Diagnosis of hyperinsulinism

Clues to diagnosis of hyperinsulinism

• Large for gestational age
• Severe, persistent hypoglycemic requiring high glucose infusion rate (GIR) (>8 mg/kg/min)
• Phenotype is variable, and some babies with HI have normal birth weights and lower GIR requirements

Laboratory findings at the time of hypoglycemia (plasma glucose < 50 mg/dL)

• Inappropriately low beta-hydroxybutyrate (<1.8 mmol/L) 
• Inappropriately low free fatty acids (<1.7 mmol/L) 
• +/- Detectable insulin (>2 uIU/mL) 
• +/- Detectable C-peptide (>0.5 ng/mL) 

Glucagon stimulation test

• When plasma glucose < 50 mg/dL administer 1 mg of glucagon IM or IV 
• Monitor plasma glucose every 10 minutes for 40 minutes; if there is no increase in plasma glucose by 20 minutes, terminate test and rescue with IV dextrose 
• A positive response is a rise of more than 30 mg/dL and indicates that the hypoglycemia is due to increased insulin action

Cautions in diagnosing HI

• Low cortisol and/or growth hormone at time of hypoglycemia is not diagnostic of cortisol or GH deficiency. Requires additional stimulation testing to prove cortisol or GH deficiency. 
• Insulin levels are not always elevated at the time of hypoglycemia in children with hyperinsulinism, but suppressed beta-hydroxybutyrate (and free fatty acids) and a positive response to glucagon are sufficient to make the diagnosis. 
• Children who have undergone a Nissen fundoplication or other gastric surgeries are at risk of postprandial hypoglycemia (“late dumping syndrome”) that is due to excessive insulin response to feeding and therefore could look like hyperinsulinism. Establishing the timing of the hypoglycemia in relationship with feedings is helpful to distinguish these cases. 

Medication trial

1st line therapy — 5-day trial of diazoxide (dosed 5-15 mg/kg/day)

• Wean GIR as tolerated to maintain plasma glucose >70 mg/dL
• After 5 days, attempt 8-18 hour (depending on the age of the child) safety fast off of IV dextrose ► if unable to fast, considered medical failure and should refer to CHOP (suggests KATP-HI)
• Side effects: fluid retention, hypertrichosis, neutropenia and thrombocytopenia. Neonates and infants require a diuretic, typically thiazide diuretic, to prevent fluid retention. Obtain ECHO prior to starting diazoxide.

If diazoxide failure, stop diazoxide and support plasma glucose with IV dextrose. Initiate glucagon infusion 1 mg/day if unable to maintain plasma glucose >70 mg/dL with IV dextrose alone.

• Do not use glucocorticoids to treat hyperinsulinism or unspecified hypoglycemia
• Do not use forced feeds or continuous feeds to control blood glucose (can develop feeding aversion)
• Octreotide, which is the 2nd-line therapy for HI, has been associated with necrotizing enterocolitis (NEC); for this reason, we do NOT recommend its usage before 2 months old

Genetic testing

• Any patient who fails diazoxide requires expedited genetic testing of ABCC8 and KCNJ11 to assess for the focal HI.
• Both the Hospital of the University of Pennsylvania or University of Chicago offer sequencing of these genes in 4-7 days.
  • For UPenn, please select tier 1 reflex tier 2 option.
  • For Chicago, please select tier 1 reflex Congenital Hyperinsulinism Panel.
• You should also should send parental samples (mother and father) at same time; Test 042- Parent testing
• For diazoxide responsive patients, consider sending comprehensive HI genetic testing.

To refer to CHOP

• Call 215-590-7682 and speak with a physician or APN.
• Refer a Patient with Congenital Hyperinsulinism

Other considerations

• Double-lumen PICC is recommended prior to transfer.
• Use higher concentrations of dextrose (D30 or D50) to reduce the risk of fluid overload. Their use requires a central line.

References

• Lord K, De León DD. Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. Int J Pediatr Endocrinol. 2013 Feb 6;2013(1):3.
• Palladino, AA., Stanley, CA. A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism. Semin Pediatr Surg. 20(1):32-7, 2011 Feb.
• De Leon DD, Arnoux JB, Banerjee I, Bergada I, et al. International guidelines for the diagnosis and management of hyperinsulinism. Horm Res Paediatr. 2024;97(3):279-298.