What is the next course of action for a patient on Eliquis (apixaban) with suspected drug-induced liver injury, presenting with dark urine, altered mental status, and abnormal liver function tests (LFTs) including elevated Alanine Transaminase (ALT), Aspartate Transaminase (AST), and Gamma-Glutamyl Transferase (GGT)?

Immediate Management of Suspected Apixaban-Induced Liver Injury

Discontinue Eliquis (apixaban) immediately and do not restart it—this patient has severe drug-induced liver injury (DILI) with ALT >500 U/L, elevated bilirubin, and symptoms including altered mental status, which meets criteria for urgent drug interruption and carries significant risk of hepatic decompensation and mortality. 1, 2

Critical First Steps

Stop the offending drug now. This patient presents with:

• ALT 550 U/L (>500 U/L threshold)
• AST 718 U/L
• Elevated GGT 512 U/L
• Bilirubinuria (indicating conjugated hyperbilirubinemia)
• Altered mental status ("foggy head")
• Dark urine

This constellation meets criteria for severe hepatocellular DILI requiring immediate drug discontinuation, as delayed discontinuation can result in irreversible liver failure and death. 2, 3 While apixaban-induced liver injury is rare, it has been documented to cause hepatocellular injury that resolves with drug cessation. 4

Immediate Laboratory Assessment (Within 24-48 Hours)

Obtain the following labs urgently:

• Total and direct bilirubin levels to quantify the degree of cholestasis and assess for Hy's Law criteria (ALT >3× ULN + total bilirubin >2× ULN predicts 10% mortality risk) 2, 5
• INR, albumin, and complete metabolic panel to assess synthetic liver function and screen for hepatic decompensation 2, 6
• Hepatitis panel (HBsAg, anti-HBc IgM, anti-HCV) to exclude viral hepatitis 6
• Autoimmune markers (ANA, anti-smooth muscle antibody) if autoimmune hepatitis is suspected 6
• Abdominal ultrasound with Doppler to exclude biliary obstruction, assess liver architecture, and evaluate hepatic vasculature 2, 6

Monitoring Protocol

Repeat liver function tests within 2-5 days given the severity of hepatocellular injury (ALT >500 U/L with symptoms). 1, 2 The specific interval should be determined by clinical condition—if the patient develops worsening mental status, jaundice, or other signs of decompensation, repeat labs immediately. 1

Continue monitoring for at least five half-lives of apixaban (approximately 60 hours for complete drug clearance), though liver test abnormalities may persist for weeks to months. 2

Assess for Hepatic Decompensation

Monitor closely for signs of acute liver failure:

• Worsening encephalopathy (the "foggy head" is concerning)
• Coagulopathy (elevated INR not attributable to anticoagulation)
• Ascites
• Progressive jaundice
• Hypoglycemia

Any evidence of hepatic decompensation mandates immediate hepatology consultation and consideration for liver transplant evaluation, as transplant-free survival in severe idiosyncratic DILI is poor. 2, 5

Anticoagulation Management

Do not restart apixaban under any circumstances. 1, 2 The medication cannot be restarted if hepatic decompensation has occurred, and this patient already shows concerning signs (altered mental status, bilirubinuria). 1

For ongoing anticoagulation needs:

• Consider bridging with unfractionated heparin (as documented in a similar apixaban hepatotoxicity case) followed by warfarin if anticoagulation remains necessary 4
• Alternative factor Xa inhibitors may carry cross-reactivity risk, though one case report showed successful use of apixaban after rivaroxaban-induced liver injury 7
• The decision to use any alternative anticoagulant should involve hepatology consultation given the severity of injury

Specialist Referral

Urgent hepatology referral is mandatory because:

• ALT >5× ULN (assuming ULN ~40 U/L, this patient has ALT ~14× ULN) 2, 6
• Presence of bilirubinuria suggesting elevated bilirubin 2
• Altered mental status suggesting possible early hepatic encephalopathy 2

Common Pitfalls to Avoid

• Do not wait to see if liver tests improve before stopping the drug—immediate discontinuation is critical for preventing progression to acute liver failure 2, 3
• Do not assume Gilbert's syndrome explains the bilirubinuria—with this degree of transaminase elevation and symptoms, this represents true hepatocellular injury with cholestasis 1
• Do not restart apixaban even at lower doses—hepatic decompensation is an absolute contraindication to rechallenge 1, 2
• Do not delay hepatology referral—this patient meets multiple criteria for urgent specialist evaluation 2, 6

Prognosis and Follow-up

Most patients with antibiotic-associated DILI have favorable outcomes, but patients with jaundice have approximately 10% risk of death from liver failure or need for liver transplantation. 8, 5 Blood tests typically return to baseline within 6 months after drug interruption in hepatocellular DILI. 1

The patient requires close follow-up until liver tests normalize completely, with repeat testing every 2-5 days initially, then weekly until downward trend is established. 1, 2