What are the implications of ketones +4 in urine with a normal glucose level, specifically 91 mg/dL (euglycemia)?

Causes of Ketones +4 in Urine with Normal Glucose (91 mg/dL)

With ketones +4 in urine and a normal glucose of 91 mg/dL, the most likely cause is starvation ketosis from reduced caloric intake, but you must immediately rule out euglycemic diabetic ketoacidosis (euDKA), especially if the patient has diabetes, is on SGLT2 inhibitors, or has any acute illness. 1, 2

Immediate Clinical Assessment Required

The presence of +4 ketones (severe ketonuria) with euglycemia is a red flag that demands urgent evaluation. You need to determine:

• Is the patient diabetic? If yes, this is euDKA until proven otherwise 1, 3
• Is the patient on SGLT2 inhibitors? These drugs cause euDKA in up to 6% of type 1 diabetics and can occur in type 2 diabetes 2, 4
• Does the patient have symptoms? Nausea, vomiting, abdominal pain, or altered mental status indicate metabolic acidosis requiring immediate intervention 5, 6

Primary Causes of Severe Ketonuria with Normal Glucose

1. Starvation Ketosis (Most Common Benign Cause)

• Occurs when patients reduce caloric intake during illness, causing the body to shift to fat metabolism for energy 1
• Characteristics: serum bicarbonate usually not lower than 18 mEq/L, blood glucose normal to mildly elevated, ketone bodies range 0.3-4 mmol/L with normal pH 7
• Up to 30% of first morning urine specimens can show positive ketones even in healthy individuals, increasing during fasting states 1, 8

2. Euglycemic Diabetic Ketoacidosis (Life-Threatening)

• Blood glucose can be <200 mg/dL (even normal) while severe ketoacidosis develops 2, 3
• SGLT2 inhibitors cause noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion, leading to euDKA 2
• Infection is the most common precipitating factor in diabetic patients, occurring in approximately 50% of DKA cases 7
• Characteristics: very high ketone bodies (>7-8 mmol/L), low systemic pH, severe metabolic acidosis despite normal glucose 7
• The absence of significant hyperglycemia delays recognition by both patients and providers, making this a diagnostic trap 2

3. Ketogenic Diet

• Patients following very-low-carbohydrate diets for weight loss may have elevated ketones 5
• This is typically intentional and asymptomatic

4. Alcoholic Ketoacidosis

• Can present with normal or low glucose levels
• Associated with recent alcohol intake and poor nutritional intake

Critical Diagnostic Algorithm

Step 1: Obtain blood ketone measurement (β-hydroxybutyrate) immediately 1, 8

• Urine dipsticks only detect acetoacetate, NOT β-hydroxybutyrate, which significantly underestimates total ketone body concentration 5, 1, 7
• Blood ketone testing is strongly preferred over urine testing for clinical decision-making 1, 7

Step 2: Check arterial blood gas, electrolytes, and anion gap 1, 3

• If pH <7.3, bicarbonate <18 mEq/L, or elevated anion gap: this is DKA regardless of glucose level 3

Step 3: Assess for precipitating factors:

• Infection, insulin pump failure, medication noncompliance, SGLT2 inhibitor use 2, 4
• Recent illness with decreased oral intake 1, 7

Management Based on Cause

If Euglycemic DKA (pH <7.3, elevated anion gap):

• Initiate IV insulin drip immediately, even with normal glucose 3
• Aggressive IV fluid resuscitation 3
• Add dextrose to IV fluids to maintain glucose 150-200 mg/dL while continuing insulin to clear ketones 3
• Monitor blood ketones every 2-4 hours until normalized 3

If Starvation Ketosis (normal pH, bicarbonate >18 mEq/L):

• Encourage oral hydration and carbohydrate intake 7
• For diabetic patients: consuming carbohydrates along with insulin can suppress ketone production 7
• Monitor clinically; typically resolves with feeding

Critical Pitfalls to Avoid

• Never assume normal glucose excludes DKA - euDKA is increasingly recognized, especially with SGLT2 inhibitors 2, 3
• Never rely solely on urine ketone testing for clinical decisions - it misses β-hydroxybutyrate, the predominant ketone in DKA 5, 1
• False-positive urine ketones can occur with sulfhydryl drugs like captopril 1, 8
• False-negative readings occur with prolonged air exposure of test strips or highly acidic urine 1, 8
• Blood pH and ketones should be checked in all ill diabetic patients regardless of blood glucose levels 3

High-Risk Populations Requiring Immediate Evaluation

• Type 1 diabetes patients 5, 2
• Any patient on SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) 2, 4, 6
• History of prior DKA 5
• Presence of acute illness, infection, or nausea/vomiting 7, 2

The presence of urine ketones is highly sensitive for DKA with high negative predictive value (97-98% sensitivity), making it useful for ruling out DKA when negative, but +4 ketones demands full evaluation 5, 9.