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congenital hyperinsulinism

MIM.256450, MIM.601820

Saturday 24 April 2004

Congenital hyperinsulinism (CHI) is biochemically characterised by the dysregulated secretion of insulin from pancreatic beta-cells. It is a major cause of persistent hyperinsulinaemic hypoglycaemia (HH) in the newborn and infancy period.

Genetically CHI is a heterogeneous condition with mutations in seven different genes described. The genetic basis of CHI involves defects in key genes which regulate insulin secretion from beta-cells.

Recessive inactivating mutations in ABCC8 and KCNJ11 (which encode the two subunits of the adenosine triphosphate sensitive potassium channels (ATP sensitive K(ATP) channels)) in beta-cells are the most common cause of CHI.

The other recessive form of CHI is due to mutations in HADH (encoding for-3-hydroxyacyl-coenzyme A dehydrogenase).

Dominant forms of CHI are due to inactivating mutations in ABCC8 and KCNJ11, and activating mutations in GLUD1 (encoding glutamate dehydrogenase) and GCK (encoding glucokinase).

Recently dominant mutations in HNF4A (encoding hepatocyte nuclear factor 4alpha) and SLC16A1 (encoding monocarboxylate transporter 1) have been described which lead to HH.

Mutations in all these genes account for about 50% of the known causes of CHI.

Morphological types

Histologically there are three (possibly others which have not been characterised yet) major subtypes of CHI: diffuse, focal and atypical forms.

The diffuse form is inherited in an autosomal recessive (or dominant manner), the focal form being sporadic in inheritance.

The diffuse form of the disease may require a near total pancreatectomy whereas the focal form requires a limited pancreatectomy potentially curing the patient.

- diffuse CHI
- focal CHI


- KATP channel-associated hyperinsulinsm (KATP-CHI, ABCC8-CHI, KCNJ11-CHI)

  • focal adenomatous hyperinsulism (focal form)
  • diffuse hyperinsulinism
    • recessive diffuse hyperinsulinism
    • dominant diffuse hyperinsulinism (12941782, 11018078)

- hyperinsulinism/hyperammonemia syndrome (HI/HA or GDH-CHI)
- glucokinase-associated CHI (GK-CHI)
- SCHAD-associated CHI (short-chain 3-hydroxyacyl-CoA dehydrogenase) (SCHAD-CHI) (14693719)

- congenital disorders of glycosylation (CDGs)

  • hyperinsulinemic hypoglycemia in congenital disorder of glycosylation Ia (CDG-Ia)
  • hyperinsulinemic hypoglycemia in congenital disorder of glycosylation Ib (CDG-Ib) (12872847)


- The genetic basis of congenital hyperinsulinism. James C, Kapoor RR, Ismail D, Hussain K. J Med Genet. 2009 May;46(5):289-99. PMID: 19254908

- Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Kapoor RR, James C, Hussain K. Nat Clin Pract Endocrinol Metab. 2009 Feb;5(2):101-12. PMID: 19165222

- Hyperinsulinaemic hypoglycaemia. Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Arch Dis Child. 2009 Jun;94(6):450-7. PMID: 19193661

- Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ. Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev. 2004 Jan;84(1):239-75. PMID: 14715916

- de Lonlay P, Touati G, Robert JJ, Saudubray JM. Persistent hyperinsulinaemic hypoglycaemia. Semin Neonatol. 2002 Feb;7(1):95-100. PMID: 12069542


Clinical references

- Long-term follow-up of patients with congenital hyperinsulinism in Austria. Mercimek-Mahmutoglu S, Rami B, Feucht M, Herle M, Rittinger O, Stoeckler-Ipsiroglu S, Schober E. J Pediatr Endocrinol Metab. 2008 Jun;21(6):523-32. PMID: 18717238

- [18F]-DOPA positron emission tomography for preoperative localization in congenital hyperinsulinism. Mohnike K, Blankenstein O, Minn H, Mohnike W, Fuchtner F, Otonkoski T. Horm Res. 2008;70(2):65-72. PMID: 18547951

- Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon. Mohnike K, Blankenstein O, Pfuetzner A, P√∂tzsch S, Schober E, Steiner S, Hardy OT, Grimberg A, van Waarde WM. Horm Res. 2008;70(1):59-64. PMID: 18493152


- Greer RM, Shah J, Jeske YW, Brown D, Walker RM, Cowley D, Bowling FG, Liaskou D, Harris M, Thomsett MJ, Choong C, Bell JR, Jack MM, Cotterill AM. Genotype-phenotype associations in patients with severe hyperinsulinism of infancy. Pediatr Dev Pathol. 2007 Jan-Feb;10(1):25-34. PMID: 17378627

- Anlauf M, Wieben D, Perren A, Sipos B, Komminoth P, Raffel A, Kruse ML, Fottner C, Knoefel WT, Monig H, Heitz PU, Kloppel G. Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes. Am J Surg Pathol. 2005 Apr;29(4):524-33. PMID: 15767809

- Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED. Histopathology of congenital hyperinsulinism: retrospective study with genotype correlations. Pediatr Dev Pathol. 2003 Jul-Aug;6(4):322-33. PMID: 14692646


- Meissner T, Mayatepek E. Clinical and genetic heterogeneity in congenital hyperinsulinism. Eur J Pediatr. 2002 Jan;161(1):6-20. PMID: 11808881


- Laparoscopic vs open pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy. Al-Shanafey S. J Pediatr Surg. 2009 May;44(5):957-61. PMID: 19433178

- Surgical versus non-surgical treatment of congenital hyperinsulinism. Mazor-Aronovitch K, Landau H, Gillis D. Pediatr Endocrinol Rev. 2009 Mar;6(3):424-30. PMID: 19396028

- Laparoscopic pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy. Al-Shanafey S, Habib Z, AlNassar S. J Pediatr Surg. 2009 Jan;44(1):134-8; discussion 138. PMID: 19159730

- at CHOP, Philadelphia
- Congenital Hyperinsulism Center at CHOP, Philadelphia
- Hyperinsulinism at infancy by Dr Loke Kah Yin, National University of Singapore