What to do for a patient with elevated bilirubin on Xtandi (Enzalutamide), Lupron (Leuprolide), and Zoladex (Goserelin) for prostate cancer?

Management of Elevated Bilirubin in Patients on Enzalutamide, Leuprolide, and Goserelin

Immediately fractionate the total bilirubin to determine if the elevation is conjugated (direct) or unconjugated (indirect), as this single test determines the entire diagnostic and management pathway. 1

Initial Diagnostic Workup

The first critical step is determining the type of hyperbilirubinemia, as conjugated and unconjugated elevations have completely different etiologies and management approaches in patients on androgen deprivation therapy 1:

Obtain These Labs Immediately:

• Fractionated bilirubin (direct and indirect) 1
• Complete hepatic panel: ALT, AST, alkaline phosphatase, GGT 1
• Synthetic function tests: albumin, prothrombin time/INR 1, 2
• Complete blood count with peripheral smear and reticulocyte count to evaluate for hemolysis 1

Management Based on Bilirubin Type

If Unconjugated Hyperbilirubinemia (Conjugated <20-30% of Total)

This is most likely Gilbert syndrome or medication-induced unconjugated hyperbilirubinemia, both of which are benign and require no treatment beyond reassurance. 1

• Gilbert syndrome is the most common cause of isolated mild unconjugated hyperbilirubinemia in asymptomatic adults, with total bilirubin rarely exceeding 4-5 mg/dL 1
• Leuprolide and goserelin can cause metabolic derangements including fatty liver disease, but typically do not cause isolated unconjugated hyperbilirubinemia 3
• No treatment is required for Gilbert syndrome—fully reassure the patient and continue cancer therapy 1
• Antiviral medications commonly cause unconjugated hyperbilirubinemia through impaired bilirubin conjugation, but this mechanism is less common with hormonal therapies 4

If Conjugated Hyperbilirubinemia (Direct >35% of Total)

This requires urgent evaluation for hepatocellular injury or cholestatic disease, and you must obtain abdominal ultrasound within 24-48 hours. 1

Immediate Actions:

1. Verify alkaline phosphatase is of hepatic origin by checking GGT or alkaline phosphatase isoenzymes 1
2. Order abdominal ultrasound immediately (98% positive predictive value for liver parenchymal disease, 65-95% sensitivity for biliary obstruction) 1
3. Check vitamin K status before attributing prolonged INR to liver dysfunction, as fat-soluble vitamin deficiencies are common in cholestatic disease and correctable 1

Drug Management Algorithm for Conjugated Hyperbilirubinemia:

Grade 1 (Total bilirubin >ULN to 1.5× ULN):

• Continue all medications with close monitoring 5
• Repeat liver tests within 1-2 weeks 1
• Monitor 1-2 times weekly if trending upward 5

Grade 2 (Total bilirubin 1.5-3× ULN):

• Hold enzalutamide temporarily 5
• Continue leuprolide/goserelin (these rarely cause hepatotoxicity) 6, 7
• Stop any other potentially hepatotoxic medications 5
• Monitor every 3 days 5
• Consider initiating corticosteroids (0.5-1 mg/kg/day prednisone) if no improvement after 3-5 days 5
• May resume enzalutamide when bilirubin returns to ≤Grade 1 5

Grade 3 (Total bilirubin 3-10× ULN) or Grade 2 with ALT >3× ULN:

• Permanently discontinue enzalutamide 5
• Continue leuprolide/goserelin as these are critical for cancer control and rarely hepatotoxic 6, 7, 8
• Start methylprednisolone 1-2 mg/kg/day immediately 5
• Monitor labs daily or every other day 5
• Consider inpatient monitoring if AST/ALT >8× ULN or total bilirubin >3× ULN 5
• If no improvement in 2-3 days, add mycophenolate mofetil 500-1000 mg twice daily and obtain hepatology consultation 5
• Consider liver biopsy if steroid-refractory 5

Grade 4 (Total bilirubin >10× ULN):

• Permanently discontinue enzalutamide 5
• Transfer to ICU for close monitoring 2
• Start IV methylprednisolone 2 mg/kg/day 5
• Urgent hepatology consultation and consider liver transplant center referral 2

Critical Nuances and Common Pitfalls

Enzalutamide-Specific Considerations:

• Enzalutamide can cause hepatotoxicity, though this is uncommon 8
• Never use infliximab for suspected drug-induced hepatitis, as it is contraindicated and can worsen liver injury 5
• The combination of enzalutamide plus leuprolide showed superior metastasis-free survival compared to leuprolide alone (87.3% vs 71.4% at 5 years), so maintaining androgen deprivation is critical even if enzalutamide must be stopped 8

Leuprolide/Goserelin Considerations:

• These GnRH analogues rarely cause direct hepatotoxicity 6, 7
• Leuprolide can induce nonalcoholic fatty liver disease through androgen-deprivation and metabolic syndrome, but this typically presents with elevated transaminases rather than isolated hyperbilirubinemia 3
• Continue leuprolide or goserelin even if enzalutamide must be stopped, as androgen deprivation remains essential for prostate cancer control 8

Imaging Escalation:

• If ultrasound shows biliary dilation or clinical suspicion remains high despite negative ultrasound, proceed to MRI with MRCP (90.7% accuracy for biliary obstruction etiology) 1
• Do not rely on ultrasound alone for distal common bile duct obstruction, as overlying bowel gas frequently causes false-negative results 1

Monitoring Strategy:

• For mild isolated elevations with normal physical examination and intact hepatic function, close clinical follow-up with serial liver chemistry testing is appropriate 1
• More frequent monitoring (2-3 times weekly) is required for higher grade elevations or if bilirubin continues to rise 1
• If alkaline phosphatase >2× baseline with total bilirubin >2× baseline, consider drug interruption 1
• If alkaline phosphatase >3× baseline without clear alternative explanation, discontinue the suspected offending agent 1