What Are Ketones?
Ketone bodies are byproducts of fat metabolism that accumulate when the body shifts from glucose metabolism to fat metabolism for energy. There are three ketone bodies:
- Acetoacetate: Primary ketone detected by urine dipstick
- Beta-hydroxybutyrate: Most abundant ketone in DKA but NOT detected by urine dipstick
- Acetone: Volatile ketone responsible for fruity breath odor in DKA
How the Test Works
Urine ketone testing uses the nitroprusside reaction, which primarily detects acetoacetate. This method has important limitations:
- Detects: Acetoacetate (and acetone to a lesser degree)
- Does NOT detect: Beta-hydroxybutyrate, the predominant ketone in severe DKA
- Clinical significance: Serum beta-hydroxybutyrate measurement is more reliable for DKA diagnosis
Critical Limitation: Urine dipstick can be negative in severe DKA when beta-hydroxybutyrate predominates. If clinical suspicion for DKA is high with negative urine ketones, order serum beta-hydroxybutyrate or check serum ketones.
Causes of Ketonuria
Diabetic Ketoacidosis (DKA)
- Mechanism: Insulin deficiency leads to uncontrolled lipolysis and ketone production
- DKA triad: Hyperglycemia (typically >250 mg/dL) + ketonemia/ketonuria + metabolic acidosis (pH <7.3)
- Additional findings: Anion gap metabolic acidosis, elevated beta-hydroxybutyrate
- Clinical presentation: Polyuria, polydipsia, nausea, vomiting, abdominal pain, fruity breath, Kussmaul respirations
Starvation Ketosis
- Prolonged fasting: >12-18 hours without food intake
- Severe malnutrition: Inadequate caloric intake
- Prolonged vomiting: Hyperemesis gravidarum, gastroenteritis, cyclic vomiting syndrome
- Key difference from DKA: Normal or low glucose, mild ketosis, no significant acidosis
Alcoholic Ketoacidosis
- Mechanism: Alcohol metabolism + poor oral intake + dehydration + starvation
- Key features: Normal or LOW glucose (hypoglycemia common), elevated anion gap, ketosis
- Treatment: IV dextrose and thiamine (not insulin)
Ketogenic Diet and Low-Carbohydrate Diets
- Nutritional ketosis: Intentional high-fat, low-carbohydrate diet
- Clinical significance: Not pathologic; ketones are expected and desired
- Differentiating feature: Patient is well-appearing, no acidosis, intentional diet
Emergency Evaluation: Any patient with ketonuria and symptoms of DKA (polyuria, polydipsia, nausea, vomiting, abdominal pain, altered mental status) requires immediate evaluation with serum glucose, electrolytes, anion gap, and arterial blood gas.
Diagnosing Diabetic Ketoacidosis (DKA)
DKA diagnostic criteria (all three must be present):
- Hyperglycemia: Blood glucose typically >250 mg/dL (may be lower in euglycemic DKA)
- Metabolic acidosis: Arterial pH <7.3 OR serum bicarbonate <18 mEq/L
- Ketonemia/Ketonuria: Positive serum or urine ketones
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| DKA Severity | pH | Bicarbonate (mEq/L) | Mental Status |
|---|---|---|---|
| Mild | 7.25-7.30 | 15-18 | Alert |
| Moderate | 7.00-7.24 | 10-14 | Alert or drowsy |
| Severe | <7.00 | <10 | Stupor or coma |
Starvation Ketosis vs DKA
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| Feature | Starvation Ketosis | Diabetic Ketoacidosis |
|---|---|---|
| Glucose | Normal or low | Elevated (>250 mg/dL) |
| pH | Normal (>7.35) | Low (<7.3) |
| Bicarbonate | Normal (>22) | Low (<18 mEq/L) |
| Anion gap | Normal or mildly elevated | Elevated (>12) |
| Clinical status | Mild symptoms | Severely ill, dehydrated |
False Positive Results
- Captopril (ACE inhibitor): Contains sulfhydryl groups that react with nitroprusside reagent
- Mesna (chemotherapy adjunct): Sulfhydryl-containing drug that causes false positive
- Phenylketones: In phenylketonuria (PKU), phenylpyruvic acid causes positive reaction
- Highly pigmented urine: Dark red or brown urine may interfere with color interpretation
- Levodopa metabolites: May cause false positive in some dipsticks
False Negative Results
- Beta-hydroxybutyrate predominance: In severe DKA, beta-hydroxybutyrate exceeds acetoacetate; dipstick may be negative
- Old/expired test strips: Reagents degrade over time
- Improper storage: Heat or humidity exposure reduces strip sensitivity
- Bacterial degradation: Prolonged specimen storage allows bacteria to metabolize ketones
Specimen Collection Issues
- Timing: Test fresh urine; ketones degrade in room temperature specimens
- Dilution: Highly dilute urine may have false negative despite ketonemia
- Volatility: Acetone evaporates from urine if left uncovered
"Dipstick doesn't detect beta-hydroxybutyrate": The urine dipstick only detects acetoacetate, not beta-hydroxybutyrate. In severe DKA, the ratio shifts toward beta-hydroxybutyrate, making the dipstick falsely reassuring. If clinical suspicion is high, order serum beta-hydroxybutyrate or serum ketones.
Clinical Pearl
Urine ketones can be negative in severe DKA: As DKA progresses and acidosis worsens, beta-hydroxybutyrate becomes the predominant ketone, but the dipstick can't detect it. Don't rule out DKA based on negative urine ketones alone - check serum ketones or beta-hydroxybutyrate if suspicion is high.
Serum ketones are more reliable than urine: Serum beta-hydroxybutyrate is the gold standard for DKA diagnosis and monitoring. Urine ketones lag behind serum levels and may remain positive even after clinical improvement, making them less useful for treatment monitoring.
Clinical Pearl
Starvation ketosis vs DKA - check the glucose: Both cause ketonuria, but the glucose level distinguishes them. Starvation ketosis has normal or LOW glucose, while DKA has elevated glucose (>250 mg/dL). Also check pH - starvation has normal pH, DKA has pH <7.3.
Ketogenic diet is not pathologic: Patients on intentional low-carb or ketogenic diets will have positive urine ketones. This is nutritional ketosis, not ketoacidosis. They have normal pH, normal glucose, and are asymptomatic. Document diet history before assuming pathology.
Alcoholic ketoacidosis has LOW or normal glucose: Unlike DKA, alcoholic ketoacidosis typically presents with hypoglycemia or normoglycemia. Patient has recent alcohol binge, poor oral intake, positive ketones, and anion gap acidosis. Treatment is IV dextrose and thiamine, NOT insulin.
Clinical Pearl
Pregnancy and ketonuria: Pregnant women are prone to starvation ketosis due to accelerated starvation. Morning ketonuria in pregnancy may indicate inadequate caloric intake overnight. Ensure adequate nutrition, but rule out hyperemesis gravidarum if severe.