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Persistent Hyperinsulinemic Hypoglycemia

  • Chapter
Inborn Metabolic Diseases

Abstract

Hyperinsulinism can occur throughout childhood but is most common in infancy. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the most important cause of hypoglycemia in early infancy. The excessive secretion of insulin is responsible for profound hypoglycemia and requires aggressive treatment to prevent severe and irreversible brain damage. Onset can be in the neonatal period or later, with the severity of hypoglycemia decreasing with age. PHHI is a heterogeneous disorder with two histopathological lesions, diffuse (DiPHHI) and focal (FoPHHI), which are clinically indistinguishable. FoPHHI is sporadic and characterized by somatic islet-cell hyperplasia. DiPHHI corresponds to a functional abnormality of insulin secretion in the whole pancreas and is most often recessive although rare dominant forms can occur, usually outside the newborn period. Differentiation between focal and diffuse lesions is important because the therapeutic approach and genetic counselling differ radically. PET scanning with 18-fluoro-dopa can distinguish between focal and diffuse PHHI. A combination of glucose and glucagon is started as an emergency treatment as soon as a tentative diagnosis of PHHI is made. This is followed by diazoxide and other medication. Patients who are resistant to medical treatment require pancreatectomy; FoPHHI can be definitively cured by a limited pancreatectomy, but DiPHHI requires a subtotal pancreatectomy, following which there is a high risk of diabetes mellitus. Persistent hyperinsulinism in older children is most commonly caused by pancreatic adenoma.

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References

  1. Stanley CA (1997) Hyperinsulinism in infants and children. Pediatr Clin North Am 44:363–374

    Article  PubMed  CAS  Google Scholar 

  2. Thomas CG Jr, Underwood LE, Carney CN et al (1977) Neonatal and infantile hypoglycemia due to insulin excess: new aspects of diagnosis and surgical management. Ann Surg 185:505–517

    PubMed  Google Scholar 

  3. Touati G, Poggi-Travert F, Ogier de Baulny H et al (1998) Longterm treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr 157:628–633

    Article  PubMed  CAS  Google Scholar 

  4. de Lonlay P, Cormier-Daire V, Fournet JC et al (2002) Facial dysmorphism in persistent hyperinsulinemic hypoglycemia. Am J Med Genet 111:130–133

    Article  PubMed  Google Scholar 

  5. de Lonlay P, Cuer M, Barrot S et al (1999) Hyperinsulinemic hypoglycemia as presenting symptom of carbohydrate-deficiency glycoproteins. J Pediatr 135:379–383

    Article  PubMed  Google Scholar 

  6. Raizen DM, Brooks-Kayal A, Steinkrauss L et al (2005) Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 146:388–394

    Article  PubMed  CAS  Google Scholar 

  7. Otonkoski T, Kaminen N, Ustinov J et al (2003) Physical exerciseinduced hyperinsulinemic hypoglycemia is an autosomal-dominant trait characterized by abnormal pyruvate-induced insulin release. Diabetes 52:199–204

    PubMed  CAS  Google Scholar 

  8. Hojlund K, Hansen T, Lajer M et al (2004) A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene. Diabetes 53:1592–1598

    PubMed  CAS  Google Scholar 

  9. Dunne MJ, Cosgrove KE, Shepherd RM et al (2004) Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 84:239–275

    Article  PubMed  CAS  Google Scholar 

  10. Thomas PM, Cote GJ, Wohllk N et al (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268:426–429

    PubMed  CAS  Google Scholar 

  11. Nestorowicz A, Wilson BA, Schoor KP et al (1996) Mutations in the sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 5:1813–822

    Article  PubMed  CAS  Google Scholar 

  12. Thomas P, Ye Y, Lightner E (1996) Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 5:1809–1812

    Article  PubMed  CAS  Google Scholar 

  13. Nestorowicz A, Inagaki N, Gonoi T et al (1997) A nonsense mutation in the inward rectifier potassium chaannel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 46:1743–1748

    PubMed  CAS  Google Scholar 

  14. Glaser B, Kesavan P, Heyman M et al (1998) Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338:226–230

    Article  PubMed  CAS  Google Scholar 

  15. Stanley CA, Lieu Y, Hsu B et al (1998) Hyperinsulinemia and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352–1357

    Article  PubMed  CAS  Google Scholar 

  16. Clayton PT, Eaton S, Aynsley-Green A et al (2001) Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 108:457–465

    Article  PubMed  CAS  Google Scholar 

  17. Thornton PS, Sumner AE, Ruchelli ED et al (1991) Familial and sporadic hyperinsulinism: histopathological findings and segregation analysis support a single autosomal recessive disorder. J Pediatr 119:721–724

    Article  PubMed  CAS  Google Scholar 

  18. de Lonlay P, Fournet JC, Rahier J et al (1997) Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyper plasia and endorses partial pancreatectomy. J Clin Invest 100:802–807

    Article  PubMed  Google Scholar 

  19. Verkarre V, Fournet JC, de Lonlay P et al (1998) Maternal allele loss with somatic reduction to homozygosity of the paternally-inherited mutation of the SUR1 gene leads to congenital hyperinsulinism in focal islet cell adenomatous hyperplasia of the pancreas. J Clin Invest 102:1286–1291

    PubMed  CAS  Google Scholar 

  20. Huopio H, Otonkosko T, Vauhkomen I et al (2003) A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 361:301–307

    Article  PubMed  CAS  Google Scholar 

  21. Larsson C, Skogseid B, Oberg K et al (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332:85–87

    Article  PubMed  CAS  Google Scholar 

  22. Demeure MJ, Klonoff DC, Karam JH et al (1991) Insulinomas associated with multiple endocrine neoplasia type 1: the need for a different surgical approach. Surgery 110:998–1004

    PubMed  CAS  Google Scholar 

  23. Bassett JH, Forbes SA, Pannett AA et al (1998) Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62:232–244

    Article  PubMed  CAS  Google Scholar 

  24. Agarwal SK, Kester MB, Debelenko LV et al (1997) Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 6:1169–1175

    Article  PubMed  CAS  Google Scholar 

  25. Guru SC, Goldsmith PK, Burns AL et al (1998) Menin, the product of the MEN1 gene, is a nuclear protein. Proc Natl Acad Sci USA 95:1630–1634

    Article  PubMed  CAS  Google Scholar 

  26. Patel P, O’Rahilly S, Buckle V et al (1990) Chromosome 11 allele loss in sporadic insulinoma. J Clin Pathol 43:377–378

    PubMed  CAS  Google Scholar 

  27. Kim H, Kerr A, Morehouse H (1995) The association between tuberous sclerosis and insulinoma. Am J Neuroradiol 16:1543–1544

    PubMed  CAS  Google Scholar 

  28. Stanley CA, Baker L (1976) Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics 57:702–711

    PubMed  CAS  Google Scholar 

  29. Sempoux C, Guiot Y, Lefevre A et al (1998) Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab 83:1455–1461

    Article  PubMed  CAS  Google Scholar 

  30. Klöppel G. (1997) Nesidioblastosis. In: Soleia E, Capella C, Klöppel G (eds) Tumors of the pancreas. AFIP, Washington, pp 238–243

    Google Scholar 

  31. Goossens A, Gepts W, Saudubray JM et al (1989) Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 3:766–775

    Article  Google Scholar 

  32. Goudswaard WB, Houthoff HJ, Koudstaal J et al (1986) Nesidioblastosis and endocrine hyperplasia of the pancreas: a secondary phenomenon. Hum Pathol 17:46–53

    PubMed  CAS  Google Scholar 

  33. Rahier J, Fält K, Müntefering H et al (1984) The basic structural lesion of persistent neonatal hypoglycaemia with hyperinsulinism: deficiency of pancreatic D cells or hyperactivity of B cells? Diabetologia 26:282–289

    Article  PubMed  CAS  Google Scholar 

  34. Jaffé R, Hashida Y, Yunis EJ (1980) Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Lab Invest 42:356–365

    PubMed  Google Scholar 

  35. Rahier J, Sempoux C, Fournet JC et al 1998) Partial or near-total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycaemia: the pathologist’s role. Histopathology 32:15–19

    Article  PubMed  CAS  Google Scholar 

  36. Lyonnet S, Bonnefont JP, Saudubray JM et al (1989) Localisation of focal lesion permitting partial pancreatectomy in infants. Lancet 2:671

    Article  PubMed  CAS  Google Scholar 

  37. Brunelle F, Negre V, Barth MO et al (1989) Pancreatic venous samplings in infants and children with primary hyperinsulinism. Pediatr Radiol 19:100–103

    Article  PubMed  CAS  Google Scholar 

  38. Dubois J, Brunelle F, Touati G et al (1995) Hyperinsulinism in children: diagnostic value of pancreatic venous sampling correlated with clinical, pathological and surgical outcome in 25 cases. Pediatr Radiol 25:512–516

    Article  PubMed  CAS  Google Scholar 

  39. Santiago-Ribeiro MJ, de Lonlay P, Delzescaux T et al (2005) Noninvasive differential diagnosis of hyperinsulinism of infancy using positron emission tomography and [18F]-fluoro-L-DOPA. J Nucl Med 46:560–566

    Google Scholar 

  40. Stanley CA, Thornton PS, Ganguly A et al (2004) Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab 89:288–296

    Article  PubMed  CAS  Google Scholar 

  41. Giurgea I, Laborde K, Touati G et al (2004) Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism. J Clin Endocrinol Metab 89:925–929

    Article  PubMed  CAS  Google Scholar 

  42. Thornthon PS, Alter CA, Levitt Katz LE et al (1993) Short-and long term use of octreotide in the tretment of congenital hyperinsulinism. J Pediatr 123:637–643

    Article  Google Scholar 

  43. Shilyanski J, Fisher S, Cutz E et al (1997) Is 95% pancreatectomy the procedure of choice for treatment of persistent hyperinslininemic hypoglycemia of the neonate? J Pediatr Surg 32:342–346

    Article  Google Scholar 

  44. de Lonlay-Debeney P, Poggi-Travert F, Fournet JC et al (1999) Clinical aspects and course of neonatal hyperinsulinism. N Engl J Med 340:1169–1175

    Article  PubMed  Google Scholar 

  45. Menni P, de Lonlay P, Sevin C et al (2001) Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 107:476–479

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Unité de Métabolisme, Département de Pédiatrie, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75743, Paris Cedex 15, France

    Pascale de Lonlay

  2. Unité de Métabolisme, Département de Pédiatrie, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75043, Paris Cedex 15, France

    Jean-Marie Saudubray

Authors
  1. Pascale de Lonlay
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  2. Jean-Marie Saudubray
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Editor information

Editors and Affiliations

  1. Department of Pediatrics, University Hospital Groningen, Burgemeester Weertslaan 31, 8162 DP, Epe, The Netherlands

    John Fernandes

  2. Unité de Métabolisme, Département de Pédiatrie, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75043, Paris Cedex 15, France

    Jean-Marie Saudubray

  3. Metabolic Research Group, Christian de Duve Institute of Cellular Pathology, University of Louvain Medical School, Avenue Hippocrate 75-39, 1200, Brussels, Belgium

    Georges van den Berghe

  4. Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester, M27 4HA, UK

    John H. Walter

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© 2006 Springer Medizin Verlag Heidelberg

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de Lonlay, P., Saudubray, JM. (2006). Persistent Hyperinsulinemic Hypoglycemia. In: Fernandes, J., Saudubray, JM., van den Berghe, G., Walter, J.H. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg . https://doi.org/10.1007/978-3-540-28785-8_10

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  • DOI: https://doi.org/10.1007/978-3-540-28785-8_10

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-28783-4

  • Online ISBN: 978-3-540-28785-8

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