Hypoglycemia due to insulin autoimmune syndrome (Hirata’s disease): a rare cause of hypoglycaemia

Although the most common cause of recurrent hypoglycaemia is diabetes mellitus as patient is on antidiabetic medications which can be prevented by modification of antidiabetic doses, nutrition therapy and lifestyle modifications. Some endogenous hyperinsulinemic conditions like insulinoma, functional beta cell disorders and insulin autoimmune syndromes, hormonal deficiencies can cause serious and sometimes life threatening hypoglycaemia. So further laboratory evaluation like plasma/serum glucose levels, c-peptide levels, insulin levels, insulin antibodies and imaging studies are needed to evaluate unexplained hypoglycaemia. Here we report a case of insulin autoimmune syndrome in a 67 year old Indian male who had presented to us with multiple episodes of spontaneous hypoglycaemia. On further workup, the patient was found to have endogenous hyperinsulinemic hypoglycemia. As the patient’s abdominal imaging revealed no apparent cause of EHH, on further evaluation he came positive for insulin antibodies. Patient was diagnosed as IAS and he was given frequent small meals and complex carbohydrate diet and he had improved symptomatically. The incidence of IAS is most common in Japan and very few cases have been reported from India, so it should be kept in differential diagnosis of recurrent hypoglycaemia.

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MON-686 Insulin Autoimmune Syndrome as a Rare Cause of Hypoglycemia

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.236 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Marwa Mokhtar ◽

Wajiha Gul ◽

Monica Skarulis

Keyword(s):

Pancreatic Head ◽

Acute Onset ◽

Insulin Antibodies ◽

Hyperinsulinemic Hypoglycemia ◽

Short Term Treatment ◽

Male Physician ◽

C Peptide ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

History Of

Abstract Background: Insulin Autoimmune Syndrome (IAS) or Hirata disease is reported more in Asians. We report the case of a patient with acute onset hypoglycemia secondary to IAS. Case Presentation: A 64 year old ARAB male physician presented with 2 weeks history of episodic hypoglycaemia with blood glucose (BG) 40–60 mg/dl, unrelated to food and occurring throughout the day. His attacks were associated with sweating, dizziness and palpitations, relieved by intake of juice. He reported 3 kg weight gain since the beginning of his symptoms. Past medical history revealed hypertension, past HCV infection with negative PCR and history of allergy to sulfa drugs. His medications included bisoprolol 2.5 mg daily. Physical exam showed no acanthosis nigericans. Laboratory investigations: Normal hepatic, renal and thyroid functions. 72 Hours fasting test was performed. at hour 3, the BG was 2.27 mmol (40.86 mg/dl), insulin > 1000 mU/ml (N: 2.6–24.9), c- peptide 15 ng/ml (N: 1.1–4.4), negative beta-hydroxybutyrate, with good glycemia response to glucagon 1mg. Urine sulfonylurea (SU) screen was negative. Insulin antibodies titre was high 8.9 nmol/L (N: 0–0.02) and Proinsulin >700 pmol/L (N: 3.6–22). MRI Abdomen showed only 3 mm lesion in the pancreatic head, likely a cyst. During hospitalization, the patient continued to have episodic hypoglycaemia and received dextrose 10% and octreotide injection. Bisoprolol was changed to amlodipine as it may mask his symptoms. Episodes of hypoglycaemia improved with octreotide but did not resolve completely. Prednisolone 30 mg daily was started with improvement and was tapered slowly after 16 weeks after mild hyperglycemia developed. Repeat work up showed reduction in insulin 67.4 mcunit/ml, C- peptide 2.66 ng/ml and insulin antibody titres to 0.24 nmol/L and remission of hypoglycemia. Discussion: Autoimmune hypoglycaemia is rare resulting from insulin antibodies(IAS), or anti-insulin receptor antibodies (Type B insulin Resistance). IAS can be triggered by drugs or viruses including hepatitis C and is associated with autoimmune diseases and hematologic malignancies. the differential diagnosis of hyperinsulinemic hypoglycemia include insulinoma, the presence of extreme levels of insulin, c-peptide and proinsulin and insulin antibodies is diagnostic of AIS. Short-term treatment with steroids was effective in treating hypoglycaemia and careful follow-up is ongoing. If the patient recurs, rituximab will be employed. References: 1-CHURCH, D., CARDOSO, L., KAY, R. G., WILLIAMS, C. L., FREUDENTHAL, B., CLARKE, C., HARRIS, J., MOORTHY, M., KARRA, E., GRIBBLE, F. M., REIMANN, F., BURLING, K., WILLIAMS, A. J. K., MUNIR, A., JONES, T. H., FUHRER, D., MOELLER, L. C., COHEN, M., KHOO, B., HALSALL, D. & SEMPLE, R. K. 2018. Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome. J Clin Endocrinol Metab, 103, 3845–3855.

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Insulin Autoimmune Syndrome: A Case of Clopidogrel-induced Autoimmune Hypoglycemia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz301 ◽

2020 ◽

Vol 105 (4) ◽

pp. 996-999

Author(s):

Genevieve L Calder ◽

Glenn M Ward ◽

Nirupa Sachithanandan ◽

Richard J MacIsaac

Keyword(s):

Active Metabolite ◽

Dual Antiplatelet Therapy ◽

Sulfhydryl Group ◽

Insulin Antibodies ◽

Hyperinsulinemic Hypoglycemia ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Oral Dexamethasone ◽

Antibody Titers ◽

Plasma Cell Dyscrasias

Abstract Context Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS. Case Description A 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective. Conclusions This case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.

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Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0079 ◽

2016 ◽

Vol 2016 ◽

Cited By ~ 6

Author(s):

Chih-Ting Su ◽

Yi-Chun Lin

Keyword(s):

High Serum ◽

Insulin Antibodies ◽

Insulin Analog ◽

Hyperinsulinemic Hypoglycemia ◽

Oral Glucose ◽

List Type ◽

Exogenous Insulin ◽

C Peptide ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome

Summary Insulin antibodies (IA) associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA) found in insulin autoimmune syndrome (IAS), which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%), high insulin concentration (111.9 IU/mL) and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly. Learning points: Insulin autoimmune syndrome (IAS) or IAS-like situation should be one of the differential diagnosis in patients with hyperinsulinemic hypoglycemia. Although less reported, insulin antibodies (IA) caused by exogenous insulin analog should be considered as the cause of hypoglycemia. Patients with suspected insulin autoimmune syndrome (IAS) should be screened for drugs related to autoimmunity to endogenous insulin.

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Primary insulin autoimmune syndrome in an Italian woman: a case report

Italian Journal of Medicine ◽

10.4081/itjm.2015.483 ◽

2015 ◽

Vol 9 (2) ◽

pp. 169 ◽

Cited By ~ 3

Author(s):

Antonio Balestrieri ◽

Elena Magnani ◽

Cecilia Ragazzini ◽

Giampiero Pasini

Keyword(s):

Case Report ◽

Insulin Antibodies ◽

Total Serum ◽

Immunoreactive Insulin ◽

High Concentration ◽

Hematological Diseases ◽

Italian Woman ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Primary Form

Insulin autoimmune syndrome (IAS) is a rare syndrome characterized by fasting or postprandial hypoglycemia, high levels of anti-insulin antibodies and high concentration of total serum immunoreactive insulin. It is relatively known in Japan, rare in remaining Asia and it is extremely uncommon in Western countries, being characterized by a different race-related incidence and associated with HLADR4 alleles. Usually IAS is related to particular drugs, or to autoimmune, rheumatologic or hematological diseases, while it is very rare as a primary form. Here we described a case of an Italian woman affected by a primary form of Hirata syndrome.

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Recurrent hypoglycaemia caused by the insulin autoimmune syndrome: the first Dutch case

The Netherlands Journal of Medicine ◽

10.1016/0300-2977(95)00085-2 ◽

1996 ◽

Vol 48 (5) ◽

pp. 188-192 ◽

Cited By ~ 15

Author(s):

R SCHLEMPER ◽

Y UCHIGATA ◽

M FROLICH ◽

A VINGERHOEDS ◽

A MEINDERS

Keyword(s):

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Recurrent Hypoglycaemia

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Pitfalls in the diagnosis of insulin autoimmune syndrome (Hirata’s disease) in a hypoglycemic child: a case report and review of the literature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0441 ◽

2019 ◽

Vol 32 (4) ◽

pp. 421-428 ◽

Cited By ~ 1

Author(s):

Tiago Jeronimo Dos Santos ◽

Caroline Gouvêa Buff Passone ◽

Marina Ybarra ◽

Simone Sakura Ito ◽

Milena Gurgel Teles ◽

...

Keyword(s):

Differential Diagnosis ◽

Previous History ◽

Human Leukocyte ◽

Hyperinsulinemic Hypoglycemia ◽

Insulin Levels ◽

Insulin Autoimmune Syndrome ◽

Endogenous Insulin ◽

Autoimmune Syndrome ◽

Insulin Autoantibody ◽

Control Food Intake

Abstract Background Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinemic hypoglycemia (HH) not addressed as a potential differential diagnosis in current pediatric guidelines. We present a case of IAS in a child with no previous history of autoimmune disease, no previous intake of triggering medications and absence of genetic predisposition. Case presentation A 6-year-old boy presented with recurrent HH (blood glucose of 26 mg/dL [1.4 mmol/L] and insulin of 686 μU/mL). Abdominal imaging was normal. After multiple therapeutic failures, we hypothesized misuse of exogenous insulin and factitious hypoglycemia. Council of Guardianship had the child separated from his mother, but insulin levels remained high. A chromatography test was then performed which showed high titers of endogenous insulin autoantibody (IAA) with early dissociation from the insulin molecule. The human leukocyte antigen (HLA) test showed a DRB1 *13:01/*08:02 genotype. The patient was advised to control food intake and physical activity routines. During a 5-year follow-up, hypoglycemic episodes were sparse, despite high insulin levels. Conclusions Misdiagnosis of IAS with factitious hypoglycemia may happen if IAS is not considered as a differential diagnosis, leading to potential traumatic consequences. Further efforts should be made to increase awareness of IAS as a differential diagnosis of hypoglycemia and to include it in pediatric guidelines.

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The insulin autoimmune syndrome (IAS) as a cause of hypoglycaemia: an update on the pathophysiology, biochemical investigations and diagnosis

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2015-1255 ◽

2016 ◽

Vol 54 (11) ◽

Cited By ~ 18

Author(s):

Adel A.A. Ismail

Keyword(s):

Glycaemic Control ◽

Clinical Manifestations ◽

Insulin Antibodies ◽

Pancreatic Hormones ◽

Insulin Mimetic ◽

Insulin Autoimmune Syndrome ◽

Endogenous Insulin ◽

Autoimmune Syndrome ◽

Potential Impact ◽

Receptor Antibodies

AbstractInsulin autoimmune syndrome (IAS) is considered to be very rare in Caucasians. Understanding its pathophysiology is paramount in (a) appreciating its potential impact on analyses of pancreatic hormones and (b) explaining its highly variable clinical manifestations in non-diabetic, non-acutely ill patients with indeterminate hypoglycaemia. The underlying aetiology of IAS is the presence of variable affinity/avidity endogenous insulin antibodies in significant amounts. The two types of insulin antibodies namely antibodies which bind insulin and/or proinsulin(s) and receptor antibodies (insulin mimetic) will be discussed. Their biochemical and immunological roles in causing hypoglycaemia will be highlighted. Clinical manifestations of IAS can vary from mild and transient to spontaneous, severe and protracted hypoglycaemia necessitating in extreme cases plasmapheresis for glycaemic control. Antibodies of IAS can interfere in pancreatic immunoassay tests causing erroneous and potentially misleading results. Thorough testing for endogenous insulin antibodies must be considered in the investigations of non-diabetic, non-acutely ill patients with indeterminate and/or unexplained hypoglycaemia.

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Insulin autoimmune syndrome: case report

Sao Paulo Medical Journal ◽

10.1590/s1516-31802004000400010 ◽

2004 ◽

Vol 122 (4) ◽

pp. 178-180 ◽

Cited By ~ 12

Author(s):

Rodrigo Oliveira Moreira ◽

Giovanna Aparecida Balarini Lima ◽

Patrícia Carla Batista Peixoto ◽

Maria Lucia Fleiuss Farias ◽

Mario Vaisman

Keyword(s):

Case Report ◽

Pancreatic Tumor ◽

Histopathological Examination ◽

Severe Trauma ◽

Insulin Antibodies ◽

Insulin Levels ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

High Insulin ◽

Biochemical Evaluation

CONTEXT: Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of hypoglycemia in Western countries. It is characterized by hypoglycemic episodes, elevated insulin levels, and positive insulin antibodies. Our objective is to report a case of IAS identified in South America. CASE REPORT: A 56-year-old Caucasian male patient started presenting neuroglycopenic symptoms during hospitalization due to severe trauma. Biochemical evaluation confirmed hypoglycemia and abnormally high levels of insulin. Conventional imaging examinations were negative for pancreatic tumor. Insulin antibodies were above the normal range. Clinical remission of the episodes was not achieved with verapamil and steroids. Thus, a subtotal pancreatectomy was performed due to the lack of response to conservative treatment and because immunosuppressants were contraindicated due to bacteremia. Histopathological examination revealed diffuse hypertrophy of beta cells. The patient continues to have high insulin levels but is almost free of hypoglycemic episodes.

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Insulin autoimmune syndrome induced by exogenous insulin injection: a four-case series

BMC Endocrine Disorders ◽

10.1186/s12902-019-0482-0 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

Yimin Shen ◽

Xiaoxiao Song ◽

Yuezhong Ren

Keyword(s):

Diabetes Mellitus ◽

Case Series ◽

Insulin Injection ◽

Insulin Autoantibodies ◽

Hyperinsulinemic Hypoglycemia ◽

Exogenous Insulin ◽

Case Presentation ◽

Insulin Autoimmune Syndrome ◽

Autoimmune Syndrome ◽

Patients With Diabetes

Abstract Background Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia and is characterized by the presence of insulin autoantibodies. Patients with IAS usually complain of hypoglycemia without any previous insulin received. Glucocorticoids and immunosuppressants are used to treat IAS. Case presentation We report four patients with diabetes who were diagnosed with non-classical IAS and describe the treatment of these patients. Moreover, the differential diagnosis with hyperinsulinism is discussed. Conclusion High levels of insulin autoantibodies, as well as hyperinsulinemic hypoglycemia, are found in patients with diabetes mellitus and prior exogenous insulin exposure. This situation that we classified as non-classical IAS should be attached importance to.

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