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Long-term incidence, risk factors, and management of biliary complications after adult living donor liver transplantation
Article first published online: 9 MAR 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 12, Issue 5, pages 831–838, May 2006
How to Cite
Hwang, S., Lee, S.-G., Sung, K.-B., Park, K.-M., Kim, K.-H., Ahn, C.-S., Lee, Y.-J., Lee, S.-K., Hwang, G.-S., Moon, D.-B., Ha, T.-Y., Kim, D.-S., Jung, J.-P. and Song, G.-W. (2006), Long-term incidence, risk factors, and management of biliary complications after adult living donor liver transplantation. Liver Transpl, 12: 831–838. doi: 10.1002/lt.20693
- Issue published online: 20 APR 2006
- Article first published online: 9 MAR 2006
- Manuscript Accepted: 29 NOV 2005
- Manuscript Received: 19 OCT 2005
A considerable proportion of adult living donor liver transplantation (LDLT) recipients experience biliary complication (BC), but there are few reports regarding BC based on long-term studies of a large LDLT population. The present study examined BC incidence, risk factors and management using single-center data from 259 adult patients (225 right liver and 34 left liver grafts) between 2000 and 2002. The mean follow-up period was 46 ± 14 months. Biliary reconstruction included single duct-to-duct anastomosis (DD, n = 141), double DD (n = 19), single hepaticojejunostomy (HJ, n = 67), double HJ (n = 28), and combined DD and HJ (n = 4). There were 12 episodes of anastomotic bile leak and 42 episodes of anastomotic stenosis in 50 recipients. Most leaks occurred within the first month, whereas stenosis occurred over 3 yr. Most stenoses were successfully treated using radiological intervention. Cumulative 1-, 3-, and 5-yr BC rates were 12.9%, 18.2%, and 20.2%, respectively. BC occurred much more frequently in right liver grafts compared to left liver grafts (P = 0.024). Stenosis-free survival curves for right liver graft recipients were similar for all reconstruction groups. When right liver graft recipients with single biliary reconstructions were grouped according to graft duct size and type of biliary reconstruction, DD involving a small-sized duct (less than 4 mm in diameter) was found to be a BC risk factor (P = 0.015), whereas HJ involving such duct sizes was not found to be associated with a higher risk (P = 0.471). In conclusion, close surveillance for BC appears necessary for at least the first 3 yr after LDLT. We found that most BC could be successfully controlled using radiological intervention. In terms of anastomotic stenosis risk, HJ appears a better choice than DD for right liver grafts involving ducts less than 4 mm in diameter. Liver Transpl 12:831–838, 2006. © 2006 AASLD.
Patient survival rates for living donor liver transplantation (LDLT) to adult recipients became favorable due to innovative surgical techniques that have overcome the anatomical limitations associated with such partial liver grafts. However, a high incidence of biliary complication (BC) remains the most intractable problem associated with LDLT.1–6 BC might reflect the anatomical and physiological limitations associated with adult LDLT, such as multiple or small-sized graft duct openings, arterial hypoperfusion of the liver graft secondary to portal hypertension, edematous bowel loops and poor blood supply to the recipient bile duct.
The classical method of biliary reconstruction in adult LDLT has been Roux-en-Y hepaticojejunostomy (HJ). In our institution, the introduction of duct-to-duct anastomosis (DD) around 2000 has resulted in DD replacing HJ due to its technical simplicity and ability to restore functional biliary drainage. However, although surgical techniques for biliary reconstruction have been refined, the incidence of BC does not appear to have diminished.1–6 Various treatment modalities including surgical, endoscopic and radiological approaches have been applied to the treatment of BC.1, 2, 7–9
There are few reports in the literature regarding long-term biliary reconstruction outcomes in large adult LDLT patient populations. The present study reports on biliary reconstruction outcomes using single-center data from 259 adult LDLT recipients who were followed-up for a mean of 46 months. The study assessed BC incidence, risk factors and management following adult LDLT.
PATIENTS AND METHODS
The adult LDLT program started at the Asan Medical Center in 1997, and the current surgical methodology became established in about late 1999. The 3 yr from January 2000 to December 2002 was chosen as the study period as it avoided potential issues relating to any major alterations in methodology, and provided a sufficiently long follow-up period. During this period, 334 adult LDLTs were performed, comprising 284 single-graft transplants and 50 dual-graft transplants. To simplify analysis, the present study excluded dual-graft transplants (n = 50), perioperative mortality cases (within 3 months) with no BC (n = 21) and re-transplantation cases (n = 4). These exclusions resulted in 259 cases selected for the study.
|Age||48 ± 7 yr (range, 24–64)|
|Hepatitis B virus-associated liver cirrhosis||220 (84.9%)|
|Fulminant hepatic failure||11 (4.2%)|
|Hepatitis C virus-associated liver cirrhosis||9 (3.5%)|
|Alcoholic liver cirrhosis||8 (3.1%)|
|Primary biliary cirrhosis||2 (0.8%)|
|Secondary biliary cirrhosis||2 (0.8%)|
|Wilson's disease||2 (0.8%)|
|Primary sclerosing cholangitis||1 (0.4%)|
|Cryptogenic cirrhosis||3 (1.2%)|
|Model for end-stage liver disease score|
|Concurrent hepatocellular carcinoma||62 (23.9%)|
Preparation of Graft and Recipient Bile Ducts
During donor surgery, the portal vein and hepatic artery were isolated without excessive periductal dissection. A radio-opaque marker tagging method with direct bile duct probing through the cystic duct was routinely used to identify an adequate location for bile duct division, minimizing the number of graft duct openings obtained from various donor bile duct anatomies.8 The liver parenchyma over the right hepatic duct was fully preserved to prevent denudation. The recipient bile duct was also dissected in a manner aimed to minimize damage thus allowing most of the peritoneal coverage over the bile duct to be fully preserved. The recipient proximal bile duct was cut at the level of the hilar plate to create multiple bile duct openings.
Biliary Reconstruction Methods
Either DD or HJ was chosen according to which best allowed reciprocal matching of the size of the graft and number of recipient duct openings. DD was preferentially performed on single and snout graft ducts if a suitable recipient duct opening was available. HJ was electively performed if the recipient duct opening was smaller than the graft duct opening. For double graft duct openings, double DD, double HJ, or a combined DD and HJ was chosen depending on the circumstances (Figs. 1 and 2). A compromise was made between DD and HJ under unfavorable bowel loop conditions, such as marked edema, peritonitis-induced thickening, or shrunken mesentery.
When performing HJ, interrupted sutures of 6-0 monofilament with 1-mm intervals were applied to the posterior and anterior anastomosis lines. A small internal stent was usually inserted except in cases of large-sized graft ducts. An external drainage tube was occasionally inserted across the HJ and passed through a Witzel tunnel (Fig. 2). Techniques for double HJ were principally the same as those for single HJ. For DD, the recipient duct opening was usually prepared such that it was one and half times larger than the size of the fully expanded graft duct opening. Anastomosis techniques for DD were similar to those for HJ, and internal stents were inserted during the first half of this study period. Intraoperative leak testing using methylene blue solution and completion cholangiography were routinely performed through the cystic duct stump.
Follow-Up and Management of Biliary Complications
Liver dynamic computed tomography was routinely performed weekly during the first month, and then 2 to 3 times over the following year, and then once or twice per year. Hepatobiliary scintigraphy (HBS) using technetium-99m diisopropyl iminodiacetic acid was also routinely performed at the same frequency as computed tomography.7 HBS was performed immediately if there was any suspicion of a bile leak or anastomotic stenosis. Endoscopic retrograde cholangiography was performed first if a DD recipient was suspected of a BC during the early postoperative period.9 Percutaneous transhepatic biliary drainage (PTBD) was undertaken if a bile leak continued over 1 week or a stenosis was diagnosed. Stenoses were treated using sequential balloon dilatation repeated every 1 to 2 months until complete resolution. Detailed procedures for endoscopic retrograde cholangiography and PTBD are described elsewhere.9
Definitions of Biliary Complication and Bile Duct Anatomy
BC was primarily classified as anastomotic leak and anastomotic stenosis. An anastomotic leak was diagnosed on the basis of a bile leak through abdominal drains, evacuation of extrahepatic biloma through a newly inserted pigtail, or identification of a leak using HBS. Bile leaks at the liver cut surface were excluded using HBS. An anastomotic stenosis was diagnosed on the basis of an overt dilatation of the intrahepatic duct according to computed tomography or ultrasonography, definite biliary stasis according to HBS, or direct visualization of stenosis using endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography.
Right hepatic ducts were anatomically classified as being one of types A to D (Fig. 3).11 Type C ducts were further classified as C1 or C2 according to the distance between the right anterior and posterior ducts. When harvesting a right liver graft, a single or snout duct (adjacent double openings resembling a figure-8) was usually obtainable from the biliary anatomy of type A; 2 adjacent ducts (less than 1 cm apart) from types B and C1; and 2 distant ducts (usually more than 1 cm apart) from types C2 and D.
The diameter of the graft bile duct was measured using digitized images of intraoperative cholangiography rather than intraoperative direct measurement as the real graft duct looked withdrawn after cutting but became larger after retraction. In cases of multiple duct openings, the smallest duct size was used for analysis.
Data are expressed as mean and standard deviation or range. Patient survival and BC-free survival rates were estimated using the Kaplan-Meier method, and compared using log-rank tests. P values of <0.05 were considered to indicate a significant difference.
Graft Duct and Biliary Reconstruction Profiles
From 259 living donors, 225 right liver grafts and 34 left liver grafts were harvested. Bile duct anatomy was classified as type A (n = 178; 68.7%), type B (n = 24; 9.3%), type C1 (n = 18; 6.9%), type C2 (n = 17; 6.6%), or type D (n = 22; 8.5%). The characteristics of graft bile ducts and the type of biliary reconstruction are summarized in Table 2. When performing a single DD on a right liver graft (n = 119), graft ducts were anastomosed to the proximal hepatic duct stump (n = 65; 54.6%), the right hepatic duct stump (n = 47; 39.5%), or the left hepatic duct stump (n = 7; 5.9%) according to duct-size matching.
|Graft duct openings||Right liver graft (n = 225)||Left liver graft (n = 34)|
|Cases||Diameter (mm)||Cases||Diameter (mm)|
|1||153 (68.0%)||4.7 ± 1.1 (3–8)||30 (88.2%)||4.5 ± 0.8 (3–7)|
|Snout||18 (8.0%)||5.2 ± 1.0 (4–8)||2 (5.9%)||5|
|2*||53 (23.6%)||2.9 ± 0.6 (2–4)||2 (5.9%)||3|
|Single DD||119 (52.9%)||22 (64.7%)|
|Double DD||18 (8.0%)||1 (2.9%)|
|Single HJ‡||57 (25.3%)||10 (29.4%)|
|Double HJ||27 (12.0%)||1 (2.9%)|
|DD and HJ||4 (1.8%)||–|
Rates of Recipient Survival and Biliary Complication
The mean follow-up time was 46 ± 14 months (range 5-68), and during this time 22 patients died and 1 patient was lost from the study due to emigration. The main causes of these late deaths were recurrence of hepatocellular carcinoma (n = 7), rejection (n = 6), and infection (n = 4). One patient died from an intractable HJ leak at 5 months, and another died at 6 months after recurrent episodes of intrahepatic abscess formation without evidence of anastomotic stricture. Overall 1-, 3-, and 5-yr survival rates for the 259 recipients were 96.1%, 91.9%, and 91.2%, respectively. Overall BC-free survival curves are shown in Fig. 4. Two cases of bile leak at the liver cut surface and 2 cases of intrahepatic biloma were included. These 4 patients also incidentally or subsequently experienced anastomotic stenoses.
Biliary Complications and Management
After implantation, 3 BC episodes occurred in 2 of 34 left liver grafts recipients, while 51 BC episodes occurred in 48 of 225 right liver graft recipients (Table 3). There were 11 anastomotic leak cases (4.9%), most of them occurring within the first month. The timing of detection of the 40 stenoses is illustrated in the stenosis-free survival curve (Fig. 4). Stenosis developed after a median period of 6 months (range 1-48 months) or after a mean period of 11.7 ± 11.8 months, with 95% occurring within the first 36 months.
|Left liver (n = 34)||Leak (n = 1)||DD (n = 1)||ENBD (n = 1)||Resolved (n = 1)|
|Stenosis (n = 2)*||DD (n = 2)||ERC (n = 1)*||Resolved (n = 2)|
|PTBD (n = 1)|
|Right liver (n = 225)||Leak (n = 11)||DD (n = 7)||ENBD (n = 3)||Resolved (n = 7)|
|PTBD (n = 4)|
|HJ (n = 4)||Abdominal drain (n = 1)||Resolved (n = 3)|
|Operative repair (n = 1)||Died from sepsis (n = 1)|
|Pigtail insertion (n = 2)|
|Stenosis (n = 40)†||DD (n = 25)||PTBD (n = 23)||Resolved (n = 22)|
|ERBD (n = 2)||Under treatment with PTBD (n = 2)|
|Died with PTBD, but BC-unrelated (n = 1)§|
|HJ (n = 15)‡||PTBD (n = 15)||Resolved (n = 12)|
|Recurred (n = 1)¶|
|Under treatment with PTBD (n = 1)|
|Died with PTBD, but BC-unrelated (n = 1)§|
BC treatment involved PTBD, endoscopic retrograde cholangiography, endoscopic retrograde biliary drainage, percutaneous pigtail insertion and surgical repair (Table 3).9 PTBD was performed in 4 of 12 leak cases and in 39 of 42 stenosis cases, and was associated with no serious complications. Two stenosis cases required the maintaining of 2 PTBD tubes in the right anterior and right posterior segmental ducts separately. PTBD tubes were maintained in position for a mean of 9.4 ± 6.6 months (range 3-36 months) before removal.
Risk Factors for Biliary Complication
In terms of BC-free survival, the 1-, 3-, and 5-yr values for the right liver graft group (n = 225) were 85.1%, 79.4%, and 77.3%, and for the left liver graft group (n = 34) were 97%, 97%, and 93.6%, respectively (P = 0.024). These data indicate that right liver grafts were more vulnerable to BC than left liver grafts.
After exclusion of left liver graft recipients, further analyses were performed using right liver graft recipients (n = 225) to identify risk factors for BC, especially in relation to anastomotic stenosis. We found that DD and HJ groups did not differ in terms of stenosis-free survival (P = 0.735; Fig. 5). In addition, there was no significant difference between single and double biliary reconstruction groups in terms of 3-yr stenosis-free survival (86% and 77%, respectively; P = 0.352). The same analysis of the single DD, double DD, single HJ, double HJ, and combined DD-HJ groups showed that there were no significant differences between these groups in terms of stenosis incidence (P = 0.684; Fig. 6).
Of 102 recipients with graft duct diameters of 5 mm or more, only 9 experienced stenosis. After exclusion of these relatively large graft duct recipients, we analyzed stenosis incidence in the remaining 123 recipients (i.e., graft duct size smaller than 5 mm) according to the 5 reconstruction types and found no significant differences between them (P = 0.903).
We analyzed BC according to graft duct diameter and reconstruction method. The 176 right lobe graft recipients with a single biliary reconstruction were subdivided into 6 groups according to graft duct size and biliary reconstruction method. Graft duct size was classified as either small (diameter less than 4 mm), medium (diameter between 4 and 5 mm), or large (diameter greater than 5 mm). Recipients of double biliary reconstructions were excluded to avoid bias from complex biliary reconstructions. Biliary reconstruction was simply classified as either single DD or single HJ. We found that DD involving a small-sized duct was a risk factor for anastomotic stenosis (P = 0.015; Fig. 7). In contrast, graft duct size was not a risk factor in the single HJ group (P = 0.471; Fig. 7).
The present study confirms that BC is the most common and intractable complication in adult LDLT.12 The incidences of BC at 1 and 3 months were 4.7% and 8.9%, respectively. While these values might not be regarded as critically high and most cases were successfully treated, delayed-onset, or late BC, which usually involved anastomotic stenosis, occurred at a considerably higher frequency, with 1-, 3-, and 5-yr BC rates of 12.9%, 18.2%, and 20.2%, respectively (Fig. 4). This late BC occurrence pattern has not been emphasized in the literature previously, probably because other studies had shorter follow-up periods.1–6, 12, 13 It appears that a mean follow-up period of at least 3 yr is required to perform a robust clinical evaluation of BC following adult LDLT.
In the present series, DD was introduced in early 2000, and selectively performed after careful consideration of graft-recipient duct-size matching. As a result, DD comprised only 29.9% of biliary reconstructions in 2000. Thereafter, both initial favorable outcomes and technical simplicity accelerated the preference of DD over HJ, and DD comprised 69.3% of procedures in 2001 and 83.7% in 2002. However, the 3-yr cumulative rate of BC increased over this period, from 13.7% in 2000 (n = 75), to 15.8% in 2001 (n = 92), and to 25.4% in 2002 (n = 92). Thus, although DD made an important contribution toward technical simplification of biliary reconstruction, its introduction appeared to be associated with poorer outcomes in terms of incidence of BC. This observation suggests that DD has inherent deficiencies that cannot be overcome by current surgical techniques.
The present study sought to identify risk factors for BC unique to DD. We found that right liver grafts were much more vulnerable to BC than left grafts, which may reflect differences in the anatomical characteristics between right and left hepatic ducts, including the arterial blood supply.14–16 Analysis according to the type and number of biliary reconstructions did not show any group to be more vulnerable to BC. However, when analysis was confined to right liver graft recipients with a single biliary reconstruction, comparison according to graft duct size and type of reconstruction showed that a graft duct size less than 4 mm in diameter was a risk factor for stenosis in the DD group, but not in the HJ group. Thus, use of DD for a right liver graft with a small-sized duct appears to increase the likelihood of anastomotic stenosis.17 These observations indicate that HJ may be preferable to DD where there is a small-sized right liver graft duct.
In this series, many of the stenoses were multiple in nature or occurred along a long segment, meaning such stenoses could be regarded as ischemic rather than focal.9, 18 This may relate to the need to maintain the presence of PTBD tubes for a relatively long time in this series when treating such anastomotic stenosis. Normally, the right hepatic duct is fed with a simultaneous bidirectional blood supply from the liver side and the common bile duct side. However, the right lobe graft duct is fed only from the liver side and is vulnerable to ischemia, especially on the medial side. Refined surgical procedures such as beveled cutting of the right hepatic duct or hepatic arterial flushing at the back table are intended to relieve such focal ischemia. We occasionally observed significant arterial collaterals after HJ, whereas it is unlikely to expect collaterals across a DD. Indeed, to date we have never observed any noticeable collateral arterial formation in tens of DD recipients during transarterial chemoembolization for recurrent hepatocellular carcinoma. HJ is undoubtedly more beneficial than DD from the viewpoint of arterial collateral formation to the graft duct stump.
Another advantage of HJ is the liberal use of a large-bored internal stent. Where the graft duct is large enough, internal stents may not be useful except for prevention of an accidental catch of the posterior wall.1, 19 However, if the graft duct is small, a sizable stent can be beneficial in preventing high-grade stenosis or total occlusion. This concept is not applicable to DD, for which only thin stents can be used in expectation of their spontaneous passage through the ampullary sphincter.
Reconstruction of double graft ducts can be achieved using several approaches, such as unification ductoplasty, double DD, double HJ, or a combination of these.1, 5, 12, 13 Where the 2 ducts are adjacent to each other, unification ductoplasty with or without septotomy may be applicable. While this approach can facilitate the feasibility of a single anastomosis, such artificial manipulation also increases the risk of bile duct stump ischemia.1 In the present study, where the 2 duct grafts were distant, double DD was feasible only when an adequate gap between the recipient duct openings was provided. If a double DD was not feasible, we chose a double HJ. However, when the double HJ looked technically difficult (e.g., a deeply located duct opening and thickened jejunal loop), a combination method involving DD and HJ was used. Interestingly, each of the double anastomosis approaches resulted in similar outcomes, which might be associated with the small number of patients.
Currently, it is very difficult to prevent BC from occurring, making BC management the main concern during follow-up of adult LDLT recipients. After experiencing a few septic episodes originating from anastomotic leaks, we established an aggressive policy to treat BC. Any evidence of a bile leak led to consecutive computed tomography scans and HBS. Any abnormal fluid collection suggesting biloma was usually evacuated using radiological intervention. As we were unable to repair bile leak sites using reexploration (other than for 1 case from an HJ site), we preferred interventional treatment rather than reexploration. Unlike bile leaks, most stenoses were detected in outpatient clinics after slight worsening of liver function, symptoms of cholangitis, intrahepatic duct dilatation on computed tomography scans, or stasis on routine HBS. These were detected at a median 6 months and mean 12 months, similar to other reports.12, 13, 20 Our initial treatment for DD recipients was endoscopic retrograde cholangiography, and if a stricture was clearly detected a PTBD was performed immediately.9 The PTBD tubes were maintained in position for over a mean of 9 months. Except for 1 patient whose stricture recurred after 13 months following PTBD tube removal, all biliary strictures resolved without recurrence over a mean follow-up of 24 months. While we are not sure whether the current duration of PTBD tube placement can be shortened, we are attempting to manage anastomotic stenoses as prudently as possible.
Our BC management policy appears to differ from that of other DLT programs that prefer surgical or endoscopic treatments.2, 12, 18 We were reluctant to correct anastomotic strictures through reexploration because such an approach to right lobe grafts appeared unnecessarily risky. We believe that radiological intervention can be successful once a guide-wire can pass through the stenosis site. Although long-term maintenance of PTBD results in serious patient discomfort, it appears to be a safer approach than further surgery. In our series, PTBD-related procedures were associated with only a few episodes of minor complication, and all were successfully controlled. In contrast, a Hong Kong group recommended not performing PTBD following episodes of fatal complications.1 While we prefer the radiological approach, a surgical approach is the only option when a wire cannot be passed through the stenosis site due to complete occlusion.
In conclusion, the present study found that close surveillance for BC appears necessary at least for the first 3 yr after adult LDLT. It addition, most BC were successfully controlled using radiological intervention. Furthermore, a right liver graft duct less than 4 mm in diameter was found to be a risk factor for anastomotic stenosis following DD, indicating HJ is a better approach under such circumstances.