What are the types of rejection post liver transplantation?

Types of Rejection Post Liver Transplantation

Liver transplant rejection can be classified into three main types: acute cellular rejection, chronic rejection, and antibody-mediated rejection, each with distinct pathological features and clinical implications. 1, 2

Acute Cellular Rejection (ACR)

• Occurs in approximately 10% of liver transplant recipients, most commonly within the first 3 months post-transplantation but can occur at any time 1, 3
• Clinical presentation includes abnormal liver function tests (hepatocellular or cholestatic pattern), fever, jaundice, and abdominal pain in advanced cases 1, 3
• Diagnosis requires liver biopsy after exclusion of vascular or biliary complications 3
• Often associated with low calcineurin inhibitor (CNI) levels and medication non-compliance, especially when occurring years after transplantation 1
• First-line treatment consists of high-dose corticosteroids, typically administered as intravenous methylprednisolone 2, 3
• Late acute rejection (occurring ≥30 days post-transplant) affects about 7.5% of liver transplant recipients and may have worse outcomes, particularly when associated with centrilobular necrosis or bile duct loss 4

Chronic Rejection

• Characterized by fibrosis and progressive disappearance of bile ducts (vanishing bile duct syndrome or ductopenic rejection) 1, 2
• Results in severe biliary obstruction, jaundice, and is frequently associated with renal dysfunction 1
• Treatment options include increasing CNI levels or adding sirolimus/everolimus to baseline immunosuppression 1, 2
• Retransplantation should be considered if significant allograft synthetic dysfunction or portal hypertensive complications exist 1, 2
• The rate of graft loss due to ductopenic rejection has significantly decreased to less than 2% with modern immunosuppression regimens 2
• May develop if acute rejection is inadequately treated or in patients with recurrent episodes of acute rejection 5

Antibody-Mediated Rejection (AMR)

• A more recently recognized form of rejection in liver transplantation compared to kidney and lung transplants 6, 7
• Diagnosed based on specific clinical and histopathologic criteria: presence of donor-specific antibodies (DSAs), C4d staining in portal areas, characteristic histopathologic findings, and exclusion of other entities 6, 7
• Can be classified as acute or chronic AMR, with chronic AMR being more challenging to diagnose due to less specific histologic features 6
• Treatment may include steroids, immune-modulating agents, intravenous immunoglobulin, plasmapheresis, and proteasome inhibitors 6
• For persistent AMR not responding to first-line therapy, rituximab (to deplete B cells) or eculizumab (to inhibit complement activation) can be considered 2, 8
• Monitoring for donor-specific antibodies (DSAs) may help identify patients at risk of antibody-mediated rejection 2

Risk Factors and Prevention

• Patients with autoimmune liver diseases are at higher risk for early and late cellular rejection 3
• CMV viremia is a risk factor for chronic rejection 2
• Medication adherence is critical, as non-compliance is associated with late rejection episodes 3, 4
• Subtherapeutic immunosuppressant levels (tacrolimus <5 ng/ml or cyclosporine <100 ng/ml) precede approximately 38% of late acute rejection episodes 4

Clinical Pitfalls and Management Considerations

• Liver biopsy remains the gold standard for definitive diagnosis of all types of rejection 2, 3
• It is crucial to differentiate rejection from other causes of allograft dysfunction, including viral hepatitis, recurrent primary liver disease, vascular complications, and biliary complications 1, 9
• Drug interactions with immunosuppressants are common and can lead to subtherapeutic levels; avoid medications that alter CNI metabolism through cytochrome P-450 3A4 and P-glycoprotein pathways 1, 3
• Regular monitoring of liver function tests and immunosuppressant drug levels is essential for early detection and management of rejection 3
• Some patients may require simultaneous treatment for both acute cellular rejection and antibody-mediated rejection with combined immunosuppressive approaches 8