Hyperinsulinism

Hyperinsulinism (HI) is the most common cause of severe, persistent hypoglycemia in infants and children.[1, 2] Infants with uncontrolled hypoglycemia caused by HI are at risk for seizures or permanent brain damage. There are two forms of HI, as follows:

• Transient neonatal HI: Develops soon after birth and generally resolves by age 6 months
• Persistent HI: Has a more protracted duration; in some cases, the symptoms may manifest after infancy

Transient HI is temporary, but it can cause brain damage if left untreated. Risk factors for this form of HI include the following:

• Maternal diabetes
• Perinatal stress
• Maternal perinatal hypertension
• Intrauterine growth restriction or large for gestational age

The causes of persistent HI are largely genetic.[2, 3, 4] Mutations in at least 11 genes that play a role in regulating beta-cell insulin secretion have been implicated in the pathogenesis of HI.[5] Genetic forms are sometimes classified into seven subtypes[6] :

• K _ATP-hyperinsulinism
• GDH-hyperinsulinism
• GK-hyperinsulinism
• SCHAD-hyperinsulinism
• UCP2-hyperinsulinism
• HNF4A and HNF1A-hyperinsulinism
• MCT1-hyperinsulinism

Several syndromic genetic forms of HI have also been identified (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes).[5]

Maternal diet apparently does not have a significant role on neonatal cord blood insulin, C-peptide, or plasma glucose levels although a lower maternal glycemic load appears to be associated with lower adiposity in infants born to these women.[7]

There remain approximately 50% of diazoxide-responsive cases and 10% of diazoxide-unresponsive cases of persistent HI with unknown etiology, suggesting that additional genes may be identified in the pathogenesis of HI.[6]

Diagnostic criteria include plasma glucose levels less than 3 mmol/L with detectable serum insulin and C-peptide, low serum ketone bodies, and low serum fatty acids. An intravenous glucose infusion rate greater than 8 mg/kg/min (normally, 4-6 mg/kg/min) strongly supports the diagnosis.[8]

Diazoxide is the first-line drug for controlling hypoglycemia in HI, but it is ineffective in some genetic forms (KATP-HI, GK-HI). Octreotide may be used in diazoxide-unresponsive patients but is often ineffective because of down-regulation of the somatostatin receptor, and it carries a risk of causing necrotizing enterocolitis and death.[5] Severe cases of congenital HI may be unresponsive to either diazoxide or octreotide and require intensive management with tube feedings, near-total pancreatectomy, or partial pancreatectomy. The image below illustrates the mechanisms of insulin secretion.

Hyperinsulinism. Mechanisms of insulin secretion.

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.

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 [G6P] 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 two 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.

Transient causes

Transient causes of hyperinsulinism 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 causes

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

Congenital causes of hyperinsulinism 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

Focal causes of hyperinsulinism 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 yr), they are increasingly more likely to have the focal form of hyperinsulinism.

• 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

Genetic causes of hyperinsulinism include those discussed below.

Pancreatic B-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 down-regulates 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): EIHI is characterized by inappropriate insulin secretion that leads to hypoglycemia during exercise. Promoter-activating mutations of SLC16A1 gene encode 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 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 is characterized by increased levels of 3-hydroxybutyryl-carnitine in blood and 3-hydroxyglutaric acid in urine. However, the precise mechanism of hyperinsulinism in patients with an 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 an important role in pancreatic development, maintenance of B-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.[9]

In the United States, hyperinsulinemia (HI) is estimated to occur in 1 in 30,000-50,000 live births.[6] In Japan, the incidence of transient neonatal HI is estimated at 1 in 17,000 births and that of persistent hypoglycemia at 1 in 35,400 births.[10] Estimates of the incidence of congenital HI range from 1 in 50,000 births in Holland to as high as 1 in 2500 in Saudi Arabia (due to high rates of consanguinity). Among Ashkenazi Jews, the incidence, based on the carrier frequency for two recessive KATP-HI founder mutations, has been estimated to be 1 in 10,816. However, these incidence rates likely underestimate the prevalence of congenital HI because they do not include other forms of the disorder.[5]

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.

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.

Multiple factors affect prognosis, such as the severity of the disease at presentation, duration of hypoglycemia, etiology of hyperinsulinism, and presence of neurologic complications. The risk of permanent brain injury in infants with HI is as high as 25–50% due to delays in diagnosis and inadequate treatment.[5]

Unfortunately, many infants with hyperinsulinism remain undiagnosed, misdiagnosed, or inadequately treated for several months before definitive management. However, definitive care is available at Children's Hospital of Philadelphia (Philadelphia, Pennsylvania), Cook Children's Health Care System (Fort Worth, Texas), Great Ormond Street Children's Hospital (London, England), Necker-Enfants Malades Hospital (Paris, France), Hadassah–Hebrew University Medical Center (Jerusalem, Israel), and New Children's Hospital (Helsinki, Finland). As with most rare diseases in children, timely referral to such centers provides optimal management.

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.[11]

Diabetes mellitus, which develops in patients with diffuse disease, is caused by dysregulation of insulin secretion in the residual beta cells after pancreatectomy.

Complications

Complications of congenital hyperinsulinism include seizures, developmental delays, and death.

In a retrospective chart review, symptomatic hypertrophic cardiomyopathy (HCM) was found in approximately 15% (95% CI, 6-23%) of infants with congenital hyperinsulinism (95% CI, 6-23%). All the affected infants had the KATP-channel form of hyperinsulinism and ultimately failed medical management and required pancreatectomy. The researchers noted that echocardiography was performed only on symptomatic children, and the incidence of cardiomyopathy in infants with congenital hyperinsulinism is likely higher. Additionally, HCM was only identified in patients who had undergone pancreatectomy, which suggests infants with more severe hyperinsulinism have a higher risk of a disturbance in cardiomyocyte growth.[12]

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. Prolonged fasting should be avoided. Seek medical attention if emesis or anorexia develops. Families should be equipped with glucagon and instructed in its use in case hypoglycemia does occur.

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.[3]

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.

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.

All patients suspected of having hyperinsulinism should have blood obtained for measurement of concentrations of plasma glucose, insulin, proinsulin, C-peptide, growth hormone, cortisol, free fatty acids, and beta-hydroxybutyrate. Arterial blood gas (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 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.

Because pancreatic adenomas are often very small and have the same density as the normal pancreas, radiographic studies such as ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) are often of limited value. Pancreatic arteriography and transhepatic pancreatic selective venous sampling have 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 Fluorine-18-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET) scanning for identifying such lesions.[14, 15, 16]

More recently, investigators have indicated that glucagon-like peptide 1 receptor (GLP-1R) PET/CT imaging with the novel radiotracer [68Ga]Ga-NODAGA-exendin-4 can be used to visualize beta-cell mass in the islets of Langerhans and thus has the potential for detecting not only insulinomas but also focal lesions in congenital hyperinsulinism (CHI).[17]

Genetic mutation testing is now well established as the standard of care to define best approaches to treatment of congenital HI.[5] Parent-of-origin testing should routinely be included at the time of patient testing. This is particularly essential if focal KATP HI is a possibility, because the demonstration of a paternally transmitted, monoallelic, recessive mutation in ABCC8 or KCNJ11 is highly accurate for predicting a potentially curable focal lesion (97% sensitivity, 92% specificity)[18] .

New methods make it possible to obtain results in less than a week, preferably within 2 or 3 days. Rapid turnaround time for genetic tests is required because treatment decisions need to be made within a few days for often severely ill infants.[5]

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.[18, 19]

Genetic testing is also essential for recognition of syndromic forms of HI such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation.[6]

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.

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

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).

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. 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.

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 an 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 hr) 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.

Medical therapy is the treatment of choice.[20] Patients with hyperinsulinism often require multiple medications to maintain normoglycemia. Medications used to treat hyperinsulinism include the following:

• Dextrose
• Diazoxide
• Octreotide
• Nifedipine
• Sirolimus

Dextrose is the most common initial approach to hypoglycemia in infants.[21] A 2 mL/kg to 3 mL/kg (200–300 mg/kg) intravenous bolus of 10% dextrose is given, followed by a continuous infusion.[22] Dextrose concentrations of up to 20-25% may be required in order to deliver glucose infusion rates in the 15-30 mg/kg/min range. If the infant’s serum glucose cannot be maintained above 60 mg/dL, other medications may be considered until a definitive diagnosis is made.[21]

Diazoxide is the first-line treatment for persistent HI and the only drug approved by the US Food and Drug Administration (FDA) for long-term treatment of hyperinsulinemic hypoglycemia. Initial administration is 10-15 mg/kg/day orally in 2 to 3 divided doses. Doses are titrated based on laboratory results. When effective, hypoglycemia normalizes within 2-4 days, although a trial of 5-8 days is required before treatment failure is determined.[22] Apart from hypertrichosis, adverse effects are generally limited to fluid retention, which, in infants needing high rates of IV dextrose, often requires prophylaxis with potent diuretics to avoid heart failure.[5]

In infants who fail to respond to diazoxide, octreotide is initiated. Initial dosage should not exceed 15 mcg/ kg/day, as serious adverse effects such as necrotizing enterocolitis (NEC), gallstones, and hepatitis are linked to higher doses.[23] Patients may have a good response to octreotide and can successfully be weaned off of dextrose infusions, while others may have no response or an incomplete response such that a continuous infusion of dextrose is still required.[22]

Nifedipine is a calcium channel antagonist used as an add-on treatment in partial diazoxide/octreotide resistance, and/or following partial pancreatectomy.[23]

Sirolimus, a mammalian target of rapamycin inhibitor, has been reported to be effective in treating congenital hyperinsulinism in infants and children unresponsive to maximal doses of diazoxide and octreotide.[24, 25, 26]

Localized resection can be curative for focal-type congenital hyperinsulinism (CHI) and insulinomas refractory to medical treatment.[27]  Near-total pancreatectomy is required for cure of diffuse-type CHI, but it is associated with complications such as diabetes, exocrine insufficiency, or persistent hypoglycemia.[27]

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

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.[11] One study showed almost 94% of focal hyperinsulinism cases required no further treatment, versus 41% with diffuse hyperinsulinism that showed continued hypoglycemia postoperatively.[28]

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.

Consultation may be required with the following specialists for diagnosis and management of hyperinsulinism:

• Pediatric endocrinologist
• Pediatric surgeon
• Neonatologist
• Geneticist (if family history is present or suspected)

Transfer to a tertiary care facility (eg, academic children's hospital) is preferred for prompt diagnosis and medical treatment or surgical intervention and possible enrollment in clinical research protocols.

The American Academy of Pediatrics (AAP) Committee on Fetus and Newborn published guidelines for the screening for neonatal hypoglycemia.[3]  The guidelines include an algorithm for determining which infants to screen, when to screen, and clinical signs. Routine screening and monitoring of blood glucose is not recommended; only infants who have clinical manifestations of neonatal hypoglycemia or asymptomatic infants with risk factors should be screened. Clinical signs and symptoms of hypoglycemia include the following:

• Jitteriness
• Cyanosis
• Seizures
• Apneic episodes
• Tachypnea
• Weak or high-pitched cry
• Floppiness
• Lethargy
• Poor feeding
• Eye-rolling

Risk factors for asymptomatic infants are as follows[3] :

• Small for gestational age
• Large for gestational age
• Born to mothers who have diabetes
• Late-preterm infants

At-risk infants should be screened with a frequency and duration related to risk factors specific to the individual infant. Screening asymptomatic at-risk infants can be performed within the first hours of birth and continued through multiple feed-fast cycles. Late-preterm infants and infants who are small for gestational age should be fed every 2 to 3 hours and screened before each feeding for at least the first 24 hours. After 24 hours, repeated screening before feedings should be continued if plasma glucose concentrations remain lower than 45 mg/dL.[3]

 Thus, recommended screening of asymptomatic neonates from birth to 24 hours is as follows[3] :

• 0-4 hours: Maintain blood glucose levels above 40 mg/dL before feeding
• 4-24 hours: Maintain blood glucose levels above 45 mg/dL. If the neonate is symptomatic , then treat the infants if their blood glucose is below 40 mg/dL.

The Pediatric Endocrine Society (PES) guidelines for evaluation and management of persistent hypoglycemia in neonates, infants, and children recommend expanding the screening list beyond the American Academy of Pediatrics (AAP) recommendations to include infants that experienced perinatal stress due to the following[4] :

• Birth asphyxia/ischemia; cesarean delivery for fetal distress
• Maternal preeclampsia/eclampsia or hypertension
• Meconium aspiration syndrome, erythroblastosis fetalis, polycythemia, hypothermia

Other risk factors that should prompt screeining include the following[4] :

• Family history of a genetic form of hypoglycemia
• Congenital syndromes (eg, Beckwith-Wiedemann), abnormal physical features (eg, midline facial malformations, microphallus)

Additionally, persistent hypoglycemia should be excluded before discharge of infants with the following[4] :

• Severe hypoglycemia (eg, episode of symptomatic hypoglycemia or need for IV dextrose to treat hypoglycemia)
• Inability to consistently maintain preprandial PG concentration >50 mg/dL up to 48 hours of age and >60 mg/dL after 48 hours of age
• Family history of a genetic form of hypoglycemia
• Congenital syndromes (eg, Beckwith-Wiedemann), abnormal physical features (eg, midline facial malformations, microphallus)

For at-risk neonates without a suspected congenital hypoglycemia disorder, the goal of treatment is to maintain a plasma glucose concentration >50 mg/dL in the first 48 hours of life and >60 mg/dL after 48 hours. For neonates with a suspected congenital hypoglycemia disorder, the goal of treatment is to maintain the plasma glucose concentration >70 mg/dL.[4]

Thus, the recommended screening for neonatal hypoglycemia from birth to 24 hours is as follows[4] :

• First 48 hours: Maintain blood glucose levels above 50 mg/dL. Infants unable to maintain these levels in this time period may be at risk for a congenital hypoglycemia disorder.
• After 48 hours: Maintain blood glucose levels above 60 mg/dL. It is recommended that infants at risk of having a persistent hypoglycemia syndrome undergo a fast challenge of 6-8 hours with maintenance of blood glucose levels above 70 mg/dL

Medications used to manage hyperinsulinism include diazoxide, octreotide, nifedipine, glucagon, growth hormone, and glucocorticoids. The choice of medications varies with the etiology and severity of hypoglycemia in individual patients.

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.

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.

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.