Endoscopic Management of Postoperative Biliary Complications in Donors for Living Donor Liver Transplantation

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2003;1:183 188 Endoscopic Management of Postoperative Biliary Complications in Donors for Living Donor Liver Transplantation KAZUNORI HASEGAWA,* SHUJIRO YAZUMI,* HIROTO EGAWA, HIROYUKI TAMAKI,* MASANORI ASADA,* YUZO KODAMA,* HIROSHI HISATSUNE,* KAZUICHI OKAZAKI,* KOICHI TANAKA, and TSUTOMU CHIBA* Departments of *Gastroenterology and Hepatology and Transplantation and Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Background & Aims: Biliary leakage and stricture are serious complications that occur in donors whose liver is resected for living donor transplantation. We assessed the usefulness of endoscopic nasobiliary drainage and endoscopic biliary stenting, respectively, in repairing biliary leakage and stricture. Methods: Between July 1999 and December 2001, a total of 276 donors underwent liver resection (left side, 118; right side, 158) for living donor transplantation at Kyoto University Hospital. Seven (2.5%) donors developed biliary leakage, which required endoscopic nasobiliary drainage; 3 of these donors also had biliary stricture. Results: All 7 patients who developed biliary leakage were the right-lobe donors. Endoscopic retrograde cholangiography identified the site of the biliary leakage in all 7 of the donors. In 6 of these donors, the biliary leakage resolved within an average of 15 days after an endoscopic nasobiliary drainage tube was placed. In the seventh donor, the biliary leakage resolved after percutaneous transhepatic biliary drainage was performed. Three patients developed biliary stricture that required endoscopic biliary stenting. The angles between common hepatic duct and the left hepatic duct were more acute in patients with stricture than in those without stricture (62 degrees vs. 119 degrees). Conclusions: Biliary complications requiring endoscopic treatment developed exclusively in donors for right-lobe living donor transplantation. Endoscopic retrograde cholangiography is a favorable modality for diagnosing and treating postoperative biliary complications in donors for living donor liver transplantation. More than 12 years have passed since living donor liver transplantation (LDLT) was first introduced in Japan. 1 Once reserved for children, right-lobe LDLT has become a more acceptable procedure for adults. We began using right-lobe living donor grafts at Kyoto University Hospital in 1998, and the number of transplantations of these grafts has increased remarkably since then. 2 Nevertheless, the most important concern in using right-lobe grafts continues to be donor safety. 3 5 One of the serious complications of LDLT we have encountered is biliary leakage. 6 Most donors who have biliary leakage improve with conservative therapy, whereas some donors require insertion of a percutaneous drainage tube for biliary fluid collection, which necessitates prolonged hospitalization. Between July 1990 and May 1999, 4 of 469 (0.8%) donors were hospitalized for more than 30 days at Kyoto University Hospital because of biliary leakage. 6 Since July 1999, we have witnessed an increasing incidence of biliary leakage of various patterns that has been concomitant with an increase in the number of right-lobe LDLTs. Herein, we retrospectively analyze the pattern of biliary leakage that occurred in our donors and demonstrate the efficacy of endoscopic treatment of biliary complications resulting from LDLT. Patients and Methods Between July 1999 and December 2001, 276 donors underwent liver resection (left side, 118; right side, 158) for LDLT at Kyoto University Hospital after giving written informed consent. The male-to-female ratio was 0.74 (117 of 159). A drainage tube was placed in the right subdiaphragmatic space at the end of operation in all donors. Despite conventional postoperative treatment, 7 (2.5%) donors developed biliary leakage after right lobe resection that required endoscopic retrograde cholangiography (ERC), and all were men (Table 1). After fasting overnight, the donors with biliary leakage were referred for ERC with a standard videoduodenoscope (JF240; Olympus Co, Tokyo, Japan). The site of the biliary leakage was confirmed with contrast medium (Figure 1A), and the maxi- Abbreviations used in this paper: ENBD, endoscopic nasobiliary drainage; ERC, endoscopic retrograde cholangiography; LDLT, living donor liver transplantation; PTBD, percutaneous transhepatic biliary drainage. 2003 by the American Gastroenterological Association 1542-3565/03/$30.00 doi:10.1053/jcgh.2003.50027

184 HASEGAWA ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 1, No. 3 Table 1. Clinical Features of Donors With Biliary Leakage Donor Age (yr) (median, 42) Gender Donated liver Days from LDLT to biliary leakage Days from LDLT to ERC 1 53 Male Right 60 a 89 2 30 Male Right Early leakage b 24 3 38 Male Right Early leakage b 20 4 19 Male Right Early leakage b 30 5 56 Male Right 193 a 194 6 64 Male Right Early leakage b 34 7 47 Male Right 38 a 78 a In donors 1, 5, and 7, minor biliary leakage occurred immediately after donation; however, it improved spontaneously without placing ENBD in the presence of a surgical drain. b Biliary leakage was observed immediately after donation. mum angle centering the site of the biliary leakage between the common hepatic duct and the left hepatic duct was measured by using a fluoroscope with movable arm (MAX-1000A, ADR-1000A; Toshiba Medical Inc., Kyoto, Japan). A 0.035- inch guidewire (Jagwire; Boston Scientific, Boston, MA) was then inserted into the intrahepatic bile duct proximal to the site of the leakage, and a 6F endoscopic nasobiliary drainage (ENBD) tube (Zenon Medical Inc., Tokyo, Japan) was placed across the site of the leakage (Figure 1B). After the biliary leakage had resolved, stricture remained in 3 of the 7 donors. A 7F endoscopic biliary stent (Olympus Co., Tokyo, Japan) was placed across the site of the stricture in each of the 3 donors. Results All 7 patients who developed biliary leakage were the right-lobe donors. There were 2 major peaks of the days to ERC after LDLT. In donors 2, 3, 4, and 6 (Table 1), biliary leakage developed immediately after donation, and fever persisted in spite of presence of a surgical drain; consequently ERC was performed at an average of 27 days (range, 20 34 days) after LDLT. On the other hand, the remaining 3 donors (donors 1, 5, and 7) had only minor biliary leakage immediately after the donation, which spontaneously disappeared without placing Figure 1. Retrograde cholangiograms demonstrating biliary leakage (patient 4). (A) Biliary leakage (arrowhead) was confirmed at the closure portion of right hepatic duct. (B) The leakage resolved within 18 days after an ENBD tube was placed. Asterisk identifies a surgical drain for biliary fluid collection. Arrow identifies the ENBD tube.

May 2003 POSTOPERATIVE BILIARY COMPLICATIONS IN LDLT 185 Table 2. Results of Treatment for Biliary Leakage in Right-Lobe Donors for LDLT Donor Type of drainage Days of drainage Biliary stricture Days of endoscopic biliary stent placement (median, 113) Angle (degrees) a 1 ENBD 7 90 2 ENBD 15 140 3 ENBD 14 120 4 ENBD 18 125 5 PTBD 10 147 75 6 ENBD 23 70 70 7 ENBD 11 123 42 ENBD, endoscopic nasobiliary drainage; PTBD, percutaneous transhepatic biliary drainage. a The angle given is between the common hepatic duct and the left hepatic duct. ENBD in the presence of a surgical drain, but several months after discharge they had to be hospitalized again because of recurrence of biliary leakage. In these 3 donors, the biliary leakage recurred at an average of 97 days (range, 38 193 days) after LDLT. Percutaneous drainage could not improve the leakage in donors 1 and 7, and eventually ERC was performed for the 3 donors at an average of 120 days (range, 78 194 days) after LDLT (Table 1). ERC disclosed that the site of biliary leakage was at the closure portion of the right hepatic duct in all 7 donors; 6 were successfully treated with placement of a 6F ENBD tube. In these 6 donors, the biliary leakage disappeared within an average of 15 days (Table 2). In one donor (donor 5), a guidewire could not be introduced into the left hepatic duct proximal to the site of the biliary leakage (Table 2; Figure 2A). Percutaneous transhepatic biliary drainage (PTBD) was performed, and the biliary leakage resolved in 10 days. Three of the donors (5, 6, and 7) developed cholestasis immediately after the ENBD was removed or PTBD was clamped. Percutaneous transhepatic cholangiography or ERC showed the angles between the common hepatic duct and the left hepatic duct to be acute in these donors, with angulated strictures causing the cholestasis (Figure 2B and E). Indeed, the angles in the donors with biliary stricture were more acute than those without stricture (median angle, 62 degrees vs. 119 degrees) (Figure 3). Endoscopic biliary stenting across the contorted stricture improved the liver dysfunction in the 3 donors. After endoscopic biliary stenting for an average of 113 days (range, 70 147 days) (Table 2), ERC demonstrated that the contorted stricture improved in 2 of 3 patients (donors 5 and 6) (Figure 2C). In donor 5, the stricture relapsed again a year after the removal of endoscopic biliary stent and required the placement of a second stent. In donor 6, there was no recurrence of cholestasis more than a year after the removal of endoscopic biliary stent. In donor 7, the contorted stricture persisted after the endoscopic biliary stent was removed (Figure 2F ), but he was able to leave the hospital a week after ERC. He has had no recurrence of cholestasis since then (follow-up period, 2 months). Discussion In our current case series, we observed that of 276 donors for LDLT, 7 right-lobe donors developed biliary leakage that required ERC. The leakage occurred at the closure portion of the right hepatic duct in all 7 of these donors. We were able to successfully treat the biliary leakage in 6 of the donors by placing an ENBD tube into the left hepatic duct across the site of the leakage; in the seventh donor, we were unable to introduce the guidewire into the left hepatic duct. On the basis of the outcomes of these 7 cases, we believe that ERC followed by ENBD is a useful and effective method not only for detecting biliary leakage but also for treating it in living liver donors. It may be considered that placing internal biliary stent is more useful for treating biliary leakage in the donors. However, we used ENBD as the first-line therapy because we were afraid that internal stent placement might cause intra-abdominal abscess formation. In our previous case series (July 1990 May 1999), only 4 (0.8%) of 469 donors for LDLT had major biliary leakage. 6 In the series we report here (July 1999 December 2001), the incidence of biliary leakage requiring ENBD rose to 2.5% of all donors as the number of right-lobe LDLTs increased. On the basis of these findings, it is reasonable to expect the incidence of biliary leakage to be higher in right-lobe LDLT donors. Our findings contrast with the previous observation by others that gastric volvulus is more common in left-lobe LDLT donors. 7 Several explanations might be considered for the exclusive development of biliary leakage in right-lobe LDLT donors. Because the anterior and the posterior segmental branches often diverge immediately proximal

186 HASEGAWA ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 1, No. 3 Figure 2. Cholangiograms showing 2 cases of biliary stricture (A C, patient 5; D F, patient 7). (A) Biliary leakage (arrowhead) relapsed within 194 days after donation. (B) The leakage was resolved after PTBD (asterisk), but the contorted stricture remained. (C) The stricture relaxed within 147 days after the endoscopic biliary stent had been placed (arrow). (D) An intraoperative cholangiogram demonstrated that the angle between the common hepatic duct and the left hepatic duct was markedly obtuse. (E) Biliary leakage (arrowhead) was confirmed at 78 days after donation. (F ) The angle between the common hepatic duct and the left hepatic duct became slightly larger within 123 days after endoscopic biliary stent placement. to the bifurcation, the right hepatic duct of the rightlobe graft must be resected only 1 to 3 mm proximal to the bifurcation. 8 In contrast, the left hepatic duct of the left lobe is resected 3 to 5 mm proximal to the bifurcation. 9 Moreover, the tissues surrounding the hepatic duct at the bifurcation often must be removed to identify the correct anatomy of the anterior and the posterior segmental branches, which might cause the residual hepatic duct to become ischemic and to subsequently constrict. Consequently, the stump of the right hepatic duct after right-lobe resection would be more fragile than that of the left hepatic duct after left-lobe resection in LDLT. In the donors with recurrent biliary leakage, minor biliary leakage had occurred immediately after LDLT, which had disappeared spontaneously in the presence of a surgical drain. Thus, it is suggested that chronic inflammation and infection due to biliary leakage with resulting scar formation and retraction of the bile duct around the site of biliary leakage contributed to the recurrence of cholestasis. The fact that not only recurrent biliary leakage but also stricture developed only in donors who had had bile leakage immediately after LDLT lends support to such an idea. In addition, compensatory hypertrophy of the residual left lobe after right-lobe donation may also have played a role in the development of recurrent biliary leakage or stricture in such patients. By using computed axial tomography, Chen et al. 10 found that complete regeneration of the liver remnant takes about 1 year after right-lobe donation. The compensatory hypertrophy of the left lobe after conventional right lobectomy rarely causes a specific anatomic situation. 11 13 After right-lobe donation, however, the residual liver rotates to the right and posterosuperiorly, causing the hilus to move higher and deeper and to twist to the right behind the overhanging hypertrophied quadrate lobe. Consequently, the angle between the common hepatic duct and the left hepatic duct appears to become smaller (Figure 4). This distortion of bile duct may also

May 2003 POSTOPERATIVE BILIARY COMPLICATIONS IN LDLT 187 Figure 3. Cholangiograms of all the patients showing biliary leakage. The maximum angle between the common hepatic duct and the left hepatic duct was measured by using fluoroscopy. Biliary leakage disappeared in patients 1, 2, 3, and 4 (A D, respectively), but a contorted stricture remained in patients 5, 6, and 7 (E G, respectively) even after the biliary leakage resolved. The angles between the ducts in patients who had a contorted stricture (E G) were more acute than those in patients who did not have a stricture (A D) (median angle, 62 degrees vs. 119 degrees). Figure 4. Mechanism for the development of recurrent biliary leakage or biliary stricture. (A) The residual biliary system after the right lobe has been resected. (B) With the compensatory hypertrophy of the residual left lobe, the hilum shifts into the vacant right subdiaphragmatic space. The angle between the left hepatic duct and the common hepatic duct consequently becomes smaller than it would immediately after left lobe resection. In addition, inflammation and infection around bifurcation due to biliary leakage immediately after donation would cause thickening of the bile duct wall and stenosis of the bile duct. Eventually, relapse of biliary leakage or biliary stricture would develop. F, the falciform ligament; P, pancreas. Arrows indicate the thickening of the bile duct wall and stenosis of the bile duct.

188 HASEGAWA ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 1, No. 3 have contributed to the development of cholestasis. In support of this possibility, we found that the angle between the common hepatic duct and the left hepatic duct is more acute in donors with biliary stricture than in those without stricture in our 7 cases. Interestingly, placement of an endoscopic biliary stent across the contorted stricture for several months improved the cholestasis in our 3 donors who had strictures, although in 1 donor the stricture relapsed a year after the endoscopic biliary stent was removed. It is possible in this donor, as has been reported for other individuals who have undergone major hepatectomy, 10 that the residual left lobe might have continued growing for a year. For this reason, it may be important to keep the endoscopic biliary stent in the left hepatic duct until the residual liver has stopped expanding. Further clinical trials, however, are required to confirm the appropriate time span of endoscopic biliary stent placement. In summary, biliary leakage and stricture are significant complications in right-lobe donors after LDLT that can be managed successfully with ENBD and endoscopic biliary stenting without the need for surgical revision. References 1. Tanaka K, Uemoto S, Tokunaga Y, Fujita S, Sano K, Nishizawa T, Sawada H, Shirahase I, Kim HJ, Yamaoka Y, Ozawa K. Surgical techniques and innovations in living related liver transplantation. Ann Surg 1993;217:82. 2. Inomata Y, Uemoto S, Tanaka K, Asonuma K, Egawa H, Kiucki T, Fujita S, Hayashi M, Kawashima M, Tanaka K. Right lobe graft in living donor liver transplantation. Transplantation 2000;69:258. 3. Grewal HP, Thistlethwaite JR, Loss GE, Fisher JS, Cronin DC, Siegel CT, Newell KA, Bruce DS, Woodle ES, Brady L, Kelly S, Boone P, Oswald K, Millis JM. Complication in 100 living-liver donors. Ann Surg 1998;228:214. 4. Malago M, Rogiers X, Burdelski M, Broeisch CE. Living related liver transplantation: 36 cases at the University of Hamburg. Transplant Proc 1994;26:3620. 5. Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000;135:336. 6. Fujita S, Kim ID, Uryuhara K, Asonuma K, Egawa H, Kiuchi T, Hayashi M, Uemoto S, Inomata Y, Tanaka K. Hepatic grafts from live donors: donor morbidity for 470 cases of live donation. Transpl Int 2000;13:333. 7. Akamatsu T, Nakamura N, Kiyosawa K, Ikegami T, Hashikura Y, Miyagawa S, Kawasaki S. Gastric volvulus in living, related liver transplantation donors and usefulness of endoscopic correction. Gastrointest Endosc 2002;55:55. 8. Egawa H, Inomata Y, Uemoto S, Asonuma K, Kiuchi T, Fujita S, Hayashi M, Matamoros MA, Itou K, Tanaka K. Biliary anastomotic complications in 400 living related liver transplantation. World J Surg 2001;2:1300. 9. Ishiko T, Egawa H, Kasahara M, et al. Duct-to-duct biliary reconstruction in living donor liver transplantation utilizing right lobe graft. Ann Surg 2002;236:235 240. 10. Chen MF, Hwang TL, Hung HF. Human liver regeneration after major hepatectomy: a study of liver volume by computed tomography. Ann Surg 1991;213:227. 11. McDermott WV, Greenberger NJ, Isselbacher KJ, Weber AL. Major hepatic resection: diagnostic techniques and metabolic problems. Surgery 1963;54:56. 12. Tekin A, Perek S. Biliary stricture due to hypertrophied liver rotation after right hepatic lobectomy. Dig Surg 2000;17:398. 13. Johnson AG, Lyon IM, Blumgart LH. Stricture of common hepatic duct after right hepatic lobectomy treated by Longmires operation. J R Soc Med 1979;72:136. Address requests for reprints to: Tsutomu Chiba, M.D., Ph.D., Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. e-mail: cteya@kuhp.kyoto-u.ac.jp; fax: (81) 75-751- 4303. The authors thank Ms. Pamela Paradis Tice, E.L.S.(D)., for editing the manuscript.