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Pajno R, Visconti C, Bucolo C, Guarneri MP, Del Barba P, Silvani P, Gregnanin M, Barera G. Diazoxide toxicity in congenital hyperinsulinism: A case report. World J Clin Pediatr 2024; 13:94156. [PMID: 39654669 PMCID: PMC11572624 DOI: 10.5409/wjcp.v13.i4.94156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/06/2024] [Accepted: 07/02/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Diazoxide is the sole approved drug for congenital hyperinsulinism; however, diuretic administration and vigilant monitoring are crucial to prevent and promptly identify potentially life-threatening adverse effects. This report aims to highlight a seldom-considered rare side effect of diazoxide. We believe that this brief report is of general interest to World Journal of Clinical Pediatric readership and increase the physicians' awareness of the guideline importance. Moreover, it underlines the importance of stopping immediately the drug if suspected side effects. CASE SUMMARY The manuscript describes a patient diagnosed with congenital hyperinsulinism (CHI) treated with diazoxide not overlapping with diuretic. He resulted in sudden respiratory distress and therefore was transferred to the Neonatal Intensive Care Unit. The cardiological evaluation showed pericardial effusion and left ventricular myocardial hypertrophy, absent before. In suspicion of an iatrogenic effect of diazoxide it was progressively reduced until stop while introducing diuretic treatment, with resolution of symptoms. Once clinically stabilized, an 18 fluoro-diydroxy-phenylalanine positron emission tomography/computed tomography (PET/CT) was performed to differentiate between a focal or diffuse form of CHI. The PET/CT highlighted the presence of a single focal accumulation of the tracer located in the pancreatic tail, consistent with a focal form of hyperinsulinism. At the age of four months, the patient underwent a distal pancreatectomy with histological confirmation of a focal form of nesidioblastosis, resulting in a curative operation. CONCLUSION Diuretic administration and vigilant monitoring of diazoxide therapy are crucial to prevent and promptly identify potentially life-threatening adverse effects.
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Affiliation(s)
- Roberta Pajno
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Camilla Visconti
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
- Università Vita-Salute San Raffaele, Facoltà di Medicina e Chirurgia, Milan 20132, Lombardy, Italy
| | - Carmen Bucolo
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Maria Pia Guarneri
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Paolo Del Barba
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Paolo Silvani
- Department of Anesthesia and Intensive Care, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan 20132, Lombardy, Italy
| | - Marco Gregnanin
- Department of Neonatology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Graziano Barera
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
- Department of Neonatology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
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Dinu D, Hagan JL, Rozance PJ. Variability in Diagnosis and Management of Hypoglycemia in Neonatal Intensive Care Unit. Am J Perinatol 2024; 41:1990-1998. [PMID: 38565171 DOI: 10.1055/s-0044-1785491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
OBJECTIVE Hypoglycemia, the most common metabolic derangement in the newborn period remains a contentious issue, not only due to various numerical definitions, but also due to limited therapeutical options which either lack evidence to support their efficacy or are increasingly recognized to lead to adverse reactions in this population. This study aimed to investigate neonatologists' current attitudes in diagnosing and managing transient and persistent hypoglycemia in newborns admitted to the Neonatal Intensive Care Unit (NICU). METHODS A web-based electronic survey which included 34 questions and a clinical vignette was sent to U.S. neonatologists. RESULTS There were 246 survey responses with most respondents using local protocols to manage this condition. The median glucose value used as the numerical definition of hypoglycemia in first 48 hours of life (HOL) for symptomatic and asymptomatic term infants and preterm infants was 45 mg/dL (2.5 mmol/L; 25-60 mg/dL; 1.4-3.3 mmol/L), while after 48 HOL the median value was 50 mg/dL (2.8 mmol/L; 30-70 mg/dL; 1.7-3.9 mmol/L). There were various approaches used to manage transient and persistent hypoglycemia that included dextrose gel, increasing caloric content of the feeds using milk fortifiers, using continuous feedings, formula or complex carbohydrates, and use of various medications such as diazoxide, glucocorticoids, and glucagon. CONCLUSION There is still large variability in current practices related to hypoglycemia. Further research is needed not only to provide evidence to support the values used as a numerical definition for hypoglycemia, but also on the efficacy of current strategies used to manage this condition. KEY POINTS · Numerical definition of glucose remains variable.. · Strategies managing transient and persistent hypoglycemia are diverse.. · There is a need for further research to investigate efficacy of various treatment options..
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Affiliation(s)
- Daniela Dinu
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Joseph L Hagan
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Paul J Rozance
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
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Kalogeropoulou MS, Couch H, Thankamony A, Beardsall K. Neonatal hyperinsulinism: a retrospective study of presentation and management in a tertiary neonatal intensive care unit in the UK. Arch Dis Child Fetal Neonatal Ed 2024:fetalneonatal-2024-327322. [PMID: 39304222 DOI: 10.1136/archdischild-2024-327322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 09/05/2024] [Indexed: 09/22/2024]
Abstract
OBJECTIVE Reports of hyperinsulinism typically focus on infants managed by highly specialised services. However, neonates with hyperinsulinism are initially managed by neonatologists and often not referred to specialists. This study aimed to characterise the diversity in presentation and management of these infants. SETTING Level 3 neonatal intensive care. PATIENTS Neonates with hyperinsulinism, defined as blood glucose <2.8 mmol/mL and insulin level >6 pmol/L. DESIGN 7-year retrospective study (January 2015-December 2021). RESULTS 99 cases were identified: severe-treated with diazoxide (20%), moderate-clinically concerning hyperinsulinism not treated with diazoxide (30%), mild-biochemical hyperinsulinism (50%). Birth weight z-score was -1.02±2.30 (mean±SD), 42% were preterm, but neither variable correlated with clinical severity. The severe group received a higher concentration of intravenous glucose (27±12%) compared with the moderate (15±7%) and mild (16±10%) groups (p<0.001). At diagnosis, the intravenous glucose intake was similar in the severe (7.43±5.95 mg/kg/min) and moderate (5.09±3.86 mg/kg/min) groups, but higher compared with the mild group (3.05+/2.21 mg/kg/min) (p<0.001). In the severe group, term infants started diazoxide earlier (9.9±4.3 days) compared with preterm (37±26 days) (p=0.002). The national congenital hyperinsulinism service was consulted for 23% of infants, and 3% were transferred. CONCLUSIONS This study highlights the diversity in clinical presentation, severity and prognosis of neonatal hyperinsulinism, irrespective of birth weight and gestational age. More infants were small rather than large for gestational age, and the majority had transient hyperinsulinism and were not referred to the national centre, or treated with diazoxide. Further research is required to understand the breadth of neonatal hyperinsulinism and optimal management.
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Affiliation(s)
| | - Helen Couch
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Ajay Thankamony
- Paediatric Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Kathy Beardsall
- Neonatal Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Academic Department of Paediatrics, University of Cambridge, Cambridge, UK
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4
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Stanley CA, De Leon DD. Etiology of the Neonatal Hypoglycemias. Adv Pediatr 2024; 71:119-134. [PMID: 38944478 DOI: 10.1016/j.yapd.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2024]
Abstract
To provide a more appropriate foundation for dealing with the problem of hypoglycemia in newborn infants, this article focuses on the mechanisms which underlie the various forms of neonatal hypoglycemia and discusses their implications for newborn care. Evidence indicates that all of the major forms of neonatal hypoglycemia are the result of hyperinsulinism due to dysregulation of pancreatic islet insulin secretion. Based on these observations, the authors propose that routine measurement of B-hydroxybutyrate should be considered an essential part of glucose monitoring in newborn infants.
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Affiliation(s)
- Charles A Stanley
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Diva D De Leon
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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Rosenfeld E, Mitteer LM, Boodhansingh K, Sanders VR, McKnight H, De Leon DD. Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome. J Endocr Soc 2024; 8:bvae101. [PMID: 38859884 PMCID: PMC11163021 DOI: 10.1210/jendso/bvae101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Indexed: 06/12/2024] Open
Abstract
Context Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI). Objective To characterize the clinical and molecular features of HI in children with KS. Design Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023. Setting The Congenital Hyperinsulinism Center of the Children's Hospital of Philadelphia. Patients Thirty-three children with KS and HI. Main Outcome Measures HI presentation, treatment, course, and genotype. Results Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (interquartile range [IQR], 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR, 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in KMT2D, 5 children (15%) had a pathogenic variant in KDM6A, and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR, 1.3-5.7 years). Conclusion Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in KMT2D and KDM6A were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, because KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI.
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Affiliation(s)
- Elizabeth Rosenfeld
- Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lauren M Mitteer
- Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Kara Boodhansingh
- Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Victoria R Sanders
- Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Heather McKnight
- Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Diva D De Leon
- Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Edmundson K, Jnah AJ. Neonatal Hypoglycemia. Neonatal Netw 2024; 43:156-164. [PMID: 38816219 DOI: 10.1891/nn-2023-0068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
Neonatal hypoglycemia (NH) is broadly defined as a low plasma glucose concentration that elicits hypoglycemia-induced impaired brain function. To date, no universally accepted threshold (reference range) for plasma glucose levels in newborns has been published, as data consistently indicate that neurologic responses to hypoglycemia differ at various plasma glucose concentrations. Infants at risk for NH include infants of diabetic mothers, small or large for gestational age, and premature infants. Common manifestations include jitteriness, poor feeding, irritability, and encephalopathy. Neurodevelopmental morbidities associated with NH include cognitive and motor delays, cerebral palsy, vision and hearing impairment, and poor school performance. This article offers a timely discussion of the state of the science of NH and recommendations for neonatal providers focused on early identification and disease prevention.
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Malhotra N, Yau D, Cunjamalay A, Gunasekara B, S A, Gilbert C, Morgan K, Dattani M, Dastamani A. Low-dose diazoxide is safe and effective in infants with transient hyperinsulinism. Clin Endocrinol (Oxf) 2024; 100:132-137. [PMID: 38059644 DOI: 10.1111/cen.14987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 12/08/2023]
Abstract
OBJECTIVE Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5-15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI. DESIGN, PATIENTS, MEASURMENTS Infants with THI (duration <6 months) were treated with low-dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000-2000 g (cohort 1), 3 mg/kg/day in those 2000-3500 g (cohort 2) and 5 mg/kg/day in those >3500 g. RESULTS A total of 73 infants with THI (77% male, 33% preterm, 52% small-for-gestational age) were commenced on diazoxide at a median age of 11 days (range 3-43) for a median duration of 4 months (0.3-6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5-10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment-related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension. CONCLUSION Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2-3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia.
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Affiliation(s)
- Neha Malhotra
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Daphne Yau
- Department of Pediatrics, Division of Endocrinology, University of Saskatchewan, Saskatoon, Canada
| | - Annaruby Cunjamalay
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Buddhi Gunasekara
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Athanasakopoulou S
- Faculty of Medicine and Dentistry, Medical School of Queen Mary University, London, UK
| | - Clare Gilbert
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Kate Morgan
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Mehul Dattani
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Antonia Dastamani
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
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8
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Huynh T. Commentary on studies investigating low-dose diazoxide in hyperinsulinism. Clin Endocrinol (Oxf) 2024; 100:138-139. [PMID: 38059616 DOI: 10.1111/cen.14996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 12/08/2023]
Affiliation(s)
- Tony Huynh
- Department of Endocrinology and Diabetes, Queensland Children's Hospital, South Brisbane, Queensland, Australia
- Children's Health Research Centre, Faculty of Medicine, The University of Queensland, South Brisbane, Queensland, Australia
- Department of Chemical Pathology, Mater Pathology, South Brisbane, Queensland, Australia
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9
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Bezirganoglu H, Okur N, Celik K, Tas FF, Ozbek MN. Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience. J Matern Fetal Neonatal Med 2023; 36:2272014. [PMID: 37860935 DOI: 10.1080/14767058.2023.2272014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/12/2023] [Indexed: 10/21/2023]
Abstract
OBJECTIVES To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). METHODS This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. RESULTS A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. CONCLUSIONS The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.
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Affiliation(s)
- Handan Bezirganoglu
- Division of Neonatology, Trabzon Kanuni Training and Research Hospital, Trabzon, Turkey
| | - Nilufer Okur
- Division of Neonatology, Diyarbakir Gazi Yasargil Training and Research Hospital, Diyarbakır, Turkey
| | - Kiymet Celik
- Division of Neonatology, Diyarbakir Gazi Yasargil Training and Research Hospital, Diyarbakır, Turkey
| | - Funda Feryal Tas
- Division of Pediatric Endocrinology, Diyarbakir Gazi Yasargil Training and Research Hospital, Diyarbakır, Turkey
| | - Mehmet Nuri Ozbek
- Department of Pediatrics, Division of Pediatric Endocrinology, Mardin Artuklu University Medical School, Mardin, Turkey
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Montani D, Antigny F, Jutant EM, Chaumais MC, Le Ribeuz H, Grynblat J, Khouri C, Humbert M. Pulmonary hypertension associated with diazoxide: the SUR1 paradox. ERJ Open Res 2023; 9:00350-2023. [PMID: 37965230 PMCID: PMC10641583 DOI: 10.1183/23120541.00350-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/04/2023] [Indexed: 11/16/2023] Open
Abstract
The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the ABCC8 gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.
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Affiliation(s)
- David Montani
- Université Paris-Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
- Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Hôpital Bicêtre, DMU 5 Thorinno, Le Kremlin-Bicêtre, France
| | - Fabrice Antigny
- Université Paris-Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | - Etienne-Marie Jutant
- CHU de Poitiers, Respiratory Department, INSERM CIC 1402, IS-ALIVE Research Group, University of Poitiers, Poitiers, France
| | - Marie-Camille Chaumais
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
- Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Pharmacy, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
- Université Paris-Saclay, Faculty of Pharmacy, Saclay, France
| | - Hélène Le Ribeuz
- Université Paris-Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | - Julien Grynblat
- Université Paris-Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | - Charles Khouri
- Univ. Grenoble Alpes, HP2 Laboratory, Grenoble, France
- Grenoble Alpes University Hospital, Pharmacovigilance Unit, Grenoble, France
| | - Marc Humbert
- Université Paris-Saclay, Faculty of Medicine, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France
- Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Hôpital Bicêtre, DMU 5 Thorinno, Le Kremlin-Bicêtre, France
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Shaikh MG, Lucas-Herald AK, Dastamani A, Salomon Estebanez M, Senniappan S, Abid N, Ahmad S, Alexander S, Avatapalle B, Awan N, Blair H, Boyle R, Chesover A, Cochrane B, Craigie R, Cunjamalay A, Dearman S, De Coppi P, Erlandson-Parry K, Flanagan SE, Gilbert C, Gilligan N, Hall C, Houghton J, Kapoor R, McDevitt H, Mohamed Z, Morgan K, Nicholson J, Nikiforovski A, O'Shea E, Shah P, Wilson K, Worth C, Worthington S, Banerjee I. Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus. Front Endocrinol (Lausanne) 2023; 14:1231043. [PMID: 38027197 PMCID: PMC10646160 DOI: 10.3389/fendo.2023.1231043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/04/2023] [Indexed: 12/01/2023] Open
Abstract
Congenital hyperinsulinism (CHI) is a condition characterised by severe and recurrent hypoglycaemia in infants and young children caused by inappropriate insulin over-secretion. CHI is of heterogeneous aetiology with a significant genetic component and is often unresponsive to standard medical therapy options. The treatment of CHI can be multifaceted and complex, requiring multidisciplinary input. It is important to manage hypoglycaemia in CHI promptly as the risk of long-term neurodisability arising from neuroglycopaenia is high. The UK CHI consensus on the practice and management of CHI was developed to optimise and harmonise clinical management of patients in centres specialising in CHI as well as in non-specialist centres engaged in collaborative, networked models of care. Using current best practice and a consensus approach, it provides guidance and practical advice in the domains of diagnosis, clinical assessment and treatment to mitigate hypoglycaemia risk and improve long term outcomes for health and well-being.
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Affiliation(s)
- M. Guftar Shaikh
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Angela K. Lucas-Herald
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Antonia Dastamani
- Department of Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Maria Salomon Estebanez
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Senthil Senniappan
- Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, United Kingdom
| | - Noina Abid
- Department of Paediatric Endocrinology, Royal Belfast Hospital for Sick Children, Belfast, United Kingdom
| | - Sumera Ahmad
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Sophie Alexander
- Department of Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Bindu Avatapalle
- Department of Paediatric Endocrinology and Diabetes, University Hospital of Wales, Cardiff, United Kingdom
| | - Neelam Awan
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Hester Blair
- Department of Dietetics, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Roisin Boyle
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Alexander Chesover
- Department of Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Barbara Cochrane
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Ross Craigie
- Department of Paediatric Surgery, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Annaruby Cunjamalay
- Department of Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Sarah Dearman
- The Children’s Hyperinsulinism Charity, Accrington, United Kingdom
| | - Paolo De Coppi
- SNAPS, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
- NIHR BRC UCL Institute of Child Health, London, United Kingdom
| | - Karen Erlandson-Parry
- Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, United Kingdom
| | - Sarah E. Flanagan
- Department of Clinical and Biomedical Science, University of Exeter, Exeter, United Kingdom
| | - Clare Gilbert
- Department of Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Niamh Gilligan
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Caroline Hall
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Jayne Houghton
- Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom
| | - Ritika Kapoor
- Department of Paediatric Endocrinology, Faculty of Medicine and Life Sciences, King’s College London, King’s College Hospital NHS Foundation Trust, London, United Kingdom
| | - Helen McDevitt
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Zainab Mohamed
- Department of Paediatric Endocrinology, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - Kate Morgan
- Department of Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Jacqueline Nicholson
- Paediatric Psychosocial Service, Royal Manchester Children’s Hospital, Manchester, United Kingdom
| | - Ana Nikiforovski
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Elaine O'Shea
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Pratik Shah
- Department of Paediatric Endocrinology, Barts Health NHS Trust, Royal London Children’s Hospital, London, United Kingdom
| | - Kirsty Wilson
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Chris Worth
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Sarah Worthington
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Indraneel Banerjee
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
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12
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Solís-García G, Yeung T, Jasani B. Does the use of diazoxide for hyperinsulinaemic hypoglycaemia increase the risk of necrotising enterocolitis in neonates? Arch Dis Child 2023; 108:775-778. [PMID: 37369382 DOI: 10.1136/archdischild-2023-325726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023]
Affiliation(s)
- Gonzalo Solís-García
- Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Telford Yeung
- Neonatology, Windsor Regional Hospital, Windsor, Ontario, Canada
| | - Bonny Jasani
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
- The Hospital for Sick Children, Toronto, Ontario, Canada
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13
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Lassoued N, Alaya W, Arfa S, Korbi M, Lassoued I, Amor SB, Zaouali F, Farhat Z, Chelly J, Habib Sfar M. A posteriori diagnosis of DRESS syndrome induced by diazoxide in a patient with an insulinoma: a case report and review of the literature. Front Med (Lausanne) 2023; 10:1196041. [PMID: 37601782 PMCID: PMC10436324 DOI: 10.3389/fmed.2023.1196041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/12/2023] [Indexed: 08/22/2023] Open
Abstract
The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome can be potentially life-threatening. The diagnosis is sometimes difficult since the clinical manifestations may be incomplete or non-specific. Insulinoma is a rare functioning neuroendocrine tumor (NET) of the pancreas. Medical therapy may be needed when surgery is contraindicated, delayed or refused. Diazoxide is widely used to control hypoglycemia in patients with insulinoma. We report a clinical case of an insulinoma in a 85-year-old patient treated with diazoxide with a fatal outcome due to a delayed diagnosis of a DRESS syndrome. This is the first case of DRESS syndrome reported after using diazoxide for insulinoma treatment in our knowledge.
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Affiliation(s)
- Najoua Lassoued
- Department of Endocrinology, Taher Sfar University Hospital, Mahdia, Tunisia
- University of Monastir, Monastir, Tunisia
| | - Wafa Alaya
- Department of Endocrinology, Taher Sfar University Hospital, Mahdia, Tunisia
| | - Sondos Arfa
- Department of Endocrinology, Taher Sfar University Hospital, Mahdia, Tunisia
| | - Mouna Korbi
- Department of Dermatology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Ines Lassoued
- Department of Gastroenterology, Taher Sfar University Hospital, Mahdia, Tunisia
| | - Soumaya Ben Amor
- Department of Gastroenterology, Taher Sfar University Hospital, Mahdia, Tunisia
| | - Fatma Zaouali
- Department of Family Medicine, Faculty of Medicine of Monastir, Monastir, Tunisia
| | - Zayneb Farhat
- Department of Family Medicine, Faculty of Medicine of Monastir, Monastir, Tunisia
| | - Jihen Chelly
- Department of Infectious Disease, Taher Sfar University Hospital, Mahdia, Tunisia
| | - Mohamed Habib Sfar
- Department of Endocrinology, Taher Sfar University Hospital, Mahdia, Tunisia
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14
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De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu J, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TL, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS. International Guidelines for the Diagnosis and Management of Hyperinsulinism. Horm Res Paediatr 2023; 97:279-298. [PMID: 37454648 PMCID: PMC11124746 DOI: 10.1159/000531766] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 05/16/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide. SUMMARY Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in "developed" countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. KEY MESSAGES This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.
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Affiliation(s)
- Diva D. De Leon
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jean Baptiste Arnoux
- Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, AP-HP, University of Paris-Cité, Paris, France
| | - Indraneel Banerjee
- Paediatric Endocrinology, Royal Manchester Children’s Hospital, University of Manchester, Manchester, UK
| | - Ignacio Bergada
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CONICET – FEI), Division de Endrocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Tricia Bhatti
- Department of Clinical Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Louise S. Conwell
- Australia and Children’s Health Queensland Clinical Unit, Department of Endocrinology and Diabetes, Queensland Children’s Hospital, Children’s Health Queensland, Greater Brisbane Clinical School, Medical School, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Junfen Fu
- National Clinical Research Center for Child Health, Department of Endocrinology, The Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Sarah E. Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - David Gillis
- Hadassah Medical Center, Department of Pediatrics, Ein-Kerem, Jerusalem and Faculty of Medicine, Hebrew-University, Jerusalem, Israel
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Klaus Mohnike
- Department of General Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Tai L.S. Pasquini
- Research and Policy Director, Congenital Hyperinsulinism International, Glen Ridge, NJ, USA
| | - Pratik Shah
- Pediatric Endocrinology, The Royal London Children’s Hospital, Queen Mary University of London, London, UK
| | - Charles A. Stanley
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Adrian Vella
- Division of Diabetes, Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA
| | - Tohru Yorifuji
- Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan
| | - Paul S. Thornton
- Congenital Hyperinsulinism Center, Cook Children’s Medical Center and Texas Christian University Burnett School of Medicine, Fort Worth, TX, USA
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15
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Hoermann H, Roeper M, Welters A, Baertling F, Mayatepek E, Meissner T, Kummer S. Delayed-Onset Transient Hyperinsulinism in Infants with Very Low and Extremely Low Birth Weights: A Cohort Study. J Pediatr 2023; 258:113399. [PMID: 37019330 DOI: 10.1016/j.jpeds.2023.113399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 02/23/2023] [Accepted: 03/29/2023] [Indexed: 04/07/2023]
Abstract
We describe 16 infants born preterm with birth weights <1500 g and transient hyperinsulinism. The onset of hyperinsulinism was delayed and often coincident with clinical stabilization. We hypothesize that postnatal stress caused by prematurity and associated problems may contribute to development of delayed-onset transient hyperinsulinism.
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Affiliation(s)
- Henrike Hoermann
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
| | - Marcia Roeper
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Alena Welters
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Fabian Baertling
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
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16
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Boskabadi SJ, Ramezaninejad S, Sohrab M, Farhadi R. Diazoxide-Induced Hypertrichosis in a Neonate With Transient Hyperinsulinism. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2023; 16:11795476231151330. [PMID: 36726424 PMCID: PMC9885027 DOI: 10.1177/11795476231151330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 12/28/2022] [Indexed: 01/28/2023]
Abstract
Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We reported a 37-week-old boy with the diagnosis of hypoglycemia. We started a dextrose infusion, but we used oral diazoxide, due to hypoglycemia episodes despite the increase in dextrose intake. The newborn had a normoglycemic condition after gradually increasing the diazoxide dose to 15 mg/kg/day. He was fully breastfed and discharged at 14 days of age with ongoing diazoxide. In weekly serial clinical follow-ups, the parents noticed an increase in the growth of forehead and facial hair that was diagnosed as diazoxide-induced hypertrichosis. Diazoxide was gradually tapered, and hypertrichosis continued until 1 month after dioxide discontinuation. Diazoxide use in NICU settings has increased over time. Diazoxide has many side effects, one of which is hypertrichosis. Many diazoxide side effects have been reported in adults or children and few studies have reported the prevalence of these adverse effects of diazoxide in neonates and infants.
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Affiliation(s)
- Seyyed Javad Boskabadi
- Department of Clinical Pharmacy,
Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sima Ramezaninejad
- Department of Clinical Pharmacy,
Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Masoumeh Sohrab
- Department of Clinical Pharmacy,
Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roya Farhadi
- Department of Neonatology, Pediatrics
Infectious Diseases Research Center, Mazandaran University of Medical Sciences,
Sari, Iran,Roya Farhadi, Department of Neonatology,
Pediatrics Infectious Diseases Research Center, Mazandaran University of Medical
Sciences, Sari, Iran; Division of neonatology, Department of Pediatrics, Boo Ali
Sina Hospital, Pasdaran Boulevard, P.O.Box 48158-38477, Sari, Iran. Emails:
;
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17
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Stanley CA, Thornton PS, De Leon DD. New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia. Front Pediatr 2023; 11:1071206. [PMID: 36969273 PMCID: PMC10036912 DOI: 10.3389/fped.2023.1071206] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/23/2023] [Indexed: 03/29/2023] Open
Abstract
For the past 70 years, controversy about hypoglycemia in newborn infants has focused on a numerical "definition of neonatal hypoglycemia", without regard to its mechanism. This ignores the purpose of screening newborns for hypoglycemia, which is to identify those with pathological forms of hypoglycemia and to prevent hypoglycemic brain injury. Recent clinical and basic research indicates that the three major forms of neonatal hypoglycemia are caused by hyperinsulinism (recognizing also that other rare hormonal or metabolic conditions may also present during this time frame). These include transitional hypoglycemia, which affects all normal newborns in the first few days after birth; perinatal stress-induced hypoglycemia in high-risk newborns, which afflicts ∼1 in 1,200 newborns; and genetic forms of congenital hyperinsulinism which afflict ∼1 in 10,000-40,000 newborns. (1) Transitional hyperinsulinism in normal newborns reflects persistence of the low glucose threshold for insulin secretion during fetal life into the first few postnatal days. Recent data indicate that the underlying mechanism is decreased trafficking of ATP-sensitive potassium channels to the beta-cell plasma membrane, likely a result of the hypoxemic state of fetal life. (2) Perinatal stress-induced hyperinsulinism in high-risk infants appears to reflect an exaggeration of this normal low fetal glucose threshold for insulin release due to more severe and prolonged exposure to perinatal hypoxemia. (3) Genetic hyperinsulinism, in contrast, reflects permanent genetic defects in various steps controlling beta-cell insulin release, such as inactivating mutations of the K ATP-channel genes. The purpose of this report is to review our current knowledge of these three major forms of neonatal hyperinsulinism as a foundation for the diagnosis and management of hypoglycemia in newborn infants. This includes selection of appropriate interventions based on underlying disease mechanism; combined monitoring of both plasma glucose and ketone levels to improve screening for infants with persistent forms of hypoglycemia; and ultimately to ensure that infants at risk of persistent hyperinsulinemic hypoglycemia are recognized prior to discharge from the nursery.
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Affiliation(s)
- Charles A. Stanley
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Paul S. Thornton
- Congenital Hyperinsulinism Center, Division of Endocrinology, Cook Children’s Medical Center, Fort Worth, TX, United States
- Department of Pediatrics, Texas Christian University Burnett School of Medicine, Fort Worth, TX, United States
- Correspondence: Paul S. Thornton Diva D. De Leon
| | - Diva D. De Leon
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
- Correspondence: Paul S. Thornton Diva D. De Leon
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18
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Diazoxide for Neonatal Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension. CHILDREN (BASEL, SWITZERLAND) 2022; 10:children10010005. [PMID: 36670556 PMCID: PMC9856357 DOI: 10.3390/children10010005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Hypoglycemia in neonates is associated with long-term neurodevelopmental effects. Hyperinsulinemic hypoglycemia (HH) is the most common cause of persistent hypoglycemia in neonatal intensive care units. Diazoxide is the only medication that is currently recommended for treatment of HH in neonates. However, the use of diazoxide in neonates is associated with pulmonary hypertension as an adverse effect. In this article, we review the literature on the mechanism of action and adverse effects with the use of diazoxide in neonatal hyperinsulinism. We then present a case series of neonates treated with diazoxide in our neonatal intensive care unit over a 5-year period. Among 23 neonates who received diazoxide, 4 developed pulmonary hypertension and 1 died. All infants who developed pulmonary hypertension were born preterm at less than 36 weeks gestation and had pre-existing risk factors for pulmonary hypertension. HH in preterm neonates, with pre-existing pulmonary hypertension or with risk factors for pulmonary hypertension requires thoughtful management.
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19
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Cuff H, Lord K, Ballester L, Scully T, Stewart N, De Leon DD. The Use of Lanreotide in the Treatment of Congenital Hyperinsulinism. J Clin Endocrinol Metab 2022; 107:e3115-e3120. [PMID: 35587448 DOI: 10.1210/clinem/dgac322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Congenital hyperinsulinism (HI) results in severe, persistent hypoglycemia and is associated with high risk of neurodevelopmental deficits. Sixty percent of HI cases are unresponsive to diazoxide, the only Food and Drug Administration-approved drug. Somatostatin analogs are used off-label as second-line treatment; the long-acting somatostatin analogue, lanreotide, has been used to treat HI over the past decade. Existing reports are limited to small case series. OBJECTIVE To assess the effectiveness and safety of lanreotide in individuals with HI. DESIGN Retrospective cohort study of individuals with HI treated with lanreotide between 2015 and 2020. SETTING The Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia. PATIENTS Fifty-four individuals with hyperinsulinism treated with lanreotide. MAIN OUTCOME MEASURES Fasting duration with plasma glucose > 70 mg/dL; frequency of lanreotide-associated side effects. RESULTS The median duration of lanreotide therapy was 28.7 (2.8-64.5) months. Thirty-four patients (63%) had HI due to inactivating mutations of the adenosine 5'-triphosphate (ATP) sensitive potassium channel (KATP-HI), and 39% had undergone a pancreatectomy. Of 52 patients receiving other HI therapies, 22 (42%) were able to discontinue other treatments and were managed on lanreotide alone. Fasting duration with plasma glucose > 70 mg/dL was significantly longer during therapy with lanreotide compared to prior to lanreotide initiation (8.6 ± 6.5 vs 5.1 ± 4.7 hours, P = 0.001). The most common side effects were subcutaneous nodules (26%) and gallstones (11%). CONCLUSIONS Lanreotide is a well-tolerated treatment for patients with HI. It results in a longer duration of fasting and a simplification of treatment regimens.
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Affiliation(s)
- Heather Cuff
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Katherine Lord
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Lance Ballester
- Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Tryce Scully
- Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Nicole Stewart
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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20
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Chandran S, R PR, Mei Chien C, Saffari SE, Rajadurai VS, Yap F. Safety and efficacy of low-dose diazoxide in small-for-gestational-age infants with hyperinsulinaemic hypoglycaemia. Arch Dis Child Fetal Neonatal Ed 2022; 107:359-363. [PMID: 34544689 DOI: 10.1136/archdischild-2021-322845] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 09/06/2021] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Diazoxide (DZX) is the drug of choice for treating hyperinsulinaemic hypoglycaemia (HH), and it has potentially serious adverse effects. We studied the safety and efficacy of low-dose DZX in small-for-gestational-age (SGA) infants with HH. DESIGN An observational cohort study from 1 September 2014 to 31 September 2020. SETTING A tertiary Women's and Children's Hospital in Singapore. PATIENTS All SGA infants with HH. INTERVENTION Diazoxide, at 3-5 mg/kg/day. MAIN OUTCOME MEASURES Short-term outcomes; adverse drug events and fasting studies to determine 'safe to go home' and 'resolution' of HH. RESULTS Among 71 836 live births, 11 493 (16%) were SGA. Fifty-six (0.5%) SGA infants with HH were identified, of which 27 (47%) with a mean gestational age of 36.4±2 weeks and birth weight of 1942±356 g required DZX treatment. Diazoxide was initiated at 3 mg/kg/day at a median age of 10 days. The mean effective dose was 4.6±2.2 mg/kg/day, with 24/27 (89%) receiving 3-5 mg/kg/day. Generalised hypertrichosis occurred in 2 (7.4%) and fluid retention in 1 (3.7%) infant. A fasting study was performed before home while on DZX in 26/27 (96%) cases. Diazoxide was discontinued at a median age of 63 days (9-198 days), and resolution of HH was confirmed in 26/27 (96%) infants on passing a fasting study. CONCLUSION Our study demonstrates that low-dose DZX effectively treats SGA infants with HH as measured by fasting studies. Although the safety profile was excellent, minimal adverse events were still observed with DZX, even at low doses.
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Affiliation(s)
- Suresh Chandran
- Department of Neonatology, KK Women's and Children's Hospital, Singapore .,Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore.,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Pravin R R
- Department of Pediatrics, KK Women's and Children's Hospital, Singapore
| | - Chua Mei Chien
- Department of Neonatology, KK Women's and Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore.,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Seyed Ehsan Saffari
- Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore
| | - Victor Samuel Rajadurai
- Department of Neonatology, KK Women's and Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore.,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Fabian Yap
- Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore .,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.,Department of Pediatrics, KK Women's and Children's Hospital, Singapore
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21
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Stefanovski D, Vajravelu ME, Givler S, De León DD. Exendin-(9-39) Effects on Glucose and Insulin in Children With Congenital Hyperinsulinism During Fasting and During a Meal and a Protein Challenge. Diabetes Care 2022; 45:1381-1390. [PMID: 35416981 PMCID: PMC9210867 DOI: 10.2337/dc21-2009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 03/16/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in children with hyperinsulinism (HI). RESEARCH DESIGN AND METHODS This was an open-label, four-period crossover study. In periods 1 and 2, the effect of three different dosing regimens of exendin-(9-39) (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) versus vehicle on fasting glucose was assessed in 16 children with HI. In periods 3 and 4, a subset of eight subjects received either vehicle or exendin-(9-39) (0.6 mg/kg) during a mixed-meal tolerance test (MMTT) and an oral protein tolerance test (OPTT). RESULTS Treatment group 2 showed 20% (P = 0.037) increase in the area under the curve (AUC) of fasting glucose. A significant increase in AUC of glucose was also observed during the MMTT and OPTT; treatment with exendin-(9-39) resulted in 28% (P ≤ 0.001) and 30% (P = 0.01) increase in AUC of glucose, respectively. Fasting AUC of insulin decreased by 57% (P = 0.009) in group 3. In contrast, AUC of insulin was unchanged during the MMTT and almost twofold higher (P = 0.004) during the OPTT with exendin-(9-39) treatment. In comparison with vehicle, infusion of exendin-(9-39) resulted in significant reduction in likelihood of hypoglycemia in group 2, by 76% (P = 0.009), and in group 3, by 84% (P = 0.014). Administration of exendin-(9-39) during the OPTT resulted in 82% (P = 0.007) reduction in the likelihood of hypoglycemia. CONCLUSIONS These results support a therapeutic potential of exendin-(9-39) to prevent fasting and protein-induced hypoglycemia in children with HI.
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Affiliation(s)
- Darko Stefanovski
- School of Veterinarian Medicine, University of Pennsylvania, Philadelphia, PA
| | - Mary E Vajravelu
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Stephanie Givler
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA
| | - Diva D De León
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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22
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Banerjee I, Raskin J, Arnoux JB, De Leon DD, Weinzimer SA, Hammer M, Kendall DM, Thornton PS. Congenital hyperinsulinism in infancy and childhood: challenges, unmet needs and the perspective of patients and families. Orphanet J Rare Dis 2022; 17:61. [PMID: 35183224 PMCID: PMC8858501 DOI: 10.1186/s13023-022-02214-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 02/06/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children, and carries a considerable risk of neurological damage and developmental delays if diagnosis and treatment are delayed. Despite rapid advances in diagnosis and management, long-term developmental outcomes have not significantly improved in the past years. CHI remains a disease that is associated with significant morbidity, and psychosocial and financial burden for affected families, especially concerning the need for constant blood glucose monitoring throughout patients' lives. RESULTS In this review, we discuss the key clinical challenges and unmet needs, and present insights on patients' and families' perspective on their daily life with CHI. Prevention of neurocognitive impairment and successful management of patients with CHI largely depend on early diagnosis and effective treatment by a multidisciplinary team of specialists with experience in the disease. CONCLUSIONS To ensure the best outcomes for patients and their families, improvements in effective screening and treatment, and accelerated referral to specialized centers need to be implemented. There is a need to develop a wider range of centers of excellence and networks of specialized care to optimize the best outcomes both for patients and for clinicians. Awareness of the presentation and the risks of CHI has to be raised across all professions involved in the care of newborns and infants. For many patients, the limited treatment options currently available are insufficient to manage the disease effectively, and they are associated with a range of adverse events. New therapies would benefit all patients, even those that are relatively stable on current treatments, by reducing the need for constant blood glucose monitoring and facilitating a personalized approach to treatment.
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Affiliation(s)
- Indraneel Banerjee
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, UK.
| | - Julie Raskin
- Congenital Hyperinsulinism International, Glen Ridge, NJ, USA
| | - Jean-Baptiste Arnoux
- Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Stuart A Weinzimer
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
| | | | | | - Paul S Thornton
- Congenital Hyperinsulinism Center, Cook Children's Medical Center, Fort Worth, TX, USA
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23
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Salguero MV, Chan K, Greeley SAW, Dyamenahalli U, Waggoner D, del Gaudio D, Rajiyah T, Lemelman M. Novel KDM6A Kabuki Syndrome Mutation with Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension requiring ECMO. J Endocr Soc 2022; 6:bvac015. [PMID: 35237736 PMCID: PMC8884118 DOI: 10.1210/jendso/bvac015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Indexed: 11/30/2022] Open
Abstract
Kabuki syndrome (KS) is a multisystem disorder estimated to occur in 1:32 000 newborns. Pathogenic mutations cause the majority but not all cases of KS in either KMT2D or KDM6A. KS can be suspected by phenotypic features, including infantile hypotonia, developmental delay, dysmorphic features, congenital heart defects, and others. Still, many of these features are not readily apparent in a newborn. Although neonatal hypoglycemia has been reported in 8% to 10% of patients with KS, the incidence and severity of hyperinsulinemic hypoglycemia (HH) is not well-studied. We present a full-term female infant with HH who was responsive to low-dose diazoxide. At 3 months of age, she was admitted for septic shock, worsening respiratory status, and severe pulmonary hypertension, requiring extracorporeal membrane oxygenation support. Her neonatal history was notable for hypotonia, dysphagia with aspiration requiring gastrostomy tube placement, and a cardiac defect—hypoplastic aortic arch requiring aortic arch repair. She has characteristic facial features, including prominent eyelashes, long palpebral fissures, and a short nasal columella. Next-generation sequencing for HH revealed a de novo likely pathogenic missense variant in KDM6A gene: c.3479G > T, p.Gly1160Val that was absent from population databases. Genetic testing for causes of HH should include testing of the KS genes KMT2D and KDM6A. Early detection of the underlying genetic defect will help guide management as all reported HH cases associated with KS have been responsive to diazoxide. Affected infants with underlying cardiac conditions may be at higher risk of serious respiratory complications such as pulmonary hypertension.
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Affiliation(s)
- Maria V Salguero
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
| | - Karen Chan
- Department of Pediatrics, University of Chicago
| | - Siri Atma W Greeley
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
| | - Umesh Dyamenahalli
- Department of Pediatrics, Section of Pediatric Cardiology, University of Chicago
| | | | | | - Tara Rajiyah
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
| | - Michelle Lemelman
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
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24
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Chen C, Sang Y. Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management. Front Endocrinol (Lausanne) 2022; 13:1102307. [PMID: 36726472 PMCID: PMC9884677 DOI: 10.3389/fendo.2022.1102307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/27/2022] [Indexed: 01/17/2023] Open
Abstract
Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.
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25
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Pasquini TLS, Mesfin M, Schmitt J, Raskin J. Global Registries in Congenital Hyperinsulinism. Front Endocrinol (Lausanne) 2022; 13:876903. [PMID: 35721728 PMCID: PMC9201947 DOI: 10.3389/fendo.2022.876903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies and children. There are many areas of need for HI research. Some of the most critical needs include describing the natural history of the disease, research leading to new and better treatments, and identifying and managing hypoglycemia before it is prolonged and causes brain damage or death. Patient-reported data provides a basis for understanding the day-to-day experience of living with HI. Commonly identified goals of registries include performing natural history studies, establishing a network for future product and treatment studies, and supporting patients and families to offer more successful and coordinated care. Congenital Hyperinsulinism International (CHI) created the HI Global Registry (HIGR) in October 2018 as the first global patient-powered hyperinsulinism registry. The registry consists of thirteen surveys made up of questions about the patient's experience with HI over their lifetime. An international team of HI experts, including family members of children with HI, advocates, clinicians, and researchers, developed the survey questions. HIGR is managed by CHI and advised by internationally recognized HI patient advocates and experts. This paper aims to characterize HI through the experience of individuals who live with it. This paper includes descriptive statistics on the birthing experience, hospitalizations, medication management, feeding challenges, experiences with glucose monitoring devices, and the overall disease burden to provide insights into the current data in HIGR and demonstrate the potential areas of future research. As of January 2022, 344 respondents from 37 countries consented to participate in HIGR. Parents or guardians of individuals living with HI represented 83.9% of the respondents, 15.3% were individuals living with HI. Data from HIGR has already provided insight into access challenges, patients' and caregivers' quality of life, and to inform clinical trial research programs. Data is also available to researchers seeking to study the pathophysiology of HI retrospectively or to design prospective trials related to improving HI patient outcomes. Understanding the natural history of the disease can also guide standards of care. The data generated through HIGR provides an opportunity to improve the lives of all those affected by HI.
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26
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Descamps J, Ruello C, Perge K, de Bellescize J, Saint-Martin C, Nicolino M. Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide. J Pediatr Endocrinol Metab 2021; 34:667-673. [PMID: 33662190 DOI: 10.1515/jpem-2020-0381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Serious hyperinsulinemic hypoglycemia (HH) is generally the main initial symptom of hyperinsulinism. Epilepsy, without any overt feature of hypoglycemia, might be a very rare initial presentation of late-onset isolated hyperinsulinism. CASE PRESENTATION We describe a case of late-onset HH in a 15-year-old boy with a history of idiopathic generalized epilepsy, now named genetic generalized epilepsy (IGE/GGE), beginning with a tonic-clonic seizure at the age of 11 years. Subsequently, absences with rare eyelid myoclonia were recorded on electroencephalogram (EEG), followed by episodes of impaired consciousness with facial myoclonia. Neurological status was normal except attention-deficit hyperactivity disorder (ADHD). At the age of 15 years, an episode of slight alteration of consciousness with neurovegetative signs could be recorded, which did not correspond to an absence status. Hypoglycemia due to hyperinsulinism was documented (clinically, biologically, and genetically). Diazoxide treatment resolved the glycopenic symptoms, the non-hypoglycemic seizures and normalized brain electrical activity allowing complete withdrawal of antiepileptic medication. CONCLUSIONS Epilepsy can be a very rare initial feature of HH starting in childhood. The occurrence of atypical features in the context of GGE as "absence statuses" with unusual vegetative symptoms and facial myoclonia might be suggestive for HH. Careful assessment and specific treatment are necessary to prevent hyperinsulinism related brain damage. Our case showed that diazoxide might also resolve seizures and normalize EEG.
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Affiliation(s)
- Justine Descamps
- Department of Pediatric Endocrinology, HFME, Hospices Civils de Lyon, Bron, France
| | - Cyril Ruello
- Department of Pediatric Endocrinology, HFME, Hospices Civils de Lyon, Bron, France
| | - Kevin Perge
- Department of Pediatric Endocrinology, HFME, Hospices Civils de Lyon, Bron, France
| | - Julitta de Bellescize
- Department of Epileptology, Sleep Disorders and Functional Pediatric Neurology, HFME, Hospices Civils de Lyon, Bron, France
| | | | - Marc Nicolino
- Department of Pediatric Endocrinology, HFME, Hospices Civils de Lyon, Bron, France.,Faculty of Medicine, Claude-Bernard Lyon 1 University, Lyon, France
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27
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Desai J, Key L, Swindall A, Gaston K, Talati AJ. The danger of diazoxide in the neonatal intensive care unit. Ther Adv Drug Saf 2021; 12:20420986211011338. [PMID: 34046157 PMCID: PMC8135194 DOI: 10.1177/20420986211011338] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/25/2021] [Indexed: 11/15/2022] Open
Abstract
Background The most common cause of persistent hypoglycemia in infancy is hyperinsulinemic hypoglycemia. When conservative measures fail, providers often use medications to treat persistent hypoglycemia. Diazoxide is first-line therapy for neonatal hypoglycemia and works by inhibiting insulin secretion. Diazoxide is associated with fluid retention, and less commonly with respiratory decompensation and pulmonary hypertension. Case reports documenting these severe adverse events exist in the literature, although the overall incidence, risk factors, and timing for these effects in a newborn are not clearly defined. Methods We performed a retrospective chart review of all infants admitted to the neonatal intensive care unit (NICU) at Regional One Health from 1 January 2013 until 15 August 2019, who received diazoxide as a treatment for persistent hypoglycemia secondary to hyperinsulinism. Patients were stratified as either having no adverse event or having an adverse outcome to the medication. A severe adverse outcome was defined as any known major side effect of the medication, which a patient developed within 2 weeks of medication initiation that led to medication discontinuation. Results From our pharmacy database, we identified a total of 15 babies who received diazoxide for persistent hypoglycemia. Of these patients, eight (53%) were classified as having a complication requiring discontinuation of the medication. Six out of eight patients required intubation with mechanical ventilation and five out of eight patients developed pulmonary hypertension. All patients returned to their baseline respiratory support after drug discontinuation. Conclusions A total of 53% of our study population had an adverse outcome to diazoxide. Previous studies suggest 5% of patients may have respiratory decompensation and require ventilatory support while on diazoxide; however, 40% of our patients deteriorated and then required mechanical ventilation. Based on our data, respiratory deterioration may be more likely to occur when diazoxide is used in preterm infants, those with lower birth weight and intrauterine growth restriction. Plain language summary The dangers in diazoxide Newborns could experience a transient period of low blood glucose levels soon after birth. However, some may progress to persistent low blood glucose levels that cannot be controlled with adequate glucose infusion and may require other ways of treatment. Diazoxide is the first-line drug approved by the US Food and Drug Administration (FDA) for this condition. However, certain cases have reported the development of respiratory deterioration, including increased blood pressure in lung circulation after its use. This prompted a black box warning in 2015 by the FDA. The incidence of neonatal low blood glucose levels seems to have increased and so has the use of this drug. Our study identifies 15 newborns who received diazoxide at Regional One Health neonatal intensive care unit in the past 6 years and reports a significantly higher rate of adverse events in our population leading to drug discontinuation in almost 53% of our cases.
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Affiliation(s)
- Jay Desai
- Department of Pediatrics, Division of Neonatal- Perinatal Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Logan Key
- Department of Pediatrics, Division of Neonatal- Perinatal Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Alyson Swindall
- Department of Pharmacy, Regional One Health Center, Memphis, TN, USA
| | - Kan Gaston
- Department of Pharmacy, Regional One Health Center, Memphis, TN, USA
| | - Ajay J Talati
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Tennessee Health Science Center, 853 Jefferson Ave #201, Memphis, TN 38103-3410, USA
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28
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Schweiger B, Sanchez-Lara PA, Markush D, Nawathe P. Reintroduction of Diazoxide after Diagnosis of Pulmonary Hypertension in a Patient with Transient Hyperinsulinism. JOURNAL OF CHILD SCIENCE 2021. [DOI: 10.1055/s-0041-1726462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
AbstractOur case describes the reintroduction of diazoxide despite life-threatening pulmonary hypertension in our infant due to lack of therapeutic options for congenital hyperinsulinism.
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Affiliation(s)
- Bahareh Schweiger
- Pediatrics Department, Cedars-Sinai Hospital, Los Angeles, California, United Sates
| | | | - Dor Markush
- Guerin Congenital Heart Program, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United Sates
| | - Pooja Nawathe
- Pediatrics Department, Cedars-Sinai Hospital, Los Angeles, California, United Sates
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29
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Efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia: A systematic review and meta-analysis. PLoS One 2021; 16:e0246463. [PMID: 33571197 PMCID: PMC7877589 DOI: 10.1371/journal.pone.0246463] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 01/19/2021] [Indexed: 12/29/2022] Open
Abstract
Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This systemic review and meta-analysis aimed to investigate the efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia (HH). The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases. The findings were summarized, and the pooled effect size and its 95% confidence interval (CI) were calculated. A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria. Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71% (95% CI 50%-93%, Pheterogeneity< 0.001, I2 = 98.3%, Peffect< 0.001). The common side effects were hypertrichosis (45%), fluid retention (20%), gastrointestinal reaction (13%), edema (11%), and neutropenia (9%). Other adverse events included pulmonary hypertension (2%) and thrombocytopenia (2%). This meta-analysis suggested that diazoxide was potentially useful in HH management; however, it had some side effects, which needed careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence.
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30
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Sullivan RT, Tillman KA, Kindel SJ, Handler SS. Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy. Pulm Circ 2021; 11:2045894020987117. [PMID: 33614015 PMCID: PMC7869162 DOI: 10.1177/2045894020987117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/18/2020] [Indexed: 11/30/2022] Open
Abstract
Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.
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Affiliation(s)
- Rachel T Sullivan
- Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
| | - Kathryn A Tillman
- Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
| | - Steven J Kindel
- Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
| | - Stephanie S Handler
- Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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31
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Keyes ML, Healy H, Sparger KA, Orth LE, Geha M, Roumiantsev S, Matute JD. Necrotizing Enterocolitis in Neonates With Hyperinsulinemic Hypoglycemia Treated With Diazoxide. Pediatrics 2021; 147:peds.2019-3202. [PMID: 33483452 PMCID: PMC7849198 DOI: 10.1542/peds.2019-3202] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2020] [Indexed: 11/24/2022] Open
Abstract
The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration-approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006-April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.
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Affiliation(s)
- Madeline L. Keyes
- Division of Neonatology and Newborn Medicine, Department of Pediatrics, and,Harvard Neonatal-Perinatal Medicine Fellowship Training Program, Boston, Massachusetts,Contributed equally as co-first authors
| | - Helen Healy
- Division of Neonatology and Newborn Medicine, Department of Pediatrics, and,Harvard Neonatal-Perinatal Medicine Fellowship Training Program, Boston, Massachusetts,Contributed equally as co-first authors
| | | | - Lucas E. Orth
- Department of Pharmacy, Massachusetts General Hospital, Boston, Massachusetts; and
| | - Mayya Geha
- Division of Neonatology and Newborn Medicine, Department of Pediatrics, and
| | - Sergei Roumiantsev
- Division of Neonatology and Newborn Medicine, Department of Pediatrics, and
| | - Juan D. Matute
- Division of Neonatology and Newborn Medicine, Department of Pediatrics, and
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32
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Brar PC, Heksch R, Cossen K, De Leon DD, Kamboj MK, Marks SD, Marshall BA, Miller R, Page L, Stanley T, Mitchell D, Thornton P. Management and Appropriate Use of Diazoxide in Infants and Children with Hyperinsulinism. J Clin Endocrinol Metab 2020; 105:5894029. [PMID: 32810255 DOI: 10.1210/clinem/dgaa543] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.
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Affiliation(s)
- Preneet Cheema Brar
- Division of Endocrinology and Diabetes, Department of Pediatrics, New York University Grossman School of Medicine, New York City, New York
| | - Ryan Heksch
- Center for Diabetes and Endocrinology, Department of Pediatrics, Akron Children's Hospital, Akron, Ohio
| | - Kristina Cossen
- Division of Pediatric Endocrinology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Manmohan K Kamboj
- Division of Endocrinology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio
| | - Seth D Marks
- Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Bess A Marshall
- Division of Endocrinology and Diabetes, Department or Pediatrics, Washington University in St. Louis, St. Louis, Missouri
| | - Ryan Miller
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Laura Page
- Division of Pediatric Endocrinology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
| | - Takara Stanley
- Division of Pediatric Endocrinology, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Deborah Mitchell
- Division of Pediatric Endocrinology, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Paul Thornton
- Congenital Hyperinsulinism Center, Cook Children's Medical Center, Fort Worth, Texas
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Garg PK, Putegnat B, Truong L, Reynolds C, Sanchez I, Nedrelow JK, Uffman J, Lokitz SJ, Nazih R, Garg S, Thornton PS. Visual interpretation, not SUV ratios, is the ideal method to interpret 18F-DOPA PET scans to aid in the cure of patients with focal congenital hyperinsulinism. PLoS One 2020; 15:e0241243. [PMID: 33108363 PMCID: PMC7591017 DOI: 10.1371/journal.pone.0241243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/11/2020] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18F-DOPA PET scans and how this can influence outcomes. MATERIALS AND METHODS After 18F-Fluoro-L-DOPA was injected intravenously into 50 subjects' arm at a dose of 2.96-5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. RESULTS Visual interpretation had the combination of the best sensitivity and positive prediction values. CONCLUSIONS In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.
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Affiliation(s)
- Pradeep K. Garg
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
- * E-mail:
| | - Burton Putegnat
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Lisa Truong
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Courtney Reynolds
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Irene Sanchez
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | | | - John Uffman
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Stephen J. Lokitz
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Rachid Nazih
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Sudha Garg
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Paul S. Thornton
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
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Chen SC, Dastamani A, Pintus D, Yau D, Aftab S, Bath L, Swinburne C, Hunter L, Giardini A, Christov G, Senniappan S, Banerjee I, Shaikh MG, Shah P. Diazoxide-induced pulmonary hypertension in hyperinsulinaemic hypoglycaemia: Recommendations from a multicentre study in the United Kingdom. Clin Endocrinol (Oxf) 2019; 91:770-775. [PMID: 31520536 DOI: 10.1111/cen.14096] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH. DESIGN AND PATIENTS Retrospective cohort study involving four UK regional HH centres; review of case notes of HH patients on diazoxide. MEASUREMENTS The diagnosis of PH was based on clinical and echocardiography evidence. Patient and treatment-related risk factors were analysed for association. RESULTS Thirteen (6 men) of 177 HH diazoxide-treated patients developed PH, an incidence of 7%. In the PH group, HH was diagnosed at median (range) of 9 (1,180) days, with diazoxide commenced 4 (0,76) days from diagnosis and reaching a maximum dose of 7 (2.5,20) mg/kg/d. The majority (8 of 13 patients) developed PH within 2 weeks of diazoxide. Complete diazoxide withdrawal, but not dose reduction, led to PH resolution at 41 (3,959) days. In three patients, PH continued beyond 12 months. Risk factors for the development of PH included the presence of congenital heart disease (CHD) (P = .008), and total fluid volume exceeding 130 mL/kg/d in the immediate 24 hours preceding diazoxide (P = .019). CONCLUSION Pulmonary hypertension can occur in 7% of diazoxide-treated HH patients. Risk factors include the presence of congenital heart disease and fluid overload. Recommendations include echocardiography and fluid restriction to 130 mL/kg/d prior to diazoxide treatment and immediate discontinuation of diazoxide if PH develops.
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Affiliation(s)
- Suet Ching Chen
- Paediatric Endocrinology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Antonia Dastamani
- Paediatric Endocrinology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Donatella Pintus
- Paediatric Endocrinology, Alder Hey Children's Hospital, Liverpool, UK
| | - Daphne Yau
- Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK
| | - Sommayya Aftab
- Paediatric Endocrinology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Louise Bath
- Paediatric Endocrinology, Royal Hospital for Sick Children, Edinburgh, UK
| | - Craig Swinburne
- Paediatric Cardiology, Royal Hospital for Children, NHS Greater Glasgow and Clyde Glasgow, Glasgow, UK
| | - Lindsey Hunter
- Paediatric Cardiology, Royal Hospital for Children, NHS Greater Glasgow and Clyde Glasgow, Glasgow, UK
| | - Alessandro Giardini
- Paediatric Cardiology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Georgi Christov
- Paediatric Cardiology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | | | - Indraneel Banerjee
- Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK
| | - Mohamad Guftar Shaikh
- Paediatric Endocrinology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Pratik Shah
- Paediatric Endocrinology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
- Genetics and Genomic Medicine Programme, University College London Great Ormond Street Institute of Child Health, London, UK
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Current and Emerging Agents for the Treatment of Hypoglycemia in Patients with Congenital Hyperinsulinism. Paediatr Drugs 2019; 21:123-136. [PMID: 31218604 DOI: 10.1007/s40272-019-00334-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycmia in neonatles and children. The inappropriate secretion of insulin by the pancreatic β-cells produces recurrent hypoglycemia, which can lead to severe and permanent brain damage. CHI results from mutations in different genes that play a role in the insulin secretion pathway, and each differs in their responsiveness to medical treatment. Currently, the only available approved treatment for hyperinsulinism is diazoxide. Patients unresponsive to diazoxide may benefit from specialized evaluation including genetic testing and 18F-DOPA PET to identify those with focal forms of CHI. The focal forms can be cured by selective pancreatectomy, but the management of diazoxide-unresponsive diffuse CHI is a real therapeutic challenge. Current off-label therapies include intravenous glucagon, octreotide and long-acting somatostatin analogs; however, they are often insufficient, and a 98% pancreatectomy or continuous feeds may be required. For the first time in over 40 years, new drugs are being developed, but none have made it to market yet. In this review, we will discuss current on-label and off-label drugs and review the currently available data on the novel drugs under development.
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