What is the initial treatment approach for patients with overlap autoimmune hepatitis?

Initial Treatment Approach for Overlap Autoimmune Hepatitis

The initial treatment for patients with overlap autoimmune hepatitis should be combination therapy with prednisolone plus azathioprine, along with ursodeoxycholic acid (UDCA) for the cholestatic component. 1

Understanding Overlap Syndromes

Overlap autoimmune hepatitis refers to conditions where features of both autoimmune hepatitis (AIH) and a cholestatic liver disease (typically primary biliary cholangitis [PBC] or primary sclerosing cholangitis [PSC]) coexist. These conditions require specific treatment approaches that address both disease components.

Diagnostic Considerations

Before initiating treatment, confirm the overlap diagnosis using established criteria:

• For PBC-AIH overlap: At least 2 of 3 criteria for each disease should be present 1
  • PBC criteria: Elevated alkaline phosphatase, positive AMA, bile duct lesions on biopsy
  • AIH criteria: ALT >5× ULN, elevated IgG/positive ASMA, interface hepatitis on biopsy
• Interface hepatitis on liver biopsy is mandatory for diagnosis 1

Treatment Algorithm

First-Line Treatment

1. Initial combination therapy:

   • Prednisolone 30 mg/day (reducing to 10 mg/day over 4 weeks) 1
   • Azathioprine 1 mg/kg/day 1
   • UDCA 13-15 mg/kg/day (for cholestatic component) 1

2. Pre-treatment considerations:

   • Measure TPMT (thiopurine methyltransferase) to exclude homozygote deficiency, especially in patients with pre-existing leucopenia 1
   • Avoid budesonide in patients with cirrhosis or peri-hepatic shunting due to risk of side effects 1

3. Monitoring response:

   • Assess biochemical response after 3 months
   • For PBC-AIH overlap: Monitor both transaminases (AIH component) and alkaline phosphatase (cholestatic component) 1

Alternative Approach

An alternative approach for PBC-AIH overlap is to:

1. Start with UDCA alone
2. Add corticosteroids if UDCA therapy does not induce adequate biochemical response within 3 months 1

Response Assessment and Adjustments

Adequate Response

• Complete normalization of transaminases and IgG levels should be the aim of treatment 1
• Continue treatment for at least 2 years and for at least 12 months after normalization of transaminases 1

Inadequate Response

• For non-responding or slowly responding patients:
  • Increase prednisolone dose (up to 1 mg/kg/day)
  • Increase azathioprine to 2 mg/kg/day 1
  • Consider tacrolimus in refractory cases 1

Special Considerations

Cirrhosis or Liver Failure

• In patients with liver failure, bridging necrosis on biopsy, or jaundice with MELD score not rapidly improving on treatment, contact a liver transplant center 1
• Avoid budesonide in cirrhotic patients due to risk of side effects 1

Side Effect Management

• Provide calcium and vitamin D supplementation to all patients on steroids 1
• Perform DEXA scanning at 1-2 yearly intervals to monitor for osteoporosis 1
• Consider budesonide (9 mg/day) plus azathioprine in non-cirrhotic patients with severe steroid-related side effects 1

Long-term Management

• Continue treatment with azathioprine 1 mg/kg/day and prednisolone 5-10 mg/day for at least 2 years 1
• Consider liver biopsy to confirm histological remission before planning treatment withdrawal 1
• For PBC-AIH overlap, long-term outcomes may be worse than in AIH without overlap, emphasizing the importance of proactive diagnosis and treatment 1

Pitfalls and Caveats

• Patients with overlap syndromes often have a worse prognosis than those with either disease alone
• UDCA monotherapy is often insufficient for PBC-AIH overlap, with fibrosis progression occurring more frequently than with combined therapy 1
• Budesonide should not be used in cirrhotic patients or those with peri-hepatic shunting due to risk of side effects 1
• Regular monitoring of blood counts is essential due to risk of azathioprine-induced marrow depression 1
• Vaccination against hepatitis A and B should be performed early in susceptible patients 1