Managing congenital hyperinsulinism: improving outcomes with a multidisciplinary approach

Figures & data

Table 1 Whipple’s triad of hypoglycemia

1. Low blood glucose 2. Signs/symptoms of hypoglycemia at the time of low blood glucose Lethargy, irritability, poor feeding, hunger, jitteriness, tachycardia, pallor, diaphoresis, hypothermia, altered mental status, seizure 3. Resolution of signs/symptoms after normalization of blood glucose

Table 2 Diagnostic fasting evaluation of hypoglycemia

1. Check blood glucose and beta-hydroxybutyrate (if possible) Every 3 hours until blood glucose <70 mg/dL (<3.9 mmol/L) Then every 1 hour until blood glucose <60 mg/dL (<3.3 mmol/L) Then every 30 minutes until blood glucose <50 mg/dL (<2.8 mmol/L) 2. when blood glucose <50 mg/dL (<2.8 mmol/L), obtain critical labs Plasma glucose Ketones (plasma beta-hydroxybutyrate, urinalysis) Electrolytes including bicarbonate insulin C-peptide Free fatty acids insulin-like growth factor binding protein-1 Growth hormone Cortisol Lactate Ammonia Free and total carnitine Acylcarnitine profile Urine organic acids 3. while blood glucose <50 mg/dL (<2.8 mmol/L), after critical labs have been drawn, give glucagon 1 mg intravenously or intramuscularly Check blood glucose every 10 minutes for 40 minutes unless patient becomes significantly symptomatic

Table 3 Laboratory findings consistent with HI

Glucose	<50 mg/dL (2.8 mmol/L)
Beta-hydroxybutyrate	<1.1 mmol/L
Free fatty acids	<0.5 mmol/L
IGFBP-1	< 125 ng/mL
Insulin	variable
C-peptide	variable
Glucagon stimulation test	Blood glucose increase of ≥30 mg/dL (1.7 mmol/L) within 40 minutes

Abbreviations: HI, hyperinsulinism; IGFBP-1, insulin-like growth factor-binding protein-1.

Table 4 Types of fasting studies

	Safety	Diagnostic	Cure
Duration (hours)
Neonates	6–12	18	18
Infants 1–12 months	12–18	24	24
Children > 1 year	18	36	36
Adolescents	18	72	72
Ending criteria
Blood glucose (mg/dL)	<65	<50	<50
BOHB (mmol/L)	≥2.5	≥2.5	≥2.5
Significant symptoms
Expected duration
Glucagon stimulation test if blood glucose <50 mg/dL	No	Yes	Yes
Labs to draw at end	None	All (see Table 2)	Glucose, BOHB, FFA, IGFBP-1, insulin, C-peptide

Abbreviations: BOHB, beta-hydroxybutyrate; FFA, free fatty acid; IGFBP-1, insulin-like growth factor-binding protein-1.

Table 5 Genetic causes of CHI

Gene	Protein	Chromosome	Diazoxide responsive	Focal or diffuse	Other clinical features
ABCC8, KCNJII	SUR1, KIR6.2	11p15			±protein sensitivity
Biallelic recessive			No	Diffuse
Monoallelic recessive			No	Typically focal	Typically paternally inherited
Monoallelic dominant			±	Diffuse	Typically maternally inherited
GLUDI, monoallelic dominant	GDH1	10q23.3	Yes	Diffuse	Protein sensitivity, hyperammonemia
GCK, monoallelic dominant	GK	7p15.3-p15.1	±	Diffuse	Hypoglycemia typically mild
HADH, biallelic recessive	SCHAD	4q22-q26	Yes	Diffuse	Protein sensitivity, abnormal acylcarnitine profile
SLCI6AI, monoallelic dominant	MCT1	1p12	±	Diffuse	Commonly exercise-induced hypoglycemia
UCP2, monoallelic dominant	UCP2	11q13	Yes	Diffuse	Transient HI resolves by 6 months to 6 years
HNFIA, monoallelic dominant	HNF1a	12q24.2	Yes	Diffuse	Transient HI resolves by 6 years, later development of MODY3
HNF4A, monoallelic dominant	HNF4a	20q13.12	Yes	Diffuse	Transient HI resolves by 4 years, later development of MODY1

Abbreviations: CHI, congenital hyperinsulinism; HI, hyperinsulinism; MODY, maturity onset diabetes of the young.

Figure 1 Multiple genetic mutations affect beta-cell insulin secretion in CHI.

Notes: Proteins with activating mutations that cause CHI are in

, and those with inactivating mutations are in

. Medications used to treat CHI are in

.

Abbreviations: CHI, congenital hyperinsulinism; SUR1, sulfonylurea receptor 1; KIR6.2, ATP-sensitive inward rectifier potassium channel 11 isoform 2; GLUT2, glucose transporter 2; GK, glucokinase; UCP2, uncoupling protein 2; SCHAD, short-chain hydroxyacyl-CoA dehydrogenase; GDH1, glutamate dehydrogenase 1; MCT1, monocarboxylate transporter 1; ATP, Adenosine triphosphate; ADP, Adenosine diphosphate.

Table 6 Medical management of HI

Medication	Mechanism of action	Typical dose	Side effects
Dextrose	Glucose source	IV 10%–50% dextrose, limit total fluid volume, use central access for > 12.5% dextrose Enteral ≤10 mg/kg/min continuous ×24 hours or overnight	Volume overload
Glucagon	Stimulates glycogenolysis and gluconeogenesis	1 mg intramuscularly or intravenously for acute hypoglycemia 1 mg/24 h continuous intravenously	Nausea
Diazoxide	Opens sulfonylurea receptor on beta-cells	5–15 mg/kg/day enterally divided bid	Salt and water retention, appetite suppression, hypertrichosis, hyperuricemia, bone marrow suppression
Octreotide	Somatostatin analog	5–17 μg/kg/day subcutaneously or intravenously, typically 2–3 doses/day or continuous	Tachyphylaxis, transaminitis, biliary sludging, hypothyroidism, growth retardation, necrotizing enterocolitis

Abbreviations: HI, hyperinsulinism; IV, intravenous; bid, twice daily.

Table 7 Recommended screening for chronic complications

	Frequency
Patients taking diazoxide
Complete blood count with differential	Annual
Basic metabolic panel	Annual
Uric acid	Annual
Patients taking octreotide
Hepatic function panel	Every 6 months
Thyroid function tests	Every 6 months
Growth factors (IGF-1, IGFBP-3)	Every 6 months
Liver/gallbladder ultrasound	Annual
Patients post near-total pancreatectomy
Fat-soluble vitamins (A, D, E, K)	Annual
Fecal elastase	Annual
Hemoglobin A1c	Annual
Oral glucose tolerance test	Annual
All patients with CHI
Neurodevelopmental assessment	12–18 months and 5 years of age

Abbreviations: IGF-1, insulin-like growth factor-1; IGFBP-3, insulin-like growth factor-binding protein-3; CHI, congenital hyperinsulinism.

Figure 2 Diagnostic and management algorithm for HI.

Note: ^aDepending on HI severity.
Abbreviations: HI, hyperinsulinism; GH, growth hormone; bid, twice daily; CHI, congenital hyperinsulinism; ¹⁸F-DOPA PET/CT, ¹⁸fluoro-l-dihydroxyphenylalanine positron emission tomography and computed tomography; GIR, glucose infusion rate; Px, pancreatectomy.