Can indomethacin (nonsteroidal anti-inflammatory drug (NSAID)) cause acute liver injury?

From the Guidelines

Indomethacin can cause acute liver damage, although it is a rare occurrence. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that is primarily used to reduce pain, inflammation, and stiffness in conditions like arthritis, gout, and ankylosing spondylitis. According to a study published in the American Family Physician in 2009 1, clinically significant hepatotoxicity associated with NSAID use was rare in the general population. However, some NSAIDs, particularly sulindac and diclofenac, showed higher rates of hepatic injury and transaminase elevation compared to placebo.

While using indomethacin, patients should be vigilant for warning signs of liver injury such as:

• Jaundice (yellowing of skin or eyes)
• Dark urine
• Right upper quadrant pain
• Fatigue
• Nausea
• Elevated liver enzymes on blood tests The risk of liver damage appears to be dose-dependent and may be higher in patients with pre-existing liver disease, advanced age, or those taking other hepatotoxic medications.

As noted in another study published in the same journal in 2009 1, primary hepatic complications from NSAIDs are rare and usually reversible. However, it is essential to avoid NSAIDs in persons with cirrhosis because of the potential for hematologic and renal complications. If signs of liver damage occur, indomethacin should be discontinued immediately, and medical attention sought. Patients with a history of liver disease should use indomethacin with caution and only under close medical supervision.

In general, NSAIDs should be used with caution in persons with an increased risk of renal complications, and monitoring of renal function after initiation of NSAIDs may be necessary in high-risk individuals 1. Additionally, patients taking other medications that might decrease renal function, such as ACE inhibitors or angiotensin receptor blockers, should be monitored closely.

Overall, while indomethacin can cause acute liver damage, the risk is relatively low, and the benefits of using the medication may outweigh the risks for many patients. However, close monitoring and caution are essential to minimize the risk of liver damage and other adverse effects.

From the FDA Drug Label

Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including indomethacin These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported Patients should be informed of the warning signs and symptoms of hepatotoxicity (e. g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

Yes, indomethacin can cause acute liver damage, as evidenced by rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure 2, 2, 2.

• Key points:
  • Borderline elevations of liver tests may occur in up to 15% of patients.
  • Notable elevations of ALT or AST have been reported in approximately 1% of patients.
  • Rare cases of severe hepatic reactions have been reported, including fatal outcomes.
  • Patients should be informed of the warning signs and symptoms of hepatotoxicity and instructed to stop therapy and seek immediate medical attention if they occur.

From the Research

Indomethacin and Liver Damage

• Indomethacin has been found to cause severe liver damage in some studies, as evidenced by increased activity of aminotransferases and alkaline phosphatase in blood serum, increased lipid peroxidation, and decreased reserves of restored glutathione 3.
• The increase in lipid peroxidation is thought to play an important role in the pathogenesis of indomethacin-induced liver lesions 3.
• In a murine model of liver injury from alpha-1-antitrypsin deficiency, indomethacin was found to increase liver damage, indicated by increased hepatocellular proliferation and activation of caspase 9 4.
• Indomethacin-induced liver injury was also associated with activation of IL-6-STAT3 signaling, increased expression of alpha(1)-AT mRNA, and greater accumulation of mutant polymerized alpha(1)-ATZ protein in livers of indomethacin-treated mice 4.

Clinical Relevance

• Abnormal liver enzymes, including aminotransferases, alkaline phosphatase, and bilirubin, can be indicative of liver damage caused by indomethacin 5.
• Medication-induced liver injury, including that caused by indomethacin, can be categorized as a hepatocellular pattern or cholestatic pattern, and can be further sub-classified based on the magnitude of aminotransferase elevation 5.
• It is crucial to interpret liver biochemical tests accurately, as appropriate further workup, treatment, and referral can greatly benefit patients with indomethacin-induced liver damage 5.

Contrasting Findings

• One study found that indomethacin-treated rats had decreased biochemical markers of liver injury, but also had decreased serum concentration of albumin, indicating impaired liver function 6.
• Another study reported the successful use of indomethacin to decrease intracranial pressure in a patient with acute liver failure, without any adverse effects attributable to indomethacin use 7.