Second-generation somatostatin analogues might be effective in reducing insulin secretion in congenital hyperinsulinism (CHI). We report the first use of pasireotide in a boy with severe therapy-resistant CHI, resulting in slightly improved glycemic control without side effects.
Congenital hyperinsulinism (CHI) is a rare disorder characterized by inappropriate insulin secretion from pancreatic beta cells in the presence of a low blood glucose concentration. CHI is the most common cause of recurrent and persistent hypoglycemia in neonates and children [
The main treatment goal in CHI is to prevent hypoglycemia and consequent neurological damage. Current treatment protocols are primarily based on dietary and pharmacological interventions [
The patient presented after birth and after an uncomplicated pregnancy of 38 weeks and 3 days as the fourth child of consanguineous Pakistani parents. There was no gestational diabetes. The boy's birthweight was 5,085 g (standard deviation score [SDS] >2.5), and vaginal delivery was complicated by shoulder dystocia. Apgar scores were 4 and 7 after 1 and 5 minutes, respectively. Directly postpartum, blood glucose levels were unmeasurably low for 3.5 hours despite administration of multiple intravenous glucose boluses and increased carbohydrate intake. Within 48 hours after birth, the carbohydrate intake had been increased to 21 mg/kg/min. A diagnosis of hyperinsulinism was biochemically confirmed by identifying an elevated insulin level of 415 pmol/L (reference range, 12–96 pmol/L) measured during hypoglycemia (glucose 1.5 mmol/L). On the second day of life, oral diazoxide treatment was started. Because no response to diazoxide (maximum dose 20 mg/kg/day) and an additional increase in carbohydrate intake (up to 26 mg/kg/min) were observed, intravenous octreotide treatment was started on the ninth day of life. As blood glucose level did not increase on continuous octreotide (maximum dose 15 μg/kg/day), continuous glucagon infusion was added on the 11th day of life, initially subcutaneous but changed to intravenous at a maximum dose of 20 μg/kg/hour after insertion of a central venous line.
At the age of 3 weeks, diagnosis of diffuse CHI was genetically confirmed. The boy was a carrier of a pathogenic homozygous
A schematic overview of pharmacological treatment (diazoxide, octreotide, glucagon, and lanreotide), carbohydrate intake, and weight progression of the boy during his first 2 months of life is shown in
The initial postoperative response was promising, and one month after surgery, glucagon was stopped and feeding frequency was reduced to every 3 hours, with a carbohydrate intake of 7.5 mg/kg/min. Postoperatively, lanreotide treatment (60 mg subcutaneous [s.c.] every 4 weeks) was continued. Unfortunately, 2 months after surgery, an unexpected decrease in blood glucose concentration occurred. Continuous drip feeding using a gastrostomy tube was required, and carbohydrate intake was increased to 12 mg/kg/min, after which weight gain increased again (
The result of this second surgical intervention was rather disappointing. Carbohydrate intake could not be reduced (carbohydrate intake of 10 mg/kg/min, feeding every 2 hours), and octreotide (40 μg/kg/day, continuous s.c.) and lanreotide (60 mg s.c. every 4 weeks) were restarted. Because pasireotide seemed to have a better effect than lanreotide, it was restarted at the age of almost 9 months (short-acting pasoreotide, 0.3 mg s.c. 3 times daily). Similar to the first period of short-acting pasireotide injections, glucose levels fluctuated, and short-acting pasireotide was substituted with long-acting pasireotide (starting dose 10 mg every 28 days). Within a few weeks, the dose was increased to 40 mg per 28 days (adult dose for acromegaly), resulting in fewer hyperglycemic episodes (
The long-acting pasireotide treatment was stopped postoperatively. To test for potential pasireotide-induced central adrenal insufficiency, low dose (1 μg) and classic (36 μg/kg) adrenocorticotropic hormone (ACTH) tests were performed, and both results were normal. The patient's carbohydrate intake could be reduced to 6.5 mg/kg/min, the interval between feedings could be increased to 4 hours, and weight gain started to normalize. Just after his first birthday, the boy was discharged from the hospital.
At the last outpatient clinic visit, at the age of 1.5 years, the boy still occasionally experienced glucose levels at the lower limit of the desired target range (around 3.0 mmol/L), required oral feeding every 3 hours during the day (enriched with maltodextrin), and feedings every 4 hours during the night via a gastrostomy tube to prevent hypoglycemia. His current carbohydrate intake was 6.5 mg/kg/min. No progressive weight gain had occurred since the last surgery, and his weight SDS improved further (weight SDS, +2.79; height SDS, +0.42). While he had shown mildly impaired psychomotor development during hospitalization, at 1.5 years of age, his psychomotor development appeared normal. Magnetic resonance imaging of the brain, performed at one month of age, showed no signs of hypoglycemic damage, and has not been repeated. Since discharge, one symptomatic hypoglycemic episode occurred, resulting in a seizure. The mild impairment in psychomotor development during hospitalization was probably of multifactorial origin: hypoglycemia, severe obesity with impaired physical activity, and under-stimulation during longterm hospitalization.
Here we report the first use of pasireotide in the treatment of a child with CHI. In this case, a homozygous
Inactivating homozygous or compound heterozygous
Second-line treatment consists of somatostatin analogues. Somatostatin is one of the main inhibitors of endocrine and exocrine hormone secretion. Somatostatin exerts its effect by binding to its receptor, of which there are 5 subtypes (SSTR1-5). Inhibition of insulin secretion is mainly mediated by SSTR2 and SSTR5. Several somatostatin analogues have been developed to treat conditions characterized by overproduction of hormones, such as acromegaly and Cushing disease. Current CHI treatment protocols include 2 long-acting somatostatin analogues, octreotide long-acting release (sandostatin-LAR) and somatuline autogel (lanreotide) [
In our patient with severe, therapy-resistant CHI, pasireotide was used in a last attempt to avoid near-total pancreatectomy. Although the treatment period was rather short (2 months), the boy did seem to show a response as short-acting pasireotide injections lead to large fluctuations in blood glucose, including hyper- and hypoglycemia (
Our patient was hospitalized during his entire first year of life. Since even severe forms of CHI have been reported to become milder over time, possibly due to apoptosis of hyperinsulinemic beta cells, the current opinion is to try to avoid surgery. That is why initially only partial rather than near-total pancreatic resection was performed. However, in hindsight, in such a severe, diffuse form of CHI, near-total pancreatectomy might have been a better choice to prevent long-lasting hospitalization.
In summary, in this case of severe CHI, a short period of pasireotide treatment slightly improved glycemic control without side effects. Unfortunately, the effect of pasireotide on glycemic control was insufficient to prevent near-total pancreatectomy. Potential side effects during prolonged treatment, such as decrease in ACTH and cortisol levels, require further investigation.
Written informed consent was obtained from the parent of the patient to publish this case.
No potential conflict of interest relevant to this article was reported.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Schematic overview of carbohydrate intake, patient's weight, and treatment during the first 56 days of life.
Schematic overview of carbohydrate intake, patient's weight, and treatment during the first year of life. Surgical treatments are indicated by the 3 arrows. Diazoxide was given 3 times a day at the maximum dose of 20 mg/kg/day. Octreotide was given for the first 2 months of life as continuous intravenous injection with a maximum dose of 15 μg/kg/day. Octreotide was given at 7–8 months of age as continuous subcutaneous injection with a maximum dose of 40 μg/kg/day. Glucagon was initially given subcutaneously and later intravenously at a maximum dose of 20 μg/kg/hr. Lanreotide was given subcutaneously with four-week intervals; indicated by triangles with doses in mg. Short-acting pasireotide was given subcutaneously, indicated by boxes, at a maximum dose of 0.3 mg 4 times daily. Long-acting pasireotide was given as indicated by triangles with doses in mg. SD, standard deviation.
Blood glucose levels (mmol/L) after initiating short-acting pasireotide (A) and after initiating long-acting pasireotide (B).