Pediatrics

Hyperinsulinism

OVERVIEW: What every practitioner needs to know about hyperinsulinemic hypoglycemia in neonates and children Are you sure your patient has hyperinsulinism? What are the typical findings for this disease?

Hyperinsulinism is the most common hypoglycemic disorder in infants and neonates. Transient neonatal hyperinsulinism is common due to perinatal stress, including birth asphyxia, preeclampsia, and intrauterine growth retardation. Congenital forms of hyperinsulinism are associated with recessive, dominant, or sporadic genetic defects in insulin regulation--particularly mutations of the beta-cell ATP-dependent potassium channel. Congenital hyperinsulinism can cause focal or diffuse disease and can usually be diagnosed based on genetic testing. Acquired hyperinsulinism due to pancreatic insulinoma or ingestion of antidiabetic drugs should be considered with new onset of hyperinsulinism in older children.

Treatment of hyperinsulinism is aimed at maintaining plasma glucose levels at greater than 70 mg/dL. Diazoxide, a potassium channel agonist, is the drug of choice for treatment of hyperinsulinism. Some infants with congenital hyperinsulinism are severely affected and require surgery if they are unresponsive to diazoxide. Surgery can be curative, especially in focal hyperinsulinism, but it requires referral to a center with special expertise. Transient neonatal hyperinsulinism can last for several days to weeks after birth and can be treated with frequent feedings or diazoxide depending on the severity.

Clinical features of hyperinsulinism may include large for gestational age (LGA) birth weight, small for gestational age (SGA) birth weight, and perinatal stress (maternal toxemia, birth asphyxia, infant of diabetic mother). Affected infants can present with seizures, lethargy, altered mental status, jitteriness, tachycardia, and hypothermia. A high glucose requirement (>6-8 mg/kg/min in neonates or >4-6 mg/kg/min in older infants) strongly suggests a diagnosis of hyperinsulinism over other etiologies of hypoglycemia. Note that hypoglycemia cannot be “defined” by any single value of plasma glucose because the spectrum of responses to brain glucose deprivation occurs over a range of plasma glucose levels (from 70 mg/dL downward) and the glucose thresholds for these responses can be modified depending on whether alternative fuels (e.g., ketones) are available or not.

Plasma glucose should be measured at the time symptoms appear (either spontaneous or during a provocative fast) by an accurate laboratory test. Hypoglycemia due to hyperinsulinism is usually easily elicited by brief periods of fasting (6-18 hours depending on the child’s age), although prolonged fasting may be needed to unmask hypoglycemia in older patients with insulinoma. The diagnosis of hyperinsulinism is based on demonstration of hypoglycemia (plasma glucose <50 mg/dL) accompanied by inappropriate suppression of ketogenesis (low plasma beta-hydroxybutyrate) and inappropriate glycemic response to glucagon (increase in plasma glucose after injection of glucagon).

What other disease/condition shares some of these symptoms?

Seizure disorder

Other causes of hypoglycemia:

  • Hypopituitarism

  • Isolated deficiencies of growth hormone and/or cortisol

  • Metabolic disorders of glycogenolysis, gluconeogenesis, fatty acid oxidation, and ketogenesis

  • Surreptitious insulin administration

What caused this disease to develop at this time?

Many infants and children with hyperinsulinism have a genetic disorder of insulin regulation, which can be recessive, dominant, or sporadic. Congenital hyperinsulinism often presents as hypoglycemia in the neonatal period, but it can present later depending on the type and severity of the underlying mutation. Infants with perinatal stress (birth asphyxia, intrauterine growth restriction, infant of diabetic mother) can have transient hyperinsulinism lasting for a few days to a few months.

Fasting or illness may unmask an underlying hyperinsulinism disorder. High-protein feedings can cause hypoglycemia in some, but not all, genetic forms of hyperinsulinism.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The diagnosis of hyperinsulinism is best made by a provocative fasting test to elicit the development of hypoglycemia. When the plasma glucose concentration falls to less than 50 mg/dL, a “critical” sample should be obtained to measure plasma glucose, insulin, beta-hydroxybutyrate, and free fatty acid levels.The fast can be ended with a glucagon stimulation test, given as glucagon 1 mg intravenously, intramuscularly, or subcutaneously, when plasma glucose is less than 50 mg/dL, followed by 20 to 40 minutes of glucose monitoring to determine the glycemic response to glucagon. Additional tests, such as plasma growth hormone and cortisol concentrations, can be done using the critical sample to rule out deficiencies of these hormones as alternative diagnoses.

Inappropriately low levels of beta-hydroxybutyrate (<1 mmol/L) and free fatty acids (<1 mmol/L), along with a non-suppressed insulin level (>2-3 µU/mL), are consistent with hyperinsulinism. A glycemic response (i.e., rise in blood glucose) to glucagon that is greater than 30 mg/dL is also consistent with hyperinsulinism. Plasma levels of cortisol (>20 µg/dL) and growth hormone (>10 ng/mL) at a time of hypoglycemia may be high enough to exclude deficiencies; however, low values cannot be used to diagnose deficiencies of these hormones. In the latter cases, separate provocative testing would be required.

Would imaging studies be helpful? If so, which ones?

Standard imaging (e.g., computed tomography, magnetic resonance imaging, and ultrasonography) is not useful in congenital focal hyperinsulinism. However, 18fluoro-L-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET) has proved very accurate in detecting and localizing focal hyperinsulinism lesions and should be performed preoperatively in all cases.

Since 18F-DOPA PET scans and expertise in surgery for focal lesions are not widely available, referral to a specialized center should be considered.

Confirming the diagnosis

Once a diagnosis of hyperinsulinism has been made (see above), mutation testing should be done. The current strategy is to test for the most common hyperinsulinism genes, ABCC8 (also called SUR1) and KCNJ11 (also called Kir6.2), and GLUD1 and GCK. If this testing is negative and congenital hyperinsulinism is strongly suspected due to presentation or positive family history, extended mutation testing for all 10 known hyperinsulinism genes can be done (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF1A, HNF4A, INSR, SLC16A1, and UCP2). These tests are available commercially (e.g., through the University of Pennsylvania or the University of Chicago).

Parental samples should also be sent for parent of origin testing at the same time patient tests are sent, since paternal transmission of a recessive ABCC8 or KCNJ11 mutation may indicate a focal hyperinsulinism lesion. If a monoallelic mutation of ABCC1 or KCNJ11 is found and parent of origin testing shows paternal transmission, the possibility of a surgically curable focal lesion should be considered (see comments above about 18F-DOPA-PET for follow-up imaging).

Diazoxide-unresponsive hyperinsulinism is most commonly associated with mutations of ABCC8 and KCNJ11 and less commonly with GCK defects. Half of infants with diazoxide-unresponsive hyperinsulinism requiring surgery have focal lesions. Some infants with Beckwith-Wiedemann Syndrome may not be responsive to diazoxide.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Hypoglycemia should be emergently corrected with a bolus of intravenous dextrose (starting with 2 mL/kg of 10% dextrose). Continuous IV dextrose should be given at a rate sufficient to maintain plasma glucose levels in the physiologically normal range (70-100 mg/dL). Glucose infusion rate (GIR) is calculated as follows:

GIR (mg/kg/min) = IV rate (mL/hr) × Dextrose concentration (g/dL) × 1000 (mg/g)

Weight (kg) × 60 (min/hr) × 100 (mL/dL)

A normal GIR in neonates is 4-5 mg/kg/min. A higher GIR (>6-8 mg/kg/min in neonates or >4-6 mg/kg/min in older infants) is suggestive of hyperinsulinism. A GIR as high as 20-30 mg/kg/min may be needed in severe hyperinsulinism. Once the child has stable plasma glucose levels and is tolerating feeding on an age-appropriate schedule, medications should be trialed to eliminate the need for ongoing IV dextrose support.

Diazoxide

Diazoxide is the drug of choice for long-term management of hyperinsulinism. Once a diagnosis of hyperinsulinism has been made, a trial of diazoxide should be initiated in most cases. Diazoxide doses of 5-10 mg/kg/day divided twice daily are usually effective in responsive infants. Doses in older children and adults are generally 100-300 mg/day rather than per kilogram. Doses up to 15 mg/kg/day should be tried before deciding that a patient is not responsive. Diazoxide is only available in oral form and cannot be used in patients that are strictly NPO.

Since the half-life of diazoxide is long (24-36 hours), it should be continued for 5 days before assessing its efficacy. For management of hyperinsulinism, the goal is to keep plasma glucose levels above 70 mg/dL on an age-appropriate feeding schedule. This means being able to skip at least two feedings for an infant (i.e., >8-10 hours) and preferably being able to fast 12-16 hours. If maximal doses of diazoxide (15 mg/kg/day) fail to maintain plasma glucose above 70 mg/dL between normal intervals of feeding for age, it should be discontinued as ineffective. If diazoxide cannot maintain plasma glucose above 70 mg/dL for at least 12-16 hours of fasting, additional therapies will be needed.

Octreotide

Subcutaneous octreotide may be used as alterative therapy to diazoxide. However, many children demonstrate tachyphylaxis due to down-regulation of plasma membrane receptors. Doses of 2-15 µg/kg/day divided every 6 or 8 hours are typical, and treatment should be started at the lowest dose and titrated upward if needed. Of note, fatal instances of necrotizing enterocolitis have been reported in neonates and infants with use of octreotide, so it should only be considered in older infants (>1-2 months of age).

Glucagon

In infants who require a high GIR, intravenous dextrose should be given through a central line, and 20%-25% dextrose should be used to prevent fluid overload. In infants who cannot receive octreotide and are unresponsive to diazoxide, a continuous glucagon infusion of 1 mg/day may help to lower the GIR requirement. However, glucagon is not a long-term option because it is not stable for continuous subcutaneous administration. Glucagon is most commonly used as a temporizing measure in medically unresponsive children who will likely require definitive surgical management.

Surgical management

In cases of congenital hyperinsulinism that cannot be well controlled with maximum doses of diazoxide (15 mg/kg/day) or other medical therapies, surgery may be required. Half of these medically unresponsive children may have a resectable focal lesion of islet adenomatosis, which could be cured with surgical excision. Those with diffuse disease (i.e., without a focal lesion) may require a near-total pancreatectomy. This should only be done after extensive attempts at medical management and at a center experienced in the procedure and postoperative management of these children. Insufficient removal of the pancreas can result in ongoing hypoglycemia. Many infants with near-total pancreatectomy may develop insulin-dependent diabetes.

Medical non-surgical management

Non-surgical management of diazoxide-unresponsive hyperinsulinism may include continuous dextrose via gastrostomy tube, octreotide injections, and frequent feedings. However, such management with continuous dextrose may not be feasible if the GIR is >8-10 mg/kg/min. For those infants with a sufficiently low GIR, intensive medical management may be an option, since the hyperinsulinism tends to become less severe when the child reaches 5-10 years of age or older.

Ineffective therapies

Force-feeding, fortified formulas, or cornstarch are not efficacious and may induce feeding refusal behavior and gastroesophageal reflux problems. Other drugs, including calcium-channel blockers and, especially, glucocorticoids are not effective and should not be used.

What are the adverse effects associated with each treatment option?

Diazoxide can cause salt and water retention, which may lead to edema, especially in infants receiving large amounts of intravenous fluids to control hypoglycemia. In the latter cases, a potent diuretic (e.g., furosemide) should be initiated with the diazoxide. For chronic therapy, thiazide diuretics are sufficient and may be needed only temporarily or not at all in those controlled on lower doses of diazoxide (<5-10 mg/kg/day). There is one report suggesting that diazoxide can precipitate pulmonary hypertension. This may reflect fluid overload from salt and water retention and emphasizes the need for preventing fluid overload with diuretics, closely monitoring fluid status, and minimizing IV fluid volume through the use of 20%-25% dextrose. Biochemical abnormalities and allergic reactions to diazoxide are very uncommon. Long-term treatment with high doses of diazoxide (>10 mg/kg/day) may rarely produce coarsening of facies, possibly due to chronic mild edema. Diazoxide commonly causes increased growth of vellus hair (hypertrichosis), which may require shaving for cosmetic reasons.

Octreotide can cause pain and lumps at injection sites, intestinal cramping, and impaired appetite. Fatal cases of necrotizing enterocolitis have been reported in infants receiving octreotide for hyperinsulinism, albeit rarely. Thus, the drug should be used only cautiously in young infants and preferably not in those less than 1-2 months of age. Although octreotide suppresses thyroid-stimulating hormone and growth hormone release, chronic therapy does not cause hypothyroidism or interfere with growth. Octreotide can impair fat absorption, and long-term treatment may cause gallstones; periodic screening by ultrasonography is recommended.

Intensive medical therapy with tube feeding may interfere with development of normal feeding behavior and may cause chronic feeding refusal or gastroesophageal reflux.

What are the possible outcomes of this disease?

If untreated, hyperinsulinism can cause episodes of severe hypoglycemia resulting in seizures, permanent brain injury, and developmental delays. Treatment is aimed to control plasma glucose and prevent episodes of hypoglycemia and permanent brain injury as much as possible. Since most cases of hyperinsulinism in infants and children are associated with genetic defects, lifelong treatment may be necessary. In many cases, diazoxide works well to control hypoglycemia, and has been used for decades with relatively minor side effects.

In cases of focal hyperinsulinism, surgical resection can be curative. Near-total pancreatectomy for diffuse hyperinsulinism carries a high risk of insulin-dependent diabetes. Intensive medical management carries major burdens for both affected infants and their families.

In some cases, hypoglycemia can become less severe as the child grows older and may be controlled with frequent meals and avoidance of fasting. However, these children still require close monitoring and supervision to avoid the possibility of permanent brain injury from a severe hypoglycemic episode.

What causes this disease and how frequent is it?

The incidence of congenital hyperinsulinism is estimated at 1/40,000; rates up to 1/2500 have been reported in Saudi Arabia due to high rates of consanguinity. Rates of transient perinatal stress hyperinsulinism are not known, but as many as 10% of SGA infants can have persistent hypoglycemia beyond 1 week of age.

Recessive forms of hyperinsulinism are associated with mutations of ABCC8, KCNJ11, and HADH. Dominant forms are associated with mutations of GLUD1, GCK, MCT1, HNF4A, HNF1A, and UCP2. Some mutations of ABCC8 and KCNJ11 are expressed in a dominant rather than the more common recessive fashion. Focal hyperinsulinism is caused by a two-hit genetic mechanism in which a paternally inherited recessive mutation of ABCC8 or KCNJ11 becomes expressed through loss of heterozygosity for the maternal 11p region, leading to a clone of islet cells that are isodisomic for the paternal mutation and overgrow as a result of loss of maternal growth-controlling genes. In addition, there are several syndromes associated with congenital hyperinsulinism, including Beckwith-Wiedemann syndrome, Kabuki syndrome, and Turner syndrome.

A careful family history searching for hypoglycemia or unexplained seizures in family members is important to detect the possibility of an inherited form of hyperinsulinism. Additionally, mutations in HNF4A or HNF1A can result in monogenic diabetes associated with neonatal hyperinsulinism (maturity-onset diabetes of the young, MODY1 and MODY3). However, since many cases of congenital hyperinsulinism are recessive or sporadic, there may be no family history.

Insulinomas may be associated with mutations of menin, which causes MEN1 syndrome (multiple endocrine neoplasia type 1). MEN1 is associated with insulinomas and other endocrine tumors, including parathyroid tumors and prolactinomas. MEN1 is inherited in dominant fashion or can occur sporadically.

How do these pathogens/genes/exposures cause the disease?

The various genetic defects associated with hyperinsulinism cause hypoglycemia because of failure to suppress insulin secretion at low plasma glucose levels. Some defects also show excessive insulin responses to leucine (GLUD1, HADH) or other amino acids (ABCC8 and KCNJ11). These defects are associated with protein-sensitive hypoglycemia, in which hypoglycemia occurs following a high protein meal.

Other clinical manifestations that might help with diagnosis and management

Two genetic forms of hyperinsulinism are associated with specific abnormal biochemical tests that help in diagnosis. Mutations of glutamate dehydrogenase (GLUD1) cause a combination of hyperinsulinism plus persistent elevations of plasma ammonia levels (usually in the range of 70-120 µmol/L, about three to five times the upper limit of normal). Mutations of SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase, HADH) cause hyperinsulinism associated with abnormal accumulation of 3-hydroxy-butyryl-carnitine in plasma (detected by acyl-carnitine mass spectrometry profile).

What complications might you expect from the disease or treatment of the disease?

Complications of hyperinsulinism include seizures, permanent brain injury, and seizures from hypoglycemia. Surgery for diffuse hyperinsulinism carries a risk of diabetes. Surgery for focal hyperinsulinism in experienced centers should not cause a risk of diabetes.

Are additional laboratory studies available; even some that are not widely available?

Genetic mutation analysis is commercially available for most of the known hyperinsulinism genes (ABCC8, KCNJ11, HADH, HNF1A, HNF4A, INSR, GCK, GLUD1, SLC1A1, and UCP2).

How can this disease be prevented?

If the genetic defect in a patient has been established, appropriate counseling for recessive or dominant inheritance should be provided for families to discuss recurrence risk. Prenatal diagnosis is possible if specific mutations have been identified. Two specific ABCC8 mutations are common in those with Ashkenazi Jewish backgrounds and prenatal (or pre-marital) testing may be sought by these families.

As noted above, some genetic forms of hyperinsulinism are associated with protein-sensitive hypoglycemia, so these individuals should be instructed to consume carbohydrates along with high protein meals.

What is the evidence?

Palladino, AA, Stanley, CA. "Nesidioblastosis no longer! It's all about genetics". J Clin Endocrinol Metab . vol. 96. 2011. pp. 617-9.

Palladino, AA, Stanley, CA. "A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism". Semin Pediatr Surg . vol. 20. 2011. pp. 32-7.

Palladino, AA, Bennett, MJ, Stanley, CA. "Hyperinsulinism in infancy and childhood: when an insulin level is not always enough". Clin Chem . vol. 54. 2008. pp. 256-63.

Ferrara, C, Patel, P, Becker, S, Stanley, CA, Kelly, A. "Biomarkers of insulin for the diagnosis of hyperinsulinemic hypoglycemia in infants and children". J Pediatr . vol. 168. 2016. pp. 212-9.

De León, DD, Stanley, CA. "Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates". Nat Clin Pract Endocrinol Metab . vol. 3. 2007. pp. 57-68.

This monograph provides in depth information on the genetic forms of hyperinsulinism, their pathophysiology, and treatment.

Stanley, CA, DeLeon, DD. "Monogenic hyperinsulinemic hypoglycemia disorders. Frontiers in Diabetes, vol 21". Karger. 2012.

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