Idiopathic Post Liver-Transplant Hepatitis Remains Obscure with Respect to Its Etiology and Relationship with Immunosuppressiona

Abstract

Aim: Idiopathic post-liver transplant hepatitis (IPTH) can lead to late graft fibrosis. The treatment for IPTH is not clearly delineated. We aimed to approach its pathophysiology and predictive factors for fibrosis progression (FP). Methods: Patients whose IPTH was diagnosed in 2006 and had undergone at least one subsequent liver biopsy (LB) were included. The index LBs were reviewed and correlated with clinical, laboratory, C4d immunostaining retrospectively performed, and histological data on the most recent LBs. Results: Among the 299 post-transplant LBs, 37 presented IPTH. The index LBs mostly displayed mild fibrosis (65%) and activity (67.5%), and non-significant C4d immunostaining (i.e., weak, focal and/or portal stroma staining, 21.6%). Liver tests were normal in 46% of patients. Virological markers including Hepatitis E were negative. Antinuclear auto-antibodies were present concurrently in four patients and appeared later in two patients, together with features of autoimmune hepatitis (AIH) in one. Isolated AIH features appeared later in one patient. One patient displayed AIH features on the index LB, with negative auto-antibodies and elevated serum IgG. Fibrosis was stable, increased or decreased in 23, 11, and three patients, respectively. FP was less frequent in tacrolimus-treated patients (p = 0.022), more frequent in cyclosporine- (p = 0.035) and MMF-treated patients (p = 0.023), and not influenced by steroid-based treatment or increased overall immunosuppression or steroids. Under multivariate analysis, MMF remained an independent predictor of FP (p = 0.048). Conclusion: The physiopathology of IPTH remained unclear. Increasing steroid doses or overall immunosuppression did not prevent FP. The potential impact of MMF on FP will require prospective studies.