What is the best course of action for a patient with worsening liver function tests while on Zetia (ezetimibe) for hyperlipidemia?

Management of Worsening Liver Function on Ezetimibe

Discontinue Zetia (ezetimibe) immediately given the significant elevation in ALT (from 46 to 125 IU/L, a 2.7-fold increase) and investigate for alternative causes of liver dysfunction, particularly hemochromatosis given the markedly elevated ferritin of 816 ng/mL. 1, 2

Rationale for Discontinuation

The FDA drug label for ezetimibe explicitly states that hepatitis has been reported in post-marketing surveillance, and elevations in liver transaminases (including elevations >5X ULN) warrant discontinuation. 1 While this patient's ALT is not yet 3X the upper limit of normal (assuming ULN ~40 IU/L), the trajectory shows worsening rather than improvement, and the FDA label emphasizes that "prompt withdrawal is mandatory in case of significant abnormality in liver testing." 1, 2

• Ezetimibe-induced hepatocellular injury is well-documented, with case reports showing serious toxic hepatitis requiring drug withdrawal for recovery 2
• The patient's ALT increased from 46 to 125 IU/L (172% increase) while on ezetimibe, suggesting drug-induced liver injury rather than improvement 2
• The FDA label notes that when ezetimibe is combined with fenofibrate, hepatic transaminase elevations ≥3X ULN occurred in 2.7% of patients 1

Investigation of Alternative Causes

The elevated ferritin (816 ng/mL) and low UIBC (133 µg/dL) strongly suggest iron overload/hemochromatosis as a contributing or primary cause of liver dysfunction. 3

Immediate workup needed:

• Transferrin saturation calculation (serum iron ÷ TIBC × 100) - if >45%, proceed with HFE gene testing for hereditary hemochromatosis 3
• Hepatitis B surface antigen and anti-hepatitis C virus antibody to exclude viral hepatitis 3
• Repeat liver function tests weekly after ezetimibe discontinuation to document improvement 3
• Consider abdominal ultrasound to assess for fatty liver disease, though this can be deferred if LFTs improve after drug withdrawal 3

Management Algorithm

Step 1: Immediate Actions (Week 0)

• Stop ezetimibe immediately 1, 2
• Order iron studies (serum iron, TIBC, transferrin saturation) and HFE genetic testing 3
• Check hepatitis B and C serologies 3
• Advise complete alcohol abstinence 3

Step 2: Short-term Monitoring (Weeks 1-4)

• Repeat ALT, AST weekly until values return to baseline or near-normal 3
• If ALT remains >200 IU/L or bilirubin >50 µmol/L after 2 weeks, refer to gastroenterology/hepatology 3
• If transferrin saturation >45% and HFE mutation confirmed, initiate phlebotomy therapy for hemochromatosis 3

Step 3: Alternative Lipid Management (After LFT Normalization)

Once liver enzymes normalize (typically 4-12 weeks after ezetimibe discontinuation), consider alternative lipid-lowering strategies: 2, 4

For severe hypertriglyceridemia (TG 394 mg/dL):

• Initiate fenofibrate 54-145 mg daily (check eGFR first; contraindicated if <30 mL/min/1.73m²) 5
• Fenofibrate addresses the triglycerides (541→394 mg/dL) which remain significantly elevated 5
• Monitor liver enzymes every 2-4 weeks for first 2 months, then every 3 months 3, 5

For persistent LDL elevation (LDL 154 mg/dL):

• Consider low-dose statin therapy (e.g., atorvastatin 10 mg or rosuvastatin 5 mg) once LFTs stable for 4 weeks 3
• Statins are predominantly metabolized by the liver and can be used cautiously with close monitoring 3
• Do NOT restart ezetimibe - the patient has demonstrated hepatotoxicity 2

Critical Monitoring Parameters

If statin or fibrate therapy is initiated after LFT normalization: 3, 5

• Check liver enzymes every 2-4 weeks for first 2 months 3
• Then every 3 months during maintenance therapy 3
• Discontinue if transaminases exceed 3X ULN 3
• Refer to gastroenterology if ALT >200 IU/L or bilirubin >50 µmol/L 3

Common Pitfalls to Avoid

• Do not attribute worsening LFTs to "disease progression" without stopping the offending drug - ezetimibe can cause serious hepatocellular injury requiring prompt withdrawal 2
• Do not ignore the iron studies - ferritin 816 ng/mL suggests hemochromatosis, which independently causes progressive liver disease and must be treated with phlebotomy 3
• Do not restart ezetimibe - this patient has demonstrated hepatotoxicity, and rechallenge risks more severe injury 2
• Do not combine ezetimibe with fenofibrate in future - this combination increases risk of hepatotoxicity (4.5% vs 2.7% transaminase elevations) 1

Special Consideration: Hemochromatosis Management

If hemochromatosis is confirmed (transferrin saturation >45% + HFE mutation), therapeutic phlebotomy is the primary treatment and will improve both iron overload and liver function independent of lipid therapy. 3 This may also improve the lipid profile as liver function normalizes, potentially reducing the need for aggressive lipid-lowering therapy.