This report by Aguilera et al. 1 is the first to link complement component 4d (C4d) immunopositivity in liver allograft biopsies to donor-specific alloreactivity that is not related to ABO incompatibility or donorspecific human leukocyte antigen antibodies (DSAs). The intensively studied patients had an unusual form of donor-specific posttransplant hepatitis that was associated with the development after transplantation of an immune response to glutathione-S-transferase (GSTT1), which had not been expressed in each patient’s native liver. Lymphoplasmacytic hepatitis then manifested in a subset of those developing high titers of circulating anti-GSTT1 antibodies. In all 9 positive biopsy samples (from 7 of 8 patients), C4d was restricted to portal tract vessels, although the staining illustrated was rather weak; interestingly however, C4d also stained small nerves when they were present (3 cases), and these were also shown to express GSTT1. This kind of hepatic nerve staining may be specific to this diagnosis. The comparison groups did not show the portal C4d pattern, with no staining for the patients with recurrent hepatitis C; however, 4 of 6 patients with chronic rejection showed sinusoidal C4d positivity, but the staining illustrated was again weak. This interesting study arrives on the heels of 2 other studies by Kozlowski et al. 2 and Musat et al., 3 who looked at DSAs after liver transplantation in select patients and also correlated them with contemporaneous C4d immunostaining. It is timely then to consider the question of C4d immunostaining in liver transplant biopsy samples and its relationship with antibody-mediated rejection (AMR). C4d immunohistochemistry has the potential to improve the recognition of AMR, but as Aguilera et al. 1 remark, the consensus for C4d staining patterns in renal allograft biopsies has not been matched for liver allografts. A variety of observations about frequencies, patterns, and clinical correlations have been reported in more than 20 publications, but only a few groups have correlated their observations with antidonor serology. Can we make any sort of working assessment about the practice and value of anti-C4d staining in liver allografts? Pure acute AMR is uncommon and potentially injurious, 4, 5 and it is a diagnostic challenge for pathologists. The early histological findings resemble those for ischemic injury or sepsis, and clinical, radiological, and serological evidence is required. 4, 5 AMR is more often accompanied by acute cellular rejection and may be unrecognized. This may matter little when both components respond to conventional therapy, but there is the risk of steroid-resistant AMR being missed or being identified only with a second biopsy procedure after the treatment (if the cellular rejection has responded to the therapy). Persistent AMR can cause ductopenic rejection (sometimes

Abbreviations: AMR, antibody-mediated rejection; C4d, complement component 4d; DSA, donor-specific human leukocyte antigen antibody; GSTT1, glutathione S-transferase T1; HLA, human leukocyte antigen.