Diagnostic Biomarkers to Diagnose Acute Allograft Rejection After Liver Transplantation: Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies

Abstract

Objective: A systematic review and meta-analysis of diagnostic biomarkers for noninvasive diagnosis of acute allograft rejection following liver transplantation. Background: Noninvasive blood and urine markers have been widely explored in recent decades for diagnosing acute rejection after liver transplantation. However, none have been translated into routine clinical use so far due to uncertain diagnostic accuracy, and liver biopsy remains the gold standard. Methods: Systematic literature searches of Medline, Cochrane and Embase were conducted up to February 2019 to identify studies evaluating the use of noninvasive markers in diagnosing allograft rejection following liver transplantation. Meta-analysis was performed using a random effects model with DerSimonian–Laird weighting and the hierarchical summary receiver operating curve. Results: Of 560 identified studies, 15 studies (1,445 patients) met the inclusion criteria. The following markers were tested: acid labile nitroso-compounds (NOx), serum amyloid A protein, procalcitonin, peripheral blood eosinophil count, peripheral blood T-cell activation and interleukin 2 (IL-2) receptor, guanylate-binding protein-2 mRNA, graft-derived cell-free DNA, pi-glutathione S-transferase, alpha-glutathione S-transferase and serum HLA class I soluble antigens. Only eosinophil count was tested in multiple studies, and they demonstrated high heterogeneity ( I 2 = 72% [95% CI: 0.5–0.99]). IL-2 receptor demonstrated the highest sensitivity (89% [95% CI: 0.78–0.96]) and specificity (81% [95% CI: 0.69–0.89]). Conclusion: IL-2 receptor expression demonstrated the highest diagnostic accuracy, while the peripheral eosinophil count was the only marker tested in more than one study. Presently, liver biopsy remains superior to noninvasive diagnostic biomarkers as most studies exhibited inferior designs, hindering possible translation into clinical application.

Deciphering the role of eosinophils in solid organ transplantation

“…Recent studies continue these correlations, proposing eosinophil blood counts as a biomarker for acute liver rejection . Yet a recent meta‐analysis of >800 patients and >1000 sample points indicated that blood eosinophil counts are highly heterogeneous and have only a 50% sensitivity for predicting acute liver rejection . Despite the fact that limited mechanistic evidence was provided by any of these studies, the destructive role of eosinophils was inferred from their increase at the time of rejection.…”

Pathology of Intestinal Transplantation: Rejection and a Case of Tolerance

“…The role of eosinophils in rejection has often been debated [33] and there is a discussion on whether eosinophils may be the target of rejection therapy [34]. An increase in the rejection of eosinophils has also been reported in the transplanted liver [35]. In the small intestine, the presence of the mucosal immune system may further complicate the graft's immunological environment.…”

Cholangitis Lenta: What Hepatologists Need to Know

“…Although noninvasive tests are currently under development, liver biopsy remains the gold standard for diagnosis of rejection. 5 Liver biopsies are able to assist in diagnosing other causes of hepatic diseases, including drug-induced liver injury, immune-mediated processes, hepatotropic viruses, and chronic biliary obstruction, in addition to providing details about the amount of fibrosis. 6…”