Ketonemia: Definition and Clinical Significance
Ketonemia is the presence of elevated ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) in the blood, which are catabolic products of free fatty acid metabolism produced in the liver. 1
Normal Physiology
Ketone bodies are normally present in blood at very low concentrations (total serum ketones <0.5 mmol/L) and serve as an alternative energy source when glucose availability is limited. 1
The three ketone bodies are acetoacetate (AcAc), β-hydroxybutyrate (βOHB), and acetone, with βOHB and AcAc typically present in approximately equimolar amounts under normal conditions. 1
Ketone bodies function as important vectors of energy transport from the liver to peripheral tissues, particularly the brain, which has no other substantial non-glucose-derived energy source. 2
Physiological (Benign) Ketonemia
Elevated ketone levels occur normally during fasting, prolonged exercise, pregnancy, the neonatal period, and when following very-low-carbohydrate (ketogenic) diets, with blood ketone concentrations ranging from 0.3-4 mmol/L while maintaining normal blood glucose and serum bicarbonate ≥18 mEq/L. 3
Up to 30% of first-morning specimens from healthy individuals show detectable ketones, especially after overnight fasting. 3
Pregnant women commonly demonstrate physiologic ketonemia as a normal metabolic adaptation to increased energy demands. 3
Pathological Ketonemia
Increased ketone concentrations in patients with known diabetes mellitus or previously undiagnosed individuals presenting with hyperglycemia suggest impending or established diabetic ketoacidosis (DKA), a medical emergency. 1
Diabetic Ketoacidosis
DKA is defined by all of the following criteria: plasma glucose >250 mg/dL, arterial pH <7.30, serum bicarbonate <15 mEq/L, positive urine or serum ketones, and anion gap >10 mEq/L. 3
The two major mechanisms responsible for high ketone concentrations in diabetes are increased production from triglycerides and decreased utilization in the liver, both resulting from absolute or relative insulin deficiency and increased counterregulatory hormones (cortisol, epinephrine, glucagon, and growth hormone). 1
SGLT2 Inhibitor-Associated Ketoacidosis
Patients treated with SGLT2 inhibitors have increased risk of euglycemic DKA, where severe ketoacidosis occurs with blood glucose <250 mg/dL, making diagnosis more challenging. 3
Blood ketone action thresholds for SGLT2 inhibitor users: <0.5 mmol/L requires no intervention, 0.5-1.5 mmol/L warrants sick-day rules, and ≥1.5 mmol/L demands immediate medical attention. 3
Other Pathological Causes
Alcoholic ketoacidosis results from ethanol metabolism depleting hepatic glycogen, leading to lipolysis and ketogenesis with positive ketones but typically without hyperglycemia. 3
Post-hypoglycemic ketonemia can occur when counter-regulatory hormone surges stimulate lipolysis during recovery from low blood sugar. 3
Critical Diagnostic Considerations
Blood β-hydroxybutyrate measurement is strongly preferred over urine testing for all clinical decision-making because standard urine dipsticks only detect acetoacetate and significantly underestimate total ketone body concentration, missing βOHB which is the predominant ketone in DKA. 3
The equilibrium between AcAc and βOHB shifts toward βOHB formation in conditions that alter the redox state of hepatic mitochondria (hypoxia, fasting, metabolic disorders including DKA, and alcoholic ketoacidosis). 1
During DKA treatment, βOHB levels fall while acetoacetate may rise, making urine dipstick results unreliable for monitoring therapeutic response. 3
Clinical Implications
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) and implement sick-day rules and/or seek medical advice if ketones are increased. 1
- Recent literature demonstrates a plausible link between elevated circulating ketones and oxidative stress, with complications of the brain, kidney, liver, and microvasculature found to be elevated in diabetic patients with elevated ketones compared to those with normal ketone levels. 4