Case Report: Onset of Type 1 Diabetes Mellitus in a Patient With Ulcerative Colitis and Sjogren’s Syndrome Under Euthyroid Hashimoto’s Thyroiditis

Type 1 diabetes mellitus (T1DM) is often complicated with some other autoimmune disorders. The complication of various autoimmune disorders is known as autoimmune polyglandular syndrome (APS). Once autoimmune thyroid disease develops, various autoimmune diseases can also occur. Such phenomena are classified as APS types 3A to 3D. In this report, we show the onset of T1DM in a patient with ulcerative colitis (UC) and Sjogren’s syndrome. The most important and interesting point in this case is that, if we did not check her thyroid-associated antibodies, we could not have diagnosed her as APS. From the data of this case, we assumed that the patient suffered from APS type 3A, 3B, and 3D variants. This case pointed out very clearly the importance of testing for thyroid-associated antibodies under various autoimmune disease conditions even if the thyroid hormone levels are euthyroid. Moreover, based on the strong linkage between inflammatory bowel disease and T1DM and the compatibility with both T1DM and APS type 3, we think it is possible that Hashimoto’s disease is present under complicated conditions together with UC and T1DM. It would be important to repeatedly check for thyroid-associated antibodies even in euthyroid patients, especially under various autoimmune disease conditions.


INTRODUCTION
Autoimmune polyglandular syndrome (APS) differs in their component diseases, which are a group of syndromes comprising a combination of endocrine and other autoimmune diseases, and in the immunological features of their pathogenesis (1,2). Four major entities are recognized-APS types 1-4 and APS type 3-with type 3 being the most common type (3). While the coexistence of autoimmune Addison's disease defines classification into APS types 1, 2, and 4, APS type 3 does not include adrenal failure. Type 1 diabetes mellitus (T1DM) is often complicated with some other autoimmune disorders. The complication of various autoimmune disorders is known as APS (1). APS type 3A consists of T1DM and autoimmune thyroid diseases such as Basedow's disease and Hashimoto's thyroiditis. However, once autoimmune thyroid disease develops, various autoimmune diseases can also occur. Such phenomena are classified as APS types 3A to 3D (2). It should be noted that, differently from the initial observations where APS constituted only of clinical autoimmune diseases, presently, APS can also be diagnosed in the presence of one or more clinical and one or more subclinical or potential (e.g., only positive for autoantibodies) autoimmune diseases (4).
Ulcerative colitis is an inflammatory bowel disease (IBD) that causes inflammation and ulcers in the digestive tract, and one possible cause considered is an immune system malfunction, although the exact cause of ulcerative colitis (UC) remains unknown. Interestingly, several studies have reported a strong linkage between IBD and T1DM. It has been suggested that these two diseases share similar immune-mediated pathogenesis, which indicates a potential epidemiologic association (5)(6)(7).
In this report, we show the onset of T1DM in a patient with UC and Sjogren's syndrome. Interestingly, the patient's antibodies for Hashimoto's thyroiditis [thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb)] were of high titers, although her thyroid hormone levels were euthyroid. From these results, we assumed that she suffered from APS type 3A, 3B, and 3D variants.

DISCUSSION
Herein, we reported a case of onset of T1DM in a patient with UC complicated with Sjogren's syndrome. Interestingly, her thyroid-associated antibodies (TPOAb and TgAb) showed high titers, even though her thyroid hormone levels were euthyroid. This result meant that, if we did not examine the thyroid-associated antibodies, this patient (with T1DM + UC + Sjogren's syndrome) would have been diagnosed as APS type 4.
In 1980, Neufeld and Blizzard organized and classified these clinical clusters into four main types defined as APS, which are summarized in Table 3 (8). The coexistence of autoimmune Addison's disease is defined as APS types 1, 2, and 4. In addition, the prevalence rates of clinical autoimmune diseases in a cumulative population with autoimmune Addison's disease were: IBD, 2.4%; Sjogren's syndrome, 2.4%; T1DM, 1.2%-20.4%; and Hashimoto's thyroiditis, 3.7%-32% (2). On the other hand, the characteristics of APS type 3 are shown in Table 4. This condition is characterized by autoimmune thyroiditis along with other organ-specific autoimmune diseases. Our patient was diagnosed with the APS type 3A, 3B, and 3D variants together with euthyroid Hashimoto's thyroiditis. Moreover, comparison of the prevalence rates between TPOAb and TgAb in healthy controls showed values of about 1.2%-27.8% and 1.2%-30%, respectively, in various places in different countries (9). Since her TPOAb and TgAb were of very high titers, she was diagnosed with euthyroid Hashimoto's thyroiditis, even though she suffered from potential Hashimoto's thyroiditis. UC is an IBD and a chronic autoimmune condition affecting the gastrointestinal tract as the pathogenesis mechanism (10), although various genetic and environmental factors have been implicated in UC susceptibility (11). It is therefore important to understand the relationship between IBD and T1DM in clinical practice. Genetic research revealed a linkage between IBD and T1DM and identified that both share risk variants at 20 loci, which is 10 times higher than that expected by chance (12). Most of the overlap genes were related to inflammatory response, which strongly indicated that the two diseases share similar immune-mediated pathogenesis (12,13), although the mechanisms of the immunological pathogenesis of the linkage between IBD and T1DM are unknown. On the other hand, some clinical research studies and meta-analyses have identified the association between IBD and T1DM (13)(14)(15). Although it is unclear whether UC is a chronic autoimmune condition, Betterle et al. recently included UC, Crohn's disease, celiac disease, and autoimmune pancreatitis as gastrointestinal autoimmune diseases in the classification of APS type 3B (4). Considering that thyroid autoimmune disease (in clinical, subclinical, or potential form) can be the most frequent disease associated with any other autoimmune diseases, we examined TPOAb and TgAb despite the presence of a normal thyroid function in a patient with multiple autoimmune diseases. On the basis of this investigation, we identified a potential combination of multiple variants of APS type 3. In this case, she suffered from APS type 3A, 3B, and 3D variants because she experienced the onset of T1DM and had thyroid autoantibodies.
The most important and interesting point in this case is that, if we did not check her thyroid-associated antibodies, we could not have diagnosed her with APS. Generally, when the thyroid hormone levels are euthyroid, thyroid-associated antibodies are not measured. However, our patient suffered from UC and Sjogren's syndrome during the onset of T1DM, suggesting that she had various autoimmune disease conditions. In addition, her  HLA DNA typing results showed DRB1 04:05 and DQB1 04:01, which were also compatible with both T1DM and APS type 3 (16). This case pointed out very clearly the importance of measuring thyroid-associated antibodies under various autoimmune disease conditions even if the thyroid hormone levels are euthyroid. Moreover, based on the strong linkage between IBD and T1DM and the compatibility with both T1DM and APS type 3, we think it is possible that

CONCLUSION
Taken together, it should be noted that a patient can suffer from APS type 3A, 3B, and 3D variants. In addition, if we did not check our patient's thyroid associated antibodies, we could not have diagnosed her with the correct APS variation. Therefore, it is important that all clinicians who follow patients with one or more autoimmune diseases must examine the thyroid associated antibodies regardless of the presence or absence of a thyroid dysfunction, at least once (or, if possible, repeatedly as much as costs permit).

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Informed consent was obtained from the patient for inclusion in the case report.

AUTHOR CONTRIBUTIONS
TA researched data and wrote the manuscript. KaT, AM, YK, and FK researched data contributed to the discussion. KK, KoT, HirK, and HidK reviewed the manuscript.  Neufeld and Blizzard (2,4,8).
APS type 1 Chronic candidiasis, chronic hypoparathyroidism, autoimmune Addison's disease (at least two present) APS type 2 Autoimmune Addison's disease + autoimmune thyroid diseases and/or type 1 diabetes mellitus (Addison's disease must always be present) APS type 3 Thyroid autoimmune diseases + other autoimmune diseases (excluding autoimmune Addison's disease, hypoparathyroidism, and chronic candidiasis) APS type 4 Two or more organ-specific autoimmune diseases (which do not fall into type 1, 2, or 3)