Ketotic hypoglycemia

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Ketotic hypoglycemia refers to any circumstance in which low blood glucose is accompanied by ketosis, the presence of ketone bodies (such as beta-hydroxybutyrate) 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]

Contents

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

Russell-Silver syndrome can cause pathologic ketotic hypoglycemia. Sindrome silver russell.jpg
Russell-Silver syndrome can cause 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]

Signs and symptoms

Ketotic hypoglycemia classically presents in male young children, typically between the ages of 10 months and 6 years, in the morning after a prolonged overnight fast. Symptoms include those of neuroglycopenia, ketosis, or both. [6] [7] Neuroglycopenic symptoms usually include lethargy and malaise, but may include unresponsiveness or seizures. Common symptoms of ketosis are anorexia, abdominal discomfort, and nausea, sometimes progressing to vomiting. [7] However, the diagnosis of ketotic hypoglycemia poses a challenge to clinicians, given how nonspecific symptoms can be and given that children in this age range are typically unable to describe their symptoms. [2] Thin or smaller children may be more prone to episodes of ketotic hypoglycemia due to reduced fasting tolerance and minimal fat storage. [2]

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] Useful diagnostic tests to aid in the diagnosis include measurement of insulin, growth hormone, cortisol, and lactic acid at the time of the hypoglycemia. [2] Plasma acylcarnitine levels and urine organic acids can help exclude other metabolic diseases that could explain the presenting symptoms.

When the episodes are recurrent or severe, the definitive test is a hospitalization for a controlled diagnostic fast. [2] The supervising clinician can then monitor glucose and beta-hydroxybutyrate levels throughout the course of the fast to generate an understanding of the child's fasting tolerance. [2] If beta-hydroxybutyrate levels continue to excessively rise or remain persistently elevated, additional workup can be performed to detect ketone transporter defects. [2]

While ketotic hypoglycemia can be definitively diagnosed in the inpatient setting, once diagnosis is established, parents can monitor frequency and duration of episodes at home using point-of-care glucose and ketone meters. [4] [2] If episodes are severe or frequent enough, continuous glucose monitoring (CGM) or continuous gastrostomy tube feeding, in which a feeding tube is directly inserted into the stomach, may become necessary. [2]

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]

Alanine is a direct precursor in gluconeogenesis and can be used for treatment of ketotic hypoglycemia. Amino acid catabolism revised.svg
Alanine is a direct precursor in gluconeogenesis and can be used for treatment of ketotic hypoglycemia.

If an episode begins, affected children should be given fluids and carbohydrate-rich foods immediately, if swallowing is not compromised. [2] A carbohydrate gel can be applied to the inside of the mouth in children who are unable to swallow. In children with severe symptoms and who seek treatment in the emergency or inpatient setting, intravenous glucose or dextrose can be given. [2] In addition to glucose or dextrose, alanine — a precursor in gluconeogenesis — can also be infused to rapidly increase plasma glucose levels. [4] Associated symptoms, such as nausea, vomiting, or abdominal pain, can be addressed as appropriate.

Once ketotic hypoglycemia has been diagnosed and other conditions excluded, long-term management aims to reduce the frequency and duration of episodes. [8] Extended fasts should be avoided. [2] [1] Children should be given a bedtime snack rich in carbohydrates and should be awakened and fed after the usual duration of sleep. If the child is underweight, a daily nutritional supplement may be recommended. For children with ketotic hypoglycemia due to a glycogen storage disease, overnight cornstarch can help maintain blood glucose levels and reduce the incidence of hypoglycemic episodes. [2] [9]

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

<span class="mw-page-title-main">Diabetic ketoacidosis</span> Medical condition

Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of consciousness. A person's breath may develop a specific "fruity" smell. The onset of symptoms is usually rapid. People without a previous diagnosis of diabetes may develop DKA as the first obvious symptom.

<span class="mw-page-title-main">Ketone bodies</span> Chemicals produced during fat metabolism

Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA —which then enters the citric acid cycle and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate.

<span class="mw-page-title-main">Ketosis</span> Using body fats as fuel instead of carbohydrates

Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional energy source for the brain in the form of ketones. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.

<span class="mw-page-title-main">Ketogenesis</span> Chemical synthesis of ketone bodies

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

<span class="mw-page-title-main">Fructose bisphosphatase deficiency</span> Medical condition

In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.

Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.

<span class="mw-page-title-main">Ketoacidosis</span> Medical condition

Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes in blood pH and requires medical attention. The most common cause of ketoacidosis is diabetic ketoacidosis but can also be caused by alcohol, medications, toxins, and rarely, starvation.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Alcoholic ketoacidosis</span> Medical condition

Alcoholic ketoacidosis (AKA) is a specific group of symptoms and metabolic state related to alcohol use. Symptoms often include abdominal pain, vomiting, agitation, a fast respiratory rate, and a specific "fruity" smell. Consciousness is generally normal. Complications may include sudden death.

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

Neuroglycopenia is a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior. Prolonged or recurrent neuroglycopenia can result in loss of consciousness, damage to the brain, and eventual death.

<span class="mw-page-title-main">Glycogen storage disease type I</span> Medical condition

Glycogen storage disease type I is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. There are also possibly rarer subtypes, the translocases for inorganic phosphate or glucose ; however, a recent study suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable, and are therefore GSD Ib.

<span class="mw-page-title-main">Diabetic hypoglycemia</span> Medical condition

Diabetic hypoglycemia is a low blood glucose level occurring in a person with diabetes mellitus. It is one of the most common types of hypoglycemia seen in emergency departments and hospitals. According to the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP), and based on a sample examined between 2004 and 2005, an estimated 55,819 cases involved insulin, and severe hypoglycemia is likely the single most common event.

<span class="mw-page-title-main">Glycogen storage disease type 0</span> Medical condition

Glycogen storage disease type 0 is a disease characterized by a deficiency in the glycogen synthase enzyme (GSY). Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified as a glycogen storage disease because it is another defect of glycogen storage and can cause similar problems. There are two isoforms (types) of glycogen synthase enzyme; GSY1 in muscle and GSY2 in liver, each with a corresponding form of the disease. Mutations in the liver isoform (GSY2), causes fasting hypoglycemia, high blood ketones, increased free fatty acids and low levels of alanine and lactate. Conversely, feeding in these patients results in hyperglycemia and hyperlactatemia.

<span class="mw-page-title-main">Ketonuria</span> Medical condition

Ketonuria is a medical condition in which ketone bodies are present in the urine.

Starvation response in animals is a set of adaptive biochemical and physiological changes, triggered by lack of food or extreme weight loss, in which the body seeks to conserve energy by reducing metabolic rate and/or non-resting energy expenditure to prolong survival and preserve body fat and lean mass.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Exogenous ketones are a class of ketone bodies that are ingested using nutritional supplements or foods. This class of ketone bodies refers to the three water-soluble ketones. These ketone bodies are produced by interactions between macronutrient availability such as low glucose and high free fatty acids or hormone signaling such as low insulin and high glucagon/cortisol. Under physiological conditions, ketone concentrations can increase due to starvation, ketogenic diets, or prolonged exercise, leading to ketosis. However, with the introduction of exogenous ketone supplements, it is possible to provide a user with an instant supply of ketones even if the body is not within a state of ketosis before ingestion. However, drinking exogenous ketones will not trigger fat burning like a ketogenic diet.

References

  1. 1 2 Kliegman RW, Nelson WE, eds. (2020). Nelson Textbook of Pediatrics. Vol. 2 (21st ed.). Philadelphia, Pa: Elsevier. ISBN   978-0-323-52950-1.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 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.
  3. ↑ 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.
  4. 1 2 3 4 5 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.
  5. ↑ 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.
  6. 1 2 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.
  7. 1 2 Meoli, Martina; Lava, Sebastiano A. G.; Bronz, Gabriel; Goeggel-Simonetti, Barbara; Simonetti, Giacomo D.; Alberti, Ilaria; Agostoni, Carlo; Bianchetti, Mario G.; Scoglio, Martin; Vismara, Stefano A.; Milani, Gregorio P. (2023-08-16). "Eu- or hypoglycemic ketosis and ketoacidosis in children: a review". Pediatric Nephrology. doi: 10.1007/s00467-023-06115-5 . ISSN   0931-041X. PMC   10899420 .
  8. ↑ "Hypoglycemia". Pediatrics Clerkship. The University of Chicago. Archived from the original on 8 July 2014.
  9. ↑ Hendriksz, Christian J.; Gissen, Paul (March 2015). "Glycogen storage disease". Paediatrics and Child Health. 25 (3): 139–144. doi:10.1016/j.paed.2014.10.007.
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