Ketotic hypoglycemia

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.

Hypoglycemia with ketosis: the broad sense
There are hundreds of causes of hypoglycemia. Normally, the defensive, physiological response to a falling blood glucose is reduction of insulin secretion to undetectable levels, and release of glucagon, adrenaline, and other counterregulatory hormones. This shift of hormones initiates glycogenolysis and gluconeogenesis in the liver, and lipolysis in adipose tissue. Lipids are metabolized to triglycerides, in turn to fatty acids, which are transformed in the mitochondria of many cells 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 ketones 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.

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 history 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 "toddler", a young child between the ages of 10 months and 4 years. Episodes nearly always occur in the morning after an overnight fast, often 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.

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. 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, carbohydrates 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 a 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.

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 deficiency, 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.

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.

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 7. 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.