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.

A retrospective study of eating and psychosocial problems in patients with hepatic glycogen storage diseases and idiopathic ketotic hypoglycemia: Towards a standard set of patient‐reported outcome measures

“…[1][2][3][4][5] The most frequent cause of hypoglycaemia in childhood is idiopathic ketotic hypoglycemia (IKH), which is a diagnosis of exclusion. 6 The primary aim of dietary treatment in both GSD patients and IKH patients is to maintain euglycemia. In GSD, equally important and related to glycaemic control is to prevent secondary metabolic derangements and long-term complications.…”

Hypoglycaemia Metabolic Gene Panel Testing

“…Hypoglycemia was reported in a NEK11 - mouse model. The described KH patient with a heterozygous NEK11 mutation showed glucagon unresponsive hypoglycemia, migraine, cognitive disability, motor impairments, mild hepatopathy, and decreased plasma IGFBP3 ( 71 , 87 ).…”

“…Patients with heterozygous or homozygous inhibiting mutations in SLC16A1 present with moderate or profound ketosis and sometimes hypoglycemia during fasting or infections, within the first years of life ( 69 , 70 ). In some patients migraine, exercise intolerance, developmental delay, microcephaly and abnormal MRI of the brain have been reported ( 71 ).…”

“…The treatment consists in prevention of hypoglycemia and protein deficiency by adequate supplementation of carbohydrates and proteins, with uncooked cornstarch, or continuous tube feeding by night. Failure to settle a proper diagnosis of IKH may lead to undertreatment ( 71 ). Indeed, the ketotic forms of GSDs are underrecognized because endocrinological and metabolic parameters are unremarkable during investigations for hypoglycemia ( 84 ).…”

Dynamic Methods for Childhood Hypoglycemia Phenotyping: A Narrative Review

“…Hence, many hypoglycemic children do not fit these textbook schemes, and additional investigation is often required. In the end, an important group of individuals is diagnosed with idiopathic ketotic hypoglycemia ( 22 , 23 ).…”