In a child with bilirubin and ketones in the urine and pink-colored urine, what are the likely causes and how should this be evaluated and managed?

Evaluation of Pink Urine with Bilirubinuria and Ketonuria in a Child

In a child presenting with pink urine, bilirubin, and ketones on urinalysis, immediately measure blood glucose to distinguish between diabetic ketoacidosis (a medical emergency) and other causes, then obtain fractionated serum bilirubin to determine if conjugated hyperbilirubinemia is present, which would indicate hepatobiliary disease or biliary obstruction. 1

Immediate Diagnostic Steps

Blood Glucose Measurement

• Check blood glucose (fingerstick or venous) immediately as the single most important initial test to differentiate between starvation ketosis and diabetic ketoacidosis (DKA). 1
• If blood glucose is >250 mg/dL with ketones present, this constitutes a medical emergency requiring immediate evaluation for DKA. 1
• DKA diagnostic criteria include: blood glucose >250 mg/dL, venous pH <7.3, bicarbonate <15 mEq/L, and moderate ketonuria or ketonemia. 1

Bilirubin Fractionation

• Only conjugated (water-soluble) bilirubin is excreted in urine; unconjugated bilirubin remains protein-bound and cannot be filtered by the kidneys. 2
• The presence of bilirubinuria reflects impaired hepatic excretion of conjugated bilirubin and indicates hepatocellular disease, cholestatic disorders, or biliary obstruction. 2
• Obtain total and direct/conjugated bilirubin immediately to determine the type of hyperbilirubinemia. 3, 2
• If total serum bilirubin (TSB) is ≤5 mg/dL, a direct or conjugated bilirubin >1.0 mg/dL is considered abnormal and warrants further investigation. 4, 3

Pink Urine Color Differential

Hematuria vs. Pigmenturia

• Even 1 mL of blood in 1000 mL of urine is sufficient to make urine appear pink or red. 5
• Perform urinalysis with microscopy immediately to distinguish true hematuria (presence of red blood cells) from pigmenturia (bilirubin, myoglobin, or other pigments). 4
• Tea-colored urine with hematuria accompanied by proteinuria (>2+ by dipstick), red blood cell casts, and deformed red blood cells suggests a glomerular source. 4
• The presence of white cells and microorganisms within the urine indicates possible urinary tract infection. 4

False-Positive Proteinuria

• When ≥2+ bilirubin and proteinuria appear together on urinalysis, false-positive proteinuria readings increase by more than 10%; this pattern suggests concurrent hepato-renal involvement or cholestatic liver disease with secondary renal effects. 2

Clinical Algorithm Based on Blood Glucose

If Blood Glucose >250 mg/dL (DKA Pathway)

• Start continuous IV regular insulin infusion at 0.1 units/kg/hour and target glucose decline of 50-75 mg/dL per hour. 1
• Provide 1.5 times the 24-hour maintenance fluid requirements. 1
• Obtain venous blood gas, complete metabolic panel, and blood ketone measurement (β-hydroxybutyrate preferred over urine ketones). 1, 6
• The nitroprusside test (urine ketone dipstick) only detects acetoacetate and does not assess the best indicator of ketone body levels (3-hydroxybutyrate), providing only semiquantitative assessment. 6

If Blood Glucose <250 mg/dL (Non-DKA Pathway)

• Ketonuria with normal or low blood glucose indicates starvation ketosis, which is common in children during illness with poor oral intake. 1, 6
• Ketones are always present in blood and their levels increase during fasting and prolonged exercise; they are also found in neonates. 6
• Focus diagnostic efforts on the bilirubinuria and pink urine color.

Evaluation of Conjugated Hyperbilirubinemia

Essential Laboratory Workup

• Obtain comprehensive liver function tests including ALT, AST, alkaline phosphatase, GGT, albumin, and prothrombin time/INR to differentiate hepatocellular injury from cholestasis. 3, 2
• Complete blood count with peripheral smear, reticulocyte count to evaluate for hemolysis. 3
• Blood type and direct antibody test (Coombs' test) if hemolytic disease is suspected. 3
• G6PD level, particularly in African American, Mediterranean, or Asian descent patients (prevalence 11-13% in African Americans). 4, 3

Critical G6PD Testing Pitfall

• During active hemolysis, G6PD enzyme levels can be falsely elevated; a normal level does not rule out G6PD deficiency in a hemolyzing child. 4, 3
• Repeat testing at 3 months is necessary if G6PD deficiency is strongly suspected. 4, 3

Imaging

• Obtain abdominal ultrasound within 24-48 hours for conjugated hyperbilirubinemia to exclude biliary obstruction and evaluate liver parenchyma. 2
• Ultrasound has 98% positive predictive value for liver parenchymal disease and 65-95% sensitivity for biliary obstruction. 2

Evaluation of Hematuria (If Red Blood Cells Present)

History and Physical Examination

• Search for recent urinary tract infection, strenuous exertion, recent trauma, menstruation (if applicable), bleeding tendency, bloody diarrhea, joint pains, rash, flank pain, frequency, and dysuria. 4
• Assess for family history of sickle cell disease, hemophilia, stone disease, hearing loss, or familial renal disease. 4
• Examine for fevers, arthritis, rashes, soft-tissue edema, nephromegaly, abdominal masses, genital or anal bleeding, and costovertebral angle tenderness. 4

Urine Culture

• Fever with turbid urine requires immediate urine culture (catheterized specimen to minimize contamination) and consideration of empiric antibiotics. 1
• UTI can occur in asymptomatic, jaundiced infants even in the first week of life, and urine culture should be considered in the bilirubin work-up of infants older than three days of age with unknown etiology. 7

Additional Testing

• Evaluate for hypercalciuria with spot urine calcium-to-creatinine ratio. 4
• If glomerulonephritis is suspected, obtain blood urea nitrogen, serum creatinine, and complete blood count with platelets. 4

Age-Specific Considerations

Neonates and Young Infants

• Jaundice appearing in the first 24 hours of life is always pathologic and demands urgent evaluation for hemolytic disease and other serious causes. 3
• Obtain TSB immediately on any infant jaundiced within 24 hours of birth; do not rely on visual assessment. 3
• Isoimmune hemolytic disease (ABO or Rh incompatibility) is the most common serious cause, along with G6PD deficiency, sepsis, and cephalohematoma or significant bruising. 3
• Jaundice at or beyond 3 weeks requires measurement of total and direct/conjugated bilirubin to identify cholestasis, plus checking newborn thyroid and galactosemia screens. 2

Older Children

• Factitious causes of "hematuria" such as food substances (beets, blackberries) or medicines coloring the urine without actually having red blood cells should be investigated. 4, 8, 9
• Variables that affect urine color include concentration, pH, ingested substances, and various metabolic abnormalities. 9

Critical Pitfalls to Avoid

• Never discharge a child with bilirubinuria without objective serum bilirubin measurement and clear follow-up plan. 3
• Do not assume pink urine is hematuria without microscopic confirmation of red blood cells. 8, 5, 9
• Do not rely on urine ketone dipstick alone for DKA diagnosis; blood glucose is mandatory. 1, 6
• Do not subtract direct bilirubin from total bilirubin when making clinical decisions. 2
• Do not order abdominal ultrasound for isolated unconjugated hyperbilirubinemia; imaging is indicated only for conjugated hyperbilirubinemia. 2
• In children with pyuria on urinalysis, only 50% may have true UTI, so urine culture is essential for confirmation. 7

Monitoring and Follow-Up

• If DKA is confirmed, expect bilirubin decrease of >2 mg/dL within 4-6 hours if phototherapy is effective (though phototherapy is typically not indicated for conjugated hyperbilirubinemia). 3
• Continue monitoring until bilirubin levels are clearly declining and below treatment thresholds. 3
• For conjugated hyperbilirubinemia without clear etiology, repeat testing within 7-10 days to verify reproducibility and evaluate the trend. 2
• If blood glucose is elevated but <250 mg/dL, initiate sick-day rules including oral hydration, additional short-acting insulin (if diabetic), oral carbohydrates, and frequent monitoring. 1