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

2016 ◽  
Vol 54 (11) ◽  
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.

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

2015 ◽  
Vol 9 (2) ◽  
pp. 169 ◽  
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.

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

2019 ◽  
Vol 32 (4) ◽  
pp. 421-428 ◽  
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.

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

2021 ◽  
Vol 8 (8) ◽  
pp. 1220
Author(s):  
Het V. Patel ◽  
Sunil Kumar ◽  
Kalpesh Moradiya ◽  
Vidhi Shah
Keyword(s):  
Nutrition Therapy ◽  
Serum Glucose ◽  
Insulin Antibodies ◽  
Laboratory Evaluation ◽  
Hyperinsulinemic Hypoglycemia ◽  
Lifestyle Modifications ◽  
Glucose Levels ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
Recurrent 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.

scholarly journals Insulin autoimmune syndrome: case report

2004 ◽  
Vol 122 (4) ◽  
pp. 178-180 ◽  
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.

scholarly journals Characterization of Insulin Antibodies by Surface Plasmon Resonance in Two Clinical Cases: Brittle Diabetes and Insulin Autoimmune Syndrome

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e84099 ◽  
Author(s):  
Aldana Trabucchi ◽  
Ruben F. Iacono ◽  
Luciano L. Guerra ◽  
Natalia I. Faccinetti ◽  
Andrea G. Krochik ◽  
...  
Keyword(s):  
Surface Plasmon Resonance ◽  
Surface Plasmon ◽  
Plasmon Resonance ◽  
Insulin Antibodies ◽  
Brittle Diabetes ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
Clinical Cases

scholarly journals A Curious Case of Hypoglycemia: A Rare Occurrence of Insulin Autoimmune Syndrome

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A360-A361
Author(s):  
Rithikaa Ellangovan ◽  
Rachana Mundada ◽  
Ajinkya Kulkarni ◽  
Robert A Ries ◽  
Sudheer Konduru ◽  
...  
Keyword(s):  
African American ◽  
African American Male ◽  
Serum Glucose ◽  
C Peptide ◽  
Insulin Levels ◽  
Insulin Autoimmune Syndrome ◽  
Endogenous Insulin ◽  
Autoimmune Syndrome ◽  
High Insulin ◽  
Recurrent Hypoglycemia

Abstract Background: Hypoglycemia can be challenging, requiring close monitoring and evaluation. Although treating diabetes can cause hypoglycemia, the coexistence of autoimmune syndromes contributes to rare etiologies. They are characterized by elevated insulin levels with either insulin autoantibodies (IAA) or insulin receptor antibodies (IRA). It has been observed commonly in Japan but is scarce among non-Asian groups. We present a unique case of insulin autoimmune syndrome (IAS) that posed a diagnostic challenge in an African American male. Case: A 73-year-old African American male was admitted with altered mental status. Medical history included type 2 diabetes, hypertension, and hyperlipidemia. Home medications were carvedilol and simvastatin. On arrival, vital signs were normal. A fingerstick glucose was 52 mg/dL with a serum level of 68 mg/dL (70–110). Other labs were normal. Given symptomatic hypoglycemia, an IV dextrose infusion was initiated. Once his mentation improved, a diet was started. Despite this, he had recurrent hypoglycemia with glucose levels as low as 22 mg/dL, predominantly in fasting state with sporadic hyperglycemia. On rare occasions, he received correctional insulin for the same. An HbA1c was <4% (4–6). Thyroid function test and AM cortisol were normal. A cosyntropin stimulation test was negative for adrenal insufficiency. A hypoglycemia panel showed inappropriately high levels of insulin, highest at 77.4 μIU/mL(<=29.1), proinsulin of 19.7 pmol/L (<=8), and C-peptide of 5.6 (0.8–3.69 ng/mL) when serum glucose was 25 mg/dL. An MRI abdomen was normal. Octreotide study was negative for insulinoma. He had a normal response to IM glucagon, inferring normal glycogen stores. He was started on Diazoxide 160 mg thrice a day for recurrent hypoglycemia. An endoscopic ultrasound and DOTATATE scan were negative. He had no hypoglycemia for a few days, attributable to lingering effects of diazoxide. Eventually, his serum glucose was 52 mg/dL. Labs prior to glucose correction included an insulin level elevated at 1,000 (normal <3 mcIU/mL), c-peptide at 0.90 ng/mL, and proinsulin of 5.6 pmol/L. Given exceedingly high insulin levels, we measured an IAA level. This was >50 u/mL (normal <0.4 u/mL). With negative imaging and high IAAs, a diagnosis of IAS was made. Discussion: IAS or Hirata disease is a rare condition with hyperinsulinemic hypoglycemia and high titers of antibodies to endogenous insulin. The binding kinetics of endogenous insulin to these antibodies causes physiologically inappropriate levels of bioavailable insulin, causing either hyper- or hypoglycemia. IAA should be measured in patients with high insulin levels that are inconsistent with C peptide levels. We believe this to be the first African American patient to have been diagnosed with Hirata disease. Making a correct diagnosis may spare a hypoglycemic patient from unnecessary pancreatic surgical intervention.

Two contrasting cases of spontaneous severe hypoglycaemia secondary to anti-insulin antibodies (Insulin Autoimmune Syndrome / Hirata disease)

2016 ◽  
Author(s):  
Myuri Moorthy ◽  
Bernard Freudenthal ◽  
David Church ◽  
Judith Kisalu ◽  
Emma Woolman ◽  
...  
Keyword(s):  
Severe Hypoglycaemia ◽  
Insulin Antibodies ◽  
Contrasting Cases ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome

scholarly journals Analysis of the clinical characteristics of insulin autoimmune syndrome induced by exogenous insulin in diabetic patients

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Zuojun Li ◽  
Dan Yi ◽  
Lijuan Zheng ◽  
Shiran Li ◽  
Weijin Fang ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Serum Insulin ◽  
Insulin Antibodies ◽  
Hypoglycemic Agents ◽  
Oral Glucose ◽  
Diabetic Patients ◽  
Exogenous Insulin ◽  
Oral Hypoglycemic Agents ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome

Abstract Background The exact incidence, clinical features and uniform diagnostic criteria of exogenous insulin autoimmune syndrome (EIAS) are still unclear. The purpose of this study is to explore the clinical characteristics of EIAS and to provide a structural approach for clinical diagnosis, treatment and prevention. Methods The literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis. Results A total of 122 patients (33 males and 73 females) were included in the study with a median age of 67 years (range 14–86) and a median HbA1c of 7.7%. EIAS mainly occurred in type 2 diabetes mellitus patients using premixed insulin. Symptoms manifested were hypoglycemia in 86.54%, recurrent episodes of symptomatic hypoglycemia in 35.58%, nocturnal hypoglycemia along with daytime hyperglycemia in 21.15% and recurrent hypoglycemia after discontinued insulin in 64.43%. The onset of symptoms occurred at night, in the early morning or during fasting, ranging from a few days to 78 months after the administration of insulin. The mean blood glucose level during the hypoglycemic phase was 2.21 mmol/L (range 1–3.4), and the serum insulin levels were mainly ≥ 100 U/mL and were associated with low C-peptide levels (≤ 10 ng/ml). Insulin autoantibodies (IAAs) were positive in all EIAS patients. The 75-g extended oral glucose tolerance test (OGTT) mainly showed a diabetic curve. Pancreatic imaging was unremarkable. Withdrawal of insulin alone or combination of oral hypoglycemic agents or replacement of insulin formulations or with corticosteroid treatment eliminated hypoglycemia in a few days to 3 months. IAA turned negative in 6 months (median, range 1–12). No hypoglycemia episodes were observed at a median follow-up of 6 months (range 0.5–60). Conclusions EIAS is an autoimmune disease caused by insulin-binding antibodies in susceptible subjects. Insulin antibodies change glucose dynamics and could increase the incidence of hypoglycemic episodes. Detection of insulin antibodies is the diagnostic test. Changing therapeutic modalities reduced the incidence of hypoglycemic episodes.

scholarly journals Severe Fasting Hypoglycemia Mimicking Insulinoma in Three Patients With Insulin Autoimmune Syndrome

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A399-A399
Author(s):  
Alessandro Rossini ◽  
Sara Cassibba ◽  
Cristiana Scaranna ◽  
Anna Corsi ◽  
Rosalia Bellante ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Glycemic Variability ◽  
Insulin Binding ◽  
Glucose Levels ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
Therapeutic Procedures ◽  
History Of ◽  
Fasting Hypoglycemia ◽  
Sulphydryl Compound

Abstract Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin autoantibodies (IAA) in patients without prior exposure to exogenous insulin. Differential diagnosis with other causes of hypoglycemia may be complex. We report three IAS cases with severe fasting hypoglycemia, referred to our Unit for the diagnostic workup of insulinoma. All three patients (two women and a man, age 66, 44, and 50 years) had history of severe fasting hypoglycemia leading to loss of consciousness along with weight gain. Both insulin and C-peptide were high, but their levels varied greatly among patients, ranging from 24 to 1500 μU/ml (n.v. <16.3) and from 11 to 27 ng/mL (n.v. < 4,2), respectively. Imaging studies for insulinoma were negative. In all patients, evidence of elevated IAA (ranging from 310 to 660 UA, n.v. < 5) allowed diagnosis of IAS. Two patients were taking alpha lipoic acid, a sulphydryl compound consistently associated to IAS, while in the other the HLA-DRB1*0403 haplotype, conferring susceptibility to IAS, was detected. Continuous monitoring glucose (CGM) (iPro2; Medtronic Diabetes, CA, USA) showed in all patients the presence of prolonged hypoglycemia (with time spent with blood glucose below 54 mg/dL ranging from 9 to 20% of total monitoring time), and in one case the coexistence of high glucose levels after meals. One patient responded well to diazoxide treatment, while the others required both chronic steroid therapy and the use of plasmaphereses. Conclusion: Clinical manifestations of IAS vary widely among patients, without a direct correlation between symptoms severity and levels of both insulin and IAA; prandial hyperglycemia may also be present, leading to increases in glycated hemoglobin. Our patients displayed severe fasting hypoglycemic attacks that initially posed the suspicion of insulinoma. The assessment of IAA is thus mandatory in cases of fasting hypoglycemia, before proceeding to more expensive and probably unnecessary diagnostic and therapeutic procedures. CGM is a useful tool in evaluation and management of IAS, allowing the assessment of hypoglycemia duration and the detection of the wide glycemic variability secondary to the complex mechanism of insulin binding to IAA.

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

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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