What is the significance of beta hydroxybutyrate in patients with diabetes or those on a ketogenic diet?

Beta-Hydroxybutyrate: Clinical Significance and Applications

What is Beta-Hydroxybutyrate?

Beta-hydroxybutyrate (β-OHB) is the predominant ketone body produced during ketogenesis and serves as both an alternative energy substrate and an important signaling molecule with regulatory functions beyond simple metabolism. 1, 2

β-OHB is produced from fatty acids in the liver when carbohydrate availability is low, serving as an alternative fuel for peripheral tissues including the brain, heart, and skeletal muscle 1. Beyond its role as a metabolite, β-OHB functions as an endogenous inhibitor of histone deacetylases and a ligand for cell surface receptors, linking environmental conditions to cellular function and gene expression 2.

Normal vs. Pathological Levels

Understanding the distinction between physiological and pathological ketosis is critical:

Physiological Ketosis

• Normal baseline: <0.5 mmol/L 1, 3
• Physiological ketosis range: 0.3-4 mmol/L 4, 5
• Maintains normal pH and physiological insulin levels 4, 5
• Normal to low blood glucose 4

Pathological Ketoacidosis

• DKA threshold: >7-8 mmol/L 4, 3
• Severe acidosis with pH ≤7.3 3
• Serum bicarbonate ≤15 mEq/L 3
• Hyperglycemia ≥250 mg/dL 3

Clinical Applications in Diabetes

Diabetic Ketoacidosis Diagnosis

Blood β-OHB measurement is the preferred test for diagnosing DKA, as recommended by the American Association of Clinical Endocrinologists and American Diabetes Association. 1, 3

Key diagnostic advantages:

• Superior accuracy: Standard nitroprusside-based urine tests only detect acetoacetate and acetone, completely missing β-OHB, which is the predominant ketone body in DKA 1, 3, 6
• Optimal cutoff: A β-OHB value of 5.3 mmol/L predicts DKA with 90.6% accuracy, with sensitivity of 76.7% and specificity of 96.4% 7
• Monitoring advantage: During DKA treatment, β-OHB falls while acetoacetate may paradoxically increase, making nitroprusside methods unreliable for monitoring therapy 3

Blood β-OHB testing reduces emergency department visits, hospitalization frequency, and time to recovery from DKA compared to urine testing 6.

Ketone Monitoring Recommendations

Individuals prone to ketosis—those with type 1 diabetes, history of DKA, or treated with SGLT2 inhibitors—should measure ketones in urine or blood if they have unexplained hyperglycemia or symptoms of ketosis (abdominal pain, nausea). 1

Critical monitoring considerations:

• SGLT2 inhibitor users: Incremental increases in baseline β-OHB and changes from baseline are associated with higher DKA risk independent of treatment 8
• Risk quantification: DKA risk increases by 18% with each 0.1 mmol/L increase in baseline β-OHB and by 8% with each 0.1 mmol/L increase from baseline 8
• Baseline BHB and age are significant predictors of DKA episodes 8

Significance in Ketogenic Diets

Metabolic Effects

Ketogenic diets induce physiological ketosis (0.3-4 mmol/L) that fundamentally differs from pathological ketoacidosis, maintaining normal pH and physiological insulin levels while providing metabolic benefits. 4, 5

The metabolic transition includes:

• Insulin resistance reduction: 57% decrease, particularly pronounced in individuals with pre-existing hyperinsulinemia 5
• Hepatic benefits: 31% reduction in intrahepatic lipid content in overweight individuals with NAFLD 1, 5
• Energy expenditure: Increases by approximately 52 kcal/day for every 10% decrease in carbohydrate contribution 5
• Appetite regulation: Ghrelin and leptin levels decrease significantly, reducing hunger 5

Mechanistic Insights

The success of ketogenic diets relates to PPARα-signaling and ketogenesis 1:

• PPARα activation: This nuclear receptor regulates fatty acid metabolism and is upregulated during ketogenic states 1
• FGF-21 induction: PPARα induces fibroblast growth factor 21, which is rapidly suppressed by refeeding 1
• Anti-inflammatory effects: PPARα exerts anti-inflammatory activities and protection from intrahepatic lipid accumulation 1

Serum β-OHB levels significantly increase after 4 weeks of alternate-day fasting, indicating successful induction of ketogenesis 1.

Starvation Ketosis

Pathophysiology

During starvation, low carbohydrate availability triggers decreased insulin and increased counterregulatory hormones, inducing hepatic ketogenesis as the body shifts to fatty acids as the primary energy source. 4

Characteristic features:

• β-OHB predominance: The equilibrium between acetoacetate and β-OHB shifts toward β-OHB formation due to increased hepatic mitochondrial NADH concentrations 1, 4
• Laboratory findings: Mildly elevated or normal plasma glucose, serum bicarbonate usually not lower than 18 mEq/L, positive ketones, elevated β-OHB 4
• Prevalence: Positive urine ketone readings occur in up to 30% of first morning urine specimens during starvation 4

Prevention

During acute illness, oral ingestion of 150-200g of carbohydrate per day is recommended to prevent starvation ketosis. 4

Critical Measurement Considerations

Testing Method Selection

Blood ketone determinations that specifically measure β-OHB are more accurate than nitroprusside-based methods for assessing ketosis. 4, 3

The limitations of traditional testing:

• Nitroprusside-based tests detect only acetoacetate and acetone 1, 3
• This can underestimate total ketone body concentration 1
• Specific β-OHB measurement is essential for accurate assessment 1, 4

Clinical Pitfalls to Avoid

1. Do not rely on urine ketone testing alone for DKA diagnosis or monitoring, as it misses the predominant ketone body 1, 3

2. Do not confuse physiological ketosis with pathological ketoacidosis—the distinction is critical for appropriate management 4, 5

3. Do not use restrictive ketogenic diets in malnourished patients or those at risk of malnutrition, as this may worsen nutritional status 5

4. Monitor diabetes medications closely when implementing ketogenic approaches, as close monitoring of blood glucose is needed due to hypoglycemia concerns 1

5. Distinguish starvation ketosis from DKA and alcoholic ketoacidosis—starvation ketosis presents with normal to low glucose and less severe acidosis 4

Monitoring During Ketogenic Interventions

For individuals following therapeutic ketogenic diets:

• β-OHB monitoring helps distinguish between physiological ketosis (0.3-4 mmol/L) and potentially dangerous levels (>7-8 mmol/L) 4, 5
• Monitor skeletal muscle mass to ensure weight loss comes predominantly from fat rather than muscle 5
• Track fluid changes to help understand short-term shifts in weight and hydration status, as initial rapid weight loss is primarily water weight from glycogen depletion 5