Treatment and complications of persistent hyperinsulinemic hypoglycemia of infancy
- Agneta Sunehag, MD, PhD
Agneta Sunehag, MD, PhD
- Associate Professor of Pediatrics
- Baylor College of Medicine
- Morey W Haymond, MD
Morey W Haymond, MD
- Professor of Pediatric Nutrition
- Baylor College of Medicine
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also referred to as, congenital hyperinsulinism, familial hyperinsulinemic hypoglycemia, and primary islet cell hypertrophy (nesidioblastosis), is the most common cause of persistent hypoglycemia in neonates and infants. PHHI is a genetic disorder with familial and sporadic forms, both of which are characterized by dysregulation of insulin secretion. Early recognition, diagnosis, and treatment are necessary to prevent or minimize neurologic damage from recurrent or prolonged episodes of hypoglycemia.
PHHI is a clinically heterogeneous disorder that depends in part on the genetic defect (table 1) [1-4]. The clinical manifestations range from life-threatening hypoglycemia presenting on the first day of life to only mildly symptomatic hypoglycemia in a child or adolescent that may be difficult to identify. The response to medical and surgical therapy also varies [1-3].
The treatment and complications of PHHI will be presented here. The pathology, genetics, clinical features, and diagnosis of PHHI and a review on islet cell tumors (insulinomas), which have similar clinical and biochemical features to PPHI, are discussed in more detail separately. (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy" and "Insulinoma".)
The primary goal of therapy in persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is the prevention of acute neurologic symptoms (eg, seizure, lethargy, coma) and long-term sequelae (eg, epilepsy, cognitive deficits, microcephaly) of prolonged and/or recurrent hypoglycemia .
●The immediate goal is to increase and maintain the blood glucose concentration in a safe range (above 70 mg/dL [3.9 mmol/L]) via intravenous administration of glucose and/or enteral feeding.
- Menni F, de Lonlay P, Sevin C, et al. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001; 107:476.
- Bruining GJ. Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr 1990; 2:758.
- Meissner T, Wendel U, Burgard P, et al. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol 2003; 149:43.
- Glaser B, Hirsch HJ, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr 1993; 123:644.
- Ehara A, Takahashi M, Nobumoto K, et al. Successful control of persistent hyperinsulinemic hypoglycemia of infancy with a high dextrin formula. Acta Paediatr Jpn 1998; 40:293.
- US Food and Drug Administration, July 16, 2015. 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 (Accessed on August 03, 2015).
- Thornton PS, Alter CA, Katz LE, et al. Short- and long-term use of octreotide in the treatment of congenital hyperinsulinism. J Pediatr 1993; 123:637.
- Demirbilek H, Shah P, Arya VB, et al. Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy. J Clin Endocrinol Metab 2014; 99:3660.
- Laje P, Halaby L, Adzick NS, Stanley CA. Necrotizing enterocolitis in neonates receiving octreotide for the management of congenital hyperinsulinism. Pediatr Diabetes 2010; 11:142.
- DeClue TJ, Malone JI, Bercu BB. Linear growth during long-term treatment with somatostatin analog (SMS 201-995) for persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr 1990; 116:747.
- Le Quan Sang KH, Arnoux JB, Mamoune A, et al. Successful treatment of congenital hyperinsulinism with long-acting release octreotide. Eur J Endocrinol 2012; 166:333.
- Modan-Moses D, Koren I, Mazor-Aronovitch K, et al. Treatment of congenital hyperinsulinism with lanreotide acetate (Somatuline Autogel). J Clin Endocrinol Metab 2011; 96:2312.
- Alexandrescu S, Tatevian N, Olutoye O, Brown RE. Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. Int J Clin Exp Pathol 2010; 3:691.
- Senniappan S, Alexandrescu S, Tatevian N, et al. Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia. N Engl J Med 2014; 370:1131.
- Baş F, Darendeliler F, Demirkol D, et al. Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy. J Pediatr Endocrinol Metab 1999; 12:873.
- Eichmann D, Hufnagel M, Quick P, Santer R. Treatment of hyperinsulinaemic hypoglycaemia with nifedipine. Eur J Pediatr 1999; 158:204.
- Shanbag P, Pathak A, Vaidya M, Shahid SK. Persistent hyperinsulinemic hypoglycemia of infancy--successful therapy with nifedipine. Indian J Pediatr 2002; 69:271.
- Darendeliler F, Fournet JC, Baş F, et al. ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. J Pediatr Endocrinol Metab 2002; 15:993.
- Stanley CA. Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. J Clin Endocrinol Metab 2016; 101:815.
- Thornton PS, Satin-Smith MS, Herold K, et al. Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant. J Pediatr 1998; 132:9.
- Kane C, Lindley KJ, Johnson PR, et al. Therapy for persistent hyperinsulinemic hypoglycemia of infancy. Understanding the responsiveness of beta cells to diazoxide and somatostatin. J Clin Invest 1997; 100:1888.
- Kubota A, Yonekura T, Usui N, et al. Two cases of persistent hyperinsulinemic hypoglycemia that showed spontaneous regression and maturation of the Langerhans islets. J Pediatr Surg 2000; 35:1661.
- Hoe FM, Thornton PS, Wanner LA, et al. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr 2006; 148:207.
- Clark W, O'Donovan D. Transient hyperinsulinism in an asphyxiated newborn infant with hypoglycemia. Am J Perinatol 2001; 18:175.
- Schultz K, Soltész G. Transient hyperinsulinism in asphyxiated newborn infants. Acta Paediatr Hung 1991; 31:47.
- Telander RL, Charboneau JW, Haymond MW. Intraoperative ultrasonography of the pancreas in children. J Pediatr Surg 1986; 21:262.
- Kapoor RR, James C, Hussain K. Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Nat Clin Pract Endocrinol Metab 2009; 5:101.
- Giurgea I, Laborde K, Touati G, et al. Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism. J Clin Endocrinol Metab 2004; 89:925.
- Sempoux C, Guiot Y, Lefevre A, et al. Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab 1998; 83:1455.
- Crétolle C, Fékété CN, Jan D, et al. Partial elective pancreatectomy is curative in focal form of permanent hyperinsulinemic hypoglycaemia in infancy: A report of 45 cases from 1983 to 2000. J Pediatr Surg 2002; 37:155.
- Simmons PS, Telander RL, Carney JA, et al. Surgical management of hyperinsulinemic hypoglycemia in children. Arch Surg 1984; 119:520.
- Laje P, Stanley CA, Palladino AA, et al. Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism. J Pediatr Surg 2012; 47:130.
- De Vroede M, Bax NM, Brusgaard K, et al. Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy. Pediatrics 2004; 114:e520.
- Bax KN, van der Zee DC. The laparoscopic approach toward hyperinsulinism in children. Semin Pediatr Surg 2007; 16:245.
- Al-Shanafey S, Habib Z, AlNassar S. Laparoscopic pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr Surg 2009; 44:134.
- Al-Shanafey S. Laparoscopic vs open pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr Surg 2009; 44:957.
- Liem NT, Son TN, Hoan NT. Laparoscopic near-total pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy: report of two cases. J Laparoendosc Adv Surg Tech A 2010; 20:115.
- Beltrand J, Caquard M, Arnoux JB, et al. Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism. Diabetes Care 2012; 35:198.
- Arya VB, Senniappan S, Demirbilek H, et al. Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism. PLoS One 2014; 9:e98054.
- Haymond MW. Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 1989; 18:211.