What is the recommended treatment and monitoring approach for a patient with autoimmune hepatitis?

Treatment and Monitoring of Autoimmune Hepatitis

Start combination therapy with prednisolone 0.5-1 mg/kg/day (typically 30-60 mg/day) plus azathioprine 1-2 mg/kg/day from the outset, as this achieves remission in 80-90% of patients while causing significantly fewer steroid-related side effects (10% versus 44%) compared to prednisolone monotherapy. 1, 2

Initial Treatment Strategy

Standard Induction Regimen

Begin with prednisolone 60 mg/day (1 mg/kg for a 60 kg patient) alone for the first 1-2 weeks, then add azathioprine 50 mg/day in week 3, increasing to 100 mg/day (1-2 mg/kg) by week 5. 1 This delayed azathioprine approach helps resolve diagnostic uncertainties and avoids confusion between azathioprine-induced hepatotoxicity and primary non-response. 1

The specific tapering schedule is: 1

• Week 1: Prednisolone 60 mg/day alone
• Week 2: Prednisolone 50 mg/day alone
• Week 3: Prednisolone 40 mg/day + Azathioprine 50 mg/day
• Week 4: Prednisolone 30 mg/day + Azathioprine 50 mg/day
• Week 5-6: Prednisolone 20-25 mg/day + Azathioprine 100 mg/day
• Week 7-9: Prednisolone 12.5-15 mg/day + Azathioprine 100 mg/day
• Week 10+: Prednisolone 10 mg/day + Azathioprine 100 mg/day

Once aminotransferases normalize, reduce prednisolone to 7.5 mg/day, then after 3 months to 5 mg/day, tapering out at 3-4 month intervals depending on response. 1

When to Use Prednisolone Monotherapy

Use prednisolone alone (without azathioprine) in these specific situations: 1

• Severe pre-existing cytopenia
• Thiopurine methyltransferase (TPMT) deficiency confirmed by testing
• Pregnancy or contemplating pregnancy
• Active malignancy
• Short treatment trial planned (≤6 months duration)

Alternative First-Line Option for Non-Cirrhotic Patients

Consider budesonide 9 mg/day plus azathioprine specifically in treatment-naive, non-cirrhotic patients without portal hypertension who face high risk of steroid side effects (postmenopausal women, young females concerned about cosmetic effects, patients with osteoporosis, brittle diabetes, labile hypertension, or obesity). 1, 3 However, budesonide has 90% first-pass hepatic clearance and must never be used in cirrhotic patients or those with portosystemic shunting. 1

Monitoring Strategy

Early Response Assessment

Check serum aminotransferases (AST/ALT) and IgG levels at 2-4 weeks after starting treatment to confirm early response, then monthly during dose adjustments. 4, 2 Serum aminotransferases typically improve within 2 weeks of starting therapy. 4

Small decrements in prednisolone dose can cause marked increases in aminotransferases, so monitor closely during tapering. 4

Treatment Goals and Endpoints

The therapeutic endpoint is complete normalization of BOTH serum aminotransferases (AST/ALT) AND IgG levels—partial improvement is insufficient. 1, 2, 3 Persistent elevation of either parameter predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes. 2, 3

Biochemical remission is typically achieved within 6-12 months in 66-91% of patients, with an average duration of 19 months. 2, 3 Histological resolution lags behind biochemical improvement by 3-8 months. 2

When to Perform Follow-Up Liver Biopsy

Liver biopsy to confirm histological remission is not required in patients showing prompt complete normalization of transaminases and IgG, as chances of significant inflammatory activity are very low. 1

Perform follow-up biopsy in patients with: 1

• Sub-optimal biochemical response to immunosuppression
• Treatment side effects requiring management changes
• Consideration of treatment withdrawal after achieving biochemical remission

Duration of Initial Treatment

Continue treatment for an average of 18-24 months until achieving complete biochemical and histological remission, then for at least 12 additional months after normalization before considering withdrawal. 4, 2, 3 The EASL guidelines recommend at least 2 years of total treatment duration. 4

Management of Inadequate Response

Treatment Failure (Worsening Despite Therapy)

If the patient deteriorates clinically with worsening jaundice, ascites, or hepatic encephalopathy despite compliance, increase to high-dose therapy: prednisolone 60 mg daily alone OR prednisolone 30 mg daily plus azathioprine 150 mg daily for at least 1 month. 1, 3 Once improvement occurs, reduce prednisolone by 10 mg and azathioprine by 50 mg monthly until reaching standard maintenance doses. 1

Incomplete Response (No Improvement After 2-3 Years)

For patients showing minimal or no improvement after 2-3 years of compliant therapy without worsening, reduce prednisolone by 2.5 mg/month to the lowest level (ideally 10 mg daily) that prevents ALT elevation, and continue indefinite azathioprine 2 mg/kg daily. 1

Steroid-Refractory Disease

For confirmed non-responders or steroid-refractory cases, consider second-line agents: 4, 3

• Mycophenolate mofetil (MMF) - most commonly used second-line option 1
• Tacrolimus
• Cyclosporine

Refer to a specialist center for confirmation of diagnosis, liver transplant evaluation, and/or alternative immunosuppressives if standard therapy fails. 1

Special Clinical Situations

Acute Severe AIH or Fulminant Hepatic Failure

Immediately start high-dose intravenous prednisolone (≥1 mg/kg or up to 100 mg IV) as early as possible. 1, 2, 3 If no improvement occurs within 7 days, list for emergency liver transplantation. 3

Cytopenia and TPMT Testing

Check thiopurine methyltransferase (TPMT) activity before starting azathioprine in patients with pre-existing cytopenia or if cytopenia develops during therapy. 1 Only 0.3-0.5% of the population has severe TPMT deficiency causing myelosuppression risk. 1 Patients with heterozygous TPMT deficiency (moderately reduced activity) tolerate azathioprine 50 mg daily satisfactorily. 1

Routine TPMT screening is not recommended for all patients given the rarity of severe deficiency and low azathioprine doses used (50-150 mg daily). 1

Pregnancy Considerations

Azathioprine has FDA pregnancy category D rating and should ideally be discontinued during pregnancy if disease control permits, though a risk-benefit analysis is required for each patient. 1, 2 Some patients require continued azathioprine for disease control. 2

Resume standard therapy 2 weeks prior to anticipated delivery and monitor closely postpartum, as exacerbation commonly occurs. 1 Monitor serum AST/ALT at 3-week intervals for at least 3 months after delivery. 1

Advanced Liver Disease and Cirrhosis

Exercise caution with azathioprine in patients with advanced liver disease, as hepatotoxicity frequency increases in this population. 1 The delayed azathioprine strategy (starting at week 2-3) is particularly helpful in these patients. 1

Never use budesonide in cirrhotic patients due to impaired first-pass metabolism. 1

Long-Term Management After Remission

Relapse After Treatment Withdrawal

Relapse occurs in 50-90% of patients within 12 months of stopping treatment, even after achieving complete biochemical and histological remission. 4, 3 Only 20-28% achieve sustained remission off therapy. 3

After relapse, re-induce remission with combination therapy, then maintain long-term with azathioprine 2 mg/kg daily alone. 4, 3 For patients who have relapsed more than once, 87% remain in remission during long-term maintenance with low-dose prednisolone, azathioprine alone, or combination therapy. 4

Monitoring During Maintenance

During long-term maintenance, monitor: 1

• Serum aminotransferases and IgG every 3 months initially, then every 6 months once stable
• Complete blood count for cytopenia (azathioprine monitoring)
• Consider FibroScan to detect disease reactivation (increased liver stiffness from inflammation/edema) or progressive fibrosis 1

Prevention of Treatment Complications

Bone Health

All patients on corticosteroids should receive calcium and vitamin D supplementation from treatment initiation. 4, 3 Monitor bone mineral density with DEXA scanning at 1-2 year intervals. 4, 3

Consider bisphosphonates, regular exercise programs, and estrogen replacement (when appropriate) for patients on long-term corticosteroids. 1

Other Preventive Measures

Vaccinate against hepatitis A and B early in susceptible patients. 4, 3

Perform periodic eye examinations for cataracts and glaucoma in patients receiving prednisolone. 1

Severe complications (osteoporosis with vertebral compression, diabetes, cataracts, hypertension, psychosis) typically develop after 18 months of therapy at prednisolone doses >10 mg daily. 4, 3 Minimize cumulative steroid exposure by using combination therapy and tapering aggressively once remission is achieved. 3

Common Pitfalls to Avoid

Do not accept partial biochemical improvement as adequate response—both aminotransferases AND IgG must completely normalize. 2, 3 Patients with normalized labs before drug withdrawal have 3-11 fold lower relapse risk. 2

Do not use budesonide in any patient with cirrhosis, portal hypertension, or portosystemic shunting. 1

Do not delay treatment in patients with severe disease (AST/ALT >10× ULN, or ≥5× ULN with globulin ≥2× ULN, or bridging/multilobular necrosis on biopsy)—untreated mortality is 60% at 6 months. 2

Do not withdraw treatment prematurely—continue for at least 12 months after achieving complete biochemical normalization to reduce relapse risk. 4, 2