What can cause a 49-year-old female to have bilirubin, ketonuria (presence of ketones), and proteinuria (presence of protein in urine) in her urine?

Differential Diagnosis of Urinalysis Findings in a 49-Year-Old Female

The combination of bilirubinuria, ketonuria (15 mg/dL), and trace proteinuria in a 49-year-old woman most likely indicates either hepatobiliary disease with concurrent metabolic stress/fasting, or undiagnosed diabetes mellitus with early liver involvement.

Ketonuria (15 mg/dL)

The presence of ketones at this level suggests one of several metabolic states:

Most Common Causes:

• Starvation/fasting ketosis: Positive urine ketones appear in up to 30% of first morning specimens during fasting states, representing a physiological shift to ketone production as an alternative energy source 1
• Undiagnosed or poorly controlled diabetes mellitus: In diabetic patients, especially type 1 diabetes, elevated ketones indicate insufficient insulin and may signal impending diabetic ketoacidosis (DKA), though 15 mg/dL represents mild ketosis 2
• Diabetic ketoacidosis (early/mild): Increased ketone concentrations in those with hyperglycemia suggest impending or established DKA, though this typically presents with higher ketone levels 3

Important Testing Limitation:

• Standard urine dipsticks using nitroprusside only measure acetoacetate and acetone, NOT beta-hydroxybutyrate, which is the predominant ketone body in DKA and starvation ketosis 3, 1
• This can lead to significant underestimation of total ketone body concentration 4, 1

Clinical Action Required:

• Check blood glucose immediately to differentiate between starvation ketosis (normal glucose) and diabetic ketosis (elevated glucose) 3
• If glucose is elevated (>250 mg/dL) with symptoms (abdominal pain, nausea), implement sick day rules and seek immediate medical evaluation 4
• Blood beta-hydroxybutyrate measurement is preferred over urine testing for accurate assessment 2

Bilirubinuria

The presence of bilirubin in urine always indicates conjugated (direct) hyperbilirubinemia, as unconjugated bilirubin is bound to albumin and cannot be filtered by the kidneys 5.

Hepatobiliary Causes:

• Hepatocellular disease: Viral hepatitis, alcoholic hepatitis, drug-induced liver injury, or cirrhosis impair hepatocyte function, reducing bilirubin conjugation and clearance 5, 6
• Cholestatic disorders: Bile duct obstruction (gallstones, strictures, malignancy) or intrahepatic cholestasis prevents bile from reaching the small bowel 6
• Inherited transport defects: Dubin-Johnson or Rotor syndrome cause predominantly conjugated hyperbilirubinemia, though these typically present earlier in life 6

Diagnostic Approach:

• Elevated bilirubin almost always indicates underlying disease and requires further evaluation 7
• Obtain liver function tests (AST, ALT, alkaline phosphatase, GGT) to differentiate hepatocellular from cholestatic patterns 7
• Imaging of the biliary tree and liver (ultrasound or CT) is essential to identify structural abnormalities 7

Trace Proteinuria

Trace protein on dipstick represents approximately 15-30 mg/dL and can result from multiple mechanisms 8.

Potential Causes:

• Benign/transient: Fever, exercise, dehydration, or orthostatic proteinuria 8
• Early glomerular disease: Diabetic nephropathy, hypertensive nephrosclerosis, or primary glomerular disorders 8
• Tubular dysfunction: Impaired reabsorption of filtered proteins 8
• Overflow proteinuria: Increased production of filterable proteins (rare at trace levels) 8

Critical Caveat:

• False-positive proteinuria is common when other urinalysis abnormalities are present, particularly with high specific gravity, hematuria, ketonuria, or bilirubinuria 9
• In one study, 98% of false-positive proteinuria results occurred when confounding factors were present, with high specific gravity and hematuria being the strongest predictors 9
• Confirmatory testing with albumin-to-creatinine ratio (ACR) is recommended when trace proteinuria occurs alongside other urinalysis abnormalities 9

Integrated Clinical Approach

Immediate Priorities:

1. Check blood glucose to rule out diabetes/DKA 3
2. Obtain liver function tests (AST, ALT, alkaline phosphatase, total/direct bilirubin) 7
3. Confirm proteinuria with ACR given the presence of confounding factors (ketonuria and bilirubinuria) 9

If Blood Glucose is Elevated (>126 mg/dL fasting or >200 mg/dL random):

• Suspect undiagnosed diabetes mellitus with possible early DKA 3
• Ketosis-prone individuals should measure ketones with unexplained hyperglycemia or symptoms of ketosis 4
• Blood beta-hydroxybutyrate >0.6 mmol/L confirms significant ketosis 3

If Blood Glucose is Normal:

• Bilirubinuria indicates hepatobiliary disease requiring imaging 7, 5
• Ketonuria likely represents starvation/fasting ketosis 1
• Assess for alcohol use, medication exposure, viral hepatitis risk factors, and right upper quadrant pain 7

Common Pitfalls to Avoid:

• Do not dismiss trace proteinuria without confirmatory ACR testing when other urinalysis abnormalities are present 9
• Do not rely solely on urine ketones to assess severity of ketosis; blood beta-hydroxybutyrate is more accurate 3, 2
• Do not assume bilirubinuria is benign; it always warrants evaluation for hepatobiliary disease 5