Plasma Cell-Rich Rejection After Liver Transplantation: New Insights into Evolving Risk Factors and Etiologies

Background/Objectives: Plasma cell-rich rejection (PCRR) is a severe form of liver allograft dysfunction that can lead to graft failure and re-transplantation. Often overlapping with antibody-mediated rejection (AMR) and T-cell-mediated rejection (TCMR), PCRR remains under-researched regarding its predisposing risk factors. This study evaluates the clinical profiles, risk factors, and outcomes of PCRR, comparing it to recurrent plasma cell hepatitis (PCH) in patients transplanted for autoimmune hepatitis (AIH). Methods: We conducted a multi-center, retrospective study of liver transplant recipients across three institutional sites with biopsy-confirmed PCRR (based on Banff 2016 criteria) and patients transplanted for AIH with biopsy-proven recurrent PCH. Clinical characteristics, donor demographics, biomarker profiles (including tissue C4d), and post-transplant outcomes were compared between the two cohorts. Results: A total of 60 patients were identified with evidence of plasma cell-rich hepatitis on liver biopsy, of whom 17 (28.3%) had a history of AIH and were identified as having recurrent PCH, and 43 (71.7%) underwent transplant for non-AIH indications and were identified as having developed PCRR. In the PCRR group, the most common etiologies for liver transplant were metabolic dysfunction-associated steatohepatitis (MASH, 27.9%) and primary sclerosing cholangitis (PSC, 25.6%). The recurrent PCH group had more females (88.2% vs. 48.8%, p = 0.008). While not statistically significant, tissue C4d positivity was found to be higher in the PCRR group (30.2% vs. 5.9%). Patients with PCRR were observed to undergo more re-transplantations than those with recurrent PCH (16.7% vs. 5.9%), but overall mortality was comparable between the two groups (29.4% in recurrent PCH vs. 23.3% in PCRR). Conclusions: To our knowledge, this represents one of the largest case series evaluating PCRR. In the direct-acting antiviral (DAA) era, MASH and PSC have replaced hepatitis C virus as the dominant pre-transplantation etiologies associated with PCRR. The high frequency of C4d positivity and PCRR development despite therapeutic immunosuppression underscores a possible underlying AMR mechanism, suggesting standard T-cell-directed therapies may be insufficient. Recognizing these modern risk profiles and humoral markers is essential for early diagnosis, targeted interventions, and improved allograft survival.