Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia

Abraham, Mary; Shetty, Vinutha B; Price, Glynis; Smith, Nicholas A.; Bock, Martin de; Siafarikas, Aris; Resnick, Steven D.; Whan, Elizabeth; Ellard, Sian; Flanagan, Sarah E.; Davis, Elizabeth A.; Jones, Timothy W.; Hussain, Khalid; Choong, Catherine S.

doi:10.1515/jpem-2015-0094

Cited by 17 publications

(10 citation statements)

References 26 publications

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“…Sirolimus has been reported to be an effective and safe drug for severe, diazoxide unresponsive, diffuse CHI with no major side effects ( 147 ). Following the first report, significant numbers of cases have been reported ( 148 , 149 , 150 , 151 , 152 , 153 , 154 ). As sirolimus has potentially adverse effects (perhaps related to dose) arising from its immunosuppressive effects, measurement of the blood levels is vitally important for reaching an optimal therapeutic level.…”

Section: Introductionmentioning

confidence: 99%

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Demirbilek¹,

Hussain²

2018

Jcrpe

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110

112

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Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH.

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Section: Introductionmentioning

confidence: 99%

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Demirbilek¹,

Hussain²

2018

Jcrpe

Self Cite

110

112

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“…They reported that all patients showed a clear glycemic response to sirolimus, but one patient required a small dose of octreotide to maintain normoglycemia. Abraham described a neonate with CHI caused by a homozygous ABCC8 mutation, who was unresponsive to diazoxide and octreotide (21). He reported achievement of euglycemia by using sirolimus therapy postoperatively.…”

Section: Discussionmentioning

confidence: 99%

A Novel Homozygous Mutation in the KCNJ11 Gene of a Neonate with Congenital Hyperinsulinism and Successful Management with Sirolimus

Ünal¹,

Gönülal²,

Uçaktürk³

et al. 2016

Jcrpe

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Congenital hyperinsulinism (CHI) is the most common cause of neonatal persistent hypoglycemia caused by mutations in nine known genes. Early diagnosis and treatment are important to prevent brain injury. The clinical presentation and response to pharmacological therapy may vary depending on the underlying pathology. Genetic analysis is important in the diagnosis, treatment, patient follow-up, and prediction of recurrence risk within families. Our patient had severe hypoglycemia and seizure following birth. His diagnostic evaluations including genetic testing confirmed CHI. He was treated with a high-glucose infusion, high-dose diazoxide, nifedipine, and glucagon infusion. A novel homozygous mutation (p.F315I) in the KCNJ11 gene, leading to diazoxide-unresponsive CHI, was identified. Both parents were heterozygous for this mutation. Our patient’s clinical course was complicated by severe refractory hypoglycemia; he was successfully managed with sirolimus and surgical intervention was not required. Diazoxide, nifedipine, and glucagon were discontinued gradually following sirolimus therapy. The patient was discharged at 2 months of age on low-dose octreotide and sirolimus. His outpatient clinical follow-up continues with no episodes of hypoglycemia. We present a novel homozygous p.F315I mutation in the KCNJ11 gene leading to diazoxide-unresponsive CHI in a neonate. This case illustrates the challenges associated with the diagnosis and management of CHI, as well as the successful therapy with sirolimus.

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“…Recently, it has been reported that sirolimus is effective and safe for the severe, diazoxide unresponsive diffuse congenital HH with no major side effects [144]. Following the first experience, several number of case reports indicating the successful use of sirolimus have been published [145–149]. …”

Section: New and Potential Future Therapiesmentioning

confidence: 99%

Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology

Demirbilek

Rahman

Büyükyılmaz

et al. 2017

Int J Pediatr Endocrinol

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Glucose homeostasis requires appropriate and synchronous coordination of metabolic events and hormonal activities to keep plasma glucose concentrations in a narrow range of 3.5–5.5 mmol/L. Insulin, the only glucose lowering hormone secreted from pancreatic β-cells, plays the key role in glucose homeostasis. Insulin release from pancreatic β-cells is mainly regulated by intracellular ATP-generating metabolic pathways. Hyperinsulinaemic hypoglycaemia (HH), the most common cause of severe and persistent hypoglycaemia in neonates and children, is the inappropriate secretion of insulin which occurs despite low plasma glucose levels leading to severe and persistent hypoketotic hypoglycaemia. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) constitute the underlying molecular mechanisms of congenital HH. Since insulin supressess ketogenesis, the alternative energy source to the brain, a prompt diagnosis and immediate management of HH is essential to avoid irreversible hypoglycaemic brain damage in children. Advances in molecular genetics, imaging methods (18F–DOPA PET-CT), medical therapy and surgical approach (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This up to date review article provides a background to the diagnosis, molecular genetics, recent advances and therapeutic options in the field of HH in children.

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Efficacy and safety of sirolimus in a neonate with persistent hypoglycaemia following near-total pancreatectomy for hyperinsulinaemic hypoglycaemia

Cited by 17 publications

References 26 publications

Congenital Hyperinsulinism: Diagnosis and Treatment Update

Congenital Hyperinsulinism: Diagnosis and Treatment Update

A Novel Homozygous Mutation in the KCNJ11 Gene of a Neonate with Congenital Hyperinsulinism and Successful Management with Sirolimus

Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology

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