What are the most common drugs that cause an elevation in Liver Function Tests (LFTs)?

Most Common Drugs That Cause Liver Function Test Elevations

The most common drugs that cause elevations in liver function tests include carbamazepine, methyldopa, minocycline, macrolide antibiotics, nitrofurantoin, statins, sulfonamides, terbinafine, chlorpromazine, and methotrexate. 1

Patterns of Drug-Induced Liver Injury

Drug-induced liver injury (DILI) can present in different patterns:

• Hepatocellular pattern: Predominantly elevated ALT/AST
• Cholestatic pattern: Predominantly elevated alkaline phosphatase and GGT
• Mixed pattern: Features of both hepatocellular and cholestatic injury 1

Most Common Hepatotoxic Medications

Antimicrobials

• Macrolide antibiotics (erythromycin, clarithromycin) - cause both direct hepatotoxicity and can increase levels of other hepatotoxic drugs by inhibiting CYP3A4 1, 2
• Sulfonamides - can cause idiosyncratic liver injury 1
• Nitrofurantoin - associated with both acute and chronic liver injury 1
• Minocycline - can cause autoimmune-like hepatitis 1
• Isoniazid - one of the most common causes of DILI 3
• Amoxicillin/clavulanate - leading cause of drug-induced liver injury in many registries 3

Anticonvulsants

• Carbamazepine - requires baseline and periodic evaluations of liver function, particularly in patients with history of liver disease 2
• Valproic acid - can cause both direct hepatotoxicity and idiosyncratic reactions 4

Psychiatric Medications

• Chlorpromazine - associated with cholestatic liver injury 1
• Duloxetine - can cause hepatocellular pattern injury with elevation of transaminases to more than twenty times the upper limit of normal 5

Cardiovascular Medications

• Statins - cause dose-dependent elevations in liver enzymes in 1-3% of patients, but serious liver injury is rare 6, 7
• Methyldopa - can cause both acute and chronic liver injury 1

Other Common Hepatotoxic Drugs

• Methotrexate - requires special monitoring to prevent dose-dependent liver fibrosis 1
• Terbinafine - associated with cholestatic liver injury 1
• NSAIDs - among the most common causes of DILI 3

Risk Factors for Drug-Induced Liver Injury

• Medication dose - higher doses increase risk 3
• Drug lipophilicity - more lipophilic drugs have higher risk 3
• Extent of hepatic metabolism - drugs with extensive hepatic metabolism pose greater risk 3
• Polypharmacy - multiple potentially hepatotoxic medications compound risk 4
• Pre-existing liver dysfunction - reduces drug metabolism capacity and increases vulnerability 4, 8

Monitoring Recommendations

• Baseline liver function tests should be obtained before starting potentially hepatotoxic medications 1
• Regular monitoring of liver tests (ALT, AST, ALP, and total bilirubin) is recommended for high-risk medications 1
• Monitoring frequency should be based on the specific drug's risk profile - typically before each treatment cycle or at least monthly for high-risk drugs 1
• Increased monitoring is warranted when liver test abnormalities are detected 1

Management of Drug-Induced LFT Elevations

Assessment

• Determine the pattern of liver enzyme elevation (hepatocellular, cholestatic, or mixed) 4
• Consider the timing of medication use relative to the liver test abnormality 1
• Rule out other causes of liver dysfunction 1

Action Based on Severity

• Mild elevations (ALT/AST <3× ULN): Increased monitoring while continuing therapy 1, 4
• Moderate elevations (ALT/AST 3-5× ULN): Consider dose reduction or temporary discontinuation of the most hepatotoxic agent 4
• Severe elevations (ALT/AST >5× ULN) or any elevation with symptoms: Discontinue all potentially hepatotoxic medications if clinically feasible 4

Follow-up

• Monitor liver function tests every 1-3 days until improvement is noted, then weekly until normalization 4
• Evaluate for signs of hepatic decompensation (encephalopathy, coagulopathy, ascites) 4
• Consider abdominal ultrasound to exclude other causes of liver dysfunction 1, 4

Important Caveats

• Most drug-induced liver injuries are idiosyncratic and unpredictable 3
• Hepatic dysfunction from medications is generally transient and does not require special treatment if the offending drug is discontinued 1
• Rechallenge with suspected hepatotoxic agents should be avoided unless absolutely necessary 4
• Statins, despite causing LFT elevations, rarely lead to serious liver injury and may actually have beneficial effects in patients with non-alcoholic fatty liver disease 7
• Drug-induced liver injury can progress despite discontinuation of the offending drugs, requiring continued vigilance 4