Insulin Mimicking Mystery: Decoding Recurrent Hypoglycemia

Abstract

Insulin antibody syndrome (IAS), also known as Hirata disease, is a rare condition characterized by spontaneous hypoglycemic episodes unrelated to exogenous insulin exposure. It is caused by elevated serum levels of insulin autoantibodies (IAA). IAS typically occurs when a triggering factor, such as medication or viral infection, interacts with a predisposing genetic background. Diagnosing IAS is challenging due to its rarity and the presence of multiple potential causes for hyperinsulinemic hypoglycemia. The presence of Whipple triad—symptoms of hypoglycemia, low plasma glucose concentration, and relief of symptoms after raising plasma glucose—strongly supports the diagnosis of IAS. However, the detection of IAA is considered the most reliable test. Timely diagnosis can facilitate appropriate treatment and prevent unnecessary imaging studies and invasive procedures, thereby reducing costs. Currently, no definitive guidelines exist for managing IAS. Most management strategies involve supportive measures due to the high rate of spontaneous remission, with hypoglycemia often managed through dietary interventions. However, a few medications have shown benefit. Although predominantly observed in the Japanese population, IAS cases have been reported in other ethnicities, including Caucasians. This report presents a unique case of IAS in an African American male.

Introduction

Hirata disease, or insulin antibody syndrome (IAS), is an autoimmune disorder characterized by the presence of autoantibodies against endogenous insulin. These antibodies bind to insulin, creating immune complexes that delay the clearance of insulin from the bloodstream, leading to episodes of hypoglycemia. IAS is typically triggered by external factors such as viral infections or medications, especially those containing sulfhydryl groups, such as methimazole and carbimazole. These triggers interact with a genetic predisposition, often linked to specific human leukocyte antigen alleles, to induce the production of insulin autoantibodies (IAA). Clinically, IAS presents with spontaneous hypoglycemic episodes, which can be severe and unpredictable.

The complexity of diagnosing IAS stems from its rarity and the need to distinguish it from other causes of hyperinsulinemic hypoglycemia. First described in Japan by Yukimasa Hirata in 1970, IAS is considered rare, with most cases reported in East Asian populations. However, IAS has been documented in other ethnic groups, albeit infrequently. Given the lack of standardized treatment guidelines, individualized patient management is crucial. This case report discusses an unusual presentation of IAS in an African American male, highlighting the diagnostic challenges and considerations in managing this rare syndrome.

Case Presentation

A 73-year-old male with a history of diabetes mellitus, cerebrovascular accident, dementia, and hypertension was brought to the emergency room from a group home with altered mentation and a low glucose level of 33 mg/dL (1.83 mmol/L) (normal reference range: 70-110 mg/dL; 3.8-6.1 mmol/L). Upon receiving glucagon from paramedics en route to the hospital, his mental status improved slightly. However, the patient was oriented only to himself and was a poor historian. He was unable to provide a reliable history apart from mentioning that he had poor oral intake over the last day. He reported taking metformin 500 mg twice daily but had no recollection of any other diabetes medications. Furthermore, there were no records of a family history of endocrine or autoimmune disorders.

Chart review revealed several similar emergency department visits over the last 12 months for altered mental status due to hypoglycemia with glucose levels below 30 mg/dL. His last hemoglobin A1c 2 months prior to presentation was recorded at 4.0% (3.8 mmol/L) (normal reference range: 4.0-6.0%; 3.8-7 mmol/L). The notably low hemoglobin A1c indicated possible recurrent hypoglycemia prior to presentation. During prior hospital visits, it was well documented that he was advised to stop metformin.

Upon presentation this time, his vital signs were within normal limits. Urinalysis indicated a urinary tract infection, for which he was started on intravenous ceftriaxone and admitted for evaluation of hypoglycemia. Despite withholding insulin, the patient continued to experience recurrent fasting hypoglycemic episodes, which temporarily improved with intravenous dextrose pushes. Endocrinology was consulted, and he underwent an extensive workup.

Diagnostic Assessment

Initial common causes for hypoglycemia were ruled out, as hepatic, renal, and thyroid function tests were all normal. Blood tests for oral antidiabetic agents were also within acceptable limits, and hemoglobin A1c was 4.2%. Moreover, other labs, including cortisol levels, the cosyntropin stimulation test, PTH, and triglycerides, were normal, indicating no adrenal insufficiency. To assess glycogen stores and rule out problems with gluconeogenesis or glycogenolysis, his hypoglycemic episodes were treated with glucagon rather than glucose, which elicited an appropriate response.

Further labs obtained during a fasting hypoglycemic episode demonstrated an elevated C-peptide (5.6 ng/mL; 1.85 nmol/L) (normal reference range: 0.8-3.9 ng/mL; 0.26-1.3 nmol/L), insulin (44.3 uIU/mL; 307.64 pmol/L) (normal reference range: ≤ 18.4 uIU/mL; ≤ 127.78 pmol/L), and proinsulin (2.83 uIU/mL; 19.7 pmol/L) (normal reference range: ≤ 1.15 uIU/mL; ≤ 8 pmol/L). These findings were suggestive of hyperinsulinemic hypoglycemia, potentially due to IAS or an insulinoma.

A computed tomography scan of the abdomen showed no pancreatic mass but revealed new intrahepatic bile duct dilatation. Due to the high suspicion of insulinoma, a magnetic resonance cholangiopancreatography was performed, which showed no pancreatic mass or ductal dilatation. An octreotide scan was also negative for insulinoma. Consequently, he was transferred to a tertiary care center for possible endoscopic pancreatic ultrasound and additional management. Given the markedly elevated insulin levels and postprandial hypoglycemia symptoms, IAS was considered. Upon further investigations, IAS testing was positive, with serum IAA level reported as >50 U/mL; >50 kU/L (normal range <0.4 U/mL; <0.4 kU/L).

Treatment

During the patient's hospital stay, he was initially managed with a 5% dextrose in lactated Ringer's solution drip and small, frequent meals. Given the findings of hyperinsulinemia and the high suspicion for insulinoma, diazoxide therapy was initiated at a dose of 3 mg/kg every 8 hours. The dosage was later increased to every 6 hours, which resulted in temporary improvement in blood glucose levels. After formal diagnosis of IAS, he was started on 10 mg of prednisone, which led to an overall improvement in his blood glucose levels. He was discharged in stable condition and advised to follow up with the endocrinology team as an outpatient.

Outcome and Follow-up

During long-term follow-up, the patient did not experience any recurrence of hypoglycemia but had persistently mild hyperglycemia. The intended long-term treatment strategy includes continued monitoring of blood glucose levels, maintaining a balanced diet, and adjusting immunosuppressive therapy as needed. Regular follow-up visits are planned to assess and manage any potential recurrence of symptoms and to ensure optimal glycemic control.

Discussion

In discussing the significance and epidemiology of IAS, it is important to note its historical and geographical context. IAS, first described by Hirata et al (1), is predominantly observed in Japan. A study by Yuchigata et al in 1992 demonstrated a strong association between and the DRB1*0406 gene among the Japanese population (2). In Japan, IAS is the third leading cause of hypoglycemia after insulinoma and extrapancreatic neoplasias (3).

The pathogenesis of IAS involves a combination of genetic predisposition and environmental factors, which together prompt the development of IAA. Triggers include certain medications, such as methimazole, carbimazole, torasemide, and hydralazine alpha-lipoic acid, as well as viral infections like measles, mumps, rubella, varicella, coxsackie, and hepatitis viruses. IAS can also occur spontaneously (4). Furthermore, IAS is often associated with other autoimmune diseases but can also present alone or as part of autoimmune polyendocrine syndromes, such as type 3A or type 4 (5).

Understanding the pathophysiology of hypoglycemia in IAS is crucial for effective diagnosis and management. Hypoglycemia in IAS is likely due to a mismatch between glucose and free insulin concentrations, secondary to insulin and IAA binding and the disproportionate release of secreted insulin. After food intake, there is an initial rise in blood glucose followed by increased insulin levels. However, insulin bound by IAA is rendered ineffective, attenuating its normal physiologic action. This results in postprandial hyperglycemia, which further stimulates the production of insulin and C-peptide. The insulin-IAA complexes create a reserve of insulin, and when dissociation occurs, there is a sustained release of free insulin in the postabsorptive state, leading to severe hypoglycemia.

Effective diagnosis of IAS requires careful consideration of its unique features. Diagnosing IAS is challenging due to the need to differentiate it from other causes of hyperinsulinemic hypoglycemia. The diagnostic approach involves confirming Whipple triad and obtaining serum insulin and C-peptide levels during hypoglycemia episodes. Typically, these levels are very high, indicating endogenous hyperinsulinemic hypoglycemia. Measurement of IAA titers is still considered the most reliable test for diagnosing IAS though (6).

Additionally, the insulin-to-C-peptide ratio can be helpful in diagnosing IAS. Under normal physiological conditions, insulin and C-peptide are cosecreted by the pancreatic β-cells, resulting in a ratio of less than 1. In IAS, the insulin half-life is prolonged due to IAA binding, while the C-peptide elimination time remains unchanged, reversing the ratio to greater than 1 (7).

Management of IAS involves addressing both immediate symptoms and long-term outcomes. IAA usually disappear over a few months (8), and Hirata et al found spontaneous remission in 82% of IAS cases (1). However, there are currently no concrete management guidelines for IAS. Mild hypoglycemic episodes are often managed with dietary interventions, such as frequent small meals, a low-sugar diet, and avoiding fasting. Cornstarch, which absorbs slowly and stabilizes glucose levels, has also been beneficial in other reported cases (9).

For more severe cases, steroids have been shown to reduce hypoglycemic episodes and lower IAA titers. High doses of prednisolone administered over 1 to 6 months have provided effective relief from hypoglycemic attacks and significantly reduced IAA levels (10). This was the strategy that we used in our patient. The use of modern immunosuppressive therapies in managing IAS have also shown promising outcomes. Recently, rituximab, an anti-CD20 monoclonal antibody, has been used to treat severe hypoglycemia in patients resistant to high-dose corticosteroids, effectively suppressing IAA titers and reducing hypoglycemic events (11). In particularly severe cases, plasmapheresis has been employed to rapidly decrease IAA titers and prevent hypoglycemia (12). Other medications that have shown efficacy include cyclophosphamide, mycophenolate mofetil, cyclosporine, and azathioprine. While no definitive guidelines currently exist for managing IAS, continuous glucose monitoring has also been recommended to closely track blood glucose levels and adjust treatment accordingly. Further research and clinical trials are needed to develop standardized treatment protocols and monitoring strategies for IAS.

In considering the findings of this case report, it is important to acknowledge its limitations. First, the rarity of IAS and the lack of standardized treatment guidelines pose challenges in generalizing the findings to broader populations. Second, while our patient responded well to treatment, he is still being followed, and we are unable to report long-term outcomes at the time of writing, which are essential for understanding the chronic management of IAS. Finally, the reliance on single-patient data restricts the ability to draw comprehensive conclusions about the effectiveness of various therapeutic approaches.

In conclusion, IAS is a rare and challenging condition that requires careful diagnostic evaluation. The presence of IAA complicates the management of hypoglycemia, necessitating individualized treatment approaches. While there are promising therapies available, further research is needed to establish universal guidelines. This case emphasizes the importance of considering IAS in the differential diagnosis of unexplained hypoglycemia and highlights the need for continued exploration of effective management strategies.

Learning Points

• Timely diagnosis of IAS allows for appropriate treatment, avoiding unnecessary imaging and invasive procedures and thus reducing costs.

• IAS should be considered in patients with hyperinsulinemic hypoglycemia who have negative imaging results for tumor localization.

• Further research is needed to establish the optimal management of IAS, as prolonged use of high-dose steroids can lead to significant side effects, including cushingoid features and osteoporosis.

Contributors

A.S., V.M., and E.R. were involved in contributing to writing and editing the case presentation. M.R. was involved in contributing to the discussion. C.H. provided assistance on drafting and editing of all sections. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.