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Insulin autoimmune syndrome (IAS) also known as Hirata's disease is a rare endocrine disease. It is a form of autoimmune endogenous hyperinsulinemic hypoglycemia, which develops when genetically predisposed individuals get exposed to triggering factors such as viral infection or certain medications containing sulfhydryl groups. It is important to consider IAS in the differential diagnosis of hypoglycemia as its incidence seems to be increasing worldwide. In this article, we summarize a report of two cases of IAS and their clinical manifestations, biochemical characteristics, their step-by-step diagnosis, and also prompt utilization of continuous glucose monitoring system as a monitoring tool for appropriate management. The first patient who presented with hypoglycemic episodes had recently suffered from a viral pneumonia, which probably acted as a superantigen and triggered development of IAS. The second patient also had hypoglycemic episodes, which were used to recover after intake of glucose-containing liquids. Alpha-lipoic acid containing multivitamin may have triggered the development of IAS in the second patient. The tests performed showed high serum insulin and C-peptide levels along with insulin autoantibody positivity confirming the diagnosis of Hirata's disease. Immunosuppression therapy was not required as both the patients responded well to diet modification and corticosteroid therapy. It is important to be mindful while prescribing alpha-lipoic acid-containing supplements though it has good antioxidant properties as it is presumed to be associated with increasing number of IAS cases.
Keywords: Alpha-lipoic acid, hypoglycemia, insulin autoantibody, insulin autoimmune syndrome
How to cite this URL:
Deshmukh S, Purandare VB, Pakale A, Unnikrishnan AG. Insulin autoimmune syndrome: A report of two cases. Chron Diabetes Res Pract [Epub ahead of print] [cited 2023 Jun 2]. Available from: https://cdrpj.org//preprintarticle.asp?id=369952 |
| Introduction | |  |
Diagnosis of autoimmune forms of hypoglycemia can be challenging and requires close monitoring and appropriate evaluation as they are relatively rare in routine clinical practice. Autoimmune forms of hypoglycemia are of two types: insulin autoimmune syndrome (IAS) in which antibodies are directed against endogenous insulin and the other being Type B insulin resistance syndrome which is characterized by the presence of anti-insulin receptor antibodies.[1],[2] IAS is characterized by recurrent spontaneous episodes of fasting or postprandial hypoglycemia in individuals who are not previously exposed to exogenous insulin and who did not carry any pathological abnormalities of pancreatic islets.[2],[3]
The key factors in the diagnosis of IAS, also known as Hirata's disease, are high levels of serum insulin, the presence of high serum concentration of insulin autoantibodies (IAAs), and Whipple triad, i.e., symptoms or signs of hypoglycemia along with documented low plasma glucose concentration and resolution of hypoglycemia symptoms or signs after glucose administration.[4] Patients of IAS present in adulthood, usually over 40 years of age, and it seems to affect both the genders equally.[3],[4],[5] From its first description till the year 2009, at least 380 cases of IAS have been identified in Japan. IAS is a leading cause of hypoglycemia in Japan but is rare in non-Asian population; however, the incidence is increasing worldwide.[6],[7] We summarize our experience of two cases of this rare disease. Informed consent was obtained from the patients for the publication.
| Case Report | | |
Case 1
A 66-year-old woman was referred to us by a physician for the further evaluation of hypoglycemic episodes. Her medical records revealed that she was recently admitted at the nearby hospital for viral pneumonia and was managed with intravenous amoxicillin and potassium clavulanate, oral oseltamivir, antihistaminic with acebrophylline, and diethylcarbamazine. She received nebulization with bronchodilators, and intravenous hydrocortisone had also been given. During hospitalization, her glycated hemoglobin (HbA1C) was 6.6%. She was discharged on oral antihistaminic, bronchodilator rotacaps, metformin, and low-dose oral prednisolone by the treating physician.
After discharge, she developed hypoglycemic episodes early morning for 3–4 days and experienced symptoms such as sweating, fatigue, increased hunger, and palpitations. Following this, on advice of the treating physician, the patient stopped taking metformin and prednisolone. After stopping metformin, she continued to experience hypoglycemic episodes with capillary blood glucose of 54 mg/dl documented on glucometer during the episode. The symptoms used to get better after taking fruit juice or carbohydrate-rich meal. She was brought to our outpatient department (OPD) clinic and was hospitalized for further evaluation.
Physical examination showed body mass index of 28.77 kg/m2 and her vital parameters were stable. There was no thyroid gland enlargement or acanthosis nigricans. No signs of systemic lupus erythematosus or thyrotoxicosis were present. Systemic examination was within normal limits. Past medical history was suggestive of long-standing hypertension and childhood asthma, which were well controlled with medications.
Routine laboratory investigations were within normal limits including hemogram, thyroid profile, renal and liver function tests, urine routine, and microscopy. During hypoglycemic episode, her random C-peptide was 18.8 ng/mL and her fasting C-peptide was 23.42 ng/mL (normal range: 1.1–4.5 ng/mL). Her serum insulin was >300 μU/mL (normal range: 2.6–24.9, peak up to 166 μU/mL). We performed Synacthen test and the basal cortisol level were measured at 30 min and 60 min after giving intramuscular injection of Synacthen 250 mg. The basal serum cortisol level was 8.9 μg/dl (normal range: 5–25 μg/dl), the 30-min poststimulation cortisol level was 21.1 μg/dl, and the 60-min poststimulation cortisol level was 24.5 μg/dl, which suggested a normal response. High serum insulin and raised C-peptide levels were suggestive of hyperinsulinemic hypoglycemia either insulin antibody syndrome or insulinoma. Ultrasound and contrast-enhanced magnetic resonance imaging (MRI) of the abdomen were done which did not show any abnormality or lesion in the pancreas. Meanwhile, the report of serum insulin autoantibody done using ELISA kit (Aeskulisa, Wendelsheim, Germany) was positive 61.5 U/mL (positive >18 U/mL), and hence, the diagnosis of IAS was confirmed.
During hospitalization, we had put the patient on freestyle libre (Abbott) continuous glucose monitoring (CGM). Initially, the CGM showed hyperglycemia followed by fasting low blood glucose levels [Figure 1]a. The hypoglycemia episodes largely improved once we started the patient on oral prednisolone 1 mg/kg with diet modification, which included small frequent low carbohydrate meals and a mandatory bedtime snack. The patient was discharged after 1 week of hospitalization. After 10 days on follow-up in the OPD, the CGM showed resolution of hypoglycemia episodes [Figure 1]b. We gradually tapered and stopped the oral prednisolone over a period of 6 weeks and advised to repeat serum insulin, C-peptide, and insulin autoantibody tests on subsequent visits. Her glucose level was within the normal range on follow-up. | Figure 1: (a) CGM graph representing fasting hypoglycemia. (b) CGM graph representing improvement in hypoglycemic episodes postdiet modification and steroid therapy. CGM: Continuous glucose monitoring
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Case 2
A 54-year-old obese woman came to OPD for evaluation of recurrent episodes of hypoglycemia. She was a known case of hypothyroidism which was well controlled with regular treatment with thyroxine. There was no other past history of major chronic diseases, autoimmune diseases, or the use of oral hypoglycemic agents. She presented with classic symptoms of hypoglycemia: giddiness, tremors, palpitations, and hunger despite having proper meals. These episodes used to subside by glucose administration in the form of fruit juices or tea with sugar at home. During the episode at home, on glucometer, her capillary blood glucose was 50 mg/dl. Her physical examination revealed a high body mass index of 34.33 kg/m2 and stable vital parameters with BP of 130/90 mmHg, pulse rate of 78/min, and respiratory rate of 16/min. On investigation, her HbA1C was 6.1% and other initial workup including hemogram, thyroid profile, liver function test, renal profile and urine routine were all normal. Electrocardiogram and chest X-ray were also normal. For further evaluation, we took help of freestyle libre (Abbott) flash glucose monitoring (FGM) which documented early morning and also late after-meal hypoglycemia episodes [Figure 2]a. Suspecting insulinoma, we performed imaging studies: contrast-enhanced MRI of the abdomen and 68-Gallium DOTATATE scanning, which excluded the presence of any lesion in the pancreas or elsewhere. A random blood test performed on an OPD basis demonstrated high serum insulin levels of >300 μU/mL done by using chemiluminescent microparticle immunoassay with a C-peptide value of >30 ng/ml, which confirmed endogenous hyperinsulinemic hypoglycemia. A provisional diagnosis of IAS was made which was later confirmed by serum ELISA testing that demonstrated a high concentration of anti-insulin antibodies 54.96 U/ml (positive >18 U/ml). At this point, the patient disclosed that for the last 1 month, she was taking a multivitamin tablet, in which we found that alpha-lipoic acid 200 mg was one of the components. Further, after diagnosis of insulin antibody syndrome, we stopped the multivitamin containing alpha-lipoic acid, started the patient on oral prednisolone 1 mg/kg, and asked her to have frequent small meals. After 1 week of treatment, FGM showed gradual disappearance of hypoglycemia episodes [Figure 2]b, and we gradually tapered the steroid therapy over a period of 6–8 weeks and recommended to repeat C-peptide, serum insulin, and insulin autoantibody tests in subsequent follow-up visits to know more about the course of disease. During the follow-up visits, it was observed that most of her glucose readings were within normal limits. | Figure 2: (a) CGM graph representing postbreakfast hypoglycemia episode. (b) CGM graph representing improvement in hypoglycemic episodes postdiet modification and steroid therapy. CGM: Continuous glucose monitoring
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| Discussion | | |
IAS is strongly associated with the presence of human leukocyte antigen DR4 and specifically DRB1*0406 and also with DRB1*0403 and DRB1*0407. We did not perform genetic testing, and the diagnosis was made clinically. Individuals who are genetically predisposed when exposed to a triggering factor such as viral infections (mumps, rubella, Coxsackie B, influenza, hepatitis C, chickenpox, and measles) or certain drugs containing sulfhydryl group may develop IAS [mentioned in [Table 1]]; a few spontaneously developed cases are also reported.[3],[4],[6] Our first patient had recently suffered from a viral pneumonia which could have been a triggering factor while the second patient gave a history of taking multivitamin containing alpha-lipoic acid for a month which could have been an important determinant in development of IAS. An increasing number of cases have been reported in recent years as alpha-lipoic acid is commonly used as an adjuvant for diabetic neuropathy and also used as a health supplement for dieting and anti-aging purpose because of its antioxidant potential.[6],[8] IAS can be associated with other autoimmune diseases such as Graves' disease and also secondary to methimazole use, systemic lupus erythematosus, rheumatoid arthritis, Type 3A or 4 autoimmune polyendocrine syndrome, and other hematological diseases such as multiple myeloma and monoclonal gammopathy of undetermined significance, which is frequently seen in Caucasian than in Asian patients.[2],[4],[9] The mechanism of development of IAS is presumed to be caused by high concentration of IAAs.[3] Hypoglycemia in IAS is probably the result of mismatch between glucose and free insulin concentration secondary to the insulin-IAA binding and release of secreted insulin disproportionate to glucose concentration.[2] After food intake, there is a rise in blood glucose, followed by increased insulin levels. Insulin is then bound by IAA, making the insulin ineffective and attenuating its normal physiologic action of binding to receptors in liver and peripheral tissues, which leads to postprandial hyperglycemia. This further stimulates the production of increased amounts of insulin and C-peptide to cope with the postprandial hyperglycemia. Insulin-IAA complexes create a reserve of insulin, and subsequently, when dissociation occurs, there is a sustained release of free insulin in the postabsorptive state, leading to more prolonged and severe hypoglycemia.[4],[10] The possible mechanism behind sulfhydryl group drugs being associated with IAS development in many cases is still debated, but it has been hypothesized that they interact with the disulfide bonds in the insulin molecule either by formation of hapten or by interposing cleavage of the disulfide bonds in insulin chains, thereby making endogenous insulin more immunogenic.[2],[4],[8] Alpha-lipoic acid is reduced by nicotinamide adenine dinucleotide phosphate to dihydrolipoic acid which has sulfhydryl group with strong reducing activity and immunogenicity, thereby triggering IAA formation.[3] Increased or normal HbA1C concentration can be found in IAS because of fluctuations in glucose concentration as transient hyperglycemic episodes are interspersed with periods of hypoglycemia.[4],[11] | Table 1: List of drugs triggering development of insulin autoimmune syndrome[3]
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Diagnosis of IAS is challenging, considering multiple differential diagnoses causing hyperinsulinemic hypoglycemia. [Table 2] summarizes various tools for diagnosis of hypoglycemia of different origins.[4] Approach to diagnosis of IAS includes the presence of Whipple triad followed by assaying serum insulin and C-peptide levels during hypoglycemia episode which are extremely high in concentration suggesting endogenous hyperinsulinemic hypoglycemia. Insulin-to-C-peptide molar ratio was considered to be an important diagnostic tool for IAS. However, because of varying binding capacity of IAA to C-peptide, insulin-to-C-peptide molar ratio may not be a reliable tool in diagnosis of IAS.[3],[5] Insulin autoantibody titer measurement is now considered the most reliable test for diagnosis of IAS.[3] Polyethylene glycol precipitation can be performed in false-negative cases as routinely available kits for IAA assaying generally detect only immunoglobulin G (IgG) class of IAA.[3],[12] High binding capacity and low affinity for endogenous insulin molecules are the characteristics of IAS antibodies.[4] Imaging studies, though expensive, are commonly performed to rule out insulinoma.[7] Drug-induced hypoglycemia which may be caused by anti-hyperglycemic agents, anti-hypertensives like beta-blockers, angiotensin converting enzyme inhibitors, and a few anti-arrhythmic and psychotropic drugs, though cause a milder form of hypoglycemia, is often seen in adults and this can be ruled out by taking a thorough medical history from the patient and testing blood samples for the presence of these medications.[13] The treatment approach has not been clearly studied as most of the cases of IAS showed spontaneous remission.[10] Withdrawal of triggering medication and dietary modification should be the first step in management.[14] Frequent and small low-carbohydrate meals and uncooked cornstarch are advised to avoid early postprandial hyperglycemia and subsequent stimulation for insulin secretion.[15] Of all pharmacological therapies available, high-dose corticosteroids show good results. In severe and refractory cases, steroid-sparing immunosuppressants such as azathioprine, monoclonal antibody rituximab, or plasmapheresis can be used.[2] In glucocorticoid contraindicated cases, plasmapheresis can be used alone to rapidly reduce IAA titers.[3] Other therapies aimed at reducing insulin secretion such as diazoxide, somatostatin analogs, acarbose, and pancreatectomy have been also proposed[2],[3],[4] Detailed studies comparing different pharmacological therapies are not available. Both our patients responded well to diet modification and steroid therapy. CGM or FGM is an important tool in the management as it helps to better understand the classic pattern of glycemic variation in insulin antibody syndrome and treat accordingly.[10] | Table 2: Various tools for diagnosis of hypoglycemia of different origins[3],[4]
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| Conclusion | | |
We have described two rare cases of IAS, and it is important to consider IAS in the differential diagnosis of evaluation of hypoglycemia to avoid unnecessary investigations and surgical interventions. Greater care should be taken while prescribing alpha-lipoic acid supplementation. Most cases of IAS have self-remitting course and can be managed with frequent small low-carbohydrate meals and by withdrawal of offending drug. CGM can be used as a crucial monitoring tool and its use should be encouraged in IAS patients to prevent life-threatening episodes of hypoglycemia.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for images and other clinical information to be reported in the journal. The patients understand that names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Correspondence Address:
Ambika G Unnikrishnan,
Department of Diabetes and Endocrinology, Chellaram Diabetes Institute, Pune, Maharashtra
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/cdrp.cdrp_24_22
[Figure 1], [Figure 2]
[Table 1], [Table 2] |
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