Journal of Hepatology
Volume 44, Issue 4 , Pages 806-817, April 2006

Ischemic cholangiopathy

  • Pierre Deltenre

      Affiliations

    • Service d'Hépato-Gastroentérologie, Hôpital de Jolimont, Haine-Saint-Paul, Belgium
    • Service d'Hépato-Gastroentérologie, Hôpital Huriez, CHRU Lille, France
    • ,
  • Dominique-Charles Valla

      Affiliations

    • Service d'Hépatologie, Hôpital Beaujon, 100, Boulevard du Général Leclerc, 92118 Clichy, France
    • Corresponding Author InformationCorresponding author. Tel.: +33 1 40 87 52 83; fax: +33 1 40 87 44 26.

published online 08 February 2006.

Article Outline

 

Ischemic cholangiopathy can be defined as a focal or extensive damage to the bile ducts due to impaired blood supply [1]. 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] 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]. 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].

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 [5], [6]. On the contrary, fibrous stenoses develop where there is progressive injury to the hepatic arterioles, for example, after several courses of intra-arterial chemotherapy [7], [8]. 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 [8], [9], [10]. Intrahepatic involvement is the least common. As a result, subcapsular needle biopsy, when performed, most often fail to sample the affected tissues [11], [12], [13], [14], 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]. 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.

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1. Consequences of the intentional blockade of hepatic arteries 

1.1. Anatomical overview 

Blood is supplied to intra- and extra-hepatic bile ducts exclusively through HAs [16]. 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]. 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]. 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]. 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]. Overall, this vascular pattern resembles that of the intestine but differs from that of liver parenchyma.

  • View full-size image.
  • Fig. 1. 

    Schematic drawing representing bile duct blood supply. The common hepatic duct and common bile duct are vascularized by axial arteries, running adjacent to the bile duct, according to a dual supply. The major supply comes from below (retroduodenal and retroportal arteries) whereas a lesser proportion comes from above (right HA). At the hepatic hilum, the PBP connects the right, middle and left HAs. The PBP drains into peribiliary venules which join the portal venous system. The veins of the extrahepatic bile duct drain into tributaries of the extrahepatic portal vein, downward to the right gastric and the posterior superior pancreaticoduodenal vein. The veins of the large or small intrahepatic bile ducts drain into neighboring portal veins. Abbreviations: BD, bile duct; CD, cystic duct; HA, hepatic artery; PBP, peribiliary plexus; PV, portal vein; RDA, retroduodenal artery; RHA, right hepatic artery.

1.2. Proximal blockade of hepatic arteries 

Proximal HA blockade alone can be achieved by means of HA ligation or arterial embolization with large particles or coils (>1mm in diameter). Outside the transplant setting, these procedures appear to induce no or limited consequences for the liver in patients or experimental animals [19], [20]. In the guinea pig, HA ligation does not lead to a decrease in bile flow or ultrastructural changes of biliary epithelium [21]. 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]. In man, arterial collaterals are discernible angiographically as early as 10–15h from HA ligation [23], [24], [25], [26]. In experimental studies, hepatic portoarterial shunting of iodized oil via the PBP has been observed in normal rats [27]. In cirrhotic rats, where PBP is enlarged, scanning electron microscopy shows portoarterial shunts that significantly increase following HA embolization [28]. In patients treated for malignant liver tumors with HA infusion, iodized oil is seen in portal veins [29]. In liver transplanted patients, retrograde bleeding from the donor HA is seen after portal venous reperfusion [30]. 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].

In the transplanted liver, however, proximal HA blockade by HA thrombosis is generally followed by severe morbidity, mainly from biliary damage [5], [6]. 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.

1.3. Distal blockade of small-sized hepatic arteries 

HA embolization with various types of particles has been used to interrupt arterial blood supply [22], [31], [32], [33], [34], [35], [36], [37], [38]. 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]. 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 500μm in diameter, vs. none of the 18 animals receiving 500–2000μm particles [39]. 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]. 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]. In the rat, large emboli such as gelatin sponge particles (212–250μm) occluded HAs near the liver hilus, but PBP remained patent. Medium-sized embolic material, such as polyvinyl alcohol particles (125–150μm), 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 (<30μm in diameter) and PBP extensively, while large HAs remained patent [32]. Moreover, small particles can occlude arterioportal shunts, suppressing a compensatory mechanism for bile ducts oxygenation [28]. Silicone [22] 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] and centrilobular necrosis in rats [33] were frequently observed. However, the embolic effect of iodized oil is strongly dependent on the type of emulsion obtained [31]. 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]. 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].

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 [41], [42], [43], [44]. To the best of our knowledge, no case of cholangiopathy has ever been reported in the absence of intra-arterial chemotherapy after embolization with gelatin sponge or other types of large-sized particles. 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 [45], [46], [47], [48], [49], [50], [51], [52]. However, bile duct necrosis has been well described following gelatin powder embolization without chemotherapy for treatment of hepatocellular carcinoma [53].

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 200μm in diameter causes ischemic cholangiopathy.

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2. Conditions where vascular involvement is a documented factor for bile duct damage 

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.

2.1. Hepatic arterial infusion of toxic agents 

The infusion of alcohol into the left HA of monkeys resulted in persistent left HA occlusion and left hepatic duct obstruction [54]. HA injection of absolute ethanol in rabbits [55], or swines [56], 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 [57], [58]. Moreover, 17 cases of cholangiopathy developing after percutaneous ethanol injection (associated with embolization of large-sized particles or not) have been reported [59], [60], [61]. 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 administered alone [7], [8], [62], [63], [64], [65], or in combination with iodized oil and/or gelatin sponge particles [53], [66], [67], [68]. As shown in Table 1, biliary strictures were observed in 28 (8%) out of 348 patients treated with HA artery infusion, vs. only 2 (0.7%) of their 276 controls [51], [69], [70], [71], [72], [73]. Some non-randomized studies also reported on biliary injury [74], [75], [76], [77], [78], [79], [80], [81]. Of 35 patients with secondary liver tumors treated with intra-arterial floxuridine (FUDR), serum alkaline phosphatase increased in all and serum transaminases and/or bilirubin in some [9]. Seven of these 35 patients were studied with cholangiography. In all cases, intrahepatic or extrahepatic bile duct anomalies were found [9]. In a retrospective study of 105 patients treated with a combination of doxorubicin, mitomycin and gelatin sponge particles for hepatocellular carcinoma, bile duct necrosis was found in four patients, and necrotizing cholecystitis in 29 [81]. Routine helical CT-scan disclosed bile duct lesions in over 75% of 81 patients treated with arterial FUDR for colorectal metastasis and there was a strong correlation with abnormal cholestatic blood tests [82]. FUDR was most frequently incriminated, but also most frequently used. By contrast, bile duct damage has not been reported in trials of intraportal infusion of fluorouracil [83], [84], or intra-arterial infusion of fluorouracil with folinic acid [85], [86].

Table 1. Biliary, gastrointestinal and thrombotic complications in randomized trials evaluating hepatic arterial chemotherapy, embolization or combination of hepatic arterial chemotherapy and embolization
Liver disease (Refs.)RegimenPatients (n)Biliary strictures (n)Other possible ischemic complications (n)
Metastases [70]HA: FUDR484Gastrointestinal (12)
IV: FUDRa510Gastrointestinal (4)
Metastases [71]HA: FUDR325Death (cholangiopathy) (1) gastrointestinal (9), thrombosis (5)
IV: FUDR320Gastrointestinal (2), thrombosis (2)
Metastases [69]HA: FUDR6710Death (cholangiopathy) (2), cholecystitis (2)
IV: FUDR760Death (gastrointestinal) (1)
Metastases [72]HA: FUDR252Gastrointestinal (4)
HA: FUDR+dexamethasone252Gastrointestinal (2)
Metastases+resection [73]HA: FDUR+dexamethasone+IV: fluorouracilb744HA thrombosis (2)
IV: fluorouracilb822None
Unresectable HCC [51]HA: gelatin sponge+doxorubicin401Cholecystitis (2), liver (1)
HA: gelatin sponge370Cholecystitis (2), liver (3), gastrointestinal (1)
No treatment350None

Abbreviations: FUDR, floxuridine; HA, hepatic artery; HCC, hepatocellular carcinoma; IV, intra venous.

aA catheter was positioned into the HA.

bWith or without leucovorin.

As a rule, pathological studies have shown gross bile duct damage and intimal fibrous thickening of the small HAs, with narrowing or obstruction of the lumina. Fibrinoid necrosis and parietal thrombi of arteries and necrotic bile ducts have also been described [63], [65], [68], [77], [87], [88], [89]. Bile duct injury can be associated with ischemic lesions of gallbladder or upper gastrointestinal tract [51], [70], [71], [74], [75], [76], [78], [79], [81].

Cholangiopathy appears to be particularly common when intra-arterial chemotherapy is combined with embolization. The most toxic combination appears to consist of chemotherapy, lipiodol and gelatin sponge [66], [68]. Other factors could exacerbate bile duct ischemia: prior liver resection [67], [90]; catheter-related HA dissection; high dose chemotherapy and large volumes of embolic agents.

2.2. AIDS-related cholangiopathy 

At an advanced stage of AIDS (CD4 counts typically <100/mm3), a combination of biliary pain, elevation of serum alkaline phosphatase and gross bile duct anomalies may occur [91], [92], [93], [94], [95], [96], [97]. In 25% of these patients, a smooth stenosis of the terminal portion of the common bile duct, so-called papillary stenosis, is observed, while the intrahepatic bile ducts are dilated but regular [97]. In the other patients, AIDS-related cholangiopathy consists of extensive irregularities of intra- and extra-hepatic bile ducts. In over 95% of cases, this latter form is associated with cytomegalovirus (CMV), cryptosporidia, or microsporidia infection, or with mixed infections with these agents [98]. The respective role of these agents has been debated [91], [99], [100], [101], [102], [103], [104]. CMV-related vasculitis inducing ischemic lesions has been well documented in other organs [105], [106], [107], and in particular the intestine [108], [109], [110]. A similar mechanism likely causes cholangiopathy in AIDS patients as CMV inclusions have been found in arterioles close to bile ducts [97] and in capillary endothelial cells of the gallbladder [97], [100], [101]. CMV infection of endothelial cells is currently believed to contribute to arterial lesions in immune competent or immune deficient patients (reviewed in Golden et al. [111]). CMV inclusion may also be found in the biliary epithelium. However, gancyclovir therapy did not alter the course of cholestatic abnormalities, which suggests that direct involvement of biliary epithelium is not the cause of cholangiopathy [98], [104], [112], [113]. Cryptosporidia and Enterocytozoon bieneusi, while they do infect cholangiocytes and enterocytes, have not been reported to cause vasculitis. These parasites induce mild inflammation of the bile ducts and intestine. They cause diarrhea through alterations in trans-intestinal movements of water and electrolytes but characteristically do not cause gastrointestinal ulcers, stenoses or gastrointestinal bleeding. However, Encephalocytozoon (Septata) intestinalis, another microsporidial species associated with AIDS-related cholangiopathy [114], can infect endothelial cells and cause vasculitis [115]. Thus, besides CMV, other opportunistic pathogens may well be implicated in AIDS-related cholangiopathy by inducing vasculitis. However, the complete microscopic examination of the bile ducts and their vessels that is necessary to diagnose vasculitis is difficult to obtain in these patients.

2.3. Liver transplantation 

Non-anastomotic biliary strictures and necrosis of bile ducts (with bilomas or biliary casts) are well described complications of liver transplantation. Several factors are likely to damage small- or large-sized HAs of the liver transplant and thereby cause ischemic cholangiopathy. Graft endothelial cells are exposed to injury from preservation and reperfusion [116], [117], [118], ABO incompatibility [14], [119], [120], rejection [121], [122], [123] or CMV infection [124], [125], [126]. In addition, stenosis or thrombosis of large HAs may occur in relation to arterial reconstruction or sepsis [5], [6], [13], [14], [116], [127].

Experimental studies in liver allograft indicate that preservation and reperfusion injury is mediated by thrombotic and ischemic events due to endothelial activation [30], [128], [129], [130], [131], [132]. In liver recipients, cholangiopathy occurs more frequently when ABO incompatible donors are used [14], [119], [120]. Cholangiopathy affects only the donor biliary tree. Expression of ABH antigens in cholangiocytes and endothelial cells makes either cellular type a potential target for an immune attack [120]. The possibility of continued ABH antigen expression in vascular endothelium after transplantation is supported by the observation of extensive deposition of IgM and C1q in the HA endothelium of ABO incompatible grafts [133]. Furthermore, the occurrence of HA thrombosis is increased in ABO incompatible allografts [120] as compared to ABO compatible grafts.

Bile ducts are involved in acute and chronic rejection [121], [123], [134], [135], [136], [137], [138]. The mechanism leading to bile duct loss (vanishing bile duct syndrome) could be either a direct immunological attack to the biliary epithelium, or an indirect, ischemic damage [121], [123]. The latter mechanism is supported by histometric analysis of chronically rejected human liver allografts showing the absence of bile duct in conjunction with arterial loss [121]. Moreover, microvascular injury appears to occur earlier than biliary damage as the number of microvascular structures per bile duct was significantly lower in acute and chronic rejection compared with normal liver [122].

CMV may infect various components of the liver, such as hepatocytes, bile duct epithelium, and vascular endothelium [124], [125], [126]. Prior to the introduction of effective prophylactic therapy, CMV infection was a cause of morbidity in about 30% of transplanted patients [126], [139], [140], [141], [142]. Moreover, CMV has been linked to allograft rejection [124], [125], [143], [144], [145]. Indeed, in rat liver allograft, CMV infection is associated with rejection and severe bile duct damage [123], and this damage may be mediated by CMV infection of small arteries [146]. Using an in situ technique, CMV-DNA was expressed in bile ducts and endothelial cells of the vascular structures of liver allograft with chronic rejection [124]. An association between CMV infection and vanishing bile duct syndrome has also been suggested [146], [147]. CMV infection is a risk factor for late HA thrombosis, a feature associated with biliary ischemia and necrosis [148]. In heart transplant recipients, CMV infection has been associated with accelerated atherogenesis and rejection [149], [150], [151], [152]. Thus, there is circumstantial, albeit abundant, evidence that cholangiopathy can be related to CMV infection through micro- or macro-vascular injury.

HA thrombosis occurs in approximately 2–20% of patients who undergo liver transplantation [5]. HA thrombosis related cholangiopathy has been amply documented [5], [6], [13], [14], [116], [127]. Early HA thrombosis induces more severe cholangiopathy than late thrombosis. Development of arterial collaterals is of importance as 50% of patients with such collaterals do not require re-transplantation after HA thrombosis [153], [154].

Thus, a likely explanation for the high incidence of cholangiopathy in liver transplant recipients is a combination of large-sized HA occlusion—due to reconstruction or sepsis—as well as damage to small-sized arteries and PBP—due to preservation, reperfusion, rejection, or CMV infection.

2.4. Hereditary hemorrhagic telangiectasia (HHT) 

Symptomatic cholangiopathy is observed in some patients with this condition (about 3% according to a recent report) [155]. Moreover, acute bile duct necrosis occurs in a high proportion of patients with HHT undergoing proximal HA embolization for treatment of high output heart failure or portal hypertension [156]. Microvascular anomalies consist of arteriovenous or arterioportal shunting through telangectasies that are randomly spread within the hepatic parenchyma and portal tracts. A likely explanation for cholangiopathy is blood-stealing away from PBP through these shunts [157].

2.5. Radiotherapy on the liver area 

Delayed gastrointestinal complications of abdominal radiotherapy are the result of radiation induced damage to intestinal microvasculature [158], involving the induction of endothelial cell apoptosis [159]. Benign biliary strictures have been attributed to previous radiotherapy when the field included the common bile duct [160], [161], [162], [163]. Atrophy of biliary epithelium and fibrosis of bile duct wall were found in conjunction with intimal thickening and obliteration of biliary arteries [160].

2.6. Polyarteritis nodosa 

Polyarteritis nodosa is characterized by medium- and small-sized arteritis which can involve almost any organ including the liver [37], [164]. Autopsy studies show biliary involvement in 10–25% of patients [165], [166]. Biliary lesions likely result from vasculitis as arterial occlusion by intimal fibrinoid necrosis, thrombosis and granulation tissue have been found around damaged bile ducts [167].

2.7. Atherosclerosis and cholesterol-crystal embolism 

Benign biliary strictures of the left hepatic duct [168] or segmental intrahepatic duct [169] have been shown to be associated with atheromatous stenosis of the corresponding arterial branch in surgically resected specimens. Moreover, acute ischemic cholecystitis due to cholesterol crystal emboli has been well documented [170]. Cholesterol crystal embolism would be a likely explanation for a case of common bile duct necrosis occurring 4 days after cardiac catheterization [171].

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3. Conditions where vascular involvement is a suspected, but not established, factor for bile duct damage 

Based on the above considerations, a paradigm has emerged that ischemic bile duct injury may occur whenever small-sized HAs or PBP are injured, whatever the injuring process. According to this paradigm, a contribution of microvascular injury to various biliary diseases has been suspected. However, as direct evidence for such injury is still lacking for these diseases, further studies are required before accepting the idea that ischemia is a primary factor.

3.1. Post-cholecystectomy biliary strictures 

Arterial supply to extrahepatic ducts has been extensively studied. The potential for injury to this arterial supply at cholecystectomy with resulting in ischemic bile duct damage has been emphasized [3], [172]. Gross and microscopic arterial supply can be damaged by inadvertent section, ligation, clipping, or thermal coagulation. Indeed, angiography detects arterial disruption in 39–47% of patients with post-cholecystectomy bile duct stenosis [173], [174]. Anecdotal cases of bile duct stenosis or necrosis, involvement of left and right hepatic duct confluence, or complex bile duct injury have been related to concomitant arterial disruption [175], [176], [177], [178], [179], [180]. By contrast, a recent study showed no difference in presentation, type of bile duct involvement, or outcome between patients with and without angiographically detectable arterial disruption [174]. However, in that study, only gross arterial disruption was identified, affecting mainly the right HA. Therefore, the possibility remains that damage to microscopic arterial supply, mainly from thermal injury, can be responsible for post-cholecystectomy bile duct stenosis in the absence of peroperative transsection of the common bile duct.

3.2. Systemic diseases with microvascular vascular involvement 

According to the above paradigm, a number of systemic diseases characterized by microvascular involvement (either vasculitis or thrombosis) could be incriminated as a cause of ischemic cholangiopathy (see Le Thi Huong et al. for a review [181]). However, direct evidence for damage to bile duct arterial supply is still lacking. Such systemic conditions where ischemic-like cholangiopathy has been reported include sickle cell disease [182], Kawasaki disease [183], Schönlein-Henoch purpura [184], systemic lupus [185], [186], [187], [188], antiphospholipid syndrome [189], and paroxysmal nocturnal hemoglobinuria [181]. Infiltration of biliary capillaries by eosinophils suggests an ischemic component to the cholangiopathy associated with the hypereosinophilic syndrome [190]. An ischemic mechanism has been considered in cases of progressive cholangiopathy occurring after septic shock [191].

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4. Conclusion 

Ischemic cholangiopathy is a rare entity that has been well identified, both experimentally and clinically. It occurs in a context where there is damage to small-sized HAs or PBP. Hepatic artery infusion with chemotherapeutic agents, advanced AIDS, liver transplantation, hereditary hemorrhagic telangiectasia, radiotherapy, polyarteritis nodosa, and atherosclerosis are the conditions where ischemic cholangiopathy has been best characterized. Vascular injury at cholecystectomy, and a host of systemic diseases could also cause ischemic cholangiopathy although for these conditions, microvascular involvement of the blood vessels to the bile ducts has to be confirmed by further studies. Before considering a diagnosis of primary sclerosing cholangitis, conditions in which vascular lesions could contribute to bile duct injury have to be ruled out.

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Acknowledgements 

We thank Doctor Frederic Frippiat for his contribution in the realization of the schematic drawing representing bile duct blood supply.

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PII: S0168-8278(06)00054-7

doi:10.1016/j.jhep.2006.01.009

Journal of Hepatology
Volume 44, Issue 4 , Pages 806-817, April 2006

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