Graft cholangiopathy: etiology, diagnosis, and therapeutic strategies

Ying Luo, Wen-Bin Ji, Wei-Dong Duan, Sheng Ye and Jia-Hong Dong

Beijing, China

Graft cholangiopathy: etiology, diagnosis, and therapeutic strategies

Ying Luo, Wen-Bin Ji, Wei-Dong Duan, Sheng Ye and Jia-Hong Dong

Beijing, China

BACKGROUND:Graft cholangiopathy has been recognized as a significant cause of morbidity, graft loss, and even mortality in patients after orthotopic liver transplantation. The aim of this review is to analyze the etiology, pathogenesis, diagnosis and therapeutic strategies of graft cholangiopathy after liver transplantation.

DATA SOURCE:A PubMed database search was performed to identify articles relevant to liver transplantation, biliary complications and cholangiopathy.

RESULTS:Several risk factors for graft cholangiopathy after liver transplantation have been identified, including ischemia/ reperfusion injury, cytomegalovirus infection, immunological injury and bile salt toxicity. A number of strategies have been attempted to prevent the development of graft cholangiopathy, but their efficacy needs to be evaluated in large clinical studies. Non-surgical approaches may offer good results in patients with extrahepatic lesions. For most patients with complex hilar and intrahepatic biliary abnormalities, however, surgical repair or re-transplantation may be required.

CONCLUSIONS:The pathogenesis of graft cholangiopathy after liver transplantation is multifactorial. In the future, more efforts should be devoted to the development of more effective preventative and therapeutic strategies against graft cholangiopathy.

(Hepatobiliary Pancreat Dis Int 2014;13:10-17)

liver transplantation;

bile ducts;

complications;

ischemia/reperfusion injury; therapy

Introduction

Biliary tract complications have been recognized as a significant cause of morbidity, graft loss, and even mortality in patients after orthotopic liver transplantation (OLT). Because of the differences in graft type and the definition of biliary complications, the reported incidence varies greatly between different studies, ranging from 10% to 30%.[1-6]Post-transplant biliary complications may be related to various factors, including technical reasons, hepatic artery thrombosis (HAT), preservation injury, infection, and rejection. The technical factors refer to imperfect anastomosis, T-tube-related problems, and the usage of partial liver grafts, such as reduced-size, splitting, and living donor liver transplantation. Early HAT may result in bile duct ischemia and eventually necrosis, which are characterized by typical biliary strictures, dilatations, and casts. However, these biliary abnormalities may also occur in the absence of HAT, and have been termed diffuse non-anastomotic biliary strictures, intrahepatic biliary strictures, ischemic cholangitis, ischemictype biliary lesions and most recently, ischemic cholangiopathy. The exact mechanisms of ischemic cholangiopathy remain unclear. However, several contributing factors have been identified (Table 1), such as ischemia/reperfusion injury,[7-9]infection,[10]immune-mediated injury,[11, 12]and bile salt toxicity.[13]To avoid the confusion and misunderstanding of the terminology of ischemic cholangiopathy, we propose a new term "graft cholangiopathy" that refers to a local or diffuse damage to bile ducts in liver grafts excluding technical reasons and HAT. In this review, we focus on the etiology, pathogenesis, diagnosis and treatment of graft cholangiopathy after OLT.

Etiology and pathogenesis

Ischemia/reperfusion injury

Ischemia/reperfusion injury is a complex process with manypathophysiological mechanisms including impairment of microcirculation, leukocyte adhesion, platelet aggregation, increased oxygen-free radical production, lipoperoxidation, and hypoxia.[14-16]It has been well documented that prolonged warm and cold ischemia time predispose the liver grafts to the development of cholangiopathy.[1, 4, 5, 8, 17]Colonna et al[1]found that the cold ischemia time for all of the 6 patients who developed intrahepatic biliary strictures in the absence of HAT exceeded 12 hours. A study from Sanchez-Urdazpal et al[8]also showed that the incidence of biliary complications was significantly increased in liver grafts with a cold ischemia time of more than 11.5 hours. Nowadays, most centers therefore try to keep the cold ischemia time below 10 hours. Many studies[17-24]indicated that liver recipients are at an increased risk of developing cholangiopathy ranging between 25% and 60% after receiving allografts from donation after cardiac death (DCD), compared with 10% to 30% seen in donation after brain death (DBD). The main difference between DCD and DBD transplantation is the warm ischemia time of liver graft. It seems intuitive that the prolonged warm ischemia time would affect adversely tissue viability and graft function, and result in a higher incidence of ischemic cholangiopathy. Therefore, most centers are reluctant to prolong the warm ischemia time to more than 30 minutes.[25, 26]

The significant correlation between ischemia/ reperfusion injury and cholangiopathy may be attributed by the direct ischemic damage of the biliary epithelium, secondary injury due to peribiliary microcirculation disturbance, and increased susceptibility of the biliary epithelium to reoxygenation injury. In a bile cytological study, Carrasco et al[27]found that prolonged cold ischemia time causes an increase in bile cell density at the expense of ductal epithelial cells, the longer the preservation time, the greater the increase. Ischemia can also lead to the change of cholangiocyte cytoskeleton. Using ischemia in intact liver and adenosine triphosphate (ATP) depletion in cultured cells to model cholangiocyte injury, Doctor et al[28]investigated the effects of metabolic inhibition on cholangiocyte viability and structure. The study indicated that cholangiocyte ATP depletion induced characteristic, domain-specific changes in the plasma membrane, and implicated alterations in the membrane-cytoskeletal interactions in the initiation of the changes. They concluded that, pending the re-establishment of the differentiated domains, the loss of specific secondary structures may contribute to impaired vectorial bile duct secretion and post-ischemic cholestasis. The bile canaliculus appears to be one of the hepatic structures most susceptible to ischemia/reperfusion injury. A morphological study showed that the appearance of bile canaliculi in human liver grafts changed dramatically after reperfusion, including significantly increased perimeter of the canaliculi and remarkable loss in the number of bile microvilli per unit of canalicular area.[29]In addition, an in vitro study by Noack et al[30]indicated that during anoxia, bile duct epithelial cells were significantly more resistant to cell killing than hepatocytes. The rates of cellular proteolysis were also 2.5-fold lower in bile duct cells than those in hepatocytes during anoxia. In contrast to anoxia, however, reoxygenation of anoxic cells increased the cell killing of bile duct cells and improved the viability of hepatocytes. The rate of toxic reactive oxygen species (ROS) formation by bile duct cells was 5-fold greater than that by hepatocytes during reoxygenation. The authors concluded that biliary epithelial cells are more susceptible to reoxygenation injury than to anoxia.[30]

A variety of experimental studies showed that failure of hepatic microcirculation is a major component of reperfusion injury in the liver.[14, 31, 32]It has been indicated that nitric oxide (NO) and endothelins (ETs), two potent vasoactive mediator systems in the liver, are involved in the pathogenesis of microcirculation impairment. The ET-induced constriction of hepatic microcirculation can be inhibited by NO-mediated vasodilatory action.[33]Recently, we also found that changes of intrahepatic biliary microcirculation were associated with the down-regulation of endothelial NO synthase (eNOS) expression and up-regulation of inducible NOS, ET-1 and intercellular adhesionmolecule-1 expressions in the endothelial cells of peribiliary vascular plexus.[34]Interestingly, the administration of exogenous L-arginine, the substrate of NOS, during liver procurement may prevent liver and biliary tract damage by an improvement of the hepatic microcirculation.[35]Moench et al[36]demonstrated that insufficient perfusion of peribiliary microcirculation contributed to the development of graft cholangiopathy. Their results indicated that the additional flushing of peribiliary plexus by arterial back-table pressure perfusion was associated with a significant reduction in the incidence of graft cholangiopathy after liver transplantation.

Table 1.Risk factors for the development of graft cholangiopathy after liver transplantation

Immunological factors

Several studies[11, 37]showed that the development of graft cholangiopathy might be associated with various immunological injuries. A significantly high incidence of graft cholangiopathy and decreased graft survival were previously noticed in liver recipients with ABO incompatible allografts. The blood group related antigens are known to be expressed not only on the surface of erythrocytes, but also on the epithelium of hepatic arteries and bile ducts.[38-40]Therefore, the liver allografts with continuous expression of these antigens may be more susceptible to the immune-mediated pathogenesis, and subsequently develop cholangiopathy after transplantation across the ABO barrier. Bile ducts are also involved in acute and chronic rejection. The prevalence of rejection in patients with graft cholangiopathy is not clear. However, many studies[41-43]indicated that there was a significant association between rejection and graft cholangiopathy. A histological study of chronically rejected human liver allografts provided an indirect evidence that both lymphocytotoxicity and ischemic damage are involved in the development of bile duct loss (vanishing bile duct syndrome). Microvascular injury appears to occur earlier than biliary damage as the number of microvascular structures per bile duct is significantly lower in chronically rejected liver as compared with normal liver.[44]Recently, the significance of antibody-mediated rejection was investigated in ABO-compatible liver transplantation. The preformed and de novo donor-specific antibody can be detected in around 8% to 10% of liver recipients.[45, 46]It was documented that preformed antibodies may contribute to the post-transplantation cholangitis in liver recipients via induction of Toll-like receptor expression on biliary epithelial cells and inflammatory chemokine production.[47]Kaneku's study[46]showed that 95% of de novo donor-specific antibodies were against HLA class II antigens. The development of de novo donor-specific antibody in recipients may be related to cholangiopathy after liver transplantation, and is also an independent risk factor for patient mortality and graft loss.[46, 48]In addition, patients who underwent liver transplantation for primary sclerosing cholangitis and autoimmune hepatitis showed a higher incidence of graft cholangiopathy.[5, 49-51]

Infection

Cytomegalovirus (CMV) infection is a major source of morbidity in transplant recipients and other immunocompromised patients. The liver graft was the most commonly affected organ in primary CMV infection.[52]CMV may infect various components of the liver, such as hepatocytes, bile duct epithelium, and vascular endothelium.[52, 53]CMV infection has been implicated in the development of graft cholangiopathy.[54, 55]The persistence of CMV was demonstrated in liver grafts that developed vanishing bile duct syndrome and chronic rejection.[56]In a rat model with acute liver graft rejection, CMV infection increased the inflammatory reaction of acute rejection, and bile duct damage was significantly more severe in CMV-infected grafts than those without infection.[10]It was postulated that CMV infection increased alloantigen expression, making the bile ducts more susceptible to the immunologic attack.[57]However, this could not always be confirmed by other studies. A recent large study of 1843 patients has demonstrated that there was no significant association between CMV infection and the development of graft cholangiopathy.[4]Therefore, the role of CMV infection in the pathogenesis of graft cholangiopathy remains to be elucidated.

Bile salt toxicity

Bile salt hepatotoxicity may be involved in the pathogenesis of graft cholangiopathy after OLT.[13, 58-61]The hydrophobic bile salts are cytotoxic due to their potent detergent properties toward cellular membranes of hepatocytes and biliary epithelial cells. Under normal circumstances, some protective mechanisms can prevent the cytotoxicity of these bile salts. For instance, these bile salts can be neutralized in the bile by complex formation with phospholipid, and some hydrophilic bile salts can stabilize cell membranes. Thus, the attenuation of the protective components will lead to the injury of bile ducts. Several studies[59, 61]have shown that bile salt secretion increased more rapidly than phospholipid secretion early after transplantation, resulting in a high biliary bile salt/phospholipid ratio, and the bile duct injury was significantly related to the bile salt secretion and high bile salt/phospholipidratio. Hoekstra et al[13]also investigated the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT by using multi-drug resistance (Mdr2+/-) gene mice. Livers from wild-type mice and Mdr2+/-mice were transplanted into wild-type recipient mice. Mdr2+/-mice secreted only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. Two weeks later after OLT, there were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2+/-donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate. Parallel to this observation, recipients of Mdr2+/-livers had significantly higher serum liver enzyme, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. The authors[13]suggested that toxic bile composition acted synergistically with cold ischemia in the pathogenesis of bile duct injury after OLT. Of interest, the injury of bile ducts can be prevented when an infusion of hydrophilic, instead of hydrophobic, bile salts is given prior to liver graft procurement.[60]

Clinical presentation and diagnosis

As described above, a number of risk factors are involved in the pathogenesis of graft cholangiopathy, strongly suggesting a multifactorial origin. Different etiological mechanisms may interact. For instance, ischemia/reperfusion injury and CMV infection are associated with the development of liver allograft rejection.[53, 62]Therefore, it is often difficult to identify the direct cause of graft cholangiopathy in an individual patient after OLT. These risk factors can result in bile duct damage, either directly or as a consequence of microcirculation impairment. Graft cholangiopathy may take the aspect of bile duct necrosis, bile leakage, biloma, bile duct fibrosis or strictures, and casts. Additionally, graft cholangiopathy could result in considerable patient morbidity including biliary sepsis and even graft failure, and more resource utilization including re-hospitalization, prolonged hospital stay and antibiotic therapy, requirements of more invasive biliary procedure, as well as higher rates of re-listing and re-transplantation.[17, 25, 63, 64]These issues may be not explicitly reflected in the typical survival metrics (Table 2), but they have significant quality of life and economic implications. It has been shown that patients who develop graft cholangiopathy after liver transplantation experience poor quality of life and pose a significant burden to the health care system.[25, 64, 66]

It has long been recognized that the bile duct damage involving the extrahepatic ducts are easier to manage than the diffused intrahepatic duct damage. For data analysis and offering prognosis, therefore, we propose to classify graft cholangiopathy based on the location and the pathogenesis of biliary abnormalities. According to the location, graft cholangiopathy can be classified into extrahepatic lesions (type I), intrahepatic lesions (type II), as well as intra- and extrahepatic lesions (type III). Type I can be further subdivided into common hepatic duct lesion (a), hepatic duct confluence lesion (b), and right or left hepatic duct lesion (c), based on location with respect to the hepatic duct confluence. Type II can be further subdivided into right or left intrahepatic duct lesion (a) and bilateral intrahepatic duct lesion (b). According to the pathogenesis, graft cholangiopathy can be classified into bile duct stricture (1), bile leakage (2), biloma (3), biliary abscess (4), and biliary sludge, cast or stones (5).

The early diagnosis of graft cholangiopathy is very important for the outcome of treatment. The majority of graft cholangiopathy are diagnosed within 6 months after OLT with an estimated one third occurring within 1 month after surgery.[67]Patients with graft cholangiopathy may present with a variety of complaints, including abdominal pain, anorexia, fever, itch and jaundice. However, the clinical symptoms are often not specific, and may be masked by administration of immunosuppressive drugs. In many patients, asymptomatic elevation of serum gammaglutamyltransferase or alkaline phosphatase is the first sign of graft cholangiopathy, prompting theinitiation of subsequent examinations. Ultrasonography is often the first step to detect complications after liver transplantation. But it is conventionally considered to have insufficient sensitivity to detect early or small ductal changes. In our experience, however, ultrasonography plays an important role in identification of biliary stones, sludge and casts, and in exclusion of HAT and major vascular obstruction. Direct visualization of the biliary tree by T-tube cholangiography, endoscopic retrograde cholangiopancreaticography, or percutaneous transhepatic cholangiography remains the gold standard for the diagnosis of graft cholangiopathy. Magnetic resonance cholangiopancreaticography has been proposed as a reliable noninvasive imaging modality with high positive or negative predictive values.[68-70]Graft biopsy can be suggested to exclude other differential diagnosis of abnormal liver function, such as rejection and recurrent viral hepatitis. However, the histological changes of graft cholangiopathy lack specific and characteristic features.[71]These changes are similar to those of other forms of biliary obstruction, including edematous expansion of the portal area, ductular proliferation, mixed inflammatory infiltrates with a predominance of neutrophils. With time, the edematous expansion of portal areas transforms to fibrosis with ductular proliferation/reaction. Therefore, it may be diff icult for pathologists to demonstrate graft cholangiopathy.

Table 2.Effect of graft cholangiopathy in liver transplantation

Prevention and treatment

According to the above etiologies, attempts have been made to operate the liver allografts to prevent the subsequent preservation and ischemia/reperfusion injury, including ischemic preconditioning,[72, 73]preservation solution with low viscosity,[4, 74]arterial pressure perfusion,[36]and protective agents.[75-77]Ischemic preconditioning is an endogenous adaptive way to assist graft preservation and to protect the graft from ischemia/ reperfusion injury during transplantation by increasing tissue tolerance. Several experimental studies showed that ischemic preconditioning offers a protective effect against ischemia/reperfusion injury of liver grafts.[72, 73]However, there are no studies yet demonstrating clinical benefits of ischemic preconditioning in patients undergoing liver transplantation. Recently, several studies indicated that the administration of highly viscous University of Wisconsin preservation solution is associated with a high incidence of graft cholangiopathy due to insufficient flush-out of the peribiliary arterial plexus.[4, 74, 78]To overcome the insufficient perfusion of the biliary system, Moench et al[36]performed additional fl ushing of the peribiliary plexus by controlled arterial back-table pressure perfusion, leading to a considerable reduction in graft cholangiopathy. Careful flushing of bile ducts is also critical to remove residual bile salts to avoid the exposure of biliary epithelium to toxic bile salts during cold preservation. In addition, several groups have attempted to protect the liver grafts against ischemia/reperfusion injury by administration of pharmacologic agents, including vitamin E, prostaglandin E, serine protease inhibitor, and platelet activating factor.[75-77]However, further studies are needed to validate the clinical value of these agents.

Treatment options of graft cholangiopathy should be chosen according to the nature of bile duct abnormalities, degree of derangement in liver function, and general condition of patients. A multidisciplinary approach is required for patient management. Nowadays, nonsurgical approaches are the standard treatment with interventional radiology and endoscopic techniques emerging as the preferred choice of treatment. Although non-surgical approaches may require repeated radiological examinations and interventions, a selected majority of patients can be treated successfully.[79-82]Success will depend mainly on the severity of the abnormalities and their location. Limited strictures of the extrahepatic bile duct and biliary casts will respond better to non-surgical therapy. Additionally, medical therapy with ursodeoxycholic acid may provide favorable changes of the bile flow and composition, improving the outcome of patient management.[79, 83]However, these approaches have had dismal results in most patients with diffused complicated cholangiopathy.[79]Surgical approaches should be considered when non-surgical therapies are unsuccessful. An early study by Schlitt et al[84]has shown that surgical treatment by resection of the extrahepatic bile ducts and high hepaticojejunostomy is a safe and highly effective approach for lesions at the level of hepatic bifurcation, leading to cure or persistent improvement in 14 of 16 (88%) patients. Finally, re-transplantation may be required when all other therapies have failed, especially in the presence of secondary biliary cirrhosis, recurrent cholangitis, or progressive cholestasis because of extensive intrahepatic cholangiopathy. Theoretically, the decision to re-list and re-transplantation should be justified by the severity of liver disease. However, it has been shown that most patients with graft cholangiopathy have to experience longer waiting time before re-transplantation due to a relatively low model for end-stage liver disease scores.[25]The prolonged waiting time may result in recurrent biliary sepsis, the development of multi-resistant organism, or fairly abrupt deterioration that could potentially exclude patients from re-transplantation.Therefore, the modification of the allocation system with model for end-stage liver disease score exceptions is necessary to truly reflect the severity of disease in these patients with graft cholangiopathy.

Conclusions

During the last decade, a significant progress has been made in understanding the pathogenesis of graft cholangiopathy after OLT. Several risk factors have been identified, including ischemia/reperfusion injury, immunological injury, infections and bile salt toxicity. It is most likely that the pathogenesis of graft cholangiopathy is multifactorial. The accurate and prompt diagnosis relies on abdominal imaging and cholangiographic studies. Several strategies have been attempted to prevent the development of graft cholangiopathy, but their efficacy needs to be evaluated in large clinical trails. The management of graft cholangiopathy depends mainly on the nature and extent of biliary abnormalities. Non-surgical approaches may offer good results in patients with extrahepatic lesions. For most patients with complex hilar and intrahepatic biliary abnormalities, however, surgical repairment or re-transplantation may be required. In the future, more efforts should be devoted to the development of more effective preventative and therapeutic strategies against graft cholangiopathy after liver transplantation.

Contributors:DJH proposed the study. LY and DJH performed research and wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. DJH is the guarantor.

Funding:This study was supported by a grant from the National Natural Science Foundation of China (81070383).

Ethical approval:Not needed.

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

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Received May 12, 2013

Accepted after revision November 4, 2013

Author Affiliations: Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China (Luo Y, Ji WB, Duan WD, Ye S and Dong JH)

Jia-Hong Dong, MD, Department of Hepatobiliary Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China (Tel: 86-10-66938030; Fax: 86-10-68241383; Email: dongjh301@163. com)

© 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60001-1