*Purpose: Although liver transplantation (LT) has become a standard therapy for end-stage liver disease, early allograft dysfunction (EAD) and graft rejection remain serious unsolved problems. Environmental-triggered chronic inflammation in the liver can cause hepatic collagen deposit, whereas early stages of fibrosis could hardly be detectable without any specific symptoms. We hypothesized that some of the donor hepatic grafts currently used might possess unrecognizable liver fibrosis, which in turn may affect the susceptibility to LT-induced stress. This study aimed to assess the impact of occult hepatic fibrosis at the time of procurement on clinical outcomes by retrospective analysis of collagen deposit in human donor livers.

*Methods: Liver biopsies (Bx) obtained during LT under IRB protocol (n=107) were stained with Sirius-red, and positive areas (SRA) were calculated in whole Bx tissue samples. In addition, clinical parameters and outcomes, including patient background, transaminase release post-LT, incidence of EAD, and severity of ischemia-reperfusion injury (IRI) were evaluated in liver Bx at 2 h post-reperfusion. Five IRI pathological grades (no, minimal, mild, moderate and severe), and rejection-free graft survival (RFGS) were analyzed retrospectively.

*Results: The median SRA in our donor LT cohort (n=107) was 10.1%. These were then classified into four groups: SRA<5% (n=12); 5≤SRA<10% (n=41); 10≤SRA<15% (n=25); and SRA≥15% (n=29). While there were no differences in patients’ demographics, LT with SRA≥15% had the highest incidence of mild-to-severe IRI/EAD/acute rejection (AR), combined with the worst RFGS, as compared with other groups. Then, 107 LT patients were divided into high-SRA (SRA≥15%, n=29) vs low-SRA (SRA<15%, n=78) groups. Recipients implanted with high-SRA donor livers experienced significantly higher incidence of EAD (41 vs 19%, p=0.019), tendency towards augmented transaminase release, and mild-to-severe IRI syndrome (66 vs 46%, p=0.075) as compared to those with low-SRA liver grafts. SRA positively correlated with post/pre-LT CCAAT-enhancer-binding protein homologous protein (CHOP) gene expression ratio (p=0.002), a marker of endoplasmic reticulum (ER) stress; and BARD score (p=0.021), which identifies advanced fibrosis in NAFLD patients. Notably, RFGS in high-SRA cases was significantly inferior as compared with low-SRA cases (p=0.026).

*Conclusions: These novel retrospective findings document the critical role of previously unappreciated occult liver fibrosis in the donor human livers on clinical outcomes in LT patients. High SRA correlated with higher incidence of EAD, ER stress, donor BARD score, and inferior RFGS. This study provides the rationale for in-depth prospective assessment of occult fibrosis in a larger LT patient cohort.

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