Can sulfasalazine cause elevated unconjugated bilirubin levels?

Sulfasalazine and Unconjugated Bilirubin Levels

Sulfasalazine does not directly cause elevated unconjugated bilirubin levels, but it can interfere with laboratory measurement of bilirubin fractions, creating falsely elevated conjugated bilirubin readings and falsely decreased unconjugated bilirubin values. 1

Laboratory Interference

• Sulfasalazine has been documented to interfere with certain laboratory methods for measuring bilirubin fractions, particularly multilayer film analyzers like the Ektachem system 1
• This interference occurs in a dose-dependent manner, with therapeutic concentrations of sulfasalazine causing falsely elevated conjugated bilirubin readings and simultaneously decreased unconjugated bilirubin values (sometimes to negative values) 1
• The interference is due to sulfasalazine's strong absorbance at 400 nm, which affects spectrophotometric bilirubin measurements 1

True Hepatotoxic Effects

• While sulfasalazine does not directly elevate unconjugated bilirubin, it can cause actual liver injury that may affect bilirubin metabolism 2
• Sulfasalazine-induced liver injury can lead to elevated total bilirubin (TBIL) along with increased alanine aminotransferase (ALT) and alkaline phosphatase (ALP) 2
• The hepatotoxic mechanism appears to involve multiple biological processes and pathways, including:
  • Alterations in drug-metabolizing enzymes (cytochrome P450 family) 2
  • Changes in glutathione metabolism 2
  • Oxidation-reduction processes 2

Monitoring Recommendations

• For patients on sulfasalazine, guidelines recommend monitoring complete blood count (CBC), liver function tests (LFTs), and renal function within the first 1-2 months of usage and every 3-4 months thereafter 3
• If clinically relevant elevations in liver function tests or decreased neutrophil or platelet counts are found, decreasing or temporarily holding the sulfasalazine dose is conditionally recommended 3

Bilirubin Binding and Neonatal Considerations

• Studies have shown that sulfasalazine has poor bilirubin-displacing capacity and does not significantly affect the reserve albumin concentration for bilirubin binding 4
• Sulfasalazine appears to bind to sites on albumin other than the high-affinity binding site for bilirubin 4
• For pregnant women on sulfasalazine, the risk of kernicterus in full-term newborns does not appear to be increased 4, 5
• However, the FDA label notes that sulfonamides (including sulfasalazine) can compete with bilirubin for binding sites on plasma proteins in newborns, so monitoring for potential kernicterus is still recommended 5

Differential Diagnosis for Unconjugated Hyperbilirubinemia

If a patient on sulfasalazine shows true unconjugated hyperbilirubinemia (not laboratory artifact), consider other causes:

• Gilbert syndrome (benign hereditary disorder affecting 5% of the American population) characterized by reduced activity of glucuronosyltransferase enzyme 6, 7
• Hemolytic anemias that increase bilirubin production 6
• Genetic variations in UDP-glucuronosyltransferase 1A1 (UGT1A1) or organic anion transporter polypeptide 2 (OATP2) 8

Clinical Implications

• When interpreting bilirubin results in patients taking sulfasalazine, be aware of potential laboratory interference 1
• If abnormal bilirubin values are found, consider:
  • Confirming results using alternative laboratory methods not affected by sulfasalazine 1
  • Evaluating for signs of actual liver injury (elevated transaminases, alkaline phosphatase) 2
  • Following monitoring guidelines for sulfasalazine, including regular liver function tests 3