What are the causes of ketonuria?

Causes of Ketonuria

Ketonuria occurs when ketone bodies are produced by the liver and excreted in urine, primarily due to carbohydrate deprivation states (starvation, fasting, ketogenic diets), pathological insulin deficiency (diabetic ketoacidosis, poorly controlled diabetes), pregnancy, alcoholic ketoacidosis, or medication effects (SGLT2 inhibitors). 1, 2, 3

Physiological (Benign) Causes

Starvation and Fasting States

• Reduced caloric intake triggers a metabolic shift to fat breakdown for energy, producing ketone bodies (β-hydroxybutyrate 0.3-4 mmol/L) with normal blood glucose and serum bicarbonate typically ≥18 mEq/L 1, 2
• Up to 30% of first morning urine specimens from healthy individuals show positive ketones, particularly after overnight fasting 1, 2
• Prolonged exercise increases ketone production as glycogen stores deplete and the body shifts to fat metabolism 4, 5

Pregnancy

• Up to 30% of first morning urine specimens from pregnant women (with or without diabetes) test positive for ketones, representing normal physiological adaptation 1, 2
• Pregnancy increases metabolic demands and accelerates the shift to fat metabolism during fasting states 5, 6

Ketogenic Diets

• Intentional carbohydrate restriction (<50g/day) induces "physiological ketosis" with ketone levels 0.3-4 mmol/L, normal pH, and normal glucose 1, 6
• This differs fundamentally from pathological ketosis by maintaining normal systemic pH and physiological insulin levels 1

Pathological Causes

Diabetic Ketoacidosis (DKA)

• Insulin deficiency combined with counterregulatory hormone excess (glucagon, catecholamines, cortisol, growth hormone) causes unrestrained lipolysis and hepatic ketone production exceeding 7-8 mmol/L 3
• DKA requires all of the following: glucose >250 mg/dL, arterial pH <7.30, serum bicarbonate <15 mEq/L, positive ketones, and anion gap >10 mEq/L 1, 2
• Infection precipitates approximately 50% of DKA cases (particularly urinary tract infections), while insulin omission accounts for most other cases 2, 3
• β-hydroxybutyrate is the predominant ketone in blood during DKA, with β-hydroxybutyrate:acetoacetate ratios reaching 10:1 (normal is 1:1) 4, 5, 7

Poorly Controlled Diabetes Without DKA

• 26% of hospitalized patients with type 2 diabetes demonstrate ketonuria despite not meeting DKA criteria, reflecting relative insulinopenia and significant hyperglycemia 8
• Persistent blood glucose >300 mg/dL in type 1 diabetes triggers ketone production even without full DKA 2

SGLT2 Inhibitor-Associated Ketosis

• SGLT2 inhibitors increase DKA risk and cause euglycemic DKA where glucose may be <250 mg/dL despite severe ketoacidosis, making diagnosis challenging 1, 2
• Blood ketone action thresholds for patients on SGLT2 inhibitors: <0.5 mmol/L (no intervention), 0.5-1.5 mmol/L (initiate sick-day rules), ≥1.5 mmol/L (immediate medical attention) 2, 9

Alcoholic Ketoacidosis

• Alcohol metabolism depletes hepatic glycogen and NAD+, promoting lipolysis and ketogenesis with positive urine ketones but hyperglycemia is typically absent 1, 2
• Alcohol-induced coagulopathy or trauma may cause concurrent hematuria 2

Post-Hypoglycemic State

• Ketones can appear after hypoglycemic episodes as counterregulatory hormones stimulate lipolysis during recovery 1

Critical Diagnostic Considerations

Testing Methodology Limitations

• Standard urine dipsticks using nitroprusside only detect acetoacetate and miss β-hydroxybutyrate (the predominant ketone in DKA), significantly underestimating total ketone burden 1, 2, 3, 4, 5
• Blood β-hydroxybutyrate measurement is strongly preferred over urine testing for all clinical decision-making 1, 2, 9, 3
• During DKA treatment, acetoacetate may increase as β-hydroxybutyrate falls, making urine ketone tests unreliable for monitoring therapy 1, 4, 7

False Results

• False-positive urine ketones occur with sulfhydryl-containing medications (captopril) 2, 9
• False-negative results occur with prolonged air exposure of test strips or highly acidic urine (after large ascorbic acid intake) 1, 2, 9

Immediate Action Required

• When ketonuria is detected, immediately check blood glucose to distinguish benign starvation ketosis (normal/low glucose) from life-threatening DKA (glucose >250 mg/dL) 2, 9
• Glucose >250 mg/dL with ketones constitutes a medical emergency requiring immediate DKA evaluation with arterial blood gas, electrolytes, and anion gap calculation 2, 9