*Purpose: Liver transplantation (LT) has become a standard therapy for the management of end-stage liver disease, while early allograft dysfunction (EAD) remains a serious problem. Chronic liver inflammation causes fibrosis (collagen deposit) that may lead to cirrhosis, whereas early stage of hepatic fibrosis develops without any symptoms, recognizable clinical variables or macroscopic abnormality on liver surface. Due to a myriad of ongoing metabolic and environmental stressors that may trigger hepatic inflammation, we hypothesized that some of the current donor liver grafts have inapparent fibrosis, which in turn may affect susceptibility against LT challenge. By retrospectively analyzing collagen deposition in LT biopsies (Bx), this study aimed to determine whether occult hepatic fibrosis at the time of procurement influences clinical outcomes.

*Methods: Liver Bx were obtained during LT surgery under IRB protocol (n=38). Hepatic Bx were stained with Sirius-red to detect collagen deposition and Sirius-red positive area (SRA) was calculated by dividing positive-stained / whole tissue area. In addition to SRA, clinical parameters including donor age/gender/BMI, recipient age/gender/BMI, donation after cardiac death, MELD score, cold ischemia time, warm ischemia time were evaluated. A multivariate analysis based on a step-wise logistic regression model and a Cox regression model were used to identify predictive factors of EAD and rejection-free recipient survival, respectively.

*Results: Of 38 cases, a median of SRA was 11.7% (range: 1.1%-29.9%) while SRA in reference normal mouse livers were 0.9±0.4%. SRA positively correlated with sALT levels at POD1 (r=0.321, p=0.049). To evaluate the predictive power of SRA for EAD, a cut-off value of 16% was decided based on the ROC curve (AUC=0.703, sensitivity=0.800, specificity=0.788), and then 38 cases were divided into low-SRA (SRA<16%, n=27) and high-SRA (SRA>16%, n=11) groups. The high-SRA cases had increased mRNA levels coding for αSMA (a fibrosis marker, 1.9±1.6 vs 0.4±0.1), experienced more frequent EAD as compared to low-SRA patient cohort (36.4 vs 3.7%, p=0.019), while a multivariable analysis identified high-SRA as a sole independent predictive factor of EAD (odds ratio=14.9 [95%CI: 1.4-155.0], p=0.024). The high-SRA cases exhibited inferior post-LT rejection-free survival (3-years: 44.6% vs 85.2%, p=0.008, median follow-up=1258 days), while a multivariable analysis identified high-SRA as an only independent predictive factor of rejection-free survival (hazard ratio=4.4 [95%CI: 1.3-14.5], p=0.015).

*Conclusions: This study documents the critical influence of occult liver fibrosis at the time of procurement on clinical LT outcomes. By shedding new light on previously unappreciated inapparent fibrosis development in the hepatic donor tissue, our findings provide a rationale for future studies with larger LT patient cohort.

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