Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International

Abstract

Background: Idiopathic Ketotic hypoglycemia (IKH) is a diagnosis of exclusion. Although considered as the most frequent cause of hypoglycemia in childhood, little progress has been made to advance the understanding of IKH since the medical term was coined in 1964. We aimed to review the literature on ketotic hypoglycemia (KH) and introduce a novel patient organization, Ketotic Hypoglycemia International (KHI).

Results: IKH may be diagnosed after the exclusion of various metabolic and hormonal diseases with KH. Although often mild and self-limiting, more severe and long-lasting IKH occurs. We therefore divide IKH in physiological KH and pathological KH, the latter defined as recurrent symptomatic, or occasionally symptomatic, episodes with beta-hydroxybutyrate ≥ 1.0 mmol/L and blood glucose < 70 mg/dL (3.9 mol/L), in the absence of prolonged fasting, acute infections and chronic diseases known to cause KH. Pathological KH may represent undiscovered diseases, e.g. glycogen storage disease IXa, Silver-Russel syndrome, and ketone transporter defects, or suggested novel disease entities identified by exome sequencing. The management of KH aims to prevent hypoglycemia, fatty acid oxidation and protein deficiency by supplying adequate amounts of carbohydrates and protein, including nutritional therapy, uncooked cornstarch, and sometimes continuous tube feeding by night. Still, intravenous dextrose may be needed in acute KH episodes. Failure to acknowledge that IKH can be more than normal variation may lead to under-treatment. KHI is a non-profit, patient-centric, global organization established in 2020. The organization was created by adult IKH patients, patient family members, and volunteers. The mission of KHI is to enhance the understanding of IKH while advocating for patients, their families and the continued research into KH.

Conclusion: IKH is a heterogeneous disorder including physiological KH and pathological KH. IKH may represent missed diagnoses or novel disease entities, but shares common management principles to prevent fatty acid oxygenation. KHI, a novel patient organization, aims to enhance the understanding of IKH by supporting IKH families and research into IKH.

Keywords: Children; Glycogen storage disease; Hypoglycemia; Idiopathic ketotic hypoglycemia; Ketone bodies; Rare disease.

Fig. 1

Selected details on the glucose and ketone body metabolism. Representation of selected details of the metabolism at the low insulin—high insulin counter-acting hormones state. Only cells of the liver, fat tissue and major fuel consuming organs are shown. Gluconeogenesis from amino acids, lactate/Cori cycle, and pathway details are omitted. Green line: Mitochondrial membrane. Blue circle: Citric acid cycle. Key enzymes in ketogenesis (arrows): (1) triglycerate lipase; (2) acetyl CoA carboxylase; (3) HMG CoA synthase. Key enzymes in ketolysis: (4) CoA-oxoacid transferase (SCOT); (5) michochondrial acetoacetyl CoA thiolase (MAT; beta-ketothiolase). Ac acetone, AcAc acetoacetate, ATP adenosine triphosphate, BOHB beta-hydroxybutyrate, FA fatty acids, OA oxaloacetate, TG triglyceride