LIVER TRANSPLANTATION 13:480-482, 2007
EDITORIAL
How to Make Steatotic Livers Suitable for Transplantation Ian P.J. Alwayn1 and Robert J. Porte2 1 Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, and 2Department of Surgery, Section Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Received September 15, 2006; accepted September 28, 2006.
See Article on Page 497 Improvements in the surgical and nonsurgical care of patients with end-stage liver disease have led to an expansion of the indications for liver transplantation, resulting in an increasing shortage of donor organs. Despite many attempts to expand the donor pool, such as utilizing split or living donor liver transplants, the amount of available organs is insufficient to meet the demand. Alternatives to human organs, such as bioartificial organs, xenotransplantation, or stem-cell technology do not appear to have widespread clinical applicability in the foreseeable future. It seems logical, therefore, to focus attention on organs from compromised donors— organs that are at a higher risk of postoperative complications, such as initial poor graft function (or even primary nonfunction) or biliary complications. Although there is no general consensus on the definition of a compromised, or extended-criteria, donor, most would include donors who are older (⬎60 years), and who have diabetes mellitus, hypertension, renal insufficiency, or hepatic steatosis in this category.1,2 Obesity, diabetes mellitus, the metabolic syndrome, and associated nonalcoholic fatty liver disease are reaching epidemic proportions throughout the world. A recent survey has indicated that up to 30% of the population in Western societies has a certain degree of hepatic steatosis.3 In case of advanced degrees of steatosis, this condition may preclude certain individuals as liver donors. Although some controversy about whether all steatotic livers should be excluded from
transplantation remains,1,2,4 and some groups have reported reasonable outcomes utilizing livers with a certain degree of steatosis,1,4,5 livers that are deemed steatotic are frequently discarded. The reason not to utilize a potential liver is frequently based on subjective findings of hepatic steatosis during the procurement of postmortem organs,6 and in most programs, potential living donors are excluded when hepatic steatosis is detected during routine preoperative evaluation. There is a growing body of evidence to argue that steatotic livers are more susceptible to ischemia-reperfusion injury4 and, following transplantation, have less favorable outcomes than nonsteatotic livers.7,8 Hence, if manipulations, in vivo or ex vivo, could increase the quality of these organs and improve their outcome following transplantation, the number of livers available for transplantation would increase and, thereby, reduce current waiting lists for liver transplantation. These manipulations can be divided into 2 groups, the first focusing on reversing hepatic steatosis. If reversal cannot be achieved, the other group can focus on protecting the liver from ischemia-reperfusion injury associated with steatosis. In this issue of Liver Transplantation, Bessems et al. present their data on hypothermic machine preservation of fatty livers in a rodent model of hepatic steatosis.9 On the basis of an elegant and well-documented study, the authors conclude that less liver damage is observed following machine preservation of steatotic livers in comparison to conventional storage and that hepatobiliary function is superior in livers preserved with machine perfusion. Although the experiments
Abbreviations: PPAR, peroxisome proliferator-activated receptor. Address reprint requests to Robert J. Porte, MD, PhD, Associate Professor of Surgery, Section Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Telephone: 31-503612896; FAX: 31-50-3614873; E-mail:
[email protected] DOI 10.1002/lt.21026 Published online in Wiley InterScience (www.interscience.wiley.com).
© 2007 American Association for the Study of Liver Diseases.
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were not performed in a liver transplantation model but rather in an isolated liver perfusion model, the results still have important implications in the light of the everincreasing donor organ shortage. The benefits of machine perfusion may not be limited to the reduction of loss of organ quality and may also include the possibility of manipulating organs before transplantation, with the aim of actually improving the organ quality. Before we can determine which manipulations may be successful in treating or preventing injury induced by steatosis, several important issues need to be addressed. First of all, we must have a basic understanding of the underlying mechanisms of hepatic steatosis. It is well known that regardless of the etiology, hepatic steatosis is the end result of abnormal triglyceride synthesis and secretion. This imbalance can be due to excessive caloric intake, with an excess ratio of carbohydrates or fat.10 In addition, essential fatty acid deficiency,11 hepatic infections,12 drug toxicity,13 hypoxia, and enteric dysfunction in parenterally fed patients14 can lead to hepatic steatosis. A limitation of manipulations in these areas is that they may only potentially affect live liver donors, as only these patients may be put on a diet or have an infection treated that could reverse hepatic steatosis. If one investigates the more fundamental mechanisms of hepatic steatosis, it becomes clear that many factors are involved. Recent literature has determined important roles for the transcription factors peroxisome proliferator-activated receptor (PPAR)-alpha and gamma,15,16 sterol-regulatory element binding proteins-1c,17,18 and nuclear factor-kappaB19 and the downstream genes they regulate that are involved in fatty acid metabolism. Additionally, roles have been described for tumor necrosis factoralpha and interleukin 6, as inflammation is an important feature of the progression of hepatic steatosis to steatohepatitis. Strategies aimed at targeting these factors have produced limited results in treating fatty liver disease but some agents appear quite promising such as the use of rosiglitazone and pioglitazone,20 both ligands of PPAR-gamma. Finally, novel pathways have been discovered that appear to influence established factors, such as matrix metalloproteins and PPAR-alpha.15 A second issue to address is whether all types of hepatic steatosis have an equal and detrimental effect on liver function. There is increasing evidence that microvesicular steatosis may not be associated with poor outcome following liver transplantation than macrovesicular steatosis. Cheng et al. described their results in a rodent model of steatosis.21 Livers with microvesicular steatosis had graft survivals approaching 100% following transplantation, while those with macrovesicular steatosis had significantly poorer outcomes. These findings were confirmed in a clinical review by Fishbein et al.22 Interestingly, it has recently been described that macrovesicular steatosis can be converted to microvesicular steatosis in a murine model of dietary-induced steatosis using an omega-3 fatty acid suspension.23 Other issues include determining the percentage of steatosis that is associated with an increased risk of
poor graft function following transplantation. Is it rational to have a cutoff point at 30%? In other words, should livers with a higher percentage of steatosis be discarded? And should the percentage of steatosis be determined by routine biopsies at procurement, or should radiological investigations such as magnetic resonance imaging24 or ultrasound25 be performed prior to procurement? Unfortunately, there is insufficient evidence to recommend the routine use of any of these tools in the workup to donation, and most often, the degree of steatosis is determined by the donor surgeon by macroscopic evaluation during the procurement. Moreover, “the eye of the surgeon” has also been shown not to be reliable in this respect.6 The study by Bessems et al.9 in the current issue strongly suggests that steatotic livers are better protected against injury that occurs during ischemia and reperfusion than livers that are preserved by simple cold storage. Steatotic livers that were perfused in a hypothermic machine perfusion system had less evidence of tissue and functional damage than similar livers stored with conventional methods, while no changes in hepatic steatosis were described. It is likely that the beneficial results obtained in this study with the machine-perfused livers are due to the combination of optimal cooling and delivery of the preservation solution and better oxygenation during preservation, rather than to manipulation of or change in the actual quality of the liver. One can envision that the additional strength of this system lies in the possibility of modifying and improving the quality of the perfused liver. Although adding drugs to the perfusion solution that interfere with lipid metabolism may not be as effective in a hypothermic perfusion system, in a normothermic system they may be quite efficient. Further along the way, the use of gene therapy in this system to deliver certain protective genes to the liver prior to transplantation may be feasible. This study opens up a whole range of potential therapeutic manipulations for marginal (liver) grafts for which follow-up studies are required.
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LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
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