Management of Cellular Rejection Post Liver Transplantation
The cornerstone of treatment for cellular rejection after liver transplantation is high-dose corticosteroids, typically administered as intravenous methylprednisolone, followed by calcineurin inhibitor optimization, with tacrolimus being the preferred agent in most centers. 1
Diagnosis and Evaluation
- Acute cellular rejection occurs in up to 10% of liver transplant recipients, most commonly within the first 3 months but can occur at any time post-transplantation 1
- Diagnosis requires liver biopsy after exclusion of vascular or biliary complications 1
- Clinical presentation may include:
- Abnormal liver function tests (hepatocellular or cholestatic pattern)
- Fever, jaundice, and abdominal pain in advanced cases 1
- Patients with autoimmune liver diseases (including PSC) are at higher risk for early and late cellular rejection than other liver transplant indications 1
First-Line Treatment
- High-dose corticosteroids are the first-line therapy for acute cellular rejection 2
- Recommended regimen: intravenous methylprednisolone 1,000 mg followed by a 6-day taper from 200 to 20 mg/day (shown to be more effective and safer than three consecutive days of 1,000 mg) 2
- This tapered approach results in:
- Higher resolution rate of acute rejection (83.3% vs 50.0%)
- Lower prevalence of infections (55.5% vs 90.0%) 2
Immunosuppression Optimization
- Calcineurin inhibitors (CNIs) are the cornerstone of maintenance immunosuppression 1
- Tacrolimus is typically preferred over cyclosporine due to:
- Lower rejection rates
- More widespread use in the United States 1
- Target tacrolimus trough levels:
- Early post-transplant: 5-15 ng/ml
- Long-term maintenance: approximately 5 ng/ml 1
- Cyclosporine trough levels:
- Early post-transplant: 200-300 ng/ml
- Long-term maintenance: 50-150 ng/ml 1
Management of Steroid-Resistant Rejection
- Steroid-resistant rejection occurs in approximately 13.7% of patients with acute rejection 3
- For steroid-resistant cases, antithymocyte globulin (ATG) is recommended:
- Success rate of approximately 83.3%
- Administered until liver function returns to normal
- Requires ganciclovir prophylaxis to prevent opportunistic infections 3
- Chronic rejection may develop if not adequately treated, presenting as:
- Vanishing bile duct syndrome (ductopenic rejection)
- Severe biliary obstruction and jaundice
- Often associated with renal dysfunction 1
Special Considerations
- Patients with primary sclerosing cholangitis (PSC) have higher risk of late acute cellular rejection (>1000 days post-transplant) 4
- Late cellular rejection (>6 months post-transplant):
- Often shows centrilobular inflammation, necrosis, and central vein endothelialitis on biopsy
- May require treatment even if not meeting full Banff criteria for rejection 5
- For patients with recurrent rejection episodes, consider:
- Double immunosuppression with addition of mycophenolate mofetil
- In some cases, maintenance low-dose prednisolone (5 mg daily) 1
Monitoring and Follow-up
- Regular monitoring of liver function tests is essential 1
- Drug level monitoring is critical due to the narrow therapeutic window of CNIs 1
- Avoid medications that affect CNI metabolism (see drug interaction considerations) 1
- Monitor for adverse effects of immunosuppression:
- Infections (bacterial, viral)
- Renal dysfunction
- Metabolic complications 1
Drug Interaction Considerations
- Avoid medications that alter CNI metabolism through cytochrome P-450 3A4 and P-glycoprotein pathways 1
- Common medications to avoid:
- NSAIDs (increase nephrotoxicity)
- Certain antibiotics (rifampin, rifabutin)
- Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
- St. John's Wort 1
- Always consult with the transplant center before initiating new medications 1