Newborn with persistent hypoglycemia

THE CASE

A full-term male infant was born to a 33-year-old gravida 3, para 3 mother. The prenatal course was uncomplicated, without gestational diabetes; the mother received prenatal care at an out-of-state institution. At the delivery, however, the baby was notably macrosomic, with shoulder dystocia and perinatal distress requiring positive pressure ventilation. 

The infant’s APGAR scores were 2 and 8 at 1 and 5 minutes, respectively. Birth anthropometrics showed a weight of 4385 grams (>97th percentile); a birth length of 58.5 cm (>97th percentile); and a head circumference of 37.5 cm (~75th percentile). Physical examination was otherwise unremarkable.

The baby’s initial point-of-care glucose value, obtained from a heel stick sample, at 2 hours of life was 22 mg/dL, with a confirmatory serum glucose of 37 mg/dL. He had no concerning symptoms such as seizures, lethargy, or poor feeding. Despite regular formula feeds, the serum glucose remained in the 40-mg/dL to 49-mg/dL range. An intravenous (IV) dextrose infusion was started with a glucose infusion rate (GIR) of 9 mg/kg/min. At this time, it was presumed that the hypoglycemia was transient, a result of the macrosomia combined with perinatal stress. The baby was evaluated for 48 hours for sepsis; his blood culture ultimately was negative.

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Over the next 3 days, the dextrose concentration in the patient’s IV fluids was increased. By the third day of life, he was maintained on a GIR of 17 mg/kg/min to keep his serum blood sugar above 60 mg/dL. The differential diagnosis at this time expanded to include: hypopituitarism, adrenal insufficiency, growth hormone deficiency, inborn errors of metabolism, and congenital hyperinsulinism.¹ A critical serum sample drawn during a hypoglycemic event of 32 mg/dL on point-of-care testing demonstrated the following: serum glucose, 41 mg/dL; cortisol, 17.6 μg/dL (normal during hypoglycemia, >17 ug/dL); growth hormone, 30.6 ng/mL (normal during hypoglycemia, >8.8 ng/mL); undetectable plasma ketones (fasting normal, 0.2-2.8 mg/dL); undetectable free fatty acids (fasting normal, 0.43-1.37 mmol/L); and insulin, 61 μU/mL (normal during hypoglycemia, <2 μU/mL).

Differential diagnosis

Glucose is the main energy source for metabolic functioning. The body regulates glucose by way of multiple hormones, the most significant of which is insulin, produced by the beta cells of the pancreas. Insulin facilitates the transport of glucose out of the bloodstream and into cells.² Additionally, insulin halts all metabolic processes that produce glucose and its metabolic substitutes, ketones and fatty acids.

Because the brain is an obligate consumer of glucose and ketones, hypoglycemia creates a dangerous situation for the neonate, risking brain injury from such an insult.³ Hypoglycemia in children has traditionally been defined as a blood glucose of <55 mg/dL to <65 mg/dL, the point at which brain glucose utilization becomes impaired. However, in neonates outside the first 48 hours of age, the value at which diagnostic workup is warranted is usually <60 mg/dL. Seizures are present in only 50% of hypoglycemic neonates, and other symptoms can be nonspecific and subtle, thus making the diagnosis challenging.^1,2 As such, conditions that cause persistent hypoglycemia beyond 2 to 3 days of life should be evaluated and managed promptly.³

Related: Dueling hypoglycemia guidelines from AAP and PES

The etiology of neonatal hypoglycemia can be categorized as: physiologic, counterregulatory hormone deficiency, hyperinsulinism, and other inborn errors of metabolism (Table 1^1,2,4). Physiologic hypoglycemia can occur initially because it can take up to 48 hours for the body to properly regulate insulin levels. Furthermore, perinatal stress can deplete hepatic glycogen stores, leading to hypoglycemia. Growth hormone or cortisol deficiency inhibits production of hepatic glucose, which will also cause hypoglycemia.

The leading cause of persistent neonatal hypoglycemia, defined as hypoglycemia beyond the first 48 hours of life, is hyperinsulinism.^3,5 Insulin can be inappropriately elevated secondary to high intrauterine production (in response to maternal hyperglycemia), overgrowth syndromes, insulin-secreting tumors, or genetic abnormalities leading to constitutively insulin dysregulation. Finally, there are inborn errors of metabolism that inhibit glucose production, such as the glycogen storage diseases and fatty acid oxidation disorders.

Diagnosis of hyperinsulinism

The diagnosis of hyperinsulinism is confirmed by laboratory testing, the most important group of which is the critical sample, a lab draw taken during the period of untreated hypoglycemia (Table 2^3,6). Because of inherent variability in point-of-care glucose finger-stick samples, a low capillary glucose value must always be confirmed by a plasma glucose sample. Additionally, insulin levels and C-peptide are drawn; however, these values are not very sensitive.⁵

The presence of hyperinsulinemia can be confirmed by checking plasma ketones (β-hydroxybutyrate or BHB), free fatty acids (FFA), and insulin-like growth factor binding protein-1 (IGFBP1)-substances that should be elevated in hypoglycemia to provide the brain with sufficient fuel, but are suppressed by insulin.⁶ Growth hormone and cortisol are counterregulatory hormones that increase in response to hypoglycemia and are not affected by hyperinsulinemia. A glucagon stimulation test can also be performed.^2,3 This dynamic test determines if there is inappropriate sequestration of hepatic glycogen during an acute hypoglycemic event. If insulin “puts the break” on glucose formation, then glucagon acts to “release the break.” If administering a 1-mg intramuscular dose of glucagon results in a glucose increase of at least 30 mg/dL, one can infer that hyperinsulinemia is the cause of hypoglycemia (Table 3^3,6).

Back to the case

Upon seeing the inappropriately high insulin level with appropriately high cortisol and growth hormone responses, the diagnosis of hyperinsulinemic hypoglycemia was made, and no glucagon stimulation test was performed. It was during this time, however, that the mother mentioned that her 13-year-old daughter had experienced the same difficulty after birth. Upon further inquiry, it was discovered that the daughter had required surgery, presumably a pancreatectomy, to “cure” her low blood sugars. The family provided her genetic testing results, which showed a mutation in the ABCC8 gene consistent with congenital hyperinsulinism secondary to a monogenic etiology. This significant family history, which had been overlooked until now, signaled that this patient’s hypoglycemia would be anything but transient.

The patient was started on oral diazoxide, titrated to a dose of 15mg/kg/day. However, he continued having intermittent hypoglycemia to the 40s to 50s on point-of-care testing and confirmed by serum glucose. A gastric tube was placed to maximize carbohydrate intake, and subcutaneous octreotide was added and titrated to a dose of 10 μg/kg every 6 hours, with only marginal improvement. Even a trial of nifedipine proved unsuccessful. A glucagon infusion was necessary as a last pharmacologic resort.

Discussion

Monogenic congenital hyperinsulinism is caused by a mutation in any 1 of 11 known genes.¹ Thus, if suspicious for a monogenic etiology, genetic testing is warranted. Incidence of this type of disorder is dependent on specific populations: ranging from 1 in 50,000 births in Holland, to 1 in 2500 births in Saudi Arabia.² The most common mutation in congenital hyperinsulinism is ABCC8, which encodes the SUR1 subunit of the beta cell’s K_ATP channel.⁴ In the absence of this functioning channel, the beta cell remains constitutively active.

Pharmacologic treatment

The acute treatment of congenital hyperinsulinism is to replace what is missing: glucose. This can be done in a stepwise fashion via oral feeds, then IV infusion. Healthy neonates require a GIR of 4-6 mg/kg/min to maintain euglycemia.⁷ However, in the setting of elevated insulin, one must titrate the GIR to maintain euglycemia, often necessitating a central line to safely deliver more concentrated quantities of dextrose.

The first-line pharmacologic treatment is diazoxide, a potassium channel agonist that binds to the sulfonylurea receptor (SUR1) component of the beta cell’s K_ATP channel, resulting in hyperpolarization of the plasma membrane and cessation of insulin secretion.⁸ It is administered orally at a dose of 10-15 mg/kg/day divided 3 times daily.⁷ Adverse effects include hypertrichosis and fluid retention, the latter of which can be managed with diuretics. Pulmonary hypertension is also a rare, albeit significant, complication of diazoxide, which resulted in a safety alert from the US Food and Drug Administration (FDA) in 2015.^9,10,11 The lack of diazoxide effectiveness in patients with the ABCC8 mutation is to be expected because the drug cannot bind to the faulty SUR1 subunit.

The second-line treatment is octreotide, a somatostatin analog that functions as a calcium channel blocker at the beta cell, effectively inhibiting insulin secretion. This drug is administered subcutaneously or via IV infusion (7-40 mg/kg/day).⁷ The short half-life (1.5 hours) and risk of tachyphylaxis make octreotide a less desirable option for treating persistent neonatal hypoglycemia. Cases of necrotizing enterocolitis also have been reported in newborns.^2,3 Long-acting somatostatin analogs that require monthly injections, such as long-acting release octreotide and lanreotide acetate, also have been used, but their effectiveness in young infants is uncertain.^1,3,12,13 Calcium channel blockers (such as nifedipine) have been used when octreotide fails, and have been deemed as clinically useful in select case reports.^1,7

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Glucagon is another adjunctive treatment for acute hypoglycemia. It can be given as a continuous infusion at 20-40 μg/kg/hr over 24 hours, or as intermittent doses (200 μg/kg every 12 hours).^7,14 Adverse effects include hyponatremia and, more rarely, thrombocytopenia. Unfortunately, glucagon tends to be not very effective for children with monogenic hyperinsulinism.⁷

Surgical treatment

When medical management fails, pancreatectomy represents the next step in treatment. Because monogenic congenital hyperinsulinism can present as either a focal or diffuse pancreatic disease, imaging via fluoro-L-dihydroxyphenylalanine (¹⁸F-DOPA) positron emission tomography (PET) scan is performed to determine the pattern and thus the type of surgical resection required.² The radiolabeled compound is taken up by pancreatic islet cells and converted to ¹⁸F-dopamine, which enters the insulin storage secretory vesicles.¹⁵ Surgical management also can be aided by genetic testing. Autosomal recessive mutations, such as ABCC8 and KJN11, tend to result in diffuse lesions, whereas paternally imprinted mutations result in focal lesions.²

Diffuse lesions require near total pancreatectomy (95%-98% of the pancreas). If hypoglycemia is still uncontrolled, a second surgery is required for a more extensive pancreatectomy.⁵ In children who undergo near-total pancreatectomies, 50% develop exocrine insufficiency, and 90% develop insulin-dependent diabetes mellitus. Up to 50% also incur developmental issues such as speech and motor delay, as well as intellectual disability, secondary to the hypoglycemia in infancy.^3,16

Patient outcome

By day of life 30, the patient underwent ¹⁸F-DOPA PET imaging that demonstrated a diffuse lesion. The following day, he had a 90% semitotal pancreatectomy, which only partially corrected his glucose. One month later, he still required diazoxide and octreotide in addition to continuous feeds, so he underwent an effective 95% semitotal pancreatectomy. He was discharged at 79 days of age, off all medications and requiring only regularly timed feeds.

Next: Pitfalls in pediatric type 1 diabetes care

Currently, at age 7 years, the boy has developed prediabetes, and he likely will develop insulin-dependent diabetes mellitus, much like his older sister did in her teenaged years. Despite the hypoglycemic episodes he experienced as a neonate, he is doing well in school. Appropriate management of his condition in infancy and close follow-up with neurodevelopmental specialists thereafter have likely contributed to his good outcome thus far.

REFERENCES

1. Stanley CA. Perspective on the genetics and diagnosis of congenital hyperinsulinism disorders. J Clin Endocrinol Metab. 2016;101(3):815-826.

2. Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63.

3. Thornton PS, Stanley CA, De Leon DD, et al; Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr. 2015;167(2):238-245.

4. Nessa A, Rahman SA, Hussain K. Hyperinsulinemic hypoglycemia-the molecular mechanisms. Front Endocrinol (Lausanne). 2016;7(29):1-14.

5. Ackermann AM, Palladino AA. Managing congenital hyperinsulinism: improving outcomes with a multidisciplinary approach. Res Rep Endocr Disord. 2015;5:103-117.

6. 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. 2016;168:212-219.

7. Sweet CB, Grayson S, Polak M. Management strategies for neonatal hypoglycemia. J Pediatr Pharmacol Ther. 2013;18(3):199-208.

8. George P, McCrimmon RJ. Diazoxide. Pract Diab. 2012;29(1):36-37.

9. US Food and Drug Administration. Proglycem (diazoxide): Drug Safety Communication-Reports of pulmonary hypertension in infants and newborns. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm455125.htm. Published July 16, 2015. Accessed November 8, 2016.

10. Demirel F, Unal S, Çetin II, Esen I, and Arasli A. Pulmonary hypertension and reopening of the ductus arteriosus in an infant treated with diazoxide. J Pediatr Endocrinol Metab. 2011;24(7-8):603-605.

11. Nebesio TD, Hoover WC, Caldwell RL, Nitu ME, Eugster EA. Development of pulmonary hypertension in an infant treated with diazoxide. J Pediatr Endocrinol Metab. 2007;20(8):939-944.

12. Le Quan Sang KH, Arnoux JB, Mamoune A, et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol. 2012;166(2):333-339.

13. Modan-Moses D, Koren I, Mazor-Aronovitch K, Pinhas-Hamiel O, Landau H. Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel). J Clin Endocrinol Metab. 2011;96(8):2312-2317.

14. Mehta A. Prevention and management of neonatal hypoglycaemia. Arch Dis Child Fetal Neonatal Ed. 1994;70(1):F54-59.

15. Ismail D, Hussain K. Role of 18F-DOPA PET/CT imaging in congenital hyperinsulinism. Rev Endocr Metab Disord. 2010;11(3):165-169.

16. Ludwig A, Ziegenhorn K, Empting S, et al; Diabetes Patienten-Verlaufsdokumentationssystem (DPV) Group. Glucose metabolism and neurological outcome in congenital hyperinsulinism. Semin Pediatr Surg. 2011;20(1):45-49.

Dr Bellfield is a pediatric endocrinology fellow at the University of Illinois College of Medicine, Chicago, Illinois. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article. Dr Boucher-Berry is assistant professor of Clinical Pediatrics, University of Illinois College of Medicine, Chicago. She reports contracted research for Novo Nordisk.