Most people who work in a clinical laboratory know a little about ketones or ketone bodies. The two facts that most people know include: 1) when you perform a urinalysis (UA), it includes a semiquantitative ketone result, and 2) high ketones are seen in diabetic ketoacidosis. But what is a ketone, where do they come from, and what are we measuring when we measure ketones?

In the laboratory medicine world, “ketones” refers specifically to acetoacetate (Acac), acetone and beta-hydroxybutyrate (BOHB). When the human body cannot utilize glucose, either because it is not present (fasting, starvation) or because it is present but cannot be used (lack of insulin to get glucose into the cells), the body instead breaks down fatty acids for energy. Fatty acids are mostly made up of long chains of carbons with hydrogens attached, so one of the main products of fat breakdown is 2-carbon acetyl-CoA. When a person is using lots of fats, like when they cannot use glucose, the production of acetyl-CoA exceeds the body’s ability to metabolize it via the Kreb’s cycle and it ties up lots of coenzyme A (CoA) needed for other processes. Thus, the body combines two excess acetyl-CoA into an acetoacetate, freeing up the CoA. The more acetyl-CoA produced from fat breakdown, the more acetoacetate produced. From there, the acetoacetate is converted to BOHB enzymatically or degrades spontaneously to acetone. BOHB is a dead end. Once there, the BOHB simply continues to build up until the production of acetyl-CoA no longer exceeds its utilization capacity. At that point, the BOHB is converted back to acetoacetate and then to acetyl-CoA for the body to be able to utilize it.

The most common form of ketoacidosis is probably diabetic ketoacidosis, in which blood glucose levels are high, but the glucose cannot get into the cells and be used, so fats are broken down for energy. At the height of a ketoacidosis, roughly 70% of the ketones in the body will be in the form of BOHB. This has implications for what we measure and for the monitoring of the treatment of ketoacidotic crises. UA dipstick ketones measure acetoacetate, and some will also detect acetone. None of the available UA methods measure BOHB. Thus, ketones measured in a UA will rise as ketoacidosis occurs, drop at the height of ketoacidosis as they are converted to BOHB, and then rise again as the condition is resolving and BOHB is converted back to Acac. A high Acac will occur both at the beginning and toward the end of the ketoacidosis, and Acac may actually be low at the height of a ketoacidotic crisis. BOHB on the other hand rises as the crisis evolves and drops as the crisis is resolved. The best test for following the resolution of a ketoacidotic crisis is repeat BOHB measurements.

BOHB is generally measured enzymatically on blood samples. BOHB response is maximal about 3 hours after glucose peaks. For example in a diabetic ketoacidosis, the peak BOHB will occur about 3 hours after the glucose peaks and in a normal patient given a glucose load, the BOHB will be lowest about 3 hours after the glucose peaks. During resolution of ketosis BOHB decreasing by half about every four hours as long as no more ketones are being produced. The test for BOHB is most commonly performed quantitatively using a kit adapted to the open channel on a chemistry analyzer. A point of care analyzer is also now available for BOHB.

Measuring ketones is most commonly used to monitor ketoacidosis, but ketone measurement can also be helpful in the differential diagnosis of some inborn errors of metabolism. For example, in fasting states, ketones should be elevated. If they are not, it can be an indication of disorders in fatty acid metabolism, or ketone metabolism itself. Additionally, in hyperammonemia states, the absence of ketones and acidosis indicates a urea cycle defect. Their presence suggests an organic acid disorder. Thus measuring ketones has multiple uses in medicine.

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

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