Laboratory Studies
All patients suspected of having hyperinsulinism should have blood obtained for measurement of concentrations of plasma glucose, insulin, proinsulin, C-peptide, growth hormone, cortisol, free fatty acids, and beta-hydroxybutyrate. Arterial blood gas (ABG) measurement and assessment of lactate, pyruvate, and alanine levels are also helpful. These studies should be performed while the patient is hypoglycemic. Because most patients in a metabolic crisis present to a general practitioner rather than to a pediatric endocrinologist, the undiagnosed patient is bemused when the practitioner obtains serum during the crisis. The practitioner should obtain 5-10 mL of whole blood in a plain red-top tube (without heparin) and instruct the laboratory to centrifuge the specimen to separate the serum for storage at -20°C within an hour of collection. This precious frozen serum from the time of the critical event can then be analyzed appropriately after consultation with the subspecialist.
A plasma insulin level higher than 2 µU/mL and a serum glucose concentration less than 60 mg/dL is diagnostic of hyperinsulinism; however, clearly elevated insulin levels are not always present at the time of hypoglycemia with hyperinsulinism. Suppressed beta-hydroxybutyrate (< 1 µmol/L) in conjunction with low levels of free fatty acids (< 1 µmol/L) during hypoglycemia may indicate hyperinsulinism. Infants with hyperinsulinism require unusually high rates of glucose infusion (>12 mg/kg/min compared with the physiologic rate of 6-8 mg/kg/min) to maintain glucose levels higher than 60 mg/dL. A glucose-to-insulin ratio below 3 and low concentrations of free fatty acids and ketones during hypoglycemia are highly suggestive of hyperinsulinism.
Finding low levels (< 120 ng/mL) of insulin-like growth factor binding protein-1 (IGFBP-1) may be useful. Insulin suppresses secretion of IGFBP-1, which normally is elevated in the fasting or hypoglycemic child, unless hyperinsulinism is present and suppresses hepatic IGFBP-1 release.
C-peptide levels should be proportionately elevated with insulin levels. A low C-peptide level with a high insulin level may indicate surreptitious insulin administration.
If ingestion of oral hypoglycemic medications is suspected, a drug screen may be beneficial.
Imaging Studies
Because pancreatic adenomas are often very small and have the same density as the normal pancreas, radiographic studies such as ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) are often of limited value. Pancreatic arteriography and transhepatic pancreatic selective venous sampling have also been used to elucidate the extent of pancreatic involvement. However, neither method is satisfactory for localizing lesions to guide surgery, and both are invasive. Open pancreatic ultrasonography at the time of surgery may be helpful in locating a pancreatic insulin-secreting adenoma. Most specialized centers now use Fluorine-18-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET) scanning for identifying such lesions. [14, 15, 16]
More recently, investigators have indicated that glucagon-like peptide 1 receptor (GLP-1R) PET/CT imaging with the novel radiotracer [68Ga]Ga-NODAGA-exendin-4 can be used to visualize beta-cell mass in the islets of Langerhans and thus has the potential for detecting not only insulinomas but also focal lesions in congenital hyperinsulinism (CHI). [17]
Genetic Testing
Genetic mutation testing is now well established as the standard of care to define best approaches to treatment of congenital HI. [5] Parent-of-origin testing should routinely be included at the time of patient testing. This is particularly essential if focal KATP HI is a possibility, because the demonstration of a paternally transmitted, monoallelic, recessive mutation in ABCC8 or KCNJ11 is highly accurate for predicting a potentially curable focal lesion (97% sensitivity, 92% specificity) [18] .
New methods make it possible to obtain results in less than a week, preferably within 2 or 3 days. Rapid turnaround time for genetic tests is required because treatment decisions need to be made within a few days for often severely ill infants. [5]
The chance of identifying a disease-causing mutation is higher in diazoxide-unresponsive cases, but in about 53-77% of diazoxide-responsive congenital hyperinsulinism cases, no known genetic alteration is identified. Children with GLUD1, HADH, HNF4A, HNF1A, and UCP2 mutations were noted to be exclusively diazoxide-responsive, whereas children with GCK mutations and recessive KATP mutations were likely to be diazoxide-unresponsive. On the other hand, children with dominant mutations of the KATP genes can be either a diazoxide responder or nonresponder. [18, 19]
Genetic testing is also essential for recognition of syndromic forms of HI such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. [6]
Other Tests
A normal blood glucose level is above 60 mg/dL at every age. In the normal child, glycogen stores are depleted by fasting in order to maintain euglycemia. Thus, glycogen is normally depleted before the onset of hypoglycemia. Such a child responds to exogenous dextrose but not to exogenous glucagon.
A glycemic response is defined as when the circulating glucose level rises (>30 mg/dL above the basal level) immediately after administration of 1 mg of glucagon (intramuscular or intravenous). Such a glycemic response to glucagon in the face of hypoglycemia (blood glucose level < 60 mg/dL) indicates inappropriately conserved glycogen stores. A glycemic response to glucagon is usually observed in hypoglycemic patients with hyperinsulinism.
L-leucine stimulates the secretion of insulin. Leucine-sensitive hypoglycemia is no longer considered to be a separate diagnostic entity. Determination of insulin concentration in response to leucine administration has been used as a test for hyperinsulinemia. This research test has no diagnostic value and can result in severe hypoglycemia.
Procedures
Perioperative pancreatic catheterization may provide vital information for determining the extent of surgery.
Histologic examination of pancreatic tissue samples (frozen section) may also provide vital information for determining the extent of surgery. Histologic examination may reveal focal islet cell disease (potentially cured by partial pancreatectomy) or diffuse disease (which indicates the need for near-total pancreatectomy).
-
Hyperinsulinism. Mechanisms of insulin secretion.
