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Review
. 2017 Dec 30;9(Suppl 2):69-87.
doi: 10.4274/jcrpe.2017.S007. Epub 2017 Dec 27.

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Hüseyin Demirbilek  1 , Khalid Hussain  2
Affiliations
Review

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Hüseyin Demirbilek et al. J Clin Res Pediatr Endocrinol. .

Abstract

Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH.

Keywords: Hyperinsulinaemic hypoglycaemia; children; congenital hyperinsulinaemia; diffuse congenital hyperinsulinism; focal congenital hyperinsulinism sirolimus..

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Figures

Figure 1
Figure 1. Regulation of insulin release from pancreatic β-cell and sites of gene mutations involved in the genetics etiology of hyperinsulinaemic hypoglycaemia SUR1: sulphonlyurea receptor 1, Kir6.2: inwardly rectifying potassium channel 6.2, K: potassium, MCT1: monocarboxylate transporter 1, Glu: glucose, P: phosphorus; PGM1: phosphoglucomutase 1, PMM2: phosphomannose-mutase 2, UCP2: mitochondrial uncoupling protein 2, NH3: ammonia, GDH: glutamate dehydrogenase, GLUD1: glutamate dehydrogenase 1 gene, SCHAD: short-chain L-3-hydroxyacyl-CoA dehydrogenase, HADH: hydroxy-acyl-CoA dehydrogenase, HNF1A and 4A: hepatocyte nuclear factor 1A and 4A, Ca+2: calcium; GAD: glutamate decarboxylase enzyme, GABA: γ-aminobutyric acid, GLP1: glucagon like peptide 1, cAMP: cyclic adenosine monophosphate (amplifier for the exocytosis of insulin secreting granule)
Figure 2
Figure 2. A schematic representation of focal and diffuse congenital hyperinsulinism. In the focal disease (A), the β-cell hyperplasia is limited to a certain are of the pancreas gland with a superficial or deep localization or invades as a tentacle shape. In the diffuse disease (B) there is a global β-cell hyperplasia throughout the whole panreas
Figure 3
Figure 3. 18F-fluoro-L-dihydroxyphenylalanine (18F-DOPA)-positron emission tomography/computed tomography scan images of focal congenital hyperinsulinism (A and C), histological figure of diffuse (B) and focal (D) disease and normal pancreas islet cell (E). Standardized uptake value (SUV) 5.3 and SUV 5.7 indicate focal uptake of 18F-DOPA, red arrows show large nuclei of β-cell in diffuse disease
Figure 4
Figure 4. An algorithm for the diagnosis and management of hyperinsulinaemic hypoglycaemia HH: hyperinsulinaemic hypoglycaemia, IGFBP-1: insulin growth factor binding protein-1, HNF4A: hepatocyte nuclear factor 4A, ABCC8: ATP binding cassette subfamily C member 8, KCNJ11: potassium voltage-gated channel subfamily J member 11, GLUD1: glutamate dehydrogenase 1, HADH: hydroxyacyl-CoA dehydrogenase, LAR: long-acting release, IUGR: intrauterine growth restriction, CDG: congenital disorders of glycosylation, SGA: small for gestational age, 18F-DOPA-PET/CT: 18F-fluoro-L-dihydroxyphenylalanine-positron emission tomography/computed tomography
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