What causes ketones in the urine?

Causes of Ketones in the Urine

Ketones in the urine primarily result from increased fatty acid metabolism due to insulin deficiency, fasting, or low carbohydrate availability, with diabetic ketoacidosis being the most serious medical cause requiring immediate intervention. 1

Primary Causes of Ketonuria

Physiological Causes

• Fasting/Starvation: Ketones appear in urine after prolonged fasting (typically after 4+ days) 2
• Very low-carbohydrate diets: Ketogenic or low-carb diets restrict carbohydrate intake, forcing the body to use fat as primary fuel 1
• Prolonged exercise: Extended physical activity depletes glucose stores, leading to ketone production 3
• Pregnancy: Normal physiological state where ketones may appear in urine (up to 30% of first morning specimens) 1

Pathological Causes

• Diabetes-related causes:

  • Type 1 diabetes with insulin deficiency 1
  • Diabetic ketoacidosis (DKA) - medical emergency 1
  • Type 2 diabetes with SGLT2 inhibitor use (increases risk of DKA) 1
  • Missed insulin doses in insulin-dependent patients 1

• Other medical conditions:

  • Alcoholic ketoacidosis (positive ketones without hyperglycemia) 1
  • Severe illness with decreased oral intake 1
  • Hyperthyroidism (increased metabolic rate)
  • Glycogen storage diseases

Mechanism of Ketone Production

Ketone bodies (primarily β-hydroxybutyrate, acetoacetate, and acetone) are produced by the liver when:

1. Insulin levels are low
2. Counterregulatory hormones (glucagon, cortisol, epinephrine) are elevated
3. Glucose availability is limited
4. Fatty acids are mobilized from adipose tissue
5. The liver converts fatty acids to ketone bodies as an alternative energy source 1, 3

Risk Factors for Pathological Ketosis

Factors that increase risk of developing significant ketosis include:

• Type 1 diabetes/absolute insulin deficiency
• Younger age
• Prior history of hyperglycemic crises
• High A1C levels
• Alcohol and/or substance use
• Very low-carbohydrate diets in combination with SGLT2 inhibitors
• Dehydration
• Prolonged fasting in diabetic patients
• Pregnancy with pre-gestational diabetes 1

Clinical Significance and Monitoring

When to Test for Ketones

• In diabetic patients with:
  • Unexplained hyperglycemia (>200 mg/dL)
  • Symptoms of ketosis (nausea, vomiting, abdominal pain)
  • Illness or missed insulin doses
  • Use of SGLT2 inhibitors with risk factors 1

Testing Methods

• Urine ketone testing:

  • Uses nitroprusside reaction to detect acetoacetate
  • Does not measure β-hydroxybutyrate (the predominant ketone in DKA)
  • May show false positives with highly colored urine 1

• Blood ketone testing:

  • More accurate, measures β-hydroxybutyrate directly
  • Better for monitoring DKA treatment
  • Recommended over urine testing for accuracy 1, 4

Important Clinical Considerations

1. Urine dipsticks have poor sensitivity for detecting mild ketosis (35-76% depending on threshold), making them unreliable for monitoring adherence to ketogenic diets 5

2. In DKA, the ratio of β-hydroxybutyrate to acetoacetate can rise from normal (1:1) to as high as 10:1, making urine ketone testing potentially misleading during treatment 3

3. Patients on SGLT2 inhibitors can develop euglycemic DKA (ketoacidosis without significant hyperglycemia), making ketone testing particularly important 1

4. Pregnant women with diabetes require vigilant monitoring as they can develop euglycemic DKA with significant feto-maternal risk 1

5. Patients at risk for DKA should be educated on sick day management, including never stopping basal insulin even when not eating 1

By understanding these causes and mechanisms, clinicians can better interpret the significance of ketones in urine and take appropriate action when necessary.