Hyperinsulinism 

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

Overview

Background

Primary hyperinsulinism is a rare but important cause of hypoglycemia in infants and children. It is the most common cause of neonatal hypoglycemia that persists beyond the first few hours of life.[1]

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 been identified.[2, 3, 4, 5, 6, 7, 8, 9, 10] See the image below.

Mechanisms of insulin secretion. Mechanisms of insulin secretion.

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 ATP to 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.

Epidemiology

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.

 

Presentation

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 2 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 gestational age (SGA), 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 in infancy is described below.

Transient hyperinsulinism of infancy causes include the following:

  • Infant of a mother with diabetes

  • Infant who is SGA

  • Perinatal stress/asphyxia

  • Erythroblastosis fetalis

  • Sepsis

  • Beckwith-Wiedemann syndrome

  • Drug-induced hyperinsulinism, as follows:

    • Surreptitious insulin administration

    • Oral hypoglycemic ingestion

    • Blood transfusion

  • Umbilical artery catheter placement

Persistent, congenital hyperinsulinism is also recognized.

Focal inborn error of insulin release (loss of heterozygosity with paternal-specific mutation) causes include the following:

  • Loss of heterozygosity with mutation of SUR1 or Kir6.2

  • Diffuse inborn error of insulin release (autosomal dominant or autosomal recessive)

  • Loss of functioning 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 include the following:

  • Infants of mothers with diabetes: During gestation, glucose is freely transferred 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 (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 includes the following:

  • 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.

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 include the following:

  • Beckwith-Wiedemann syndrome includes symptoms 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 spontaneously resolves when the infant is aged several weeks or months.

Focal causes include the following:

  • Focal disease was 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 (>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 Le Bonheur Children's Hospital (Memphis, Tennessee), The Children's Hospital of Philadelphia (Philadelphia, Pennsylvania), 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). As with most rare diseases in children, timely referral to such centers provides optimal management.

  • A study that used preoperative pancreatic catheterization and intraoperative histologic studies suggested 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 causes include the following:

  • Pancreatic β-cell KATP channel defects are recognized.

  • 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.

  • GCK (encoding glucokinase) mutations: Mutations of the GCK gene can be autosomal dominant or recessive. 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 (HH) syndrome due to GLUD1 mutation, as follows:

    • GLUD1 mutations reported to date have been transmitted in an autosomal dominant inheritance. 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 µmol/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. GLUD1 mutations tend to display less severe hypoglycemia and respond to diazoxide.

  • Exercise-induced hyperinsulinism (EIHI): Exercise-induced hyperinsulinism (EIHI) is characterized by inappropriate insulin secretion that leads to hypoglycemia during exercise. Promoter-activating mutations of SLC16A1 gene encoding a monocarboxylate transporter (MCT1) that mediates the movement of lactate and pyruvate across cell membranes and causes anaerobic exercise-induced hypoglycemia as a dominantly inherited trait. Patients typically become hypoglycemic 30-45 minutes after a period of intensive exercise.

  • Uncoupling protein 2 (UCP2): Loss-of-function mutations encoding UCP2 leads to an increased ATP synthesis and enhanced glucose-stimulated insulin secretion. Diazoxide responsive this rare form of defuse HH syndrome is thought to be transient.

  • 3-Hydroxyacyl-CoA Dehydrogenase (HADH): HADH (formerly known as short chain L-3-hydroxyacyl-CoA dehydrogenase) inherited as an autosomal recessive manner. Diazoxide responsive this rare disorder characterized by increased levels of 3-hydroxybutyryl-carnitine in blood and 3-hydroxyglutaric acid in urine. However precise mechanism of hyperinsulinism in patients with a HADH deficiency is not well understood.

  • HNF-4A: Hepatocyte nuclear factor 4 alpha (HNF-4 encoded by the HNF4A gene) is a transcription factor that plays important role in pancreatic development, maintenance of β-cell mass and regulation of insulin secretion. HNF4A gene mutations can cause increased birth weight, macrosomia, and transient HH syndrome in the neonatal period, which evolves to decreased insulin secretion and maturity-onset diabetes of the young type 1 (MODY1) later in life.[11]

 

DDx

Diagnostic Considerations

Patients with hyperinsulinism usually have elevated levels of insulin for their glucose concentration, meaning even if they do not have hypoglycemia, their insulin level is inappropriately high for their glucose levels (ie, 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 use 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

Differential Diagnoses

 

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.

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.

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]

Procedures

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

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).

 

Treatment

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

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.[15] One recent study showed almost 94% of focal hyperinsulinism cases required no further treatment, versus 41% with diffuse hyperinsulinism that showed continued hypoglycemia postoperatively.[16]

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

See the list below:

  • 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

Medication Summary

Medical therapy is the treatment of choice.[17] 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.

Insulin secretion inhibiting agents

Class Summary

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 (ATP–sensitive potassium-dependent channels, composed of the SUR1 and 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 appears to be clinically ineffective.

Diazoxide (Proglycem)

First-line treatment. PO diazoxide (Proglycem) opens KATP channels and inhibits insulin secretion. The IV preparation (Hyperstat) is not used in hyperinsulinism.

Octreotide (Sandostatin)

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.

Nifedipine (Adalat, Procardia)

Blocks calcium channels and insulin release. Also used to treat hypertension and angina.

Dextrose and glucose release stimulators

Class Summary

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

Dextrose (D-glucose)

IV glucose is used to elevate serum glucose levels promptly. PO glucose is rapidly absorbed from intestine and stored or used by the tissues. Parenterally injected dextrose is used in patients unable to sustain adequate PO intake. Direct PO absorption results in a rapid increase in blood glucose concentrations. Dextrose is effective in small doses, and no evidence exists that it may cause toxicity. Concentrated dextrose infusions provide higher amounts of glucose in a small volume of fluid but require central venous access for concentrations above 12.5% to reduce hyperosmolar damage to smaller peripheral blood vessels.

Glucagon

Stimulates hepatic glycogenolysis and gluconeogenesis.

Drugs inhibiting insulin effect

Class Summary

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 may also enhance ketogenesis and increase the availability of alternative fuels.

Hydrocortisone (Hydrocortone, Cortef, Solu-Cortef)

Possesses glucocorticoid activity and weak mineralocorticoid effects. Causes peripheral insulin resistance, gluconeogenesis, and, with prolonged therapy, increased pancreatic release of glucagon (which promotes glycogenolysis).

Growth hormone, human (Genotropin, Humatrope, Nutropin)

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.

 

Follow-up

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.

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.

Inpatient & Outpatient Medications

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

See the list below:

  • 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.