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. 2000 Mar;82(2):F98–F107. doi: 10.1136/fn.82.2.F98

Practical management of hyperinsulinism in infancy

A Aynsley-Green, K Hussain, J Hall, J Saudubray, C Nihoul-Fekete, P De Lonlay-Debeney, F Brunelle, T Otonkoski, P Thornton, K Lindley
PMCID: PMC1721064  PMID: 10685981

Abstract

Hyperinsulinism in infancy is one of the most difficult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without difficulty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It offers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment.



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Selected References

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  1. Abernethy L. J., Davidson D. C., Lamont G. L., Shepherd R. M., Dunne M. J. Intra-arterial calcium stimulation test in the investigation of hyperinsulinaemic hypoglycaemia. Arch Dis Child. 1998 Apr;78(4):359–363. doi: 10.1136/adc.78.4.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aguilar-Bryan L., Bryan J. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev. 1999 Apr;20(2):101–135. doi: 10.1210/edrv.20.2.0361. [DOI] [PubMed] [Google Scholar]
  3. Aynsley-Green A., Barnes N. D., Adrian T. E., Kingston J., Boyes S., Bloom S. R. Effect of somatostatin infusion on intermediary metabolism and entero-insular hormone release in infants with hyperinsulinaemic hypoglycaemia. Acta Paediatr Scand. 1981 Nov;70(6):889–895. doi: 10.1111/j.1651-2227.1981.tb06246.x. [DOI] [PubMed] [Google Scholar]
  4. Aynsley-Green A., Dunne M. J., James R. F., Lindley K. J. Ions and genes in persistent hyperinsulinaemic hypoglycaemia in infancy: a commentary on the implications for tailoring treatment to disease pathogenesis. J Pediatr Endocrinol Metab. 1998 Mar;11 (Suppl 1):121–129. doi: 10.1515/jpem.1998.11.s1.121. [DOI] [PubMed] [Google Scholar]
  5. Aynsley-Green A., Jenkins P., Tronier B., Heding L. G. Plasma proinsulin and C-peptide concentrations in children with hyperinsulinaemic hypoglycaemia. Acta Paediatr Scand. 1984 May;73(3):359–363. doi: 10.1111/j.1651-2227.1994.tb17748.x. [DOI] [PubMed] [Google Scholar]
  6. Aynsley-Green A., Polak J. M., Keeling J., Gough M. H., Baum J. D. Averted sudden neonatal death due to pancreatic nesidioblastosis. Lancet. 1978 Mar 11;1(8063):550–551. doi: 10.1016/s0140-6736(78)90569-x. [DOI] [PubMed] [Google Scholar]
  7. Aynsley-Green A., Weindling A. M., Soltész G., Jenkins P. A. Transient lactic acidosis and hyperalaninaemia associated with neonatal hyperinsulinaemic hypoglycaemia: the effects of dichloroacetate (DCA). Eur J Pediatr. 1983 Dec;141(2):114–117. doi: 10.1007/BF00496802. [DOI] [PubMed] [Google Scholar]
  8. Brown G., Brown R., Hey E. Fetal hyperinsulinism in rhesus isoimmunization. Am J Obstet Gynecol. 1978 Jul 15;131(6):682–686. doi: 10.1016/0002-9378(78)90832-3. [DOI] [PubMed] [Google Scholar]
  9. Collins J. E., Leonard J. V. Hyperinsulinism in asphyxiated and small-for-dates infants with hypoglycaemia. Lancet. 1984 Aug 11;2(8398):311–313. doi: 10.1016/s0140-6736(84)92685-0. [DOI] [PubMed] [Google Scholar]
  10. Cornblath M., Schwartz R., Aynsley-Green A., Lloyd J. K. Hypoglycemia in infancy: the need for a rational definition. A Ciba Foundation discussion meeting. Pediatrics. 1990 May;85(5):834–837. [PubMed] [Google Scholar]
  11. Dunne M. J., Petersen O. H. Potassium selective ion channels in insulin-secreting cells: physiology, pharmacology and their role in stimulus-secretion coupling. Biochim Biophys Acta. 1991 Mar 7;1071(1):67–82. doi: 10.1016/0304-4157(91)90012-l. [DOI] [PubMed] [Google Scholar]
  12. Finegold D. N., Stanley C. A., Baker L. Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism. J Pediatr. 1980 Feb;96(2):257–259. doi: 10.1016/s0022-3476(80)80817-1. [DOI] [PubMed] [Google Scholar]
  13. Glaser B., Furth J., Stanley C. A., Baker L., Thornton P. S., Landau H., Permutt M. A. Intragenic single nucleotide polymorphism haplotype analysis of SUR1 mutations in familial hyperinsulinism. Hum Mutat. 1999;14(1):23–29. doi: 10.1002/(SICI)1098-1004(1999)14:1<23::AID-HUMU3>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  14. Glaser B., Hirsch H. J., Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr. 1993 Oct;123(4):644–650. doi: 10.1016/s0022-3476(05)80970-9. [DOI] [PubMed] [Google Scholar]
  15. Glaser B., Kesavan P., Heyman M., Davis E., Cuesta A., Buchs A., Stanley C. A., Thornton P. S., Permutt M. A., Matschinsky F. M. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998 Jan 22;338(4):226–230. doi: 10.1056/NEJM199801223380404. [DOI] [PubMed] [Google Scholar]
  16. Glaser B., Thornton P. S., Herold K., Stanley C. A. Clinical and molecular heterogeneity of familial hyperinsulinism. J Pediatr. 1998 Dec;133(6):801–802. doi: 10.1016/s0022-3476(98)70160-x. [DOI] [PubMed] [Google Scholar]
  17. Glaser B., Thornton P., Otonkoski T., Junien C. Genetics of neonatal hyperinsulinism. Arch Dis Child Fetal Neonatal Ed. 2000 Mar;82(2):F79–F86. doi: 10.1136/fn.82.2.F79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Greene S. A., Aynsley-Green A., Soltesz G., Baum J. D. Management of secondary diabetes mellitus after total pancreatectomy in infancy. Arch Dis Child. 1984 Apr;59(4):356–359. doi: 10.1136/adc.59.4.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hawdon J. M., Aynsley-Green A., Alberti K. G., Ward Platt M. P. The role of pancreatic insulin secretion in neonatal glucoregulation. I. Healthy term and preterm infants. Arch Dis Child. 1993 Mar;68(3 Spec No):274–279. doi: 10.1136/adc.68.3_spec_no.274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hawdon J. M., Aynsley-Green A., Bartlett K., Ward Platt M. P. The role of pancreatic insulin secretion in neonatal glucoregulation. II. Infants with disordered blood glucose homoeostasis. Arch Dis Child. 1993 Mar;68(3 Spec No):280–285. doi: 10.1136/adc.68.3_spec_no.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kane C., Lindley K. J., Johnson P. R., James R. F., Milla P. J., Aynsley-Green A., Dunne M. J. Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of beta cells to diazoxide and somatostatin. J Clin Invest. 1997 Oct 1;100(7):1888–1893. doi: 10.1172/JCI119718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kane C., Shepherd R. M., Squires P. E., Johnson P. R., James R. F., Milla P. J., Aynsley-Green A., Lindley K. J., Dunne M. J. Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med. 1996 Dec;2(12):1344–1347. doi: 10.1038/nm1296-1344. [DOI] [PubMed] [Google Scholar]
  23. Koh T. H., Aynsley-Green A., Tarbit M., Eyre J. A. Neural dysfunction during hypoglycaemia. Arch Dis Child. 1988 Nov;63(11):1353–1358. doi: 10.1136/adc.63.11.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koh T. H., Eyre J. A., Aynsley-Green A. Neonatal hypoglycaemia--the controversy regarding definition. Arch Dis Child. 1988 Nov;63(11):1386–1388. doi: 10.1136/adc.63.11.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Labrune P., Lechevallier S., Rault M., Odievre M. Diabetes mellitus 14 years after a subtotal pancreatectomy for neonatal hyperinsulinism. J Pediatr Surg. 1990 Dec;25(12):1246–1247. doi: 10.1016/0022-3468(90)90519-f. [DOI] [PubMed] [Google Scholar]
  26. Leibowitz G., Glaser B., Higazi A. A., Salameh M., Cerasi E., Landau H. Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: high incidence of diabetes mellitus and persistent beta-cell dysfunction at long-term follow-up. J Clin Endocrinol Metab. 1995 Feb;80(2):386–392. doi: 10.1210/jcem.80.2.7852494. [DOI] [PubMed] [Google Scholar]
  27. Levitt Katz L. E., Satin-Smith M. S., Collett-Solberg P., Thornton P. S., Baker L., Stanley C. A., Cohen P. Insulin-like growth factor binding protein-1 levels in the diagnosis of hypoglycemia caused by hyperinsulinism. J Pediatr. 1997 Aug;131(2):193–199. doi: 10.1016/s0022-3476(97)70153-7. [DOI] [PubMed] [Google Scholar]
  28. Lindley K. J., Dunne M. J., Kane C., Shepherd R. M., Squires P. E., James R. F., Johnson P. R., Eckhardt S., Wakeling E., Dattani M. Ionic control of beta cell function in nesidioblastosis. A possible therapeutic role for calcium channel blockade. Arch Dis Child. 1996 May;74(5):373–378. doi: 10.1136/adc.74.5.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. MacFarlane W. M., Chapman J. C., Shepherd R. M., Hashmi M. N., Kamimura N., Cosgrove K. E., O'Brien R. E., Barnes P. D., Hart A. W., Docherty H. M. Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy. J Biol Chem. 1999 Nov 26;274(48):34059–34066. doi: 10.1074/jbc.274.48.34059. [DOI] [PubMed] [Google Scholar]
  30. Mathew P. M., Young J. M., Abu-Osba Y. K., Mulhern B. D., Hammoudi S., Hamdan J. A., Sa'di A. R. Persistent neonatal hyperinsulinism. Clin Pediatr (Phila) 1988 Mar;27(3):148–151. doi: 10.1177/000992288802700307. [DOI] [PubMed] [Google Scholar]
  31. Meissner T., Brune W., Mayatepek E. Persistent hyperinsulinaemic hypoglycaemia of infancy: therapy, clinical outcome and mutational analysis. Eur J Pediatr. 1997 Oct;156(10):754–757. doi: 10.1007/s004310050706. [DOI] [PubMed] [Google Scholar]
  32. Micic D., Casabiell X., Gualillo O., Pombo M., Dieguez C., Casanueva F. F. Growth hormone secretagogues: the clinical future. Horm Res. 1999;51 (Suppl 3):29–33. doi: 10.1159/000053159. [DOI] [PubMed] [Google Scholar]
  33. Milner R. D. Nesidioblastosis unravelled. Arch Dis Child. 1996 May;74(5):369–372. doi: 10.1136/adc.74.5.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Moncrieff M. W., Lacey K. A., Malleson P. N. Management of prolonged hypoglycaemia in Beckwith's syndrome. Postgrad Med J. 1977 Mar;53(617):159–161. doi: 10.1136/pgmj.53.617.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Morris A. A., Thekekara A., Wilks Z., Clayton P. T., Leonard J. V., Aynsley-Green A. Evaluation of fasts for investigating hypoglycaemia or suspected metabolic disease. Arch Dis Child. 1996 Aug;75(2):115–119. doi: 10.1136/adc.75.2.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Otonkoski T., Ammälä C., Huopio H., Cote G. J., Chapman J., Cosgrove K., Ashfield R., Huang E., Komulainen J., Ashcroft F. M. A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. Diabetes. 1999 Feb;48(2):408–415. doi: 10.2337/diabetes.48.2.408. [DOI] [PubMed] [Google Scholar]
  37. Rahier J., Fält K., Müntefering H., Becker K., Gepts W., Falkmer S. The basic structural lesion of persistent neonatal hypoglycaemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of B cells? Diabetologia. 1984 Apr;26(4):282–289. doi: 10.1007/BF00283651. [DOI] [PubMed] [Google Scholar]
  38. Ryan F., Devaney D., Joyce C., Nestorowicz A., Permutt M. A., Glaser B., Barton D. E., Thornton P. S. Hyperinsulinism: molecular aetiology of focal disease. Arch Dis Child. 1998 Nov;79(5):445–447. doi: 10.1136/adc.79.5.445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sener A., Malaisse-Lagae F., Malaisse W. J. Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5460–5464. doi: 10.1073/pnas.78.9.5460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Shepherd R. M., Cosgrove K. E., O'Brien R. E., Barnes P. D., Ammälä C., Dunne M. J. Hyperinsulinism of infancy: towards an understanding of unregulated insulin release. European Network for Research into Hyperinsulinism in Infancy. Arch Dis Child Fetal Neonatal Ed. 2000 Mar;82(2):F87–F97. doi: 10.1136/fn.82.2.F87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Soltész G., Aynsley-Green A. Hyperinsulinism in infancy and childhood. Ergeb Inn Med Kinderheilkd. 1984;51:151–202. doi: 10.1007/978-3-642-69070-9_4. [DOI] [PubMed] [Google Scholar]
  42. Soltész G., Jenkins P. A., Aynsley-Green A. Hyperinsulinaemic hypoglycaemia in infancy and childhood: a practical approach to diagnosis and medical treatment based on experience of 18 cases. Acta Paediatr Hung. 1984;25(4):319–332. [PubMed] [Google Scholar]
  43. Stanley C. A., Lieu Y. K., Hsu B. Y., Burlina A. B., Greenberg C. R., Hopwood N. J., Perlman K., Rich B. H., Zammarchi E., Poncz M. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998 May 7;338(19):1352–1357. doi: 10.1056/NEJM199805073381904. [DOI] [PubMed] [Google Scholar]
  44. Thornton P. S., Satin-Smith M. S., Herold K., Glaser B., Chiu K. C., Nestorowicz A., Permutt M. A., Baker L., Stanley C. A. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. J Pediatr. 1998 Jan;132(1):9–14. doi: 10.1016/s0022-3476(98)70477-9. [DOI] [PubMed] [Google Scholar]
  45. Touati G., Poggi-Travert F., Ogier de Baulny H., Rahier J., Brunelle F., Nihoul-Fekete C., Czernichow P., Saudubray J. M. Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr. 1998 Aug;157(8):628–633. doi: 10.1007/s004310050900. [DOI] [PubMed] [Google Scholar]
  46. de Lonlay-Debeney P., Poggi-Travert F., Fournet J. C., Sempoux C., Dionisi Vici C., Brunelle F., Touati G., Rahier J., Junien C., Nihoul-Fékété C. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med. 1999 Apr 15;340(15):1169–1175. doi: 10.1056/NEJM199904153401505. [DOI] [PubMed] [Google Scholar]
  47. de Lonlay P., Fournet J. C., Rahier J., Gross-Morand M. S., Poggi-Travert F., Foussier V., Bonnefont J. P., Brusset M. C., Brunelle F., Robert J. J. Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest. 1997 Aug 15;100(4):802–807. doi: 10.1172/JCI119594. [DOI] [PMC free article] [PubMed] [Google Scholar]

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