Treatment and outcomes of congenital hyperinsulinism

INTRODUCTION — Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants and children. Dysregulated insulin secretion leads to severe recurrent hypoglycemia and suppresses production of ketone bodies, a crucial alternative fuel for the brain. These metabolic abnormalities result in a high risk of brain damage and subsequent neurologic sequelae, such as development delays and epilepsy [1]. The goal of HI management is to prevent hypoglycemia through the use of appropriate medical therapy, or surgical intervention in the case of the focal form. Genetic testing and advanced imaging techniques have allowed for more tailored approaches to treatment, resulting in improved outcomes.

An overview of the treatment, complications, and long-term outcomes of HI will be presented here. The pathophysiology, genetics, clinical features, and diagnosis of HI are discussed in more detail separately. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

TREATMENT GOALS — The main principles of HI management are:

●Rapid correction of hypoglycemia, followed by measures to maintain plasma glucose within the normal range (plasma glucose >70 mg/dL).

●Initiation of optimal therapy for the specific HI type (presumed or confirmed), while allowing normal feeding behavior for patient age.

●Prevention or mitigation of brain damage by maintaining euglycemia, with early identification of any deficits through periodic developmental assessments to permit appropriate therapies or educational interventions (table 1).

ACUTE TREATMENT — Administer an intravenous (IV) dextrose bolus (2 mL/kg of 10% dextrose [0.2 g dextrose per kg of body weight]) to rapidly bring plasma glucose into the normal range. If IV access cannot be readily obtained, 1 mg of glucagon can be given intramuscularly to rapidly increase the glucose in children with known HI. A sample of blood should be taken for diagnostic testing ("critical sample") before administering the dextrose bolus, provided that it does not delay treatment.

Following the initial dextrose bolus, an IV dextrose infusion should be started at a glucose infusion rate (GIR) of 5 to 6 mg/kg/min and titrated up to achieve a plasma glucose >70 mg/dL. The initial titration should be performed rapidly (eg, measuring plasma glucose every 30 to 60 minutes and adjusting the GIR accordingly) until a stable plasma glucose within the normal range is established. Infants with HI often require GIRs >10 mg/kg/min and some require GIRs of 20 to 30 mg/kg/min to maintain euglycemia. However, it is important to note that some infants with hyperinsulinism have lower GIR requirements (<10 mg/kg/min). To minimize fluid overload, higher concentrations of dextrose (20 to 50%) can be administered via a central venous catheter.

A concurrent continuous IV infusion of glucagon (eg, 1 mg/day) can be considered if the GIR is high and fluid overload is a concern, while the child awaits definitive treatment [2]. It can lower GIR requirements and prevent or mitigate fluid overload. Due to its poor solubility, glucagon must be administered through IV and therefore is not a long-term management option. New formulations with improved solubility are in development, which will allow for subcutaneous administration via an insulin pump [3].

Additional details on the acute treatment of hypoglycemia are provided in a separate topic review. (See "Approach to hypoglycemia in infants and children".)

INITIAL MANAGEMENT

Diagnosis — A diagnostic evaluation for causes of hypoglycemia should be undertaken once the child is clinically stable. Key steps are confirmation of HI by tests performed on the "critical sample" collected during an episode of hypoglycemia (table 2), followed by a trial of diazoxide, and identifying the type of HI based on the response to diazoxide and genetic testing results (algorithm 1). (See "Approach to hypoglycemia in infants and children" and "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

Nutrition — Infants should be allowed to feed on demand and/or receive appropriate feeding volumes based on age and weight. Similarly, older children should be maintained on an age-appropriate diet. Nutritional modifications, such as fortified feeds, alone are not sufficient to treat HI. Moreover, forced feeds or continuous feedings lead to poor feeding skills and long-term feeding aversion [4].

Diazoxide trial — Once the diagnosis of HI has been made, the critical next step is to determine if the child responds to diazoxide (algorithm 1). This trial establishes therapeutic benefit and also provides important phenotype information. Diazoxide is the first-line agent for the treatment of HI and is the only oral agent available. An agonist of the sulfonylurea receptor (SUR-1), it opens the adenosine triphosphate-sensitive potassium (K_ATP) channel and inhibits insulin secretion [5]. The majority of children with K_ATP-HI will not respond to diazoxide, because they do not express SUR-1 on the beta cell plasma membrane.

●Initiation – Diazoxide is initiated at 5 mg/kg/day (or 10 mg/kg/day in more severe cases, such as those requiring a glucose infusion rate [GIR] >10 mg/kg/min). If hypoglycemia persists after two to three days on the initial dose, diazoxide should be titrated up to a maximum of 15 mg/kg/day (maximum dose 500 mg twice daily for an adult).

●Test for diazoxide responsiveness – After five days on a stable dose, a carefully monitored fast ("safety fast") should be performed to determine whether the diazoxide treatment has corrected the cardinal feature of HI, which is hypoketotic hypoglycemia during fasting (algorithm 1).

Safety fast protocol:

•Start of test – The fast typically begins after dinner, bedtime snack, or evening feed

•Monitoring – Obtain bedside plasma glucose and beta-hydroxybutyrate (BOHB), if available, every three hours while plasma glucose is >70 mg/dL (3.9 mmol/L)

•Endpoint of test – The test should be ended when any of the following conditions are met:

-Plasma glucose is <70 mg/dL (3.9 mmol/L)

-Bedside plasma BOHB is >2.5 mmol/L

-A specific duration has been reached (12 hours if <1 year old, 18 hours if >1 year old)

-Child develops symptoms of neuroglycopenia

●Interpretation – Diazoxide responsiveness is defined by the following glucose and/or ketone response during the safety fast [6]:

•Plasma glucose maintained ≥70 mg/dL, or

•BOHB rises to >2 mmol/L before plasma glucose drops below 50 to 60 mg/dL

Subsequent medical therapy is guided by the results of this trial, as outlined in the next section.

DIAZOXIDE-RESPONSIVE PATIENTS — Children who respond to diazoxide may be safely discharged on diazoxide, with home glucose monitoring (algorithm 1). Comprehensive HI genetic testing should be considered to assist with prognosis and guide duration of therapy as well as future family planning. The main side effect seen with diazoxide is fluid overload, which can result in respiratory and cardiac complications in younger patients [7]. Neonates and infants treated with diazoxide should also be placed on a diuretic such as chlorothiazide to reduce this risk (chlorothiazide dose 10 to 30 mg/kg/day, in two divided doses) (table 3). Diazoxide may also result in nausea, decreased appetite, and, in rare cases, feeding intolerance. Reports suggest that use of diazoxide in neonates may be associated with an increased risk of necrotizing enterocolitis, but additional studies are needed to better understand the association [8,9].

DIAZOXIDE-UNRESPONSIVE PATIENTS — For children who do not respond to diazoxide, diazoxide should be discontinued and the hypoglycemia treated with intravenous (IV) dextrose, while proceeding with expedited genetic testing (algorithm 1). An IV infusion of glucagon may be used if needed if the glucose infusion rate (GIR) is high and fluid overload is a concern. (See 'Acute treatment' above.)

Genetic testing — Genetic testing is imperative for all of these children because approximately 90 percent of children with diazoxide-unresponsive HI carry a mutation in the ABCC8 or KCNJ11 genes, and some of these children have a focal form of HI that can be cured by surgery (algorithm 1) [10]. Approximately 50 to 60 percent of patients with adenosine triphosphate-sensitive potassium (K_ATP)-HI (the most common genetic type) have the focal form. Referral to a center specializing in the care of HI patients should be considered for interpretation of the results and further evaluation. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism", section on 'Genetic testing'.)

18F-DOPA PET scan — The 18-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography (¹⁸F-DOPA PET) scan is used to localize focal lesions prior to surgery [11,12]. This scan and surgery require referral to a specialized center. Surgical resection of the focal lesion is curative, so identifying patients with focal HI and localizing the lesion in the pancreas is critical to their treatment.

●Indications – Indications for an ¹⁸F-DOPA PET scan include:

•Genetic testing consistent with focal HI (paternally inherited recessive mutation in the ABCC8 or KCNJ11 genes).

•Negative genetic analysis in a child with diazoxide-unresponsive HI. This includes cases in which no mutations were identified, as well as cases with variants of unknown significance in ABCC8 or KCNJ11.

•Suspected Beckwith-Wiedemann syndrome and severe HI requiring pancreatectomy.

¹⁸F-DOPA PET scans are not indicated for children who have diazoxide-responsive HI or children whose genetic testing is consistent with diffuse disease, such as biallelic recessive mutations in ABCC8 or KCNJ11 or mutations in GCK.

●Test characteristics – ¹⁸F-DOPA is taken up by neuroendocrine tissue in the pancreas. The ¹⁸F-DOPA PET scan should be utilized primarily to localize focal lesions in those children with suspected focal HI. In focal HI, there is increased tracer uptake in a specific area of the pancreas, corresponding to the focal lesion (image 1). In diffuse HI, there is uniform uptake of the tracer throughout the pancreas.

Studies have demonstrated that 90 to 100 percent of focal lesions are correctly localized in the pancreas [13-15]. Development of this scan was a significant advance in the treatment of children with focal HI, allowing for accurate localization of the lesion prior to surgery and minimizing the extent of pancreas resected [13]. Conventional imaging such as computed tomography (CT) or magnetic resonance imaging (MRI) cannot detect focal lesions, and interventional radiology techniques are invasive and only marginally effective at localizing lesions [16].

Patients with focal hyperinsulinism — Patients with focal HI, as determined by ¹⁸F-DOPA PET scanning, should undergo surgical resection of the lesion, which is curative [17]. Children with focal HI should undergo treatment at a specialized HI center where a multidisciplinary team has the necessary expertise to ensure successful outcomes [18]. In addition to the presurgical ¹⁸F-DOPA PET scan, intraoperative ultrasound can be utilized to identify the focal lesion. Frozen section analysis during surgery is necessary to confirm complete resection of the focal lesion. In a large study of children with HI undergoing pancreatectomy, 97 percent of children with focal HI were cured through partial pancreatectomy and the majority required less than 50 percent of their pancreas removed [17].

Patients with diffuse hyperinsulinism — For children with diffuse HI who do not respond to diazoxide, the next step is either a trial of intensive medical therapy or referral for near-total pancreatectomy (algorithm 1). Intensive medical therapy is generally associated with a greater risk for hypoglycemia compared with near-total pancreatectomy, as well as the risk of side effects from prolonged somatostatin analog use. However, it avoids an invasive surgical procedure and the long-term risk of diabetes and exocrine insufficiency that come with a near-total pancreatectomy. The management of these children is complex and requires careful consideration of the risks and benefits of each approach, which vary with patient characteristics (eg, a high glucose requirement [GIR] may favor the surgical approach), as well as the family's preferences and values. These decisions should be made by a team experienced in the care of HI patients, in close collaboration with the family.

Intensive medical therapy — For children with diffuse HI who do not respond to diazoxide, intensive medical management initially involves treatment with enteral dextrose, followed by introduction of octreotide after two to three months of life. While research into new therapies is ongoing, options for medical therapy are limited (table 3).

●Enteral dextrose – A continuous enteral infusion of dextrose is administered via nasogastric or gastrostomy tube. This typically consists of a 20% solution of dextrose, with a maximum GIR of 10 mg/kg/min [19]. This approach is preferred over continuous enteral nutrition, which can result in long-term feeding aversion. While a dextrose infusion provides a small portion of the child's caloric needs, the majority of the nutritional needs are supplied by oral feeding.

●Somatostatin analogs – Octreotide, a short-acting somatostatin analog, is effective for short-term management of refractory hypoglycemia, but its use is limited by tachyphylaxis and the burden of multiple subcutaneous injections per day [20]. The dose is 2 to 20 mcg/kg/day, divided every six to eight hours (maximum total dose 500 mcg/day for an adult).

Octreotide may be associated with fatal necrotizing enterocolitis in young infants [21-23]. Therefore, in infants younger than eight weeks of age, octreotide should be used with extreme caution and only if there are no other risk factors for necrotizing enterocolitis. Other potential adverse effects include gallstones, aminotransferase elevations, malabsorption, and hypothyroidism.

Lanreotide is a long-acting somatostatin analog administered as a monthly injection [24]. The dosing range is 60 to 120 mg every 28 days. Given limited safety data, lanreotide is typically reserved for children aged one year or older.

The side effect profiles of octreotide and lanreotide are similar. These are second-line agents in the treatment of HI and should only be considered for use in children who are not responsive to diazoxide.

Other medications have been trialed as treatment for HI with limited success. Steroids have no efficacy in HI and expose children to unnecessary side effects. They should not be used as a treatment for HI. Calcium channel blockers, such as nifedipine, have also been trialed without success [25]. A mammalian (mechanistic) target of rapamycin (mTOR) inhibitor, sirolimus, was initially reported as an effective treatment, but subsequent studies failed to show efficacy [26,27]. Sirolimus is not recommended to treat children with HI, due to the risk of immune compromise [28].

Near-total pancreatectomy — Children with diffuse HI who fail medical therapy undergo a near-total (98 percent) pancreatectomy and gastrostomy tube placement [17]. This surgery is palliative only, and the majority of children have ongoing hypoglycemia, albeit less severe [29,30]. The gastrostomy tube helps to facilitate enteral administration of dextrose postoperatively. Long-term outcomes for patients who undergo near-total pancreatectomies, including development of diabetes, are discussed below.

OUTCOMES

Neurocognitive outcomes — Brain damage is a well-known consequence of hypoglycemia. In children with HI, the risk is particularly high due to the severity of the hypoglycemia as well as suppression of ketone production, a critical alternative fuel for the brain. The prevalence of neurodevelopmental deficits in children with HI is 26 to 48 percent, and the prevalence of epilepsy is 13 to 29 percent [31-34]. Behavioral problems, speech delays, and learning disabilities are the most common neurodevelopmental abnormalities reported [32]. Despite the difference in long-term hypoglycemia outcomes, children with diffuse and focal HI have similar rates of developmental abnormalities. Children with transient forms of HI are also at risk of abnormal development. The proportion of developmental delays in children with transient HI is not statistically different from those with the congenital forms [35,36].

Despite significant advances in prompt diagnosis and management of HI, the prevalence of neurodevelopmental deficits has not decreased over time [32]. Therefore, early identification and treatment of developmental issues are essential. All children with HI, regardless of type or treatment, should have periodic developmental assessments and, if an abnormality is found, be quickly referred for therapy (table 1).

Postpancreatectomy outcomes — Children who undergo near-total pancreatectomy are at high risk of diabetes and exocrine insufficiency. In a study of 105 children with HI who underwent pancreatectomy, 100 percent of patients with the diffuse form had documented hyperglycemia at age 13 years and 91 percent required insulin at age 14 years [30]. The median age of diabetes diagnosis is approximately eight years [30-32]. Children with postpancreatectomy diabetes have lower insulin requirements than those with type 1 diabetes, although hemoglobin A1c levels are compatible between the two groups [37]. The development of exocrine insufficiency has not been extensively examined yet. One study of 45 children who underwent near-total pancreatectomy for diffuse HI found that 72 percent had an undetectable fecal elastase and 49 percent had clinical symptoms consistent with exocrine insufficiency [38]. Screening for diabetes and exocrine insufficiency is recommended for any child who has undergone a near-total pancreatectomy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in infants and children".)

SUMMARY AND RECOMMENDATIONS

●Clinical importance and goals – Hyperinsulinism (HI) is associated with a high risk of neurologic damage due to the severity of the hypoglycemia and the suppression of ketones, a critical alternative fuel for the brain. To mitigate the risk of long-term neurologic sequela, principles of management include early identification of patients and initiation of appropriate therapy to maintain euglycemia (plasma glucose ≥70 mg/dL). (See 'Treatment goals' above.)

●Diazoxide-responsive patients – Management of HI is summarized in the algorithm (algorithm 1). The first step is a therapeutic trial of diazoxide, which is an adenosine triphosphate-sensitive potassium (K_ATP) channel agonist (table 3). Diazoxide should be continued in those who respond well to this treatment, ie, children who are able to maintain euglycemia on an age-appropriate diet and while fasting. (See 'Diazoxide trial' above.)

●Diazoxide-unresponsive patients – Children who do not respond to diazoxide may have focal HI, which can often be cured by surgery. Next steps are (algorithm 1):

•Genetic testing – To evaluate for focal HI, perform expedited genetic analysis of the ABCC8 or KCNJ11 genes, using a laboratory that can provide results within four to seven days. Mutations in these genes are responsible for 90 percent of cases of diazoxide-unresponsive HI. A paternally inherited recessive mutation in ABCC8 or KCNJ11 has a 94 percent positive predictive value for focal HI. (See 'Genetic testing' above.)

•¹⁸F-DOPA PET (selected patients) – For all children with a paternally inherited recessive mutation in the ABCC8 or KCNJ11 genes or those with a negative genetic analysis (but not those with biallelic recessive mutations in ABCC8 or KCNJ11 or mutations in GCK), perform 18-fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography (¹⁸F-DOPA PET). The purpose of this scan is to localize the lesion prior to surgery (image 1). This scan is also indicated for patients with suspected Beckwith-Wiedemann syndrome and severe HI requiring pancreatectomy. (See '18F-DOPA PET scan' above.)

•Patients with focal HI – Surgical intervention is indicated for children with focal HI who fail medical management (algorithm 1) [17]. Resection of the focal lesion via partial pancreatectomy is curative for children with focal disease. (See 'Patients with focal hyperinsulinism' above.)

•Patients with diffuse HI – For children with diffuse HI who do not respond to diazoxide, the next step is either a trial of intensive medical therapy or referral for a near-total pancreatectomy (algorithm 1). Deciding between the medical and surgical approaches requires careful consideration of their risks and benefits, as well as close collaboration between the family and a team specializing in the care of children with HI. (See 'Patients with diffuse hyperinsulinism' above.)

-Intensive medical therapy consists of continuous dextrose administration via gastrostomy tube, combined with a somatostatin analog (after age two months). This approach is generally associated with a greater risk for hypoglycemia compared with near-total pancreatectomy, as well as the risk of side effects from prolonged somatostatin analog use (table 3). (See 'Intensive medical therapy' above.)

-After near-total pancreatectomy, the majority of children will continue to have hypoglycemia, albeit less severe, and all children will eventually develop insulin-dependent diabetes [30]. (See 'Postpancreatectomy outcomes' above.)

●Neurocognitive outcomes – Despite advances in the field, the risk of neurocognitive abnormalities in children with HI remains high. Developmental deficits occur in 26 to 48 percent of individuals with HI, and 13 to 26 percent have epilepsy [31-34]. This elevated risk occurs in both transient and monogenic forms [35]. Early identification and treatment of developmental issues are essential. All children with HI, regardless of type or treatment, should have periodic developmental assessments (table 2). If an abnormality is found, the child should be promptly referred for therapy. (See 'Neurocognitive outcomes' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Agneta Sunehag, MD, PhD, and Morey W Haymond, MD, who contributed to an earlier version of this topic review.