Ketotic hypoglycemia
Encyclopedia
Ketotic hypoglycemia is a medical term used in two ways: (1) broadly, to refer to any circumstance in which low blood glucose
is accompanied by ketosis
, and (2) in a much more restrictive way to refer to recurrent episodes of hypoglycemic symptoms with ketosis and, often, vomiting
, in young children. The first usage refers to a pair of metabolic states (hypoglycemia plus ketosis) that can have many causes, while the second usage refers to a specific "disease
" called ketotic hypoglyemia.
to a falling blood glucose is reduction of insulin
secretion to undetectable levels, and release of glucagon
, adrenaline, and other counterregulatory hormone
s. This shift of hormone
s initiates glycogenolysis
and gluconeogenesis
in the liver
, and lipolysis
in adipose tissue. Lipid
s are metabolized to triglyceride
s, in turn to fatty acid
s, which are transformed in the mitochondria
of liver and kidney cell
s to the ketone bodies
— acetoacetate, beta-hydroxybutyrate
, and acetone
. Ketones can be used by the brain as an alternate fuel when glucose is scarce. A high level of ketone
s in the blood, ketosis
, is thus a normal response to hypoglycemia in healthy people of all ages.
The presence or absence of ketosis is therefore an important clue to the cause of hypoglycemia in an individual patient. Absence of ketosis ("nonketotic hypoglycemia") most often indicates excessive insulin
as the cause of the hypoglycemia. Less commonly, it may indicate a fatty acid oxidation disorder.
can be described. It remains one of the more common causes of hypoglycemia in the age range.
, ketosis
, or both. The neuroglycopenic symptoms usually include lethargy and malaise, but may include unresponsiveness or seizure
s. The principal symptoms of ketosis are anorexia, abdominal discomfort, and nausea, sometimes progressing to vomiting
.
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.
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, carbohydrate
s and a few hours of sleep will be enough to end the symptoms.
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.
, hypopituitarism
, adrenal insufficiency
, and identifiable inborn errors of metabolism such as fatty acid oxidation disorders and organic acidoses.
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.
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.
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
is accompanied by ketosis
Ketosis
Ketosis is a state of elevated levels of ketone bodies in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when the liver glycogen stores are depleted...
, and (2) in a much more restrictive way to refer to recurrent episodes of hypoglycemic symptoms with ketosis and, often, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, in young children. The first usage refers to a pair of metabolic states (hypoglycemia plus ketosis) that can have many causes, while the second usage refers to a specific "disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
" called ketotic hypoglyemia.
Hypoglycemia with ketosis: the broad sense
There are hundreds of causes of hypoglycemia. Normally, the defensive, physiological responseHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
to a falling blood glucose is reduction of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion to undetectable levels, and release of glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
, adrenaline, and other counterregulatory hormone
Counterregulatory hormone
A counterregulatory hormone is a hormone that opposes the action of another.The action of insulin is counterregulated by glucagon, adrenaline , noradrenaline , cortisol, and growth hormone...
s. This shift of hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s initiates glycogenolysis
Glycogenolysis
Glycogenolysis is the conversion of glycogen polymers to glucose monomers. Glycogen is catabolized by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1-phosphate...
and gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, and lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
in adipose tissue. Lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s are metabolized to triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s, in turn to fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s, which are transformed in the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
of liver and kidney cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s to the ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...
— acetoacetate, beta-hydroxybutyrate
Beta-hydroxybutyrate
beta-Hydroxybutyric acid is a ketone body. It is a chiral compound having two enantiomers, D-3-hydroxybutyric acid and L-3-hydroxybutyric acid. Like the other ketone bodies , levels of beta-hydroxybutyrate are raised in ketosis...
, and acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
. Ketones can be used by the brain as an alternate fuel when glucose is scarce. A high level of ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
s in the blood, ketosis
Ketosis
Ketosis is a state of elevated levels of ketone bodies in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when the liver glycogen stores are depleted...
, is thus a normal response to hypoglycemia in healthy people of all ages.
The presence or absence of ketosis is therefore an important clue to the cause of hypoglycemia in an individual patient. Absence of ketosis ("nonketotic hypoglycemia") most often indicates excessive insulin
Hyperinsulinemic hypoglycemia
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.-Causes:...
as the cause of the hypoglycemia. Less commonly, it may indicate a fatty acid oxidation disorder.
Ketotic hypoglycemia: the "disease"
Ketotic hypoglycemia more commonly refers to a common but mysterious "disease" of recurrent hypoglycemic symptoms with ketosis in young children. The cause and the homogeneity of the condition remain uncertain, but a characteristic presentation, precipitating factors, diagnostic test results, treatment, and natural historyNatural history
Natural history is the scientific research of plants or animals, leaning more towards observational rather than experimental methods of study, and encompasses more research published in magazines than in academic journals. Grouped among the natural sciences, natural history is the systematic study...
can be described. It remains one of the more common causes of hypoglycemia in the age range.
Clinical features
The typical patient with ketotic hypoglycemia is a young child between the ages of 10 months and 4 years. Episodes nearly always occur in the morning after an overnight fast, often one that is longer than usual. Symptoms include those of neuroglycopeniaNeuroglycopenia
Neuroglycopenia is a medical term that refers to a shortage of glucose in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior...
, ketosis
Ketosis
Ketosis is a state of elevated levels of ketone bodies in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when the liver glycogen stores are depleted...
, or both. The neuroglycopenic symptoms usually include lethargy and malaise, but may include unresponsiveness or seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s. The principal symptoms of ketosis are anorexia, abdominal discomfort, and nausea, sometimes progressing to vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
.
If severe, parents usually take the child to a local emergency department
Emergency department
An emergency department , also known as accident & emergency , emergency room , emergency ward , or casualty department is a medical treatment facility specialising in acute care of patients who present without prior appointment, either by their own means or by ambulance...
, 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
CO2 content
content is a blood test that usually appears on a "Chem 19" or an electrolyte panel. The value measures the total dissolved Carbon dioxide in blood...
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
Saline (medicine)
In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...
and dextrose, the child improves dramatically and is usually restored to normal health within a few hours.
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, carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s and a few hours of sleep will be enough to end the symptoms.
Precipitating factors, conditions that trigger an episode, may include extended fasting (e.g., missing supper the night before), a low carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
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
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....
. Overweight children are rarely affected.
Diagnosis
The diagnosis is based on a combination of typical clinical features and exclusion by a pediatric endocrinologist of other causes of "hypoglycemia with ketosis," especially growth hormone deficiencyGrowth hormone deficiency
Growth hormone deficiency is a medical condition in which the body does not produce enough growth hormone . Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction...
, hypopituitarism
Hypopituitarism
Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...
, adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
, and identifiable inborn errors of metabolism such as fatty acid oxidation disorders and organic acidoses.
The most useful diagnostic tests include measurement of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
, cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
, and lactic acid
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
at the time of the hypoglycemia. Plasma acylcarnitine levels and urine organic acids
Urine organic acids
Urine organic acids is a medical diagnostic test used to exclude the possibility that a person has an inborn error of metabolism, usually one of the organic acidemias. The usual method of analysis is tandem mass spectrometry. In most cases a random specimen of as little as 1-5 ml is enough for...
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.
Treatment
Once ketotic hypoglycemia is suspected and other conditions excluded, appropriate treatment reduces the frequency and duration of episodes. Extended fasts should be avoided. The child should be given a bedtime snack of 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. 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.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.
Natural history
Children "outgrow" ketotic hypoglycemia, presumably because fasting tolerance improves as body mass increases. In most the episodes become milder and more infrequent by 4 to 5 years of age and rarely occur after age 9. Onset of hypoglycemia with ketosis after age 5 or persistence after age 7 should elicit referral and an intensive search for a more specific disease.Is ketotic hypoglycemia a disease?
Despite much investigation for fifty years, it has not been possible to demonstrate any metabolic difference that sets these children apart from the normal population except the shortened fasting tolerance. It has been proposed that this condition simply represents the extreme edge of the normal population in terms of tolerance for fasting and ability to maintain normoglycemia. It is also possible that some children given this diagnosis have still-undiscovered defects of metabolism which will eventually be identified.See also
- Glycogen storage disease type IGlycogen storage disease type IGlycogen storage disease type I or von Gierke's disease, is the most common of the glycogen storage diseases. This genetic disease results from deficiency of the enzyme glucose-6-phosphatase. This deficiency impairs the ability of the liver to produce free glucose from glycogen and from...
- One of several diseases that cause ketotic hypoglycemia.