AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Primary hyperinsulinism is a rare but important cause of hypoglycemia in infants and children. It is the most common cause of neonatal hypoglycemia persisting beyond the first few hours of life.

The clinical presentation varies with the age of the child. Early diagnosis and treatment are essential to prevent seizures and neurologic sequelae. Persistent hypoglycemia and inappropriately high concentrations of circulating insulin are diagnostic findings. The concentrations of free fatty acids (FFAs) and ketones (ie, beta-hydroxybutyrate, acetoacetate) are low. Several genetic causes of persistent hyperinsulinism have recently been identified.

Pathophysiology

The differential diagnosis of hypoglycemia is extensive, and determining the underlying cause is often difficult. An understanding of glucose homeostasis can help narrow the differential diagnosis. In the fasting state, glucose is provided through glycogenolysis in the liver. After a few hours of fasting, insulin levels fall, and increased lipolysis creates free fatty acids and glycerol. Fatty acids do not cross the blood-brain barrier and, therefore, are not used by the brain. However, fatty acids are used by the heart and muscle. Increased free fatty acids result in production of ketones, and the brain is able to metabolize ketones as an alternative source of fuel.

• Disorders that result from defective glycogenolysis in the liver lead to hypoglycemia within a few hours of fasting. This hypoglycemia occurs in the setting of low insulin levels.
• Disorders of fat metabolism result in the unavailability of free fatty acids and ketones as alternative fuels. Hypoglycemia occurs after several hours of fasting. Circulating insulin levels also are low.
• Growth hormone deficiency and hypocortisolemia also can cause hypoglycemia associated with low insulin levels, possibly by unopposed insulin action and decreased ketogenesis.
• Hypoglycemia associated with elevated insulin levels makes certain disorders unlikely, such as defects in gluconeogenesis, free fatty acid synthesis, and ketogenesis; growth hormone deficiency; and cortisol deficiency. Conversely, hypoglycemia associated with ketonuria makes hyperinsulinism less likely. Ketonuria does not rule out hyperinsulinemia.

Glucose and several amino acids stimulate insulin secretion under physiologic conditions, and the sequence of events leading to insulin secretion is well delineated. The rate of insulin secretion is dependent on the ratio of adenosine triphosphate to adenosine diphosphate (ATP/ADP) within the beta cell. The rate of glucose entry into the beta cell is facilitated by a glucose transporter, and the entry rate exceeds the oxidation rate of glucose. Glucokinase is the rate-limiting step of glycolysis (ATP production), not glucose transport.

The first step in glycolysis (ie, conversion of glucose to glucose-6-phosphate [G-6-P] by glucokinase) is the rate-limiting step in glucose metabolism. Thus, glucokinase regulates the rate of glucose oxidation and subsequent insulin secretion. An increase in the intracellular ATP/ADP ratio activates ATP-sensitive potassium-dependent channels (KATPs) in the cell membrane. KATP consists of 2 subunits, the sulfonylurea receptor (SUR1) and the potassium inward rectifier channel (Kir6.2). Activation leads to closure of the potassium channel and depolarization of the cell membrane. Opening of a voltage-gated calcium channel allows influx of calcium and results in insulin secretion.

Transient hyperinsulinism usually results from environmental factors such as maternal diabetes and birth asphyxia. However, children with persistent hyperinsulinism may have a genetic defect that results in inappropriate secretion of insulin.

Frequency

United States

Hyperinsulinemia is estimated to occur in 1 in 50,000 live births.

International

Autosomal recessive forms of hyperinsulinemic hypoglycemia are more common in inbred populations of Saudi Arabia and among Ashkenazi Jews.

Mortality/Morbidity

Glucose is the primary substrate used by the CNS. Free fatty acids do not cross the blood-brain barrier; however, the brain can metabolize ketones. Unrecognized or poorly controlled hypoglycemia may lead to persistent severe neurologic damage. Patients with hyperinsulinism are at high risk of developing seizures, mental retardation, and permanent brain damage.

Age

Transient hyperinsulinism is relatively common in neonates. An infant of a diabetic mother, an infant who is small or large for gestational age, or any infant who has experienced severe stress may have high insulin concentrations. In contrast, congenital hyperinsulinism is rare.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Pregnancy and birth history may reveal risk factors that could predispose an infant to hyperinsulinism. Maternal diabetes, poor fetal growth, and birth asphyxia all can lead to excessive insulin release.
• Signs and symptoms associated with hyperinsulinemic hypoglycemia result from two physiologic processes: hypoglycemia triggers autonomic nervous system activation and epinephrine release, and CNS glucopenia leads to neurologic manifestations.
• • Infants may present with cyanosis, respiratory distress, apnea, lethargy, sweating, hypothermia, jitteriness, irritability, poor feeding, seizures, tachycardia, and vomiting.
  • Older children may present with sweating, shakiness, anxiety, hunger and increased appetite, staring or strabismus, lethargy, nausea and vomiting, headache, behavior and mental status changes, inattention, loss of consciousness, tachycardia, hypothermia, and seizures.

Physical

• Macrosomia reflects the anabolic effects of prolonged hyperinsulinemia in utero in infants who are large for their gestational age and in infants of diabetic mothers.
• Microsomia can occur in infants who are small for their gestational age (particularly those who have experienced maternal toxemia). Infants with microsomia may require high rates of glucose infusion initially to maintain euglycemia.
• Some neonates have physical signs consistent with Beckwith-Wiedemann syndrome. Signs may include fetal overgrowth, omphalocele, macroglossia, visceromegaly, and creases of the ear lobe.

Causes

• Classification of hyperinsulinism of infancy is based on the following:
• • Transient hyperinsulinism of infancy
    • Infant of a mother with diabetes
    • Infant small for gestational age (SGA)
    • Perinatal stress/asphyxia
    • Erythroblastosis fetalis
    • Sepsis
    • Beckwith-Wiedemann syndrome
    • Drug-induced hyperinsulinism
      • Surreptitious insulin administration
      • Oral hypoglycemic ingestion
      • Blood transfusion
    • Umbilical artery catheter placement
  • Persistent, congenital hyperinsulinism
  • Focal inborn error of insulin release (loss of heterozygosity with paternal-specific mutation)
    • Loss of heterozygosity with mutation of SUR1 or Kir6.2
    • Diffuse inborn error of insulin release (autosomal dominant or autosomal recessive)
    • Loss of functioning sulfonylurea receptor (SUR1)
    • Loss of functioning inward rectifying potassium channel (Kir6.2)
    • Loss of allosteric inhibition in glutamate dehydrogenase–1 (GLUD1), the cause of the hyperinsulinism-hyperammonemia syndrome
    • Activating glucokinase mutation (low intrinsic Km [Michaelis-Menten constant]) (GCK)
• A useful classification of acquired hyperinsulinism beyond infancy is as follows:
  • Adenoma
  • Drug-induced hyperinsulinism
    • Surreptitious insulin administration
    • Oral hypoglycemic ingestion
  • Transient causes
    • Infants of mothers with diabetes: During gestation, glucose is transferred freely across the placenta. Prolonged hyperglycemia in poorly controlled maternal diabetes results in fetal hyperglycemia. Fetal hyperglycemia induces fetal pancreatic beta-cell hyperplasia with resultant hyperinsulinemia and macrosomia. Withdrawal of the transplacental supply of glucose after birth leads to a precipitous drop in the concentration of glucose. When neonates present with signs and symptoms of hypoglycemia, many require infusion of large quantities of glucose to maintain normal blood glucose levels. Hyperinsulinism typically resolves within 1-2 days following birth. For a full discussion, see Infant of Diabetic Mother.
  • • Prolonged hyperinsulinism in infants who are SGA and asphyxiated newborns: Infants who are SGA, experience maternal toxemia, or have birth asphyxia are at increased risk for developing hypoglycemia. These infants have high rates of glucose metabolism and may require dextrose infusions as high as 20 mg/kg/min to maintain euglycemia. Some evidence suggests that this may be due to hyperinsulinemia, although the exact mechanisms are still unclear. These patients may have prolonged hypoglycemia for as long as 2-4 weeks following birth. Afterward, the hypoglycemia appears to resolve completely.
    • Erythroblastosis fetalis: Neonates with severe Rh isoimmunization have islet cell hyperplasia and hyperinsulinism. The cause of hyperinsulinism is unknown. Researchers hypothesize that elevated levels of glutathione from massive hemolysis may serve as a stimulus for insulin release.
    • Drug-induced hyperinsulinism
      • Surreptitious insulin administration: This phenomenon is rare but may occur in the setting of Munchausen syndrome by proxy. The timing of hypoglycemia is unpredictable and occurs when the offender has access to the patient. Laboratory evaluation reveals elevated insulin levels and a low serum C-peptide level.
      • Ingestion of oral hypoglycemic agents: Toddlers may accidentally ingest drugs prescribed for adult diabetics (eg, sulfonylureas). Depending on the half-life of the preparation ingested, the duration of hypoglycemia varies. Glucose infusion (to maintain normoglycemia) is the treatment of choice. On rare occasions, diazoxide may be needed to suppress insulin secretion.
      • Blood transfusion: Certain preparations of blood products (eg, citrated blood) have large amounts of dextrose. During transfusion, the high glucose load triggers insulin secretion. Problems arise when the transfusion is completed. Elevated insulin levels could lead to a precipitous drop in blood glucose levels. This fall typically occurs about 2 hours after transfusion.
• Umbilical artery catheter placement: Malposition of the umbilical artery catheter in neonates may be associated with hypoglycemia and hyperinsulinemia. Repositioning of the catheter usually resolves the hypoglycemia and hyperinsulinemia. Theoretically, this problem may be caused by a high glucose load administered to the celiac axis. Localized hyperglycemia would induce insulin secretion and result in hypoglycemia in the systemic circulation.
• Congenital causes
• • Beckwith-Wiedemann syndrome includes signs of omphalocele, macroglossia, and visceromegaly.
  • These infants have generalized islet cell hyperplasia.
  • Hyperinsulinemic hypoglycemia may be difficult to control. These patients require large quantities of glucose. Treatment with diazoxide is often needed to control hyperinsulinemia. Hyperinsulinism usually resolves spontaneously when the infant is aged several weeks or months.
• Focal causes
  • Focal disease (formerly called nesidioblastosis, islet adenomatosis, or beta-cell adenoma: Dozens of patients with congenital hyperinsulinism demonstrate focal histologic abnormalities, which most pathologists label as islet adenomatosis or beta-cell adenoma. As patients present with hyperinsulinemic hypoglycemia at older ages (beyond age 1 y), they are increasingly more likely to have the focal form of hyperinsulinism.
  • Unfortunately, many infants with hyperinsulinism remain undiagnosed, misdiagnosed, or inadequately treated for several months before definitive management. Currently, definitive care is available at CHRISTUS Santa Rosa Children's Hospital (San Antonio, Tex), The Children's Hospital of Philadelphia (Philadelphia, Pa), Great Ormond Street Children's Hospital (London, England), Necker-Enfants Malades Hospital (Paris, France), Hadassah–Hebrew University Medical Center (Jerusalem, Israel), and The Children's Hospital (Helsinki, Finland). It cannot be overemphasized that, as with most rare diseases in children, timely referral to such centers provides optimal management.
  • A recent study employing preoperative pancreatic catheterization and intraoperative histologic studies suggests that as many as half of all neonates presenting with congenital hyperinsulinism have focal islet cell hyperplasia. Focal causes of hyperinsulinism can be treated, and possibly cured, with partial pancreatectomy.
  • Patients with inborn genetic defects of insulin release have congenital hyperinsulinism. Other terms for this disorder that have fallen out of favor include persistent hyperinsulinemic hypoglycemia of infancy (PHHI), leucine-sensitive hypoglycemia, islet cell dysmaturation syndrome, and nesidioblastosis.
• Genetic forms of congenital hyperinsulinism include the following:
• • Autosomal recessive mutations
    • Recessive mutations on chromosome 11 lead to alterations in the potassium channel on the plasma membrane of pancreatic beta cells. Mutations in the SUR1 and Kir6.2 genes create a nonfunctional potassium channel with membrane depolarization and unchecked insulin secretion. Mutations of the SUR1 gene are more common than mutations of the Kir6.2 gene. SUR1 mutations have been found more frequently in the less heterogeneous populations of Saudi Arabia and Ashkenazi Jews.
    • Patients with the autosomal recessive disorder present with high birth weights from the anabolic effects of insulin in utero. These disorders cannot be controlled with diazoxide, which binds to the cell surface of SUR1 to suppress insulin secretion. Thus, pancreatectomy is often required. For this subset of patients, near-total pancreatectomy achieves the best glycemic control during infancy.
  • Autosomal dominant mutations
    • Mutations of the GCK gene or the SUR1 gene can be autosomal dominant or recessive. GLUD1 mutations reported to date have been transmitted in an autosomal dominant inheritance. Infants with GCK or GLUD1 mutations tend to display less severe hypoglycemia and respond to diazoxide. Molecular mechanisms in other autosomal dominant cases of hyperinsulinism are emerging.
    • The GCK mutations increase the affinity of glucokinase for glucose (ie, lower intrinsic Km for the glucose binding site). Accelerated rates of glycolysis result in an increased ATP/ADP ratio and increased insulin secretion. Patients with these mutations have a milder form of hyperinsulinism than patients with potassium channel defects. These patients also respond well to diazoxide treatment. In some patients, treatment can be discontinued after several years.
  • Hyperinsulinism-hyperammonemia syndrome due to glutamate dehydrogenase (GLUD1) mutation
    • Early in infancy, patients with this genetic mutation present with hypoglycemic seizures, which are unrelated to the hyperammonemia per se. Delayed diagnosis and definitive care is unfortunately common because of the rarity of this disease.
    • GLUD1 mutation affects both hepatocytic and islet function. Two metabolic pathways use glutamate dehydrogenase: leucine glutamate dehydrogenase–mediated oxidation in beta cells produces ATP, which induces insulin release; glutamate dehydrogenase also reduces intrahepatocytic glutamate concentration, and glutamate depletion downregulates the first step of the urea cycle to convert ammonium to urea.
    • Excessive activity of glutamate dehydrogenase thus increases the rate of insulin release by beta cells in the pancreas and impairs the detoxification of ammonia by hepatocytes in the liver. Patients with one of these GLUD1 gene mutations present with low blood glucose levels and persistent mild elevations of serum ammonia to 100-200 mmol/L. This hyperammonemia is not affected by fasting, intravenous L-leucine challenge, oral L-leucine challenge, or glycemic control by medication. Indeed, the hyperammonemia itself has not been associated with clinical consequences, in contrast to the hypoglycemia that can cause permanent brain damage.

DIFFERENTIALS

Section 4 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Patients with hyperinsulinism usually have elevated levels of insulin for their glucose concentration (ie, even if they do not have hypoglycemia, their insulin level is inappropriately high for their glucose levels: plasma insulin level > 2 µU/mL when blood glucose level is <60 mg/dL). In contrast, patients with the following disorders have an appropriate concentration of insulin for the simultaneous glucose concentration:

• Adrenal insufficiency
• Disorders of branched-chain amino acids
• Enzymatic block in the Cori and alanine cycles
• Fatty acid release/oxidation (ketone synthesis) disorders
• Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase deficiency
• Ketone utilization disorders
• Mitochondrial succinyl–coenzyme A transferase deficiency
• Mitochondrial acetyl–coenzyme A acyltransferase deficiency
• Fructosemia
• Galactosemia
• Glycerokinase deficiency
• Glycogen storage disease type Ia and type Ib (von Gierke disease, glucose-6-phosphatase deficiency)
• Glycogen storage disease type III (Cori disease; amylo-1, 6-glucosidase deficiency)
• Glycogen storage disease type VI (Hers disease, phosphorylase deficiency)
• Growth hormone deficiency

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• All patients suspected of having hyperinsulinism should have blood drawn for measurement of concentrations of glucose, insulin, growth hormone, cortisol, free fatty acids, and beta-hydroxybutyrate. It is also useful to measure arterial blood gas, lactate, pyruvate, and alanine levels. 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, it bemuses the undiagnosed patient when the practitioner collects serum during the crisis. The practitioner should collect 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.
• • Glucose and insulin
    • A plasma insulin level higher than 2 µU/mL in the face of a serum glucose concentration less than 60 mg/dL is diagnostic of hyperinsulinism.
    • Infants with hyperinsulinism require unusually high rates of glucose infusion (>12 mg/kg/min, vs 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.
  • Low levels of beta-hydroxybutyrate ( <1 mmol/L) in conjunction with low levels of free fatty acids ( <1 mmol/L) during hypoglycemia may indicate hyperinsulinism.
  • Finding low levels of insulin-like growth factor binding protein-1 (IGFBP-1 <120 ng/mL) 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 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

• Imaging studies (eg, pancreatic ultrasonography, CT scan, MRI) generally are 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 scan has been used for the localization of islet cell adenomas in adults.

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 will respond to exogenous dextrose but not to exogenous glucagon.
• A glycemic response is defined as when the circulating glucose level rises (more than 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 is invasive but has been useful in delineating an adenoma, even in infants and young children. Transhepatic pancreatic selective venous sampling also has been used to elucidate the extent of pancreatic involvement. Open pancreatic ultrasonography at the time of surgery may be helpful in locating a pancreatic insulin-secreting adenoma. More recently, positron emission tomography (PET) scanning has been effective in identifying such lesions.

Procedures

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

Histologic Findings

Histologic examination of pancreatic tissue samples (frozen section) also may 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).

TREATMENT

Section 6 of 11  

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• Follow-up
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• Multimedia
• References

Medical Care

• Maintaining normoglycemia is essential to prevent neurologic sequelae. Infants with hyperinsulinism are at higher risk of neurologic sequelae than infants with hypoglycemia from other causes. Because insulin inhibits lipolysis and ketogenesis, hyperinsulinism results in the paucity of alternative fuel used by the brain.
• The glucose output from the liver is 2-3 mg/kg/min in adults. Infants and children have a greater need for glucose and have a maximal output estimated at 5-7 mg/kg/min. Patients with hyperinsulinism may require very high glucose infusion rates (20-30 mg/kg/min) to maintain normoglycemia. Attempts should be made to keep blood glucose levels at 60 mg/dL or higher at all times.
• Healthy neonates and infants can fast for 6 hours without experiencing hypoglycemia. This equates to skipping one feeding in the infant who is fed ad libitum.
• Medications should be administered to suppress insulin secretion or stimulate glucose release.

Surgical Care

• Gastrostomy tube placement may be indicated in extreme cases to administer food if the infant is unable to handle the increased glucose requirements.
• Partial or near-total pancreatectomy
• • Pancreatectomy is reserved for infants who fail to establish adequate control on medical therapy.
  • Although most surgeons initially remove 95% of the pancreas, a near-total (98%) pancreatectomy appears to be most effective in preventing hypoglycemia in the newborn period for those with diffuse potassium channel disease (SUR1 or Kir6.2 mutations). Remarkably, the elevated lifelong risk of diabetes mellitus is more closely related to the intrinsic error in regulated insulin release, rather than to the extent of pancreatectomy.
  • Close monitoring of blood glucose levels is indicated to ensure glycemic control and to minimize hypoglycemia. If hypoglycemia persists, medical therapy should be reattempted. If medical therapy is unsuccessful, a second pancreatectomy may be indicated. The authors' experience indicates that clinically significant pancreatic regrowth can occur in infants after near-total pancreatectomy. A Whipple procedure is unwarranted because it cannot guarantee remission of diffuse disease.
  • Limited pancreatectomy is indicated for patients with focal disease.
  • Complications include pancreatic exocrine insufficiency, diabetes mellitus, and injury to the common bile duct.

Consultations

• Pediatric endocrinologist
• Pediatric surgeon
• Neonatologist
• Geneticist (if family history is present or suspected)
• Closest tertiary referral center (academic children's hospital) for possible enrollment in clinical research protocols

Diet

Frequent feedings by gastrostomy help maintain euglycemia but do not prevent the need for intravenous dextrose administration before surgery.

MEDICATION

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Medical therapy is the treatment of choice. Patients with hyperinsulinism often require multiple medications to maintain normoglycemia. Patients with severe hyperinsulinism may be refractory to medical therapy and may require excision of a portion of or the entire pancreas. In general, maintenance of normoglycemia should be attempted before pancreatectomy is considered. At the same time, because hypoglycemia can result in irreversible brain damage, surgical excision should not be delayed in patients with severe hypoglycemia.

Drug Category: Insulin secretion inhibiting agents

Insulin secretion may be altered by various mechanisms. Oral diazoxide inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release, which elevates blood glucose levels. Octreotide is a peptide with pharmacologic action similar to that of somatostatin, which inhibits insulin secretion. KATPs (adenosine triphosphate–sensitive potassium-dependent channels; composed of the sulfonylurea receptor [SUR1] and the potassium inward rectifier channel [Kir6.2]) are inactive in diffuse disease. These channels initiate depolarization of the beta-cell membrane and opening of calcium channels. The resultant increase in intracellular calcium triggers insulin secretion. Calcium channel blockers block the activation of these calcium channels, decreasing insulin secretion. Nifedipine is the only calcium channel blocker that has been used for the treatment of hyperinsulinism in humans, and it appears to be clinically ineffective.

Drug Name	Octreotide (Sandostatin)
Description	Somatostatin analogue, activates G-protein K channel. Hyperpolarization of beta cell results in inhibition of calcium influx and insulin release. Octreotide also used for acromegaly, carcinoid tumors, and VIPomas.
Adult Dose	50 mcg SC q12-24h initially; may gradually titrate upward while monitoring blood glucose levels; alternatively, may administer daily dose as a continuous SC infusion
Pediatric Dose	5-40 mcg/kg/d SC divided q4-6h or administered as continuous SC infusion; titrate to effect Precipitates or sludges when mixed with glucagon; octreotide must be given as intermittent SC injection when coadministered with continuous SC glucagon infusion
Contraindications	Documented hypersensitivity
Interactions	May decrease absorption of orally administered drugs; may decrease blood levels of cyclosporine; patients may require dose adjustments of insulin, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balances while on this drug
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause GI toxicity (eg, steatorrhea, diarrhea, vomiting, abdominal distention, biliary sludge); cholelithiasis may occur; hyperglycemia; hypothyroidism; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; caution in renal impairment (decrease dose)

Drug Name	Nifedipine (Adalat, Procardia)
Description	Blocks calcium channels and insulin release. Also used to treat hypertension and angina.
Adult Dose	10 mg PO tid initially; may gradually titrate upward to 80 mg PO tid as determined by blood glucose
Pediatric Dose	0.25-0.7 mg/kg/d PO divided q8h
Contraindications	Documented hypersensitivity
Interactions	Caution with coadministration of any agent that can lower BP, including beta blockers and opioids; H2 blockers (eg, cimetidine) may increase toxicity; may increase serum levels of digoxin or quinidine; nifedipine levels may be affected by CYP3A4 inhibitors (eg, erythromycin, itraconazole) or inducers (eg, carbamazepine, rifampin)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause lower extremity edema or hypotension; allergic hepatitis has occurred but is rare

Drug Category: Dextrose and glucose release stimulators

Emergent blood glucose elevation requires IV dextrose. Glucagon enhances release of hepatic glycogen as glucose.

Drug Name	Glucagon
Description	Stimulates hepatic glycogenolysis and gluconeogenesis.
Adult Dose	1 mg (1 unit) IV/IM/SC
Pediatric Dose	2-10 mcg/kg/h IV; alternatively, 0.2 mg/kg IV/IM/SC bolus; not to exceed 1 mg/dose
Contraindications	Documented hypersensitivity; pheochromocytoma
Interactions	Effects of anticoagulants may be enhanced by glucagon (although onset may be delayed); monitor prothrombin activity and for signs of bleeding in patients receiving anticoagulants; adjust dose accordingly
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Useful only if liver glycogen stores are adequate; may lead to elevated blood pressure from stimulation of catecholamine release; may result in nausea and vomiting

Drug Category: Drugs inhibiting insulin effect

In refractory cases, cortisol and growth hormone have been used with variable rates of success to inhibit insulin effects. Both diminish the hypoglycemic effects of insulin. They also may enhance ketogenesis and increase the availability of alternative fuels.

Drug Name	Growth hormone, human (Genotropin, Humatrope, Nutropin)
Description	Recombinant hGH. Some patients demonstrate reduced glucose requirement and improved glycemic control. Stimulates growth of linear bone, skeletal muscle, and organs. Stimulates erythropoietin, which increases red blood cell mass. Should not be considered an alternative to continuous SC glucagon, intermittent octreotide, or pancreatectomy.
Pediatric Dose	0.05-0.06 mg/kg/d SC as single daily injection
Contraindications	Documented hypersensitivity; actively growing intracranial tumor
Interactions	Glucocorticoids may decrease growth-promoting effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Reconstitute with sterile water for injection if administering to newborns

FOLLOW-UP

Section 8 of 11  

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit patients for stabilization of blood glucose, further testing, and medical or surgical care.
• Blood glucose level should be determined before each oral feeding and when any symptom or sign of hypoglycemia is present. The most accurate blood glucose assessment is made by free blood drawn into a NaF-containing tube (gray top), with immediate processing to avoid spuriously low measurements resulting from glycolysis. A bedside glucometer can provide faster results, which need to be confirmed in the central laboratory only when the bedside value is below 60 mg/dL.
• All portable glucometers are inaccurate by as much as 20% when the measured blood glucose level is below 70 mg/dL. To reduce the possibility of neurologic injury, the blood glucose level should be maintained above 60 mg/dL at all times.
• Before discharging the patient from the hospital, perform a short fasting study (6-8 h) to ensure that the infant can safely tolerate a missed or inadequate feeding at home. The infant must be able to maintain a blood glucose level above 60 mg/dL throughout the fast.
• Ensure the training of caretakers and adequate home healthcare support for pump infusions (octreotide or glucagon) before discharging the patient from the hospital.

Further Outpatient Care

• Monitor medication dosages and side effects carefully, with frequent glucose level determinations.
• Monitor for symptoms and signs of hypoglycemia.
• Train caretakers to monitor blood glucose levels and to administer all medications at home.

In/Out Patient Meds

• Medications include diazoxide, octreotide, nifedipine, glucagon, growth hormone, and glucocorticoids. The choice of medications varies with etiology and severity of hypoglycemia.

Transfer

• Transfer of patient to a tertiary care facility is required to provide prompt diagnosis and medical treatment or surgical intervention. Referral to one of the aforementioned centers (see above) is preferred.

Deterrence/Prevention

• Avoid prolonged fasting. Seek medical attention if emesis or anorexia develops.
• Have source of glucose and glucagon emergency kit readily available if hypoglycemic symptoms appear.

Complications

• Seizures
• Permanent brain damage
• Death

Prognosis

• Multiple factors affect prognosis, such as the severity of the disease at presentation, duration of hypoglycemia, etiology of hyperinsulinism, and presence of neurologic complications.
• Improving diagnostic techniques make earlier and more appropriate surgical intervention (partial pancreatectomy or near-total pancreatectomy) possible.
• Patients who have had near-total pancreatectomy are at risk for developing exocrine pancreatic insufficiency and diabetes mellitus. Diabetes mellitus, which develops in patients with diffuse disease, is caused by dysregulation of insulin secretion in the residual beta cells after pancreatectomy.

Patient Education

• Counsel the patient, family members, and school personnel how to recognize the symptoms of hypoglycemia and how to administer glucose in the event of a hypoglycemic episode.
• Families should be equipped with glucagon and instructed in its use in case hypoglycemia does occur.

MISCELLANEOUS

Section 9 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to recognize and treat hypoglycemia
• Failure to recognize the cause of hypoglycemia
• Failure to counsel family how to recognize signs and symptoms of hypoglycemia and how/when to administer glucose or glucagon
• Failure to recognize associated conditions, such as cardiomyopathy in infants of diabetic mothers and associated problems with asphyxia

Special Concerns

• Some children with a known history of hypoglycemia may not be symptomatic. A high index of suspicion is essential for early detection and therapy.

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Mechanisms of insulin secretion.
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REFERENCES

Section 11 of 11

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Sep 14, 2006