Genetic Association between Type-1 Diabetes and Thyroid Autoimmunity and Thyroid Disease in Children and Adolescents. Essentials of Simultaneous Management

Type-1 diabetes (T1DM), an autoimmune lifelong disease, is also associated genetically with other autoimmune disorders such as autoimmune thyroid disease (AITD). Both of them share genetic, environmental and autoimmune pathophysiological factors. After the diagnosis of T1DM, AITD is usually diagnosed after a few years or even earlier; and sometimes AITD is subclinical (without any signs or symptoms) and if its diagnosis is delayed, may impair glycemic control. Hence, early screening and diagnosis for AITD is essential to prevent further clinical complications. Current research paper focuses on both diseases together, their genetics and autoimmunity. Both diseases should be considered together, from the diagnosis of type-1 diabetes and thereafter with follow up visits. Early screening and detection of AITD antibodies in the serum of type-1 diabetics is recommended and this will also assist in the achievement of glycemic targets and better diabetes control of these patients. If thyroid antibodies are found to be negative, yearly screening is recommended, even in the absence of signs and symptoms. To follow current clinical diabetes and endocrine guidelines is also recommended at tertiary care centers and hospitals.

Type 1 diabetes (T1DM) and autoimmune thyroid disease (AITD) are the most common autoimmune diseases worldwide. The incidence is also variable worldwide indicating that environmental factors also play a significant role [1, 2]. Current data has indicated that the highest incidence rates are at ages 4 to 10 years in girls and 11 to 15 in boys [3-7]. AITD comprises of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT); and these are defined as the positive thyroid antibodies in the serum. Moreover, the prevalence of subclinical hyperthyroidism is 6–10% among Type-1 diabetic patients [8-10].

In the context of endocrine medicine, the presence and association of at least two autoimmune-induced glandular disorders is defined as autoimmune polyglandular syndrome (APS). T1DM, is an autoimmune T-cell mediated chronic disorder characterized by destruction of pancreatic β-cells.[11,‎ 12]. Similarly, Graves’ disease (a primary hyperthyroid disorder) is also an autoimmune-induced hyperthyroidism together with the presence of thyrotropin receptor autoantibodies (TSH-R-Ab) in general and stimulatory TSH-R-Ab (TSAb) in particular [13‎-15]; Hashimoto’s thyroiditis (a primary hypothyroid disorder) also demonstrates an increased serum level of serum thyroid peroxidase (TPO) Ab and/or blocking TSH-R-Ab (TBAb). According to the current research evidence, approximately 25% of adolescents with T1D have thyroid-related Ab and long-term follow-up in outpatients has suggested that 30% of patients with T1D will develop AITD within next few years [‎16‎-18]. Therefore, early screening for thyroid disorders is recommended especially in type-1 diabetic patients to initiate treatment as soon as diagnosis is confirmed.

Pathogenesis and Genetic Associations

Genetic research and analysis of patients with autoimmune diseases (including T1DM and GD/HT with thyroid Ab positive serum) have demonstrated specific, strong and significant contribution of HLA alleles, majority with HLA class II, to the genetic predisposition to autoimmune diseases. Hence, It has been demonstrated and established that HLA genes are strongly linked with thyroid autoimmunity in patients with T1DM; HLA regions, including DR3, DR4, in association with DQ2 and DQ8 are also significantly associated with T1D, AITD, and APS-3a. [‎19, ‎20], Moreover, research evidence has suggested that infectious agents are also important triggers and initiators of autoimmune diseases via molecular mimicry mechanisms, polyclonal T-cell activation, and HLA class II antigen induction [‎21, ‎22].

These data and currently available research and genetic analysis strongly suggest that the two diseases, TIDM and AITH (Graves’ disease and Hashimoto’s thyroiditis) are significantly associated with each other as they share common genetic predisposition and autoimmunity pathogenesis; and both diseases should be considered together while managing such patients, especially Type-1 diabetic subjects [‎23, ‎24].

In the context of above-mentioned research data, the coexistence of TIDM and AITD in the same patient or family is explained by sharing a common genetic pathophysiology as well as environmental factors with a defective immune regulation and modulation. Furthermore, and according to our clinical experience in diabetes and endocrine center, it has been observed that the subjects requiring treatment with L-thyroxine has significantly increased among young patients and adolescents with Type-1 diabetes. This is correlating with the research from other centers as well that 18-20% of the patients before the age of 18 (especially female gender) will require treatment for thyroid disease at any stage. Nonetheless, the data has also demonstrated association between subclinical hypothyroidism and development of diabetic kidney disease (DKD), which emphasizes the early screening and initiating thyroid drug treatment [25]. In summary and conclusion, the progression to the increase in TSH and ultrasound abnormal findings are usually observed within five years of diagnosis. However, progression and development of thyroid autoimmunity may also occur at any stage after diagnosis of Type-1 diabetes, and particularly is observed during early puberty. Delay in screening and diagnosis of other autoimmune disorders (including AITD) will impair glycemic control in type-1 diabetics. Conversely, detection of other autoimmune disorders simultaneously will assist in the clinical management of type-1 diabetes.   

Therefore, it is highly recommended that screening for thyroid disease should be initiated at the diagnosis of T1DM in all pediatric patients with anti-TPO, anti-TG, TSH, T3, and T4 (with ultrasound examinations if required) to detect early thyroid disorders. Treatment with L-thyroxine may be required if significant thyroid disease is detected. However, If the initial thyroid screening is negative, annual measurements of antibodies (anti-TPO) and TSH, even in the absence of clinical signs, is recommended among T1DM subjects according to the current clinical evidence [26], especially from the age of 10 years or from the onset of puberty. It is highly recommended to follow recent endocrine and diabetes guidelines for the management of diabetic patients with autoimmune disorders.

Conflict of Interest 

All authors declare no conflict of interest. 

Acknowledgement

Authors are thankful for Eissa Ali Karn for his support for official documentation work. 

Funding

This project was not funded by any organization and authors themselves reviewed the medical literature, collected data, written and edited the manuscript.