Beta-Hydroxybutyrate

β-hydroxybutyrate is a ketone bodies. Ketone body contains 3 molecules: β-hydroxybutyrate, acetone, and acetoacetate. Acetyl-CoA metabolism release acetoacetate. Reduction of acetoacetate release β-hydroxybutyrate, Decarboxylation of acetoacetate release acetone. In body to maintain the metabolic homeostasis during the prolonged starvation, ketone bodies are essential. The brain uses glucose to fulfil the metabolic needs since it can not use fatty acid to produce the energy. In cases of starvation or fasting, ketone bodies play a major role to produce energy for brain cells and prevent amino acids from catabolism into gluconeogenesis precursors which is used as an energy source to brain. After prolonged starvation or fasting, ketone bodies provide about 2/3 of the energy needs to brain.

Ketone bodies are dissociated in the blood and strong organic acids. When body produces excessive ketone bodies which lead to saturation of buffer system and decrease the pH of the blood, this condition is known as ketoacidosis. Alcoholic ketoacidosis and diabetic ketoacidosis are the 2 clinical situations for ketoacidosis.

Diabetic ketoacidosis

Measurement of β-hydroxybutyrate is important to diagnose, manage, and monitor diabetic ketoacidosis. During the different stages of insulin deficiency, lipolysis, which is stimulated by deficiency of insulin, provides a fatty acid burden on the liver at the adipose tissue. Metabolism of fatty acids produce acetyl-coenzyme A which cannot go to citric acid cycle in the mitochondria because of the deficiency of oxaloacetate. Acetyl-CoA produces ketone body via several enzymes and produce acetoacetate. Acetoacetate reduced to 3-β-hydroxybutyrate by the help of 3-β-hydroxybutyrate dehydrogenase.

The NAD+/NADH ratio measures the redox state of the liver mitochondria and determines the ratio of acetoacetate to 3-β-hydroxybutyrate. The ratio of β-hydroxybutyrate to acetoacetate is about 1 in normal conditions. This ratio increases to 7 to 10 in diabetic ketoacidosis.

The diabetic ketoacidosis is diagnosed by the detection of ketone bodies in the urine by using the method the legal reaction. In this, acetoacetate reacts with nitroprusside in the presence of alkali and produce a complex in purple colour on a test strip. Some of the drawbacks of this method are that it is a semiquantitative method and is not sensitive for both blood and urine equally.

Ketone bodies in urine are not an accurate measure of ketone bodies in blood, and not all the diabetic ketoacidosis patients are ready to provide a urine samples at the time of presentation. Most importantly, β-hydroxybutyrate is the most predominant ketone body present in diabetic ketoacidosis. The concentration of β-hydroxybutyrate is 3 to 10 times more than the acetoacetate. As the diabetic acidosis is getting treated, serum β-hydroxybutyrate is converted to acetoacetate because of the normalizing the mitochondrial redox state, increasing the urine acetoacetate level and creating false belief that patient is not responding to the treatment.

Urine ketone strips may give the false negative result when urine is acidic, or it has been exposed to air for a longer period. It may give false positive result when patient is taking drugs of sulfhydryl groups. Disadvantages of this method makes to develop a more accurate and reliable method to diagnose and manage the diabetic ketoacidosis.

A number of investigations have shown the capacity of β-hydroxybutyrate to assess the patients who have diabetic ketoacidosis. In many studies, the cutoff level for diabetic ketoacidosis is 1.5 to 3.5 mmol/L and the blood volume requires for measuring the β-hydroxybutyrate is 5 to 10 μL.

The level of β-hydroxybutyrate greater than 1.5 mmol/L had the specificity of 78.6 to 93.3 % and sensitivity of 98 to 100 % to diagnose the diabetic ketoacidosis in diabetic patients who have the ED with level of blood glucose greater than 250 mg/dL. In other 2 studies, a cutoff level of 3 mmol/L in patients who have ED with hyperglycemia and had sensitivity of about 100 % and specificity of about 92.89 to 94 % to diagnose the diabetic ketoacidosis. Some major manufacturers suggest 1.5 mmol/L threshold and other have suggested greater than 2 mmol/L or even 3.5 mmol/L to maximum in order to get the diagnostic yield of test.

Many studies have shown that the advantage of β-hydroxybutyrate in blood and urine in patients who have diabetes and hyperglycemia with diabetic ketoacidosis. The point-of-care β-hydroxybutyrate test is significantly faster than the ketone test in urine. It is readily available and not dependent on the production of urine in patient. The sensitivity of β-hydroxybutyrate and urine ketone is similar. β-hydroxybutyrate has been continuously shown more specificity for both 1.5 mmol/L and 3 mmol/L endpoint and a higher positive predictive level.

Concentration of β-hydroxybutyrate is more strongly correlate with the anion gap with acetoacetate, anion gap in diabetic ketoacidosis and pCO2. By using a β-hydroxybutyrate end point early ICU discharge is possible and 6.5 hour will reduce in ICU stay, 375 less laboratory investigations, and 2950 Euros decrease per patient without any compromise in safety of patient.

Alcoholic ketoacidosis

Alcoholic ketoacidosis is the second common cause of ketoacidosis. Patients typically report heavy alcohol consumption during fasting. The ratio of β-hydroxybutyrate to acetoacetate is very high, and β-hydroxybutyrate level can be useful to diagnose and manage alcoholic ketoacidosis.