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Volume: 12 Issue: 6 December 2014


A Clinical Algorithm To Guide the Need for Endoscopic Retrograde Cholangiopancreatography To Evaluate Early Postliver Transplant Cholestasis

Objectives: Severe cholestasis after liver transplant is common. In this study, our aim was to develop an algorithm to guide biliary intervention in these patients.

Materials and Methods: A retrospective review was performed on patients who had undergone a hepatobiliary scan, with or without subsequent endoscopic retrograde cholangiogram, during the immediate postoperative period. These findings were evaluated along with laboratory values to determine the benefit for this evaluative process. Biliary duct obstruction was defined as > than a 50% reduction in serum bilirubin within 48 hours of endoscopic retrograde cholangiogram intervention.

Results: Twelve patients had endoscopic retrograde cholangiogram with 6 stents in 25 patients with normal a hepatobiliary scan, and 2 patients met criteria for biliary duct obstruction. Twenty-two patients had endoscopic retrograde cholangiogram with 14 stents in 32 patients with delayed uptake, suggesting hepatocellular dysfunction on a hepatobiliary scan, and 4 patients met criteria for biliary duct obstruction. In the 57 patients with severe hyperbilirubinemia, 6 patients (11%) had biliary duct obstruction as a cause. Among the 34 endoscopic retrograde cholangiograms performed, 17% had biliary obstruction. On multivariate analysis, patients having both serum aspartate transaminase concentrations < 1500 IU/L and serum total bilirubin levels > 257 μmol/L had an odds ratio of 25.1 for predicting biliary obstruction (95% CI: 6-37; P = .002).

Conclusions: A hepatobiliary scan with a com-bination peak serum aspartate transaminase and peak serum total bilirubin levels offer a valuable tool to identify patients with hepatocellular dysfunction and can avoid endoscopic retrograde cholangiogram in the immediate posttransplant period.

Key words : HIDA scan, ERCP, Liver transplantation


Severe cholestasis immediately after liver transplant can be caused by delayed graft function, reperfusion injury, vascular complications, or biliary stricture.1-3 This clinical situation is more common when using extended criteria donors (eg, steatotic livers and donations after cardiac death). Ischemic injury to the liver results in high transaminases and hyperbilirubinemia, which gradually resolves in a few days. However, when high bilirubin concentrations persist beyond the first week of transplant, further diagnostic tests are required to rule out a stricture at the choledocho-choledochal anastomosis. Endo­scopic retrograde cholangiopancreatography (ERCP) remains the criterion standard for diagnosing biliary stricture. The safety and effectiveness of ERCP in managing late-onset biliary strictures is well established.4-8 However, ERCP has some limitations and risks during the immediate posttransplant period.5

Endoscopic retrograde interpretation is difficult in these patients, especially if there is a size-mismatch between the donor and recipient ducts. Moreover, edema around the anastomotic site often masquerades as anastomotic stricture prompting stent placement. Delayed clearance of contrast from the donor also may prompt the endoscopist to place a stent suspecting a physiological obstruction owing to edema or anatomic discontinuity. Additionally, there is the potential risk of disrupting the new anastomosis in the immediate postoperative period. Patients may require general anesthesia for the ERCP that can add more risk to the procedure. While it is important to rule out anastomotic stricture, the risks and limitations of ERCP should be weighed against the potential benefits. A hepatobiliary iminodiacetic acid (HIDA) scan is a noninvasive test and could have potential use in guiding the further care in these patients.9 However, using a HIDA scan can be limited in these patients because of severe cholestasis and inability of the liver to take up the tracer. Reports on the use of a HIDA scan in liver transplant recipients yield conflicting results.10,11

We aimed to use a HIDA scan in evaluating severe cholestasis in the immediate posttransplant period (7-30 d), and to try to develop an algorithm where the combination of a HIDA and clinical information can guide biliary intervention in these patients.

Materials and Methods

Since 2006, there have been more than 800 adult liver transplants performed at the University of Tennessee/Methodist University Hospital Transplant Institute in Memphis, Tennessee, USA. In our center, a HIDA scan always has been used as the initial screening tool in patients with persistent hyperbilirubinemia in the immediate posttransplant period. The primary aim of a HIDA scan is to rule out a bile leak and biliary obstruction at the choledochocholedochostomy. A HIDA scan results were classified as normal, hepatocellular dysfunction if there is delayed uptake of the tracer, or bile leak. Endoscopic retrograde cholangiopancreatography was performed if a HIDA scan showed a bile leak, or whether there was further clinical suspicion of biliary obstruction. Biliary stents were placed if anastomotic narrowing was present, or if there was delayed drainage of the contrast material from the donor ducts at the interpretation of the endoscopist. The study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration.

A retrospective review of 815 liver transplant procedures was performed to identify 63 patients (7%) that had a HIDA scan in our transplant center within 30 days of a liver transplant. Data collection included demographics, liver function tests, and the need for ERCP with findings requiring stent placement. Serum total bilirubin levels within 48 hours of ERCP were used to determine the success of biliary stenting. If there was a reduction of more than 50% in bilirubin levels within 48 hours of ERCP intervention, the cause of high bilirubin concentrations was considered to be biliary obstruction. We chose this clinical outcome as the defining criteria for biliary obstruction, given the pitfalls of ERCP in the immediate postliver transplant period. In those patients in whom an ERCP intervention resulted in deductions of more than 50% in bilirubin levels, the HIDA scan was considered false negative.

Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21.0, IBM Corporation, Armonk, NY, USA). The Mann-Whitney U test and the chi-square tests were used for continuous and dichotomous variables. We used a binary logistic regression to identify the factors that predicted biliary obstruction as an endpoint (defined by a reduction of serum total bilirubin > 50% at 48 hours after ERCP). Because low serum aspartate aminotransferase (AST) levels and high serum total bilirubin concentrations are associated with biliary obstruction, we identified a combination of peak serum AST and peak serum total bilirubin levels that would have the highest predictability of biliary obstruction. For all analysis, P values < .05 were considered statistically significant.


A cholescintigraphy scan
Sixty three-patients were identified with an early postoperative HIDA scan to identify possible biliary complications. Five patients were excluded from further analyses because of the presence of a bile leak. In our cohort of 57 patients, (age 49 ± 10 y, 20 women, peak bilirubin levels 325 ± 188 μmol/L, peak AST concentrations 2363 ± 2980 IU/L, and MELD scores of 25 ± 7), twenty-five patients (peak bilirubin levels 307 ± 171 μmol/L and peak AST concentrations 2828 ± 3878 IU/L) were found to have normal HIDA, and 32 patients (peak bilirubin levels 325 ± 188 μmol/L and peak AST concentrations 2000 ± 2032 IU/L) had delayed uptake, suggesting hepatocellular dysfunction (Figure 1). No patient was suspected of having an obstruction of the bile duct reported on the HIDA scan. Of the 57 patients, 17 patients had more than a 50% decrease in total bilirubin concentration after a HIDA was performed (8 patients with no ERCP and 9 patients after ERCP).

Endoscopic retrograde cholangiopancreatography (Figure 1)
Thirty-four patients required an ERCP with 20 patients (58%) requiring stents at the discretion of the endoscopist. Among the 34 patients, the 25 with normal HIDA scans, 12 patients had ERCP, 6 of whom required a biliary stent. Two of the 6 stented patients had a decrease of more than 50% in serum total bilirubin within 48 hours (biliary obstruction = 8%; false negative rate of HIDA 8%). Of the 32 patients with delayed uptake on the HIDA scan, 22 patients had an ERCP with 14 requiring stents. Four of these 14 stented patients had more than a 50% decrease in serum total bilirubin within 48 hours (biliary obstruction, 12.5%; false negative rate of HIDA, 12.5%). Three patients with hepatocellular dysfunction by HIDA had decreases in bilirubin concentrations greater than 50%, forty-eight hours after an ERCP without a stent being placed.

In the 57 patients with HIDA for severe hyperbilirubinemia in the immediate postoperative period, 11% had a large duct obstruction as the cause of the hyperbilirubinemia. A cholescintigraphy scan is accurate 89% of the time, suggesting no biliary obstruction. More importantly, of the 34 ERCPs performed, only 6 (17%) had biliary obstructions. Even in the 20 patients with stent placement, in which the endoscopist suspected obstruction, clinically signi-ficant obstruction was seen in only 6 patients (30%).

Serum aspartate transaminase and total bilirubin
The peak serum AST levels among patients with biliary obstruction was lower at 1005 ± 364 IU/L compared with those patients without biliary obstruction at 2522 ± 3177 IU/L (P = .035). The peak serum total bilirubin levels among patients with biliary obstruction was greater than those patients without biliary obstruction (411 ± 188 μmol/L vs 307 ± 171 μmol/L; P = .02). On further analyses, we found that patients having both AST levels < 1500 IU/L, and bilirubin concentrations > 257 μmol/L had odds ratios of 25.1 (95% CI: 6-37; P = .002) when it came to predicting biliary obstruction and benefiting from ERCP. A receiver operating characteristic of 0.80 among the 6 patients (95% CI: 0.61-0.99; P = .017) who had more than a 50% improvement in bilirubin level, after having had a stent placement. If we included all 9 patients (6 with stent and 3 without stent) who had a greater than 50% decrease in bilirubin concentration, the receiver operating characteristic is less robust at 0.71 (95% CI: 53-0.91; P = .39).


Persistent and severe hyperbilirubinemia during the postoperative period is a complex clinical issue for transplant physicians. Delayed graft function or reperfusion injury can be clinically identified in many patients, and careful monitoring is required. However, in some patients, the clinical course may point to biliary obstruction prompting additional tests. Our intention in this study was to determine whether clinical parameters can reliably predict clinically significant biliary obstruction that could be corrected by biliary intervention.

Only 57 patients (7%) that we transplanted had postoperative hyperbilirubinemia, which required additional evaluation by a HIDA scan or both a HIDA and an ERCP. Of the 57 patients, clinical suspicion was high in 34 patients, who ultimately underwent an ERCP. However, even in 34 patients who proceeded to have an ERCP, only 25% responded to the ERCP, suggesting that 75% of ERCPs could have been avoided.

Elevated serum transaminases are common immediately after liver transplant. Usually, serum transaminase levels increase steadily for the first few hours after transplant before returning to normal, and the degree of elevation in transaminases is a clinical indicator for severity of ischemia before and after reperfusion. Severe ischemia also is likely to cause significant elevation in serum bilirubin levels in the absence of biliary obstruction. Hence, we reasonably assume the cause of severe hyperbilirubinemia in the presence of high AST concentrations was caused by ischemic injury to the liver. Conversely, low AST concentrations in the presence of high bilirubin concentrations points to a possible bile duct obstruction.

Our data show that peak serum AST con-centrations among patients with biliary obstruction was lower at 1005 ± 364 IU/L (vs 2522 ± 3177 IU/L; P = .035). Combining low serum AST concentrations and high bilirubin levels had a high odds ratio of predicting success with an ERCP stent placement. Among these 34 patients, adding clinical parameters of peak AST concentrations < 1500 IU/L and peak bilirubin levels > 257 μmol/L could identify a subset of patients who benefited from ERCP.

Based on this, we developed an algorithm (Figure 2). We incorporated the clinical parameters as an important indication for ordering an ERCP. In the absence of the clinical parameters, most patients will likely improve without further intervention. Magnetic resonance cholangiopancreatography could be used as a backup in patients whose serum bilirubin concentrations remain elevated during the observation period.12 However, in the immediate postoperative period, owing to edema at the anastomotic site, magnetic resonance cholangio-pancreatography could lead to a false diagnosis of stricture. Based on this concern, we do not perform magnetic resonance cholangiopancreatography during the immediate posttransplant period.

Our data are limited, owing to the retrospective nature of the study. However, we had the same set of transplant physicians during the study that followed the general protocol to evaluate these patients making the clinical decision points less likely to be influenced by interoperator variability. Moreover, one transplant hepatologist physician (SN) performed all the ERCPs, eliminating interobserver variations in interpreting ERCP findings and the need for stent placement. We chose a strict definition for success of ERCP. Bilirubin can decrease spontaneously in patients because of improvement in graft function and better clearance of bilirubin because of improved renal function. Hence, having a stricter definition was important for this study to minimize false positives.

In conclusion, a normal HIDA scan along with the combination of peak AST and peak bilirubin levels offer a valuable way of identifying patients who will not benefit from ERCP. Using these parameters, many ERCPs could be avoided in the immediate posttransplant period.


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Volume : 12
Issue : 6
Pages : 543 - 547
DOI : 10.6002/ect.2014.0067

PDF VIEW [338] KB.

From the University of Tennessee Health Sciences Center, Methodist University Transplant Institute, Memphis, TN, 38104 USA
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare. These results presented in this paper have not previously been published, in whole or part, except in abstract form.
Corresponding author: Satheesh Nair, MD, AGAF, FACP, Professor of Medicine, University of Tennessee Health Science Center, Methodist University Transplant Institute, Memphis, TN, 38104 USA
Phone: +1 901 516 9179