What causes ketonuria?

Causes of Ketonuria

Ketonuria occurs when the body shifts to fat metabolism for energy, producing ketone bodies that spill into the urine—this happens in both benign physiological states (fasting, low-carbohydrate intake, pregnancy) and pathological conditions (diabetic ketoacidosis, alcoholic ketoacidosis, SGLT2-inhibitor use). 1

Physiological (Benign) Causes

• Starvation or fasting triggers hepatic fat oxidation when carbohydrate intake falls below 50 g/day, producing blood β-hydroxybutyrate levels of 0.3–4 mmol/L while maintaining normal blood glucose and serum bicarbonate ≥18 mEq/L. 1

• Up to 30% of first-morning urine specimens from healthy individuals test positive for ketones, especially after an overnight fast, representing a normal metabolic adaptation. 1, 2

• Pregnancy causes physiologic ketonuria in approximately 30% of first-morning samples (with or without diabetes) due to increased energy demands and altered metabolism. 1

• Prolonged exercise increases ketone production as the body mobilizes fat stores for energy. 3

Pathological Causes

Diabetic Ketoacidosis (DKA)

• DKA is diagnosed when all of the following are present: plasma glucose >250 mg/dL, arterial pH <7.30, serum bicarbonate <15 mEq/L, positive urine or serum ketones, and anion gap >10 mEq/L. 1, 2

• Infection precipitates approximately 50% of DKA cases, with urinary tract infections being particularly frequent triggers; other precipitants include insulin omission and new-onset diabetes. 1, 4

• SGLT2 inhibitors increase DKA risk and can cause euglycemic DKA where glucose may be <250 mg/dL despite severe ketoacidosis, making diagnosis more challenging. 1, 4

Alcoholic Ketoacidosis

• Ethanol metabolism depletes hepatic glycogen and NAD⁺, leading to lipolysis and ketogenesis with positive urine ketones but typically without hyperglycemia—this distinguishes it from DKA. 1, 2

Post-Hypoglycemic Ketosis

• Counter-regulatory hormone surges after hypoglycemic episodes stimulate lipolysis, producing transient ketonuria during recovery. 1

Type 2 Diabetes

• Ketonuria occurs in 26–49% of hospitalized patients with type 2 diabetes, reflecting relative insulinopenia and significant hyperglycemia even without frank ketoacidosis. 5, 6

• Independent predictors of ketonuria in type 2 diabetes include younger age, higher hemoglobin A1c, and history of substance abuse. 6

Critical Diagnostic Considerations

Testing Limitations

• Standard urine dipsticks using nitroprusside detect only acetoacetate and acetone, missing β-hydroxybutyrate—the predominant ketone body in DKA—thereby substantially underestimating total ketone burden. 1, 2, 4, 3

• Blood β-hydroxybutyrate measurement is strongly preferred over urine testing for all clinical decision-making because it directly measures the predominant ketone and provides quantitative results. 1, 2, 4

• During DKA treatment, β-hydroxybutyrate levels fall while acetoacetate may paradoxically rise, making urine dipstick results unreliable for monitoring therapeutic response. 1, 3

False Results

• False-positive urine ketones occur with sulfhydryl-containing medications such as captopril. 1, 2

• False-negative results occur when test strips are exposed to air for prolonged periods or when urine is highly acidic (e.g., after large ascorbic acid intake). 1, 2

Risk Stratification and Action Thresholds

High-Risk Patients Requiring Immediate Evaluation

• Type 1 diabetes, history of prior DKA, current SGLT2 inhibitor use, or unexplained hyperglycemia with symptoms (nausea, vomiting, abdominal pain, altered mental status). 1, 2, 4

• Blood glucose >250 mg/dL with ketones indicates a medical emergency requiring immediate DKA evaluation with arterial pH, serum bicarbonate, anion gap, and blood β-hydroxybutyrate. 1, 2

Blood Ketone Action Thresholds

• <0.5 mmol/L: No intervention required. 1

• 0.5–1.5 mmol/L: Initiate sick-day rules (oral hydration, supplemental short-acting insulin with carbohydrate intake, frequent glucose/ketone monitoring). 1

• ≥1.5 mmol/L: Seek immediate medical attention; intravenous insulin therapy typically required. 1

Lower-Risk Patients

• No diabetes history, normal blood glucose, recent decreased oral intake, and no abdominal pain or altered mental status suggest benign starvation ketosis. 1, 2

Common Pitfalls

• Do not rely on urine ketone testing to rule in or monitor DKA treatment—the sensitivity for mild-to-moderate ketosis can be as low as 35–52%, and results become misleading as β-hydroxybutyrate converts to acetoacetate during recovery. 1

• Do not assume ketonuria always indicates DKA—physiologic ketonuria is common in healthy individuals, especially in the morning, during pregnancy, and after fasting. 1, 2

• Do not overlook infection as a precipitant—febrile or acutely ill diabetic patients require bacterial cultures of urine, blood, and other sites as indicated. 1, 4