What drugs can cause transaminitis (elevated liver enzymes)?

Drugs Causing Transaminitis

Numerous medications can cause elevated liver enzymes (transaminitis), with antituberculosis drugs—particularly isoniazid and rifampin—representing some of the most clinically significant hepatotoxic agents, alongside statins, certain antibiotics, and antiepileptic drugs.

Antituberculosis Medications

Isoniazid

• Isoniazid causes hepatotoxicity in approximately 1% of patients overall, with age-related risk escalating from essentially 0% in patients under 20 years to 2.3% in those over 50 years 1
• Asymptomatic transaminase elevation occurs in 10-20% of patients, typically appearing within the first 1-3 months of therapy 2
• Daily alcohol consumption increases the risk of isoniazid hepatitis fourfold 1
• Concomitant acetaminophen use may potentiate hepatotoxicity through P-450IIE1 enzyme induction 2
• Transaminase monitoring should be obtained monthly in high-risk patients (age >35, daily alcohol users, chronic liver disease, injection drug users, postpartum minority women) 2
• Discontinue isoniazid if transaminases exceed 3-5 times the upper limit of normal 2
• Fulminant hepatic failure requiring liver transplantation has been reported, though rare 3

Rifampin and Pyrazinamide

• Rifampin was the most commonly implicated drug causing adverse reactions in 12% of HIV-positive TB patients in one retrospective study 1
• The rifampin/pyrazinamide combination shows similar hepatotoxicity rates to isoniazid in clinical trials 1

Second-Line Antituberculosis Drugs

• Ethionamide and para-aminosalicylic acid can cause gastrointestinal and hepatic toxicity 4
• Linezolid causes hepatic transaminase elevation in some patients, with 16 cases (15%) showing increased transaminases in one study, of which 13 resolved 1

Risk Factors for TB Drug Hepatotoxicity

• HIV-infected patients with concurrent hepatitis C virus infection have a 14-fold increased relative risk of drug-induced hepatotoxicity compared to those without these infections 1
• Concomitant methotrexate or sulfasalazine may increase isoniazid hepatotoxicity risk in rheumatologic disease, though this association is not established in inflammatory bowel disease 1

Statins

• Elevated hepatic transaminases occur in 0.5-2.0% of statin users in a dose-dependent manner 1
• Transaminase elevation with statins does not necessarily constitute true hepatotoxicity, and progression to liver failure is exceedingly rare 1
• Reversal frequently occurs with dose reduction, and elevations often do not recur with rechallenge or switching to another statin 1
• Statins have not been shown to worsen outcomes in patients with chronic hepatitis B or C, and may actually improve transaminases in fatty liver disease 1

Antibiotics

Cefoperazone

• For transaminitis during cefoperazone therapy, continue monitoring for mild elevations (<3× upper limit of normal) but consider discontinuation for elevations >3× ULN 5
• Discontinue immediately if severe hepatotoxicity occurs (AST or ALT >5× ULN and/or total bilirubin >3× ULN), and consider hepatology consultation 5
• Cephalosporins have lower hepatotoxicity risk compared to sulfonamides or macrolides 5

Antiepileptic Drugs

Lamotrigine

• Can cause severe transaminitis as part of anticonvulsant hypersensitivity syndrome, with reported cases showing AST up to 6079 IU/L and ALT up to 6900 IU/L 6
• Typically presents with rash, nausea, and elevated liver enzymes 6
• Monitor hepatic function in patients newly initiated on lamotrigine, especially if jaundice develops 6
• Resolution occurs after drug withdrawal with supportive management 6

Levetiracetam

• Despite renal clearance and no CYP450 metabolism, levetiracetam can still cause hepatotoxicity 7
• Close monitoring of liver enzymes remains necessary even though levetiracetam is often chosen for patients with hepatic dysfunction 7

Biologic Agents

IL-23 Inhibitors (Guselkumab, Tildrakizumab)

• Rare cases of increased liver transaminase levels have occurred 1
• Combination with methotrexate increases infection risk, which may indirectly affect liver enzymes 1

Monitoring Recommendations

For any drug causing transaminitis:

• Evaluate for alternative causes including viral hepatitis, alcohol use, and other hepatotoxic medications 5
• Mild elevations (<3× ULN without symptoms) can be monitored; moderate elevations (3-5× ULN) warrant strong consideration for discontinuation 1, 5, 2
• Severe elevations (>5× ULN) or any elevation with jaundice or hepatitis symptoms require immediate drug cessation 1, 5
• Monitor liver enzymes until normalization after discontinuation 5

Common Pitfalls

• Assuming all transaminase elevations represent true hepatotoxicity rather than benign, reversible enzyme induction 1
• Failing to screen for viral hepatitis and alcohol use before attributing transaminitis solely to medications 5
• Not recognizing that drugs with primarily renal clearance (like levetiracetam) can still cause hepatotoxicity 7
• Overlooking drug-drug interactions that potentiate hepatotoxicity, such as isoniazid with acetaminophen 2