Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management

Abstract

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

Keywords: 18F-DOPA-PET; Hyperinsulinism; Hypoglycemia; Lanreotide; Sirolimus; Transition to adult services.

Fig. 1

Diagrammatic representation of β-cell function. Genetic defects associated with CHH are included in red. Postprandial glucose is taken into the β-cells via the glucose transporter 2 (GLUT2). Glucose then enters the glycolysis pathway followed by mitochondrial citric acid cycle (TCA) yielding the high-energy molecule, adenosine triphosphate (ATP). ATP molecules travel to and inhibit the potassium-dependent ATP channels (K_ATP), which prevents influx of potassium resulting in membrane depolarization. This triggers voltage-gated calcium channels to open and influx of calcium (Ca²⁺) occurs. The Ca²⁺ activates the enzyme phospholipase C (PLC) to produce inositol 1, 3, 5 triphosphate (IP₃) and diacylglycerol (DAG) from phosphatidyl 1, 3 bisphosphate (PIP₂). The IP3 molecule binds to the protein receptor on the endoplasmic reticulum (ER) to promote a release of Ca²⁺ from the ER. This subsequently increase in cytoplasmic Ca²⁺ promotes exocytosis of the pre-packaged mature insulin and active C-peptide, which are released into circulation. GLUT2: Glucose transporter 2; Glucokinase (GCK) encoded by GCK gene; ADP: Adenosine diphosphate; ATP: Adenosine triphosphate; Monocarboxylate transporter (MCT1) encoded by SLC16A1 gene; Glutamate dehydrogenase (GDH) encoded by GLUD1 gene; Uncoupling protein 2 (UCP2) encoded by UCP2 gene; L-3-hydroxyacyl-coenzyme A dehydrogenase (HADH) encoded by HADH gene; SUR1 subunit of the K_ATP channel encoded by the ABCC8 gene; Kir6.2 subunit of the K_ATP channel encoded by KCNJ11 gene; Hepatocyte nuclear factor 4α (HNF4α) encoded by HNF4A gene; Hepatocyte nuclear factor 1α (HNF1α) encoded by HNF1A gene; HK1: Hexokinase 1 encoded by the gene HK1; CACNA1D: calcium voltage-gated channel subunit alpha1 D. Mutations in Forkhead Box Protein A2 (FOXA2), Phosphoglucomutase 1 (PGM1) and Phosphomannomutase 2 (PMM2) are not included in the cartoon.

Fig. 2

Diffuse and focal form of HH with 18F-DOPA-PET-CT images. A – Diagrammatic representation of diffuse form of CHH and B – 18F-DOPA-PET image of diffuse form of CHH. C – Diagrammatic representation of focal form of CHH (showing different types of focal lesions) and D – 18F-DOPA-PET-CT image of focal lesion in the head of pancreas. SUV – Standardized uptake value.

Fig. 3

Flow chart of the stages in planning transition. Various factors should be considered before the young person is actually transitioned to adult services. The timing of transition is critical and should be individualized according to the assessment of the multi-disciplinary team. Box 1 Quotes from patients, carers and other family members on the ideal features of a transition clinic. Seeing older patients in clinic waiting areas who might be in the advanced stages of the same condition is scary. Understanding that there are other conditions in the same clinic, or that treatments have changed, helps to remove some of the fear. Young people are often used to being told off and will sometimes try to avoid this by simply not going to an appointment if they are running late. Knowing who they can contact can help prevent this. Will we see one of a team or a named Consultant? I’d like to see the same person for the first few appointments so that we can establish a good relationship.