What are the signs and symptoms of liver transplant rejection?

Signs and Symptoms of Liver Transplant Rejection

The primary signs and symptoms of liver transplant rejection include abnormal liver function tests, fever, jaundice, and abdominal pain, with advanced rejection often presenting with more severe manifestations of these symptoms. 1

Types of Liver Transplant Rejection

Acute Rejection

• Laboratory abnormalities: Most commonly presents with hepatocellular abnormalities in liver function tests, though cholestatic patterns can also occur 1
• Systemic symptoms: Fever, jaundice, and abdominal pain may suggest advanced rejection 1
• Timing: Most common within first 3 months post-transplant but can occur at any time 1
• Risk factors: Often associated with low calcineurin inhibitor levels and medication noncompliance when occurring years after transplantation 1

Chronic Rejection

• Clinical presentation: Characterized by progressive fibrosis and disappearance of bile ducts (vanishing bile duct syndrome or ductopenic rejection) 1
• Symptoms: Severe biliary obstruction, jaundice, and frequently associated renal dysfunction 1
• Incidence: Has declined to approximately 4-8% in recent years (compared to 15-20% in earlier transplant eras) 2
• Timing: Usually presents within the first year post-transplantation 2

Diagnostic Evaluation

1. Laboratory tests:

   • Liver function tests (elevated transaminases, bilirubin, alkaline phosphatase)
   • Complete blood count
   • Tacrolimus/cyclosporine trough levels 3

2. Liver biopsy: Gold standard for diagnosing rejection and differentiating from other causes of allograft dysfunction 3

3. Imaging studies:

   • Abdominal ultrasound with Doppler to evaluate hepatic artery patency, portal and hepatic veins, and biliary tract 3

Differential Diagnosis

Liver allograft dysfunction may be caused by several conditions that should be distinguished from rejection:

1. Viral infections:

   • CMV infection (most common infectious cause in first few months) - presents with fever, headaches, myalgias, leukopenia, thrombocytopenia, and hepatitis 1
   • Other herpes family viruses
   • Hepatitis A, B, or C

2. Vascular complications (occur in up to 10% of liver transplant recipients):

   • Hepatic artery thrombosis
   • Portal or hepatic vein thrombosis 1

3. Biliary complications:

   • Strictures
   • Leaks
   • Obstruction 1

4. Recurrence of primary liver disease:

   • Hepatitis C (universal recurrence)
   • Hepatitis B
   • Autoimmune diseases (AIH, PBC, PSC) 1

5. Medication toxicity:

   • Drug-induced liver injury
   • Immunosuppressant toxicity 1

Risk Factors for Rejection

1. Patient factors:

   • Female gender 4
   • Younger recipient age 4
   • Primary diagnosis (higher risk with autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis) 2, 4

2. Immunosuppression-related:

   • Low calcineurin inhibitor levels
   • Medication noncompliance 1
   • Post-transplant lymphoproliferative disorder (PTLD) management 4

3. Infection-related:

   • CMV infection 2

Management Considerations

• Acute rejection is typically treated with increased immunosuppression, including high-dose corticosteroids 1
• Chronic rejection may be treated by increasing calcineurin inhibitor levels or adding sirolimus 1
• Approximately 52% of patients with chronic rejection may respond to addition of mTOR inhibitors (sirolimus/everolimus) 5
• Retransplantation should be considered for significant allograft synthetic dysfunction or portal hypertensive complications 1

Prognosis

• Early acute rejection (within 28 days) typically responds well to additional immunosuppression and has little clinical significance 2
• Late acute rejection (beyond 6 months) is associated with poorer patient and graft survival 4
• Steroid-resistant acute rejection carries a high mortality rate (approximately 28.6%) 6
• Chronic rejection may lead to irreversible graft failure requiring retransplantation 7

Key Points to Remember

• Abnormal liver function tests are often the first sign of rejection
• Fever, jaundice, and abdominal pain suggest more advanced rejection
• Liver biopsy remains the gold standard for diagnosis
• Always consider other causes of allograft dysfunction in the differential diagnosis
• Early recognition and treatment are essential for preventing progression to irreversible graft damage