b-Hydroxybutyric Acid

Optimal Result: 3.2 - 116.4 nmol/mg Creatinine.

b-hydroxybutyrate is one of the ketone bodies. 

The term ketone body describes any of 3 molecules: acetoacetate, b-hydroxybutyrate, or acetone. Acetoacetate is produced by acetyl-CoA metabolism, b-hydroxybutyrate is the result of acetoacetate reduction, and acetone is produced by the spontaneous decarboxylation of acetoacetate.

Ketone bodies are fundamental for metabolic homeostasis during 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 fasting or starvation, ketone bodies become a major fuel for brain cells, sparing amino acids from being catabolized to gluconeogenesis precursors to be used to supply the brain with energy. 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 fully dissociate in blood. When ketone body production becomes uncontrollable, the buffering systems are saturated, and blood pH drops; this is a condition known as ketoacidosis.

The two common clinical scenarios for ketoacidosis are diabetic ketoacidosis and alcoholic ketoacidosis.

Diabetic ketoacidosis

The most clinically relevant application of b-hydroxybutyrate determination involves the diagnosis, management, and monitoring of diabetic ketoacidosis. During states of insulin deficiency, lipolysis at the adipose tissue (stimulated by insulin deficiency) provides a huge fatty acid load to the liver. Fatty acids are initially metabolized to acetyl-coenzyme A that cannot enter the citric acid cycle in the mitochondria due to oxaloacetate deficiency. Thus, acetyl-coenzyme A is diverted to ketone body production through the activity of several enzymes, producing acetoacetate. Acetoacetate is then reduced to 3-b-hydroxybutyrate by 3-b-hydroxybutyrate dehydrogenase.

The ratio of acetoacetate to 3-b-hydroxybutyrate depends on the redox status in the liver mitochondria (ie, the NAD+/NADH ratio). Under normal circumstances, the b-hydroxybutyrate to acetoacetate ratio is around 1; however, in diabetic ketoacidosis, this may increase to 7-10. Acetone is produced by the spontaneous decarboxylation of acetoacetate.

Traditionally, the diagnosis of diabetic ketoacidosis 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 semiquantitative and not equally sensitive for urine and blood.

Moreover, not all the patients with diabetic ketoacidosis are able to provide a urine sample upon presentation, and ketones in urine are not a precise estimation of blood ketones. Most importantly, the most abundant ketone body during diabetic ketoacidosis is b-hydroxybutyrate, with a concentration 3-10 times higher of that of acetoacetate. As diabetic ketoacidosis is treated, serum b-hydroxybutyrate is transformed to acetoacetate due to the correction of the mitochondrial redox status, 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 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 diabetic ketoacidosis.

Alcoholic ketoacidosis

This is the second most common cause of ketoacidosis, although significantly less common than diabetic ketoacidosis. In most cases, patients report significant alcohol consumption accompanied by fasting. From a biochemical point of view, ethanol is metabolized to acetoacetate and then acetate, producing significant amounts of NADH. In order to regenerate NAD+, pyruvate is metabolized to lactate and oxaloacetate is consumed to produce malate, depleting gluconeogenesis precursors. During starvation, insulin levels are extremely low and facilitate acyl-CoA entry into mitochondria, producing significant amounts of acetyl-CoA that cannot be metabolized in the Krebs cycle and is diverted towards ketone body synthesis.

In alcoholic ketoacidosis, the b-hydroxybutyrate to acetoacetate ratio is extremely high and b-hydroxybutyrate levels may be useful in the diagnosis and management of alcoholic ketoacidosis. However, no studies have been performed to actually compare b-hydroxybutyrate (serum or blood) with the traditional diagnostic parameters for alcoholic ketoacidosis and thus no recommendations can be made in favor or against its use in this setting.

What does it mean if your b-Hydroxybutyric Acid result is too low?

β-hydroxybutyric acid is a ketone and a byproduct of fatty acid metabolism and makes up ~70% of ketones produced in liver mitochondria.

Low levels of 3-Hydroxybutyric acid (=beta-hydroxybutyrate) may occur if there are low levels of precursors (fat, amino acids), if there are nutritional enzyme inhibitions, or if a low-activity enzyme variant is inherited. Ketone bodies are derived from fatty acids, levels may be lower on high carbohydrate diets. Ketogenesis occurs within the liver mitochondria, which are sensitive to oxidative stress and environmental toxins. Liver disorders may impair ketone synthesis and abnormally low levels of ketone bodies may impair liver functions.

Low levels of malate or orotate may also impair liver function.

→ Consider supporting synthesis pathways with vitamin B3 and phosphatidyl choline. Increasing healthy dietary fats, digestion and absorption may improve beta-hydroxybutyrate levels.

→ Review Citric Acid Cycle Metabolites and consider nutritional support for mitochondria.

What does it mean if your b-Hydroxybutyric Acid result is too high?

Elevated serum b-hydroxybutyrate levels can be observed in various conditions associated with metabolic substrate use disorders, insulin deficiency, and altered redox status, including the following:

→ Diabetic ketoacidosis: Ketone body production is stimulated by dehydration and insulin deficiency. Levels are usually more than 3 mmol/L.

→ Alcoholic ketoacidosis: Ketone body production is stimulated by altered redox status within the liver mitochondria.

→ High fat diet

→ Steroid or growth hormone deficiency

→ Salicylate poisoning

→ Fasting and starvation: Serum b-hydroxybutyrate levels are increased after approximately 3 days, rising to a plateau after 4 weeks of food deprivation.

→ Lactation: Ketone body production is stimulated by the high-fat content of milk.

→ Ketogenic diets: These diets are popular for the control of refractory seizures and body weight in obese individuals.

→ Glycogen-storage diseases and other metabolic disorders

A prospective study by Flores-Guerrero et al indicated that high plasma levels of b-hydroxybutyrate signal an increased risk of heart failure with reduced ejection fraction (HFrEF), especially in females. In terms of incident HF (which in these results was primarily due to HFrEF), the hazard ratio per one standard deviation increase in the b-hydroxybutyrate concentration was 1.40. More specifically, in women, one standard deviation was associated with a hazard ratio for HFrEF of 1.73, compared with 1.14 in men.

References:

Flores-Guerrero JL, Westenbrink BD, Connelly MA, Otvos JD, Groothof D, Shalaurova I, Garcia E, Navis G, de Boer RA, Bakker SJL, Dullaart RPF. Association of beta-hydroxybutyrate with development of heart failure: Sex differences in a Dutch population cohort. Eur J Clin Invest. 2021 May;51(5):e13468. doi: 10.1111/eci.13468. Epub 2020 Dec 18. PMID: 33616911; PMCID: PMC8244065.

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