Diagnostic Considerations

Patients with hyperinsulinism usually have elevated levels of insulin for their glucose concentration, meaning even if they do not have hypoglycemia, their insulin level is inappropriately high for their glucose levels (ie, plasma insulin level >2 µU/mL when blood glucose level is < 60 mg/dL). In contrast, patients with the following disorders have an appropriate concentration of insulin for the simultaneous glucose concentration:

Adrenal insufficiency
Disorders of branched-chain amino acids
Enzymatic block in the Cori and alanine cycles
Fatty acid release/oxidation (ketone synthesis) disorders
Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase deficiency
Ketone use disorders
Mitochondrial succinyl–coenzyme A transferase deficiency
Mitochondrial acetyl–coenzyme A acyltransferase deficiency
Fructosemia
Galactosemia
Glycerokinase deficiency
Glycogen-storage disease type Ia and type Ib (von Gierke disease, glucose-6-phosphatase deficiency)
Glycogen-storage disease type III (Cori disease; amylo-1, 6-glucosidase deficiency)
Glycogen-storage disease type VI (Hers disease, phosphorylase deficiency)
Growth hormone deficiency

Differential Diagnoses

Workup

Yorifuji T. Congenital hyperinsulinism: current status and future perspectives. Ann Pediatr Endocrinol Metab. 2014 Jun. 19 (2):57-68. [QxMD MEDLINE Link].
Abdulhadi-Atwan M, Bushmann J, et al. Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence. Diabetes. 2008 Jul. 57(7):1935-40. [QxMD MEDLINE Link].
Arbizu Lostao J, Fernandez-Marmiesse A, Garrastachu Zumarran P, et al. [18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism.]. An Pediatr (Barc). 2008 May. 68(5):481-5. [QxMD MEDLINE Link].
Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998. 338:226-30. [QxMD MEDLINE Link].
Grimberg A, Ferry RJ Jr, Kelly A, et al. Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes. 2001. 50:322-8. [QxMD MEDLINE Link].
Shah JH, Maguire DJ, Munce TB, Cotterill A. Alanine in HI: a silent mutation cries out!. Adv Exp Med Biol. 2008. 614:145-50. [QxMD MEDLINE Link].
Stanley CA, Baker L. The causes of neonatal hypoglycemia. N Engl J Med. 1999 Apr 15. 340(15):1200-1. [QxMD MEDLINE Link].
Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998. 338:1352-7. [QxMD MEDLINE Link].
Suchi M, MacMullen CM, Thornton PS. Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol. 2006. 19:122-9. [QxMD MEDLINE Link].
Thomas PM, Cote GJ, Wohllk N, et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995. 268:426-9. [QxMD MEDLINE Link].
Pearson ER, Boj SF, Steele AM, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007 Apr. 4(4):e118. [QxMD MEDLINE Link]. [Full Text].
Hardy OT, Hernandez-Pampaloni M, Saffer JR, et al. Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab. 2007. 92:4706-11. [QxMD MEDLINE Link].
Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013 Feb. 98(2):E355-63. [QxMD MEDLINE Link]. [Full Text].
Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol. 2013 Apr. 168(4):557-64. [QxMD MEDLINE Link]. [Full Text].
Lord K, Radcliffe J, Gallagher PR, Adzick NS, Stanley CA, De León DD. High risk of diabetes and neurobehavioral deficits in individuals with surgically treated hyperinsulinism. J Clin Endocrinol Metab. 2015 Sep 1. jc20152539. [QxMD MEDLINE Link].
Lord K, Dzata E, Snider KE, Gallagher PR, De León DD. Clinical presentation and management of children with diffuse and focal hyperinsulinism: a review of 223 cases. J Clin Endocrinol Metab. 2013 Nov. 98(11):E1786-9. [QxMD MEDLINE Link]. [Full Text].
Khawash P, Hussain K, Flanagan SE, Chatterjee S, Basak D. Nifedipine in Congenital Hyperinsulinism-A Case Report. J Clin Res Pediatr Endocrinol. 2015 Jun 5. 7 (2):151-4. [QxMD MEDLINE Link].
Cherubini V, Bagalini LS, Ianilli A, Marigliano M, Biagioni M, Carnielli V, et al. Rapid genetic analysis, imaging with 18F-DOPA-PET/CT scan and laparoscopic surgery in congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2010. 23:171-7. [QxMD MEDLINE Link].
Craver RD, Hill CB. Cure of hypoglycemic hyperinsulinism by enucleation of a focal islet cell adenomatous hyperplasia. J Pediatr Surg. 1997. 32:1526-7. [QxMD MEDLINE Link].
Cucchiaro G, Markowitz SD, Kaye R, et al. Blood glucose control during selective arterial stimulation and venous sampling for localization of focal hyperinsulinism lesions in anesthetized children. Anesth Analg. 2004. 99:1044-8, table of contents. [QxMD MEDLINE Link].
[Guideline] De Leon DD, Stanley CA. Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab. 2007. 3:57-68. [QxMD MEDLINE Link].
de Lonlay-Debeney P, Poggi-Travert F, Fournet JC. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med. 1999. 340:1169-75. [QxMD MEDLINE Link].
Ferry RJ Jr, Franklin SL, Geffner ME. Hypoglycemia. Kappy MS, Allen DB, Geffner ME, eds. Principles and Practice of Pediatric Endocrinology. Springfield, Ill: Charles C Thomas Publisher, Ltd; 2005. 607-34.
Ferry RJ Jr, Kelly A, Grimberg A, et al. Calcium-stimulated insulin secretion in diffuse and focal forms of congenital hyperinsulinism. J Pediatr. 2000. 137:239-46. [QxMD MEDLINE Link].
Hoe FM, Thornton PS, Wanner LA. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr. 2006 Feb. 148(2):207-12. [QxMD MEDLINE Link].
Hussain K, Aynsley-Green A, Stanley CA. Medications used in the treatment of hypoglycemia due to congenital hyperinsulinism of infancy (HI). Pediatr Endocrinol Rev. 2004 Nov. 2 Suppl 1:163-7. [QxMD MEDLINE Link].
Kane C, Shepherd RM, Squires PE, et al. Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med. 1996. 2:1344-7. [QxMD MEDLINE Link].
Levitt Katz LE, Satin-Smith MS, Collett-Solberg P, et al. Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism. J Pediatr. 1997 Aug. 131(2):193-9. [QxMD MEDLINE Link].
Lovvorn HN III, Nance ML, Ferry RJ Jr. Congenital hyperinsulinism and the surgeon: lessons learned over 35 years. J Pediatr Surg. 1999. 34:786-92; discussion 792-3. [QxMD MEDLINE Link].
Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin Chem. 2008. 54:256-63. [QxMD MEDLINE Link].
Stanley CA. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab. 2004 Apr. 81 Suppl 1:S45-51. [QxMD MEDLINE Link].
Steinkrauss L, Lipman TH, Hendell CD. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs. 2005 Apr. 20(2):109-18. [QxMD MEDLINE Link].
Suchi M, Thornton PS, Adzick NS, et al. Congenital hyperinsulinism: intraoperative biopsy interpretation can direct the extent of pancreatectomy. Am J Surg Pathol. 2004 Oct. 28(10):1326-35. [QxMD MEDLINE Link].

Media Gallery

Mechanisms of insulin secretion.

of 1

Author

Sunil Kumar Sinha, MD Clinical Assistant Professor, Division of Pediatric Endocrinology, University of Arizona College of Medicine

Sunil Kumar Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Kenneth Kwok-Chun Chan, MD Consulting Staff, Department of Pediatrics, Andover Pediatrics

Kenneth Kwok-Chun Chan, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Ab Sadeghi-Nejad, MD Chief, Division of Pediatric Endocrinology and Metabolism, Tufts Medical Center; Professor of Pediatrics, Tufts University School of Medicine

Ab Sadeghi-Nejad, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Massachusetts Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Acknowledgements

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Sections Hyperinsulinism
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
Follow-up
References

Hyperinsulinism Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

References

Tables

Contributor Information and Disclosures

What would you like to print?