Chrysalis Bautista, an eighteen-year-old diabetic, forgets to bring her afternoon insulin injection today. Heading back home, she falls unconscious at the bus station. The operator calls the ambulance but the rescue team arrives forty minutes later due to traffic. While on transit, Bautista’s respirations become very shallow. A tube is inserted to assist her breathing, and its placement confirmed very low oxygen levels. Upon their arrival at the emergency department, blood pressure drops as her heart accelerates, and the glucometer indicates a finger stick blood sugar reading of “panicky high.”
Chrysalis develops a life-threatening condition called diabetic ketoacidosis (DKA). In DKA, the body shifts from its normal fed metabolism (using carbohydrates for fuel) to a fasting state (using fat for fuel) due to insufficient insulin. The resulting ketone production to facilitate fat breakdown increases blood acidity and triggers the kidney to release extra sugar in the urine through excessive urination. In a matter of minutes, a diabetic patient can develop dehydration, electrolyte imbalance, and mental changes. DKA accounts for 14 percent of all hospital admissions of patients with diabetes, and 16 percent of all diabetes-related fatalities.
In the last two decades, diabetes management has undergone paradigm shifts with increased public health education, improved insulin delivery methods, better targeting of oral diabetic drugs, and more intensive monitoring. It is likely that these initiatives have resulted in changes in the incidence, early metabolic control, survival and accurate identification of DKA.
Beta-hydroxybutyrate, the most important ketone
Acetoacetate, β-hydroxybutyrate (β-OHB) and acetone, collectively known as ketone bodies, are fundamental for periods of prolonged starvation. The brain cannot use fatty acids for energy production and usually depends on glucose to meet its metabolic needs. In cases of starvation, ketone bodies become a major fuel for brain cells, sparing amino acids (protein builders) from being used to supply the brain with energy. In fact, even after prolonged starvation, ketone bodies can provide as much as two-thirds of the brain's energy needs.
Ketone bodies are strong organic acids that easily disintegrate in blood. When ketone body production becomes uncontrollable, the buffering systems are loaded, and blood pH drops. This condition is known as ketoacidosis.
The most clinically relevant application of β-OHB determination involves the diagnosis, management, and monitoring of DKA. β-OHB accounts for about 75 percent of ketones in ketoacidosis, and when available it is preferred for monitoring DKA over the nitroprusside method, which only measures acetoacetate.
Traditionally, the diagnosis of DKA was based on the detection of ketones in urine using the Legal reaction, during which acetoacetate reacts in the presence of alkali with nitroprusside to produce a purple-colored complex on a test strip. However, this method has significant drawbacks. It is semi-quantitative and not equally sensitive for urine and blood.
Moreover, not all the patients with DKA are able to provide a urine sample upon presentation, and ketones in urine are not a precise estimation of blood ketones. As DKA is treated, serum β-OHB (the most abundant ketone) is transformed to acetoacetate due to the correction of bodily processes, elevating urine acetoacetate levels and giving the false impression that the patient has not responded to treatment.
Lastly, urine ketone strips can give false positive results in patients receiving drugs with sulfhydryl groups (e.g. diphenhydramine for allergy) and false-negative results when they have been exposed to air for a long period of time or when the urine is acidic. These disadvantages necessitate the evolution of a more reliable method for the diagnosis and management of DKA.
A significant number of studies have evaluated the ability of β-OHB to detect patients with DKA. In various studies, the cut-off value for DKA diagnosis ranges from 1.5 to 3.5 mmol/L, and the blood volume necessary for β-OHB measurement is 5 to 10 μL.
Numerous studies have demonstrated the superiority of blood β-OHB versus urine ketones in the patient with diabetes and hyperglycemia with possible DKA. The β-OHB test is much faster than the classic urine ketone test, can be easily obtained on arrival, and does not depend on the patient producing urine. Whereas the sensitivity of urine ketones is similar to that of β-OHB, the latter has been persistently shown to be more specific and also has a greater positive predictive value.
In one comparative study, urine dipstick testing for ketones had a sensitivity of 98 percent, specificity of 35 percent, and a positive predictive value of 15 percent. Serum testing for β -OHB had a sensitivity of 98 percent, a specificity of 79 percent, and a positive predictive value of 34 percent (using a cutoff of greater than 1.5 mmol per L), allowing for more accurate diagnosis of DKA. The American Diabetes Association has revised its position on ketone analysis in favor of serum testing, probably taking into consideration the ratio of β -OHB to acetate may increase to 8:1 ratio in severe diabetics, making nitroprusside test insensitive for early stages of DKA. The experts also concluded that capillary measurement is equivalent to venous measurement.
As far as treatment monitoring is concerned, β-OHB concentrations correlate more strongly compared with acetoacetate in patients with DKA. In several pediatric studies, the use of a β-OHB levels for DKA recovery has led to earlier ICU discharge (17 hours vs 28 hours), a 6.5-hour reduction in ICU stay duration, 375 less laboratory investigations per patient, and an accumulative decrease of 2,950 Euros per patient without compromising patient safety compared with standard management using urine samples. Recent adult studies have also shown that β -OHB levels correlate better with the changes in acid-base status during the course of treatment for DKA. It was found that when insulin therapy adjustment was based on β–OHB instead of glucose levels, the resolution of ketone production occurred 14 hours earlier.
In addition to DKA, elevated serum β-OHB levels can be observed in various conditions associated with metabolic substrate use disorders, insulin deficiency, and altered redox status including alcoholic ketoacidosis, high-fat diet, steroid or growth hormone deficiency, aspirin (salicylate) poisoning, fasting and starvation, lactation (ketone body production is stimulated by the high-fat content of milk), ketogenic diets (popular for the control of refractory seizures and body weight in obese individuals), and glycogen-storage diseases as well as other metabolic disorders.
To conclude, DKA is a serious complication of diabetes that occurs when your body produces high levels of blood acids called ketones secondary to insulin insufficiency. Early diagnosis of DKA patients is critical because of the high mortality rate. Therefore, the use of more specific ketone tests like capillary/serum blood β-OHB levels contributes to better and faster DKA diagnosis and management.