Long-term, Continuous SC Octreotide for Hyperinsulinism
Long-term, Continuous SC Octreotide for Hyperinsulinism
Objective To evaluate the efficacy of long-term, continuous, subcutaneous octreotide infusion for congenital hyperinsulinism caused by mutations in the KATP-channel genes, KCNJ11 and ABCC8.
Patients Fifteen Japanese patients with diazoxide-unresponsive, KATP-channel hyperinsulinism.
Methods Molecular diagnoses were made by sequencing and multiple ligation-dependent probe amplification analysis. In patients with paternally inherited, monoallelic mutations, 18F-DOPA PET scans were performed to determine the location of the lesion. The patients were treated with continuous, subcutaneous octreotide infusion at a dosage of up to 25 μg/kg/day, using an insulin pump to maintain blood glucose levels higher than 3·33 mmol/l. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed. The efficacy of the treatment was assessed in patients who received octreotide for 4 months to 5·9 years.
Results Three patients had biallelic mutations, and 12 had monoallelic, paternally inherited mutations. Four patients with monoallelic mutations showed diffuse 18F-DOPA uptake, whereas seven patients showed focal uptake. Octreotide was effective in all the patients. The patients with biallelic mutations required a higher dosage (17–25 μg/kg/day), and two patients required additional treatments. By contrast, the patients with monoallelic mutations required a lower dosage (0·5–21 μg/kg/day) irrespective of the PET results and mostly without additional treatments. Treatment was discontinued in three patients at 2·5, 3·3 and 5·9 years of age, without psychomotor delay. Except for growth deceleration at a higher dosage, no significant adverse effects were noted.
Conclusions Long-term, continuous, subcutaneous octreotide infusion is a feasible alternative to surgery especially for patients with monoallelic KATP-channel mutations.
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in the neonatal and infantile periods with an incidence of approximately 1 in 40 000 births in Japan.
Although a variety of causative genes have been identified for this disorder, when restricted to diazoxide-unresponsive cases, defects in the ATP-sensitive potassium channel (KATP-channel) are by far the most commonly associated alterations, accounting for 92% in our series of 48 Japanese cases of diazoxide-unresponsive persistent CHI (our unpublished results).
KATP CHI is caused by loss-of-function mutations in 1 of 2 genes, ABCC8 or KCNJ11, encoding the two subunits of the pancreatic KATP-channel, SUR1 and Kir6·2, respectively. Two major histological forms of KATP CHI are known: the diffuse and focal forms. In the diffuse form, insulin-oversecreting abnormal β cells are distributed throughout the pancreas, whereas in the focal form, abnormal β cells occupy a restricted area in the pancreas. The diffuse forms are caused either by biallelic, recessively inherited KATP-channel mutations, or by monoallelic, dominantly inherited mutations. On the contrary, the focal forms are found in individuals with a paternally inherited, monoallelic KATP-channel mutation. Subsequent somatic loss of the maternal allele caused by paternal isodisomy leads to a loss of the activities of the KATP-channel and the adjacent tumour suppressors (H19 and CDKN1C) normally expressed by the maternal allele. These cells gain a growth advantage, eventually forming a focal lesion of insulin-overproducing β cells.
Traditionally, patients with CHI showing a poor response to medical treatment have been treated by subtotal pancreatectomy, removing > 95% of the pancreas to prevent serious neurological sequelae of hypoglycaemia. The results of the procedure, however, were rarely satisfactory. Some were left with residual hypoglycaemia, and even when hypoglycaemia was controlled, most of the patients developed diabetes mellitus postoperatively.
This situation has changed recently. When a focal lesion is identified preoperatively, the patient can be cured by partial resection of the pancreas, without postoperative complications. With the recent development of diagnostic modalities for the identification and localisation of focal lesions, surgical treatment by a multidisciplinary approach has become the mainstay of treatment for focal diazoxide-unresponsive CHI.
Even today, however, patients with the diffuse form of KATP CHI often require subtotal pancreatectomy with frequent postoperative complications. In addition, when a focal lesion is identified, surgical resection is not always easy if the lesion is in the head of the pancreas and potentially adjacent to the main pancreatic duct or the common bile duct. Total removal of the head of the pancreas and drainage of the distal pancreas into the Roux-en-Y jejunal loop has been advocated for such cases. The procedure, however, can be difficult for paediatric surgeons who do not routinely perform surgery for the correction of this rare disorder, and the frequency of long-term postoperative complication is not known. Because approximately two-thirds of the focal lesions arise in the head or the uncus of the pancreas (our unpublished results in Japan), this problem occurs frequently.
Octreotide, a synthetic somatostatin analogue, is currently used for treatment of CHI. Although long-term treatment with octreotide has been reported,[15–18] the treatment regimen differs from centre to centre, and few reports have correlated its efficacy and safety with subtypes of hyperinsulinism. In this study, we evaluated the efficacy and safety of long-term octreotide treatment in Japanese patients with genetically proven KATP CHI. The amount of octreotide to control hypoglycaemia was then correlated with the genotype and 18F-DOPA PET findings.
Abstract and Introduction
Abstract
Objective To evaluate the efficacy of long-term, continuous, subcutaneous octreotide infusion for congenital hyperinsulinism caused by mutations in the KATP-channel genes, KCNJ11 and ABCC8.
Patients Fifteen Japanese patients with diazoxide-unresponsive, KATP-channel hyperinsulinism.
Methods Molecular diagnoses were made by sequencing and multiple ligation-dependent probe amplification analysis. In patients with paternally inherited, monoallelic mutations, 18F-DOPA PET scans were performed to determine the location of the lesion. The patients were treated with continuous, subcutaneous octreotide infusion at a dosage of up to 25 μg/kg/day, using an insulin pump to maintain blood glucose levels higher than 3·33 mmol/l. Additional treatments (IV glucose, glucagon or enteral feeding) were administered as needed. The efficacy of the treatment was assessed in patients who received octreotide for 4 months to 5·9 years.
Results Three patients had biallelic mutations, and 12 had monoallelic, paternally inherited mutations. Four patients with monoallelic mutations showed diffuse 18F-DOPA uptake, whereas seven patients showed focal uptake. Octreotide was effective in all the patients. The patients with biallelic mutations required a higher dosage (17–25 μg/kg/day), and two patients required additional treatments. By contrast, the patients with monoallelic mutations required a lower dosage (0·5–21 μg/kg/day) irrespective of the PET results and mostly without additional treatments. Treatment was discontinued in three patients at 2·5, 3·3 and 5·9 years of age, without psychomotor delay. Except for growth deceleration at a higher dosage, no significant adverse effects were noted.
Conclusions Long-term, continuous, subcutaneous octreotide infusion is a feasible alternative to surgery especially for patients with monoallelic KATP-channel mutations.
Introduction
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in the neonatal and infantile periods with an incidence of approximately 1 in 40 000 births in Japan.
Although a variety of causative genes have been identified for this disorder, when restricted to diazoxide-unresponsive cases, defects in the ATP-sensitive potassium channel (KATP-channel) are by far the most commonly associated alterations, accounting for 92% in our series of 48 Japanese cases of diazoxide-unresponsive persistent CHI (our unpublished results).
KATP CHI is caused by loss-of-function mutations in 1 of 2 genes, ABCC8 or KCNJ11, encoding the two subunits of the pancreatic KATP-channel, SUR1 and Kir6·2, respectively. Two major histological forms of KATP CHI are known: the diffuse and focal forms. In the diffuse form, insulin-oversecreting abnormal β cells are distributed throughout the pancreas, whereas in the focal form, abnormal β cells occupy a restricted area in the pancreas. The diffuse forms are caused either by biallelic, recessively inherited KATP-channel mutations, or by monoallelic, dominantly inherited mutations. On the contrary, the focal forms are found in individuals with a paternally inherited, monoallelic KATP-channel mutation. Subsequent somatic loss of the maternal allele caused by paternal isodisomy leads to a loss of the activities of the KATP-channel and the adjacent tumour suppressors (H19 and CDKN1C) normally expressed by the maternal allele. These cells gain a growth advantage, eventually forming a focal lesion of insulin-overproducing β cells.
Traditionally, patients with CHI showing a poor response to medical treatment have been treated by subtotal pancreatectomy, removing > 95% of the pancreas to prevent serious neurological sequelae of hypoglycaemia. The results of the procedure, however, were rarely satisfactory. Some were left with residual hypoglycaemia, and even when hypoglycaemia was controlled, most of the patients developed diabetes mellitus postoperatively.
This situation has changed recently. When a focal lesion is identified preoperatively, the patient can be cured by partial resection of the pancreas, without postoperative complications. With the recent development of diagnostic modalities for the identification and localisation of focal lesions, surgical treatment by a multidisciplinary approach has become the mainstay of treatment for focal diazoxide-unresponsive CHI.
Even today, however, patients with the diffuse form of KATP CHI often require subtotal pancreatectomy with frequent postoperative complications. In addition, when a focal lesion is identified, surgical resection is not always easy if the lesion is in the head of the pancreas and potentially adjacent to the main pancreatic duct or the common bile duct. Total removal of the head of the pancreas and drainage of the distal pancreas into the Roux-en-Y jejunal loop has been advocated for such cases. The procedure, however, can be difficult for paediatric surgeons who do not routinely perform surgery for the correction of this rare disorder, and the frequency of long-term postoperative complication is not known. Because approximately two-thirds of the focal lesions arise in the head or the uncus of the pancreas (our unpublished results in Japan), this problem occurs frequently.
Octreotide, a synthetic somatostatin analogue, is currently used for treatment of CHI. Although long-term treatment with octreotide has been reported,[15–18] the treatment regimen differs from centre to centre, and few reports have correlated its efficacy and safety with subtypes of hyperinsulinism. In this study, we evaluated the efficacy and safety of long-term octreotide treatment in Japanese patients with genetically proven KATP CHI. The amount of octreotide to control hypoglycaemia was then correlated with the genotype and 18F-DOPA PET findings.
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