What causes ketones in the urine of diabetic and non-diabetic patients?

What Causes Ketones in Urine

Ketones appear in urine primarily due to two mechanisms: benign starvation ketosis from inadequate caloric intake (the most common cause in non-diabetics), or pathological insulin deficiency in diabetic patients where increased production from triglycerides and decreased hepatic utilization create dangerously high ketone concentrations. 1

Physiological (Benign) Causes

• Starvation ketosis is the most common benign explanation, occurring when reduced caloric intake forces the body to shift to fat metabolism for energy production 2
• Up to 30% of first morning urine specimens show positive ketones even in healthy individuals, with this percentage increasing during fasting states 2
• Prolonged exercise and fasting states trigger ketone production as the liver converts circulating free fatty acids into ketone bodies (primarily beta-hydroxybutyrate and acetoacetate) to serve as alternative fuel when glucose is not readily available 3, 4
• Pregnancy and the neonatal period are normal physiological states associated with elevated ketone levels 4

Pathological Causes in Diabetic Patients

• Diabetic ketoacidosis (DKA) results from absolute or relative insulin deficiency combined with increased counterregulatory hormones (cortisol, epinephrine, glucagon, growth hormone), causing both increased ketone production from triglycerides and decreased hepatic utilization 1
• In diabetic patients, ketones indicate insufficient insulin and may signal impending or established DKA—a medical emergency requiring immediate intervention 2
• Infection precipitates DKA in approximately 50% of cases in diabetic patients with fever, so even trace ketones warrant closer monitoring 5
• SGLT2 inhibitor use increases the risk of ketoacidosis and requires immediate evaluation for pathological ketosis when ketones are detected 6, 2
• Inadequate insulin dosing or treatment discontinuation leads to hyperglycemia and ketoacidosis, particularly in type 1 diabetes 7

Critical Diagnostic Distinction

• The first critical step when detecting urine ketones is to immediately check blood glucose to distinguish benign starvation ketosis from life-threatening DKA 5, 6
• If blood glucose >250 mg/dL with ketones present, this constitutes a medical emergency requiring immediate DKA evaluation 5, 6
• DKA diagnostic criteria require: glucose >250 mg/dL, venous pH <7.3, bicarbonate <15 mEq/L, and moderate ketonuria or ketonemia 5

Important Testing Limitations

• Urine dipsticks only detect acetoacetate, NOT beta-hydroxybutyrate, which significantly underestimates total ketone body concentration since beta-hydroxybutyrate is the predominant ketone in blood during DKA 1, 2, 3
• Blood beta-hydroxybutyrate measurement is strongly preferred over urine testing for all clinical decision-making because it provides quantitative results and directly measures the predominant ketone body 5, 6, 2
• During DKA resolution, beta-hydroxybutyrate is oxidized to acetoacetate (the predominant ketone in urine), creating a lag where urine ketone tests might be increasing even as DKA is resolving 3

Additional Pathological Causes

• Alcoholic ketoacidosis occurs when conditions alter the redox state of hepatic mitochondria to increase NADH concentrations, shifting equilibrium toward beta-hydroxybutyrate formation 1
• Type 2 diabetic patients may present significantly increased fasting ketone levels (351 vs 159 μmol/L in controls) despite not being insulin deficient, with ketone levels directly correlated with both plasma glucose and free fatty acid concentrations 8
• Hypoxia and metabolic disorders alter hepatic mitochondrial redox state, promoting ketone body production 1

Common Pitfalls

• False-positive ketones can occur with sulfhydryl drugs like captopril 5, 2
• False-negative results occur with prolonged air exposure of test strips or highly acidic urine 5, 2
• Highly colored urine may produce false-positive results 1