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Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy

Agneta Sunehag, MD, PhD
Morey W Haymond, MD
Section Editor
Joseph I Wolfsdorf, MB, BCh
Deputy Editor
Alison G Hoppin, MD


Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also referred to as congenital hyperinsulinism, familial hyperinsulinemic hypoglycemia, and primary islet cell hypertrophy (nesidioblastosis), is the most common cause of persistent hypoglycemia in neonates and infants. PHHI is a genetic disorder with both familial and sporadic forms, characterized by dysregulation of insulin secretion. Early recognition, diagnosis, and treatment are necessary to prevent or minimize neurologic damage from recurrent or prolonged episodes of hypoglycemia.

PHHI is a clinically and genetically heterogeneous disorder [1-4]. The clinical manifestations range from life-threatening hypoglycemia presenting on the first day of life to only mildly symptomatic hypoglycemia in a child or adolescent that may be difficult to identify. The response to medical and surgical therapy also varies [1-3].

An overview of the pathology, genetics, clinical features, and diagnosis of PHHI will be presented here. The treatment and complications of PHHI and a review on islet cell tumors (insulinomas), which have similar clinical and biochemical features to PHHI, are discussed in more detail separately. (See "Treatment and complications of persistent hyperinsulinemic hypoglycemia of infancy" and "Insulinoma".)


The incidence of PHHI in individuals of northern European extraction is approximately 1:30,000 live births [1,3]. The incidence is increased in genetically isolated populations with a high prevalence of consanguinity or a founder effect (eg, 1:2675 in Saudi Arabia and 1:3200 in central Finland) [5,6].


When the plasma glucose concentration decreases to below 60 mg/dL (3.3 mmol/L) in children who do not have PHHI, only small amounts of insulin are secreted. In children who have PHHI, the normal relationship between plasma glucose concentration and insulin secretion is disturbed, so that insulin is released even during periods of hypoglycemia. This disturbance of the normal feedback relationship between the plasma glucose concentration and insulin secretion can be caused by a variety of genetic mutations, as discussed below, most commonly by mutations causing abnormal function or regulation of the ATP-dependent potassium (KATP) channel of the pancreatic beta cells (figure 1) [7-9]. Other mutations interfere with the function or regulation of glutamate dehydrogenase, which is necessary for normal control of insulin secretion.

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Literature review current through: Oct 2017. | This topic last updated: Jul 11, 2016.
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  1. Fournet JC, Junien C. The genetics of neonatal hyperinsulinism. Horm Res 2003; 59 Suppl 1:30.
  2. Meissner T, Mayatepek E. Clinical and genetic heterogeneity in congenital hyperinsulinism. Eur J Pediatr 2002; 161:6.
  3. de Lonlay P, Fournet JC, Touati G, et al. Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases. Eur J Pediatr 2002; 161:37.
  4. Nestorowicz A, Glaser B, Wilson BA, et al. Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet 1998; 7:1119.
  5. Mathew PM, Young JM, Abu-Osba YK, et al. Persistent neonatal hyperinsulinism. Clin Pediatr (Phila) 1988; 27:148.
  6. Otonkoski T, Ammälä C, Huopio H, et al. A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. Diabetes 1999; 48:408.
  7. Huopio H, Shyng SL, Otonkoski T, Nichols CG. K(ATP) channels and insulin secretion disorders. Am J Physiol Endocrinol Metab 2002; 283:E207.
  8. 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.
  9. Stanley CA. Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. J Clin Endocrinol Metab 2016; 101:815.
  10. Dunne MJ, Kane C, Shepherd RM, et al. Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997; 336:703.
  11. Kane C, Lindley KJ, Johnson PR, et al. Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of beta cells to diazoxide and somatostatin. J Clin Invest 1997; 100:1888.
  12. Shyng SL, Ferrigni T, Shepard JB, et al. Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes 1998; 47:1145.
  13. Nestorowicz A, Inagaki N, Gonoi T, et al. A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 1997; 46:1743.
  14. Sharma N, Crane A, Gonzalez G, et al. Familial hyperinsulinism and pancreatic beta-cell ATP-sensitive potassium channels. Kidney Int 2000; 57:803.
  15. Flanagan SE, Kapoor RR, Hussain K. Genetics of congenital hyperinsulinemic hypoglycemia. Semin Pediatr Surg 2011; 20:13.
  16. GeneReviews monograph on Familial Hyperinsulinism, available at:: http://www.ncbi.nlm.nih.gov/books/NBK1375/ (Accessed on July 06, 2016).
  17. González-Barroso MM, Giurgea I, Bouillaud F, et al. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion. PLoS One 2008; 3:e3850.
  18. Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996; 5:1809.
  19. Kukuvitis A, Deal C, Arbour L, Polychronakos C. An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. J Clin Endocrinol Metab 1997; 82:1192.
  20. Thornton PS, Satin-Smith MS, Herold K, et al. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. J Pediatr 1998; 132:9.
  21. Huopio H, Reimann F, Ashfield R, et al. Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 2000; 106:897.
  22. Huopio H, Otonkoski T, Vauhkonen I, et al. A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 2003; 361:301.
  23. Alexandrescu S, Tatevian N, Olutoye O, Brown RE. Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. Int J Clin Exp Pathol 2010; 3:691.
  24. Nestorowicz A, Wilson BA, Schoor KP, et al. Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 1996; 5:1813.
  25. Tanizawa Y, Matsuda K, Matsuo M, et al. Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. Diabetes 2000; 49:114.
  26. Ohkubo K, Nagashima M, Naito Y, et al. Genotypes of the pancreatic beta-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy. Clin Endocrinol (Oxf) 2005; 62:458.
  27. Pinney SE, MacMullen C, Becker S, et al. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 2008; 118:2877.
  28. Flanagan SE, Kapoor RR, Banerjee I, et al. Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. Clin Genet 2011; 79:582.
  29. de Lonlay P, Fournet JC, Rahier J, et al. 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; 100:802.
  30. Verkarre V, Fournet JC, de Lonlay P, et al. Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 1998; 102:1286.
  31. Fournet JC, Mayaud C, de Lonlay P, et al. Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Am J Pathol 2001; 158:2177.
  32. Kassem SA, Ariel I, Thornton PS, et al. p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy. Diabetes 2001; 50:2763.
  33. Sempoux C, Guiot Y, Dahan K, et al. The focal form of persistent hyperinsulinemic hypoglycemia of infancy: morphological and molecular studies show structural and functional differences with insulinoma. Diabetes 2003; 52:784.
  34. 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.
  35. Stanley CA. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 2004; 81 Suppl 1:S45.
  36. De Lonlay P, Benelli C, Fouque F, et al. Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. Pediatr Res 2001; 50:353.
  37. Hsu BY, Kelly A, Thornton PS, et al. Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism/hyperammonemia syndrome. J Pediatr 2001; 138:383.
  38. Huijmans JG, Duran M, de Klerk JB, et al. Functional hyperactivity of hepatic glutamate dehydrogenase as a cause of the hyperinsulinism/hyperammonemia syndrome: effect of treatment. Pediatrics 2000; 106:596.
  39. Raizen DM, Brooks-Kayal A, Steinkrauss L, et al. Central nervous system hyperexcitability associated with glutamate dehydrogenase gain of function mutations. J Pediatr 2005; 146:388.
  40. Bahi-Buisson N, Roze E, Dionisi C, et al. Neurological aspects of hyperinsulinism-hyperammonaemia syndrome. Dev Med Child Neurol 2008; 50:945.
  41. Stanley CA, Fang J, Kutyna K, et al. Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators. Diabetes 2000; 49:667.
  42. Fourtner SH, Stanley CA, Kelly A. Protein-sensitive hypoglycemia without leucine sensitivity in hyperinsulinism caused by K(ATP) channel mutations. J Pediatr 2006; 149:47.
  43. Matschinsky F, Liang Y, Kesavan P, et al. Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest 1993; 92:2092.
  44. Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998; 338:226.
  45. Kassem S, Bhandari S, Rodríguez-Bada P, et al. Large islets, beta-cell proliferation, and a glucokinase mutation. N Engl J Med 2010; 362:1348.
  46. Cuesta-Muñoz AL, Huopio H, Otonkoski T, et al. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes 2004; 53:2164.
  47. Wabitsch M, Lahr G, Van de Bunt M, et al. Heterogeneity in disease severity in a family with a novel G68V GCK activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy. Diabet Med 2007; 24:1393.
  48. Pinney SE, Ganapathy K, Bradfield J, et al. Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr 2013; 80:18.
  49. Kapoor RR, James C, Flanagan SE, et al. 3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. J Clin Endocrinol Metab 2009; 94:2221.
  50. Clayton PT, Eaton S, Aynsley-Green A, et al. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest 2001; 108:457.
  51. Molven A, Matre GE, Duran M, et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 2004; 53:221.
  52. Stanescu DE, Hughes N, Kaplan B, et al. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab 2012; 97:E2026.
  53. Pearson ER, Boj SF, Steele AM, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007; 4:e118.
  54. Flanagan SE, Kapoor RR, Mali G, et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol 2010; 162:987.
  55. Otonkoski T, Jiao H, Kaminen-Ahola N, et al. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet 2007; 81:467.
  56. van Hasselt PM, Ferdinandusse S, Monroe GR, et al. Monocarboxylate transporter 1 deficiency and ketone utilization. N Engl J Med 2014; 371:1900.
  57. Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 2014; 370:533.
  58. Goudswaard WB, Houthoff HJ, Koudstaal J, Zwierstra RP. Nesidioblastosis and endocrine hyperplasia of the pancreas: a secondary phenomenon. Hum Pathol 1986; 17:46.
  59. Jaffe R, Hashida Y, Yunis EJ. Pancreatic pathology in hyperinsulinemic hypoglycemia of infancy. Lab Invest 1980; 42:356.
  60. Rahier J. Relevance of endocrine pancreas nesidioblastosis to hyperinsulinemic hypoglycemia. Diabetes Care 1989; 12:164.
  61. de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, et al. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999; 340:1169.
  62. Meissner T, Wendel U, Burgard P, et al. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 2003; 149:43.
  63. Schwitzgebel VM, Gitelman SE. Neonatal hyperinsulinism. Clin Perinatol 1998; 25:1015.
  64. Hoe FM, Thornton PS, Wanner LA, et al. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr 2006; 148:207.
  65. Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in infancy and childhood: when an insulin level is not always enough. Clin Chem 2008; 54:256.
  66. Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000; 82:F98.
  67. Aynsley-Green A, Polak JM, Bloom SR, et al. Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycaemia. Arch Dis Child 1981; 56:496.
  68. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr 2015; 167:238.
  69. Glaser B, Landau H, Permutt MA. Neonatal Hyperinsulinism. Trends Endocrinol Metab 1999; 10:55.
  70. Service FJ, O'Brien PC, McMahon MM, Kao PC. C-peptide during the prolonged fast in insulinoma. J Clin Endocrinol Metab 1993; 76:655.
  71. Ferrara C, Patel P, Becker S, et al. Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children. J Pediatr 2016; 168:212.
  72. Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics 1976; 57:702.
  73. Wolfsdorf JI, Sadeghi-Nejad A, Senior B. Ketonuria does not exclude hyperinsulinemic hypoglycemia. Am J Dis Child 1984; 138:168.
  74. Wildenhoff KE. The renal excretion of acetoacetate and 3-hydroxybutyrate during absolute fasting. Acta Med Scand 1972; 192:475.
  75. Kelly A, Tang R, Becker S, Stanley CA. Poor specificity of low growth hormone and cortisol levels during fasting hypoglycemia for the diagnoses of growth hormone deficiency and adrenal insufficiency. Pediatrics 2008; 122:e522.
  76. Stanley CA, Baker L. Hyperinsulinism in infants and children: diagnosis and therapy. Adv Pediatr 1976; 23:315.
  77. Bianchi C, Corbella E, Beccaria L, et al. A case of familial nesidioblastosis: prenatal diagnosis of foetal hyperinsulinism. Acta Paediatr 1992; 81:853.
  78. Aparicio L, Carpenter MW, Schwartz R, Gruppuso PA. Prenatal diagnosis of familial neonatal hyperinsulinemia. Acta Paediatr 1993; 82:683.
  79. Meintjes M, Endozo R, Dickson J, et al. 18F-DOPA PET and enhanced CT imaging for congenital hyperinsulinism: initial UK experience from a technologist's perspective. Nucl Med Commun 2013; 34:601.
  80. Blomberg BA, Moghbel MC, Saboury B, et al. The value of radiologic interventions and (18)F-DOPA PET in diagnosing and localizing focal congenital hyperinsulinism: systematic review and meta-analysis. Mol Imaging Biol 2013; 15:97.
  81. Treglia G, Mirk P, Giordano A, Rufini V. Diagnostic performance of fluorine-18-dihydroxyphenylalanine positron emission tomography in diagnosing and localizing the focal form of congenital hyperinsulinism: a meta-analysis. Pediatr Radiol 2012; 42:1372.
  82. Capito C, Khen-Dunlop N, Ribeiro MJ, et al. Value of 18F-fluoro-L-dopa PET in the preoperative localization of focal lesions in congenital hyperinsulinism. Radiology 2009; 253:216.
  83. Arsenault DA, Potemkin AK, Robinson EM, et al. Surgical intervention in the setting of parenteral nutrition-associated cholestasis may exacerbate liver injury. J Pediatr Surg 2011; 46:122.
  84. Masue M, Nishibori H, Fukuyama S, et al. Diagnostic accuracy of [¹⁸F]-fluoro-L-dihydroxyphenylalanine positron emission tomography scan for persistent congenital hyperinsulinism in Japan. Clin Endocrinol (Oxf) 2011; 75:342.
  85. Hashimoto Y, Sakakibara A, Kawakita R, et al. Focal form of congenital hyperinsulinism clearly detectable by contrast-enhanced computed tomography imaging. Int J Pediatr Endocrinol 2015; 2015:20.
  86. Chigot V, De Lonlay P, Nassogne MC, et al. Pancreatic arterial calcium stimulation in the diagnosis and localisation of persistent hyperinsulinemic hypoglycaemia of infancy. Pediatr Radiol 2001; 31:650.
  87. Henwood MJ, Kelly A, Macmullen C, et al. Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes. J Clin Endocrinol Metab 2005; 90:789.
  88. Stanley CA, Thornton PS, Ganguly A, et al. 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 2004; 89:288.
  89. Giurgea I, Laborde K, Touati G, et al. Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism. J Clin Endocrinol Metab 2004; 89:925.
  90. Owen L, Ellis M, Shield J. Deliberate sulphonylurea poisoning mimicking hyperinsulinaemia of infancy. Arch Dis Child 2000; 82:392.
  91. Das CJ, Debnath J, Gupta AK, Das AK. MR imaging appearance of insulinoma in an infant. Pediatr Radiol 2007; 37:581.
  92. Geneviève D, Amiel J, Viot G, et al. Atypical findings in Kabuki syndrome: report of 8 patients in a series of 20 and review of the literature. Am J Med Genet A 2004; 129A:64.
  93. Alkhayyat H, Christesen HB, Steer J, et al. Mosaic Turner syndrome and hyperinsulinaemic hypoglycaemia. J Pediatr Endocrinol Metab 2006; 19:1451.
  94. Cappella M, Graziani V, Pragliola A, et al. Hyperinsulinemic Hypoglycaemia in a Turner Syndrome with Ring (X). Case Rep Pediatr 2015; 2015:561974.