Ketotic hypoglycemia
Ketotic hypoglycemia refers to any circumstance in which low blood glucose is accompanied by ketosis, the presence of ketone bodies in the blood or urine. This state can be either physiologic or pathologic; physiologic ketotic hypoglycemia is a common cause of hypoglycemia in children, often in response to stressors such as infection or fasting.[1] Pathologic ketotic hypoglycemia is typically caused by metabolic defects, such as glycogen storage disorders.[2]
Causes
Physiologic ketotic hypoglycemia
The body's physiologic response to falling glucose levels is a suppression of insulin secretion from the pancreas, which decreases the amount of glucose available to most tissue but instead prioritizes the remaining amount for the brain.[2] Hormones such as glucagon, cortisol, and adrenaline are then released to stimulate glycogenolysis and gluconeogenesis in the liver, in addition to lipolysis in adipose tissue. As glycogen stores start to be depleted, the liver begins oxidizing fatty acids to ultimately yield ketone bodies, which can serve as an alternative fuel source for the brain in the absence of glucose.[3] Therefore, the combination of low glucose (hypoglycemia) and the presence of ketone bodies yields the state known as ketotic hypoglycemia. Such a physiologic response is common in adults during periods of fasting, and is particularly common in ill younger children who cannot tolerate long periods of fasting.[4] Episodes of physiologic ketotic hypoglycemia in children decrease with increasing age, presumably because fasting tolerance improves with increasing body mass. Such episodes are rare after the age of nine; persisting episodes past this age should raise suspicion for an underlying pathologic cause.[4]
Pathologic ketotic hypoglycemia
Any genetic or metabolic defect that interferes with the body's ability to maintain glucose homeostasis can trigger pathologic ketotic hypoglycemia, in which episodes of ketotic hypoglycemia persist in children despite increasing age.[2] Examples include glycogen storage diseases, disorders of fatty acid metabolism, and disorders of gluconeogenesis, among several others.[2][4] Less common genetic causes, such as Russell-Silver syndrome, have also been described.[5] A non-exhaustive list of causes of pathologic ketotic hypoglycemia is listed below:[2]
- Growth hormone deficiency
- Glycogen storage diseases
- Maple syrup urine disease
- Prader-Willi syndrome
- Pyruvate carboxylase deficiency
Signs and symptoms
The typical patient with ketotic hypoglycemia is a young child between the ages of 10 months and 6 years. Episodes nearly always occur in the morning after an overnight fast, often one that is longer than usual. Symptoms include those of neuroglycopenia, ketosis, or both. The neuroglycopenic symptoms usually include lethargy and malaise, but may include unresponsiveness or seizures. The principal symptoms of ketosis are anorexia, abdominal discomfort, and nausea, sometimes progressing to vomiting.[citation needed]
If severe, parents usually take the child to a local emergency department, where blood is drawn. The glucose is usually found to be between 35 and 60 mg/dl (1.8-3.1 mmol/L). The total CO2 is usually somewhat low as well, (14-19 mmol/L is typical), and if urine is obtained, high levels of ketones are discovered. Ketones can also be measured in the blood at the bedside (Medisense glucometer). Other routine tests are normal. If given intravenous fluids with saline and dextrose, the child improves dramatically and is usually restored to normal health within a few hours. These symptoms are normally seen because of the child being unadapted to using fat as energy, typically when the child's daily glucose intake might be too high (more than 50g/day for a child). This is also associated with fluctuant glycemia throughout the day.[6]
A first episode is usually attributed to a viral infection or acute gastroenteritis. However, in most of these children one or more additional episodes recur over next few years and become immediately recognizable to the parents. In mild cases, carbohydrates and a few hours of sleep will be enough to end the symptoms.[citation needed]
Precipitating factors, conditions that trigger an episode, may include extended fasting (e.g., missing supper the night before), a low carbohydrate intake the previous day (e.g., a hot dog without a bun), or stress such as a viral infection. Most children affected by ketotic hypoglycemia have a slender build, many with a weight percentile below height percentile, though without other evidence of malnutrition. Overweight children are rarely affected.[citation needed]
Ketotic hypoglycemia in glycogen storage disease
Some of the subtypes of glycogen storage disease show ketotic hypoglycemia after fasting periods. Especially glycogen storage disease type IX can be a common cause for ketotic hypoglycemia, with the most common sub-type IXa mainly affecting boys.[7] With glycogen storage disease type XIa, children can usually appear overweight for height, but this is attributed to an enlarged liver (hepatomegaly).[citation needed]
Natural history
Children "outgrow" ketotic hypoglycemia, presumably because fasting tolerance improves as body mass increases. In most children, the episodes become milder and less frequent by four to five years of age and rarely occur after age nine.[8] Onset of hypoglycemia with ketosis after age five or persistence after age seven should elicit referral and an intensive search for a more specific disease.[citation needed]
Diagnosis
The advocacy organization Ketotic Hypoglycemia International defines pathologic ketotic hypoglycemia as recurrent, symptomatic episodes in which patients have beta-hydroxybutyrate levels ≥ 1.0 mmol/L and blood glucose levels < 70 mg/dL in the absence of triggers that would otherwise explain ketotic hypoglycemia.[2]
The most useful diagnostic tests include measurement of insulin, growth hormone, cortisol, and lactic acid at the time of the hypoglycemia. Plasma acylcarnitine levels and urine organic acids exclude some of the important metabolic diseases. When the episodes are recurrent or severe, the definitive test is a hospitalization for a supervised diagnostic fast. This usually demonstrates "accelerated fasting"—a shorter time until the glucose begins to fall, but normal metabolic and counterregulatory responses as the glucose falls. As the glucose reaches hypoglycemic levels, the insulin is undetectable, counterregulatory hormones, fatty acids, and ketones are high, and glucagon injection elicits no rise of glucose.[citation needed]
Treatment
The mainstay of physiologic ketotic hypoglycemia treatment typically includes management of the underlying cause, fluid resuscitation, and dietary supplementation of sugars and carbohydrates.[2] In children, alanine — a precursor in gluconeogenesis — can be infused to rapidly increase plasma glucose levels.[9]
Once ketotic hypoglycemia is suspected and other conditions excluded, appropriate treatment reduces the frequency and duration of episodes.[10] Extended fasts should be avoided. The child should be given a bedtime snack of carbohydrates (e.g. spaghetti or pasta or milk) and should be awakened and fed after the usual duration of sleep. If the child is underweight, a daily nutritional supplement may be recommended. Raw cornstarch dissolved in a beverage helps individuals with hypoglycemia, especially that caused by Glycogen Storage Disease, sustain their blood sugars for longer periods of time and may be given at bedtime.[citation needed]
If a spell begins, carbohydrates and fluids should be given promptly. If vomiting prevents this, the child should be taken to the local emergency department for a few hours of intravenous saline and dextrose. This treatment is often expedited by supplying the parents with a letter describing the condition and recommended treatment.[citation needed]
References
- ^ Kliegman RW, Nelson WE, eds. (2020). Nelson Textbook of Pediatrics. Vol. 2 (21st ed.). Philadelphia, Pa: Elsevier. ISBN 978-0-323-52950-1.
- ^ a b c d e f g Drachmann D, Hoffmann E, Carrigg A, Davis-Yates B, Weaver V, Thornton P, et al. (April 2021). "Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International". Orphanet Journal of Rare Diseases. 16 (1): 173. doi:10.1186/s13023-021-01797-2. PMC 8045369. PMID 33849624.
- ^ Ruppert, Philip M.M.; Kersten, Sander (November 2023). "Mechanisms of hepatic fatty acid oxidation and ketogenesis during fasting". Trends in Endocrinology & Metabolism. doi:10.1016/j.tem.2023.10.002. ISSN 1043-2760.
- ^ a b c Kliegman, Robert M.; Nelson, Waldo E., eds. (2020). Nelson textbook of pediatrics. volume 2: Volume 2 (Edition 21 ed.). Philadelphia, Pa: Elsevier. ISBN 978-0-323-52950-1.
- ^ Eggermann, Thomas (2010-08-15). "Russell–Silver syndrome". American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 154C (3): 355–364. doi:10.1002/ajmg.c.30274. ISSN 1552-4868.
- ^ Manninen AH (December 2004). "Metabolic effects of the very-low-carbohydrate diets: misunderstood "villains" of human metabolism". Journal of the International Society of Sports Nutrition. 1 (2): 7–11. doi:10.1186/1550-2783-1-2-7. PMC 2129159. PMID 18500949.
- ^ Brown LM, Corrado MM, van der Ende RM, Derks TG, Chen MA, Siegel S, et al. (May 2015). "Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children". Journal of Inherited Metabolic Disease. 38 (3): 489–493. doi:10.1007/s10545-014-9744-1. PMID 25070466. S2CID 35228297.
- ^ Hoffmann GF, Zschocke J, Nyhan WL, eds. (2010). Inherited Metabolic Diseases: A Clinical Approach. Berlin Heidelberg: Springer. doi:10.1007/978-3-540-74723-9. ISBN 978-3-540-74722-2.
- ^ Kliegman, Robert M.; Nelson, Waldo E., eds. (2020). Nelson textbook of pediatrics. volume 2: Volume 2 (Edition 21 ed.). Philadelphia, Pa: Elsevier. ISBN 978-0-323-52950-1.
- ^ "Hypoglycemia". Pediatrics Clerkship. The University of Chicago. Archived from the original on 8 July 2014.