What is the best course of action for a female patient with epigastric abdominal pain, abnormal liver function tests (LFTs), and a history of irritable bowel syndrome (IBS), chronic fatigue syndrome, and fibromyalgia, who has been taking Excedrin (acetaminophen) for migraines and Zepbound (tirzepatide) for weight loss?

Discontinue Zepbound and Excedrin Immediately, Investigate for Drug-Induced Liver Injury

This patient's fluctuating transaminitis (ALT 360→108→normal) with RUQ/epigastric pain that began 4 months ago—coinciding exactly with Zepbound initiation—strongly suggests drug-induced liver injury (DILI) from tirzepatide, compounded by chronic acetaminophen use from Excedrin. The contracted gallbladder on ultrasound is likely secondary to GLP-1 agonist effects rather than primary pathology, given the normal HIDA scan.

Immediate Actions Required

Stop Hepatotoxic Medications

• Discontinue Zepbound (tirzepatide) immediately, as GLP-1 receptor agonists can cause hepatobiliary adverse events and the temporal relationship (symptoms starting in the month Zepbound was initiated) is highly suspicious for DILI 1
• Stop all acetaminophen-containing products including Excedrin, as the FDA warns that severe liver damage may occur with chronic use, particularly when combined with other hepatotoxic agents 2
• The patient uses Excedrin 4-5 times monthly for migraines, and acetaminophen should be avoided in patients with liver disease 2

Repeat Comprehensive Liver Evaluation

• Obtain a complete liver aetiology screen (core panel) including: hepatitis B surface antigen, hepatitis C antibody, autoimmune markers (ANA, anti-smooth muscle antibody, immunoglobulins), ferritin and transferrin saturation, and fasting lipid profile 1
• Repeat ALT, AST, alkaline phosphatase, bilirubin, and INR to establish current hepatic function 1
• The pattern of marked elevations (ALT 360, AST 311, ALP 260) followed by normalization suggests resolving hepatocellular injury, but confirmation is essential 1

Address the Underlying Functional Disorder

Positive Diagnosis of IBS

• This patient meets criteria for IBS with mixed bowel habits (IBS-M), given her history of IBS, chronic abdominal pain without organic findings on CT and ultrasound, and the episodic nature of symptoms 1
• The presence of fibromyalgia and chronic fatigue syndrome are extraintestinal symptoms that frequently coexist with IBS and add diagnostic value 1
• Explain to the patient that IBS is a disorder of gut-brain interaction with a benign but relapsing/remitting course, and that her current pain episodes fit this pattern 3

First-Line Treatment for IBS-M

• Prescribe regular physical exercise as the foundation of treatment for all IBS patients 3, 4
• Start soluble fiber (ispaghula/psyllium) 3-4 g/day, building up gradually to avoid bloating, which is effective for global symptoms and abdominal pain 3, 4
• Avoid insoluble fiber (wheat bran) as it consistently worsens IBS symptoms 3

Pharmacological Management of Abdominal Pain

• Replace bentyl (dicyclomine) with a tricyclic antidepressant (TCA) as first-line neuromodulator therapy 1, 5, 3
• Start amitriptyline 10 mg once daily at bedtime, titrating slowly by 10 mg weekly to a maximum of 30-50 mg daily 1, 5, 3
• TCAs are the most effective treatment for global symptoms and abdominal pain in IBS, with high-quality evidence supporting their use 5, 4, 6
• Explain carefully that this medication is used as a gut-brain neuromodulator, not for depression, to ensure patient acceptance 3
• Continue for at least 6 months if symptomatic response occurs 1

Alternative Antispasmodic if TCA Not Tolerated

• If amitriptyline causes intolerable side effects, consider peppermint oil as an alternative antispasmodic with fewer systemic effects 5, 6
• Antispasmodics with anticholinergic properties like dicyclomine can be effective but commonly cause dry mouth, visual disturbance, and dizziness 1, 3

Address Migraine Management Without Acetaminophen

• Discontinue Excedrin permanently due to acetaminophen content and switch to alternative migraine therapy 2
• Consider triptans, NSAIDs (if no contraindications), or preventive therapy depending on migraine frequency and severity
• The FDA explicitly warns against using acetaminophen with other drugs that may affect the liver 2

Psychological Therapy Consideration

• Refer for IBS-specific cognitive behavioral therapy (CBT) or gut-directed hypnotherapy if symptoms persist after 3 months of pharmacological treatment 1, 5, 3
• Given her history of chronic fatigue syndrome and fibromyalgia (functional somatic disorders that frequently coexist with IBS), earlier referral may be appropriate 1
• The patient reported symptoms started during a stressful period, suggesting stress as a trigger that could benefit from psychological intervention 3

Critical Pitfalls to Avoid

• Do not pursue cholecystectomy despite the ultrasound findings of contracted gallbladder with possible calculi/sludge, as the normal HIDA scan (visualization of gallbladder, no cystic duct obstruction, normal ejection fraction) excludes biliary dyskinesia 1
• The contracted gallbladder is likely a consequence of GLP-1 agonist therapy (delayed gastric emptying and reduced gallbladder contractility) rather than primary gallbladder disease
• Do not continue to repeat liver function tests without investigating the cause, as 84% of abnormal liver enzymes remain abnormal at 1 month and 75% at 2 years 1
• Avoid opioids for chronic abdominal pain management due to risks of dependence, narcotic bowel syndrome, and worsening of IBS symptoms 1, 3
• Do not order extensive additional imaging or endoscopy in the absence of alarm features (she has no unintentional weight loss, blood in stool, fever, anemia, or family history of colon cancer) 3, 7

Follow-Up Plan

• Repeat liver function tests 2-4 weeks after discontinuing Zepbound and Excedrin to confirm normalization 1
• Review treatment efficacy after 3 months and discontinue amitriptyline if no response 1, 3
• If liver enzymes remain elevated after stopping suspected offending agents, proceed with extended liver aetiology screen and consider hepatology referral 1
• Monitor for symptom improvement with IBS-directed therapy; if refractory after 12 months of pharmacological treatment, intensify psychological therapy referral 1, 3