A Study of Endocrine, Metabolic, and Genetic Risk Factors of Pediatric Persistent Hypoglycemia at Sohag University Hospital

Glucose is the key metabolic substrate for tissue energy production. In the perinatal period, the mother supplies glucose to the fetus, and for most of the gestational period, the normal lower limit of fetal glucose concentration is around 54 mg/dl (3 mmol/L)(1). During the first 24-48 hours of life, as normal neonates transition from intrauterine to extrauterine life, their plasma glucose (PG) concentrations are typically lower than later in life (2). Distinguishing between transitional neonatal glucose regulation in normal newborns and hypoglycemia that persists or occurs for the first time beyond the first 3 days of life is important for prompt diagnosis and effective treatment to avoid serious consequences, including seizures and permanent brain injury (2) The definition of hypoglycemia remains controversial in neonates and children. Some approaches define hypoglycemia on the basis of symptoms, others on the PG value. According to the American Academy of Pediatrics (AAP) and Pediatric Endocrine Society (PES), hypoglycemia is diagnosed when plasma glucose is, respectively, \<47 mg/dL and \<50 mg/dL in at term newborns during the first 48 h of life. Different threshold values have been proposed for pre-term infants (3,4) .

In at-term newborns after the first 48 h of life, infants and younger children, hypoglycemia is defined when plasma glucose is \<50 mg/dL. This threshold value is low enough to avoid false-positive results, but is unlikely to lead to permanent neurological damage. In older children, it is possible to use Whipple's triad characterized by signs and/or symptoms of hypoglycemia, reduced plasma glucose concentration and resolution of these signs/symptoms after acquisition of normoglycemic status(3,4). Per the AAP guidelines, if it is not possible to maintain a glucose concentration >45 mg/dL after 24 hours with using a glucose infusion rate (GIR) rate of 5-8 mg/kg/min, consideration should be given to the possibility of a disorder causing persistent hypoglycemia (5,6) Also, Persistent hypoglycemia (PH) beyond 3 days of life warrants investigation. (7) Blood glucose concentrations are maintained within this range by a complex interplay of hormones that control glucose production and utilization. The key hormones that regulate glucose homeostasis include insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. Pathological endocrine and metabolic conditions that affect either glucose production or utilization can lead to hypoglycemia (8) The most common causes of hypoglycemia in children are diabetes and idiopathic ketotic hypoglycemia. Hypoglycemia also occurs in other endocrine disorders and inborn errors of metabolism (IEMs). In most cases, hypoglycemia is due to increased usage of glucose (hyperinsulinism, fatty acid oxidation disorders (FAODs), sepsis), decreased nutritional supply (gastroenteritis), or decreased endogenous production of glucose (adrenal insufficiency, IEMs, liver failure) (8). The primary endocrine cause of persistent neonatal hypoglycemia is hyperinsulinism (HI), where dysregulated insulin secretion suppresses ketone production and deprives the brain of alternative fuels. HI can be genetic, such as mutations in the KATP channel genes, or acquired due to perinatal stress factors like intrauterine growth restriction. Hormone deficiencies, including hypopituitarism with cortisol and growth hormone deficiency, can also present with hypoglycemia in the newborn period (4). Metabolic disorders causing hypoglycemia include fatty acid oxidation disorders, which prevent fat breakdown and result in hypoketotic hypoglycemia with potential liver or cardiac involvement. Glycogen storage diseases impair glucose release from glycogen stores and gluconeogenesis, leading to severe fasting hypoglycemia accompanied by elevated lactate and hepatomegaly. Disorders of gluconeogenesis similarly disrupt the liver's ability to convert substrates like alanine and glycerol into glucose (4). Genetic causes of hypoglycemia in children include monogenic defects such as mutations in ABCC8 and KCNJ11 causing congenital hyperinsulinism, as well as genes involved in glycogen storage diseases (e.g., G6PC, PYGL), gluconeogenesis (e.g., FBP1), and hormonal regulation (e.g., GLUD1, HNF4A). Advances in next- generation sequencing have enabled the identification of both common and rare genetic etiologies, improving diagnostic accuracy and personalized management (4).

Retrospective studies suggest the rate of undiagnosed endocrine or metabolic disorders in pediatric patients with recurrent hypoglycemia is as high as 8-28% (9,10) In our study, we will use a stepwise approach to help early and accurate diagnosis of endocrine, metabolic, and suspected genetic causes of persistent hypoglycemiaamong children at Sohag University Hospital.