Causes and consequences of ischemic-type biliary lesions after liver transplantation

Abstract

Biliary complications are a major source of morbidity, graft loss, and even mortality after liver transplantation. The most troublesome are the so-called ischemic-type biliary lesions (ITBL), with an incidence varying between 5% and 15%. ITBL is a radiological diagnosis, characterized by intrahepatic strictures and dilatations on a cholangiogram, in the absence of hepatic artery thrombosis. Several risk factors for ITBL have been identified, strongly suggesting a multifactorial origin. The main categories of risk factors for ITBL include ischemia-related injury; immunologically induced injury; and cytotoxic injury, induced by bile salts. However, in many cases no specific risk factor can be identified. Ischemia-related injury comprises prolonged ischemic times and disturbance in blood flow through the peribiliary vascular plexus. Immunological injury is assumed to be a risk factor based on the relationship of ITBL with ABO incompatibility, polymorphism in genes coding for chemokines, and pre-existing immunologically mediated diseases such as primary sclerosing cholangitis and autoimmune hepatitis. The clinical presentation of patients with ITBL is often not specific; symptoms may include fever, abdominal complaints, and increased cholestasis on liver function tests. Diagnosis is made by imaging studies of the bile ducts. Treatment starts with relieving the symptoms of cholestasis and dilatation by endoscopic retrograde cholangiopancreaticography (ERCP) or percutaneous transhepatic cholangiodrainage (PTCD), followed by stenting if possible. Eventually up to 50% of the patients with ITBL will require a retransplantation or may die. In selected patients, a retransplantation can be avoided or delayed by resection of the extra-hepatic bile ducts and construction of a hepaticojejunostomy. More research on the pathogenesis of ITBL is needed before more specific preventive or therapeutic strategies can be developed.

The Protective Role of CD59 and Pathogenic Role of Complement in Hepatic Ischemia and Reperfusion Injury

“…[2][3][4] IRI also initiates later graft failure by triggering irreversible intrahepatic biliary tract injury (ischemic-type biliary lesion) or by promoting rejection through activation of innate immunity. 5 At present, because of the shortage of organs for transplantation, the donor pool has been expanded by utilization of marginal organs from old donors or non-heart-beating donors, as well as grafts with prolonged cold storage, and even allografts donated after cardiac death. It is conceivable that grafts from such donors could cause severe liver injury, because they have usually experienced a long ischemia time.…”

Ischemic Type Biliary Lesions

“…ITBL seems to be a polygenic disease, influenced by a whole variety of confounders. Currently identified risk factors may be divided into four major pathogenetic columns: peri-operative ischemia (including preserving solution), immunologic damage, toxicity of bile salts and epidemiological confounders [1,27]. The degree and relation of the functional impact among risk factors are not fully investigated.…”

“…Hereby, ischemic injury seems to be the most important factor including cold and warm ischemia during transplantation, disturbed blood flow in the peribiliary plexus resulting from an inappropriate procurement of the donor liver with little periductal tissue, and hypoxemia during the postoperative period [12,27]. Immunological injury including ABO-incompatibility, rejection, pre-existing liver disease with autoimmune component, CMV-Infection, immunosuppressive medication and chronic rejection also seem to play a role in the development of the non-anastomotic strictures [1,27,28]. Moreover, bile fluid has been shown to be toxic for the vulnerable biliary epithelium of the graft [29].…”

“…Although biliary strictures have been reported to be more frequent in transplant patients with hepatico-jejunostomy, they may occur, disregarding the type of biliary tract reconstruction [6,30]. Finally, factors related to epidemiology (older donor age, advanced stage of pre-transplant liver disease) and donation (preservation solution, perfusion technique) also seem to be relevant in the pathogenesis of ITBL [1,27,31]. Table 1 summarizes currently known risk factors.…”

“…Classical symptoms are pruritus, jaundice and fever. Untreated ITBL may lead to cholangiosepsis, graft insufficiency and patient death [27]. Clinically, ITBL closely resembles liver diseases with chronic inflammation of the biliary tract (PSC, SSC, cholangitis) [1].…”