What is the clinical significance of urine ketones in non-diabetic (non-diabetic) individuals?

Clinical Significance of Urine Ketones in Non-Diabetic Individuals

Urine ketones in non-diabetic individuals are generally not clinically significant and often represent physiologic ketosis due to fasting, prolonged exercise, low-carbohydrate diets, or pregnancy, rather than pathological states requiring intervention. 1

Normal Ketone Physiology

Ketone bodies (acetoacetate, acetone, and β-hydroxybutyrate) are normal catabolic products of free fatty acids that are:

• Present in urine and blood at low concentrations (<0.5 mmol/L) in healthy individuals 1
• Produced by the liver when glucose is not readily available 2
• Utilized peripherally as an alternative energy source

Common Non-Pathological Causes of Ketones in Non-Diabetics

Several physiological conditions can cause ketone production in non-diabetic individuals:

• Fasting/Starvation: Prolonged periods without food naturally increase ketone production 2
• Prolonged Exercise: Extended physical activity depletes glycogen stores, leading to ketogenesis 2
• Pregnancy: Up to 30% of pregnant women may show positive ketones, especially in morning specimens, without any pathology 1
• Very Low-Carbohydrate Diets: Nutritional ketosis is an expected finding in those following ketogenic diets 1

Ketone Testing Methods

Understanding the limitations of ketone testing is crucial:

• Urine ketone testing primarily detects acetoacetate, not β-hydroxybutyrate (the predominant ketone in pathological states) 1

  • High sensitivity (99%) but lower specificity (69%)
  • May underestimate total ketone body concentration
  • Can produce false-positive results 2

• Blood ketone testing measures β-hydroxybutyrate directly and is more accurate for total ketosis assessment 1

  • More reliable for clinical decision-making
  • Requires specialized equipment

When to Be Concerned About Ketones in Non-Diabetics

While usually benign, ketones in non-diabetics may occasionally warrant further investigation:

• Unexplained metabolic acidosis: Ketones with acidosis in a non-diabetic should prompt evaluation for:

  • Undiagnosed diabetes (particularly if accompanied by hyperglycemia) 3
  • Alcoholic ketoacidosis
  • Starvation ketosis (severe)
  • Other metabolic disorders

• Symptoms of illness with ketosis: Nausea, vomiting, abdominal pain, or malaise with ketones may require further evaluation 1

Important Clinical Pitfalls

1. Overlooking undiagnosed diabetes: Ketones may be the first sign of previously undiagnosed diabetes, as seen in cases where patients present with moderate ketosis before formal diabetes diagnosis 3

2. Misattributing ketones to fasting: Assuming ketones are due to fasting/starvation when they actually represent early diabetic ketoacidosis can delay appropriate treatment 3

3. Euglycemic DKA: Non-diabetics taking SGLT2 inhibitors for other conditions (like weight loss) can develop euglycemic DKA with ketosis despite near-normal blood glucose levels 4, 5

Clinical Approach to Ketones in Non-Diabetics

When encountering ketones in a non-diabetic patient:

1. Assess clinical context:

   • Is there a clear physiologic explanation (fasting, exercise, low-carb diet, pregnancy)?
   • Are there concerning symptoms (nausea, vomiting, abdominal pain, altered mental status)?

2. Check for acidosis:

   • Calculate anion gap: [Na⁺] - ([Cl⁻] + [HCO₃⁻])
   • Values >12 mEq/L suggest metabolic acidosis requiring further investigation 1

3. Evaluate glucose metabolism:

   • Check blood glucose and HbA1c to rule out undiagnosed diabetes 3
   • Consider glucose tolerance testing if results are equivocal

4. Review medication history:

   • Particularly focus on SGLT2 inhibitors, which can cause euglycemic ketoacidosis 4, 5

5. Consider additional testing if clinically indicated:

   • Blood gases to assess acid-base status
   • Comprehensive metabolic panel
   • Blood ketone measurement (β-hydroxybutyrate) if available 6

In most cases of non-diabetic ketosis without acidosis or concerning symptoms, reassurance and addressing the underlying physiologic cause (e.g., increasing carbohydrate intake, treating dehydration) is sufficient.