Identification and treatment of biliary complications after liver transplantation: more relevant than ever

Liver transplantation remains the treatment of choice for patients with end-stage liver diseases. Given the increasing demand for liver transplantation, the spectrum of potential grafts has been widened and includes now not only regular grafts from donation after brain death (DBD) but also organs from donation after cardiac death (DCD), split liver and living donor grafts, as well as so-called “marginal grafts” from donors with extended criteria such as significant steatosis hepatis or older age (1). These grafts are associated with higher rates of early allograft dysfunction and primary non-function—which stresses the healthcare system with increased length of hospital stay for patients and higher costs (2,3). Moreover, marginal grafts are at risk for biliary complications such as anastomotic and non-anastomotic strictures as well as biliary leakages, which is caused by more severe ischemia reperfusion injury and in consequence reduced micro perfusion of the biliary tract (4). One currently emerging technology to improve the preservation, evaluate graft quality, and potentially avoid early allograft dysfunction or biliary complications is ex vivo liver machine perfusion, either Hypothermic Oxygenated Perfusion (HOPE) or normothermic ex vivo liver machine perfusion (NEVLP) (5). The recent review by Magro et al. (6) from the University of Palermo is more relevant than ever in this context, providing a structured approach describing the risk factors, etiology and treatment of biliary complications after liver transplantation.

Magro et al. (6) address the ongoing discussion of the type of biliary anastomosis (duct to duct with end-to-end or side-to-side anastomosis, or hepaticojejunostomy) and whether a T-tube should be used. They conclude that the overall inconclusive data for the insertion a T-tube possibly might reflect a trend for more duct-to-duct anastomosis, if technically feasible. Especially, if a tension free anastomosis is possible, reduced surgery time might be an additional argument for omitting the T-tube. The removal of the T-tube might require another clinic visit (depending on local standards) and can be associated with further complications. Moreover, shortage of T-tube supply, which is currently the case in Germany, limits the everyday availability.

The authors also discuss donor and recipient characteristics as well as risk scores to predetermine graft failure. Instead of the donor risk index, which is based on donor data only, recent publications focus on more comprehensive postoperative recipient characteristics such as the Early Allograft Failure Simplified Estimation (EASE) and L-Graft Score that might predict graft loss more precisely (3,7,8). However, none of these scores has been shown to predict biliary complications. Marginal grafts are especially susceptible to ischemia reperfusion injury (IRI), especially if exposed to prolonged cold ischemia. This combination can increase the risk of non-anastomotic biliary strictures, especially in DCD organs (9). For example, three out of ten initially declined DCD liver grafts that were transplanted after passing quality assessment by NEVLP as part of the Viability Testing and Transplantation of Marginal Livers (VITTAL) trial developed biliary complications and required retransplantation (9).

Ischemic type biliary lesions often require prolonged endoscopic treatment with balloon dilatation and stenting. Magro et al. (6) provide a diagnostic flow-chart in case of suspicion of biliary complications with a focus on diagnostics and then intervention. Especially in centers without high expertise, the authors propose that retrograde cholangiopancreatography should be the last modality of choice, given the relatively high rates of complications such as pancreatitis and cholangitis.

Prevention of IRI through the means of ex vivo liver machine perfusion seems like the logical next step to prevent biliary complications. However, research regarding perfusion duration and modality, as well as regarding robust parameter for hepatocellular and cholangiocellular viability is still ongoing (10). Multicenter trials are necessary to analyze the effects of machine perfusion, either hypothermic or normothermic concepts, on the prevention and identification of biliary complications. Animal models with clinically available liver machine perfusions can be used with porcine livers, however, costs and logistics are both quite high. Small animal models for liver machine perfusion can therefore be a solution, as previously proposed (11,12). In small animal models of NEVLP, dual vessel perfusion and modification of vasodilation improved the viability of the bile duct. Analysis of bile pH, bicarbonate and glucose have additionally been proposed as markers of viability in NEVLP (13,14). Furthermore, defatting strategies have been proposed to reduce the impact of IRI in grafts with macrovesicular steatosis (15,16).

Since the liver transplantation community continues to pioneer machine perfusion and the limits of donor marginality, identification and treatment of biliary complications is more relevant than ever. Magro et al. (6) provide a thoughtful insight with their review of literature of biliary complications. We expect more research detailing the prevention or reduction of biliary complications through HOPE or NEVLP to be of outmost relevance for clinical practice in the near future.

Acknowledgments

Funding: This work was supported through institutional funding of the Charité-Universitätsmedizin Berlin. SM and NR are participants in the BIH Charité Clinician Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-111/coif). JP serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dutkowski P, Schlegel A, Slankamenac K, et al. The use of fatty liver grafts in modern allocation systems: risk assessment by the balance of risk (BAR) score. Ann Surg 2012;256:861-8; discussion 868-9. [Crossref] [PubMed]
2. Moosburner S, Sauer IM, Förster F, et al. Early Allograft Dysfunction Increases Hospital Associated Costs After Liver Transplantation-A Propensity Score-Matched Analysis. Hepatol Commun 2020;5:526-37. [Crossref] [PubMed]
3. Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010;16:943-9. [Crossref] [PubMed]
4. Hirao H, Nakamura K, Kupiec-Weglinski JW. Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol 2022;19:239-56. [Crossref] [PubMed]
5. Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018;557:50-6. [Crossref] [PubMed]
6. Magro B, Tacelli M, Mazzola A, et al. Biliary complications after liver transplantation: current perspectives and future strategies. Hepatobiliary Surg Nutr 2021;10:76-92. [Crossref] [PubMed]
7. Agopian VG, Markovic D, Klintmalm GB, et al. Multicenter validation of the liver graft assessment following transplantation (L-GrAFT) score for assessment of early allograft dysfunction. J Hepatol 2021;74:881-92. [Crossref] [PubMed]
8. Avolio AW, Franco A, Schlegel A, et al. Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure Among Patients Requiring Early Liver Retransplant. JAMA Surg 2020;155:e204095. [Crossref] [PubMed]
9. Mergental H, Stephenson BTF, Laing RW, et al. Development of Clinical Criteria for Functional Assessment to Predict Primary Nonfunction of High-Risk Livers Using Normothermic Machine Perfusion. Liver Transpl 2018;24:1453-69. [Crossref] [PubMed]
10. van Leeuwen OB, de Vries Y, de Meijer VE, et al. Hypothermic machine perfusion before viability testing of previously discarded human livers. Nat Commun 2021;12:1008. [Crossref] [PubMed]
11. Gassner JMGV, Nösser M, Moosburner S, et al. Improvement of Normothermic Ex Vivo Machine Perfusion of Rat Liver Grafts by Dialysis and Kupffer Cell Inhibition With Glycine. Liver Transpl 2019;25:275-87. [Crossref] [PubMed]
12. Claussen F, Gassner JMGV, Moosburner S, et al. Dual versus single vessel normothermic ex vivo perfusion of rat liver grafts using metamizole for vasodilatation. PLoS One 2020;15:e0235635. [Crossref] [PubMed]
13. Matton APM, de Vries Y, Burlage LC, et al. Biliary Bicarbonate, pH, and Glucose Are Suitable Biomarkers of Biliary Viability During Ex Situ Normothermic Machine Perfusion of Human Donor Livers. Transplantation 2019;103:1405-13. [Crossref] [PubMed]
14. Michelotto J, Gassner JMGV, Moosburner S, et al. Ex vivo machine perfusion: current applications and future directions in liver transplantation. Langenbecks Arch Surg 2021;406:39-54. [Crossref] [PubMed]
15. Boteon YL, Attard J, Boteon APCS, et al. Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery. Liver Transpl 2019;25:1007-22. [Crossref] [PubMed]
16. Raigani S, Carroll C, Griffith S, et al. Improvement of steatotic rat liver function with a defatting cocktail during ex situ normothermic machine perfusion is not directly related to liver fat content. PLoS One 2020;15:e0232886. [Crossref] [PubMed]