What is more likely to cause elevated Alanine Transaminase (ALT) levels in a patient taking paracetamol (acetaminophen) and ketoconazole?

From the Guidelines

Paracetamol (acetaminophen) is more likely to cause elevated Alanine Transaminase (ALT) levels in a patient taking paracetamol and ketoconazole.

Reasons for this likelihood

• Dose-related toxicity: Paracetamol is a dose-related toxin, and most ingestions leading to Acute Liver Failure (ALF) exceed 10 gm/day, although severe liver injury can occur rarely when doses as low as 3-4 gm/day are taken 1.
• Metabolism and hepatotoxicity: Paracetamol is metabolized by p450s leading to N-acetyl-p-benzoquinoneimine (NAPQI) when intracellular glutathione levels are saturated, resulting in centrilobular hepatocyte necrosis 1.
• Liver injury risk: Even therapeutic doses of paracetamol may produce liver injury in chronic alcohol users, whether or not associated with cirrhosis and malnutrition, due to the complex relationship between alcohol and acetaminophen metabolism 1.
• Ketoconazole interaction: While ketoconazole is not directly implicated in causing elevated ALT levels, its interaction with paracetamol metabolism is not well-established, and caution is advised when administering therapeutic doses of paracetamol to patients taking ketoconazole.

Key considerations

• Monitoring and caution: Patients taking paracetamol, especially those with a history of alcohol use or liver disease, should be closely monitored for signs of liver injury, and caution is advised when administering therapeutic doses of paracetamol 1.
• N-acetylcysteine administration: In suspected paracetamol-induced liver injury, administration of N-acetylcysteine should be considered in addition to stopping the drug 1.

From the FDA Drug Label

WARNINGS Hepatotoxicity, primarily of the hepatocellular type, has been associated with the use of ketoconazole tablets, including rare fatalities. The hepatic injury has usually, but not always, been reversible upon discontinuation of ketoconazole tablet treatment. Transient minor elevations in liver enzymes have occurred during treatment with ketoconazole tablets.

Ketoconazole is more likely to cause elevated Alanine Transaminase (ALT) levels in a patient taking paracetamol (acetaminophen) and ketoconazole, as the drug label directly states that hepatotoxicity and elevations in liver enzymes have been associated with the use of ketoconazole tablets 2.

From the Research

Causes of Elevated Alanine Transaminase (ALT) Levels

Elevated ALT levels can be caused by various factors, including:

• Acetaminophen (paracetamol) overdose, as seen in a study published in 2015 3
• Therapeutic doses of acetaminophen, which can cause asymptomatic ALT elevations in some individuals 4, 5
• Ketoconazole-induced hepatotoxicity, particularly in individuals with arylacetamide deacetylase (AADAC) defects 6
• Other causes such as acute ischaemia, acute viral hepatitis, and common bile duct stones 7

Comparison of ALT Level Elevations

Comparing the likelihood of elevated ALT levels in a patient taking paracetamol and ketoconazole:

• Paracetamol is known to cause ALT elevations, especially at high doses or with prolonged use 3, 4, 5
• Ketoconazole can also cause hepatotoxicity, particularly in individuals with AADAC defects, leading to elevated ALT levels 6
• The combination of paracetamol and ketoconazole may increase the risk of ALT level elevations due to their potential hepatotoxic effects

Key Findings

Key findings from the studies include:

• ALT levels can rise rapidly after acetaminophen overdose, with a peak typically occurring within 24-48 hours 3
• Therapeutic doses of acetaminophen can cause asymptomatic ALT elevations in some individuals, which may resolve spontaneously with continued use 4, 5
• Ketoconazole-induced hepatotoxicity can be exacerbated by AADAC defects, leading to increased ALT levels and liver injury 6