CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Amy Carpenter
December 2023—The third and latest edition of recommendations for laboratory analysis in diagnosing and managing diabetes mellitus, released this summer, provide guidance on, among other things, ketone testing, glycolysis, and point-of-care testing (Sacks DB, et al. Diabetes Care. 2023;46[10]:e151–e199; Sacks DB, et al. Clin Chem. 2023;69[8]:808–868). The last such recommendations were published in 2011.
David B. Sacks, MB, ChB, senior investigator and chief of clinical chemistry, National Institutes of Health Department of Laboratory Medicine, and a member of the CAP Clinical Chemistry Committee, was chair of the expert committee that compiled the evidence, invited review, presented the recommendations for public comment, and obtained approval from the American Association for Clinical Chemistry (now ADLM) and American Diabetes Association. He was first asked nearly 25 years ago to chair a committee of experts to establish laboratory analysis guidelines. “I said, ‘There’s no point in doing this unless the American Diabetes Association participates,’” he tells CAP TODAY.
Dr. Sacks convinced the ADA of its importance, and it has been an active participant since the first laboratory analysis guidelines were published in 2002. The ADA is “very strongly behind this,” he says. The more than 80 recommendations in the latest publication have the ADA’s endorsement. “They carry a lot of weight,” he says.
All of the authors of the 2011 guidelines returned to work on the update. The group consists of five patient-facing physicians, one chemist, and three clinical laboratory medicine experts—Dr. Sacks, David Bruns, MD, of the University of Virginia School of Medicine, and Andrea R. Horvath, MD, PhD, of Prince of Wales Hospital in Sydney.
The recommendations are graded for their strength and rated for the quality of the underlying body of evidence. “Many don’t have quite as strong a recommendation because the studies that were evaluated were not designed to look at the performance of the lab test,” Dr. Sacks says. “Most of the studies are clinical.”
Some recommendations advise against tests that lack evidence for their use—for example, routine use of blood glucose meters for people with type 2 diabetes treated with diet and/or oral agents alone. “There’s no evidence to support it,” Dr. Sacks says. The evidence at the time of the 2011 guidelines “was debatable, and some people said it was useful,” he says. But studies published since then have shown “it isn’t, so therefore the recommendation is, ‘Don’t do it.’”
On the topic of ketone testing, the recommendation for diagnosis of diabetic ketoacidosis reinforces earlier recommendations in advising the specific measurement of beta-hydroxybutyrate (βOHB) in blood. The measurement may also be used for monitoring during treatment of DKA.
“People should measure only beta-hydroxybutyrate and not total ketones because that’s a much better reflection of the state of ketosis in the blood,” Dr. Sacks explains.
Dr. Sacks and coauthors last year detailed the controversies around the measurement of blood ketones to diagnose and manage diabetic ketoacidosis (Kilpatrick ES, et al. Diabetes Care. 2022;45[2]:267–272). In their article they reported that CAP records revealed “a split in what is measured, such that, in 2020 (KET-04), 1,785 laboratories were measuring specifically BOHB while 840 were measuring a reaction using nitroprusside. In contrast,” they wrote, “the equivalent quality schemes in the U.K. show that no laboratories measure blood ketones using the nitroprusside test.”
Dr. Sacks’ European coauthors of that article and others “were shocked that in the U.S.,” he says, “so many labs use total ketones and don’t measure beta-hydroxybutyrate.”
In their 2022 article on the controversies, they wrote that the nitroprusside test principally measures acetoacetate, not βOHB, and since βOHB predominates in ketoacidosis, the degree of ketonemia using nitroprusside initially could be underestimated. In addition, they said, when the acidosis has resolved, βOHB is more readily oxidized to acetoacetate, “so overall ketosis paradoxically may appear to be worsening when the converse is true.”
Blood ketone βOHB can be measured not only in the laboratory but also at the point of care, but Dr. Sacks and coauthors noted that concern has been voiced about how reliable the POC instruments are for measuring βOHB concentrations. However, the issue, they said, is usually at concentrations greater than 5 mmol/L, “which is well in excess of any DKA diagnostic threshold.”
“This issue might not only impact the identification of hyperketonemia but also, together with meter result imprecision, cause unreliable tracking in the rate of fall of BOHB concentrations,” they added.
Point-of-care testing in the U.K. is common. In the U.S. it’s difficult to determine the proportion of blood ketone measurements that are POC versus laboratory tests because the blood ketone meters are waived, Dr. Sacks and coauthors note. Point-of-care testing questions need to be resolved, Dr. Sacks tells CAP TODAY: “The evidence needs to be generated, and people need to do the studies.”
Point-of-care testing is also an issue when measuring HbA1c.
One recommendation calls for restricting HbA1c POC testing for diabetes screening and diagnosis to FDA-approved devices at CLIA-certified laboratories that perform testing of moderate complexity or higher.
“The issue is that in the U.S., these devices are waived,” Dr. Sacks says. “Numerous studies have shown that in general most point-of-care devices are not as accurate as those in the central lab, which should be no surprise to anybody.”
No proficiency testing is required for the waived point-of-care HbA1c devices, “and a large component of the improvement in the quality of hemoglobin A1c testing has resulted from standardization,” he says. The CAP plays an important role in standardizing and improving the precision of HbA1c testing because of the CAP Surveys, Dr. Sacks says, noting that the proficiency testing program for HbA1c is accuracy-based. “That has been one of the cornerstones of improvement.”
For HbA1c testing, laboratories should be aware of potential interferences, including hemoglobin variants that may affect results depending on the method used. A new recommendation says assays of other glycated proteins, such as fructosamine or glycated albumin, may be used where abnormalities in red blood cell turnover, hemoglobin variants, or other interfering factors compromise the interpretation of HbA1c results. (See CAP TODAY, https://bit.ly/3ungGtl.)