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An Overview of Hypoglycemia in Children Including a Comprehensive Practical Diagnostic Flowchart for Clinical Use

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REVIEW published: 02 August 2021 doi: 10.3389/fendo.2021.684011 An Overview of Hypoglycemia in Children Including a Comprehensive Practical Diagnostic Flowchart for Clinical Use Alberto Casertano 1†, Alessandro Rossi 2,3†, Simona Fecarotta 2*, Francesco Maria Rosanio 1, Cristina Moracas 4, Francesca Di Candia 1, Giancarlo Parenti 2,5, Adriana Franzese 1 and Enza Mozzillo 1* 1 Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II Edited by: University of Naples, Naples, Italy, 2 Department of Translational Medical Science, Section of Pediatrics, Metabolic Diseases Stefano Zucchini, Unit, Federico II University of Naples, Naples, Italy, 3 Section of Metabolic Diseases, Beatrix Children’s Hospital, University Sant’Orsola-Malpighi Polyclinic, Italy Medical Centre Groningen, University of Groningen, Groningen, Netherlands, 4 Department of Translational Medical Science, Reviewed by: Section of Pediatrics, Federico II University of Naples, Naples, Italy, 5 Telethon Institute of Genetics and Medicine, Federico Baronio, Pozzuoli, Italy IRCCS S. Orsola-Malpighi, Italy Vandana Jain, All India Institute of Medical Sciences, Hypoglycemia is the result of defects/impairment in glucose homeostasis. The main India etiological causes are metabolic and/or endocrine and/or other congenital disorders. *Correspondence: Despite hypoglycemia is one of the most common emergencies in neonatal age and Enza Mozzillo childhood, no consensus on the definition and diagnostic work-up exists yet. Aims of this [email protected] Simona Fecarotta review are to present the current age-related definitions of hypoglycemia in neonatal- [email protected]; pediatric age, to offer a concise and practical overview of its main causes and [email protected] management and to discuss the current diagnostic-therapeutic approaches. Since a †These authors have contributed equally to this work and systematic and prompt approach to diagnosis and therapy is essential to prevent share first authorship hypoglycemic brain injury and long-term neurological complications in children, a comprehensive diagnostic flowchart is also proposed. Specialty section: This article was submitted to Keywords: neonatal hypoglycemia, childhood hypoglycemia, inborn errors of metabolism, endocrine Pediatric Endocrinology, hypoglycemia, glucose homeostasis, congenital hyperinsulinism a section of the journal Frontiers in Endocrinology Received: 22 March 2021 Abbreviations: AAP, American Academy of Pediatrics; ACTH, Adreno–CorticoTropic Hormone; AI, Adrenal Insufficiency; Accepted: 31 May 2021 BAPM, British Association for Perinatal Medicine; CAH, Congenital Adrenal Hyperplasia; CAI, Central Adrenal Insufficiency; Published: 02 August 2021 CDG, Congenital Disorders of Glycosylation; CH, Congenital Hyperinsulinism; CoA, Coenzyme A; CPT, Carnitine Palmitoyl–Transferase; CRH, Corticotropin–Releasing Hormone; DZX, Diazoxide; FAOD, Fatty Acid Oxidation Disorders; Citation: FBPase, Fructose 1,6 bisphosphatase; FFA, Free Fatty Acids; G6Pase, Glucose–6–Phosphatase; GALT, Galactose–1–phosphate Casertano A, Rossi A, Fecarotta S, uridyltransferase; GDH, Glutamate Dehydrogenase Enzyme; GH, Growth Hormone; GHD, Growth Hormone Deficiency; Rosanio FM, Moracas C, Di Candia F, GHRH, Growth Hormone–Releasing Hormone; GKD, Glycerol Kinase Deficiency; GLP–1, Glucagon–Like Peptide–1; GSD, Parenti G, Franzese A and Mozzillo E Glycogen Storage Disease; HFI, Hereditary Fructose Intolerance; HY, Hypoglycemia; IGF1, Insulin Growth Factor1; IMD, (2021) An Overview of Hypoglycemia Inborn Metabolic Disorder; IVA, Isovaleric Acidemia; KB, Ketone Bodies; LGA, Large for Gestational Age; MMA, in Children Including a Comprehensive Methylmalonic Acidemia; MRI, Magnetic Resonance Imaging; NBS, Newborn Screening; NGS, Next Generation Practical Diagnostic Sequencing; OA, Organic Acidemias; OXPHOS, Oxidative Phosphorylation; PA, Propionic Acidemia; PAI, Primary Flowchart for Clinical Use. Adrenal Insufficiency; PC, Pyruvate Carboxylase; PEPCK, Phosphoenolpyruvate Carboxykinase; PES, Pediatric Endocrine Front. Endocrinol. 12:684011. Society; PET, Positron Emission Tomography; PG, Plasma Glucose; SGA, Small for Gestational Age; UCCS, Uncooked doi: 10.3389/fendo.2021.684011 cornstarch; UDP, Uridine Di–Phosphate; UOA, Urine Organic Acids. Frontiers in Endocrinology | www.frontiersin.org 1 August 2021 | Volume 12 | Article 684011 Casertano et al. Pediatric Hypoglycemia Diagnostic Flowchart INTRODUCTION adaptation to extrauterine life, characterized by immature hormonal and enzymatic pathways, and the higher glucose Hypoglycemia (HY) in pediatric age shows some peculiarities requirement of the brain, lead to a higher HY risk compared regarding its diagnosis and management, mostly linked to age to older children and adults (9). Infants and children, have less dependent features in glucose homeostasis and to the broad glycogen storage and a higher substrates demand. spectrum of causes. Such causes can initially present with the HY definition remains controversial in neonates and children. same unspecific picture, but they require different treatment (1). Some approaches define HY on the basis of symptoms, others on While being frequent but hard to detect in neonatal age, it is less the plasma glucose value. In adolescents and adults, HY common in infants and toddlers, even rarer in older children definition is based on the so-called “Whipple triad” (1–3). In childhood, HY is a common metabolic-endocrine [(I) symptoms of HY, (II) blood glucose level below 60 mg/dl, emergency possibly causing permanent neurological (III) resolutions of symptoms after glucose intake]. This consequences. It is therefore essential to promptly detect and definition appears inadequate for neonates and children in treat children with HY as well as those at risk. It is crucial to which symptoms are often subtle, and with the child being appropriately investigate its specific etiology for providing unable to communicate them (10). In addition, it is difficult to adequate and specific therapy (3, 4). In this review, we present identify a single plasma glucose (PG) value below which current knowledge on management of HY in neonates and symptoms of HY appear: in fact, symptoms appearance children including difficulties in establishing thresholds for depends on additional factors, including the availability of both definition and therapeutic intervention and providing a alternative energy substrates (e.g. ketone bodies) and the comprehensive overall diagnostic approach through the use of a severity, duration, and recurrence of low PG (7). Neurogenic simple practical flowchart (5–8). symptoms are secondary to the neuroendocrine response, while neuroglycopenic symptoms are due to the low glucose availability to the brain. In neonates and infants, neurogenic CONTROVERSIES ABOUT CLINICAL and neuroglycopenic symptoms are not specificforHY. Therefore HY can be defined as the individualized condition in AND BIOCHEMICAL DEFINITION which PG concentration is low enough to cause symptoms and/ OF HYPOGLYCEMIA or signs of impaired brain function (11). Based on the above-mentioned considerations, three age- Glucose is the primary energy source for central nervous system based different clinical scenarios exist: metabolism, independently from the feeding state (1). Several metabolic pathways cooperate to ensure normal blood glucose i. Neonates <48 h of life: signs or symptoms of neonatal HY concentrations in the fasted state (Figure 1). Such pathways are may vary from severe (e.g. lethargy, tachypnea, tightly regulated by the hormonal (insulin, glucagon, cortisol, hemodynamic instability, apnea, seizures, or even cardiac and growth hormone) and autonomic (catecholamines) arrest) to milder (e.g. abnormal cry, decreased feeding, response. In case of impaired metabolic pathways and/or jitteriness, irritability, pallor, cyanosis, hypothermia, or altered hormonal regulation, glucose could become too low to diaphoresis) (12). In neonates showing specific symptoms, satisfy neuronal demand, causing classical symptoms of HY. In HY is diagnosed when PG is lower than a specific threshold: pediatric age, both glucose homeostasis and clinical presentation 47 mg/dl according to American Academy of Pediatrics of HY show peculiarities compared to adults. In newborns, the (AAP) (13, 14), and 50 mg/dl according to Pediatric FIGURE 1 | Schematic representation of the major metabolic pathways involved in glucose homeostasis during absorptive phase and fasting including exogenous carbohydrates (brown), glycogenolysis (red), gluconeogenesis (blue), fatty acid oxidation (green), ketogenesis and ketolysis (yellow). These mechanisms are tightly controlled by hormonal regulation. Defects in specific enzymes or transporters involved in those pathways as well as endocrine disorders may result in fasting intolerance and hypoglycemia. FFA, free fatty acids, KB, ketone bodies. Frontiers in Endocrinology | www.frontiersin.org 2 August 2021 | Volume 12 | Article 684011 Casertano et al. Pediatric Hypoglycemia Diagnostic Flowchart Endocrine Society (PES) (7). A different glucose threshold intravenous glucose infusion as indicative for persistent HY and has been proposed for pre-term newborns (15). anamnestic and clinical features could help to identify neonates at ii. Neonates >48 h of life, infants, and younger children unable to risk of persistent HY (18). Various glucose monitoring schemes communicate:HYisdefined as PG <50–70 mg/dl (i.e. the have been proposed
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