Can Imuran (azathioprine) cause elevated total bilirubin with normal liver function tests?

Can Imuran Cause Isolated Elevation of Total Bilirubin with Normal Liver Enzymes?

Yes, azathioprine (Imuran) can cause isolated hyperbilirubinemia with normal transaminases, though this pattern is uncommon and requires careful evaluation to exclude other causes before attributing it to the drug.

Understanding Azathioprine-Related Bilirubin Elevation

Azathioprine hepatotoxicity typically presents with elevated transaminases and/or alkaline phosphatase, but isolated bilirubin elevation can occur through several mechanisms 1, 2:

• The FDA label explicitly states that hepatotoxicity manifests as elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases, indicating bilirubin can be elevated as part of azathioprine toxicity 1
• In a retrospective study of azathioprine hepatotoxicity, the median peak total bilirubin was only 1.0 mg/dL, with mixed hepatocellular-cholestatic patterns being most common (50%), followed by cholestatic (37.5%) and hepatocellular (12.5%) 2
• Importantly, isolated bilirubin elevation without elevated aminotransferases should generally not be considered drug-induced liver injury (DILI) according to consensus guidelines, though this may not apply to all clinical contexts 3

Critical Differential Diagnosis

Your total bilirubin of 1.2 mg/dL is only mildly elevated. Before attributing this to azathioprine, you must exclude:

Gilbert's Syndrome (Most Likely Alternative)

• Affects 5-10% of the population and causes intermittent unconjugated hyperbilirubinemia with normal liver enzymes 3
• Total bilirubin in Gilbert's syndrome is usually mildly elevated but rarely exceeds 4-5 mg/dL 3
• Diagnosis is confirmed by calculating conjugated (direct) bilirubin, which should be less than 20-30% of total bilirubin 3
• Genetic testing for UGT1A1 mutations can confirm diagnosis if uncertain 3

Hemolysis

• Check complete blood count, reticulocyte count, haptoglobin, and LDH to exclude hemolysis 3
• Azathioprine can cause bone marrow suppression and anemia, though hemolytic anemia is less common 1

Regarding the Uric Acid Level

The uric acid of 3.6 mg/dL is actually low, not elevated. This is unlikely related to azathioprine and may reflect:

• Nutritional factors
• Medications affecting uric acid excretion
• Underlying renal tubular dysfunction
• This finding is not a recognized adverse effect of azathioprine 1

Recommended Diagnostic Approach

Measure direct (conjugated) bilirubin immediately 3:

• If direct bilirubin is <20-30% of total bilirubin (i.e., <0.24-0.36 mg/dL), this suggests Gilbert's syndrome rather than azathioprine toxicity
• If direct bilirubin is >35% of total bilirubin, this is more consistent with drug-induced liver injury 3

Monitor for progression 4:

• Repeat liver function tests including ALT, AST, alkaline phosphatase, and total/direct bilirubin within 2-5 days 3
• Azathioprine hepatotoxicity can occur even after 1 year of treatment 5
• The British Journal of Dermatology recommends monitoring LFTs at least every 3 months for patients on stable azathioprine doses 4

Management Decision Algorithm

If direct bilirubin <20-30% of total (suggesting Gilbert's syndrome):

• Continue azathioprine with routine monitoring 3
• No dose adjustment needed
• Reassure patient this is a benign hereditary condition

If direct bilirubin >35% of total (suggesting drug effect):

• Continue azathioprine but increase monitoring frequency to every 2 weeks 6, 4
• Watch for clinical symptoms: fatigue, nausea, vomiting, right upper quadrant pain, jaundice 6
• Stop azathioprine if bilirubin rises to ≥2× ULN (≥2.4 mg/dL) along with any transaminase elevation 6

If bilirubin continues to rise or symptoms develop:

• Discontinue azathioprine 6, 1
• Consider alternative immunosuppressants such as mycophenolate mofetil, tacrolimus, or cyclosporine 3, 6
• Azathioprine can be cautiously reintroduced at 50% of the previous dose after normalization if clinically necessary 6

Important Caveats

• Azathioprine-induced cholestasis can be prolonged (>2 months) even after drug discontinuation, though complete recovery is typical 2
• Rare but serious complications include nodular regenerative hyperplasia and hepatic veno-occlusive disease, which can occur with minimal LFT abnormalities 1, 7
• The FDA recommends periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin for early detection of hepatotoxicity 1