What are the causes and implications of having bilirubin and ketones in urine?

Causes of Bilirubin and Ketones in Urine

The simultaneous presence of bilirubin and ketones in urine most commonly indicates either alcoholic ketoacidosis with liver injury or diabetic ketoacidosis with concurrent hepatobiliary pathology, requiring immediate assessment of blood glucose, liver function tests, and clinical context to differentiate between these conditions.

Causes of Urine Ketones

Physiological (Benign) Causes

• Starvation ketosis from reduced caloric intake is the most common benign explanation, occurring when patients feel unwell and eat less, causing the body to shift to fat metabolism for energy 1
• Up to 30% of first morning urine specimens can show positive ketones even in healthy individuals, and this increases during fasting states 2, 1
• Prolonged fasting or low-carbohydrate diets trigger physiological ketone production as a normal metabolic adaptation 3

Pathological Causes

• In diabetic patients, ketones indicate insufficient insulin and may signal impending or established diabetic ketoacidosis (DKA), which is a medical emergency 2, 1
• Infection is the most common precipitating factor for DKA in diabetic patients, occurring in approximately 50% of cases 3
• Alcoholic ketoacidosis occurs commonly in chronic alcoholics, with a prevalence of 34% in Japanese alcoholic men, and is frequently accompanied by alcoholic liver injury 4
• SGLT2 inhibitor use in diabetic patients can precipitate euglycemic DKA, requiring immediate evaluation 1

Causes of Urine Bilirubin

Hepatocellular Disease

• Alcoholic liver injury frequently presents with both elevated bilirubin and ketones, particularly when serum total bilirubin is ≥2.0 mg/dL and AST is ≥200 IU/L 4
• Acute or chronic hepatitis from any cause (viral, autoimmune, drug-induced) can result in conjugated hyperbilirubinemia and bilirubinuria 5

Cholestatic/Obstructive Causes

• Biliary obstruction from gallstones, strictures, or malignancy causes conjugated bilirubin to spill into urine 5
• Intrahepatic cholestasis from medications or primary biliary disorders results in bilirubinuria 5

Important Caveat About Bilirubin Testing

• Urine dipstick bilirubin has a high false-positive rate, with only 60% of positive results corresponding to abnormal liver function tests within 2 weeks 6
• However, among unexpected positive urine bilirubin results (those without recent abnormal LFTs), 85% subsequently had abnormal liver function tests, suggesting clinical significance despite the low overall yield of 0.13% 6

Clinical Significance of Combined Findings

Alcoholic Ketoacidosis with Liver Injury

• This is a particularly common scenario where higher urine ketone levels are associated with higher serum total bilirubin, AST, ALT, and GGT levels 4
• Risk factors include slow-metabolizing ADH1B genotype, consumption of distilled spirits (whiskey, shochu), hypoglycemia <80 mg/dL, lower BMI, and smoking 4

Diabetic Ketoacidosis with Hepatic Involvement

• Severe DKA can cause secondary hepatic dysfunction from hypoperfusion or metabolic derangement 3
• The combination requires immediate measurement of blood glucose, and if >250 mg/dL, obtaining blood beta-hydroxybutyrate, electrolytes, and arterial blood gas 1, 3

Hyperbilirubinemia-Associated Tubular Injury

• Higher urinary bilirubin levels are associated with greater numbers of granular casts and renal tubular epithelial cells, suggesting an association between hyperbilirubinemia/hyperbilirubinuria and tubular injury 5

Critical Testing Considerations

Ketone Testing Limitations

• Urine dipsticks only detect acetoacetate, NOT beta-hydroxybutyrate, which can significantly underestimate total ketone body concentration 1, 3, 7
• In acute DKA, the ketone body ratio (beta-hydroxybutyrate:acetoacetate) rises from normal (1:1) to as high as 10:1, meaning urine tests miss the predominant ketone 7
• Blood ketone testing is strongly preferred over urine testing for any clinical decision-making as it directly measures beta-hydroxybutyrate and provides quantitative results 2, 1, 3
• False-positive ketones can occur with sulfhydryl drugs like captopril 2, 1
• False-negative ketone results occur with prolonged air exposure of test strips or highly acidic urine 2, 1

Bilirubin Testing Limitations

• Urine bilirubin dipstick results should prompt liver function testing rather than being used as a standalone diagnostic tool 6

Immediate Management Algorithm

Step 1: Determine Diabetic Status

• If diabetic (especially Type 1) or on SGLT2 inhibitors: Measure blood glucose immediately; if >250 mg/dL or symptomatic, obtain blood beta-hydroxybutyrate, electrolytes, and arterial blood gas to evaluate for DKA 1, 3
• Check for DKA precipitants: infection, medication non-compliance, acute illness 3

Step 2: Assess for Alcohol Use

• If history of alcohol use: Consider alcoholic ketoacidosis with liver injury, particularly if patient has been drinking distilled spirits and has reduced food intake 4
• Obtain liver function tests (AST, ALT, GGT, total bilirubin) immediately 4

Step 3: Evaluate Hepatobiliary System

• Obtain liver function tests in all patients with positive urine bilirubin, as 85% of unexpected positives will have abnormal results 6
• Assess for signs of hepatocellular injury versus cholestasis based on pattern of enzyme elevation 5

Step 4: Distinguish Starvation from Pathological Ketosis

• Starvation ketosis characteristics: serum bicarbonate usually not lower than 18 mEq/L, blood glucose normal to mildly elevated, ketone bodies 0.3-4 mmol/L with normal pH 3
• Pathological ketosis (DKA) characteristics: very high ketone bodies (>7-8 mmol/L), low systemic pH, hyperglycemia typically present 3

Step 5: Initiate Treatment Based on Diagnosis

• For diabetic patients with ketosis: Increase oral fluid intake, monitor blood glucose and ketone levels every 3-4 hours, consider additional short or rapid-acting insulin if ketone levels increase 2
• For non-diabetic patients with physiological ketosis: Encourage oral hydration and carbohydrate intake 3
• For alcoholic ketoacidosis: Provide IV fluids with dextrose, thiamine supplementation, and address underlying alcohol use disorder 4