What are the next steps for a patient who started Zepbound (tirzepatide) and recently experienced abdominal pain and potential liver injury, with occasional use of Excedrin (acetaminophen) for migraines?

Management of Abdominal Pain and Potential Liver Injury in a Patient on Zepbound (Tirzepatide)

Immediately discontinue Zepbound and obtain comprehensive liver function tests (ALT, AST, alkaline phosphatase, total bilirubin) along with a complete hepatotoxicity workup to exclude alternative causes of liver injury. 1, 2

Immediate Actions and Diagnostic Workup

Stop Tirzepatide Now

• Discontinue Zepbound immediately given the temporal relationship between drug initiation and symptom onset, as tirzepatide-associated liver injury most commonly occurs within the first 6 months of treatment and has been documented in recent case series 2
• The FDA label for tirzepatide does not require dose adjustment for hepatic impairment, but this applies to pre-existing stable liver disease, not acute liver injury 1

Comprehensive Liver Injury Evaluation

Obtain the following tests to establish the pattern and severity of liver injury and exclude competing causes 3:

First-line laboratory testing:

• Complete hepatic panel: ALT, AST, alkaline phosphatase, total bilirubin, INR
• Serum creatine kinase (to exclude muscle injury mimicking hepatic injury) 3
• Acetaminophen level (even with reported infrequent use, as levels may be detectable and contributory) 3
• Viral hepatitis serologies: Anti-HAV IgM, HBsAg, anti-HBc (IgG and IgM), HBV DNA, anti-HCV, HCV RNA 3
• Anti-HEV IgM and IgG (hepatitis E, especially if recent travel history) 3
• Autoimmune markers: ANA, anti-smooth muscle antibody, quantitative immunoglobulins 3
• Right upper quadrant ultrasound to exclude biliary obstruction, gallstones, or hepatic vein thrombosis 3

Document the following historical details:

• Complete medication list including all over-the-counter products, herbal supplements, and dietary supplements taken in the past year 3
• Precise timing and quantity of Excedrin use (contains acetaminophen, aspirin, and caffeine) 3
• Alcohol consumption history 3, 4
• Recent illicit drug use 3

Determine Pattern and Severity of Liver Injury

Define the Hepatotoxicity Pattern

Calculate the R value to classify injury type 3:

• R value = (ALT/ULN) ÷ (ALP/ULN)
• R ≥5: Hepatocellular injury (most common with tirzepatide) 2
• R 2-5: Mixed injury
• R <2: Cholestatic injury

Assess Severity Using Hy's Law Criteria

Drug-induced liver injury is severe if 3:

• ALT or AST >3× ULN with symptoms of hepatitis, OR
• ALT or AST >5× ULN without symptoms, OR
• Total bilirubin >2× ULN (particularly concerning when combined with elevated transaminases)

Acetaminophen Considerations

Evaluate for Acetaminophen Contribution

Even with reported infrequent use (4 times per month), acetaminophen remains relevant 3, 5:

• Excedrin contains 250 mg acetaminophen per tablet; determine total monthly exposure
• Acetaminophen can cause hepatotoxicity at doses as low as 3-4 grams per day in susceptible individuals, particularly with concomitant medications or risk factors 3
• The combination of tirzepatide (which may affect drug metabolism) and acetaminophen requires careful evaluation 5

If Acetaminophen Level is Detectable or Recent Use Confirmed

• Administer N-acetylcysteine (NAC) if there is any evidence of hepatotoxicity with detectable acetaminophen, even if ingestion was not recent 3
• NAC dosing: 150 mg/kg IV loading dose over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 3
• NAC may benefit patients with acute liver failure from any cause, not just acetaminophen, showing mortality reduction even in non-acetaminophen liver failure 3

Tirzepatide-Specific Liver Injury Management

Recognize Tirzepatide Hepatotoxicity Patterns

Recent case reports document that tirzepatide can cause 2:

• Acute liver injury (not mentioned in original FDA labeling)
• Most cases occur at lower doses (2.5-5 mg) within 1-6 months of initiation
• Hepatocellular pattern is most common
• 74% of cases assessed as "probable" drug causality

Monitor for Associated Complications

Patients on tirzepatide with liver injury require surveillance for 2:

• Ketoacidosis (reported adverse event not in original labeling)
• Severe gastrointestinal symptoms (nausea, vomiting, abdominal pain)
• Dehydration and renal function deterioration 1

Ongoing Management Strategy

If Liver Injury is Confirmed (ALT/AST >3× ULN with symptoms or >5× ULN)

Do not restart tirzepatide 3, 2, 6:

• 15 of 43 reported cases discontinued tirzepatide permanently 2
• No established role for corticosteroids in tirzepatide-induced liver injury unless autoimmune features are present 6
• Supportive care is the mainstay of treatment 6

Monitor Recovery

• Repeat liver function tests weekly until ALT/AST <2× ULN and symptoms resolve 4
• If ALT/AST remain elevated >2 weeks, consider hepatology consultation for possible liver biopsy 3

Acetaminophen Avoidance

Permanently discontinue all acetaminophen-containing products including Excedrin 3, 4:

• The FDA recommends limiting acetaminophen to 325 mg per dosage unit in combination products due to hepatotoxicity risk 3
• For migraine management, consider alternative therapies that do not contain acetaminophen
• NSAIDs may be used cautiously if no contraindications exist, with proton pump inhibitor gastroprotection 3

Critical Pitfalls to Avoid

• Do not continue tirzepatide pending workup results—the temporal relationship and emerging safety data warrant immediate discontinuation 2
• Do not dismiss low-frequency acetaminophen use as irrelevant—even therapeutic doses can contribute to hepatotoxicity, especially with concomitant medications 3, 5
• Do not assume normal baseline liver tests exclude drug-induced injury—tirzepatide hepatotoxicity develops after drug initiation 2
• Do not overlook herbal/dietary supplements in the medication history, as these are common causes of liver injury 3