Insulin autoimmune syndrome in a patient with vitiligo: a case report and review of literature

Abstract

Background

Hirata syndrome is a rare cause of hypoglycemia characterized by high insulin levels and the presence of insulin autoantibodies. This case report aims to introduce Hirata syndrome as a cause of fasting hypoglycemia in a patient with autoimmune diseases, such as vitiligo. Notably, this is the first reported case of insulin autoimmune syndrome in Iran.

Case presentation

A 47-year-old Iranian female with no prior history of diabetes but a 10-year history of vitiligo experienced recurrent hypoglycemia symptoms as evidenced by neuroglycopenia and neurological symptoms. Biochemical evaluation revealed fasting hypoglycemia (35 mg/dL), hyperinsulinemia (> 2000 µIU/mL), elevated C-peptide (23 ng/mL), and negative sulfonylurea screening. Imaging studies excluded other causes, such as insulinoma. Considering the high level of insulin autoantibodies, the final diagnosis was insulin autoimmune syndrome. A small, frequent, low carbohydrate diet was considered as the treatment plan to relieve the hypoglycemic symptoms. The patient provided written consent authorizing the utilization of her medical data and the publication of this case study.

Conclusion

In patients without diabetes with autoimmune diseases, such as vitiligo, who present with hyperinsulinemic hypoglycemia accompanied by elevated C-peptide levels, insulin autoimmune syndrome can be considered as a diagnosis.

Background

Hypoglycemia is a rare condition in people not being treated for diabetes mellitus [1, 2]. Insulin autoimmune syndrome (IAS), a rare cause of hypoglycemia, is characterized by recurrent hypoglycemia (fasting, postprandial hypoglycemia, or both), elevated serum insulin, normal to elevated C-peptide, and the presence of insulin autoantibodies (IAAs) without evidence of insulinoma on imaging or sulfonylurea consumption [3]. Although the cause of IAS is not fully understood, it has been reported that IAS can occur concurrently with autoimmune diseases such as Graves’ disease. In addition, some patients have taken medications before developing drug-induced IAS, which most frequently occurs after using methimazole. Eastern Asia, specifically Japan, has the highest number of IAS cases, and Hirata et al. reported the first case in 1970; this disorder is infrequent outside of Japan [4, 5]. Owing to its rarity, lack of awareness, and self-limitation, it is not easy to estimate the exact prevalence of this disease [6].

This manuscript presents the second case report highlighting that patients with vitiligo can experience fasting hypoglycemia as a result of Hirata syndrome [6]. Remarkably, this is the first documented instance of Hirata syndrome in Iran, marking a significant milestone, as it extends beyond East Asia.

Case presentation

A 47-year-old Iranian female was referred to our endocrinology clinic for hypoglycemic management, which had been ongoing for 1 month. Prior to that time, fasting during Ramadan was not accompanied by any symptoms. During the episodes, she experienced blurred vision, as evidenced by neuroglycopenia, while headache, tremors, and sweating were identified as neurological symptoms. According to her, the episodes typically occurred before lunch and then subsided after eating. She received treatment for hypoglycemic episodes at a rural hospital. Whipple’s triad was confirmed when she exhibited hypoglycemic symptoms with a blood sugar level of 46 mg/dl, which was alleviated after receiving 50% dextrose.

Since she was 37 years old, she has suffered from vitiligo. Her body mass index (BMI) was determined to be 27.24 kg/m² on the basis of a height of 158 cm and a weight of 68 kg. There was no family history of any diseases, and the patient had no history of medication use.

After admission to our hospital, a 72-hour fasting test was performed as the first diagnostic approach. The initial blood sugar level was 135 mg/dl. After 5 hours, symptoms of hypoglycemia, such as palpitations, sweating, nausea, dizziness, and blurred vision appeared, and the blood sugar was 35 mg/dL at that time. The results of the fasting test are presented in Table 1. All symptoms subsided after dextrose administration. Considering the elevated serum C-peptide and insulin levels during the fasting test, the differential diagnoses were limited to sulfonylureas consumption, insulinoma, nesidioblastosis, IAS, and type B insulin resistance syndrome (TBIRS). Imaging results, including endoscopic ultrasound (EUS) and abdominal computerized tomography (CT) scan, did not reveal any pancreatic lesions. The results of investigating sulfonylurea derivatives in urine using gas chromatography–mass spectrometry (GC–MS) were negative (Table 2). The diagnosis of IAS was confirmed by elevated IAA levels detected through enzyme-linked immunosorbent assay (ELISA) testing. To evaluate the coexistence of IAS and thyroid disease, thyroid function tests were performed, indicating a euthyroid status.

Table 1 72-hour fasting test results

Table 2 Sulfonylurea derivatives in urine using gas chromatography–mass spectrometry

Owing to the patient’s preference for avoiding medications such as corticosteroids, a small, frequent, low-carbohydrate diet was recommended under nutritional expert guidance. Owing to financial constraints, the patient declined to undergo laboratory tests during follow-up. Consequently, we monitored her condition on the basis of clinical symptoms. Her modified diet pattern has prevented her from developing repeated episodes of hypoglycemia for 5 years so far. For the use of her data and the publication of this case report, written informed consent was obtained from the patient.

Discussion

IAS, also known as Hirata’s disease, is a rare form of hyperinsulinemic hypoglycemia that has equal prevalence among men and women. The majority of reported cases come from Eastern Asia, with reports from other countries being rare [5, 7]. Even though it is rare, owing to its self-limiting nature, which obviates the necessity for invasive treatment, it should still be considered when diagnosing hyperinsulinemic hypoglycemia in patients without diabetes.

IAS can be classified as either drug-induced or idiopathic. Over 50% of IAS cases are induced by sulfhydryl groups [8]. Drug-induced IAS is most commonly related to methimazole, tiopronin, alpha lipoic acid, and insulin aspartate 30 [5]. Our patient denied taking any medications.

In addition, 80% of IAS cases coexist with other autoimmune diseases, such as Graves’ disease, Hashimoto thyroiditis, rheumatoid arthritis, multiple myeloma, and systemic lupus erythematosus [5]. According to autoimmunity theory, vitiligo may develop in tandem with other autoimmune diseases. For instance, vitiligo could be associated with autoimmune endocrine diseases, such as thyroid disease, Addison’s disease, and type I diabetes mellitus. This is the second case of IAS reported in a patient with vitiligo, suggesting that IAS is one of the various endocrinopathies that can arise in such patients [9].

There is no clear understanding of the exact physiopathology of IAS. Insulin autoantibodies in AIS form a complex with insulin. Insulin production in the beta cells continues until the binding capacity of the antibodies is exceeded, which could lead to hyperinsulinemia. IAAs in IAS demonstrate greater binding capacity and reduced insulin affinity relative to antibodies induced by exogenous insulin therapy. Moreover, some studies suggest a shorter half-life of IAAs compared with insulin, which could cause hypoglycemia [3, 5, 10]. Hypoglycemia that presents with neuroglycopenic and neurogenic symptoms may occur after meals, fasting periods, and intensive activities [11]. In our case, hypoglycemia occurred just during fasting times, which was reported in 32% of previous cases [5]. During the night, the body undergoes changes that may cause insulin antibodies to release insulin that was bound during the day. With fewer antibodies binding insulin at night, more free insulin circulates in the blood, potentially leading to lower blood sugar levels in a fasting state [12, 13].

Laboratory tests and imaging could help in identifying the causes of hypoglycemia. Insulin and C-peptide levels are the first tests to be requested in hypoglycemic conditions. Pancreatic B cells make insulin, and C-peptide is made from proinsulin. The liver metabolizes insulin after 5–10 minutes, and the kidney metabolizes C-peptide after 30–35 minutes, so in a physiological state, the insulin/C-peptide molar ratio is < 1. In the hypoglycemic setting, when significantly elevated insulin concentrations were reported with normal to elevated C-peptide levels, the diagnosis was limited to sulfonylurea, insulinoma, nesidioblastosis, IAS, and TBIRS. The insulin/C-peptide ratio is > 1 in patients with IAS because the complex of IAAs and insulin acts as a barrier for metabolizing insulin, while the C-peptide half-life is normal. The C-peptide level can either increase or not, depending on IAA’s ability to bind to it, which can result in a long half-life. In addition, some variations of the IAAs could interfere with the C-peptide measurement immunoassay [14,15,16]. The key points that could differentiate endogenous hyperinsulinemic hypoglycemia are presented in Table 3 [5, 13, 17].

Table 3 Causes of fasting endogenous hyperinsulinemia hypoglycemia

The primary treatment of IAS is a small, frequent, low-carbohydrate diet. Withdrawal of the related medicine is usually enough in patients with IAS triggered by medication. The disease is usually self-limiting, with regression in 3–6 months after the trigger is removed. Although there is no specific treatment, some agents, such as α-glucosidase inhibitors (acarbose) and corticosteroids (prednisone), have been used effectively. Acarbose is recommended for postprandial hypoglycemia owing to delaying carbohydrate absorption, while corticosteroids are used in severe hypoglycemic episodes. Corticosteroids are effective in preventing hypoglycemia and lowering the IAA titers. In patients with corticosteroid-resistant severe hypoglycemia, treatment with rituximab and azathioprine has been associated with favorable results [3]. In this case, IAS was managed with a modified diet, and she did not experience any hypoglycemic episodes during the 5 years of follow-up.

This case report adds to the relatively limited pool of data on Hirata syndrome, particularly in patients with coexisting autoimmune conditions such as vitiligo. The patient’s long-term follow-up (5 years) without hypoglycemic episodes demonstrates the effectiveness of dietary management. Owing to financial constraints, follow-up laboratory tests were not conducted, which limits the ability to monitor biochemical markers over time.

Conclusion

In patients without diabetes with autoimmune diseases, such as vitiligo, who present with unexplained hypoglycemia, it is important to consider IAS as a possible diagnosis. This case highlights the significance of recognizing IAS in such patients, particularly when hyperinsulinemic hypoglycemia accompanied by elevated C-peptide levels is observed. In addition, this case is novel as it is the first reported instance of IAS from Iran.