Ischemic cholangiopathy

Abstract

Ischemic cholangiopathy can be defined as a focal or extensive damage to the bile ducts due to impaired blood supply [[1]Sherlock S. Overview of chronic cholestatic conditions in adults: terminology and definitions.Clin Liver Dis. 1998; 2 ([vii]): 217-233Abstract Full Text Full Text PDF PubMed Google Scholar]. This entity may be observed in various circumstances discussed below, and is of clinical importance for practitioners involved in gastroenterology, oncology, abdominal surgery, liver transplantation and in the management of patients with AIDS or systemic diseases. It is commonly referred to as ischemic cholangitis [[2]Batts K.P. Ischemic cholangitis.Mayo Clin Proc. 1998; 73: 380-385Abstract Full Text Full Text PDF PubMed Google Scholar] although inflammation does not appear to be a primary factor. Blood is supplied to the bile ducts through a network of arterioles and capillaries, called the peribiliary vascular plexus (PBP), coming from hepatic arteries (HAs) [[3]Northover J.M. Terblanche J. A new look at the arterial supply of the bile duct in man and its surgical implications.Br J Surg. 1979; 66: 379-384Crossref PubMed Scopus (0) Google Scholar]. In this paper, we will discuss (1) the consequences of an intentional hepatic artery (HA) blockade; (2) the conditions where vascular involvement is a documented factor for bile duct injury; and (3) the conditions where vascular lesions could contribute to bile duct injury. Acalculous cholecystitis will not be considered although there may be much in common with ischemic cholangiopathy. Clinical features of ischemic cholangiopathy may be latent during the initial period of the disease, the diagnosis being made when abnormal biochemical liver tests are discovered. These consist mainly in elevated levels of serum alkaline phosphatase and gamma-glutamyltransferase. Progressive cholestasis and angiocholitis are the two major presenting features. At a later stage of the disease, itching and jaundice appear, and hepato-cellular failure may develop. Some patients may have a minor form of the disease and probably will never suffer from this [[4]Sherlock S. Dooley J. Slerosing cholangitis.in: Blackwell Publishing Diseases of the liver and biliary system. 11th ed. Rotolito Lombarda, Milan2002: 255-265Google Scholar]. Ischemic biliary injury may take the aspect of bile duct necrosis, bile leakage, biloma, bile duct fibrosis or stenosis. Bile duct necrosis and bilomas develop predominantly where there is an abrupt and complete interruption of arterial blood supply, for example when HA thrombose in a liver transplant recipient [5Valente J.F. Alonso M.H. Weber F.L. Hanto D.W. Late hepatic artery thrombosis in liver allograft recipients is associated with intrahepatic biliary necrosis.Transplantation. 1996; 61: 61-65Crossref PubMed Scopus (69) Google Scholar, 6Abbasoglu O. Levy M.F. Vodapally M.S. Goldstein R.M. Husberg B.S. Gonwa T.A. et al.Hepatic artery stenosis after liver transplantation—incidence, presentation, treatment, and long term outcome.Transplantation. 1997; 63: 250-255Crossref PubMed Scopus (129) Google Scholar]. On the contrary, fibrous stenoses develop where there is progressive injury to the hepatic arterioles, for example, after several courses of intra-arterial chemotherapy [7Siegel J.H. Ramsey W.H. Endoscopic biliary stent placement for bile duct stricture after hepatic artery infusion of 5-FUDR.J Clin Gastroenterol. 1986; 8: 673-676Crossref PubMed Google Scholar, 8Aldrighetti L. Arru M. Ronzoni M. Salvioni M. Villa E. Ferla G. Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer.Hepatogastroenterology. 2001; 48: 1302-1307PubMed Google Scholar]. Cholangiographic findings include diffuse and multiple bile ducts lesions. Bile ducts are affected in a pauci- or pluri-focal pattern. The predominant site of involvement is the middle third of the common bile duct, followed by the hepatic duct confluence [8Aldrighetti L. Arru M. Ronzoni M. Salvioni M. Villa E. Ferla G. Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer.Hepatogastroenterology. 2001; 48: 1302-1307PubMed Google Scholar, 9Hohn D. Melnick J. Stagg R. Altman D. Friedman M. Ignoffo R. et al.Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine.J Clin Oncol. 1985; 3: 98-102Crossref PubMed Google Scholar, 10Shea Jr, W.J. Demas B.E. Goldberg H.I. Hohn D.C. Ferrell L.D. Kerlan R.K. Sclerosing cholangitis associated with hepatic arterial FUDR chemotherapy: radiographic–histologic correlation.AJR Am J Roentgenol. 1986; 146: 717-721Crossref PubMed Google Scholar]. Intrahepatic involvement is the least common. As a result, subcapsular needle biopsy, when performed, most often fail to sample the affected tissues [11Starzl T.E. Demetris A.J. Liver transplantation: a 31-year perspective. Part I.Curr Probl Surg. 1990; 27: 49-116PubMed Google Scholar, 12Demetris A.J. Ischemic cholangitis.Mayo Clin Proc. 1992; 67: 601-602Abstract Full Text Full Text PDF PubMed Google Scholar, 13Ludwig J. Batts K.P. MacCarty R.L. Ischemic cholangitis in hepatic allografts.Mayo Clin Proc. 1992; 67: 519-526Abstract Full Text Full Text PDF PubMed Google Scholar, 14Sebagh M. Farges O. Kalil A. Samuel D. Bismuth H. Reynes M. Sclerosing cholangitis following human orthotopic liver transplantation.Am J Surg Pathol. 1995; 19: 81-90Crossref PubMed Google Scholar], and the pathologist is usually forced to rely on surrogate changes in the parenchyma. Therefore, ischemic cholangiopathy may be difficult to demonstrate. Primary sclerosing cholangitis is a slowly progressive disease of the bile ducts of unknown origin. The term ‘primary’ is used to distinguish this condition from others that may lead to a similar clinical and cholangiographic syndrome [[15]Lee Y.M. Kaplan M.M. Primary sclerosing cholangitis.N Engl J Med. 1995; 332: 924-933Crossref PubMed Scopus (372) Google Scholar]. Thus tumor, primary stones or foreign material within the bile ducts have to be excluded using appropriate investigations before a diagnosis of primary sclerosing cholangitis can be made. Similarities between ischemic cholangiopathy and primary sclerosing cholangitis suggest that ischemia may participate in some instances in the pathogenesis of the latter. Therefore, primary sclerosing cholangitis should only be considered when conditions in which vascular lesions could contribute to bile duct injury have been ruled out. Blood is supplied to intra- and extra-hepatic bile ducts exclusively through HAs [[16]Takasaki S. Hano H. Three-dimensional observations of the human hepatic artery (arterial system in the liver).J Hepatol. 2001; 34: 455-466Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. Over 50% of the blood conveyed by HAs is primarily destined to the bile ducts. The rest of hepatic arterial blood is mainly distributed to the liver capsule, to vasa vasora for portal and hepatic veins, and to hepatic venous tracts [[17]Ekataksin W. Zou Z.Z. Wake K. Chunhabundit P. Somana R. Nishida J. et al.The hepatic microcirculatory subunits: an over-three-century-long search for the missing link between an exocrine unit and an endocrine unit in mammalian liver nodules.in: Motta P.M. Recent advances in microscopy of cells, tissues and organs. University of Rome La Sapienza Press, Rome1997: 375-380Google Scholar]. In addition to intra- and extra-hepatic branches of HAs coming from celiac axis, and entering the liver at porta hepatis, there are up to 30 branches entering the liver through its surface, coming from splanchnic or non-splanchnic arteries (e.g. right phrenic arteries) [[18]Campra J.L. Reynolds T.B. The hepatic circulation.in: Arias I.M. Jakoby W.B. Popper H. Schachter D. Shafritz D.A. The liver biology and pathobiology. Raven Press, New York1988: 911-930Google Scholar]. Intrahepatic arteries run close to bile ducts. They resolve into PBP, a rich microvascular network surrounding bile ducts as schematically depicted in Fig. 1 [[17]Ekataksin W. Zou Z.Z. Wake K. Chunhabundit P. Somana R. Nishida J. et al.The hepatic microcirculatory subunits: an over-three-century-long search for the missing link between an exocrine unit and an endocrine unit in mammalian liver nodules.in: Motta P.M. Recent advances in microscopy of cells, tissues and organs. University of Rome La Sapienza Press, Rome1997: 375-380Google Scholar]. Peribiliary plexus extensively connects with the terminal HAs. Blood supplying the bile ducts drains into venules joining the intrahepatic portal system, and then reaches sinusoids; or the draining portal venules can directly reach sinusoids [[17]Ekataksin W. Zou Z.Z. Wake K. Chunhabundit P. Somana R. Nishida J. et al.The hepatic microcirculatory subunits: an over-three-century-long search for the missing link between an exocrine unit and an endocrine unit in mammalian liver nodules.in: Motta P.M. Recent advances in microscopy of cells, tissues and organs. University of Rome La Sapienza Press, Rome1997: 375-380Google Scholar]. Overall, this vascular pattern resembles that of the intestine but differs from that of liver parenchyma. Proximal HA blockade alone can be achieved by means of HA ligation or arterial embolization with large particles or coils (>1 mm in diameter). Outside the transplant setting, these procedures appear to induce no or limited consequences for the liver in patients or experimental animals [19Mays E.T. Observations and management after hepatic artery ligation.Surg Gynecol Obstet. 1967; 124: 801-807PubMed Google Scholar, 20Kim D.K. Kinne D.W. Fortner J.G. Occlusion of the hepatic artery in man.Surg Gynecol Obstet. 1973; 136: 966-968PubMed Google Scholar]. In the guinea pig, HA ligation does not lead to a decrease in bile flow or ultrastructural changes of biliary epithelium [[21]Tavoloni N. Schaffner F. The intrahepatic biliary epithelium in the guinea pig: is hepatic artery blood flow essential in maintaining its function and structure?.Hepatology. 1985; 5: 666-672Crossref PubMed Google Scholar]. The good tolerance achieved can be explained by a rapid development of collaterals shunting the blocked arteries, and by retrograde portal blood supply to bile ducts. In monkeys, when HAs are proximally occluded with large sized gelatin particles, arterial collaterals open or develop rapidly, and liver function remains normal [[22]Doppman J.L. Girton M. Kahn R. Proximal versus peripheral hepatic artery embolization experimental study in monkeys.Radiology. 1978; 128: 577-588Crossref PubMed Google Scholar]. In man, arterial collaterals are discernible angiographically as early as 10–15 h from HA ligation [23Bengmark S. Rosengren K. Angiographic study of the collateral circulation to the liver after ligation of the hepatic artery in man.Am J Surg. 1970; 119: 620-624Abstract Full Text PDF PubMed Google Scholar, 24Redman H.C. Reuter S.R. Arterial collaterals in the liver hilus.Radiology. 1970; 94: 575-579Crossref PubMed Google Scholar, 25Mays E.T. Wheeler C.S. Demonstration of collateral arterial flow after interruption of hepatic arteries in man.N Engl J Med. 1974; 290: 993-996Crossref PubMed Google Scholar, 26Koehler R.E. Korobkin M. Lewis F. Arteriographic demonstration of collateral arterial supply to the liver after hepatic artery ligation.Radiology. 1975; 117: 49-54Crossref PubMed Google Scholar]. In experimental studies, hepatic portoarterial shunting of iodized oil via the PBP has been observed in normal rats [[27]Kan Z. Ivancev K. Lunderquist A. Peribiliary plexa—important pathways for shunting of iodized oil and silicon rubber solution from the hepatic artery to the portal vein. An experimental study in rats.Invest Radiol. 1994; 29: 671-676Crossref PubMed Scopus (31) Google Scholar]. In cirrhotic rats, where PBP is enlarged, scanning electron microscopy shows portoarterial shunts that significantly increase following HA embolization [[28]Demachi H. Matsui O. Kawamori Y. Ueda K. Takashima T. The protective effect of portoarterial shunts after experimental hepatic artery embolization in rats with liver cirrhosis.Cardiovasc Intervent Radiol. 1995; 18: 97-101Crossref PubMed Google Scholar]. In patients treated for malignant liver tumors with HA infusion, iodized oil is seen in portal veins [[29]Nakamura H. Hashimoto T. Oi H. Sawada S. Iodized oil in the portal vein after arterial embolization.Radiology. 1988; 167: 415-417Crossref PubMed Google Scholar]. In liver transplanted patients, retrograde bleeding from the donor HA is seen after portal venous reperfusion [[30]Fisher A. Miller C.H. Ischemic-type biliary strictures in liver allografts: the Achilles heel revisited?.Hepatology. 1995; 21: 589-591Crossref PubMed Google Scholar]. An additional explanation for the capacity of bile ducts to withstand the absence of HA perfusion is that oxygen may simply diffuse from the terminal portal venule into the biliary epithelia cells as close contacts are observed between terminal portal venules and bile duct cells [[21]Tavoloni N. Schaffner F. The intrahepatic biliary epithelium in the guinea pig: is hepatic artery blood flow essential in maintaining its function and structure?.Hepatology. 1985; 5: 666-672Crossref PubMed Google Scholar]. In the transplanted liver, however, proximal HA blockade by HA thrombosis is generally followed by severe morbidity, mainly from biliary damage [5Valente J.F. Alonso M.H. Weber F.L. Hanto D.W. Late hepatic artery thrombosis in liver allograft recipients is associated with intrahepatic biliary necrosis.Transplantation. 1996; 61: 61-65Crossref PubMed Scopus (69) Google Scholar, 6Abbasoglu O. Levy M.F. Vodapally M.S. Goldstein R.M. Husberg B.S. Gonwa T.A. et al.Hepatic artery stenosis after liver transplantation—incidence, presentation, treatment, and long term outcome.Transplantation. 1997; 63: 250-255Crossref PubMed Scopus (129) Google Scholar]. The transplanted liver differs from the non-excised liver in that excision interrupts arterial blood supply from transcapsular peripheral arteries, and therefore compromises collateralization through this route. Furthermore, several possible factors inducing injury to graft microvessels may be present, which will be discussed later. HA embolization with various types of particles has been used to interrupt arterial blood supply [22Doppman J.L. Girton M. Kahn R. Proximal versus peripheral hepatic artery embolization experimental study in monkeys.Radiology. 1978; 128: 577-588Crossref PubMed Google Scholar, 31de Baere T. Dufaux J. Roche A. Counnord J.L. Berthault M.F. Denys A. et al.Circulatory alterations induced by intra-arterial injection of iodized oil and emulsions of iodized oil and doxorubicin: experimental study.Radiology. 1995; 194: 165-170PubMed Google Scholar, 32Demachi H. Matsui O. Takashima T. Scanning electron microscopy of intrahepatic microvasculature casts following experimental hepatic artery embolization.Cardiovasc Intervent Radiol. 1991; 14: 158-162Crossref PubMed Google Scholar, 33Kan Z. Ivancev K. Hagerstrand I. Chuang V.P. Lunderquist A. In vivo microscopy of the liver after injection of Lipiodol into the hepatic artery and portal vein in the rat.Acta Radiol. 1989; 30: 419-425Crossref PubMed Google Scholar, 34Kan Z. Sato M. Ivancev K. Uchida B. Hedgpeth P. Lunderquist A. et al.Distribution and effect of iodized poppyseed oil in the liver after hepatic artery embolization: experimental study in several animal species.Radiology. 1993; 186: 861-866PubMed Google Scholar, 35Kishi K. Sonomura T. Satoh M. Nishida N. Terada M. Shioyama Y. et al.Acute toxicity of lipiodol infusion into the hepatic arteries of dogs.Invest Radiol. 1994; 29: 882-889Crossref PubMed Scopus (15) Google Scholar, 36Cho K.J. Lunderquist A. The peribiliary vascular plexus: the microvascular architecture of the bile duct in the rabbit and in clinical cases.Radiology. 1983; 147: 357-364PubMed Google Scholar, 37Doppman J.L. Dunnick N.R. Girton M. Fauci A.S. Popovsky M.A. Bile duct cysts secondary to liver infarcts: report of a case and experimental production by small vessel hepatic artery occlusion.Radiology. 1979; 130: 1-5Crossref PubMed Google Scholar, 38White Jr, R.I. Strandberg J.V. Gross G.S. Barth K.H. Therapeutic embolization with long-term occluding agents and their effects on embolized tissues.Radiology. 1977; 125: 677-687Crossref PubMed Google Scholar]. In animals, the degree of bile duct damage is mainly related to the size of embolic particles. In monkeys, as mentioned above, proximal occlusion of HA with large-sized gelatin particles was well tolerated. However, in that study, distal occlusion with silicone induced bile duct ischemia [[22]Doppman J.L. Girton M. Kahn R. Proximal versus peripheral hepatic artery embolization experimental study in monkeys.Radiology. 1978; 128: 577-588Crossref PubMed Google Scholar]. In dogs in which HA was embolized with gelatin sponge particles, bile duct injury was found in five of six animals when particles were less than 500 μm in diameter, vs. none of the 18 animals receiving 500–2000 μm particles [[39]Sonomura T. Optimal size of embolic material in transcatheter arterial embolization of the liver.Nippon Igaku Hoshasen Gakkai Zasshi. 1994; 54: 489-499PubMed Google Scholar]. Embolization with polyvinyl alcohol particles produced a striking elevation in serum alkaline phosphatases and bilirubin and ‘focal infarction’ in one of five dogs, although cholangiopathy was not specifically reported [[40]Chuang V.P. Wallace S. Hepatic artery embolization in the treatment of hepatic neoplasms.Radiology. 1981; 140: 51-58PubMed Google Scholar]. Of three pigs infused with isobutyl 2-cyanoacrylate in the HA, one developed a liver abscess, and two ‘sterile biliary cysts surrounded by scars from hepatic infarction’ [[38]White Jr, R.I. Strandberg J.V. Gross G.S. Barth K.H. Therapeutic embolization with long-term occluding agents and their effects on embolized tissues.Radiology. 1977; 125: 677-687Crossref PubMed Google Scholar]. In the rat, large emboli such as gelatin sponge particles (212–250 μm) occluded HAs near the liver hilus, but PBP remained patent. Medium-sized embolic material, such as polyvinyl alcohol particles (125–150 μm), occluded smaller sized HAs and the capillary layers of PBP supplied by these arteries. Small-sized particles such as gelatin powder blocked very small arteries (<30 μm in diameter) and PBP extensively, while large HAs remained patent [[32]Demachi H. Matsui O. Takashima T. Scanning electron microscopy of intrahepatic microvasculature casts following experimental hepatic artery embolization.Cardiovasc Intervent Radiol. 1991; 14: 158-162Crossref PubMed Google Scholar]. Moreover, small particles can occlude arterioportal shunts, suppressing a compensatory mechanism for bile ducts oxygenation [[28]Demachi H. Matsui O. Kawamori Y. Ueda K. Takashima T. The protective effect of portoarterial shunts after experimental hepatic artery embolization in rats with liver cirrhosis.Cardiovasc Intervent Radiol. 1995; 18: 97-101Crossref PubMed Google Scholar]. Silicone [[22]Doppman J.L. Girton M. Kahn R. Proximal versus peripheral hepatic artery embolization experimental study in monkeys.Radiology. 1978; 128: 577-588Crossref PubMed Google Scholar] or isobutyl 2-cyanoacrylate solidify after injection in the HA and occlude small-sized vessels. Catheter-related HA injury (e.g. dissection), and superimposed thrombosis downstream of embolized material may also play a role. Thus, although limited in number, experimental data clearly show that distal occlusion of small arteries or PBP is required for bile duct injury to occur. It is noticeable that iodized oil has been observed in the lumen of small HAs and PBP. However, there has been no report of cholangiopathy induced by this agent alone, while microscopic cholangitis in dogs [[35]Kishi K. Sonomura T. Satoh M. Nishida N. Terada M. Shioyama Y. et al.Acute toxicity of lipiodol infusion into the hepatic arteries of dogs.Invest Radiol. 1994; 29: 882-889Crossref PubMed Scopus (15) Google Scholar] and centrilobular necrosis in rats [[33]Kan Z. Ivancev K. Hagerstrand I. Chuang V.P. Lunderquist A. In vivo microscopy of the liver after injection of Lipiodol into the hepatic artery and portal vein in the rat.Acta Radiol. 1989; 30: 419-425Crossref PubMed Google Scholar] were frequently observed. However, the embolic effect of iodized oil is strongly dependent on the type of emulsion obtained [[31]de Baere T. Dufaux J. Roche A. Counnord J.L. Berthault M.F. Denys A. et al.Circulatory alterations induced by intra-arterial injection of iodized oil and emulsions of iodized oil and doxorubicin: experimental study.Radiology. 1995; 194: 165-170PubMed Google Scholar]. The type of emulsion varies with its extemporaneous preparation. Moreover, iodized oil is frequently found in sinusoids and portal veins showing that it can cross PBP or arterioportal shunts without blocking PBP [[33]Kan Z. Ivancev K. Hagerstrand I. Chuang V.P. Lunderquist A. In vivo microscopy of the liver after injection of Lipiodol into the hepatic artery and portal vein in the rat.Acta Radiol. 1989; 30: 419-425Crossref PubMed Google Scholar]. That iodized oil may still have an embolic potential is indicated by the finding of lethal hepatic necrosis when oil was combined to gelatin sponge particle embolization in pigs whereas pure oil or pure gelatin particle embolization was well tolerated [[34]Kan Z. Sato M. Ivancev K. Uchida B. Hedgpeth P. Lunderquist A. et al.Distribution and effect of iodized poppyseed oil in the liver after hepatic artery embolization: experimental study in several animal species.Radiology. 1993; 186: 861-866PubMed Google Scholar]. Because of the animal data discussed above, small-size particle embolization has been rarely used alone in humans, which can explain why reports of cholangiopathy following embolization alone are so scarce. Studies comparing imaging and pathological findings after intrahepatic arterial injection of pure iodized oil did not mention biliary tract changes [41Bizollon T. Rode A. Bancel B. Gueripel V. Ducerf C. Baulieux J. et al.Diagnostic value and tolerance of Lipiodol-computed tomography for the detection of small hepatocellular carcinoma: correlation with pathologic examination of explanted livers.J Hepatol. 1998; 28: 491-496Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 42Bhattacharya S. Dhillon A.P. Rees J. Savage K. Saada J. 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In the context of cirrhosis with hepatocellular carcinoma (HCC), biliary complications of embolization with iodized oil and/or gelatin sponge particles have not been mentioned despite a large number of available studies [45Soyer P. Van Beers B. Goffette P. Zeitoun G. Pringot J. Levesque M. The role of embolization and chemo-embolization in the emergency treatment of hemoperitoneum caused by spontaneous rupture of hepatocellular carcinoma.Gastroenterol Clin Biol. 1993; 17: 643-648PubMed Google Scholar, 46Bruix J. Castells A. Montanya X. Calvet X. Bru C. Ayuso C. et al.Phase II study of transarterial embolization in European patients with hepatocellular carcinoma: need for controlled trials.Hepatology. 1994; 20: 643-650Crossref PubMed Google Scholar, 47Chang J.M. Tzeng W.S. Pan H.B. Yang C.F. Lai K.H. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. 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In summary, there is strong evidence that in the native liver, obstruction of large-sized HAs does not induce bile duct injury, whereas occlusion of arteries less than 200 μm in diameter causes ischemic cholangiopathy. In order to ascribe a condition to this category, several criteria must be met: (a) there are focal or diffuse abnormalities of the bile ducts that cannot be explained by other causes; and (b) there are primary lesions of blood vessels supplying the bile ducts. Several conditions fulfill these criteria: HA infusion with chemotherapeutic agents, advanced AIDS, liver transplantation, hereditary hemorrhagic telangiectasia (HHT), radiotherapy, polyarteritis nodosa, and atherosclerosis. An animal model reproducing vascular and biliary lesions is a strong additional criterion for considering a condition as a definite cause of ischemic cholangiopathy but such a criterion is lacking in many instances. The infusion of alcohol into the left HA of monkeys resulted in persistent left HA occlusion and left hepatic duct obstruction [[54]Doppman J.L. Girton M.E. Bile duct scarring following ethanol embolization of the hepatic artery: an experimental study in monkeys.Radiology. 1984; 152: 621-626PubMed Google Scholar]. HA injection of absolute ethanol in rabbits [[55]Matsui O. Kawamura I. Kadoya M. Takashima T. Nakanuma Y. Hepatic artery embolization of experimental hepatic tumors with absolute ethanol.Cardiovasc Intervent Radiol. 1986; 9: 146-151Crossref PubMed Scopus (6) Google Scholar], or swines [[56]Stridbeck H. Ekelund L. Jonsson N. Segmental hepatic arterial occlusion with absolute ethanol in domestic swine.Acta Radiol Diagn (Stockh). 1984; 25: 331-335PubMed Google Scholar], induced diffuse and prolonged obstruction of intrahepatic arteries together with biliary damage. In man, intentional intra-arterial injection of alcohol has rarely been used. Several cases of extensive bile duct injury following HA infusion of ethanol or sodium morrhuate in patients suffering from symptomatic hepatic hemangioma have been described [57Koniaris L.G. Seibel J.A. Geschwind J.F. Sitzmann J.V. Can ethanol therapies injure the bile ducts?.Hepatogastroenterology. 2003; 50: 69-72PubMed Google Scholar, 58Huang Z.Q. Huang X.Q. Changing patterns of traumatic bile duct injuries: a review of forty years experience.World J Gastroenterol. 2002; 8: 5-12PubMed Google Scholar]. Moreover, 17 cases of cholangiopathy developing after percutaneous ethanol injection (associated with embolization of large-sized particles or not) have been reported [59Koda M. Okamoto K. Miyoshi Y. Kawasaki H. Hepatic vascular and bile duct injury after ethanol injection therapy for hepatocellular carcinoma.Gastrointest Radiol. 1992; 17: 167-169Crossref PubMed Google Scholar, 60Shibata T. Yamamoto Y. Yamamoto N. Maetani Y. Ikai I. Terajima H. et al.Cholangitis and liver abscess after percutaneous ablation therapy for liver tumors: incidence and risk factors.J Vasc Interv Radiol. 2003; 14: 1535-1542Abstract Full Text Full Text PDF PubMed Google Scholar, 61Sasahira N. Tada M. Yoshida H. Tateishi R. Shiina S. Hirano K. et al.Extrahepatic biliary obstruction after percutaneous tumour ablation for hepatocellular carcinoma: aetiology and successful treatment with endoscopic papillary balloon dilatation.Gut. 2005; 54: 698-702Crossref PubMed Scopus (13) Google Scholar]. Ethanol-related arterial injury may be implicated in these cases. Clinically significant bile duct damage occurs in 5–20% of patients treated with hepatic arterial chemotherapy whatever the chemotherapeutic agent used, whether it is admin