Evidence for Alloimmune Sinusoidal Injury in De Novo Nodular Regenerative Hyperplasia After Liver Transplantation

Abstract

Posttransplant nodular regenerative hyperplasia (NRH) mostly remains unexplained. Microvascular injury due to antibody-mediated rejection (AMR) is suspected, but lack of donor specific antibody (DSA) testing makes it difficult to prove. Centered around a 1-year period of routine DSA testing, concomitant protocol, and indicated posttransplant liver biopsies (LB), recipients with NRH (n = 18) were compared with a matched control group (n = 36). All index, previous, and subsequent LB were reviewed. Both groups were similar in terms of demographics, timing of index LB, and DSA. In the index LB, the NRH group had higher sinusoidal C4d positivity (p = 0.029) and perisinusoidal fibrosis (p = 0.034), both independently associated with NRH (p = 0.038 and 0.050, respectively). Features of "possible" chronic AMR were detected in 28.5% of the NRH group without a known cause and 0% of the control group (p = 0.009). The NRH group had more preceding indicated LB with increased incidence of rejection and biliary obstruction pattern. In the follow-up histology, overall, sinusoidal and portal C4d positivity, sinusoidal microvasculitis, and perisinusoidal fibrosis were also higher (all p < 0.050). In conclusion, we provide evidence towards the hypothesis that some cases of posttransplant NRH are related to preceding active and persistent AMR. Large multicenter studies with protocol DSA testing are required to confirm.

Keywords: Banff criteria; C4d; chronic antibody-mediated rejection; liver transplantation; nodular regenerative hyperplasia; pathology.

FIGURE 1

Representative images of NRH and “sinusoidal microvasculitis.” Alternating widened and atrophic hepatic plates in a nodular architecture, consistent with NRH on Hematoxylin eosin staining (A) and Gordon Sweet’s silver staining (B). At high magnification, so-called “sinusoidal microvasculitis” (C) by analogy with portal capillaritis, defined by the presence of marginated monocytes/macrophages within dilated sinusoids.

FIGURE 2

Representative images of C4d in patients with NRH. (A) An example of minimal (<10% staining) C4d positivity in an index LB with NRH. C4d positivity is observed within the sinusoidal microvasculature. (B) Focal (10%–50% staining) C4d positivity within the sinusoidal microvasculature in an explant with NRH. C4d deposition on the elastic fibers of arterioles was regarded as a positive internal control. (C) Diffuse (>50% staining) C4d positivity in an explant with NRH. C4d positivity is observed within the portal venules, capillaries and inlet venules, and sinusoids.

FIGURE 3

Shift toward a pathogenic phenotype in HSC and LSEC over time. By comparing similarly-sized portal tracts, central veins, and sinusoids in the index LB (A) versus last follow up histology (B), there was an increase in CD34 expression in peri-portal, sinusoidal, or peri-venular regions, and in α-SMA expression diffusely.

FIGURE 4

Sinusoidal MHC class II overexpression in NRH. Low MHC class II expression limited focally on sinusoidal endothelium in the index (A) and last follow up LB (B) from a control patient. Sinusoidal MHC class II overexpression in the index (C) and last follow up LB (D) from a NRH patient. Portal-based dendritic cells served as internal positive controls.