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Review
. 2025;98(3):246-257.
doi: 10.1159/000538483. Epub 2024 Mar 21.

Idiopathic Pathological Ketotic Hypoglycemia: Finding the Needle in a Haystack

Joseph I Wolfsdorf  1 , Terry G J Derks  2 , Danielle Drachmann  3 , Pratik Shah  4 , Paul S Thornton  5 , David A Weinstein  6
Affiliations
Review

Idiopathic Pathological Ketotic Hypoglycemia: Finding the Needle in a Haystack

Joseph I Wolfsdorf et al. Horm Res Paediatr. 2025.

Abstract

Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age. Ketosis and hypoglycemia are now well understood to be normal physiologic responses of young children to prolonged fasting.There is now substantial evidence that the term KH describes a variety of conditions including both the lower end of the normal distribution of fasting tolerance in young children as well as numerous rare disorders that impair fasting adaptation. Recent advances in molecular genetic testing have led to the discovery of these rare disorders. Idiopathic pathological KH is a diagnosis of exclusion that describes rare children who have abnormally limited fasting tolerance, experience recurrent episodes of KH, or develop symptoms of hypoglycemia despite elevated ketone levels, and in whom an explanation cannot be found despite extensive investigation. This review provides an approach to distinguishing between physiological KH and pathological KH and includes recommendations for management.

Keywords: Hypoglycemia; Ketones; Pathological ketotic hypoglycemia; Physiological ketotic hypoglycemia.

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Conflict of interest statement

J.W. is compensated for services as a member of the Central Independent Committee for the DTX401-CL301 study sponsored by Ultragenyx Pharmaceuticals and receives royalties for service as a section editor for UpToDate. D.D. is an employee of Evidera (PPD), a contract research organization. No funding from Evidera, PPD, or related entities was received for this publication. T.G.J.D. for all private-public relationships, all contracts are via UMCG Contract Research Desk, and all payments are to UMCG. There are confidentiality agreements with third parties. In the past 36 months, there have been consultation agreements (with Danone, Ultragenyx Pharmaceutical Inc, ModernaTX Inc, and Beam Therapeutics), contracts for financial research support for investigator-initiated research (NCT04311307) and sponsor-initiated research (NCT03517085, NCT03970278, NCT05139316, and NCT05196165), honoraria for lectures or presentations (by MEDTalks, Prelum, and Danone), and participation in a Data Safety Monitoring Board (NCT05095727) and Advisory Boards (Ultragenyx Pharmaceutical Inc, ModernaTX Inc, and Beam Therapeutics). P.S. has received honoraria for lectures/advisory from Novo Nordisk and Merck. He also serves as Patron of Children’s Hyperinsulinism Charity (CHC) UK. P.S.T. has received research funding from Zealand Pharmaceuticals, Rezolute, Spruce and consulting fees from Zealand, Rezolute, Spruce, Neurocrine, Crinetics. D.A.W. has consulted for the following companies over the past 3 years: Ultragenyx, Beam Therapeutics, Prime Medicine, Moderna, Danone, Alltrna, Golden Heart Flower, Exsilio Therapeutics, Grace Science, Zip Bio, Chaim Medicine, Vitaflo, Siren Biotechnology, and Cometa Therapeutics. He also served as SVP at Passage Bio and interim GMO at Grace Science during this period.

Figures

Fig. 1.
Fig. 1.
Approach to the management of a child presenting to an ED with KH. At many European centers, hypoglycemia is defined as ≤3 mmol/L (54 mg/dL). See text for details. Tables 1 and 2 show expected durations of fasting tolerance in different age groups. Prolonged fasting may be defined as >15 h, >24 h, and >24–36 h in children aged <1, 1–5, and >5 years, respectively. Further investigation should include monitoring fasting plasma glucose and BOHB concentrations. Overnight fasting plasma BOHB ≥1 mmol/L may indicate a pathologic cause of KH and should prompt a more comprehensive evaluation. If necessary, a diagnostic fasting study should be performed when the child is healthy and eating normally to define the evolution of ketosis (and safety parameters for management) and to obtain a critical sample in a controlled setting if this was not already obtained at the time of spontaneous hypoglycemia in the ED.
Fig. 2.
Fig. 2.
GSD, glycogen storage disease; GNG, gluconeogenesis (adapted from Thornton and Hawkes [53]).
See this image and copyright information in PMC

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