What are the possible causes of elevated serum acetone in a patient, particularly those with a history of diabetes?

Elevated Serum Acetone: Causes and Clinical Context

Elevated serum acetone is primarily caused by diabetic ketoacidosis (DKA), starvation ketosis, alcoholic ketoacidosis, and ketogenic diets, with acetone being derived from spontaneous decarboxylation of acetoacetate during states of increased ketone body production. 1

Primary Pathophysiologic Mechanism

Acetone is formed through spontaneous decarboxylation of acetoacetate (AcAc), one of the principal ketone bodies produced during lipolysis. 1 The equilibrium between acetoacetate and β-hydroxybutyrate shifts toward β-hydroxybutyrate formation in conditions that alter hepatic mitochondrial redox state and increase NADH concentrations. 1

Major Clinical Causes

Diabetic Ketoacidosis (Most Critical)

• DKA represents a medical emergency and is the most important pathological cause of elevated blood ketones, including acetone. 1, 2
• Results from absolute or relative insulin deficiency combined with increased counterregulatory hormones (cortisol, epinephrine, glucagon, growth hormone). 1
• Plasma acetone concentrations in DKA range from 1.55-8.91 mM and are often greater than acetoacetate concentrations. 3
• Acetone production rates in DKA range from 68 to 581 μmol/min/1.73 m², accounting for approximately 52% of estimated acetoacetate production. 3
• Euglycemic DKA (glucose <250 mg/dL) is increasingly common with SGLT2 inhibitors and can present with significantly elevated acetone despite only mild hyperglycemia. 4, 5

Alcoholic Ketoacidosis

• Occurs in the context of alcohol use with glucose levels ranging from mildly elevated to hypoglycemic. 4
• Represents a condition that alters hepatic mitochondrial redox state, increasing NADH and shifting ketone body equilibrium. 1

Starvation/Fasting Ketosis

• Ketone levels increase during fasting and prolonged exercise as the body shifts to fat metabolism for energy. 2
• Glucose rarely exceeds 250 mg/dL and bicarbonate usually remains above 18 mEq/L, distinguishing it from DKA. 4
• Approximately 75% of acetone undergoes in vivo metabolism at low plasma concentrations. 3

Ketogenic Diets

• Very-low-carbohydrate diets for weight loss or diabetes control produce physiologic ketosis with elevated acetone. 1
• Individuals following these diets may check blood or urine ketones at home. 1

Metabolic Conditions Altering Redox State

• Any condition that increases hepatic mitochondrial NADH concentrations can elevate acetone, including hypoxia, metabolic disorders, and conditions affecting hepatic metabolism. 1

High-Risk Populations Requiring Vigilance

Individuals prone to ketosis include those with type 1 diabetes, history of DKA, or treatment with SGLT2 inhibitors, who should measure ketones with unexplained hyperglycemia or symptoms of ketosis (abdominal pain, nausea). 1

Critical Diagnostic Considerations

Acetone Measurement Limitations

• Acetone is usually present in only small quantities compared to β-hydroxybutyrate and acetoacetate. 1
• The nitroprusside test does not detect acetone or β-hydroxybutyrate, only measuring acetoacetate, which can provide misleading clinical information by underestimating total ketone body concentration. 1, 2
• Direct measurement of β-hydroxybutyrate in blood is preferred over nitroprusside methods for diagnosing and monitoring ketosis. 6, 4

Acetone Elimination Patterns

• At low plasma acetone concentrations, approximately 20% is eliminated via breath, while at high concentrations, approximately 80% is exhaled. 3
• Urinary excretion accounts for only about 7% of acetone production rate regardless of plasma concentration. 3
• Skin acetone concentrations correlate with blood β-hydroxybutyrate (r=0.669) and can reach 940 ppb in DKA, falling to 80 ppb after insulin therapy. 7

Common Pitfalls to Avoid

• Do not dismiss the possibility of DKA based solely on glucose levels below 250 mg/dL, as euglycemic DKA with elevated acetone is increasingly recognized, particularly with SGLT2 inhibitor use. 4, 5
• Avoid relying on urine ketone testing alone, as it only detects acetoacetate and provides semiquantitative results with potential false-positives. 1, 2
• Recognize that acetone can contribute significantly to serum osmolality in severe ketoacidosis, with concentrations reaching 93 mg/dL or higher. 5, 8
• During DKA treatment, β-hydroxybutyrate converts to acetoacetate, which can paradoxically make nitroprusside tests appear worse even as the patient improves clinically. 6

Neonates and Pregnancy

• Ketone bodies, including acetone, are normally found in the blood of neonates and pregnant women at higher levels than non-pregnant adults. 2