Daly LP, Osterhoudt KC, Weinzimer SA.
Presenting features of idiopathic ketotic hypoglycemia.
J Emerg Med. 2003 Jul;25(1):39-43. doi: 10.1016/s0736-4679(03)00100-8.
Abstract/Text
Idiopathic ketotic hypoglycemia (IKH) is an important cause of emergent hypoglycemia among children. We present a case series of 24 patients with IKH in an effort to provide a current clinical description of this disorder. Secondly, we provide a crude lower-bound estimate of the incidence of IKH in an Emergency Department (ED) setting. The charts of 94 non-diabetic patients presenting to an ED during a period of 64 months with a diagnosis of hypoglycemia as identified via ICD-9 codes were reviewed. Eleven patients, accounting for 24.4% of all significant hypoglycemic episodes unrelated to diabetes in children over 6 months of age, were diagnosed with IKH. These patients accounted for 31.4% of hypoglycemic episodes among previously heathy children older than 6 months. A further review of 13 individuals with IKH identified from an endocrinology specialty clinic was also performed. Among all 24 individuals identified with IKH, the mean age of presentation was 30.8 months. We have found IKH to be the most common cause of hypoglycemia among previously healthy ED patients during childhood. In our series, patients with IKH presented initially before 5 years of age with symptomatic hypoglycemia during the morning hours after a moderate fast. These patients were found to have ketonuria with symptoms resolving after glucose administration. Patients with IKH were more likely to be Caucasian, male gender, and have a low body weight.
Monde AA, Djessou SP, Camara CM, Tiahou GG, Koffi G, Djohan F, Adonis-Koffi L, Sess Essiagne DE.
[Prevalence of ketotic hypoglycaemia among schoolchildren in the village of Ahoué in Côte-d'Ivoire].
Bull Soc Pathol Exot. 2010 May;103(2):96-9. doi: 10.1007/s13149-010-0040-5. Epub 2010 Feb 27.
Abstract/Text
To determine the prevalence of ketotic hypoglycemia among schoolchildren, a descriptive cross-sectional study was conducted in preschools and schools in rural areas that involved 102 schoolchildren, from 4 to 7 years old, comprised 51 girls and 51 boys. Index WHZ was used to evaluate the children's nutritional status. The sampling was obtained by a drop of capillary blood in the pulp of the finger. The determination of glucose was realized by glucose oxidase method using an ultra sensitive and fast (One Touch Ultra) glucometer, and ketonuria was detected by dipstick "Ketodiastix." The clinical results revealed that most of children had a normal birth weight with an average of 2.885 g, a good Apgar's score superior to 7, and then the nutritional index WHZ revealed 3% of severe malnutrition and 34% of moderate malnutrition. Ten children (9.8%) had a hypoglycemia with a median of 0.51 g/l and extreme values going from 0.42 to 0.59 g/l. Seven children had a hypoglycemia associated with ketonuria. The prevalence of ketotic hypoglycemia was 7% in this study, and more frequent in the children between 4 and 5 years with 57% of cases in this age group. Thus, this condition, found in Western countries is a reality in Côte d'Ivoire, where the diathesis of malnutrition (37% of the population of the study) is a favorable factor. Therefore, it is useful to prevent protein-energy malnutrition by a balanced food by avoiding fasting before school by diet management.
Huidekoper HH, Duran M, Turkenburg M, Ackermans MT, Sauerwein HP, Wijburg FA.
Fasting adaptation in idiopathic ketotic hypoglycemia: a mismatch between glucose production and demand.
Eur J Pediatr. 2008 Aug;167(8):859-65. doi: 10.1007/s00431-007-0598-5. Epub 2007 Oct 13.
Abstract/Text
In order to study the pathophysiology of hypoglycemia in idiopathic ketotic hypoglycemia (KH), glucose kinetics during fasting in patients with KH were determined. A fasting test was performed in 12 children with previously documented KH. Besides determination of glucoregulatory hormones, plasma ketones, FFA and alanine, the rates of endogenous glucose production (EGP), glucose uptake, gluconeogenesis (GNG) and glycogenolysis (GGL) were quantified using the [6,6-(2)H(2)] glucose isotope dilution method and the deuterated water method. The five youngest subjects (age 2.5-3.9 years) became hypoglycemic (glucose <3.0 mmol/l) during the test. Mean differences in glucose kinetics between overnight fasting and the end of the test in the hypoglycemic vs. the normoglycemic subjects were: EGP: -31.9% vs. -17.9% (p = 0.007), GGL: -66.2% vs. -50.8% (p = 0.465) and GNG 6.8% vs. 19.5% (p = 0.465). Plasma alanine levels were significantly lower (p = 0.028) at the end of the test in the hypoglycemic subjects. Plasma ketones and FFA levels were in the normal range for fasting duration in all subjects. We conclude that hypoglycemia in KH is caused by the inability to sustain an adequate EGP during fasting in view of the higher glucose requirement in young children. The decrease in GGL is not accompanied by a significant increase in GNG, possibly because of a limitation in the supply of alanine. Our results support the hypothesis that KH represents the lower tail of the Gaussian distribution of fasting tolerance in children.
Marcus C, Alkén J, Eriksson J, Blom L, Gustafsson J.
Insufficient ketone body use is the cause of ketotic hypoglycemia in one of a pair of homozygotic twins.
J Clin Endocrinol Metab. 2007 Nov;92(11):4080-4. doi: 10.1210/jc.2007-0661. Epub 2007 Aug 7.
Abstract/Text
CONTEXT: Childhood ketotic hypoglycemia (KH) is a disease characterized by fasting hypoglycemia and increased levels of ketone bodies. The cause is unknown.
OBJECTIVE: The objective of the study was to study a pair of homozygotic twin boys, one of whom had severe KH from the age of 14 months, whereas the other boy was apparently healthy.
DESIGN AND RESULTS: At the age of 6 yr, the boys were thoroughly investigated. During a 24-h fasting tolerance test, the twin with KH showed hypoglycemia (blood glucose 2.0 mmol/liter) after 18 h. Three h before the occurrence of hypoglycemia, he had had 10 times higher beta-hydroxybutyrate levels than his brother, who showed no signs of hypoglycemia. Their glucose production rates were normal and similar (23.3 and 21.7 micromol/kg body weight per minute in the healthy and KH twin, respectively) as well as their lipolysis rates (5.8 and 6.8 micromol/kg body weight per minute, respectively). During repeated 60-min infusions of beta-hydroxybutyrate, the plasma level of beta-hydroxybutyrate increased 5-10 times more in the twin with KH (mean 1.1 mmol/liter in the healthy and 10.8 mmol/liter in the KH twin), indicating a disturbed clearance or metabolism of beta-hydroxybutyrate. No mutations were found in genes involved in ketone body metabolism or transport.
CONCLUSION: In the affected boy, KH seems to be the result of a reduced capacity to use ketone bodies, leading to increased peripheral metabolism of glucose that cannot be met by hepatic glucose production. Because the boys are homozygotic twins and only one of them is affected, the ketotic hypoglycemia is most likely caused by an altered imprinting of gene(s) involved in regulating metabolic pathways.
van Veen MR, van Hasselt PM, de Sain-van der Velden MG, Verhoeven N, Hofstede FC, de Koning TJ, Visser G.
Metabolic profiles in children during fasting.
Pediatrics. 2011 Apr;127(4):e1021-7. doi: 10.1542/peds.2010-1706. Epub 2011 Mar 21.
Abstract/Text
BACKGROUND: Hypoglycemia is one of the most common metabolic derangements in childhood. To establish the cause of hypoglycemia, fasting tolerance tests can be used. Currently available reference values for fasting tolerance tests have limitations in their use in daily practice.
OBJECTIVE: The aim of this study was to determine the reference values of metabolites involved in glucose homeostasis during fasting in healthy children.
METHODS: This study included a retrospective analysis of 488 fasting tests. All tests of patients (n = 321) with disorders, including metabolic and endocrine disorders, were excluded, as were tests performed in children who were over- or underweight.
RESULTS: In 167 fasting tests performed in the study, hypoglycemia was reached in 52 (31%) tests. On the basis of the time until hypoglycemia was reached, 3 age groups could be defined: (1) children aged 0 to 24 months (median 15 months) (n = 49); (2) children aged 25 to 84 months (median 45 months) (n = 79); (3) and children aged 85 to 216 months (median 106 months) (n = 39). In all groups, a significant increase in ketone body levels and a significant decrease in glucose levels in plasma were observed during fasting. Younger children had a faster increase in ketone body levels and a faster decrease in glucose levels in plasma than older children.
CONCLUSIONS: Reference values of the metabolites involved in glucose homeostasis during fasting in children were generated. Those values can be used to determine whether a child has a normal fasting response. For high-risk children, guidelines concerning maximum fasting time and dietary intervention during illness are of the utmost importance.
Brown LM, Corrado MM, van der Ende RM, Derks TG, Chen MA, Siegel S, Hoyt K, Correia CE, Lumpkin C, Flanagan TB, Carreras CT, Weinstein DA.
Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children.
J Inherit Metab Dis. 2015 May;38(3):489-93. doi: 10.1007/s10545-014-9744-1. Epub 2014 Jul 29.
Abstract/Text
INTRODUCTION: Ketone formation is a normal response when hypoglycemia occurs. Since the majority of children with recurrent hypoglycemia cannot be diagnosed with a known endocrine or metabolic disorder on a critical sample, ketotic hypoglycemia has been described as the most common cause of low blood glucose concentrations in children. Critical samples, however, will miss the ketotic forms of glycogen storage disease (GSD), which present with elevated ketones, hypoglycemia, and normal hormonal concentrations.
RESULTS: A total of 164 children (96 boys, 68 girls) were enrolled in the study. Prediction of pathogenicity of DNA changes using computer modeling confirmed pathology in 20 individuals [four GSD 0, two GSD VI, 12 GSD IX alpha, one GSD IX beta, one GSD IX gamma] (12%). Boys were most likely to have changes in the PHKA2 gene, consistent with GSD IX alpha, an X-linked disorder.
CONCLUSIONS: Mutations in genes involved in glycogen synthesis and degradation were commonly found in children with idiopathic ketotic hypoglycemia. GSD IX is likely an unappreciated cause of ketotic hypoglycemia in children, while GSD 0 and VI are relatively uncommon. GSD IX alpha should particularly be considered in boys with unexplained hypoglycemia.
