfunction, such as an abnormal growth rate or unexplained glycemic excursions, or if thyromegaly is detected [7].

●Antithyroid antibodies – We measure TPO-Ab and Tg-Ab at or soon after diagnosis, consistent with American and International guidelines [7,22]. An alternative strategy is to measure these antibodies only if abnormalities of thyroid function are detected. In patients with autoimmune thyroid disease, TPO-Ab is more likely to be positive than is Tg-Ab [25].

If the initial antibody test is positive or if there is a family history of autoimmune thyroid disease, the patient should be monitored closely by measuring TSH annually and if any symptoms of hyper- or hypothyroidism develop. Repeat antibody testing is not needed.

Diagnosis and next steps — Abnormal screening results fall into one of the following categories:

●Hypothyroidism – If TSH is elevated with low fT4 (or T4), treat with thyroid hormone replacement therapy. The presence of TPO-Ab and/or Tg-Ab confirms an autoimmune etiology. Patients with hypothyroidism and negative TPO-Ab and Tg-Ab require further evaluation to determine the cause. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

●Subclinical hypothyroidism – If TSH is elevated with normal fT4 (or T4), repeat the test within a few weeks before making a treatment decision. In addition, measure antithyroid antibodies (TPO-Ab and Tg-Ab), if they were previously negative or not already done. Patients with positive antithyroid antibodies are at risk of developing overt hypothyroidism over time.

Treatment decisions depend on the degree of TSH elevation. For those with TSH persistently >10 mU/L, there is general agreement to treat, based on expert opinion. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Indications for levothyroxine'.)

●Hyperthyroidism – If TSH is low (suppressed) with elevated fT4, the patient has hyperthyroidism. Further evaluation is warranted to determine the cause (ie, Graves disease versus thyrotoxic phase of autoimmune thyroiditis [Hashimoto thyroiditis]). (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Diagnostic evaluation'.)

CELIAC DISEASE

Epidemiology — Approximately 5 to 10 percent of patients with T1DM have serologic evidence of celiac disease (anti-endomysial antibodies or tissue transglutaminase [tTG] antibodies) [6,26,27], and approximately 5 percent have celiac disease confirmed by small bowel biopsy [28-31]. 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 [32]. 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) [33].

Risk factors for celiac disease include female sex, younger age of onset and longer duration of T1DM, and presence of thyroid disease [6,34-36]. The study cited above suggests that early life sequential infections may increase the risk of celiac disease [33]. The genetic susceptibility to celiac disease and T1DM has been attributed to specific shared alleles [37]. 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 [38,39].

Clinical manifestations — 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 [40-45]. In addition, bone mineralization may be reduced [46].

Celiac surveillance — Because of the prevalence of celiac disease and its potential clinical impact on patients with T1DM, all children with T1DM should have regular surveillance for celiac disease (table 1) [7]. Serologic testing for celiac disease is valid only when the child is being exposed to dietary gluten; false negative results may occur if the test is performed while on a gluten-free diet. (See "Diagnosis of celiac disease in children", section on 'Patients already on a gluten-free diet'.)

Surveillance for and diagnosis of celiac disease in children with T1DM and other high-risk groups are summarized in the algorithm (algorithm 2).

●Test for celiac disease by measuring tTG-immunoglobulin A antibodies (tTG-IgA) soon after the diagnosis of T1DM [7]. 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 tTG-IgG. (See "Diagnosis of celiac disease in children", section on 'Pretesting diet'.)

Testing for HLA DQ2/DQ8 to determine genetic susceptibility to celiac disease is not a useful method to screen for celiac disease in this population, because a majority of individuals with T1DM carry these risk alleles [47].

●If the screening test is positive (tTG >3 times the upper limit of normal), refer the patient to a gastroenterologist for further evaluation, which usually includes a small bowel biopsy. (See "Diagnosis of celiac disease in children".)

●If the screening test is negative, patients should be rescreened for celiac disease within two years of diagnosis and then again after five years [7,22]. 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. Repeated measurement of serum IgA levels is not necessary. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)

Management — If the further evaluation confirms the diagnosis of celiac disease, management is with a gluten-free diet. 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".)

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

Benefits and risks of treatment

●General benefits – The main benefits of treatment are to reduce symptoms, optimize growth (for those with impaired growth), and reduce long-term adverse health risks associated with celiac disease. These benefits are similar to patients with celiac disease but without T1DM. Although a gluten-free diet is an additional burden, one study reported that the development of celiac disease in children with T1DM had minimal impact on quality of life [48]. (See "Management of celiac disease in children", section on 'Rationale for strict gluten avoidance'.)

●Glycemic control – 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 [49-51]. Some studies have shown that a gluten-free diet was associated with a trend toward an increased body mass index and improved bone health, without any change in insulin requirements [49,50]. Other studies have reported a reduction in severe hypoglycemic episodes but unchanged hemoglobin A1c levels and an increased insulin requirement [52], reported increased postprandial glycemic excursions [27,53], or reported no significant changes [54]. In one small study, a gluten-free diet did not seem to alter risks for chronic complications of diabetes during adulthood [55]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Autoimmune disease'.)

●Disordered eating – 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 [56]. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Eating disorders'.)

●Nutrition quality – Some have reported an imbalance in macronutrients in patients on a gluten-free diet [57], while others have reported unchanged folate and hemoglobin levels. 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 [58].

OTHER AUTOIMMUNE DISORDERS — Other autoimmune disorders that are associated with T1DM but are uncommon include:

●Primary adrenal insufficiency (Addison disease) – Less than 1 percent of children with T1DM have autoimmune adrenalitis, which is characterized by low cortisol and aldosterone levels, high adrenocorticotropic hormone (ACTH), and positive 21-hydroxylase antibodies. In one report, approximately 2 percent of children with type 1 disease had circulating antibodies to steroid 21-hydroxylase [59]. 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 [14]. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis'.)

●IPEX – This syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is characterized by severe immune deficiency, with 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 the CD25, STAT5b, and ITCH genes and gain-of-function mutations in the STAT1 gene [60]. (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 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

●Autoimmune thyroiditis

•Prevalence and clinical forms – Children and adolescents with type 1 diabetes mellitus (T1DM) have increased risks for each of the following manifestations of autoimmune thyroid disease compared with the general population (see 'Epidemiology' above):

-Antithyroid antibodies – Antithyroid antibodies are present in up to 25 percent. The prevalence is higher in females than males and increases with age and diabetes duration. These patients may remain euthyroid or they may develop subclinical (compensated) or overt hypothyroidism (or, less commonly, hyperthyroidism).

-Hypothyroidism – Clinical autoimmune hypothyroidism develops in up to 10 percent before adulthood. Overt hypothyroidism is diagnosed based on elevated thyroid-stimulating hormone (TSH) and low total or free thyroxine (fT4). Other patients have subclinical (or compensated) hypothyroidism (elevated TSH and normal total or fT4).

-Hyperthyroidism – Develops in up to 1 percent; this is usually caused by Graves disease or, occasionally, by Hashimoto thyroiditis (thyrotoxic phase of autoimmune thyroiditis).

•Surveillance – For all children and adolescents with T1DM, routine surveillance for autoimmune thyroiditis consists of measuring TSH, with reflexive testing for fT4 (or total T4) if TSH is abnormal. The first test should be performed after metabolic control has been established, usually several weeks after the diagnosis of T1DM (algorithm 1). In addition, we measure antithyroid antibodies (antithyroid peroxidase [TPO-Ab] and antithyroglobulin [Tg-Ab]), soon after diagnosis. (See 'Thyroid surveillance' above.)

If TSH is normal, repeat the test every one to two years or sooner if the patient has clinical symptoms or signs suggesting hypothyroidism or hyperthyroidism (table 1). If TPO-Ab and/or Tg-Ab are positive, they do not need to be repeated. If both are negative initially, they should be repeated if hypothyroidism develops.

•Diagnosis and next steps – Patients with hypothyroidism or hyperthyroidism require further evaluation and treatment. Management of subclinical hypothyroidism depends upon the degree of TSH elevation. (See 'Diagnosis and next steps' above.)

●Celiac disease

•Prevalence and clinical manifestations – Approximately 5 percent of patients with T1DM have celiac disease. These patients sometimes present with gastrointestinal symptoms but more commonly are asymptomatic or have episodes of hypoglycemia or poor growth. Untreated celiac disease is associated with gastrointestinal symptoms and growth delay in some patients, decreased bone mineral accrual, and other long-term health risks. (See 'Epidemiology' above and 'Clinical manifestations' above.)

•Screening – Surveillance for celiac disease begins with routine measurement of tissue transglutaminase-immunoglobulin A antibodies (tTG-IgA) soon after the diagnosis of T1DM. Patients with positive results should be referred to a gastroenterologist for further evaluation, which usually includes a small bowel biopsy, as outlined in the algorithm (algorithm 2). (See 'Celiac surveillance' above.)

If the initial tTG-IgA test is negative, it should be repeated within two years after diagnosis of T1DM and again after five years or whenever the patient exhibits symptoms that suggest celiac disease (table 1). More frequent testing should be considered in those with a first-degree relative with celiac disease.

•Management – 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. Patients require special guidance to ensure that their diet is optimized for both diseases as well as surveillance and prevention of disordered eating patterns. (See 'Management' above and 'Benefits and risks of treatment' above.)