Insulin Autoimmune Syndrome Associated With Hashimoto Thyroiditis and Nodular Thyroid Disease: Clinical Management With Flash Glucose Monitoring and Prednisolone Therapy

Introduction

Insulin autoimmune syndrome (IAS) is a rare disorder first described by Hirata et al in 1970 [1]. It is characterized by spontaneous episodes of hypoglycemia in individuals with elevated concentration of insulin autoantibodies, despite no prior exposure to exogenous insulin. These hypoglycemic episodes can occur either in the fasting state or postprandially [2]. IAS is most prevalent in Japan, where it ranks among the leading causes of hypoglycemia, which is believed to be influenced by genetic predisposition. Nonetheless, the number of reported cases from non-Asian populations is steadily increasing, reflecting a growing global awareness of the condition [3]. Certain medications, particularly those containing sulfhydryl groups, such as methimazole or alpha-lipoic acid, have been found to trigger IAS [2,4].

Given its autoimmune basis, IAS can coexist with other autoimmune disorders, such as Graves’ disease or Hashimoto’s thyroiditis [4,5]. IAS is typically a self-limiting condition; therefore, management is primarily supportive. Withdrawal of the triggering medication and dietary modifications aimed at preventing hypoglycemic episodes are usually sufficient. In more severe cases, pharmacological intervention can be necessary [4].

Although IAS is predominantly reported in Asian populations, clinicians should also consider this diagnosis in non-Asian patients presenting with unexplained hyperinsulinemic hypoglycemia. Awareness of this rare but important condition may prevent unnecessary invasive diagnostic procedures.

Case Report

We present a case of a 63-year-old White woman who was hospitalized for further evaluation of recurrent hypoglycemia and suspected insulinoma. The patient reported a 4-week history of sudden-onset symptoms, including generalized weakness, episodes of loss of consciousness, and profuse sweating, primarily occurring at night and postprandially. Several weeks before the first episode of hypoglycemia, she experienced a single episode of a pruritic rash, which resolved spontaneously. She was evaluated by a dermatologist, but because the rash disappeared rapidly and did not recur, no allergy or skin testing was performed. Home glucometer readings documented severe hypoglycemia, with the lowest recorded value being 27 mg/dL. Upon admission, the patient was in good general condition. She had no significant past medical history and no known family history of diabetes, thyroid dysfunction, autoimmune diseases, or malignancy. She denied using any prescribed or over-the-counter medications or dietary supplements. During hospitalization, routine blood test results revealed normal electrolytes, renal, and hepatic function. Repeated laboratory testing showed extremely elevated insulin concentrations (19 300, 16 700, and 12 000 μU/mL; reference range, 2.6–24.9 μU/mL) and increased C-peptide concentrations (13.8 and 14.1 ng/mL; reference range, 1.1–4.4 ng/mL:), with a HbA1c of 5.3% (reference range, 4.0–6.0], and fasting glucose of 108 mg/dL (reference range, 70–99 mg/dL). To further investigate the etiology, abdominal contrast-enhanced magnetic resonance imaging was performed, which revealed no abnormalities suggestive of insulinoma. Other potential causes of hypoglycemia, including factitious hypoglycemia, Munchausen syndrome, and dumping syndrome, were also considered and clinically excluded based on patient history and biochemical results. Recurrent episodes of hypoglycemia with elevated insulin levels were documented, suggesting inappropriate endogenous hyperinsulinemia. The FreeStyle Libre 2 flash glucose monitoring system (Abbott Diabetes Care Inc, Alameda, CA, USA) was used, revealing frequent nocturnal and postprandial hypoglycemic episodes. A 10% glucose solution was administered for symptomatic management (Figure 1). Blood samples were collected to evaluate the presence of anti-insulin autoantibodies. The insulin autoantibody level was measured using a radioimmunoassay with 125I-labeled insulin (DIASource, Belgium) and was found to be extremely elevated at 99.9% (reference range <8.2%). The diagnosis of IAS was made based on the presence of classic hypoglycemic symptoms, documented low plasma glucose concentrations, elevated serum insulin and C-peptide concentrations, and positive insulin autoantibodies. The patient was screened for other autoimmune diseases. She was diagnosed with Hashimoto’s thyroiditis (anti-thyroid peroxidase antibody concentration, 494 IU/mL; reference range, <34 IU/mL; anti-thyroglobulin antibody concentration, 34.7 IU/mL; reference range, <115 IU/mL), with subclinical hypothyroidism. The coexistence of Hashimoto’s thyroiditis with IAS is unusual in White patients and suggests a shared autoimmune predisposition. Thyroid ultrasound revealed a non-enlarged, normoechoic gland with inhomogeneous parenchyma, without neck lymphadenopathy. A left lobe EU-TIRADS 4 lesion with peripheral vascularization, measuring 15×13×16 mm, was visualized (Figure 2). The nodule was confirmed as benign (Bethesda II) by fine-needle aspiration biopsy cytology. The treatment options were discussed with the patient. Initial therapeutic measures included dietary modifications, including frequent small meals and restriction of simple carbohydrates. Dietary measures were considered inadequate as, despite diet modification, the flash glucose monitoring system continued to show multiple nocturnal and postprandial hypoglycemic episodes. Subsequently, as behavioral interventions were insufficient, corticosteroid therapy with prednisolone at a dose of 20 mg twice daily was introduced. The starting dose of prednisolone (approximately 0.5 mg/kg/day) was based on previously published case reports and adjusted according to the patient’s body weight and clinical response, as there are currently no standardized dosing guidelines for IAS [2].

The patient responded positively with clinical stabilization and improved glycemic control. Prednisolone dose was tapered by 5 mg/day at 7-day intervals. The lowest recorded blood glucose concentration following initiation of therapy was 69 mg/dL (Figure 3). The patient was discharged in good general condition, with recommendations for dietary management and regular glycemic monitoring. Levothyroxine therapy was initiated at a dose of 50 μg daily. During follow-up visits, owing to sustained improvement in glycemic control, the dose of prednisolone was gradually lowered and finally withdrawn after 16 weeks of treatment. At the most recent follow-up, scheduled 4 months after initial diagnosis, the patient remained in good general condition. Flash glucose monitoring revealed an average glucose level of 113 mg/dL, with an estimated HbA1c of 6.0%, and no recorded episodes of hypoglycemia (Figure 4). Laboratory tests performed at the last check-up showed no significant abnormalities in complete blood count, serum electrolytes, or renal and hepatic function. Fasting glucose was 91 mg/dL; insulin (46.9 μU/mL) and C-peptide (2.8 ng/mL) were decreased, compared with previous values, consistent with clinical improvement. An evaluation of thyroid hormones confirmed euthyroidism. Screening for adrenal insufficiency after corticosteroid tapering was negative (morning serum cortisol concentration: 15 μg/dL, ACTH stimulation test showed an adequate cortisol response, with peak cortisol concentration of 22.2 μg/dL). The patient is followed in the outpatient endocrinology clinic every 3 months for signs and symptoms of recurrent hypoglycemia. She has been scheduled for repeated thyroid ultrasound in 2 years.

Discussion

We described a rare case of primary IAS in a White woman, without a known trigger.

IAS occurs much more frequently in Asian populations, especially in Japan, and the condition ranks among the most common causes of hypoglycemia [3]. In contrast, IAS in White patients remains exceedingly rare, with idiopathic forms occasionally reported without identifiable drug triggers. Concerns were raised due to inappropriate high glycemia for extremely elevated insulin concentrations, irregular pattern of symptoms, and negative imaging. The diagnosis was confirmed by high titers of insulin autoantibodies. The patient was successfully treated with prednisone, resulting in complete resolution of hypoglycemia. As observed in most cases described in the literature, our patient experienced postprandial hypoglycemic episodes, along with occurrences of nocturnal hypoglycemia. In IAS, insulin autoantibodies bind to endogenous insulin, forming complexes that temporarily inactivate insulin’s biological activity. During periods of fasting, such as overnight, these complexes can dissociate, leading to a sudden increase in free insulin levels. This unanticipated surge in insulin activity can result in hypoglycemia, even in the absence of recent food intake [6]. Differential diagnosis in patients presenting with hyperinsulinemic hypoglycemia must include the exclusion of other conditions, particularly pancreatic. In contrast to insulinomas, hypoglycemic episodes in IAS are typically milder, whereas insulin concentrations are disproportionately higher in IAS [2]. Given that insulinomas can evade detection through conventional imaging methods [7], the definitive approach for distinguishing between the 2 entities is the detection of insulin autoantibodies, which are present in IAS but usually absent in insulinoma. Other rare conditions that should be considered in the differential diagnosis of IAS include Munchausen syndrome and advanced dumping syndrome [8,9] (Table 1).

IAS can be classified into drug-induced and idiopathic (or primary) forms [2]. It is indicated that nearly 50% of individuals diagnosed with IAS report prior use of medications [4]. The medications most frequently implicated in drug-induced IAS etiology are compounds containing sulfhydryl groups, for example methimazole [5] and alpha-lipoic acid [10]. It is hypothesized that these substances may enhance the immunogenicity of insulin by modifying its disulfide bonds, thereby promoting the formation of autoantibodies [6].

Genetic susceptibility plays a significant role in the development of IAS, with a well-documented association with specific HLA class II alleles. HLA-DRB10406 has been strongly linked to IAS in Japanese populations, while HLA-DRB10403 appears more frequently in White populations, albeit with a weaker association [11]. In the case of our patient, HLA class II genotyping was not performed. The management of IAS can be complex. Due to the high likelihood of spontaneous remission, initial treatment often involves discontinuation of the suspected triggering agent, along with dietary modification. A frequent, low-carbohydrate meal plan is typically recommended to blunt postprandial hyperglycemia and reduce insulin secretion [2]. Uchigata et al [12] reported that approximately 82% of IAS cases (in the Japanese population) resolved spontaneously without the need for immunosuppressive therapy. To date, no standardized pharmacologic regimen has been established for IAS, as no clinical trials have been conducted to guide treatment protocols. However, medications such as glucocorticoids [13], rituximab [14], and other immunosuppressants [4] have been applied. In the present case, due to an insufficient response to non-pharmacologic strategies, glucocorticoid therapy with oral prednisolone was initiated with a very good clinical outcome.

Autoimmune conditions are frequently observed in IAS, with autoimmune thyroid diseases, particularly Graves’ disease, being the most common. Although Hashimoto thyroiditis has also been reported in several case studies, its prevalence appears to be significantly lower [4]. In the present case, Hashimoto’s thyroiditis was diagnosed simultaneously with IAS. The absence of a pharmacological trigger and the coexistence of Hashimoto’s thyroiditis make this case particularly uncommon among reported White patients. Both conditions likely share an autoimmune pathogenesis, possibly influenced by yet unidentified environmental factors.

Chronic inflammation is recognized as a key contributor to cancer development [15]; therefore Hashimoto’s thyroiditis has been studied as a potential risk factor for thyroid carcinoma [16]. Xiaojie Hu et al [17] demonstrated in a meta-analysis that patients with Hashimoto’s thyroiditis may carry a significantly increased risk of developing thyroid cancer. Insulin resistance, as an entity leading to increased insulin concentrations commonly observed in metabolic disorders, has also been associated with a higher incidence of thyroid nodules, possibly due to its proliferative effects on thyroid tissue. Elevated insulin levels and insulin resistance have been correlated with increased thyroid volume and thyroid nodularity [18]. Yin et al [19] reported an elevated risk of thyroid cancer in individuals with insulin resistance (relative risk, 1.59; 95% CI, 1.12–2.27; P=0.01), as well as in those with metabolic syndrome and its components. Although IAS, due to its underlying mechanism and frequently self-limiting course, does not appear to be a direct risk factor for thyroid cancer, the co-occurrence of autoimmune thyroiditis underlines the need for careful evaluation of any incidentally detected thyroid lesions.

Most idiopathic IAS cases resolve within months; however, recurrence has been documented in approximately 10% to 15% of cases, typically within the first year after remission and in patients with persistent insulin autoantibodies [2,12]. Given these considerations, long-term follow-up remains essential to monitor for potential recurrence of hypoglycemia.

According to the 2015 American Thyroid Association guideline, in case of thyroid nodules with low-to-intermediate ultrasound features with benign cytology, thyroid ultrasound should be repeated in 1 to 2 years after initial diagnosis. Repeat fine-needle aspiration biopsy is indicated if the thyroid nodule increases in size by more than 20% in at least 2 dimensions or develops new suspicious ultrasonographic features [20]. The European Thyroid Association guideline recommends single ultrasound re-evaluation after 3 to 5 years in cytology-benign EU-TIRADS 4 nodules larger than 15 mm [21].

Conclusions

IAS should be considered in patients with spontaneous hyperinsulinemic hypoglycemia and negative imaging studies, even in non-Asian populations. Demonstrating high insulin autoantibody titers together with a characteristic pattern on flash glucose monitoring can secure the diagnosis without unnecessary invasive and costly evaluation for insulinoma.

In our patient, prednisolone treatment led to complete resolution of hypoglycemia, allowing gradual tapering and discontinuation of therapy within 4 months. Given the autoimmune pathogenesis of IAS and its frequent coexistence with other autoimmune diseases, the diagnostic process should include screening for concurrent autoimmunity, especially thyroid diseases such as Hashimoto’s thyroiditis. IAS itself is unlikely to independently predispose to thyroid cancer, but the presence of autoimmune thyroiditis warrants cautious evaluation of incidental thyroid findings.