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Autoimmune conditions associated with type 1 diabetes.

Approximately 215,000 people under 20 years of age have diabetes, representing about 1 in 400 individuals in this age group (American Diabetes Association [ADA], 2014a). With 15,600 children and youth newly diagnosed annually (ADA, 2014a), type 1 diabetes is the most commonly seen pediatric endocrine condition. Type 1 diabetes, or insulin-dependent diabetes, usually occurs in children and adolescents, and is characterized by pancreatic beta cell failure, necessitating life-long parenteral insulin replacement.

Type 1 diabetes is an autoimmune disease. In autoimmunity, self-antigens are no longer recognized as such, resulting in a self-destructive process (Doyle & Grey, 2010). Islet cell antibodies can be detected in many individuals newly diagnosed with type 1 diabetes, and evidence of an autoimmune response may be present up to nine years before the onset of symptoms (Bingley, Bonfacio, & Gale, 1993). Type 1 diabetes is associated with other autoimmune mediated diseases, especially Hashimoto's thyroiditis and celiac disease. Thus, it is essential for the primary care provider to be cognizant of potential signs and symptoms of these two conditions, and to know how and when to screen for them.

Hashimoto's Thyroiditis

Chronic lymphocytic thyroiditis, commonly known as Hashimoto's thyroiditis, is an autoimmune disease first described in 1912 by Dr. Hashimoto. Although it occurs in 1% of children and adolescents in the general population (Buyukgebiz, 2007), Hashimoto's thyroid disease occurs in 17% to 30% of youth with type 1 diabetes (Roldan, Alonso, & Barrio, 1999). Approximately 25% of all children with type 1 diabetes have thyroid antibodies, indicating the presence of autoimmunity at the time of diagnosis (Triolo et al., 2011). Piatkowska and Szalecki (2011) state that at time of diagnosis of type 1 diabetes, the incidence of elevated thyroid antibodies is greater in females and among children 10 years of age and older. The presence of such thyroid antibodies is predictive of future thyroid dysfunction (ADA, 2014b). The thyroid dysfunction is usually Hashimoto's thyroiditis, but it may also be hypothyroidism, or less commonly, hyperthyroidism or Graves' disease (Korndonouri et al., 2002).

Signs and Symptoms of Hashimoto's Thyroiditis

The course of Hashimoto's thyroiditis can vary greatly. Two-thirds of children have a goiter (Buyukgebiz, 2007), which may become smaller, disappear spontaneously, or persist unchanged for years. Although some youth who were originally euthyroid may develop hypothyroidism over time, other adolescents can achieve a spontaneous remission. Thus, periodic diagnostic testing for thyroid levels is required both in treated as well as in untreated children (Buyukgebiz, 2007). Most endocrinology practices caring for children with Hashimoto's thyroiditis in addition to type 1 diabetes check these levels approximately every six months.

Clinicians need to assess for symptoms of a hypothyroidism because this can develop in some youth with Hashimoto's thyroiditis. In addition to the presence of a goiter, affected children often present with a deceleration in linear growth, are overweight for their height but not obese, and have delayed puberty. Cold intolerance, pale, cold, and dry skin, and dry hair may also develop (Buyukgebiz, 2007). Children with diabetes and hypothyroidism can also have unexplained variation in their glucose levels, affecting the metabolic control of their diabetes (ADA, 2014b).

Screening for Hashimoto's Thyroiditis in Youth With Type 1 Diabetes

In the most current practice guidelines, the ADA (2014b) recommends screening children newly diagnosed with type 1 diabetes for autoimmune thyroid disease by checking antithyroid peroxidase and antithyroglobulin antibodies. Once blood glucose control has been established soon after the diagnosis, thyroid-stimulating hormone (TSH) should also be measured. If normal, then the levels should be checked ever 1 to 2 years, particularly if youth develop symptoms of thyroid dysfunction, an abnormal growth rate, goiter, or unusual variation in glucose levels (ADA, 2014b).

Diagnosis of Hashimoto's Thyroiditis

Hashimoto's thyroiditis causes a goiter in about two-thirds of children affected as a result of lymphocytic infiltration into the gland from the stimulatory effect of TSH (Buyukgebiz, 2007). Those affected can present in a euthyroid, hypothyroid, or hyperthyroid state (Buyukgebiz, 2007), making the diagnosis sometimes difficult if based on thyroid function tests alone. However, with autoimmune thyroiditis, a thyroid ultrasound has specific characteristics (scattered hypoechogenicity), and a thyroid antibody panel (usually ordered by the endocrine specialist) can help make the diagnosis (Buyukgebiz, 2007). Thyroid peroxidase antibodies (TPOAbs) are present in 90% of children with Hashiomoto's thyroiditis. Anti-thyroglobulin antibodies (TGAbs), on the other hand, while common in adults, occur in a smaller percentage of children. Thyrotropin receptor-blocking antibodies are frequently seen in children with hypothyroid Hashiomoto's thyroiditis, and are believed to be the cause of the hypothyroidism (Buyukgebiz, 2007). Interestingly, Marwaha and colleagues (2013) have shown higher incidences of glutamic acid decarboxylase antibodies (associated with type 1 diabetes) and tissue transglutaminase antibodies (associated with celiac disease) in both children and adults with thyroid autoimmunity.

Treatment of Hashimoto's Thyroiditis

If necessary, thyroid replacement is usually managed by the specialist. Treatment is usually initiated when the TSH level is greater than 10 U/ml. The drug of choice is Na L-thyroxine (T4) and is given once daily, 30 minutes before breakfast. The initial dose is often based on age and then adjusted based on periodic thyroid function tests. The goiter, if present, may decrease in size or can persist for years (Buyukgebiz, 2007).

Celiac Disease

Celiac disease, or gluten-sensitive enteropathy, is an autoimmune-mediated enteropathy triggered by the ingestion of gluten in genetically pre-disposed individuals. "Gluten" is a broad term to describe grain proteins (grass-related) typically found in wheat, barley, and rye (Runge & Nguyen, 2010). In affected individuals, ingestion of gluten triggers a complex inflammatory T cell-meditated immune process, eventually causing mucosal damage from the chronic inflammation, resulting in small intestinal villous atrophy and crypt hyperplasia, this negatively affects the absorption capability of the small intestine leading to the nutritional deficiencies found with celiac disease (Runge & Nguyen, 2010). The diagnosis is usually made based on serum antibody titers followed by an endoscopy with a small bowel biopsy showing the characteristic villous atrophy and cryptic hyperplasia (Runge & Nguyen, 2010).

The Celiac Disease Foundation estimates that 1 in 100 people worldwide are affected with celiac disease; however, there may be as many as 2.5 million Americans who are undiagnosed and at risk for long-term complications from the condition (Celiac Disease Foundation, 2014). Celiac disease is more common in children and youth with type 1 diabetes with a prevalence rate of 4.4% to 11.1% (Camarca et al., 2012), Children who were diagnosed with type 1 diabetes under five years of age are more likely to develop celiac disease as they get older than children diagnosed over five years of age or adolescents (Pham-Short, Donaghue, Ambler, Chan, & Craig, 2012).

Signs and Symptoms of Celiac Disease

The most common symptoms of celiac disease are related to the disease process in the small intestine resulting in malabsorption. These symptoms include diarrhea or constipation, failure to thrive, abdominal pain, and bloating (Runge & Nguyen, 2010). Children with diabetes may have very mild or no identifiable symptoms of celiac disease (silent CD), and the diagnosis is often made as a result of recommended screening tests and not signs and symptoms (Camarca et al., 2012).

Screening for Celiac Disease in Youth with Type 1 Diabetes

The ADA (2014b) recommends that children with type 1 diabetes be screened for celiac disease soon after the diagnosis of diabetes. They suggest that an IgA antitissue transglutaminase (TTG IgA) or an antiendomysial level (EMA IgA) be measured once there is documentation of normal total serum IgA levels (ADA, 2014b). However, the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) (Hill et al., 2005) recommends the use of TTG IgA because the EMA IgA, although equally accurate, is more expensive, time-consuming, and prone to operator error.

Testing for celiac disease should also be considered for children with diabetes who have a positive family history of celiac disease, growth failure, failure to gain weight, or weight loss. Children who complain of diarrhea, flatulence, or abdominal pain, or who exhibit signs of malabsorption, should also be tested. Lastly, celiac disease should also be considered for children with diabetes who exhibit frequent, unexplained low blood glucose levels or an unexplained deterioration in metabolic control (ADA, 2014b). Because of the higher incidences of celiac disease in children diagnosed with type 1 diabetes at a young age, it is recommended to screen all children and youth for celiac disease at diagnosis, and continue to rescreen (many practices do this annually) over the next 10 years (Pham-Short et al., 2012). However, in their most recent practice guidelines, screening based on family history and/or the presence of signs and symptoms is recommended by the ADA because they believe the effectiveness and optimal frequency for screening asymptomatic individuals with diabetes remains unclear (ADA, 2014b). Further research is necessary to determine the optimal screening frequency for these youth. Because many youth with diabetes diagnosed with celiac disease are asymptomatic (Camarca et al., 2012), such research is essential.

Diagnosis of Celiac Disease

Children found to have positive tissue transglutaminase antibodies should be referred to a pediatric gastroenterologist for an evaluation with a possible endoscopy and small bowel biopsy for the confirmation of the diagnosis, particularly for those children with positive antibody levels and no symptoms (ADA, 2014b). The characteristic histological features of mucosal inflammation, villous atrophy, crypt hyperplasia, and lymphocyte infiltration of the epithelium confirm the diagnosis (Runge & Nguyen, 2010). Popp and colleagues (2013) in a study with a small sample size, demonstrated that asymptomatic children with type 1 diabetes with high titers of TTG IgA were found to have celiac disease on biopsy, and thus questioned the need for the small bowel biopsy to confirm the diagnosis. The referral pediatric gastroenterologist will determine the need for confirmatory intestinal biopsy. The child should not begin a gluten-free diet prior to screening for celiac disease because this may result in a false-negative serum screening test and a false negative intestinal biopsy.

Treatment of Celiac Disease

The only known treatment for celiac disease is a lifelong adherence to a gluten-free diet (Runge & Nguyen, 2010). This can be especially challenging, since often gluten is "hidden" in many different foods. The ADA (2014b) recommends that children with biopsy-confirmed celiac disease should have consultation with a dietitian experienced in managing both celiac disease and diabetes.

Summary for Primary Care Givers

Type 1 diabetes is the most common endocrine disorder in pediatrics. This autoimmune condition is often associated with other autoimmune diseases, particularly Hashimoto's thyroiditis and celiac disease. Although celiac disease tends to occur more often in children diagnosed with type 1 diabetes at a younger age (Pham-Short et al., 2012), autoimmune thyroid disease tends to be more common in children diagnosed with type 1 diabetes when older (over 10 years of age) (Piatkowska & Szalecki, 2011). Thus it is essential for primary care providers to assess for mild signs and symptoms of these two conditions in their children with type 1 diabetes, and coordinate the completion of the recommended screening tests with the endocrinology specialists.

The Primary Care Approaches section focuses on physical and developmental assessment and other topics specific to children and their families. If you are interested in author guidelines and/or assistance, contact Patricia L. Jackson Allen at pat.jacksonallen@yale.edu

References

American Diabetes Association (ADA). (2014a). Diabetes facts. Retrieved from http://www.diabetes.org

American Diabetes Association (ADA). (2014b). Standards of medical care in diabetes--2014. Diabetes Care, 37(Suppl. 1), S14-S80.

Bingley, P.J., Bonfacio, E., & Gale, E.A.M. (1993). Can we really predict IDDM? Diabetes, 42, 213-220.

Buyukgebiz, A. (2007). Newborn screening, hypothyroidism in infants, children, and adolescents. In G.E. Krassas, & S.A. Rivkees (Eds.), Diseases of the thyroid in children and adolescent (11th ed., pp. 128-141). Basel, Switzerland: Karger Publishers.

Camarca, M.E., Mozillo, D., Nugnes, R., Zito, E., Falco, M., Fattorusso, V., ... Franzese, A. (2012). Celiac disease in type 1 diabetes. Italian Journal of Pediatrics, 38, 10.

Celiac Disease Foundation. (2014). What is celiac disease? Retrieved from http://celiac.org/celiac-disease/what-is-celiac-disease/

Doyle, E.A., & Grey, M. (2010). Diabetes mellitus (type 1 and 2). In P. Jackson Allen, J.A. Vessey, & N.A. Schapiro (Eds.), Primary care of the child with a chronic condition (5th ed., pp. 427-446). St. Louis, MO: Mosby.

Hill, I., Dirks, M.H., Liptak, G.S., Colletti, R.B., Fasano, A., Guandalini, S., ... Seidman, E.G. (2005). Guidance for the diagnosis and

treatment of celiac disease in children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Journal of Pediatric Gastroenterology and Nutrition, 40, 1-19.

Korndonouri, O., Deiss, D., Danne, T, Dorow, A., Bassir, C., & Gruters-Kieslick, A. (2002). Predictivity of thyroid autoantibodies for the development of thyroid disorders in children and adolescents with type 1 diabetes. Diabetic Medicine, 19, 70-73.

Marwaha, R.K., Garg, M.K., Tandon, N., Ratnesh, K., Narang, A., Sastry, A., ... Bhadra, K. (2013). Glutamine acid decarboxylase (anti-GAD) & tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity. Indian Journal of Medical Research, 137(1), 82-86.

Pham-Short, A., Donaghue, K.C., Ambler, G., Chan, A.K., & Craig, M.E. (2012). Celiac disease in type 1 diabetes from 1990-2009: Higher incidence in young children after longer diabetes duration. Diabetic Medicine, 29(9), e286-e289.

Piatkowska, E., & Szalecki, M. (2011). Autoimmune thyroiditis in children and adolescents with type 1 diabetes. Pediatric Endocrinology Diabetes and Metabolism, 17(4), 173-177.

Popp, A., Mihu, M., Munteanu, M., Ene, A., Dutescu, M., Colcer, F., ... Maki, M. (2013). Prospective antibody case finding of celiac disease in type 1 diabetes children: Need of biopsy revisited. Acta Pediatrica, 102(3), e102-e106.

Roldan, M.B., Alonso, M., & Barrio, R. (1999). Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitis. Diabetes, Nutrition, and Metabolism, 12, 27-31.

Runge, K., & Nguyen, K.K. (2010). Celiac disease. In P. Jackson Allen, J.A. Vessey, & N. Schapiro (Eds.), Primary care of the child with a chronic condition (5th ed., pp. 313-325). St. Louis: C.V. Mosby.

Triolo, T.M., Armstrong, T.K., McFann, K., Yu, L, Rewers, M.J., Klingensmith, G.J., ... Barker, J.M. (2011). Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care, 34, 1211-1213.

Elizabeth A. Doyle, DNP(c), APRN, PPCNP-BC, BC-ADM, CDE, is an APRN and Quality Assurance Specialist, Yale Center for Clinical Investigation, and an APRN, Yale Diabetes Bridge Clinic, both part of the Yale University School of Medicine, New Haven, CT. She is also a Doctoral Student, Fairfield University School of Nursing, Fairfield, CT.
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Title Annotation:Primary Care Approaches
Author:Doyle, Elizabeth A.
Publication:Pediatric Nursing
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2015
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