In a post‑liver transplant patient with plasma cells identified on the allograft biopsy, what is the clinical significance and what immediate diagnostic and therapeutic steps should be taken?

Plasma Cells in Post-Liver Transplant Biopsy

Plasma cell infiltration on liver allograft biopsy should immediately trigger evaluation for antibody-mediated rejection (AMR) and de novo autoimmune hepatitis, with urgent donor-specific antibody (DSA) testing and assessment of graft function being the critical first steps. 1

Immediate Diagnostic Workup

Essential Laboratory Testing

• Obtain DSA testing immediately using solid-phase assays with mean fluorescence intensity (MFI) quantification and complement-fixing capacity (C1q or C3d binding) 1, 2
• Measure liver function tests (ALT, AST, alkaline phosphatase, bilirubin) and immunoglobulin levels, particularly IgG 1, 3
• Check autoantibody panel including ANA, SMA, and anti-LKM1 to evaluate for de novo autoimmune hepatitis 1

Histopathologic Evaluation

• Request C4d and C3d immunostaining on the biopsy specimen to assess for complement activation, which is diagnostic for AMR 1, 2, 4
• Quantify the percentage of plasma cells in the portal infiltrate: >10% plasma cells indicates moderate-to-severe rejection, while >30% is associated with severe rejection 5
• Evaluate for interface hepatitis and assess fibrosis stage to distinguish between AMR and de novo autoimmune hepatitis 1, 3

Clinical Significance and Risk Stratification

Antibody-Mediated Rejection

Plasma cell infiltration is a key histologic feature of chronic AMR and correlates with DSA presence 1, 4. The 2024 EASL guidelines emphasize that:

• High-risk features include DSA MFI >10,000, which persists in 95% of patients at 5 years and carries significantly higher risk of allograft loss 1, 2
• Complement-fixing DSAs (C1q or C3d positive) are associated with increased risk of allograft loss and rejection 1, 2
• De novo DSAs (developing post-transplant) are particularly concerning, with 63% frequency in some cohorts and strong association with inflammation and fibrosis 1

De Novo Autoimmune Hepatitis

Plasma cells are characteristic (though not pathognomonic) of autoimmune hepatitis, and "de novo AIH" or "post-transplant plasma cell hepatitis" can develop after liver transplantation for non-autoimmune indications 1, 3. This entity:

• Presents with elevated transaminases, hypergammaglobulinemia (particularly IgG), and positive autoantibodies 1
• Requires differentiation from AMR through DSA testing and C4d staining 1, 3
• Benefits from increased immunosuppression rather than reduction 1

Severity Grading

The percentage of plasma cells correlates directly with rejection severity 5:

• Any plasma cells present: associated with higher-grade rejection (P=0.006)

• 10% plasma cells: indicates moderate or severe rejection

• 30% plasma cells: indicates severe rejection exclusively

Immediate Therapeutic Approach

If AMR is Confirmed (DSA+ with C4d/C3d staining)

First-line therapy for acute AMR:

• High-dose methylprednisolone 500-1000 mg IV daily for 3 days 1, 2
• Plasmapheresis (plasma exchange) to remove circulating antibodies, typically daily for 5-7 days exchanging twice the blood volume 1, 2
• Intravenous immunoglobulin (IVIG) following plasmapheresis 1, 2, 6
• Strengthen baseline immunosuppression: increase tacrolimus target levels and/or add mycophenolate mofetil or corticosteroids 1

Second-line therapy for persistent AMR:

• Rituximab (anti-CD20) to deplete B cells 1, 2, 6
• Consider bortezomib (proteasome inhibitor) or daratumumab for plasma cell-directed therapy in refractory cases 2
• Eculizumab (complement inhibitor) may be considered for complement-mediated injury 1, 6

If De Novo Autoimmune Hepatitis is Suspected (DSA negative, autoantibody positive)

• Increase immunosuppression rather than decrease it 1
• Prednisone 0.5-1 mg/kg daily with gradual taper based on biochemical response 1
• Assess medication compliance, as nonadherence can precipitate autoimmune-like rejection 1
• Add or optimize mycophenolate mofetil if not already on therapy 1, 7

Critical Management Pitfalls

Immunosuppression Minimization

Do not attempt immunosuppression minimization in patients with:

• High MFI DSAs unless allograft damage has been excluded by biopsy 1
• Plasma cell-rich infiltrates on biopsy 1, 5
• Evidence of interface hepatitis or significant fibrosis 1

The 2024 EASL guidelines explicitly state that "in the presence of high mean fluorescence intensity DSAs, minimisation is not advisable unless allograft damage has been excluded by performing a liver biopsy" 1.

Monitoring Strategy

• Serial DSA monitoring every 2-4 weeks during treatment to assess response 2
• Protocol biopsies at 3,6, and 12 months post-diagnosis for risk stratification 2
• Maintain therapeutic tacrolimus levels (10-15 ng/mL in early post-rejection period) 2
• Consider transient elastography or HVPG measurement to assess fibrosis progression non-invasively 1

Distinguishing AMR from Other Entities

The presence of plasma cells alone is not specific 1, 5. Key differentiating features:

• AMR: DSA positive, C4d/C3d positive, microvascular inflammation 1, 4
• De novo AIH: Autoantibodies positive, interface hepatitis, DSA negative 1
• Severe acute cellular rejection: Plasma cells present but DSA/C4d negative, responds to steroids 5
• Chronic hepatitis C recurrence (historical concern): HCV RNA positive, but now largely eliminated with DAA therapy 1

Long-Term Implications

Patients with plasma cell infiltrates and confirmed AMR or de novo AIH require indefinite surveillance 2:

• DSA MFI >10,000 persists in 95% at 5 years versus 68% for MFI 1000-10,000 1
• Chronic AMR with significantly raised transaminases and moderate inflammatory damage requires strengthened immunosuppression 1
• Integration of DSA testing with clinical parameters, graft function, and histology improves risk stratification 1