Research progress on the pathogenesis of ischemic bile duct injury after liver TACE_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

SHU Peng ^1,2 , CHENG Long ¹ , XIE Chuan ^1,3 , DAI Xin ^1,3 , WANG Qiang ^1,3 ,  WANG Tao ^1,2

1. Department of General Surgery, General Hospital of Western Theater Command, Chengdu 610083, P. R. China;
2. Department of Hepatobiliary Surgery, School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
3. Department of Hepatobiliary Surgery, School of Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

WANG Tao, Email: watopo@163.com

Keywords：

ischemic bile duct injury; transcatheter arterial chemoembolization; pathological mechanism; research progress

DOI：

10.7507/1007-9424.202011106

Video：

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Objective To summarize the research progress on the pathogenesis of ischemic bile duct injury after transcatheter arterial chemoembolization (TACE).Method The recent studies on the incidence, pathological features and related mechanisms of ischemic bile duct injury and ischemic bile duct injury after TACE were reviewed.Results The incidence of ischemic bile duct injury after liver TACE fluctuated greatly and was related to different chemoembolization methods. At present, the causes of ischemic bile duct injury were attributed to the bile duct ischemia caused by embolization and the toxic effects of chemotherapeutic drugs. The destruction of protective mechanism of bile duct epithelium and the expression of transforming growth factor-β might play an important role in ischemic bile duct injury.Conclusions After liver TACE, in addition to the direct injury of bile duct caused by the toxic effects of ischemia and chemotherapy drugs, the damage of bile duct epithelial protection mechanism caused by ischemia and chemotherapy drugs makes the toxic effects of bile acids play a very important role in the ischemic bile duct injury. However, there is still no direct evidence of bile duct epithelial protection mechanism in ischemic bile duct injury after liver TACE. Further clarifying the role of bile duct epithelial protection mechanism in ischemic bile duct injury after liver TACE will be helpful to explore its prevention and treatment measures, and provide new insights for the further studies in future.

Citation： SHU Peng, CHENG Long, XIE Chuan, DAI Xin, WANG Qiang, WANG Tao. Research progress on the pathogenesis of ischemic bile duct injury after liver TACE. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(10): 1378-1383. doi: 10.7507/1007-9424.202011106 Copy

1.	Deltenre P, Valla DC. Ischemic cholangiopathy. Semin Liver Dis, 2008, 28(3): 235-246.
2.	Paul SB, Gamanagatti S, Sreenivas V, et al. Trans-arterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma: Experience from a tertiary care centre in India. Indian J Radiol Imaging, 2011, 21(2): 113-120.
3.	Monier A, Guiu B, Duran R, et al. Liver and biliary damages following transarterial chemoembolization of hepatocellular carcinoma: comparison between drug-eluting beads and lipiodol emulsion. Eur Radiol, 2017, 27(4): 1431-1439.
4.	戴欣, 耿小平. 缺血性胆管损伤的病因学研究进展. 中华普通外科杂志, 2012, 27(1): 79-81.
5.	Nakada S, Allard MA, Lewin M, et al. Ischemic cholangiopathy following transcatheter arterial chemoembolization for recurrent hepatocellular carcinoma after hepatectomy: an underestimated and devastating complication. J Gastrointest Surg, 2020, 24(11): 2517-2525.
6.	de Vries Y, von Meijenfeldt FA, Porte RJ. Post-transplant cholangiopathy: classification, pathogenesis, and preventive strategies. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1507-1515.
7.	Dhamija E, Paul SB, Gamanagatti SR, et al. Biliary complications of arterial chemoembolization of hepatocellular carcinoma. Diagn Interv Imaging, 2015, 96(11): 1169-1175.
8.	兰阳军. 胆管血供与缺血性胆管损伤. 局解手术学杂志, 2003, 12(3): 231-233.
9.	Guiu B, Deschamps F, Aho S, et al. Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs drug-eluting beads. J Hepatol, 2012, 56(3): 609-617.
10.	Aal AKA, Moawad S, Lune PV, et al. Survival outcomes of very small drug-eluting beads used in chemoembolization of unresectable hepatocellular carcinoma. J Vasc Interv Radiol, 2019, 30(9): 1325-1334.
11.	Lucatelli P, Ginnani Corradini L, De Rubeis G, et al. Balloon-occluded transcatheter arterial chemoembolization (b-TACE) for hepatocellular carcinoma performed with polyethylene-glycol epirubicin-loaded drug-eluting embolics: safety and preliminary results. Cardiovasc Intervent Radiol, 2019, 42(6): 853-862.
12.	Wang Q, Hodavance M, Ronald J, et al. Minimal risk of biliary tract complications, including hepatic abscess, after transarterial embolization for hepatocellular carcinoma using concentrated antibiotics mixed with particles. Cardiovasc Intervent Radiol, 2018, 41(9): 1391-1398.
13.	Ren J, Lu MD, Zheng RQ, et al. Evaluation of the microcirculatory disturbance of biliary ischemia after liver transplantation with contrast-enhanced ultrasound: preliminary experience. Liver Transpl, 2009, 15(12): 1703-1708.
14.	Gaudio E, Onori P, Pannarale L, et al. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: a morphological study. Gastroenterology, 1996, 111(4): 1118-1124.
15.	Alabdulghani F, Healy GM, Cantwell CP. Radiological findings in ischaemic cholangiopathy. Clin Radiol, 2020, 75(3): 161-168.
16.	黄捷, 黄汉飞, 段键, 等. 肝移植缺血性胆管损伤的发生机制及其研究进展. 国际移植与血液净化杂志, 2014, 12(1): 4-7.
17.	Mancinelli R, Glaser S, Francis H, et al. Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors. Am J Physiol Gastrointest Liver Physiol, 2015, 309(11): G865-873.
18.	Doctor RB, Dahl RH, Salter KD, et al. Reorganization of cholangiocyte membrane domains represents an early event in rat liver ischemia. Hepatology, 1999, 29(5): 1364-1374.
19.	Keppler U, Moussavian MR, Jeanmonod P, et al. Neither isolated hepatic arterial clamping nor hepatic arterial ligation induce ischemic type biliary lesions in rats. Ann Transplant, 2016, 21: 649-659.
20.	Op den Dries S, Sutton ME, Lisman T, et al. Protection of bile ducts in liver transplantation: looking beyond ischemia. Transplantation, 2011, 92(4): 373-379.
21.	Wang R, Sheps JA, Liu L, et al. Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2^-/- mice. J Lipid Res, 2019, 60(1): 85-97.
22.	Engin A. Bile acid toxicity and protein kinases. Adv Exp Med Biol, 2021, 1275: 229-258.
23.	Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol, 2011, 178(1): 175-186.
24.	Popov Y, Patsenker E, Fickert P, et al. Mdr2 (Abcb4)^-/-mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol, 2005, 43(6): 1045-1054.
25.	Xia X, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes. World J Gastroenterol, 2006, 12(22): 3553-3563.
26.	Fiorucci S, Rizzo G, Donini A, et al. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med, 2007, 13(7): 298-309.
27.	Khan AA, Chow EC, Porte RJ, et al. Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos, 2009, 30(5): 241-258.
28.	Zhang Y, Jackson JP, St Claire RL, et al. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. Pharmacol Res Perspect, 2017, 5(4): e00329.
29.	程龙. 移植肝胆管细胞胆汁酸转运蛋白在胆管损伤中的作用实验研究. 重庆: 第三军医大学, 2010.
30.	Cheng L, Tian F, Tian F, et al. Repression of Farnesoid X receptor contributes to biliary injuries of liver grafts through disturbing cholangiocyte bile acid transport. Am J Transplant, 2013, 13(12): 3094-3102.
31.	Hohenester S, Wenniger LM, Paulusma CC, et al. A biliary HCO₃^- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology, 2012, 55(1): 173-183.
32.	Beuers U, Hohenester S, de Buy Wenniger LJ, et al. The biliary HCO₃^- umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology, 2010, 52(4): 1489-1496.
33.	Sasaki M, Miyakoshi M, Sato Y, et al. Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis. Liver Int, 2013, 33(2): 312-320.
34.	van Niekerk J, Kersten R, Beuers U. Role of bile acids and the biliary HCO₃^-umbrella in the pathogenesis of primary biliary cholangitis. Clin Liver Dis, 2018, 22(3): 457-479.
35.	Maillette de Buy Wenniger LJ, Hohenester S, Maroni L, et al. The cholangiocyte glycocalyx stabilizes the ‘biliary HCO₃ umbrella’: an integrated line of defense against toxic bile acids. Dig Dis, 2015, 33(3): 397-407.
36.	Chen G, Wang S, Bie P, et al. Endogenous bile salts are associated with bile duct injury in the rat liver transplantation model. Transplantation, 2009, 87(3): 330-339.
37.	Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol, 2009, 15(14): 1677-1689.
38.	Urbano J, Echevarria-Uraga JJ, Ciampi-Dopazo JJ, et al. Multicentre prospective study of drug-eluting bead chemoembolisation safety using tightly calibrated small microspheres in non-resectable hepatocellular carcinoma. Eur J Radiol, 2020, 126: 108966.
39.	Duan XH, Li H, Ren JZ, et al. Hepatic arterial chemoembolization with arsenic trioxide eluting callispheres microspheres versus lipiodol emulsion: pharmacokinetics and intratumoral concentration in a rabbit liver tumor model. Cancer Manag Res, 2019, 11: 9979-9988.
40.	Zhang S, Huang C, Li Z, et al. Comparison of pharmacokinetics and drug release in tissues after transarterial chemoembolization with doxorubicin using diverse lipiodol emulsions and CalliSpheres Beads in rabbit livers. Drug Deliv, 2017, 24(1): 1011-1017.
41.	Hu HH, Chen DQ, Wang YN, et al. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact, 2018, 292: 76-83.
42.	Dhar A, Ray A. The CCN family proteins in carcinogenesis. Exp Oncol, 2010, 32(1): 2-9.
43.	George J, Tsutsumi M, Tsuchishima M. MMP-13 deletion decreases profibrogenic molecules and attenuates N-nitrosodimethylamine-induced liver injury and fibrosis in mice. J Cell Mol Med, 2017, 21(12): 3821-3835.
44.	Kim J, Kang W, Kang SH, et al. Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis. Sci Rep, 2020, 10(1): 21018.
45.	卢家美, 张晶晶, 吕毅, 等. 二甲双胍抑制大鼠胆管成纤维细胞胶原生成的分子信号机制. 南方医科大学学报, 2020, 40(5): 640-646.
46.	李立军, 王向昱, 张普, 等. TGF-β1及CTGF在胆管缺血性损伤修复过程中的表达及意义. 肝胆胰外科杂志, 2011, 23(4): 336-339.

1. Deltenre P, Valla DC. Ischemic cholangiopathy. Semin Liver Dis, 2008, 28(3): 235-246.
2. Paul SB, Gamanagatti S, Sreenivas V, et al. Trans-arterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma: Experience from a tertiary care centre in India. Indian J Radiol Imaging, 2011, 21(2): 113-120.
3. Monier A, Guiu B, Duran R, et al. Liver and biliary damages following transarterial chemoembolization of hepatocellular carcinoma: comparison between drug-eluting beads and lipiodol emulsion. Eur Radiol, 2017, 27(4): 1431-1439.
4. 戴欣, 耿小平. 缺血性胆管损伤的病因学研究进展. 中华普通外科杂志, 2012, 27(1): 79-81.
5. Nakada S, Allard MA, Lewin M, et al. Ischemic cholangiopathy following transcatheter arterial chemoembolization for recurrent hepatocellular carcinoma after hepatectomy: an underestimated and devastating complication. J Gastrointest Surg, 2020, 24(11): 2517-2525.
6. de Vries Y, von Meijenfeldt FA, Porte RJ. Post-transplant cholangiopathy: classification, pathogenesis, and preventive strategies. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1507-1515.
7. Dhamija E, Paul SB, Gamanagatti SR, et al. Biliary complications of arterial chemoembolization of hepatocellular carcinoma. Diagn Interv Imaging, 2015, 96(11): 1169-1175.
8. 兰阳军. 胆管血供与缺血性胆管损伤. 局解手术学杂志, 2003, 12(3): 231-233.
9. Guiu B, Deschamps F, Aho S, et al. Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs drug-eluting beads. J Hepatol, 2012, 56(3): 609-617.
10. Aal AKA, Moawad S, Lune PV, et al. Survival outcomes of very small drug-eluting beads used in chemoembolization of unresectable hepatocellular carcinoma. J Vasc Interv Radiol, 2019, 30(9): 1325-1334.
11. Lucatelli P, Ginnani Corradini L, De Rubeis G, et al. Balloon-occluded transcatheter arterial chemoembolization (b-TACE) for hepatocellular carcinoma performed with polyethylene-glycol epirubicin-loaded drug-eluting embolics: safety and preliminary results. Cardiovasc Intervent Radiol, 2019, 42(6): 853-862.
12. Wang Q, Hodavance M, Ronald J, et al. Minimal risk of biliary tract complications, including hepatic abscess, after transarterial embolization for hepatocellular carcinoma using concentrated antibiotics mixed with particles. Cardiovasc Intervent Radiol, 2018, 41(9): 1391-1398.
13. Ren J, Lu MD, Zheng RQ, et al. Evaluation of the microcirculatory disturbance of biliary ischemia after liver transplantation with contrast-enhanced ultrasound: preliminary experience. Liver Transpl, 2009, 15(12): 1703-1708.
14. Gaudio E, Onori P, Pannarale L, et al. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: a morphological study. Gastroenterology, 1996, 111(4): 1118-1124.
15. Alabdulghani F, Healy GM, Cantwell CP. Radiological findings in ischaemic cholangiopathy. Clin Radiol, 2020, 75(3): 161-168.
16. 黄捷, 黄汉飞, 段键, 等. 肝移植缺血性胆管损伤的发生机制及其研究进展. 国际移植与血液净化杂志, 2014, 12(1): 4-7.
17. Mancinelli R, Glaser S, Francis H, et al. Ischemia reperfusion of the hepatic artery induces the functional damage of large bile ducts by changes in the expression of angiogenic factors. Am J Physiol Gastrointest Liver Physiol, 2015, 309(11): G865-873.
18. Doctor RB, Dahl RH, Salter KD, et al. Reorganization of cholangiocyte membrane domains represents an early event in rat liver ischemia. Hepatology, 1999, 29(5): 1364-1374.
19. Keppler U, Moussavian MR, Jeanmonod P, et al. Neither isolated hepatic arterial clamping nor hepatic arterial ligation induce ischemic type biliary lesions in rats. Ann Transplant, 2016, 21: 649-659.
20. Op den Dries S, Sutton ME, Lisman T, et al. Protection of bile ducts in liver transplantation: looking beyond ischemia. Transplantation, 2011, 92(4): 373-379.
21. Wang R, Sheps JA, Liu L, et al. Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2^-/- mice. J Lipid Res, 2019, 60(1): 85-97.
22. Engin A. Bile acid toxicity and protein kinases. Adv Exp Med Biol, 2021, 1275: 229-258.
23. Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol, 2011, 178(1): 175-186.
24. Popov Y, Patsenker E, Fickert P, et al. Mdr2 (Abcb4)^-/-mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol, 2005, 43(6): 1045-1054.
25. Xia X, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes. World J Gastroenterol, 2006, 12(22): 3553-3563.
26. Fiorucci S, Rizzo G, Donini A, et al. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med, 2007, 13(7): 298-309.
27. Khan AA, Chow EC, Porte RJ, et al. Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos, 2009, 30(5): 241-258.
28. Zhang Y, Jackson JP, St Claire RL, et al. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. Pharmacol Res Perspect, 2017, 5(4): e00329.
29. 程龙. 移植肝胆管细胞胆汁酸转运蛋白在胆管损伤中的作用实验研究. 重庆: 第三军医大学, 2010.
30. Cheng L, Tian F, Tian F, et al. Repression of Farnesoid X receptor contributes to biliary injuries of liver grafts through disturbing cholangiocyte bile acid transport. Am J Transplant, 2013, 13(12): 3094-3102.
31. Hohenester S, Wenniger LM, Paulusma CC, et al. A biliary HCO₃^- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology, 2012, 55(1): 173-183.
32. Beuers U, Hohenester S, de Buy Wenniger LJ, et al. The biliary HCO₃^- umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology, 2010, 52(4): 1489-1496.
33. Sasaki M, Miyakoshi M, Sato Y, et al. Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis. Liver Int, 2013, 33(2): 312-320.
34. van Niekerk J, Kersten R, Beuers U. Role of bile acids and the biliary HCO₃^-umbrella in the pathogenesis of primary biliary cholangitis. Clin Liver Dis, 2018, 22(3): 457-479.
35. Maillette de Buy Wenniger LJ, Hohenester S, Maroni L, et al. The cholangiocyte glycocalyx stabilizes the ‘biliary HCO₃ umbrella’: an integrated line of defense against toxic bile acids. Dig Dis, 2015, 33(3): 397-407.
36. Chen G, Wang S, Bie P, et al. Endogenous bile salts are associated with bile duct injury in the rat liver transplantation model. Transplantation, 2009, 87(3): 330-339.
37. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol, 2009, 15(14): 1677-1689.
38. Urbano J, Echevarria-Uraga JJ, Ciampi-Dopazo JJ, et al. Multicentre prospective study of drug-eluting bead chemoembolisation safety using tightly calibrated small microspheres in non-resectable hepatocellular carcinoma. Eur J Radiol, 2020, 126: 108966.
39. Duan XH, Li H, Ren JZ, et al. Hepatic arterial chemoembolization with arsenic trioxide eluting callispheres microspheres versus lipiodol emulsion: pharmacokinetics and intratumoral concentration in a rabbit liver tumor model. Cancer Manag Res, 2019, 11: 9979-9988.
40. Zhang S, Huang C, Li Z, et al. Comparison of pharmacokinetics and drug release in tissues after transarterial chemoembolization with doxorubicin using diverse lipiodol emulsions and CalliSpheres Beads in rabbit livers. Drug Deliv, 2017, 24(1): 1011-1017.
41. Hu HH, Chen DQ, Wang YN, et al. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact, 2018, 292: 76-83.
42. Dhar A, Ray A. The CCN family proteins in carcinogenesis. Exp Oncol, 2010, 32(1): 2-9.
43. George J, Tsutsumi M, Tsuchishima M. MMP-13 deletion decreases profibrogenic molecules and attenuates N-nitrosodimethylamine-induced liver injury and fibrosis in mice. J Cell Mol Med, 2017, 21(12): 3821-3835.
44. Kim J, Kang W, Kang SH, et al. Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis. Sci Rep, 2020, 10(1): 21018.
45. 卢家美, 张晶晶, 吕毅, 等. 二甲双胍抑制大鼠胆管成纤维细胞胶原生成的分子信号机制. 南方医科大学学报, 2020, 40(5): 640-646.
46. 李立军, 王向昱, 张普, 等. TGF-β1及CTGF在胆管缺血性损伤修复过程中的表达及意义. 肝胆胰外科杂志, 2011, 23(4): 336-339.

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Research progress on the pathogenesis of ischemic bile duct injury after liver TACE

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