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 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.

Insulin Autoimmune Syndrome (Hirata Disease) as Differential Diagnosis in Patients with Hyperinsulinemic Hypoglycemia

Pancreas ◽  
2006 ◽  
Vol 32 (4) ◽  
pp. 431-432 ◽  
Author(s):  
Ellen S. Paiva ◽  
Amanda E. Pereira ◽  
Maria Teresa F.C. Lombardi ◽  
Sonia K. Nishida ◽  
Teresinha T. Tachibana ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Hyperinsulinemic Hypoglycemia ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome

Human monoclonal IgG1 insulin autoantibody from insulin autoimmune syndrome directed at determinant at asparagine site on insulin B-chain

Diabetes ◽  
1989 ◽  
Vol 38 (5) ◽  
pp. 663-666 ◽  
Author(s):  
Y. Uchigata ◽  
K. Yao ◽  
S. Takayama-Hasumi ◽  
Y. Hirata
Keyword(s):  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
Insulin Autoantibody

scholarly journals Spontaneously remitting insulin autoimmune syndrome in a patient taking alpha-lipoic acid

2018 ◽  
Vol 2018 ◽  
Author(s):  
D Cappellani ◽  
C Sardella ◽  
M C Campopiano ◽  
A Falorni ◽  
P Marchetti ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Lipoic Acid ◽  
University Hospital ◽  
Hypoglycaemic Episode ◽  
List Type ◽  
Alpha Lipoic Acid ◽  
Previous Exposure ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome

Summary Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS. Learning points: Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid. Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available. The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.

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.

Insulin Autoimmune Syndrome After Exposure to Clopidogrel: A Case Report

2020 ◽  
Vol 20 (8) ◽  
pp. 1355-1362 ◽  
Author(s):  
Yihong Jiang ◽  
Lihua Wang ◽  
Fanghong Shi ◽  
Huan Zhou ◽  
Jun Zheng ◽  
...  
Keyword(s):  
Case Report ◽  
Multidisciplinary Team ◽  
Evaluation Process ◽  
First Episode ◽  
C Peptide ◽  
Prednisone Therapy ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
Insulin Autoantibody ◽  
Sh Group

Background: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia that is characterized by hyperinsulinemia, hypoglycemia, and a high autoantibody titer. About 50% of patients with IAS have taken a medication containing sulfhydryl (-SH) groups. We present a case of IAS that developed after taking clopidogrel, a drug with an active metabolite that contains an SH-group. Case report: IAS was suspected in a 63-year-old Chinese man because of high concentrations of insulin and C-peptide during hypoglycemic episodes, and positivity for anti-insulin autoantibody (IAA). During his first episode of hypoglycemia, no trigger medication was identified and prednisone therapy was effective. However, imaging examination revealed a colonic carcinoma and the patient was discharged to undergo surgery. He had no episodes of hypoglycemia for 10 weeks after discontinuation of the prednisone, but then hypoglycemia recurred. A review of his medication revealed that he had taken a 10-day course of clopidogrel just before the recurrence. Therefore, a specialized multidisciplinary team consisting of endocrinologists, dieticians, and clinical pharmacists took charge of his management. Prednisone therapy was restarted and tapered off over 16 weeks. The patient also consumed small, frequent, low-carbohydrate meals and was instructed to avoid trigger medications. No further episodes of hypoglycemia were detected. His insulin and C-peptide concentrations and his anti-IAA index normalized during the follow-up period. Conclusion: SH-group-containing drugs might induce or exacerbate hypoglycemia in patients with a history of IAS. Furthermore, patients with IAS can benefit from multidisciplinary team management. We suggest herein an evaluation process for patients suspected of IAS.

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

2019 ◽  
Vol 19 (1) ◽  
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.

scholarly journals A novel approach to a rare case of non-islet cell hypoglycaemia

2021 ◽  
Vol 2021 ◽  
Author(s):  
R K Dharmaputra ◽  
K L Wan ◽  
N Samad ◽  
M Herath ◽  
J Wong ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Islet Cell ◽  
B Lymphocyte ◽  
Serum Insulin ◽  
Insulin Antibody ◽  
Lymphocyte Depletion ◽  
Insulin Levels ◽  
Insulin Autoimmune Syndrome ◽  
Autoimmune Syndrome ◽  
High Insulin

Summary Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab. Learning points Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded. Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia. Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS). Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

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