
==== Front
BMC Cancer
BMC Cancer
BMC Cancer
1471-2407
BioMed Central London

12864
10.1186/s12885-024-12864-9
Research
Predictors and risk factors of bile duct injury after transcatheter arterial chemoembolization for hepatocellular carcinoma
Lu Haohao 12
Liang Bin 12
Xia Xiangwen 492657906@qq.com

12
Zheng Chuansheng 1354039648@qq.com

12
1 grid.33199.31 0000 0004 0368 7223 Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022 China
2 grid.412839.5 0000 0004 1771 3250 Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022 China
2 9 2024
2 9 2024
2024
24 108520 1 2024
27 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Purpose

Bile duct injury is a serious complication after transcatheter arterial chemoembolization (TACE). If it is not detected early and treated actively, it will not only affect the subsequent tumor-related treatment of hepatocellular carcinoma (HCC) patients, but also may lead to serious consequences such as infection, liver failure and even death. To analyze the risk factors of bile duct injury after TACE in patients with HCC and explore the predictive indicators of bile duct injury after TACE, which is helpful for doctors to detect and intervene early and avoid the occurrence of serious complications.

Method

We retrospectively analyzed the clinical data of 847 patients with primary hepatocellular carcinoma who underwent TACE for the first time in our interventional department. Patients were divided into two groups according to whether bile duct injury occurred after TACE: (1) bile duct injury group, N = 55; (2) no bile duct injury group, N = 792. The basic data, intraoperative conditions and the outcome of bile duct injury were analyzed. The chi-square test was used for comparison of enumeration data. The Mann-Whitney U test was used for comparison of measurement data. Risk factor analysis was performed using binary logistic regression analysis.

Results

Basic data and intraoperative conditions were compared between the bile duct injury group and the group without bile duct injury: preoperative alkaline phosphatase (ALP) (103.24 ± 32.77U/L vs. 89.17 ± 37.35U/L, P = 0.003); history of hepatobiliary surgery (36.4% vs. 20.8%, P = 0.011); intraoperative lipiodol volume (P = 0.007); combined use of gelatin sponge particles (65.5% vs. 35.0%, P < 0.001); hypovascularity (58.2% vs. 24.5%, P < 0.001); and embolization site (P < 0.001). Comparison of postoperative liver function between bile duct injury group and non-bile duct injury group: postoperative total bilirubin (43.34 ± 25.18umol/L vs. 21.94 ± 9.82umol/L, P < 0.001); postoperative γ-glutamyltransferase(GGT) (188.09 ± 55.62U/L vs. 84.04 ± 36.47U/L, P < 0.001); postoperative ALP(251.51 ± 61.51U/L vs. 99.92 ± 45.98U/L, P < 0.001).

Conclusion

The dosage of lipiodol in TACE, supplementation of gelatin sponge particles, embolization site, and hypovascularity of the tumor are risk factors for biliary duct injury after TACE. After TACE, GGT and ALP increased ≥ 2 times compared with preoperative indicators as predictors of bile duct injury. Bile duct injury occurring after TACE can achieve good outcomes with aggressive management.

Keywords

Hepatocellular carcinoma
Transcatheter arterial chemoembolization
Bile duct injury
Biloma
Bile duct necrosis
Risk factors
Predictors
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcHepatocellular carcinoma (HCC) is a common malignant tumor. Its incidence rate and mortality rate rank sixth and third among all tumors in the world [1]. It is a serious threat to people’s life and health. It is also rising year by year in some countries and regions [2]. Due to the lack of specific clinical symptoms in patients with primary hepatocellular carcinoma in the early stage, many patients are already in the middle and advanced stage when diagnosed [3]. In 1976, H M Goldstei first reported transcatheter arterial chemoembolization (TACE) [4]. For patients with advanced hepatocellular carcinoma, TACE is one of the commonly used treatments. Studies have confirmed that TACE can prolong the survival time of patients with advanced hepatocellular carcinoma [5, 6]. TACE is a minimally invasive treatment, but there are still some complications. The most common complication after TACE is post-embolization syndrome [7], which includes pain, fever, nausea and vomiting [8].Riccardo Lencioni et al. [9] reported that about 47.7% of patients had post embolism syndrome after TACE, which was relieved after symptomatic treatment. TACE also has some serious complications with low incidence [10], such as bile duct injury [11], liver abscess, liver failure [12], oncolytic syndrome [13], gastrointestinal bleeding, etc. [7]. Research reports that the incidence of bile duct injury after TACE is 0.5–9.6% [14–18]. Its common clinical manifestations are abdominal pain, fever, jaundice, etc. If it cannot be detected early and treated actively, serious consequences such as infection, liver failure and even death may occur [14, 19]. Houyun Xu et al. [15] reported that 21 (4.3%) of 483 patients with hepatocellular carcinoma had bile duct injury after receiving 693 times of TACE. Once bile duct injury occurs, it will also affect the subsequent tumor-related treatment of patients with hepatocellular carcinoma, such as TACE, targeted drug therapy, immunotherapy, etc., thus affecting the efficacy and survival of patients. This study retrospectively analyzed the clinical data of HCC patients who underwent TACE in our hospital, aiming to explore the risk factors of bile duct injury after TACE, and to find the predictive indicators of bile duct injury after TACE, so as to help doctors to detect and intervene in the early stage of bile duct injury after TACE, and finally reduce the incidence of serious complications.

Materials and methods

General information

Collect the clinical data of 847 HCC patients who received TACE treatment for the first time from January 2016 to December 2021 in the Intervention Department of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. Inclusive criteria: (1) Clinical or pathological diagnosis of primary hepatocellular carcinoma; (2) Have not received TACE treatment in the past; (3) Liver function Child-Pugh A or B, performance score (ECOG) 0–1; (3) Age 18-70y; (4) No heart, lung or kidney insufficiency; (5) There is no severe coagulation dysfunction and it cannot be corrected. Exclusion criteria: (1) Extensive distant metastasis or cachexia; (2) The portal vein was completely occluded with few collateral vessels; (3) Biliary stricture, bile duct dilatation or bile tumor have been complicated. The patients were divided into two groups according to whether there was bile duct injury after TACE: (1) Bile duct injury group, N = 55; (2) No bile duct injury group, N = 792.

The basic data of the patients were collected, including gender, age, etiology of cirrhosis, preoperative Child-Pugh classification of liver function [20], BCLC stage of HCC, tumor location, maximum diameter of tumor and blood biochemical parameters. The patient’s past medical history was recorded, including diabetes, hypertension, hepatobiliary surgery, etc. The type of chemotherapeutic drugs used in TACE, lipiodol volume, whether gelatin sponge particles were used, the site of embolized artery, tumor blood supply, and whether molecular targeted drugs were used in combination were recorded.

Methods

After disinfection and draping, the puncture site was locally anesthetized with 2% lidocaine. The femoral artery was then punctured using the Seldinger technique and a 5 F vascular sheath was placed. Digital subtraction angiography(DSA) was performed using a 5 F Yashino catheter cannulated into the celiac trunk and superior mesenteric artery to identify the nutrient artery of the tumor. According to the blood supply of the tumor, a 2.7 F microcatheter was cannulated into the target artery (liver lobe, liver segment, liver subsegment or distal), and an emulsion mixed with an appropriate amount of lipiodol and chemotherapeutic drugs was slowly injected for embolization. Whether gelatin sponge particles with a particle size of 300–500 μm were supplemented according to the blood flow was decided, and the embolization endpoint was stagnation of forward blood flow in the tumor feeding artery. Chemotherapeutic agents used in TACE were divided into two types: (1) lobaplatin 50 mg; (2) epirubicin 30 mg. The amount of lipiodol is 5-20 ml.

In this study, the indications and operation specifications of TACE refer to “Chinese Guidelines for Diagnosis and Treatment of Primary Liver Cancer” and “Barcelona Clinic Liver Cancer prognosis and treatment strategy”. Materials and drugs used for TACE: 5 F vascular sheath (TERUMO5F-10CM, Terumo, Japan), 0.035 inch (RFGA35153M, Terumo, Japan), 5 F Yashino catheter (Terumo, Japan), 2.7 F microcatheter (Terumo, Japan). Lipiodol (GYZZ H20163348,Jiangsu Hengrui Pharmaceutical Co., Ltd, China). Lobaplatin (GYZZ H20050308, Hainan Chang’an International Pharmaceutical Co., Ltd., China), epirubicin (GYZZ H19990280, Zhejiang Hisun Pharmaceutical Co., Ltd., China). Gelfoam (CFDA 20193131657,Hangzhou ALICON Pharmaceutical Technology Co., Ltd, China).

Serum biochemistry was reexamined one week after TACE, and CT or MRI was reexamined every 4–6 weeks after TACE. Imaging findings of bile duct injury after TACE include biliary stricture, intrahepatic bile duct dilatation, or biloma [21–23].

Observations

(1) The occurrence of bile duct injury after TACE, including bile duct stenosis, bile duct dilatation and biloma;

(2) The changes of serum biochemical indexes after TACE in two groups;

(3) Treatment and outcome of patients with bile duct injury.

Statistical analysis

SPSS software was used for statistical analysis (version 24.0, IBM, Armonk, NewYork). Enumeration data were expressed as number of cases (percentage), and differences between groups were analyzed by chi-square test, including Pearson Chi-Square and Fisher’s Exact Test. Measurement data were expressed as mean ± standard deviation, and differences between groups were analyzed by Mann-Whitney U test. Risk factor analysis was performed using binary logistic regression analysis using entry and comparison using indicator (first). P < 0.05 was considered to indicate a statistically significant difference.

Results

Basic information of patients (shown in table 1)

Table 1 Basic data of all the patients

		Mea ± Std. Deviation	Count (Percentage)	
Age(years)		51.4 ± 11.6		
Preoperative total bilirubin (umol/L)		17.69 ± 8.43		
Preoperative ALT(U/L)		42.24 ± 19.16		
Preoperative AST(U/L)		41.04 ± 19.43		
Preoperative GGT(U/L)		68.87 ± 25.63		
Preoperative ALP(U/L)		90.09 ± 37.22		
Gender (N = 847)	Female		258(30.5%)	
Male		589(69.5%)	
Child-Pugh classification of liver function (N = 847)	Child A		612(72.3%)	
Child B		235(27.7%)	
Etiology of liver cirrhosis (N = 847)	Hepatitis B		609(71.9%)	
Hepatitis C		136(16.1%)	
Alcoholic cirrhosis		48(5.7%)	
Others		54(6.3%)	
BCLC Stage (N = 847)	A		123(14.5%)	
B		507(59.9%)	
C		127(25.6%)	
tumor location (N = 847)	hilar		310(36.6%)	
peripheral		537(63.4%)	
maximum diameter of tumor(N = 847)	< 5 cm		400(47.2%)	
≥ 5 cm		447(52.8%)	
History of hepatobiliary surgery (N = 847)	No		662(78.2%)	
Yes		185(21.8%)	
History of diabetes (N = 847)	No		680(80.3%)	
Yes		167(19.7%)	
History of hypertension (N = 847)	No		622(73.4%)	
Yes		225(26.6%)	

The age of all patients was 51.4 ± 11.6 years. 258(30.5%) women and 589(69.5%) men. Liver function grade: Child A, 612(72.3%) cases; Child B, 235(27.7%) cases. The etiology of cirrhosis: hepatitis B, 609(71.9%) cases; hepatitis C ,136(16.1%) cases; alcoholic cirrhosis, 48(5.7%); others, 54(6.3%) cases. BCLC staging of tumor: Phase A, 123(14.5%) cases; Phase B, 507(59.9%) cases; Phase C, 127(25.6%) cases. Tumors were located at the hilar in 310 (36.6%) patients and peripherally in 537 (63.4%) patients. 400(47.2%) patients had tumor diameter < 5 cm, 447(52.8%) patients had tumor diameter ≥ 5 cm. 185(21.8%) patients had a history of hepatobiliary surgery, 167(19.7%) patients had a history of diabetes, and 225(26.6%) patients had a history of hypertension. Total bilirubin before TACE was 17.69 ± 8.43 umol/L, ALT before TACE was 42.24 ± 19.16 U/L, AST before TACE was 41.04 ± 19.43 U/L, GGT before TACE was 68.87 ± 25.63 U/L, and ALP before TACE was 90.09 ± 37.22 U/L.

Comparison of preoperative basic data and intraoperative conditions between bile duct injury group (N = 55) and non bile duct injury group (N = 792) (shown in Table 2)

Table 2 Comparison of basic data and TACE related conditions between the two groups

		Bile duct injury			
		No(N = 792)	Yes(N = 55)	Mann-Whitney U test (P value)	Chi-square test(P value)	
Age(years)		51.2 ± 11.7	53.6 ± 9.6	0.237		
Preoperative total bilirubin (umol/L)		17.18 ± 8.64	16.40 ± 4.06	0.830		
Preoperative ALT(U/L)		42.42 ± 18.81	39.53 ± 23.72	0.150		
Preoperative AST(U/L)		40.86 ± 19.39	43.67 ± 20.00	0.243		
Preoperative GGT(U/L)		68.59 ± 16.15	72.93 ± 15.86	0.246		
Preoperative ALP(U/L)		89.17 ± 37.35	103.24 ± 32.77	0.021		
Gender	Female	213(26.9%)	18(32.7%)		0.350	
Male	579(73.1%)	37(67.3%)		
Child-Pugh classification of liver function	Child A	577(72.9%)	35(63.6%)		0.161	
Child B	215(27.1%)	20(36.4%)		
Etiology of liver cirrhosis	Hepatitis B	562(71.0%)	47(85.4%)		0.106	
Hepatitis C	133(16.8%)	3(5.5%)		
Alcoholic cirrhosis	46(5.8%)	2(3.6%)		
Others	51(6.4%)	3(5.5%)		
BCLC Stage	A	114(14.4%)	9(16.4%)		0.606	
B	472(59.6%)	35(63.6%)		
C	206(26.0%)	11(20.0%)		
tumor location	hilar	289(36.5%)	21(38.2%)		0.885	
peripheral	503(63.5%)	34(61.8%)		
maximum diameter of tumor	< 5 cm	372(47.0%)	28(50.9%)		0.580	
≥ 5 cm	420(53.0%)	27(49.1%)		
Lipiodol dosage in TACE	< 5 ml	218(27.5%)	6(10.9%)		0.007	
5-10 ml	359(45.3%)	36(65.5%)		
> 10 ml	215(27.2%)	13(23.6%)		
Chemotherapeutic Agents	Epirubicin	516(65.2%)	29(52.7%)		0.080	
Lobaplatin	276(34.8%)	26(47.3%)		
Gelfoam Granules Supplemented	No	515(65.0%)	19(34.5%)		< 0.001	
Yes	277(35.0%)	36(65.5%)		
Embolization site	Hepatic lobe	84(10.6%)	20(36.4%)		< 0.001	
Hepatic segment	363(45.8%)	19(34.5%)		
Hepatic subsegment and distal	345(43.6%)	16(29.1%)		
Tumor blood supply	Hypovascularity	194(24.5%)	32(58.2%)		< 0.001	
Hypervascularity	598(75.5%)	23(41.8%)		
History of hepatobiliary surgery	No	627(79.2%)	35(63.6%)		0.011	
Yes	165(20.8%)	20(36.4%)		
History of diabetes	No	637(80.4%)	43(78.2%)		0.726	
Yes	155(19.6%)	12(21.8%)		
History of hypertension	No	583(73.6%)	39(70.9%)		0.639	
Yes	209(26.4%)	16(29.1%)		
Combined targeted drug therapy	No	484(61.1%)	28(50.9%)		0.154	
Yes	308(38.9%)	27(49.1%)		

Among 847 patients, 55 (6.5%) had bile duct injury after TACE. There was no significant statistical difference between the two groups in terms of gender, age, liver function grade, etiology of cirrhosis, BCLC stage, tumor location, maximum diameter of tumor, history of diabetes, history of hypertension, whether combined with targeted drugs, preoperative total bilirubin, ALT, AST, GGT. The preoperative ALP of patients with bile duct injury was 103.24 ± 32.77U/L, and that of patients without bile duct injury was 89.17 ± 37.35 U/L, P = 0.021. There were 20 (36.4%) patients with previous hepatobiliary surgery in the bile duct injury group, and 165 (20.8%) patients with previous hepatobiliary surgery in the non bile duct injury group, P = 0.011. There was no significant difference in the use of chemotherapy drugs between the two groups. Comparison of intraoperative usage of lipiodol (P = 0.007): In bile duct injury group, 6 (10.9%) patients used lipiodol < 5 ml, 36 (65.5%) patients used lipiodol 5-10 ml, and 13 (23.6%) patients used lipiodol > 10 ml; In the group without bile duct injury, 218 (27.5%) cases were treated with lipiodol < 5 ml, 359 (45.3%) cases were treated with lipiodol 5-10 ml, and 215 (27.2%) cases were treated with lipiodol > 10 ml. Gelatin sponge particles were used in 36 cases (65.5%) in bile duct injury group and 277 cases (35.0%) in non bile duct injury group, P < 0.001. The embolic sites of the two groups were compared (P < 0.001). In bile duct injury group, the embolic sites were 20 (36.4%) in hepatic lobe, 19 (34.5%) in hepatic segment, and 16 (29.1%) in hepatic subsegment and beyond; In the group without bile duct injury, the embolic sites were 84 (10.6%) in the hepatic lobe, 363 (45.8%) in the hepatic segment, and 345 (43.6%) in the hepatic subsegment and beyond. There were 32 cases (58.2%) of hypovascular manifestations in the bile duct injury group and 194 cases (24.5%) of hypovascular manifestations in the group without bile duct injury, P < 0.001.

Comparison of liver function between the two groups (shown in table 3)

Table 3 Comparison of liver function after TACE between the two groups

	Bile duct injury		
	No(N = 792)	Yes(N = 55)	Mann-Whitney U test (P value)	
Postoperative total bilirubin (umol/L)	21.94 ± 9.82	43.34 ± 25.18	< 0.001	
Postoperative ALT(U/L)	55.72 ± 23.30	58.65 ± 12.72	0.180	
Postoperative AST(U/L)	52.72 ± 20.54	53.05 ± 19.25	0.948	
Postoperative GGT(U/L)	84.04 ± 36.47	188.09 ± 55.62	< 0.001	
Postoperative ALP(U/L)	99.92 ± 45.98	251.51 ± 61.51	< 0.001	

There was no significant difference in AST and ALT between the two groups after TACE (P > 0.05). Comparison between bile duct injury group and no bile duct injury group: Postoperative total bilirubin was 43.34 ± 25.18 umol/L vs. 21.94 ± 9.82 umol/L (P < 0.001); The postoperative GGT was 188.09 ± 55.62 U/L vs. 84.04 ± 36.47 U/L (P < 0.001); The postoperative ALP was 251.51 ± 61.51 U/L vs. 99.92 ± 45.98 U/L (P < 0.001).

The relationship between the changes of total bilirubin, GGT, ALP and biliary tract injury after TACE (shown in Table 4)

Table 4 Relationship between changes of total bilirubin, GGT, ALP and biliary duct injury one week after TACE in the two groups

		Bile duct injury	Chi-square test(P value)	
		No(N = 792)	No(N = 792)	Fisher’s Exact Test	
Postoperative total bilirubin	< 2 times	472(59.6%)	26(47.3%)	0.089	
≥ 2 times	320(40.4%)	29(52.7%)	
Postoperative GGT	< 2 times	452(57.1%)	16(29.1%)	< 0.001	
≥ 2 times	340(42.9%)	39(70.9%)	
Postoperative ALP	< 2 times	484(61.1%)	12(21.8%)	< 0.001	
≥ 2 times	308(38.9%)	43(78.2%)	

There were statistical differences in total bilirubin, GGT and ALP between the two groups. We divided the patients’ total bilirubin, GGT and ALP into two categories after comparison with those before operation: changes < 2 times compared with those before operation and changes ≥ 2 times compared with those before operation. Total bilirubin after TACE was more than 2 times higher than that before TACE: 29 (52.7%) cases in bile duct injury group and 320 (40.4%) cases in no bile duct injury group, P = 0.089. GGT after TACE was more than 2 times higher than that before TACE: 39 (70.9%) cases in bile duct injury group and 340 (42.9%) cases in non bile duct injury group, P < 0.001. The ALP after TACE was more than 2 times higher than that before TACE: 43 (78.2%) cases in bile duct injury group and 308 (38.9%) cases in non bile duct injury group, P < 0.001.

Multivariate regression analysis of the relationship between postoperative liver function changes and biliary tract injury (shown in Table 5)

Table 5 Multivariate regression analysis of the relationship between liver function changes and biliary duct injury after TACE

		P value	Exp(B)	
Step 1a	Change in bilirubin (1)	0.206	0.693	
Changes in GGT (1)	0.001	0.344	
Change in ALP (1)	< 0.001	0.191	

The binary logistic regression analysis showed that the increase of GGT and ALP after TACE was ≥ 2 times higher than that before TACE as a predictor of bile duct injury. (P < 0.05)

Multivariate regression analysis of risk factors for biliary tract injury after TACE (shown in Table 6)

Table 6 Multivariate regression analysis of risk factors for biliary duct injury after TACE

Variables in the Equation		
	P value	Exp(B)	95% C.I.for EXP(B)	
Lower	Upper	
Step 1a	Gender (1)	0.068	1.881	0.769	4.092	
Child-Pugh classification of liver function (1)	0.926	1.032	0.470	2.361	
Etiology of liver cirrhosis	0.217				
Etiology of liver cirrhosis (1)	0.809	0.846	0.382	2.023	
Etiology of liver cirrhosis (2)	0.113	0.237	0.095	0.831	
Etiology of liver cirrhosis (3)	0.511	0.493	0.239	1.264	
BCLC Stage	0.145				
BCLC Stage (1)	0.051	3.029	1.166	7.180	
BCLC Stage (2)	0.229	1.619	0.574	3.795	
tumor location(1)	0.723	0.851	0.263	2.508	
maximum diameter of tumor(1)	0.517	1.331	0.475	4.326	
Lipiodol dosage in TACE	0.004				
Lipiodol dosage in TACE (1)	0.010	0.203	0.108	0.742	
Lipiodol dosage in TACE (2)	0.570	1.272	0.970	2.157	
Chemotherapeutic Agents (1)	0.746	0.879	0.214	1.691	
Gelfoam Granules Supplemented (1)	< 0.001	0.267	0.115	0.942	
Embolization site	0.029				
Embolization site (1)	0.048	2.561	1.227	5.632	
Embolization site (2)	0.562	0.795	0.109	2.758	
Tumor blood supply (1)	< 0.001	3.353	1.128	9.502	
Combined targeted drug therapy (1)	0.335	1.429	0.357	3.595	
History of hepatobiliary surgery (1)	0.134	0.591	0.186	1.652	
History of diabetes (1)	0.772	1.140	0.272	3.019	
History of hypertension (1)	0.894	0.948	0.451	2.178	

Binary logistic regression analysis showed that lipiodol dosage, gelatin sponge particle supplementation, embolization site, and tumor hypovascularity in TACE were risk factors for biliary tract injury after TACE. (P < 0.05)

Treatment and outcome of patients with bile duct injury (shown in table 7)

Table 7 Treatment and outcome of patients with bile duct injury after TACE

Treatment of bile duct injury (N = 55)	Count (Percentage)	Outcome	
Conservative treatment	30(54.5%)	Recovering	
Percutaneous drainage	19(34.5%)	Recovering	
Puncture aspiration or drainage + sclerosing agent injection	6(11.0%)	Recovering	

Bile duct injury occurred in 55 (6.5%) patients. Among them, 30 cases had no obvious clinical symptoms, and imaging examination revealed bile duct dilatation or biloma. After cholagogue and anti-infection treatment, bile duct dilatation and biloma disappeared in 12 cases, the extent of bile duct dilatation became smaller or biloma became smaller in 10 cases, and bile duct dilatation or biloma did not change significantly in 8 cases. After percutaneous drainage in 19 patients, biloma and bile duct dilatation disappeared and were successfully extubated, and the clinical symptoms were relieved. After percutaneous aspiration or drainage, a large amount of bile was still excreted in 6 patients, and sclerotherapy was performed by injecting absolute ethanol after cholangiography confirmed that they did not communicate with the biliary system, and the biloma shrank and the symptoms were relieved.

Discussion

Pathogenesis of bile duct injury after TACE

Patients with advanced hepatocellular carcinoma often lose the opportunity of surgical resection [24], and TACE is one of the commonly used effective treatments for advanced hepatocellular carcinoma(HCC) in clinical practice [9]. The main principle of TACE for HCC is to place a catheter in the tumor feeding artery, and then inject chemotherapeutic drugs and embolic agents through the catheter [25]. The cytotoxic effect of chemotherapeutic drugs can induce the apoptosis of tumor cells and inhibit the proliferation of tumor cells. After tumor feeding artery embolization, tumor necrosis can also be caused by tumor tissue ischemia and hypoxia [26]. Therefore, TACE is effective in reducing tumor burden, and studies have reported that TACE can significantly prolong Overall Survival(OS) and Progression Free Survival(PFS) in patients [27]. Masatoshi Kudo et al. [28] reported that 76 patients with unresectable HCC underwent TACE alone, and the mPFS was 13.5 months and the 1-year OS rate was 82.7%.

The blood supply of the biliary system mainly comes from the hepatic artery. The branches of hepatic artery form peribiliary vascular plexus(PVP) around the bile duct [29], provide oxygen rich blood to nourish the bile duct system, and maintain the transport of substances reabsorbed from bile to liver parenchyma cells [30, 31]. Possible causes of bile duct injury after TACE [18, 32] include: (1) toxic effect of chemotherapeutic drugs directly leads to necrosis of bile duct epithelial cells [7]; (2) Ischemia of bile duct caused by arterial embolization leads to necrosis of bile duct epithelial cells [33]; (3) The bile duct ischemia caused by embolism and the toxic effect of chemotherapy drugs lead to the destruction of the protective mechanism of bile duct epithelium, which enables the toxic effect of bile acid to play and further damages the bile duct epithelium [34]. Bile duct injury after TACE is characterized by focal or diffuse biliary stricture or dilatation and biloma formation [35]. S Kobayashi et al. [36]. performed pathological examination of hilar tissue in 32 HCC patients who underwent transcatheter embolization and found that peribiliary vascular plexus (PVP) vessels derived from hepatic artery branches were significantly reduced, and peribiliary fibrosis, biliary epithelial injury, and bile duct necrosis were pathologically found. In our study, the incidence of bile duct injury after TACE was 6.5%. The incidence of bile duct injury reported in different studies is not completely the same, which may be related to the inconsistent baseline level of patients and the specific procedures of TACE. Zhijun Wang et al. [14] reported that 10 patients (0.5%) suffered bile duct injury after TACE in 1992 patients with hepatocellular carcinoma. Shiro Miyayama et al. [37] reported that 18 (4.0%) of 446 HCC patients had bile duct injury after TACE. KK Kim et al. [16] reported that 17 (2%) of 807 HCC patients had bile duct injury after TACE.

Risk factors of bile duct injury after TACE

We compared the baseline data and intraoperative conditions of patients with bile duct injury after TACE with those without bile duct injury. The results showed that the preoperative ALP of patients with bile duct injury was higher than that of patients without bile duct injury (103.24 ± 32.77 U/L vs. 89.17 ± 37.35 U/L, P = 0.021). Alkaline phosphatase (ALP) is an enzyme that is widely distributed in human liver, bone, intestine, kidney, placenta and other tissues and is excreted out of the bile through the liver. This enzyme catalyzes the removal of the 5 ‘phosphate group from nucleic acid molecules, thereby converting the 5’-P terminus of DNA or RNA fragments into a 5’-OH terminus. Clinically, ALP is mainly used for the diagnosis and differential diagnosis of hepatobiliary system and skeletal system diseases. When the liver is injured, it enters the blood through lymphatic channels and hepatic sinuses. At the same time, due to the obstruction of bile excretion in the intrahepatic biliary tract, it flows back into the blood, causing a significant increase in serum alkaline phosphatase. To analyze the cause of preoperative ALP elevation in patients with bile duct injury, it may be caused by bile excretion disorder before TACE in these patients. Many previous studies have reported [38] that the preoperative serum ALP level is related to the effect of TACE treatment in HCC patients. Han Wang et al. [39] analyzed the data of 271 HCC patients who received TACE treatment, and they concluded that patients with higher preoperative ALP was an independent risk factor for poor OS. Kavous Firouznia et al. [40] analyzed 32 patients with unresectable HCC treated with TACE, and they concluded that the survival rate of patients was related to the preoperative serum ALP level (< 300U/L vs. ≥ 300U/L, P < 0.043). The results of this study show that patients with high preoperative serum ALP level have a higher probability of bile duct injury after TACE, which may have a potential mechanism similar to these studies.

The results of this study showed that there were statistically significant differences in tumor blood supply characteristics and lipiodol dosage between bile duct injury group and non-bile duct injury group. Intraoperative DSA showed that the proportion of patients with hypovascular tumors was higher in the group of patients who developed bile duct injury than in the group who did not develop bile duct injury (58.2% vs. 24.5%, P < 0.001). The proportion of patients with intraoperative lipiodol consumption of 5–10 ml was higher in the bile duct injury group than in the group without bile duct injury (65.5% vs. 45.3%). Analyzing the reasons, there may be the following aspects. When lipiodol is used < 5 ml, even if lipiodol enters the feeding artery of the biliary duct, it is not enough to cause bile duct injury due to the small amount of lipiodol. When the lipiodol dosage is > 10 ml, the tumor burden is often large or the tumor blood supply is rich. In this case, most lipiodol enters the tumor tissue due to the “siphon effect” of the tumor, but it is not easy to enter the biliary feeding artery and damage the bile duct. However, the tumor burden of patients with lipiodol dosage of 5-10 ml is at a moderate level or hypovascular tumor, and the “siphon effect” of tumor tissue is not strong, which is more likely to cause reflux and lead to bile duct injury. Houyun Xu et al. [15] reported that among 21 patients with bile duct injury after TACE, 3 patients found iodized oil deposition around the bile duct wall during non-enhanced CT one week after TACE. They believed that this sign was a predictor of bile duct injury after TACE. Nikhil Bhagat et al. [41] reported that the incidence of bile duct injury after TACE for HCC with tumor diameter > 5 cm or multiple lesions was low, because the blood supply of such tumors was rich, most of the embolic agents injected entered the tumor tissue, which had little impact on the blood supply of normal bile duct. H K Kim et al. [16] reported that the formation of bilioma after TACE may be caused by the embolization of lipiodol, rather than the role of gelatin sponge particles.

In TACE, lipiodol injection followed by supplemental injection of gelatin sponge particles is a commonly used therapeutic strategy [42]. Shiro Miyayama et al. [43] reported that the standard technique of conventional transarterial chemoembolization(C-TACE) for hepatocellular carcinoma was lipiodol combined with gelatin sponge embolization; according to a national survey in Japan, the 5-year survival rate of C-TACE for HCC patients with single tumor of Child-Pugh class A liver function was 52%. The results showed that the use rate of gelatin sponge particles in the bile duct injury group was significantly higher than that in the non-bile duct injury group (65.5% vs. 35.0%, P < 0.001). We analyze the causes of this phenomenon. Although gelfoam particles are degradable embolic agents, the use of gelatin sponge particles after embolization with lipiodol injection will more completely block arterial blood flow, and the clearance of lipiodol in the bile duct supplying artery will be more difficult, so the damage of bile duct system is more likely to occur. Lei Zhang et al. [44] compared the postoperative complications of 394 patients with Drug-Eluting Beads transarterial chemoembolization(DEB-TACE) and 608 patients with C-TACE. The incidence of bile duct injury in the two groups was 15.5% vs. 7.4%, P < 0.001. This study also shows that the use of particulate embolic agent will increase the incidence of bile duct injury.

In our research, we also found that there was a statistical difference in the location of hepatic artery embolism between the two groups. The proportion of patients with bile duct injury undergoing hepatic lobe embolism was significantly higher than that of patients without bile duct injury (36.4% vs. 10.6%). Hepatic lobe embolization has more extensive influence on arterial blood flow, more influence on the blood supply artery of bile duct system, and higher probability of bile duct injury.In addition, the blood supply arteries of the bile duct in the porta hepatis area mostly originate from the main hepatic artery and its primary branches. Once the bile duct in the porta hepatis area is affected, the risk of bile duct injury and complications is higher. Ichiro Sakamoto et al. [45] reported that the incidence of bile duct injury in TACE was 7.8% when the embolization site was at the level of the proper hepatic artery and the left and right hepatic arteries, which was significantly higher than the incidence of embolization site at the level of the segmental and subsegmental hepatic arteries (1.0%).H K Kim et al. [16] suggested that the dosage of lipiodol and gelatin sponge particles should be weighed and the appropriate embolization site should be selected in TACE, which can reduce the incidence of postoperative bile duct injury. S Kobayashi et al [18] found that bile duct injury was associated with peribiliary vascular plexus injury around the biliary duct after autopsy in 56 HCC patients who underwent transcatheter arterial chemotherapy or transcatheter arterial embolization, and the area of transcatheter arterial embolization was positively correlated with bile duct injury.

In the comparison of patients’ previous medical history, we found that patients in the bile duct injury group had a higher proportion of previous hepatobiliary surgery history than those in the non-bile duct injury group (36.4% vs. 20.8%, P = 0.011). A history of previous hepatobiliary surgery may have disrupted the normal blood distribution of the biliary system. In such patients, the blood supply to the bile duct is more fragile and is more susceptible to be affected and destroyed after TACE. The previous history of hepatobiliary surgery will also affect the excretion and absorption function of the intrahepatic and extrahepatic bile ducts. The impact on the biliary blood supply system after TACE may aggravate the abnormal function of the patients’ bile ducts. Shinichiro Nakada et al. [46] reported that HCC patients receiving TACE treatment in the near future after hepatectomy is a high-risk factor for bile duct injury after TACE.

Logistic regression analysis showed that the dose of lipiodol, the amount of gelatin sponge particles, the site of embolization and the blood supply of tumor were the risk factors of biliary tract injury after TACE (P < 0.05). This result suggests that when we make a comprehensive assessment, if the patients incorporate the above risk factors, the patients have a higher risk of bile duct injury after TACE. This will help us to formulate more rational and individualized treatment methods. It is also helpful to pay attention to high-risk groups after TACE, and take relevant measures to prevent bile duct injury and reduce the occurrence of complications.

Predictors of bile duct injury after TACE

Although TACE is a minimally invasive local treatment, it has an impact on patients’ liver function, which has been confirmed in many clinical studies. In this study, we compared liver function outcomes in patients with and without bile duct injury 1 week after TACE. We found that bilirubin, gamma-glutamyl transpeptidase(GGT), alkaline phosphatase(ALP) in patients with bile duct injury were higher than those in patients without bile duct injury (P < 0.05). Gamma-glutamyl transpeptidase(GGT) is mainly involved in glutathione metabolism in vivo, and GGT in normal human serum mainly comes from the liver. GGT is widely distributed in the liver on one side of the bile capillaries of hepatocytes and throughout the biliary system, and increases in serum when intrahepatic synthesis is hyperactive or bile excretion is blocked. Yejin Mok et al. [47]. investigated the relationship between serum GGT and tumorigenesis in 1.6 million Koreans, with GGT having the strongest association with liver cancer. Similarly, elevated ALP and serum total bilirubin can also reflect abnormal biliary metabolism in the hepatobiliary system. Due to the presence of intrahepatic bile duct dilatation and biloma in patients with bile duct injury, intrahepatic bile excretion and metabolism disorder, bilirubin, GGT and ALP increased significantly after TACE, and laboratory tests provided evidence of bile duct injury. J S Yu et al. [48] reported that among 11 patients with TACE related bile duct injury, 8 patients had elevated serum ALP above 200 U/L. Boris Guiu et al. [49] reported that the occurrence of bile tumor after TACE was related to the increase of ALP and GGT (p = 0.012, p = 0.006).

Bilirubin, GGT and ALP after TACE were divided into two groups: lower than 2 times higher than those before TACE and higher than 2 times higher than those before TACE.We found that after TACE, the proportion of patients with GGT and ALP increased by ≥ 2 times compared with those before TACE was significantly higher in the group with bile duct injury than in the group without bile duct injury (P < 0.05). Using binary logistic regression analysis, it was shown that postoperative GGT and ALP increase ≥ 2 times compared with preoperative were predictive indicators of bile duct injury. This coincides with some other findings. Houyun Xu et al. [15]. reported that ALP > 200U/L was a predictor of bile duct injury when examined one week after TACE. The biochemical indexes of short-term reexamination after operation can predict the possibility of bile duct injury, and help to early detection and early intervention to avoid serious complications.

Treatment and outcome of bile duct injury after TACE

In our study group, 55 patients had bile duct injuries. 30 patients were improved or stabilized after conservative treatment. 19 cases were relieved after percutaneous drainage. After percutaneous aspiration or drainage plus sclerotherapy in 6 patients, the biloma shrank and the symptoms were relieved. Most studies have reported that bile duct injury occurring after TACE can be relieved by the above treatment. Houyun Xu et al. [15] reported that 47.6% (10/21) of patients with bile duct injury after TACE improved after symptomatic treatment, and 19% (4/21) of patients improved after biliary drainage. Mathieu Boulin et al. [50] reported that most bile duct injuries after TACE can be relieved through symptomatic treatment or clinical follow-up. Ichiro Sakamoto et al. [45] reported that if biloma has no symptoms or progressive enlargement, biloma after TACE can be treated conservatively. Liang Yan et al. [51] reported that 58 patients with HCC located in the caudal lobe had biliary duct injury in 2 cases after TACE, and one case needed biliary drainage. A V Bazayev et al. [52]. reported a case of intrahepatic biloma treated by sclerotherapy with absolute ethanol. Mortality rates associated with biloma following TACE are 5–10% [14, 19]. Therefore, attention should be paid to the early detection and early intervention of bile duct injury after TACE.

Conclusion

Bile duct injury is one of the rare complications after TACE for primary hepatocellular carcinoma. The dosage of lipiodol in TACE, supplementation of gelatin sponge particles, embolization site, and hypovascularity of the tumor are risk factors for biliary duct injury after TACE. After TACE, GGT and ALP increased ≥ 2 times compared with preoperative indicators as predictors of bile duct injury. After TACE, patients with high risk factors should be monitored for changes in biochemical parameters, which is helpful for early detection and treatment of patients with bile duct injury, so as to avoid the occurrence of serious complications. Bile duct injury occurring after TACE can achieve good outcomes with aggressive management.

The shortcoming of this study is that the data are from a single center. As a result, it is a retrospective study with limited sample size. It is feasible for the prospective study with multicenter and large-sample at a later stage, which will provide more help for clinical work.

Acknowledgements

Thank Pro. Huimin Liang for his help in English writing. Thank Dr. Fan Yang for her help in data collection. Thank Dr. Xin Li for his help in references. Thank you for all those who offer help and support in this research.

Author contributions

Haohao Lu have made substantial contributions to the conception and design of the work, and the acquisition, analysis of data, as well as manuscript writing. Chuansheng Zheng have made contributions to the design of the work. Bin Liang have made contributions to the acquisition, analysis of data. Xiangwen Xia have made contributions to analysis, interpretation of data, and manuscript writing. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work.

Funding

No funding is provided in this study.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The medical ethics committee at Union Hospital, Tongji Medical College, Huazhong University of science and technology, Wuhan, Hubei Province approved the retrospective study. The requirement for informed consent was waived by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of science and technology due to the retrospective nature of the study. During follow-up, we informed patients about the study and they agreed to use their data. We confirmed that all methods were performed in accordance with the relevant guidelines and Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiangwen Xia and Chuansheng Zheng contributed equally to this work.
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