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      Long-Term Non-Surgical Therapy of Severe Persistent Congenital Hyperinsulinism with Glucagon

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          Abstract

          Background: Congenital hyperinsulinism (CHI) is characterized by severe hypoglycemia caused by dysregulated insulin secretion. The long-term outcome is dependent on prevention of hypoglycemic episodes to avoid the high risk of permanent brain damage. Severe cases are usually resistant to diazoxide or nifedipine. In addition, somatostatin analogues are ineffective in a subgroup of patients to achieve stable euglycemia. In these infants the only remaining long-term option has been subtotal pancreatectomy with high risk of diabetes mellitus. Intravenous infusions of glucagon are used as immediate treatment to stabilize euglycemia in affected newborns. The rationale of this treatment comes from the observation of an increased glycogen content of the liver when glycogenolysis is inhibited by insulin. Objective: To review the efficacy and safety of long-term subcutaneous glucagon infusion as a potential therapeutic option for blood glucose stabilization in infants with severe CHI without the need of additional intravenous glucose or immediate surgical intervention. Method: Retrospective review of 9 children with CHI who received continuous subcutaneous infusion of glucagon for weeks or months. Glucagon was added to octreotide to replace octreotide-induced suppression of endogenous glucagon secretion, thereby liberating glucose by stimulation of hepatic glycogenolysis. In 3 cases, a stabilized formulation of glucagon was used to prevent glucagon crystallization that frequently occurs in smaller volumes. Results: Introduction of glucagon allowed the reduction or discontinuation of central glucose infusion in all children studied. In 2 patients, glucagon was introduced due to recurrent hypoglycemia despite subtotal pancreatectomy. Six out of 9 children were discharged home on this treatment, which their parents were able to continue without further symptomatic hypoglycemia, convulsions or unconsciousness. In 3 children, subcutaneous glucagon was continuously administered for 1–4 years leading to stable euglycemia. However, 2 children with diffuse type still required subtotal pancreatectomy. As a possible side effect, 2 children developed erythema necrolyticum, which resolved after discontinuation of the glucagon infusion. This has been described before in glucagonoma. Conclusion: In this retrospective series, combination therapy of low-dose octreotide and subcutaneous glucagon infusion has been effective in preventing hypoglycemic episodes in severe CHI. We propose this may serve as a therapeutic option in place of high rates of glucose infusion through a central venous catheter and as an alternative to subtotal pancreatectomy in diffuse type of CHI.

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          Most cited references34

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          Practical management of hyperinsulinism in infancy.

          Hyperinsulinism in infancy is one of the most difficult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without difficulty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It offers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment.
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            Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia.

            To evaluate the neurologic outcomes of neonates and infants suffering from persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The neurologic development of 90 PHHI patients was studied retrospectively. Sixty-three patients were treated surgically and 27 were treated medically. Fifty-four patients were neonates, of whom 8 were treated medically and 46 were operated on (19 for a focal adenomatous hyperplasia and 27 for diffuse hyperinsulinism). Thirty-six patients had infancy-onset hyperinsulinism, of whom 19 were treated medically and 17 underwent pancreatectomy (10 patients for a focal adenomatous hyperplasia and 7 for diffuse hyperinsulinism). Severe psychomotor retardation was found in 7 patients, 6 with neonatal-onset PHHI. Intermediate psychomotor disability existed in 12 patients; epilepsy existed in 16. Neonatal-onset was the main risk factor for severe retardation or epilepsy. Medically treated patients were less severely affected than those treated by surgery, and there was no difference between the diffuse and focal forms of hyperinsulinism. Neonatal hyperinsulinemic hypoglycemia is still a severe disease with an important risk to rapidly develop severe mental retardation and epilepsy.
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              Hyperinsulinism in infancy: from basic science to clinical disease.

              Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+ channel. From gene defects in ion channel subunits to defects in beta-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2008
                July 2008
                21 May 2008
                : 70
                : 1
                : 59-64
                Affiliations
                aDepartment of Pediatrics, Otto von Guericke University of Magdeburg and bCharité University of Medicine, Berlin, Germany; cPharmaceutical Discovery Corp., Elmsford, New York, N.Y., USA; dDepartment Pediatrics, University of Vienna, Austria; eDivision of Pediatric Endocrinology, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA, and fDepartment of Pediatric Endocrinology, University Hospital of Groningen, The Netherlands
                Article
                129680 Horm Res 2008;70:59–64
                10.1159/000129680
                18493152
                a3ff486f-2ef7-4eae-a9d2-5cca9193bc35
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 15 August 2006
                : 17 October 2007
                Page count
                Tables: 1, References: 40, Pages: 6
                Categories
                Novel Insights from Clinical Practice

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Diazoxide-resistant congenital hyperinsulinism,Octreotide and subcutaneous glucagon infusion,Hypoglycemic episodes,Continuous subcutaneous glucagon infusion,Congenital hyperinsulinism,Severe persistent congenital hyperinsulinism

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