Reference Range

Acetoacetate, beta-hydroxybutyrate, and acetone are ketone bodies. In carbohydrate-deficient states, fatty-acid metabolism spurs acetoacetate accumulation. The reduction of acetoacetate in the mitochondria results in beta-hydroxybutyrate production. Beta-hydroxybutyrate and acetoacetate, the predominant ketone bodies, are rich in energy. Beta-hydroxybutyrate and acetoacetate transport energy from the liver to other tissues.

Acetone forms from the spontaneous decarboxylation of acetoacetate. Acetone is the cause of the sweet odor on the breath in persons with ketoacidosis.^{[1, 2, 3]}Ketone bodies fuel the brain with an alternative source of energy (close to two thirds of its needs) during periods of prolonged fasting or starvation, when the brain cannot use fatty acids for energy.

The reference range for ketone is a negative value, at less than 1 mg/dL (< 0.1 mmol/L).^[4]

Interpretation

The following conditions increase ketone values:

Diabetic ketoacidosis
Starvation ketosis
Isopropyl alcohol ingestion
Salicylate overdose
Pregnancy
Cortisol deficiency
Growth hormone deficiency
Alcoholic ketoacidosis
High-fat diet
Vomiting
Diarrhea
Hyperthyroidism
Certain rare inborn errors of metabolism (cystinuria)
Febrile state (especially in children)
Hypoglycemia

A prospective study by Flores-Guerrero et al indicated that high plasma levels of β-hydroxybutyrate signal an increased risk of heart failure with reduced ejection fraction (HFrEF), especially in females. In terms of incident HF (which in these results was primarily due to HFrEF), the hazard ratio per one standard deviation increase in the β-hydroxybutyrate concentration was 1.40. More specifically, in women, one standard deviation was associated with a hazard ratio for HFrEF of 1.73, compared with 1.14 in men.^[5]

The following conditions spur false-positive results^{[6, 7]}:

Some Parkinson medications
Stimulant laxative (eg, Ex-Lax)

Collection and Panels

Collection details are as follows:

Yellow tube for serum ketones
Urinalysis test strips to detect ketonuria

Panels are as follows:

Serum ketones
Urinalysis

Description

Acetone forms from the spontaneous decarboxylation of acetoacetate. Acetone is the cause of the sweet odor on the breath in persons with ketoacidosis. Ketone bodies fuel the brain with an alternative source of energy (close to two thirds of its needs) during periods of prolonged fasting or starvation, when the brain cannot use fatty acids for energy.

Although ketones are omnipresent in the blood (< 1 mg/dL), levels increase during periods of fasting and prolonged exercise.^[6]The nitroprusside test only detects acetoacetate in blood and urine; however, it does not assess beta-hydroxybutyrate, the most accurate indicator of ketone body levels. The nitroprusside test is only a semiquantitative assessment that is associated with false-positive results.^[6]

Beta-hydroxybutyrate, acetoacetate, and acetone are endogenous ketone bodies. Note, however, that beta-hydroxybutyrate is not technically a ketone; it is a carboxylic acid.^[6]Tissues outside the liver transfer coenzyme A from succinylcoenzyme A to acetoacetate, and, via the citric acid cycle, metabolize the active acetoacetate to carbon dioxide and water. Similarly, ketone bodies are metabolized using other pathways. Acetone discharge occurs in expired air and in urine.^[8]Ketonuria ensues in actual or functional carbohydrate-deficient states when metabolism switches from using carbohydrates to using fat to produce energy. These states can include uncontrolled diabetes mellitus, insufficient intake of carbohydrates owing to starvation or weight reduction, pregnancy, or vomiting.^[9]

In normal states, ketones are not present in the urine. However, increased urinary ketone levels may occur with fasting, in postexercise states, and in pregnancy. In individuals with diabetes, urinary ketone levels are often increased before an elevation occurs in the serum.^{[10, 11]}Dehydration and the presence of levodopa metabolites, mesna (sodium mercaptoethanesulfonate), and other sulfhydryl-containing compounds may cause false-positive testing results.^[10]

Serum ketone testing measures acetoacetate; acetone is weakly reactive and beta-hydroxybutyrate is not detected at all. In alcoholic ketoacidosis, initial ketone values may be low or results may be negative. However, with recovery, acetoacetate increases and assay results become positive.^[12]The elevated anion gap (see the Anion Gap calculator) found in alcoholic ketoacidosis is primarily due to beta-hydroxybutyrate.^{[13, 14]}

Indications

See the list below:

Considerations

Urinary acetoacetate and breath acetone assessments are good predictors of ketosis. Breath acetone analysis is a noninvasive test and is usually associated with minimal patient discomfort. It can also be used to monitor the efficacy of therapeutic diets (eg, epilepsy patients on ketogenic diets, as ketones are indicators of ketosis).^[15]Hypoglycemia in the presence of urinary ketones suggests organic acidemias; however, hypoglycemia in the absence of urinary ketones may be seen in a fatty-acid defect.^[16]

The pathological conditions most commonly associated with ketosis are as follows:^[6]

Diabetic ketoacidosis
Alcoholic ketoacidosis (withdrawal following binge drinking)
Salicylate overdose
Isopropyl alcohol ingestion

Using the Kids’ Inpatient Database (KID), Everett et al found that in the United States between 2006 and 2016, the number of pediatric admissions for diabetic ketoacidosis increased by just over 40%, from 32,612 to 46,006, with the rate rising from 120.5 to 217.7 cases per 10,000 pediatric admissions. Higher admission rates per 10,000 pediatric were associated with characteristics such as age between 18 and 20 years, female sex, non-Hispanic Black ethnicity, lack of private insurance, low socioeconomic status, nonurban residence, and care at smaller hospitals.^[17]

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Blaikie TP, Edge JA, Hancock G, Lunn D, Megson C, Peverall R, et al. Comparison of breath gases, including acetone, with blood glucose and blood ketones in children and adolescents with type 1 diabetes. J Breath Res. 2014 Nov 25. 8 (4):046010. [Medline].
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Flores-Guerrero JL, Westenbrink BD, Connelly MA, et al. Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort. Eur J Clin Invest. 2021 May. 51 (5):e13468. [Medline].
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Ceriotti F, Kaczmarek E, Guerra E, Mastrantonio F, Lucarelli F, Valgimigli F, et al. Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside. J Diabetes Sci Technol. 2015 Mar. 9 (2):268-77. [Medline].
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