Can NSAIDs Elevate Total Bilirubin?
Yes, NSAIDs can elevate total bilirubin levels through two distinct mechanisms: true hepatotoxicity causing liver injury, and laboratory interference from drug metabolites producing falsely elevated readings.
True Hepatotoxicity and Bilirubin Elevation
NSAIDs cause genuine hepatic injury that can elevate bilirubin levels, though this is relatively uncommon. Borderline elevations of liver tests occur in up to 15% of patients taking NSAIDs, but meaningful elevations (>3 times upper limit of normal) occur in only about 1% of patients 1. More severe reactions are rare but documented:
- Diclofenac shows meaningful AST elevations in approximately 2% of patients, with marked elevations (>8 times ULN) in about 1% of cases 2
- Severe hepatic reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure have been reported, some with fatal outcomes 1
- Postmarketing surveillance has documented cases of severe hepatic reactions that can occur at any time during treatment, though most meaningful elevations are detected within the first 2 months of therapy 2
The American Academy of Family Physicians notes that hepatic damage from NSAIDs is rare, but these medications should not be used in persons with cirrhotic liver disease because bleeding problems and renal failure become more likely 3.
Laboratory Interference Causing False Elevations
A critical and often overlooked mechanism is direct laboratory interference, particularly with naproxen overdose. A 2023 case report documented that supratherapeutic naproxen ingestion can produce falsely elevated total bilirubin readings due to O-desmethylnaproxen (ODMN), a naproxen metabolite that interferes with certain bilirubin assays 4. This interference:
- Produces elevated total bilirubin without corresponding elevation in direct bilirubin 4
- Occurs specifically when naproxen is ingested above therapeutic doses 4
- Resolves rapidly (within 24 hours) as the drug is cleared 4
- Does not reflect true hepatic dysfunction 4
Bilirubin and its by-products cause interference in enzymatic colorimetric assays used to measure various analytes, and this interaction can be bidirectional - hyperbilirubinemia can cause false-positive readings for other drugs, and certain drug metabolites can cause false-positive bilirubin readings 5.
Clinical Context: NSAIDs in Liver Disease
When evaluating bilirubin elevations in NSAID users, consider the baseline hepatic status:
- NSAIDs should be avoided in patients with cirrhosis and ascites due to extremely high risk of acute renal failure, hyponatremia, and diuretic resistance 6
- In patients with chronic hepatitis C and advanced fibrosis, NSAID use has been associated with gastric antral vascular ectasia (GAVE) features, with independent correlates including higher serum bilirubin levels 7
- The American Academy of Family Physicians recommends avoiding NSAIDs in persons with preexisting cirrhosis to prevent acute renal failure 3
Monitoring Recommendations
If abnormal liver tests persist or worsen, or if clinical signs consistent with liver disease develop (nausea, fatigue, lethargy, jaundice, right upper quadrant tenderness), NSAIDs should be discontinued immediately 2. For patients requiring long-term NSAID therapy:
- Measure transaminases at baseline and periodically during treatment 2
- Monitor transaminases within 4 to 8 weeks after initiating treatment, though severe hepatic reactions can occur at any time 2
- If total bilirubin is elevated without corresponding direct bilirubin elevation and without clinical signs of hepatic dysfunction, consider laboratory interference, particularly with recent naproxen use 4
Special Population: Neonates
In preterm infants, ibuprofen administration has been associated with higher peak total serum bilirubin levels (9.0 ± 2.5 mg/dL vs 7.3 ± 3.3 mg/dL in unexposed infants), likely due to competition between ibuprofen and bilirubin in the hepatic glucuronidation pathway 8. This resulted in more frequent need for phototherapy (95% vs 87.6%) and longer phototherapy duration 8.