What causes a urinalysis to show a significant presence of ketones, indicating a potential metabolic condition such as diabetic ketoacidosis?

Causes of Ketones in Urinalysis

Elevated ketones in urinalysis (40 mg/dL) primarily indicate a state of increased ketone body production due to insulin deficiency or metabolic stress, with diabetic ketoacidosis being the most concerning medical cause requiring prompt evaluation.1, 2

Physiological Causes of Ketones in Urine

• Ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone) are normally present in blood and urine but usually at concentrations below detection limits of routine testing methods 2
• Fasting state - ketones may represent a normal physiological response to prolonged fasting or low carbohydrate intake 2
• Pregnancy - up to 30% of first morning urine specimens from pregnant women may show positive ketones 2
• Prolonged exercise - can increase ketone production as the body utilizes fat for energy 3

Pathological Causes of Ketones in Urine

Diabetes-Related Causes

• Insulin deficiency is the main precipitating factor for diabetic ketoacidosis (DKA) 4
• In diabetic patients, especially those with type 1 diabetes, elevated ketones suggest insufficient insulin and may indicate impending or established DKA 2
• The presence of urine ketones is highly sensitive for DKA with high negative predictive value 1

Non-Diabetic Pathological Causes

• Alcoholic ketoacidosis - occurs in individuals with chronic alcohol abuse, particularly after binge drinking followed by reduced food intake 1
• Starvation ketosis - prolonged fasting or severe caloric restriction 4
• Low-carbohydrate diets - intentional dietary restriction of carbohydrates 5
• Illness or infection - metabolic stress increases counterregulatory hormones 2, 6
• Medication effects - SGLT2 inhibitors can increase risk of ketosis even with normal blood glucose levels 5

Pathophysiology of Ketone Production

• Ketone bodies are produced by the liver when glucose is not readily available as an energy source 3
• Insulin deficiency results in increased rates of lipolysis, providing increased free fatty acids for ketogenesis 7
• The three main ketone bodies are acetoacetate (AcAc), β-hydroxybutyrate (βOHB), and acetone, with βOHB and AcAc typically present in approximately equimolar amounts 6
• In diabetic ketoacidosis, the ketone body ratio (βOHB:AcAc) rises from normal (1:1) to as high as 10:1 3
• Hyperglucagonemia can augment ketogenesis further in the setting of insulin deficiency 7

Clinical Significance of Ketone Levels

• Mild ketosis (1+ ketones) may be normal in certain conditions but requires monitoring in high-risk individuals 2
• For ketosis-prone individuals, such as those with type 1 diabetes, history of DKA, or on SGLT2 inhibitors, even mild ketosis with normal blood glucose requires monitoring 6
• Common symptoms of developing DKA include polyuria with polydipsia (98%), weight loss (81%), fatigue (62%), dyspnea (57%), vomiting (46%), abdominal pain (32%), and polyphagia (23%) 4
• If ketone levels increase above 1.5 mmol/L despite interventions, or if symptoms of ketoacidosis develop, individuals should seek medical advice 6

Important Testing Considerations

• Urine ketone tests using nitroprusside-containing reagents only detect acetoacetate and not β-hydroxybutyrate, which is the predominant ketone body in DKA 2
• Blood ketone testing is preferred over urine ketone testing as it measures β-hydroxybutyrate directly 2, 6
• False-positive urine ketone results can occur with highly colored urine or with several sulfhydryl drugs, including captopril 2
• False-negative readings can occur when test strips have been exposed to air for an extended period or when urine specimens are highly acidic 2

Management Recommendations for Patients with Elevated Ketones

• Increase oral fluid intake to prevent dehydration 6
• Monitor blood glucose and ketone levels every 3-4 hours 6
• For diabetic patients, consider additional short or rapid-acting insulin if ketone levels increase or symptoms develop 6, 8
• For diabetic patients with normal blood glucose but elevated ketones, consuming some carbohydrates along with insulin may help suppress ketone production 6
• If symptoms of DKA develop (drowsiness, fruity breath odor, nausea, vomiting, abdominal pain), seek immediate medical attention 8