Risk factors of choledocholithiasis formation after liver transplantation

Hangzhou, China

Risk factors of choledocholithiasis formation after liver transplantation

Zhi-Yong Yu, Min Zhang, Yun-Sheng Qin, Xiao-Ping Zhou, Ming-Yue Cai, Song-Feng Yu, Qing-Hong Ke and Shu-Sen Zheng

Hangzhou, China

Systematic study of risk factors for biliary stone post-liver transplantation is rarely performed. To investigate the risk factor of choledocholithiasis formation after liver transplantation, we c onducted a case-control study. Fourteen patients were selected into a study group. The stones of the bile duct of the patients were conf i rmed and treated successfully by endoscopic retrograde cholangiopancreatography. For univariate analysis, we selected carefully some potential risk factors such as cold ischemia time, warm ischemia time, and biliary stricture. The results revealed that cold ischemia time and biliary stenosis were signif i cant predictors. But multivariate analysis revealed that only biliary stenosis was a signif i cant risk factor. In conclusion, biliary stenosis is a risk factor of bile duct stones formation after liver transplantation. Endoscopic retrograde cholangiopancreatography is effective and safe in the diagnosis or treatment of bile duct stones after liver transplantation.

liver transplantation; endoscopic retrograde cholangiopancreatography;choledocholithiasis; biliary tract diseases; common bile duct stone; gallstones

Introduction

Biliary stone is the third common complication in the biliary system after liver transplantation, and its incidence rate is around 3.8%-18%.[1,2]Reports have shown that biliary stone is closely related to patient survival and quality of life, but systematic study of biliary stone after liver transplantation is still rare. Hence we reviewed the data of liver transplantation recipients in our center and evaluated the potential risk factor of formation of bile duct stones after liver transplantation.

Methods

We performed a case-control study of 761 consecutive adult liver transplantation recipients from 1999 to 2010 in our center. Inclusion criteria for the study group included adult liver transplant patients (>18 years) who developed biliary stones after liver transplant conf i rmed by endoscopic retrograde cholangiopancreatography (ERCP). The control group consisted of adult liver transplant patients without the occurrence of biliary stones after liver transplant. The controls were selected from the total adult liver transplant patients randomly matched to those by year of transplantation. The ratio of case-to-control was 1:2. Liver transplant patients were excluded if they had had a foreign body placed into the bile duct before they developed biliary stones, fore example, stent or T-tube. We analyzed a number of possible risk factors for susceptibility to biliary stones, such as gender, age, indications for liver transplantation, drug use, cold ischemia time, warm ischemia time, ABO blood group match, ischemic reperfusion injury (def i ned as a total bilirubin peak within the fi rst 10 days post-transplant), serum cholesterol, serum triglyceride, biliary strictures and hepatic artery stenosis or thrombosis. Age, cold ischemia time, warm ischemiatime, ischemic reperfusion injury, serum cholesterol, serum triglycerides and bile duct stenosis were chosen for univariate analysis and multivariate analysis.

Continuous variables were compared with the unpairedttest and categorical variables were compared with the Chi-square test. Data were presented as percentage and mean±SD. All variables were further analyzed in a multivariate logistic regression model. APvalue <0.05 was considered statistically signif i cant.

Results

Twenty-one patients developed biliary stones after liver transplant. We excluded 4 patients due to lack of information and another 3 patients for stent placement before occurrence of blilary stones. We put the rest 14 patients into the study group. The 14 patients were male, and 12 (85.7%) of them had biliary stenosis. The average time for the occurrence of biliary stones was 48.2 months after liver transplantation. We took 28 patients as the control group. Both the study group and control group used University of Wisconsin solution for organ preservation, and all of them underwent piggyback liver transplantation. The mean age of the study and control groups was 50.6 and 52.5 years, respectively.Liver cirrhosis was the most common indication for liver transplantation; in the study group its incidence was about 57.1% and in the control group, 60.7% (Table 1). Followed by hepatocellular carcinoma with HBV background, the incidence in the study group was 28.6%, and in the control group it was 21.4%.

Table 1.Indications for liver transplantation in two groups (n, %)

Table 2.Potential risk factors for bile duct stone post-liver transplant: univariate and multivariate analysis

Univariate analysis showed that cold ischemia time (P<0.01) and biliary stenosis (P<0.01) were signif i cant predictors of bile duct stones after liver transplantation (Table 2). But multivariate analysis revealed that only biliary stenosis was the independent risk factor of bile duct stones after liver transplantation (Table 2). Whereas age, warm ischemia time, ischemia reperfusion injury, serum triglyceride and serum cholesterol were not markedly correlated with biliary stones formation after liver transplantation. Bile duct stones were removed successfully in all patients by ERCP and none of the patients developed serious complication.

Discussion

Bile duct stones can cause severe complications, such as cholangitis, pancreatitis or biliary cirrhosis, which can further result in severe damage of liver graft. It is well known that biliary stone formation has to do with bile cholesterol, phospholipid and bile acid. When imbalance exists among them, biliary stone formation will occur. Hyperlipidemia and hypercholesterolemia are reported as risk factors of biliary lithiasis.[2-4]In contrast, our study showed that the levels of serum cholesterol and serum triglyceride were not signif i cantly related to biliary stones formation after liver transplantation.

Bile duct cells are very sensitive to ischemia. In the procedure of liver transplantation, donor liver must withstand three episodes: cold ischemia, warm ischemia, and ischemia reperfusion. These three events may result in severe damage to the biliary system, fi nally bile duct endothelial cell necrosis and abnormal bile secretion.[5]Both abnormal bile secretion and bile duct endothelial cell necrosis could lead to bile duct stone formation. In our study, warm ischemia time and ischemia reperfusion injury were not signif i cantly different between the study group and the control group. In contrast to multivariate analysis, univariate analysis showed that cold ischemia time was signif i cantly associated with bile duct stones formation after liver transplantation.

In general population, bile duct stenosis easily leads to stone formation. In our study, 85.7% of the patients in the study group presented with bile duct stenosis, whereas 7.1% in the control group only. The difference was signif i cantly different. Univariate analysis and multivariate analysis also revealed that biliary stricturewas a risk factor after liver transplantation.

ERCP is a safe and effective treatment for common bile duct stones in general population. In our study, all patients with biliary stones were successfully diagnosed and treated by ERCP and none of them developed severe complication.

In summary, our study shows that biliary stricture is a high risk factor for biliary stone formation after liver transplantation. ERCP is a safe and effective method for the diagnosis and therapy of biliary stones after liver transplantation.

Contributors:ZM and ZSS proposed the study. YZY performed research and wrote the fi rst draft. QYS, ZXP, CMY, YSF and KQH collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantor.

Funding:This study was supported by grants from the Team Program of Science and Technology Bureau of Zhejiang Province (2009R50038) and the Health Bureau of Zhejiang Province Foundation (B1652).

Ethical approval:Not needed.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 Cillo U, Burra P, Norberto L, D'Amico D. Bile duct stones and casts after liver transplantation: Different entities but similar prevention strategy? Liver Transpl 2008;14:1400-1403.

2 Spier BJ, Pfau PR, Lorenze KR, Knechtle SJ, Said A. Risk factors and outcomes in post-liver transplantation bile duct stones and casts: A case-control study. Liver Transpl 2008;14: 1461-1465.

3 Smelt AH. Triglycerides and gallstone formation. Clin Chim Acta 2010;411:1625-1631.

4 Pinheiro-Júnior S, Pinhel MA, Nakazone MA, Pinheiro A, Amorim GF, Florim GM, et al. Effect of genetic variants related to lipid metabolism as risk factors for cholelithiasis after bariatric surgery in Brazilian population. Obes Surg 2012;22:623-633.

5 Maheshwari A, Maley W, Li Z, Thuluvath PJ. Biliary complications and outcomes of liver transplantation from donors after cardiac death. Liver Transpl 2007;13:1645-1653.

Received June 27, 2012

Accepted after revision January 18, 2013

(Hepatobiliary Pancreat Dis Int 2013;12:215-217)

AuthorAff i liations:Division of Hepatobiliary and Pancreatic Surgery; Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; and Key Laboratory of Organ Transplantation Zhejiang Province, First Aff i liated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Yu ZY, Zhang M, Qin YS, Zhou XP, Cai MY, Yu SF, Ke QH and Zheng SS)

Shu-Sen Zheng, MD, PhD, FACS, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Aff i liated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: 86-571-87236570; Email: shusenzheng@zju.edu.cn)

? 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60034-X