What medications can increase transaminases, especially in patients with a history of liver disease?

Medications That Increase Transaminases

The most common medications that increase transaminases are statins (particularly high-dose atorvastatin and simvastatin), lomitapide, mipomersen, and tolvaptan, with statins causing elevations in 0.5-2% of patients and specialized lipid-lowering agents carrying black box warnings for hepatotoxicity. 1, 2, 3

High-Risk Lipid-Lowering Agents

Lomitapide and Mipomersen (Highest Risk)

• Lomitapide carries a black box warning for hepatotoxicity, requiring measurement of ALT, AST, alkaline phosphatase, and total bilirubin before initiation, with dose adjustment if ALT or AST ≥3× ULN and discontinuation for clinically significant liver toxicity. 1

• Lomitapide increases hepatic fat (hepatic steatosis) with or without concomitant transaminase increases, which may be a risk factor for progressive liver disease including steatohepatitis and cirrhosis, and is only available through a REMS program. 1

• Mipomersen causes injection site reactions, flu-like symptoms, and elevations in serum transaminases, specifically ALT, with increases in hepatic fat that may lead to progressive liver disease; it is also available only through a REMS program. 1

• Both agents are FDA-approved only for homozygous familial hypercholesterolemia (HoFH) and require intensive monitoring due to hepatotoxicity risk. 1

Statins (Moderate Risk, Dose-Dependent)

• High-dose atorvastatin (80 mg) causes transaminase elevations >3× ULN in approximately 3.3% of patients compared to 1.1% with pravastatin 40 mg (odds ratio 3.01,95% CI 1.87-4.85). 4

• High-dose simvastatin (80 mg) shows 0.84% ALT elevation versus 0.36% with lower doses (OR 2.35,95% CI 1.03-5.38). 4, 2

• Intensive statin therapy increases the risk for elevated hepatic transaminases (ALT and/or AST) >2-3× ULN more than moderate-dose statin therapy. 4

• Persistent increases to more than 3× ULN in serum transaminases occur in approximately 0.7-1% of patients receiving statins in clinical trials. 2, 3

• Transaminase elevations with statins are typically dose-dependent, appear soon after initiation, are transient, not accompanied by symptoms, and resolve with continued therapy or brief interruption. 4, 2, 3

• Progression to liver failure specifically due to statins is exceedingly rare, if it ever occurs. 4

Tolvaptan (Moderate Risk, Time-Dependent)

• Approximately 5% of patients with ADPKD treated with tolvaptan display transaminase increases above 3× ULN, compared to 1% receiving placebo. 1

• Increases in ALT occur most often during the first 18 months of treatment and resolve within 1-4 months after tolvaptan cessation. 1

• Monthly monitoring of liver function tests is mandatory for the first 18 months, then every 3 months until drug discontinuation. 1

• Tolvaptan should be held if AST or ALT increases to ≥3× ULN or >2× baseline (even if <2× ULN), with repeat testing within 48-72 hours. 1

• Permanently discontinue tolvaptan if transaminases remain ≥3× ULN unless another explanation for liver injury exists and the injury resolves. 1

Monitoring and Management Algorithm

For Patients Starting Statins

• Obtain baseline liver function tests before initiating statin therapy to interpret potential future results. 1, 4, 3

• Routine periodic monitoring of liver enzymes after statin initiation is NOT recommended, as serious liver injury is rare and unpredictable, and monitoring does not appear effective in detecting or preventing this adverse effect. 4

• Measure hepatic function only if symptoms of hepatotoxicity arise (unusual fatigue, weakness, loss of appetite, abdominal pain, dark urine, or jaundice). 4, 3

For Patients with Transaminase Elevations on Statins

• Continue current statin dose and recheck liver enzymes at a shorter interval for elevations up to 2.5× ULN; the threshold for action is ≥3× ULN, not 2.5× ULN. 4

• Reduce statin dose or temporarily withhold only if transaminases rise to >3× ULN, after ruling out other causes (alcohol, NAFLD, viral hepatitis, other hepatotoxic medications). 4

• Discontinue the statin only if liver enzymes remain >3× ULN despite dose reduction. 4

• Reversal of transaminase elevation frequently occurs with dose reduction, and elevations do not often recur with either re-challenge or selection of another statin. 4

Special Considerations for Patients with Pre-existing Liver Disease

• Statins are safe and recommended in patients with compensated liver disease, including NAFLD, chronic hepatitis B and C, and compensated cirrhosis, as cardiovascular benefits outweigh theoretical liver risks. 4, 5

• Statins may actually improve transaminase elevations in individuals with fatty liver disease rather than worsen them. 4, 5

• Statins are contraindicated only in decompensated cirrhosis, acute liver failure, and active hepatitis with fluctuating or worsening liver function tests. 4, 2, 3

• Pravastatin has the safest hepatic profile among statins, with only 1.1% ALT elevation in clinical trials, and is the statin of choice in liver transplant recipients due to minimal drug interactions. 4

Other Medications That Increase Transaminases

Antiretroviral Therapy

• HIV-infected patients frequently present with elevated liver transaminases due to hepatotoxicity from ART, requiring additional visits for laboratory studies and clinical assessments, often undergoing interruptions and changes in therapy. 6

Drugs Affecting Gluconeogenesis

• α-glucosidase inhibitors and fibrates slightly increase transaminase activities through modification of gluconeogenesis and lipid metabolism, but there is little evidence this is related to drug-induced liver injury (pharmacology-related elevation). 7

• The combination of statin and fibrate (particularly gemfibrozil) may increase the risk of myopathy and should be used with caution; fenofibrate is preferred over gemfibrozil if combination therapy is necessary. 5, 2

Critical Pitfalls to Avoid

• Do not routinely monitor transaminases in asymptomatic patients with normal baseline values, as this leads to unnecessary testing and potential false-positive results. 4

• Do not discontinue statins for elevations <3× ULN, as this prematurely removes cardiovascular protection; the cardiovascular benefits outweigh the risks of mild transaminase elevation. 4

• Do not withhold statins from patients with NAFLD or compensated cirrhosis, as cardiovascular disease is the leading cause of death in this population and statins reduce this risk. 4, 5

• Avoid high-dose atorvastatin (80 mg) and simvastatin (80 mg) in patients with elevated baseline liver enzymes, liver disease, or those taking multiple medications metabolized by CYP3A4 due to significantly increased hepatotoxicity risk. 4

• Do not use AST alone for monitoring, as ALT is more sensitive and liver-specific. 4