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.
Acknowledgments
The authors want to acknowledge Leandra Steinmetz, MD, MSc, Hilton Kuperman, MD, PhD, Hamilton Menezes, MD, Louise Cominato, MD, MSc, and Ruth Rocha Franco, MD, MSc, all medical staff at the Children’s Institute – University of São Paulo, for their assistance in the case and contribution to solve the diagnosis during grand rounds. Our recognitions to Roberta Salvodelli, MD, PhD, and Débora Athaíde Menezes, MD, for their contribution with patient care, and previous poster presentation in medical meetings, respectively. Also to Prince Kevin Danieles for proofreading this manuscript and Andraea Von Hulst, RN, PhD, and Luiz Fernando Ybarra, MD, MBA, PhD, for proofreading and reviewing this manuscript. Our special acknowledgments to Fleury Laboratory team, particularly to Claudia Maria Ferrer and Teresinha Tamie Tachibana, for their availability to accept to perform a non-routine experiment like the chromatography test.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Uchigata Y, Eguchi Y, Takayama-Hasumi S, Omori Y. Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract 1994;22:89–94.10.1016/0168-8227(94)90040-XSearch in Google Scholar
2. Ismail AA. The insulin autoimmune syndrome (IAS) as a cause of hypoglycaemia: an update on the pathophysiology, biochemical investigations and diagnosis. Clin Chem Lab Med 2016;54:1715–24.10.1515/cclm-2015-1255Search in Google Scholar PubMed
3. Demirbilek H, Rahman SA, Buyukyilmaz GG, Hussain K. Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology. Int J Pediatr Endocrinol BioMed Central 2017;2017:9.10.1186/s13633-017-0048-8Search in Google Scholar PubMed PubMed Central
4. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, et al. Evaluation and management of adult hypoglycemic disorders: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2009;94:709–28.10.1210/jc.2008-1410Search in Google Scholar PubMed
5. Savas-Erdeve S, Agladioglu SY, Onder A, Kendirci HN, Bas VN, et al. An uncommon cause of hypoglycemia: insulin autoimmune syndrome. Horm Res Paediatr 2014;82:278–82.10.1159/000362758Search in Google Scholar PubMed
6. Gomez Cruz MJ, Jabbar M, Saini N, Eng D, Crawford B, et al. Severe hypoglycemia secondary to methimazole-induced insulin autoimmune syndrome in a 16 year old African-American male. Pediatr Diabetes 2012;13:652–5.10.1111/j.1399-5448.2012.00884.xSearch in Google Scholar PubMed
7. Meschi F, Dozio N, Bognetti E, Carrà M, Cofano M, et al. An unusual case of recurrent hypoglycemia: 10-year follow up of a child with insulin auto-immunity. Eur J Pediatr 1992;151:32–4.10.1007/BF02073886Search in Google Scholar PubMed
8. Alves C, Constança J, De León DD, Snider K, Stanley C. A novel atypical presentation of insulin autoimmune syndrome (Hirata’s disease) in a child. J Pediatr Endocrinol Metab 2013;26:1163–6.10.1515/jpem-2013-0215Search in Google Scholar PubMed PubMed Central
9. Goldman J, Baldwin D, Rubenstein AH, Klink DD, Blackard WG, et al. Characterization of circulating insulin and proinsulin-binding antibodies in autoimmune hypoglycemia. J Clin Invest 1979;63:1050–9.10.1172/JCI109374Search in Google Scholar PubMed PubMed Central
10. Zhao WC, Jin J, Zhang JZ. Insulin autoimmune syndrome induced bymethimazole in a patient with Graves’ disease. J Endocrinol Invest 2013;36:450–1.10.1007/BF03347108Search in Google Scholar PubMed
11. Nakagawa S, Suda N, Kudo M, Kawasaki M. A new type of hypoglycaemia in a newborn infant. Diabetologia 1973;9:367–75.10.1007/BF01239429Search in Google Scholar
12. Rovira A, Valverde I, Escorihuela R, Lopez-Linares M. Autoimmunity to insulin in a child with hypoglycemia. Acta Paediatr Scand 1982;71:343–5.10.1111/j.1651-2227.1982.tb09430.xSearch in Google Scholar
13. Sharwood EF, Hughes IP, Pretorius CJ, Trnka P, Peake J, et al. Therapeutic plasma exchange normalizes insulin-mediated response in a child with type 1 diabetes and insulin autoimmune syndrome. Pediatr Diabetes 2018;19:171–9.10.1111/pedi.12522Search in Google Scholar
14. Trabucchi A, Iacono RF, Guerra LL, Faccinetti NI, Krochik AG, et al. Characterization of insulin antibodies by surface plasmon resonance in two clinical cases: Brittle diabetes and insulin autoimmune syndrome. PLoS One 2013;8:1–7.10.1371/journal.pone.0084099Search in Google Scholar
15. Meissner T, Wendel U, Burgard P, Schaetzle S, Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 2003;149:43–51.10.1530/eje.0.1490043Search in Google Scholar
16. Uchigata Y, Kuwata S, Tokunaga K, Eguchi Y, Takayama-Hasumi S, et al. Strong association of insulin autoimmune syndrome with HLA-DR4. Lancet (London, England) 1992;339:393–4.10.1016/0140-6736(92)90080-MSearch in Google Scholar
17. Church D, Cardoso L, Bradbury S, Clarke C, Stears A, et al. Diagnosis of insulin autoimmune syndrome using polyethylene glycol precipitation and gel filtration chromatography with ex vivo insulin exchange. Clin Endocrinol (Oxf) 2017;86:347–53.10.1111/cen.13179Search in Google Scholar PubMed PubMed Central
18. Sperling MA. Pediatric endocrinology. In: Sperling MA, editor. Pediatric endocrinology. 4th ed. Philadelphia: Elsevier Saunders, 2014:930–1.Search in Google Scholar
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2018-0441).
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