After initiating Rezdiffra (generic name) in a patient with normal baseline liver enzymes, at what ALT or AST elevation levels (and bilirubin thresholds) at the 3‑month follow‑up should the medication be discontinued?

Rezdiffra Liver Enzyme Monitoring: Discontinuation Thresholds at 3 Months

Critical Discontinuation Thresholds

For patients starting Rezdiffra with normal baseline liver enzymes, discontinue the medication at 3 months if ALT or AST rises to ≥8× the upper limit of normal (ULN), or if ALT/AST reaches ≥3× ULN combined with total bilirubin ≥2× ULN. 1

Specific Numeric Thresholds

Using standard laboratory reference ranges:

• For males: Discontinue if ALT ≥320 IU/L (8× ULN of ~40 IU/L) 1
• For females: Discontinue if ALT ≥200 IU/L (8× ULN of ~25 IU/L) 1, 2
• Hy's Law pattern: Discontinue immediately if ALT/AST ≥3× ULN (≥120 IU/L for males, ≥75 IU/L for females) AND total bilirubin ≥2× ULN (typically ≥2.4 mg/dL) 1

Stepwise Monitoring Algorithm at 3 Months

Scenario 1: ALT/AST ≥5× ULN but <8× ULN (200-320 IU/L for males, 125-200 IU/L for females)

• Repeat ALT, AST, alkaline phosphatase, and total bilirubin within 2-5 days 1
• Initiate evaluation for competing etiologies (viral hepatitis, autoimmune hepatitis, biliary obstruction, ischemic hepatitis) 1
• Follow up for hepatic symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain, jaundice) 1
• Continue Rezdiffra only if another etiology is identified and enzymes are declining 1

Scenario 2: ALT/AST ≥8× ULN (≥320 IU/L for males, ≥200 IU/L for females)

• Interrupt Rezdiffra immediately 1
• Initiate close monitoring and comprehensive workup for competing etiologies 1
• Rezdiffra can be restarted only if another aetiology is definitively identified and liver enzymes return to baseline 1

Scenario 3: ALT/AST ≥3× ULN with Total Bilirubin ≥2× ULN (Hy's Law)

• Interrupt Rezdiffra immediately—this pattern predicts high risk of acute liver failure 1
• Initiate close monitoring and urgent workup for competing etiologies 1
• Rezdiffra can be restarted only if another aetiology is identified and liver abnormalities return to baseline 1

Scenario 4: ALT/AST ≥5× ULN with Hepatic Symptoms

Even if bilirubin is normal, interrupt Rezdiffra if ALT/AST ≥5× ULN and the patient develops severe fatigue, nausea, vomiting, right upper quadrant pain, or jaundice 1

Additional Monitoring Considerations

Establishing True Baseline

• Baseline ALT should be derived from an average of two pre-treatment measurements at least 2 weeks apart 1
• If the two baseline values differ by >50%, obtain a third measurement to establish a reliable baseline 2

Frequency of Monitoring

• Check liver enzymes at 2 weeks, 4 weeks, 8 weeks, and 12 weeks during the first 3 months 1, 2
• If ALT rises to ≥3× ULN at any point, repeat testing within 2-5 days 1, 2

Laboratory Panel at Each Visit

Include:

• ALT, AST, alkaline phosphatase, GGT 2
• Total and direct bilirubin 1, 2
• Albumin and INR (to assess synthetic function) 2

Common Pitfalls to Avoid

Don't Wait for Symptoms

Asymptomatic ALT elevation ≥8× ULN requires immediate drug interruption even without symptoms 1. Drug-induced liver injury can progress rapidly, and waiting for symptoms increases the risk of irreversible hepatic injury.

Don't Ignore the Bilirubin

The combination of ALT ≥3× ULN plus bilirubin ≥2× ULN (Hy's Law) carries a 10-50% risk of acute liver failure and mandates immediate discontinuation 1. This threshold is more critical than isolated transaminase elevation.

Don't Assume NASH Progression

ALT elevation ≥5× ULN is rare in NASH alone and should not be attributed to disease progression without excluding drug-induced liver injury 2. In clinical trials of NASH therapies, such elevations typically represent drug hepatotoxicity rather than underlying disease.

Don't Forget to Check Creatine Kinase

AST can be elevated from muscle injury; check CK to differentiate hepatic from muscular origin 2. This is particularly important if the patient has recently increased physical activity or experienced muscle trauma.

Divergent Evidence Considerations

The 2019 NASH clinical trial guidelines 1 provide the most specific thresholds for drug-induced liver injury in patients with normal baseline enzymes, recommending interruption at ALT ≥8× ULN. However, the 2020 cholestatic liver disease guidelines 1 use a lower threshold (ALT ≥5× baseline) for patients with elevated baseline enzymes. Since Rezdiffra is initiated in patients with normal baseline enzymes, apply the 8× ULN threshold from the 2019 NASH guidelines 1.

The acitretin monitoring guidelines 1 suggest discontinuation at ALT >3× ULN, but this is for a different drug class and patient population. For NASH therapies like Rezdiffra, the higher 8× ULN threshold is more appropriate unless bilirubin is also elevated 1.

When to Resume Rezdiffra After Interruption

• Liver enzymes must return to baseline values 1
• Another definitive etiology for the elevation must be identified (e.g., acute viral hepatitis, biliary obstruction, ischemic hepatitis) 1
• Close monitoring is required after restarting to exclude recurrence 1
• If hepatic decompensation occurred (ascites, encephalopathy, coagulopathy), Rezdiffra cannot be restarted 1