The importance of ketones from a clinical and medical perspective

When cells cannot access glucose as an energy source, the body turns to alternative fuels, such as fat. This process produces substances known as ketones, which can accumulate in blood and urine. In this interview, News-Medical spoke with Marcin Pacek about the importance of ketone measurements and about how, why, and when to take measurements.

Could you introduce yourself and provide us with an overview of what ketones are?

My name is Marcin Pacek, and I am the Senior Director of Medical and Scientific Affairs in Europe at Nova Biomedical.

Are there different types of ketones?

How does the body use ketones, and what is their function?

Ketone body metabolism includes ketone body synthesis, known as ketogenesis, and breakdown, or ketolysis. When the body goes from a fed to a fasted state, the liver switches from carbohydrate utilization and fatty acid synthesis to fatty acid oxidation and ketone body production.

What are the risks of an increase in the concentration of ketones in the body?

Could you elaborate on diabetic ketoacidosis and the precise role ketones play in the development of this condition?

Diabetic ketoacidosis is a severe complication of diabetes that occurs when the body starts to overproduce ketones.

Diabetic ketoacidosis develops when the body does not have enough insulin to allow glucose to enter the cells. As a result, the body begins to use fat as its fuel, breaking it down instead of glucose. This process produces a build-up of ketones in the bloodstream, eventually leading to diabetic ketoacidosis if unchecked.

An infection or other type of illness can cause the body to produce a higher level of certain hormones such as adrenaline or cortisol. These hormones counter the effect of insulin, sometimes triggering an episode of diabetic ketoacidosis.

How exactly can ketones be measured?

Ketone bodies can be measured in a central lab or using point-of-care meters.

The method used most widely in the central lab measures B-Hydroxybutyrate dehydrogenase levels photometrically.

Other ketones can be measured semi-quantitatively using urine dip sticks.

What is the most effective way to measure ketone levels in the body? 

It is essential to measure ketones when glucose levels are high in diabetic patients. Ketone measurement is essential in DKA.

How do the guidelines and recommended standards help when it comes to measuring ketones?

Various clinical guidelines contain recommendations regarding ketone testing. The medical guidelines from the American Diabetic Association, Diabetes UK, and the European Society for Pediatric Endocrinology agree that glucose typically greater than 250 mg per deciliter combined with elevated blood ketones indicate probable DKA.

According to the guidelines, indications for ketone testing in the hospital include all cases of hyperglycemia where glucose levels are above 250 mg per deciliter in combination with an acute clinical condition such as emergency, post-operative period, intensive care, significant dehydration, or anuria.

Additionally, they include all cases of hyperglycemia when a diabetic patient is hospitalized, during acute illness or stress, or when blood glucose levels are consistently elevated.

The International Society for Pediatric and Adolescent Diabetes (ISPAD) advocates the use of capillary blood ketone testing methods that quantifies BHB for diagnosis and monitoring treatment of DKA.

Adopting these guidelines will significantly increase whole-blood ketone testing in hospitals and could result in more combined glucose and ketone diagnostic approaches for patient management.

What are the main benefits of detecting increased ketone levels early on?

In 2007, Charles et al. stated that blood ketone measurement is a useful tool that allows clinicians to distinguish between simple hyperglycemia and potentially life-threatening ketotic states immediately. In 2006, Nannheim et al. stated that the point-of-care test for BHB is more valuable than glucose alone for diagnosing DKA and offers an immediate diagnosis of patients at triage.

The Joint British Diabetes Society recommends using whole blood BHB testing for diagnosing and monitoring the treatment of DKA. They also advise that patient management is based on reducing blood ketone levels in conjunction with other established parameters, meaning monitoring and measuring ketones in blood over time.

What measurement methods work best for ketone analysis?

In the guidelines for the management of diabetic ketoacidosis written by the British Society of Pediatric and Endocrinology and Diabetes, the authors recommend using capillary blood ketone measurements during treatment and blood ketone measurements if pH is not improving.

What are the differences between blood ketone measurements and urine measurements?

In urine, contrary to blood measurements, ketones may be present for several hours before the sample is collected and the testing performed, as urine can be in the bladder for some time. Therefore, testing for urine ketones is historic rather than real-time monitoring. Urine testing primarily measures acetoacetate and acetone, not BHB, which is the primary cause of ketoacidosis and therefore is the best ketone to monitor. As noted above, acetone can linger in the urine for up to several days after DKA has resolved, thus not providing a clear picture.

Additionally, DKA patients are often dehydrated and unable to provide urine samples. Severe DKA patients might be unconscious and, therefore, unable to urinate. The American Diabetes Association recommends that urine ketones not be used to diagnose or monitor the treatment of DKA. They recommend whole blood testing for BHB.

Urine test strips are easy to misinterpret since, over time, exposure to air results in incorrect readings. Urine test strips also typically have a short shelf life, so users must be careful to avoid expired strips.

Urine testing has many interferences that may give false positives, including nitroprusside, a common agent used for blood pressure management.

Urine measurement can be done in the lab or in a point of care (POC) format, and it is always semi-quantitative. Most importantly, it measures acetoacetate and acetone, not BHB. Beta-hydroxybutyrate represents over 80% of the total ketones, and providers can measure BHB in serum/plasma in a central lab, or the whole blood as a point-of-care test.

Would you say that blood testing for Beta-Hydroxybutyrate offers the best overview of a patient’s condition?

Many papers talk about the importance of ketone measurements, specifically BHB. In a paper by Rewers et al. from 2006, the author stated clearly that BHB testing is faster and more sensitive than urine ketone testing for detecting DKA.

Ketone testing is also useful in outpatient centers and diabetic clinics. It provides a simple patient monitoring tool for blood ketones during sick day visits.

It also provides rapid identification of developing ketosis and may prevent hospitalization through the simple verification of a patient's ketone and glucose levels after insulin pump failures or in a non-compliant patient. It is also a better alternative and more accurate than urine ketone strips.

Are there any other key benefits to measuring ketone levels in diabetic patients?

In a recent publication, a case study related to diabetic patients infected with COVID-19, the authors highlight that viral infections can lead to so-called acute diabetes. Diabetes is the most common comorbidity in COVID-19 patients, and that includes Type I and Type II diabetes.

Over 30% of diabetic patients died when they were infected with COVID-19. Diabetic patients that are COVID-19 positive have a significantly increased risk for severe outcomes and show the highest risk of DKA development.

Would early detection of DKA improve the clinical outcome for COVID-19 patients?

Therefore, early diagnosis and treatment of DKA are essential in managing COVID-19 and reducing morbidity and mortality. It is estimated that 50% of hospital admission for DKA could be prevented with improved outpatient treatment and self-care.

About Dr. Pacek

About Nova Biomedical

Nova has manufacturing facilities in Waltham and Billerica, Massachusetts; and Taipei, Taiwan. Nova is one of the 25 largest in vitro diagnostic companies in the world and the largest privately owned in vitro diagnostic company in the United States.

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