Hyperinsulinism Workup

Updated: Dec 16, 2015
  • Author: Sunil Kumar Sinha, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
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Workup

Laboratory Studies

All patients suspected of having hyperinsulinism should have blood obtained for measurement of concentrations of glucose, insulin, growth hormone, cortisol, free fatty acids, and beta-hydroxybutyrate. 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 elevated 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.

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Imaging Studies

Imaging studies (eg, pancreatic ultrasonography, CT scan, MRI) are generally not very useful. However, pancreatic angiography and pancreatic venous sampling have successfully been used in selective cases to identify and localize focal causes of hyperinsulinism. Also, spiral CT scanning has been used for the localization of islet cell adenomas in adults.

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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.

Because pancreatic adenomas are often very small and have the same density as the normal pancreas, radiographic studies such as ultrasound, CT scan, and MRI are often of limited value. Pancreatic arteriography and transhepatic pancreatic selective venous sampling has 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 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET) scanning for identifying such lesions. [3, 12]

Genetic testing

Recent studies demonstrate how genotype and phenotype correlation may assist in clinical decision making and predicting therapeutic response. Genetic testing for candidate gene can be very helpful, especially in diazoxide-unresponsive cases. 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. [13, 14]

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Procedures

Perioperative pancreatic catheterization may provide vital information for determining the extent of surgery.

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Histologic Findings

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).

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