Editorial

Ischemic-Type Biliary Strictures in Liver Allografts: The Achilles Heel Revisited?

Nonanastomotic or “ischemic-type’’ biliary strictures develop in 2% to 19% of liver transplant recipient^.'.^ Because these patients have considerable morbidity and mortality and increased costs, further understand- ing of the etiology of these strictures coupled with a method for obviating stricture formation would be a noteworthy advance in liver transplantation.

Biliary strictures have been associated with pro- longed cold ischemia time,1,2s4r6 hepatic artery thrombo- sis, ABO incompatibility, primary sclerosing cholan- gitis, and rejection and other immunologic injury, such as positive lymphocytotoxic crossmatches.6-’1 In addi- tion, we have demonstrated an association between prolonged preservation in University of Wisconsin solu- tion and hepatic arterial thrombosis.12 These clinical associations suggest that damage to the hepatic arte- rial plexus is an intermediate step in ischemic biliary strictures. Therefore, the etiology of biliary strictures is complex and multifactorial. Any or all of these associ- ations may be operant in any single case yet inapparent in any retrospective analysis, particularly if sample size and stricture incidence are low.

In addition to these clinical associations, evidence from experimental models of liver allograft injury pro- vides additional, indirect clues to the mechanisms of biliary stricture formation. These data suggest that critical injuries incurred by the liver during cold preser- vation and reperfusion can be ascribed to thrombotic and ischemic events mediated by endothelial activation and injury.13,14 At numerous points, the process of transplantation exposes the endothelial cells to injury: before and during cold preservation; during reperfu- sion, with injury mediated by platelet activating factor, reactive oxygen species, and leukocyte products; and in the posttransplantation period, with immunologic assaults. Any such injury may contribute to hepatic arteriolar arteriopathy, vasoconstriction, and subse- quent segmental microvascular thrombosis.

Such injuries to the endothelial cells become mani- fest as a global allograft injury and cause serious micro- circulatory disturbance^.'^-^' Modalities that reduce en- dothelial injury or dilate the hepatic vasculature

From the Department of Surgery, Division of Liver Transplantation, The

Received September 16, 1994; accepted November 17, 1994. Address reprint requests to: Charles M. Miller, MD, Division of Liver Trans-

plantation, The Mount Sinai Medical Center, Box 1104, One Gustave L. Levy Place, New York, NY 10029.

Copyright 0 1995 by the American Association for the Study of Liver Diseases.

0270-9139/95/2102-0044$3.00/0

Mount Sinai Medical Center, New York, NY.

appear to decrease these disturbances and improve graft function.’s~’9~21

In summary, the salient injury and the final common pathway for ischemic strictures is generally considered to be severe peribiliary arteriolar endothelial injury and resultant irreversible microvascular thrombosis.22

In the January issue, Sankary et alZ3 propose that a period of direct, global ischemia to the biliary epithe- lium generates nonanastomotic strictures. They sug- gest that the interval of relative warm ischemia to which the biliary tree is subjected during staged revas- cularization causes nonanastomotic biliary strictures and that simultaneous revascularization of hepatic al- lografts with both portal venous and hepatic arterial blood reduces the incidence of this c~mplication.~~

Sankary et a1 23 compared stricture occurrence in their most recent 45 patients, in whom simultaneous reperfusion of portal vein and hepatic artery was used, with that in the previous 83 patients, who underwent staged revascularization with initial reperfusion via the portal vein alone. Although simultaneous revascu- larization required 20 extra minutes, peak aspartate transaminase was not increased. The authors conclude that simultaneous revascularization produces no addi- tional hepatocellular injury, causes fewer nonanasto- motic strictures (study group, 1 stricture; control group, 7 strictures), and, therefore, is superior to initial graft reperfusion by the portal vein alone.23

Before we address the premise that direct epithelial ischemia causes nonanastomotic strictures, several methodological issues must be considered. First, al- though the numbers of patients with sclerosing cholan- gitis in the control and study groups are not statisti- cally different, a shift in disease demographics in the study population would invalidate use of the institu- tional historical control group. The reduction in stric- tures may simply reflect current performance of liver transplantation in a population less likely to stricture irrespective of graft reperfusion technique. This effect would be magnified by the small size of these groups and the low stricture rate; the occurrence of one more stricture in the most recent group would eliminate the reported statistical significance. Furthermore, the con- trol group is drawn from the authors’ early experience with liver transplantation, raising “learning curve” is- sues. What, for instance, is the stricture incidence in the 45 patients transplanted immediately before insti- tution of the simultaneous technique? In addition, we suggest that with respect to prolonged implantation time, early postoperative graft function is the key issue rather than biochemical evidence of injury. Rather than peak aspartate transaminase levels alone, para-

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590 FISHER AND MILLER HEPATOLOGY February 1995

menters of graft function (e.g., prothrombin time, peak bilirubin, bile production and quality, and incidence of poor early graft function and/or primary nonfunction) would be pertinent. Finally, because anastomotic stric- tures are traditionally attributed to technical flaws, the authors analyzed only nonanastomotic strictures. However, we suggest that the distal element of the donor duct, by rights the most ischemic tissue in this end-arterial system, is also subject to ischemic stric- ture.

Given the prevailing clinical and experimental evi- dence in favor of an arteriolar endothelial basis for in- jury leading to stricture, several arguments disputing a direct epithelial origin naturally arise. After the liver has been revascularized with portal venous blood but before the hepatic artery has been reperfused, the bili- ary tree remains deprived of its normal physiological blood supply. However, the degree to which ischemia during this period is physiologically significant is un- known. Retrograde bleeding from the donor hepatic ar- tery seen after portal venous reperfusion clearly indi- cates cross circulation between the portal venous and hepatic arterial circuits. Whereas the oxygen satura- tion of this effluent may be suboptimal, it is probably still adequate to sustain the duct, particularly in light of the fact that patients are hyperoxgenated intraoper- atively, while oxygen extraction by the gut simultane- ously decreases. Portal venous PO, is thus higher dur- ing this brief interval of portal venous perfusion than it is in chronically dearterialized livers. Evidence from general hepatic surgery shows that use of the Pringle maneuver, a pure form of warm ischemia during which the liver is deprived of both portal and hepatic arterial flow for up to 85 minutes,24 is not fraught with signifi- cant biliary stricture formation.

The fact that most “ischemic-type” strictures are multiple and segmental argues for segmental peribili- ary arteriolar thrombosis and not a diffuse warm isch- emic injury. Uncontrolled variables (e.g., inadequate heparinization before cross-clamping of the donor aorta and/or nonuniform aortic cold flush) may allow for such events. It is interesting that the authors find a correla- tion between donor dopamine dose and stricture, lend- ing support to the notion that events within the hepatic arterial tree contribute to stricture formation. If this association is confirmed, administration of a potent va- sodilator, such as phentolamine or d i l t i a ~ e m , ~ ~ before crossclamp might help prevent stricture formation in recipients of organs from pressor-dependent donors. Additionally, the variable time course of stricture ap- pearance (2 to 18 months post transplantation) sug- gests a variable and sequential course of injury rather than a single intraoperative insult.

Sankary et alZ3 have proposed a new paradigm for biliary stricture formation, albeit without a mechanism of pathogenesis, that calls standard graft implantation procedures into question. One way to reconcile this par- adigm with current evidence is to postulate that after portal venous reperfusion, stagnation occurs within the peribiliary hepatic arteriolar plexus and initiates mi-

crovascular thrombosis. Such a process might explain why, in our experience, patients with essentially nor- mal coagulation parameters (e.g., those with primary sclerosing cholangitis) are more susceptible to stricture formation than patients with coagulopathy and throm- bocytopenia. In any case, the authors’ recommenda- tions could reduce late morbidity and must be given careful consideration.

In deciding whether to adopt such a change in techni- cal routine, one must consider the potential risks and pitfalls. Prolongation of implantation may well have a negative impact on early graft function despite the authors’ report of equivalent aspartate transaminase levels; these two parameters do not always coincide. Improved early and late allograft function may be bet- ter achieved by minimizing implantation time than by attempting to maintain an adequately cold allograft in a “hostile” warm environment.

As implantation time is extended, so, by definition, is the anhepatic phase. This state may be of no conse- quence to the stable patient with reasonable coagula- tion parameters and minimal comorbidity, but it car- ries the potential for a markedly worsened fibrinolytic state as well as for hemodynamic instability in debili- tated or critically ill patients.

Simultaneous revascularization also implies that dissection and mobilization of the recipient hepatic ar- tery must be completed before reperfusion of the allo- graft. In patients with severe coagulopathy andor sig- nificant portal hypertension, this dissection can cause unnecessary hemorrhage and risks hepatic arterial in- jury and should be delayed until after portal reperfu- sion.

In summary, Sankary et alZ3 offer a provocative pos- tulate and a thoughtful approach to a significant, vex- ing issue in liver transplantation. Although we are not yet inclined to accept a single origin for nonanastomotic stricture development, their technical modification cer- tainly warrants further discussion and study. Given the multiplicity of potential culprits and the infre- quency of nonanastomotic stricture development, a large, carefully controlled, randomized, prospective trial will be necessary to judge the importance of the warm ischemic interval of standard implantation.

ADRIAN FISHER, MD CHARLES M. MILLER, MD Department of Surgery Division of Liver Transplantation The Mount Sinai Medical Center New York, NY REFERENCES

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