What is the recommended initial dose and monitoring protocol for starting a patient on Azathioprine (Imuran) for autoimmune hepatitis?

Starting Azathioprine for Autoimmune Hepatitis

Start prednisolone first at 30 mg/day, then add azathioprine 50 mg/day after 2 weeks (or when bilirubin is below 6 mg/dL), increasing to a maintenance dose of 1-2 mg/kg/day while tapering the prednisolone to 10 mg/day over 4 weeks. 1

Pre-Treatment Assessment

Before initiating azathioprine, you must address several critical safety considerations:

• Check TPMT (thiopurine methyltransferase) activity to identify patients at risk for severe myelosuppression, particularly those with pre-existing leucopenia 1, 2
• Obtain baseline complete blood count (CBC), liver function tests (LFTs), and renal function 2, 3
• Screen for hepatitis B, hepatitis C, and HIV 2
• Verify varicella zoster immunity and vaccinate if seronegative 2

Important caveat: While TPMT testing is recommended, routine screening has a low yield (15% deficiency rate) for predicting azathioprine toxicity during conventional low-dose therapy in autoimmune hepatitis 4. However, homozygous TPMT deficiency is an absolute contraindication to azathioprine use 1, 2.

Initial Dosing Protocol

The timing and dosing of azathioprine initiation follows a specific sequence:

Week 1-2: Prednisolone Monotherapy

• Start prednisolone 30 mg/day (or up to 1 mg/kg/day in severe cases) 1
• Higher initial prednisolone doses may achieve faster transaminase normalization but use caution in frail elderly patients 1

Week 2-4: Add Azathioprine

• Initiate azathioprine at 50 mg/day when bilirubin is below 6 mg/dL (100 μmol/L) 1
• The 2-week delay allows prednisolone to begin controlling inflammation before adding azathioprine 1
• Take azathioprine with food to minimize gastrointestinal side effects 5

Week 4 Onward: Dose Escalation

• Increase azathioprine to maintenance dose of 1-2 mg/kg/day based on tolerance and TPMT status 1
• For normal TPMT activity: target 1-2 mg/kg/day 1
• For intermediate TPMT activity: reduce to 1-1.5 mg/kg/day 1, 2
• Simultaneously taper prednisolone to 10 mg/day over the first 4 weeks as transaminases fall 1

Monitoring Protocol

The intensity of monitoring varies with treatment phase:

First Month (Weeks 1-4)

• Monitor CBC and LFTs weekly during initial dose escalation 1, 2, 3
• This detects early myelosuppression or hepatotoxicity 3

Months 2-3

• Continue weekly CBC and LFT monitoring until maintenance dose is stable 2, 3

After Stabilization

• Reduce to monitoring every 3 months once on stable maintenance therapy 1, 2, 3
• More frequent monitoring is required if doses are increased or in patients with intermediate TPMT activity 2

Response Assessment

• Assess treatment response at 4-8 weeks, expecting serum aminotransferases to improve within 2 weeks 6
• Monitor transaminases monthly during dose adjustments, as small prednisolone decrements can cause marked transaminase increases 6
• If no improvement occurs within 3 months, reconsider the diagnosis or evaluate adherence 2

Critical Drug Interactions

Avoid allopurinol or febuxostat during azathioprine therapy, as xanthine oxidase inhibitors block azathioprine metabolism and cause severe toxicity 3. If concomitant use is unavoidable, reduce azathioprine to 25-33% of the usual dose 3.

Exercise caution with aminosalicylates (sulfasalazine, mesalazine, olsalazine), which inhibit TPMT and may increase toxicity 3.

Avoid ribavirin, as it causes severe pancytopenia when combined with azathioprine by inhibiting inosine monophosphate dehydrogenase 3.

Steroid Tapering Strategy

Once azathioprine reaches maintenance dose and clinical response is evident:

• Reduce prednisolone by 2.5 mg/month while monitoring liver tests 1, 5, 6
• Target prednisolone dose of 5-10 mg/day for long-term maintenance 1
• The goal is complete prednisolone withdrawal while maintaining remission on azathioprine monotherapy, though this is achievable in only a minority of patients 5, 6

Treatment Duration

• Continue combination therapy for at least 2 years and for at least 12 months after transaminase normalization 1, 6
• Complete normalization of transaminases and IgG levels should be the treatment goal, as persistent elevations predict relapse, ongoing histological activity, progression to cirrhosis, and poor outcomes 1, 6

Bone Protection

All patients require calcium and vitamin D supplementation from treatment initiation 1, 6. Perform DEXA scanning at 1-2 year intervals while on corticosteroids and actively treat osteopenia and osteoporosis 1, 6.

Management of Inadequate Response

If transaminases fail to normalize despite confirmed adherence:

• Increase azathioprine to 2 mg/kg/day while maintaining prednisolone at 5-10 mg/day 1
• Consider alternative agents (tacrolimus, cyclosporine) if azathioprine escalation fails, but seek expert consultation 1
• Repeat liver biopsy after 12-18 months to assess histological response 1

Special Considerations for Severe Disease

In patients with acute severe autoimmune hepatitis, liver failure, or bridging necrosis:

• Use high-dose intravenous corticosteroids (≥1 mg/kg) immediately 1
• Contact a liver transplant center if MELD score does not rapidly improve within 7 days 1
• These patients have high mortality without transplantation 1

Therapeutic Drug Monitoring

While not routinely required, thioguanine nucleotide (TGN) levels >220 pmol/8×10⁸ RBCs are associated with maintained remission (odds ratio 7.7) 7. TGN measurement may help identify inadequate immunosuppression in patients who fail to achieve remission despite apparent adequate dosing 7.