Diagnostic Evaluation of Hypoglycemia

When any child is believed to have hypoglycemia, a low blood glucose value is quickly confirmed with a test strip. Sufficient blood always should be obtained before therapeutic intervention to confirm the diagnosis. Semiquantitative methods for estimating the concentration of glucose in the blood are useful for monitoring the condition of patients with suspected hypoglycemia.

Because these methods are not reliable when glucose concentration is less than 2.8 mmol/L (50 mg·dL-1), the diagnosis of hypoglycemia must rest on samples obtained in a quantitative analysis of plasma derived from blood placed in a tube containing NaFl (to inhibit erythrocyte glycolysis) and a method specific for glucose (most commonly, glucose oxidase).

If possible, adequate blood should be obtained to allow initial evaluation of plasma concentrations of hormones (insulin, C-peptide, cortisol, GH, IGF-I, IGF-II, and IGFBP-1) and substrates (β-hydroxybutyrate, lactate, ammonium, free fatty acids, amino acids, and free and total carnitine).

Historical factors helpful in defining the cause of hypoglycemia include the presence or absence of hypoglycemic symptoms at birth, age at onset, growth and development, frequency of hypoglycemic episodes, specific food intolerance or aversions, temporal relation to meals, family history, potential drug exposure, and unexplained infant death.

The findings from the history, physical examination, initial plasma sample (if available), and a provocative fast guide further testing. However, no elective fast is undertaken until the patient is shown to have normal plasma free and total carnitine concentrations because under most circumstances, fasting is contraindicated if carnitine level is low. Hypoglycemia in the face of relatively low plasma concentrations of ketone bodies, free fatty acids, or IGFBP-1 immediately focuses attention on abnormalities of insulin secretion. Hyperinsulinism is best documented with simultaneous measurement of plasma levels of glucose and insulin at times of hypoglycemia. Levels greater than 3 to 5 uU/mL when plasma level of glucose is less than 2.2 mmol/L (40 mg/dL) whether or not the patient is fed or fasted indicate the need for further studies to document hyperinsulinism. Intravenous glucagon (0.03 mg·kg-1, maximum 1 mg) at the time of hypoglycemia can be both therapeutic and diagnostic.

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A clear glycemic response (increase greater than 1 mmol/L or 15 to 20 mg/dL) over the first 10 to 20 minutes after administration of glucagon reflects inappropriate sequestration of hepatic glycogen and strongly suggests hyperinsulinemia or glucagon deficiency. When hyperinsulinemia is strongly suspected or proved, blood is obtained for DNA analysis to identify (1) any of the sulfonylurea receptor or potassium channel defects, (2) increased expression of IGF-II gene on chromosome 11p15.5 (Beckwith-Wiedemann syndrome), and (3) mutations of the glutamate dehydrogenase gene (suspected when hypoglycemia is associated with hyperammonemia). Levels of IGFBP-1 can be of diagnostic value in differentiating hyperinsulinism from other hypoglycemic disorders. During fast-induced hypoglycemia, IGFBP-1 concentration does not increase or increases minimally in children with hyperinsulinism. In healthy children and children with ketotic hypoglycemia, IGFBP-1 concentration increases severalfold.

When a child has hypoglycemia as a part of multiorgan symptoms such as enteropathy, coagulopathy, and neuropathy, carbohydrate-deficient glycoprotein syndrome is suspected. Hypoglycemia in association with hypoketonemia but high plasma concentrations of free fatty acids directs the investigation toward fatty acid oxidation disorders. Symptomatic fasting hypoglycemia associated with ketonuria and ketonemia without hepatomegaly and with an onset after 18 months of age strongly suggests the diagnosis of ketotic hypoglycemia. The diagnosis of galactosemia or hereditary fructose intolerance is considered when an infant has hypoglycemia in the immediately postprandial period, particularly with hepatomegaly and failure to thrive. Fasting hypoglycemia, hepatomegaly, and metabolic acidosis associated with episodic hyperventilation are highly suggestive of glucose-6-phosphatase or fructose-1,6-bisphosphatase deficiency.

Diagnostic approach to hypoglycemia among children. IDM and IGDM = infants of mothers with insulin-dependent or gestational-onset diabetes, respectively; PHHI = persistent hyperinsulinemic hypoglycemia of infancy; MEN = multiple endocrine neoplasia syndrome; FFA = free fatty acid; EtOH = Alcohol; F-1,6-Dpase = fructose 1,6 diphosphatase; G-6-pase = glucose-6-phosphatase; PEPCK = phosphoenolpyruvate carboxykinase; PC = pyruvate carboxylase; IDDM = insulin dependent diabetes mellitus.

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HAYMOND MW: Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 18:211-252, 1989

HAYMOND MW , SUNEHAG A: Controlling the sugar bowl: regulation of glucose homeostasis in children. Endocrinol Metab Clin North Am 28:663-694, 1999

KATZ LE , FERRY RJ JR , STANLEY CA , COLLETT-SOLBERG PF , BAKER L , COHEN P: Suppression of insulin oversecretion by subcutaneous recombinant human insulin-like growth factor I in children with congenital hyperinsulinism due to defective beta-cell sulfonylurea receptor. J Clin Endocrinol Metab 84:3117-24, 1999

SCHWITZGEBEL VM , GITELMAN SE: Neonatal hyperinsulinism. Clin Perinatol, 25:1015-1038, 1998

STANLEY CA , LIEU YK , HSU BY , et al: Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352-1357, 1998

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