What are the typical biopsy features in a patient with antibody-mediated rejection after a liver transplant?

Antibody-Mediated Rejection in Liver Transplantation: Biopsy Features

Diagnostic Histopathologic Features

The diagnosis of antibody-mediated rejection (AMR) after liver transplantation requires identification of specific histologic features on H&E staining, including portal vein endothelial cell hypertrophy, portal eosinophilia, eosinophilic central venulitis, and cholestasis, combined with C4d immunostaining and donor-specific antibody (DSA) testing. 1, 2, 3, 4

Core Histologic Features on H&E Staining

The most discriminating features that should trigger suspicion for AMR include:

• Portal vein endothelial cell hypertrophy - endothelial cells appear enlarged and activated 4
• Portal eosinophilia - prominent eosinophils within portal tracts 4
• Eosinophilic central venulitis - inflammation of central veins with eosinophil predominance 4
• Cholestasis - bile accumulation correlating with AMR severity 4
• Portal inflammation with endothelialitis and bile duct injury 5, 6
• Extensive centrilobular (centrizonal) necrosis in severe cases 5

Features That Argue Against AMR

Importantly, certain findings are inversely correlated with AMR and suggest alternative diagnoses:

• Lymphocytic venulitis - suggests T-cell mediated rejection rather than AMR 4
• Lymphocytic portal inflammation - more typical of acute cellular rejection 4

Quantitative Scoring System

A validated acute AMR score (aAMR score) has been developed across multiple institutions to screen for AMR 4:

aAMR Score Formula:

• (Portal vein endothelial hypertrophy + Portal eosinophilia + Eosinophilic venulitis) ÷ (Lymphocytic portal inflammation + Lymphocytic venulitis) 4

Interpretation thresholds:

• Score >1.75 = high specificity (86%) for AMR, warranting immediate DSA and C4d testing 4
• Score >1.0 = high sensitivity (81%) for AMR, should prompt further workup 4

Essential Confirmatory Testing

Immunohistochemistry

• C4d staining (by immunoperoxidase or immunofluorescence) is required to demonstrate complement activation 1, 7, 6
• Diffuse C4d positivity in portal areas strongly supports AMR diagnosis 6, 4
• C3d staining may provide additional diagnostic value 7

Serologic Correlation

• Donor-specific anti-HLA antibodies (DSA) must be present for definitive AMR diagnosis 1, 2, 7
• DSA testing should include both Class I and Class II antibodies 1
• MFI >1000 is the typical threshold for clinical significance, though MFI >10,000 indicates substantially higher risk of allograft loss 1, 7
• Complement-fixing capacity (C1q-binding) of DSAs provides additional prognostic information 1, 7

Distinguishing AMR from Acute Cellular Rejection

This distinction is critical as treatment differs fundamentally:

Acute Cellular Rejection Features

• Mixed portal inflammation with lymphocyte predominance 2, 8
• Bile duct inflammation/damage 2, 8
• Endothelialitis (can overlap with AMR) 2, 8
• Responds to corticosteroids 2, 8

Key Differentiating Points

• AMR shows eosinophil predominance rather than lymphocytic infiltrate 4
• AMR requires positive C4d staining and DSA presence 1, 6
• Simultaneous acute cellular rejection and AMR can occur, requiring dual treatment approaches 6

Critical Clinical Pitfalls

Effect of Pre-Treatment on Histology

Portal inflammation and endothelialitis resolve rapidly with immunosuppression, but bile duct damage persists longer - this creates a diagnostic trap 9:

• Patients pretreated with steroids or increased immunosuppression before biopsy show significantly less portal inflammation (P<0.001) and less endothelialitis (P<0.001) 9
• Bile duct inflammation/damage does NOT significantly decrease with pretreatment (P=0.32) 9
• Therefore, isolated bile duct injury without portal inflammation should raise suspicion for partially treated AMR, not exclude the diagnosis 9

Timing Considerations

• AMR can present as hyperacute rejection (0-7 days post-transplant) in sensitized recipients 1
• Early AMR occurs within the first month 1
• Acute liver failure from AMR, though rare, can occur and may require urgent retransplantation 5

Diagnostic Algorithm

When evaluating a post-transplant liver biopsy for suspected rejection:

1. Calculate aAMR score from routine H&E features 4
2. If score >1.0, immediately order C4d immunostaining and serum DSA testing 4
3. Assess for pretreated rejection if isolated bile duct damage is present without portal inflammation 9
4. Confirm allograft dysfunction with liver function tests 7
5. Exclude alternative diagnoses: recurrent disease, viral infection, drug toxicity, vascular complications 2, 8

Prognostic Implications

• AMR with DSA MFI >10,000 carries significantly higher risk of allograft loss compared to MFI 1000-10,000 7
• Complement-fixing DSAs indicate worse prognosis and may guide treatment intensity 1, 7
• Early recognition is essential as AMR can progress to acute liver failure requiring retransplantation if untreated 5
• Despite aggressive treatment, DSA MFI >10,000 persists in 95% of patients at 5 years, requiring indefinite surveillance 7