Methimazole-induced insulin autoimmune syndrome

Abstract

Background:

Hypoglycemia in a critical care setting is often multifactorial with iatrogenic insulin use, sulfonylurea (SU) use, sepsis, adrenal insufficiency and insulinoma among the common causes. Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin-binding autoantibodies to the sulfhydryl group-containing agents. We report a case of methimazole-induced IAS managed in the intensive care unit.

Case presentation:

A 76-year-old woman with a history of primary hyperthyroidism was sent from a nursing home for unresponsiveness. Vital signs were significant for hypotension (74/46) and low blood sugars. Fluid resuscitations with normal saline and 50% dextrose stabilized the blood pressure (BP) to 135/75 and her blood glucose to 264. Due to respiratory distress and septic appearance, she required emergency intubation. Nursing home medications were noted for methimazole and absence of any insulin or SU use. Empiric antibiotic treatment was started and fluid resuscitation was continued while home medications were held. Her laboratory values were significant for elevated creatinine, lactic acid, serum cortisol, C-peptide, and insulin. Her cultures, SU screen and computerized tomography (CT) scan were negative for significant findings. On day 2, in addition to 10% dextrose, octreotide was initiated for recurrent hypoglycemia. Her blood glucose (BG) continued to drop throughout the day for which she required glucagon support and a D20 infusion. By day 4, the rate of infusion was titrated up and her BG continued to drop to <60 mg/dl despite D20, octreotide and tube feeds with concentrated calories (1.5 cal/ml). Due to her declining health, her family endorsed palliative care and she was extubated. After day 11, her hypoglycemic episodes resolved and she remained endogenously euglycemic.

Conclusions:

IAS is associated with methimazole use due to formation of autoantibodies to insulin after its interaction with Sulfhydryl (SH) group in methimazole. While IAS is a rare entity, it demands consideration in hypoglycemia in patients with autoimmune conditions.

Introduction

First reported in Japan, insulin autoimmune syndrome (IAS) is characterized by the presence of spontaneous hypoglycemia [Okabe et al. 1999; Wang et al. 2015; Zhang and Zhao, 2014]. High concentrations of total immunoreactive insulin and insulin-binding autoantibodies (IAAs) in IAS lead to severe, recurrent, fasting or late postprandial hypoglycemia [Hakamata et al. 1995; Zhang and Zhao, 2014]. Since the initial discovery of IAS, there have been a small number of reported cases predominantly in Japan where IAS is the third leading cause of spontaneous hypoglycemia, following insulinoma and diffuse islet-cell hyperplasia [Hirata et al. 1972; Masjhur and Hirata, 1983; Zhang and Zhao, 2014]. It remains under-reported and under-diagnosed in the United States (US).

Hypoglycemia in the critical care setting is seldom investigated, as it is reversible with immediate treatment. It is often multifactorial and the true cause is obscured by the acute condition at hand. Sepsis, ingestion of substances, alcohol intoxication, malnutrition, insulin and drug overdose are familiar causes. Other sources include adrenal insufficiency and excess insulin production from insulinoma, islet hyperplasia or IAS. We present a case of an elderly woman with hyperthyroidism presenting with persistent hypoglycemia secondary to methimazole use.

Case report

A 76-year-old African–American woman with a history of toxic multinodular goiter was sent from a nursing home (NH) for unresponsiveness. As per emergency medical services, she was hypotensive (blood pressure, BP, 74/46 mmHg) with immeasurably low blood glucose (BG) by glucometer. After infusing 4 l saline and multiple 50% Dextrose (D50) administration, her BP and BG improved to 135/75 mmHg and 264 mg/dl, respectively. Due to respiratory distress and septic appearance, she required emergency intubation. An hour later, her BG was 61 mg/dl, requiring another ampule of D50 and initiation of 10% dextrose infusion at 150 ml/h. NH medications included methimazole, olanzapine and furosemide but no history of sulfonylurea (SU) or insulin use. Cultures were sent and empirical vancomycin and piperacillin/tazobactam were started along with stress-dose hydrocortisone. All NH medications, including methimazole were held for concern of accidental overdose. The pertinent laboratory investigations were lactic acid 6.8 mmol/l, creatinine 3.1 mg/dl, serum cortisol (prior to steroid administration) 109.7 µg/ml, C-peptide 8 ng/ml (0.8–3.8 ng/ml) and insulin 70.9 mIU/l (4.2–27 mIU/l) (Table 1). Thyroid stimulating hormone (TSH) and free thyroxine (T4) on admission were 6.71 mIU/l and 0.94 ng/dl respectively, changed from 0.229 mIU/l and 1.51 ng/dl 5 weeks before admission; when hyperthyroidism was diagnosed and methimazole initiated. Her cultures, SU screen and CT scan were negative for significant findings.

Table 1.

Serum insulin, C-peptide and cortisol levels.

	Normal	Patient
Serum total insulin (mIU/l)	4.2–27	70.9
Serum C-peptide (ng/ml)	0.8–3.8	8.0
Serum cortisol (µg/ml)	2–30	109.7

20% dextrose at 75 ml/h and octreotide at 100 µg subcutaneous (SC) Q8h were initiated next day for recurrent hypoglycemia. Despite an improvement in her mentation, her BG continued to drop to <60 mg/dl several times/day, requiring additional glucagon support and switching to higher rates of D20. Her BG still continued to fall to <60 mg/dl during the week despite continuous D20 infusion, octreotide and concentrated calories through tube feeds. During the course of her hospitalization, her accuchecks and chemistry panel was significant for recurrent episodes of hypoglycemia (as shown in Figure 1).

Figure 1.

Serum glucose levels (mg/dl) and total daily dextrose (grams) administered.

Due to her declining health, her family endorsed palliative care and the patient was transferred out of the intensive care unit after extubation. Her tube feeds were continued along with additional oral carbohydrate supplementation. Her mentation progressively improved over the next few days and interestingly, her hypoglycemic episodes resolved after day 11.

Conclusion

IAS is a clinically rare cause of hypoglycemia in non-Asian adults [Hirata and Uchigata, 1994]. Failure to diagnose or misdiagnosis obscures its true prevalence in the US. While mostly reported in Asians, there are a few published cases among whites and African Americans in the US [Basu et al. 2005; Cruz et al. 2012].

While the cause of IAS is not completely understood, previous exposure to Sulfhydryl (SH) group containing medications and certain Human Leukocyte Antigen (HLA) types are involved in the pathogenesis of this syndrome. Table 2 highlights some of the common drugs associated with IAS. This immune-mediated condition is associated with other autoimmune syndromes, commonly with Graves’ disease, but also with systemic lupus erythematosus, systemic sclerosis and acanthosis nigricans.

Table 2.

Common medications associated with IAS.

Methimazole	Captopril	Penicillamine	Mercaptopropionylglycine
Propylthiouracil	Hydralazine	Imipenem

IAS, insulin autoimmune syndrome.

There has been a significantly strong genetic predisposition in the development of IAS. Administration of methimazole in hyperthyroidism could serve as a potential risk factor. Graves’ disease patients with allelic combination Bw62/Cw4/DR4 carrying DRB1*0406 are at higher risk of developing IAS from methimazole use. This pattern was also found in patients with IAS from other causes [Burch et al. 1992; Uchigata et al. 1993, 2009].

It has been studied that the ‘TSICSLYQLE’ motif of human insulin α-chain binds with high affinity to the DRB1*0406 using its IxxLxQ motif. This fragment exists in very low concentrations under normal physiological conditions due to the presence of the disulfide bonds. The SH group of methimazole cleaves the disulfide bond of insulin molecule, leaving the linear fragment on the α-chain exposed to the DRα-DRB1*0406 on antigen presenting cells that binds to it with high affinity. This interaction triggers activation of self-insulin specific T-helper cells and formation of IAAs [Matsushita et al. 1994]. The binding is reversible but transiently lowers the serum insulin levels stimulating further intrinsic insulin production. The unbinding of the IAA complexes later results in a surge of circulating insulin, causing hypoglycemia. Discontinuation of the offending drug is associated with remission, while resumption of the medication causes recurrence of hypoglycemia. Withdrawal of methimazole decreases the production of immunoglobulin (Ig)G or IgE autoantibodies and BG gradually normalizes after initiation of diet and removal of autoantibodies from circulation [Cruz et al. 2012; Lupsa et al. 2009].

Hypoglycemia is usually related to antidiabetic medications. However, in nondiabetic patients, the cause for sustained hypoglycemia should be sought. Malnutrition was an underlying factor in our case and the diagnosis was clouded by a sepsis-like presentation. However, it did not explain the elevated insulin levels and the recurrent hypoglycemia despite dextrose infusion and steroids. Negative SU screen, CT and a lack of response to octreotide ruled out SU ingestion and insulinoma. To our regret, IAS was a diagnosis of exclusion, since IAA levels were not collected in time. The hyperinsulinemic hypoglycemic state with methimazole use, and its resolution after 10 days of its cessation was highly suggestive of methimazole-induced IAS.

Hospitalization for correction of metabolic abnormalities along with prompt discontinuation of the suspected medication is the mainstay of treatment. Prednisone, diazoxide and propranolol are also used to treat IAS and hyperthyroidism [Cruz et al. 2012]. Acarbose, octreotide or diazoxide, along with a diet restricting carbohydrates, decrease endogenous insulin secretion [Schlemper et al. 1996]. Immunosuppression with rituximab and plasmapheresis can also be used to suppress antibody response [Jassam et al. 2014].

While the syndrome itself is rare and remains a diagnosis of exclusion, it demands consideration in recurrent hypoglycemia with no apparent cause.