今日の臨床サポート

ケトン血性低血糖症(小児科)

著者: 長尾芳朗 高島平中央総合病院検査科

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2021/07/14
患者向け説明資料

概要・推奨   

  1. 6カ月~5歳くらいまでの幼児が、元気がない、顔色不良、食欲不振、腹痛、頭痛、嘔吐などを主訴に受診した場合に本症の可能性を考慮する(推奨度1)。
  1. 問診で重要なことは最後に摂った食事の時間と量である(推奨度1)。
  1. 本症を疑った場合は血液および尿の検査から、低血糖とケトーシスの存在を証明する(推奨度2)。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
長尾芳朗 : 特に申告事項無し[2021年]
監修:五十嵐隆 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 近年ケトン血性低血糖症の原因として、糖原病9型が注目されており、臨床的に本症と診断される症例の中には糖原病を含む先天性代謝異常症が含まれている可能性がある。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. ケトン血性低血糖症は6カ月~5歳頃までの乳幼児に認められる疾患で、この時期の低血糖の原因として最も頻度が高いとされる。2003年に報告された論文では、64カ月の観察期間にフィラデルフィア小児病院の救急部に受診した児で、糖尿病などの基礎疾患のない6カ月以上の小児の低血糖症の31.4%が本症であったとしている[1]。2010年にフランスのグループが報告したケトン血性低血糖症の有病率に関する研究では、4~7歳の低血糖症の7%が本症であったが、4~5歳に限ると低血糖症の57%が本症であったとしている[2]
  1. 理由は不明だが、最近20年余りでこの疾患の頻度は減少している[3]。しかし、SGA(small for gestational age)児に本症の頻度が高いことから[4]、近年の周産期医療の進歩に伴って本症が再び増加する可能性がある。
  1. 臨床症状は低血糖とケトーシス(血中ケトン体の上昇)の症状が基本である。
  1. 本症の病態生理は不明である。低血糖の原因として肝臓における糖新生の障害や、インスリン、グルカゴン、コルチゾールの異常などは確認されていない。逆にそれらの異常が原因の場合は本症とは診断できない。すなわち、本来ケトン血性低血糖症とは内分泌・代謝異常症を除外診断したうえで下される診断名である。
  1. 経口あるいは輸液で糖を補充することによって低血糖の症状は速やかに改善することが多いが、ケトーシスが消失しないことが多い。
  1. 予後に関しては良好な疾患であるといえる。
問診・診察のポイント  
  1. 本症の症状は低血糖とケトーシスから惹起されるものである。

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文献 

著者: Lauren P Daly, Kevin C Osterhoudt, Stuart A Weinzimer
雑誌名: J Emerg Med. 2003 Jul;25(1):39-43.
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.

PMID 12865107  J Emerg Med. 2003 Jul;25(1):39-43.
著者: A A Monde, S P Djessou, C M Camara, G G Tiahou, G Koffi, F Djohan, L Adonis-Koffi, D E Sess Essiagne
雑誌名: 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.

PMID 20195932  Bull Soc Pathol Exot. 2010 May;103(2):96-9. doi: 10.100・・・
著者: Hidde H Huidekoper, Marinus Duran, Marjolein Turkenburg, Mariëtte T Ackermans, Hans P Sauerwein, Frits A Wijburg
雑誌名: 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.

PMID 17934759  Eur J Pediatr. 2008 Aug;167(8):859-65. doi: 10.1007/s00・・・
著者: Claude Marcus, Jenny Alkén, Jens Eriksson, Leif Blom, Jan Gustafsson
雑誌名: 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.

PMID 17684053  J Clin Endocrinol Metab. 2007 Nov;92(11):4080-4. doi: 1・・・
著者: A N Lteif, W F Schwenk
雑誌名: Endocrinol Metab Clin North Am. 1999 Sep;28(3):619-46, vii.
Abstract/Text Hypoglycemia is more common in the pediatric patient than in adults. This article discusses the many diagnoses that can be associated with hypoglycemia in infancy and childhood. A guide to help practitioners evaluate such patients and suggested treatments for many of these disorders are provided. As genetic diagnosis continues to develop, it is anticipated that the list of specific disorders associated with hypoglycemia in infancy and childhood will increase.

PMID 10500934  Endocrinol Metab Clin North Am. 1999 Sep;28(3):619-46, ・・・
著者: Merel R van Veen, Peter M van Hasselt, Monique G M de Sain-van der Velden, Nanda Verhoeven, Floris C Hofstede, Tom J de Koning, Gepke Visser
雑誌名: 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.

PMID 21422093  Pediatrics. 2011 Apr;127(4):e1021-7. doi: 10.1542/peds.・・・
著者: Laurie M Brown, Michelle M Corrado, Rixt M van der Ende, Terry G J Derks, Margaret A Chen, Sara Siegel, Kate Hoyt, Catherine E Correia, Christopher Lumpkin, Theresa B Flanagan, Caroline T Carreras, David A Weinstein
雑誌名: 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.

PMID 25070466  J Inherit Metab Dis. 2015 May;38(3):489-93. doi: 10.100・・・

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