What is the most likely cause of elevated serum glutamic‑pyruvic transaminase (ALT) in a patient with lung carcinoma receiving gefitinib?

Elevated SGPT (ALT) in Lung Cancer Patients on Gefitinib

Gefitinib-induced hepatotoxicity is the most likely cause of elevated SGPT (ALT) in this patient, as hepatotoxicity occurs in 11.4% of gefitinib-treated patients and is a well-recognized adverse effect requiring routine monitoring. 1

Direct Drug-Induced Hepatotoxicity

Gefitinib causes hepatotoxicity through direct drug effects on hepatocytes:

• Grade 3 or higher ALT elevations occur in 5.1% of gefitinib-treated patients, with AST elevations in 3.0% 1
• In comparative trials, gefitinib caused grade 3-4 ALT/AST elevations in 6.1%/13.0% of patients, significantly higher than erlotinib (2.2%/3.3%) 2
• The median time to develop liver dysfunction is 4 months (range 1-23 months) after starting gefitinib 3
• Hepatotoxicity incidence increases with prolonged therapy: 52.0% in patients treated >14 months versus 27.5% in those treated <14 months 3

FDA-Mandated Monitoring Requirements

The FDA label explicitly addresses this issue:

• Withhold gefitinib for NCI CTCAE Grade 2 or higher ALT and/or AST elevations (up to 14 days) 1
• Permanently discontinue gefitinib in patients with severe hepatic impairment 1
• Obtain periodic liver function testing throughout treatment 1
• Fatal hepatotoxicity, though rare (0.04% incidence), has been reported 1

Contributing Risk Factors to Evaluate

Several factors may increase hepatotoxicity risk in this patient:

• Concomitant medications: H2 antagonists and proton pump inhibitors increase hepatotoxicity risk by 1.5- to 1.7-fold 4
• Age <65 years: Shows 1.6 times higher hepatotoxicity compared to older patients 4
• EGFR mutation status: Patients with EGFR mutations have approximately 2-fold higher hepatotoxicity, particularly exon 19 deletions (32.7% incidence) 4
• Drug-drug interactions: Gefitinib is metabolized by CYP3A4, CYP2C8, and UGT1A1; concomitant CYP inhibitors may elevate gefitinib levels 2, 5
• Genetic polymorphisms: UGT1A1 and CYP3A5 poor metabolizer phenotypes predispose to severe hepatotoxicity 5

Alternative Differential Diagnoses to Exclude

While gefitinib is the primary culprit, systematically exclude:

• Hepatic metastases: 31% of lung cancer patients with liver metastases have baseline ALT >ULN 2
• Concomitant hepatotoxic medications: Review all medications for potential drug-drug interactions 2
• Viral hepatitis or pre-existing liver disease: Should be assessed before attributing solely to gefitinib 2
• Biliary obstruction from tumor: Check alkaline phosphatase and bilirubin patterns 2

Management Algorithm

Step 1: Assess severity using NCI CTCAE grading 1

Step 2: For Grade 2+ elevations:

• Withhold gefitinib immediately (up to 14 days) 1
• Provide hepatoprotective therapy 6, 3
• Monitor liver enzymes closely 2

Step 3: Upon resolution to Grade 1 or baseline:

• Resume gefitinib at same dose if resolved within 14 days 1
• In most patients (80%), normal liver function is restored without discontinuing gefitinib permanently 3

Step 4: For persistent or severe (Grade 3+) hepatotoxicity:

• Switch to erlotinib, which has lower hepatotoxicity rates (2.2%/3.3% for ALT/AST) 2, 7
• Alternative: Switch to afatinib, which is not metabolized via CYP450 pathways and may avoid hepatotoxicity in patients with metabolic enzyme polymorphisms 5
• Do not rechallenge with gefitinib if Grade 4 hepatotoxicity occurred 6

Critical Monitoring Recommendations

Routine monitoring is mandatory per both FDA labeling and clinical guidelines:

• Baseline liver function tests before initiating gefitinib 2, 1
• Periodic monitoring throughout treatment, especially in first 6 months 1, 3
• More frequent monitoring for patients on concomitant PPIs/H2 antagonists, age <65, or with EGFR mutations 4
• Close monitoring of PT-INR if patient is on warfarin, as gefitinib inhibits warfarin metabolism 2

Common Pitfall to Avoid

Do not assume all transaminase elevations are from tumor progression—gefitinib-induced hepatotoxicity is common (39.6% develop abnormal hepatic function) and often reversible with appropriate management 3. The British Journal of Pharmacology guidelines specifically recommend routine liver transaminase monitoring in all gefitinib-treated patients 2.