Hypoglycemia of infancy and childhood

Hypoglycemia of infancy and childhood represents a treatable cause of mental retardation and seizures. Most neonates with hypoglycemia have transient disorders, but with persistent hypoglycemia one must consider hyperinsulinism, hypopituitarism, or hereditary hepatic enzyme deficiencies. Outside of the neonatal period, ketotic hypoglycemia is the most common cause of hypoglycemia in childhood. One cannot overemphasize the value of obtaining certain diagnostic tests at the presentation of spontaneous hypoglycemia, including blood for insulin, cortisol, growth hormone, and urine for ketone bodies. Supportive treatment with intravenous glucose to maintain the blood glucose greater than 50 mg/dl is important until a diagnosis is established allowing specific therapy aimed at the underlying disorder.     

Prolonged hyperinsulinemic hypoglycemia in a small for date preterm

Hyperinsulinism is an important cause of hypoglycemia in early infancy. Many forms of hyperinsulinemic hypoglycemia are described: transient, prolonged, persistent. Transient forms are well recognized in infants of diabetic mother; prolonged forms are responsible for the hypoglycemia in small-for-date (SGA) infants and asphyxiated newborns. Persistent hyperinsulinemic hypoglycemia occurs in a group of congenital disorders associated with an abnormality of beta-cell regulation throughout the pancreas. Accurate diagnosis and treatment are essential in all various forms of hyperinsulinism also because newborns are at high risk of permanent brain damage. We report a case of prolonged hyperinsulinemic hypoglycemia in a SGA preterm, immediately treated with a high dose of glucose and glucocorticoid and then with diazoxide. Hypoglycemia was continued until 2 months of age when it resolved spontaneously and completely.     

Hypoglycemia in childhood: long-term effects

Glucose is the main cerebral fuel throughout life. Inadequate cerebral glucose supply, due to recurrent episodes of severe hypoglycemia during the neonatal period or infancy, when the brain is still developing, lead to serious long-term neurological impairments, ranging from mild neurocognitive dysfunction to severe mental retardation, epilepsy, microcephaly or even hemiparesis or aphasia. Moreover, in the most common form of severe recurrent hypoglycemia of infancy due to hyperinsulinism, not only abnormalities in neurocognitive function, but also the later development of diabetes mellitus are observed. Furthermore, recurrent hypoglycemia, supervening as a side-effect of intensified insulin treatment in young diabetic children, may also induce mild neurocognitive dysfunction and, specifically, memory deficits that predispose these children to new hypoglycemic episodes and hypoglycemia unawareness. In conclusion, prompt and meticulous management of hypoglycemia and its prevention during the neonatal period, infancy and childhood constitute the main goal of physicians taking care of these patients in order to ascertain a long-standing quality of life devoid of long-term sequelae.     

Persistent hyperinsulinemic hypoglycemia of infancy: case report

OBJECTIVE: To report a case of Persistent Hyperinsulinemic Hypoglycemia in twins which is a situation not yet reported in the literature. METHODS: Report of seizures in identical twins, from consanguineous parents, with persistent hypoglycemia as cause of the seizures. Laboratory tests, performed for etiological investigation of the hypoglycemia, included thyroid hormones (T4/TSH), insulin, cortisol, growth hormone, stimulation test with glucagon (to evaluate the insulin/glucose relation), and histopathological study of the pancreas. RESULTS: Laboratorial investigation revealed a persistent hypoglycemia with hyperinsulinism which were confirmed with the stimulation test with glucagon. The histopathological exam showed a persistence of first generation pancreatic islet, confirming the diagnosis of Persistent Hyperinsulinemic Hypoglycemia in Infancy (the new denomination of Nesidioblastosis). CONCLUSION: Although rare, this condition must be early suspected early in the evaluation of hypoglycemia of the young infant, even out of the neonatal period, specially if the parents are consanguineous. The adequate therapy must be quickly initiated in order to prevent neurological damage.     

Nesidioblastosis. Apropos of 12 new cases

Two new cases of diffuse hyperplasia of the pancreas are reported. This infrequent condition is caused by intermittent and variable insulin hypersecretion. The hyperinsulinism is responsible for severe, lasting and intractable hypoglycemia that causes seizures and mental retardation. Onset usually occurs in the neonatal period. The diagnosis of hyperinsulinism rests on four criteria: the presence of increased insulin levels in the face of hypoglycemia, the low urinary excretion of ketone bodies during hypoglycemic episodes, the need for more than 15/mg/kg/min glucose to maintain the serum glucose level above 2 mmol/l, and a positive response to glucagon. The topographic diagnosis is often disappointing. Medical treatment of the hypoglycemia with diazoxide is a transient measure. Subtotal pancreatectomy is indispensable. Postoperative results are variable. Insulin deficiency diabetes mellitus is common and unusual in that insulin induces an exaggerated response. Recovery can be observed. If hypoglycemia recurs, diazoxide is often effective.     

Apparent hypocortisolism in an infant with prolonged hyperinsulinism

We report a case of transient hyperinsulinism with hypocortisolemia in a preterm small for date neonate with recurrent hypoglycemia and perinatal stress. Investigation revealed increased Insulin level with subnormal cortisol level even during hypoglycemia. Hypoglycemia resolved by its own by 22nd day of life with normal insulin and cortisol level thereafter.     

Laparoscopic diagnosis and cure of hyperinsulinism in two cases of focal adenomatous hyperplasia in infancy

Persistent hyperinsulinemic hypoglycemia of infancy or congenital hyperinsulinism of the neonate is a rare condition that may cause severe neurologic damage if the disease is unrecognized or inadequately treated. Current treatment aims to restore normal blood glucose levels by providing a carbohydrate-enriched diet and drugs that inhibit insulin secretion. If medical treatment fails, then surgery is required. Because congenital hyperinsulinism may be caused either by diffuse involvement of pancreatic beta-cells or by a focal cluster of abnormal beta-cells, the extent of pancreatectomy varies. We report on 2 patients with a focal form of the disease for whom diagnosis was made with laparoscopy. Laparoscopic enucleation of the lesion was curative.     

Neonatal Hypoglycemia

Glucose is essential for cerebral metabolism. Unsurprisingly therefore, hypoglycemia may result in encephalopathy. Knowledge of the homeostatic mechanisms that maintain blood glucose concentrations within a tight range is the key for diagnosis and appropriate management of hypoglycemia. Neonatal hypoglycemia can be transient and is commonly observed in at-risk infants. A wide range of rare endocrine and metabolic disorders can present with neonatal hypoglycemia, of which congenital hyperinsulinism is responsible for the most severe form of hypoglycemia. Collection of appropriate blood samples for hormones and intermediary metabolites during an episode of hypoglycemia is critical for diagnosis and appropriate management. Prompt diagnosis with aggressive early intervention remains the mainstay of treatment to avert irreversible brain damage.     

Prediction of neonatal hypoglycemia in infants of diabetic mothers by glucose disappearance in the first hour of life

Whole blood glucose determinations were obtained in the first hour of life in 44 infants of diabetic mothers in order to predict the occurrence of subsequent hypoglycemia by means of the calculated glucose disappearance rate. Hypoglycemia (whole blood glucose < 20 mg/dl) occurred in 10 infants with linear glucose disappearance of whom 9 had a glucose disappearance rate ? 3.0% per min (90% sensitivity). Nine of 11 infants with glucose disappearance rates ? 3.0% per min had hypoglycemia (82% specificity). This relatively simple procedure offers an accurate method for prediction of neonatal hypoglycemia due to reactive hyperinsulinemia in infants of diabetic mothers.     

Dumping syndrome: an unusual cause of severe hyperinsulinemic hypoglycemia in neurologically impaired children with gastrostomy

This paper describes severe hyperinsulinemic hypoglycemia during bolus enteral feeding in two neurologically impaired children. Both children were affected by dysphagia with swallowing difficulties; caloric intake was inadequate. For these reasons, percutaneous endoscopic gastrostomy had been positioned during the first months of life. In one patient due to persisting vomiting, after a few months, a gastrojejunal tube (PEG-J) was inserted. Hypoglycemia was revealed by routine blood tests, without evidence of specific symptoms. Continuous subcutaneous glucose monitoring showed wide glucose excursions, ranging from hypoglycemia to hyperglycemia. Extremely high levels of insulin were detected at the time of hypoglycemia. A diagnosis of dumping syndrome (DS) was suspected in both children. In the child with PEG, the tip of the gastrostomy catheter was found to be lying in the bulbus duodeni. Once this had been pulled back, hypoglycemic episodes disappeared. The child with PEG-J needed continuous enteral feeding to reach a normal glucose balance. DS is a relatively common complication in children with gastrostomy, but extremely irregular glucose levels, ranging from hypoglycemia to hyperglycemia, and increased insulin secretion had not been previously demonstrated. The incidence of DS is probably underestimated in children receiving enteral feeding for neurological impairment. In these patients intensive monitoring of blood glucose levels should be performed to calibrate meals. Repeated underestimated hypoglycemic episodes could worsen neurological damage and cause a deterioration in clinical conditions.     

Glucose disappearance in infants of diabetic mothers. III. Relationship of spontaneous glucose disappearance to glucose tolerance,neonatal hypoglycemia and lowest blood glucose

Spontaneous glucose disappearance in the first 90 min of life and glucose disappearance following an intravenous injection of 1 g/kg dextrose were measured in 23 infants of insulin-dependent diabetic mothers. Spontaneous disappearance was log-linear in 12/23 infants, providing for calculation of an endogenous K_t which correlated significantly (P < 0.01) with the exogenous Kt determined after the dextrose injection, r = 0.74.Hypoglycemia <20 mg/dl occurred in 4/23 infants, and was identified during the spontaneous glucose disappearance (3 infants) and/or predicted by an endogenous K_t > 3.0%/min (2 infants). There was also a significant inverse correlation (P < 0.01) of the lowest blood glucose obtained within the first 24 h of life with the endogenous K_t, r = 0.61. There was no correlation of the endogenous or exogenous Kt, lowest blood glucose or hypoglycemia with White's classification of the maternal diabetes, diabetic control during pregnancy, the maternal blood glucose at delivery or the cord blood glucose.These data indicate that determination of spontaneous glucose disappearance within the first 90 min of life is useful in identifying infants of diabetic mothers with hypoglycemia or those who will subsequently develop hypoglycemia.     

Familial hyperinsulinism-hyperammonemia syndrome in a family with seizures: case report

Hyperinsulinism-hyperammonemia (HI/HA) syndrome is the second most frequent cause of congenital hyperinsulinism (CHI) and it is characterized by recurrent symptomatic hypoglycemia and persistent hyperammonemia. We describe the familial case of a 2-year-old child and her 32-year-old mother who, having suffered from tonic-clonic seizures since infancy, had both been diagnosed with epilepsy and treated with sodium valproate. Hypoglycemia was identified in the child in routine analysis. Six days after admission, a complete study of hypoglycemia showed test results compatible with hyperinsulinemic hypoglycemia and hyperammonemia. A mutation in the GDH gene (Arg269His) confirmed the diagnosis in both the mother and the child. An important peculiarity of this case is the diagnosis of a 32-year-old woman, previously diagnosed with epilepsy through her daughter's diagnosis at a Pediatric Endocrinology Department and subsequently treated ineffectively with sodium valproate. We conclude that, as hypoglycemia may be subtle, the diagnosis of HI/HA should be considered in children or adults with seizures/epilepsy and hyperammonemia, serum ammonia being a simple screening test for the disease.     

新生儿高胰岛素-高血氨综合征

新生儿高胰岛素-高血氨综合征是一种谷氨酸脱氢酶基因突变导致的遗传性疾病,临床表现为低血糖、高胰岛素和轻度高血氨.进食蛋白质可迅速诱发低血糖,新生儿期起病者少见,易被忽视或延误诊治,导致严重神经系统后遗症.本文就该疾病的发病机制、临床表现及诊疗现状加以概述总结.     

Hyperinsulinism associated with gestational exposure to bupropion in a newborn infant

This case report describes severe hyperinsulinism in a term newborn infant without typical perinatal risk factors for transient hyperinsulinism. The mother had received bupropion, an antidepressant and aid to smoking cessation, throughout pregnancy. The infant presented with profound hypoglycemia and seizures on the 3rd day of life. Laboratory investigation confirmed hyperinsulinism. Stable euglycemia could be achieved only after starting diazoxide. The infant was weaned from diazoxide by 10 weeks of age without recurrence of hypoglycemia, signifying the transient nature of hyperinsulinism. This is the first reported case of a potential association between maternal bupropion use during pregnancy and neonatal hyperinsulinism, and highlights the importance of close monitoring of similar infants.     

Congenital Hypoglycemia Disorders: New Aspects of Etiology,Diagnosis, Treatment and Outcomes

Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (HI) is the most common and severe cause of persistent hypoglycemia in neonates and children. Recent discoveries of the genetic causes of HI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a summary of a recent international symposium on congenital hypoglycemia disorders with emphasis on novel molecular mechanisms resulting in HI, genetic diagnosis, overall approach to management, novel therapies under development, and current outcomes.     

Hypoglycemia in the neonate

Hypoglycemic episodes occurring during the newborn period are often due to transient immaturity of glucoregulatory pathways. Normal feeding is generally the only measure required to treat such episodes. After the first few hours of life, however, hyperinsulinism (HI) is the most common cause of neonatal hypoglycemia. HI may persist for the first weeks/months of life and then remit spontaneously, particularly in low birth weight neonates and those exposed to perinatal stresses; hypoglycemia in such infants can nearly always be medically controlled using diazoxide. There are also several forms of congenital hyperinsulinism presenting with hypoglycemia in neonates that does not remit. Depending on the type of genetic mutation, hypoglycemia in these infants with congenital hyperinsulinism may be controlled medically or may require surgery. The extent of surgery required in infants with ATP-dependent potassium channel mutations unresponsive to diazoxide is dependent upon histological subtype: focal vs. diffuse disease. Disease-specific diagnoses and treatments are therefore essential for effective management of the various forms of neonatal hyperinsulinism.     

PLASMA INSULIN AND BLOOD GLUCOSE DURING LONG-TERM TREATMENT WITH DIAZOXIDE FOR INFANT HYPOGLYCEMIA

Abstract. Victorin, L. H. and Thorell, J. (Department of Paediatrics, University of Göteborg, Göteborg, and the Isotope Laboratory, Lund University at the General Hospital, Malmö, Sweden). Plasma insulin and blood glucose during long-term treatment with diazoxide for infant hypoglycemia. Acta Paediat Scand, 63: 302, 1974.–Hypoglycemia of varying etiology is a mayor therapeutic problem in infancy and childhood. It has been shown that diazoxide may increase blood glucose, presumably mainly by prevention of excess insulin release from the pancreas. A case is reported where diazoxide has been used for more than three years in a boy with neurological symptoms due to severe idiopathic hypoglycemia with leucine intolerance where dietary treatment had proved insufficient. A profound improvement in blood glucose level and suppression of pathologic insulin response to both glucose and leucine loads was noted with a diazoxide dose of 15 mg/kg/day which, however, had to be abandoned due to side effects. Over a period of months without diazoxide, insulin responses to glucose and leucine loads progressively increased with recurrence of clinical symtoms. Over the last three years a dose of 5 mg/kg/day has proved effective in keeping clinical symptoms down without side effects. During these years a marked improvement has taken place in neurological, mental and physical development. It is concluded that when due consideration is given to known side effects diazoxide is a valuable adjuvant for long-term treatment of infantile hypoglycemia.     

Congenital hyperinsulinism caused by mutations in ABCC8 (SUR1) gene

Congenital hyperinsulinism is the most frequent cause of severe, persistent hypoglycemia in infancy and childhood. We report a 2.5 year old girl with severe congenital hyperinsulinism. Mutation analysis showed that the child is a compound heterozygote for two missense mutations in the ABCC8 gene.     

Neonatal hyperinsulinemic hypoglycemia. Two case reports

Neonatal hyperinsulinemic hypoglycemia must be suddenly and appropriately diagnosed and treated to prevent any further neurological dysfunction and damage. Therefore, we report two cases of our observation. Case 1: birth asphyxia, episodes of hypoglycemia after delivery, hyperinsulinism and reduced IGFBP1 blood concentration. Clinical and laboratory pictures resolved progressively after 8 days of life, perfusions were stopped and the neonate began to suck breast milk. Case 2: negative familial and perinatal history. On the 3rd day of life he developed cyanosis, hypotonia, tremors and hypoglycemia. He was discharged with a diagnosis of cerebral injury and neonatal hypoglycemia. At 1 year of life the child showed progressive and heavy neurological damage. The RMN of the brain showed: enlarged ventricles and liquor spaces around the brain, particularly in the frontal region. Hyperinsulinism was diagnosed in our Clinic. He began pharmacological treatment with Diazoxide that permitted euglycemia. The ammonium was normal and excluded glutamate dehydrogenase deficiency (mutation of GLUD1 gene); Diazoxide responsivity excluded mutations of SUR1 and KIR6.3 genes. At 9 years of life he showed motor and language retardation. Newborns with perinatal history of asphyxia may develop transient hyperinsulinism with absent neurological consequences. Persistent hypoglycemic or epileptic-like episodes, in particular on waking up, after meals or during banal infections, must be studied to reveal hyperinsulinism.     

Hypoglycemic brain injury

Hypoglycemia frequently occurs in newborn infants who previously have suffered asphyxia, who are offspring of diabetic mothers, or who are low birthweight for gestational age (IUGR). Many infants who are hypoglycemic do not exhibit clinical manifestations, while others are symptomatic and at risk for the occurrence of permanent brain damage. This review emphasizes the clinical, neuropathologic, and neuro-imaging features of hypoglycemia in newborn infants, especially those who are symptomatic. Neurologic morbidity occurs particularly in those infants who have suffered severe, protracted, or recurrent symptomatic hypoglycemia. Experimental observations emphasize the resistance of the immature brain to the damaging effect of hypoglycemia; such resistance occurs as a consequence of compensatory increases in cerebral blood flow, lower energy requirements, higher endogenous carbohydrate stores, and an ability to incorporate and consume alternative organic substrates to spare glucose for energy production. Hypoglycemia combined with hypoxia-ischemia (asphyxia) is more deleterious to the immature brain than either condition alone.