From the Guidelines
Antibody-mediated rejection (AMR) in liver transplantation is characterized by several key histopathological features, including portal vein and capillary endothelial cell swelling, C4d deposition in portal veins and sinusoids, portal microvascular disruption, and portal microvasculitis with neutrophilic infiltration, as described in the most recent guidelines 1. The most salient findings in AMR of the liver include:
- Portal vein and capillary endothelial cell swelling
- C4d deposition in portal veins and sinusoids
- Portal microvascular disruption
- Portal microvasculitis with neutrophilic infiltration Other important features that may be present include:
- Ductular reaction
- Cholestasis
- Hepatocyte ballooning
- Sinusoidal congestion The presence of donor-specific antibodies (DSAs) often correlates with these findings, particularly those against HLA class II antigens, although the current Banff criteria for chronic AMR lack specificity and are not backed up by mechanistic studies supporting a direct pathogenic role of DSAs 1. Histologically, AMR may show a pattern of preservation injury with neutrophilic portal microvasculitis, and in severe cases, there may be confluent parenchymal necrosis, highlighting the importance of prompt diagnosis and treatment to prevent graft dysfunction and failure 1. The diagnosis typically requires demonstration of DSAs in serum, C4d positivity in tissue samples, and compatible histological changes, although C4d staining patterns in liver AMR can be more variable and may be focal rather than diffuse, unlike kidney transplants 1.
From the Research
Histopathological Features of Antibody-Mediated Rejection (AMR) in the Liver
The salient histopathological features of AMR in the liver include:
- Portal eosinophilia
- Portal vein endothelial cell hypertrophy
- Eosinophilic central venulitis
- Central venulitis severity
- Cholestasis 2 These features are incorporated into the acute antibody-mediated rejection score (aAMR score), which is used to screen patients for acute AMR via routine H&E staining of indication liver transplant biopsy samples.
Role of C4d Immunohistochemistry in Diagnosing AMR
C4d immunohistochemistry is used to diagnose AMR in liver transplant patients. Linear C4d endothelial staining or staining seen in 50% or more of the portal tracts is considered positive 3. However, C4d positivity in isolation has limited diagnostic value, and the presence of diffuse C4d immunostaining should prompt testing for donor-specific antibodies (DSAs) 4.
Diagnostic Criteria for AMR
The diagnosis of AMR requires a combination of clinical work-up, histopathology, C4d staining, and donor-specific antibody (DSA) testing 5. Strict criteria for defining "pure" AMR in the liver allograft include:
- Graft dysfunction associated with compatible histological findings
- Presence of DSAs
- Diffusely positive staining for C4d 4 These criteria are used to diagnose AMR and distinguish it from other causes of liver allograft dysfunction.
Clinical Relevance of AMR
AMR is a significant contributor to early liver allograft loss, and patients with preformed DSAs are at risk for clinically significant allograft injury and possibly loss from AMR 6. The presence of DSAs is associated with inferior long-term outcomes, and characterization of pathogenic DSAs continues to progress 5.