Ischemic-type Biliary Stricture Research Articles

Should advanced donor age be a deterrent in the utilization of grafts from donation after cardiac death in deceased donor liver transplantation? The Toronto experience.

Advanced donor age paired with donation after cardiac death (DCD) increases the risk of transplantation, precluding widespread use of grafts from such donors worldwide. Our aim was to analyze outcomes of liver transplantation using grafts from older DCD donors and donation after brain death (DBD) donors. Patients who underwent liver transplantation using grafts from deceased donors between January 2016 and December 2021 were included in the study. Short-and long-term outcomes were analyzed for 4 groups of patients: those who received DCD and DBD grafts from younger (< 50 yr) and older (≥ 50 yr) donors. Of the 807 patients included in the analysis, 44.7% (n = 361) of grafts were received from older donors, with grafts for older DCD donors comprising 4.7% of the total cohort (n = 38). Patients who received grafts from older donors had a lower incidence of biliary strictures than those who received grafts from younger donors (7.9% v. 20.0% for DCD donation, p = 0.14, and 4.9% v. 6.8% for DBD donation, p = 0.34), with a significantly lower incidence of ischemic-type biliary strictures in patients who received grafts from older versus younger DCD donors (2.6% v. 18.0%, p = 0.04). There was no difference in 1- and 3-year graft survival rates among patients who received grafts from older and younger DCD donors (92.1% v. 90.8% and 80.2% v. 80.9%, respectively) and those who received grafts from older and younger DBD donors (90.1% v. 93.2% and 85.3% v. 84.4%, respectively) (p = 0.85). Pretransplantation admission to the intensive care unit (hazard ratio [HR] 9.041, p < 0.001) and nonalcoholic steatohepatitis (HR 2.197, p = 0.02) were found to significantly affect survival of grafts from older donors. Donor age alone should not be the criterion to determine the acceptability of grafts in liver transplantation. With careful selection criteria, older DCD donors could make a valuable contribution to expanding the liver donor pool, with grafts that produce comparable results to those obtained with standard-criteria grafts.

Ex Situ Liver Machine Perfusion: The Impact of Fresh Frozen Plasma.

The primary aim of this single-center, phase 1 exploratory study was to investigate the safety, feasibility, and impact on intrahepatic hemodynamics of a fresh frozen plasma (FFP)-based perfusate in ex situ liver normothermic machine perfusion (NMP) preservation. Using an institutionally developed perfusion device, 21 livers (13 donations after brain death and 8 donations after circulatory death) were perfused for 3hours 21minutes to 7hours 52minutes and successfully transplanted. Outcomes were compared in a 1:4 ratio to historical control patients matched according to donor and recipient characteristics and preservation time. Perfused livers presented a very low resistance state with high flow during ex situ perfusion (arterial and portal flows 340±150 and 890±70mL/minute/kg liver, respectively). This hemodynamic state was maintained even after reperfusion as demonstrated by higher arterial flow observed in the NMP group compared with control patients (220±120 versus 160±80mL/minute/kg liver, P=0.03). The early allograft dysfunction (EAD) rate, peak alanine aminotransferase (ALT), and peak aspartate aminotransferase (AST) levels within 7 days after transplantation were lower in the NMP group compared with the control patients (EAD 19% versus 46%, P=0.02; peak ALT 363±318 versus 1021±999 U/L, P=0.001; peak AST 1357±1492 versus 2615±2541 U/L, P=0.001 of the NMP and control groups, respectively). No patient developed ischemic type biliary stricture. One patient died, and all other patients are alive and well at a follow-up of 12-35 months. No device-related adverse events were recorded. In conclusion, with this study, we showed that ex situ NMP of human livers can be performed safely and effectively using a noncommercial device and an FFP-based preservation solution. Future studies should further investigate the impact of an FFP-based perfusion solution on liver hemodynamics during ex situ normothermic machine preservation.

Thrombolytic protocol minimizes ischemic-type biliary complications in liver transplantation from donation after circulatory death donors.

Liver transplantation (LT) with donation after circulatory death (DCD) donors has been associated with a high rate of ischemic-type biliary strictures (ITBSs) and inferior graft survival. To investigate the impact of an intraoperative tissue plasminogen activator (tPA) on outcomes following DCD LT, we conducted a retrospective analysis of DCD LT at the Toronto General Hospital (TGH) and the Ochsner Medical Center (OMC). Between 2009 and 2013, 85 DCD LTs were performed with an intraoperative tPA injection (n = 30 at TGH, n = 55 at OMC), and they were compared with 33 DCD LTs without a tPA. Donor and recipient characteristics were similar in the 2 groups. There was no significant difference in the intraoperative packed red blood cell transfusion requirement (3.2 ± 3.4 versus 3.1 ± 2.3 U, P = 0.74). Overall, biliary strictures occurred less commonly in the tPA-treated group (16.5% versus 33.3%, P = 0.07) with a much lower rate of diffuse intrahepatic strictures (3.5% versus 21.2%, P = 0.005). After 1 and 3 years, the tPA group versus the non-tPA group had superior patient survival (97.6% versus 87.0% and 92.7% versus 79.7%, P = 0.016) and graft survival (96.4% versus 69.7% and 90.2% versus 63.6%, P < 0.001). In conclusion, a tPA injection into the hepatic artery during DCD LT reduces ITBSs and improves graft and patient survival without increasing the risk for bleeding.

Normothermic Acellular Ex Vivo Liver Perfusion (NEVLP) Reduces Liver and Bile Duct in DCD Liver Grafts

It is important to develop a large animal model that closely resembles ischemic type biliary stricture (ITBS) in donation after cardiac death (DCD) grafts. The studies by Brunner et al (3) and Hansen et al (4) investigated common bile duct biopsies in humans after cold storage and reperfusion. In both studies, the biopsies were taken from the most distal part of the common bile duct, which is usually not used for the anastomosis.

Endoscopic Management of Biliary Complications following Liver Transplantation after Donation from Cardiac Death Donors

Previous studies have shown a higher incidence of biliary complications following donation after cardiac death (DCD) liver transplantation compared with donation after brain death (DBD) liver transplantation. The endoscopic management of ischemic type biliary strictures in patients who have undergone DCD liver transplants needs to be characterized further. A retrospective institutional review of all patients who underwent DCD liver transplant from January 2006 to September 2011 was performed. These patients were compared with all patients who underwent DBD liver transplantation in the same time period. A descriptive analysis of all DCD patients who developed biliary complications and their subsequent endoscopic management was also performed. Of the 36 patients who received DCD liver transplants, 25% developed biliary complications compared with 13% of patients who received DBD liver transplants (P=0.062). All DCD allograft recipients who developed biliary complications became symptomatic within three months of transplantation. Ischemic type biliary strictures in DCD allograft recipients included disseminated biliary strictures in two patients, biliary strictures of the hepatic duct bifurcation in three patients and biliary strictures of the donor common hepatic duct in three patients. There was a trend toward increasing incidence of total biliary complications in recipients of DCD liver allografts compared with those receiving DBD livers, and the rate of diffuse ischemic cholangiopathy was significantly higher. Focal ischemic type biliary strictures can be treated effectively in DCD liver transplant recipients with favourable results. Diffuse ischemic type biliary strictures in DCD liver transplant recipients ultimately requires retransplantation.

Use of Tissue Plasminogen Activator in Liver Transplantation from Donation After Cardiac Death Donors

Ischemic-type biliary stricture (ITBS) occurs in up to 50% after liver transplantation (LT) from donation after cardiac death (DCD) donors. Thrombus formation in the peribiliary microcirculation is a postulated mechanism. The aim was to describe our experience of tissue plasminogen activator (TPA) administration in DCD-LT. TPA was injected into the donor hepatic artery on the backtable (n = 22). Two recipients developed ITBS including one graft failure. Although excessive postreperfusion bleeding was seen in 14 recipients, the amount of TPA was comparable between those with and without excessive bleeding (6.4 ± 2.8 vs. 6.6 ± 2.8 mg, p = 0.78). However, donor age (41 ± 12 vs. 29 ± 9 years, p = 0.02), donor BMI (26.3 ± 5.5 vs. 21.7 ± 3.6 kg/m(2) , p = 0.03), previous laparotomy (50% vs. 0%, p = 0.02) and lactate after portal reperfusion (6.3 ± 4.6 vs. 2.8 ± 0.9 mmol/L, p = 0.005) were significantly greater in recipients with excessive bleeding. In conclusion, the use of TPA may lower the risk of ITBS-related graft failure in DCD-LT. Excessive bleeding may be related to poor graft quality and previous laparotomy rather than the amount of TPA. Further studies are needed in larger population.

Single-Center Experience of Therapeutic Management of Hepatic Artery Stenosis after Orthotopic Liver Transplantation

Background/Aims: Hepatic artery stenosis (HAS) is a potentially life-threatening complication of liver transplantation because the associated mortality and morbidity rates are high. Surgical reconstruction was recommended as first choice of treatment and interventional radiologic techniques have been introduced recently. However, the mid- or long-term outcomes of HAS were unclear. The purpose of this study was to evaluate the efficacy of interventional therapy and clinical outcomes of HAS following liver transplantation. Methods: A retrospective analysis was performed for 20 cases of HAS documented by angiography from October 2003 to August 2007 at the authors’ institution. All patients underwent transluminal interventional therapy including percutaneous transluminal angioplasty and endovascular stent placement. The technical results, hepatic artery patency and clinical outcome were reviewed. Results: All patients were treated with interventional management. Technical and immediate success was 100%. Of 8 patients with early HAS (within 1 month of transplantation), 1 underwent retransplantation due to deterioration of liver function. One died of acute liver failure waiting for retransplantation. Of 12 patients with late HAS (after 1 month of liver transplantation), 1 died of severe sepsis 38 days after transplantation. Five patients underwent late retransplantation due to ischemic-type biliary strictures or recurrent attacks of cholangitis. One of these patients died 11 days after retransplantation. The median follow-up of all 20 patients was 14.4 months after liver transplantation. The Kaplan-Meier curve of patency showed that cumulated primary patency of hepatic artery interventional treatment at 3, 6 and 12 months was 94, 87 and 79%, respectively. Two patients died of causes unrelated to HAS. Three patients developed recurrent HAS and were successfully treated with second interventional therapy. Eight patients (40%) developed ischemic-type biliary strictures and 7 underwent endoscopic treatment or percutaneous transhepatic cholangiodrainage. Graft function in 5 patients improved. The Kaplan-Meier curve of survival showed that the 1- and 2-year cumulated survival rates of early and late HAS were 87.5 and 43.8% and 81.5 and 61.1%, respectively. There was no significant difference in 1- and 2-year survival rates between early and late HAS (log-rank test, p = 0.928). Conclusion: Interventional therapy is an effective treatment for both early and late HAS with excellent short- and mid-term outcomes, while without irreversible graft dysfunction resulted from HAS. However, the patients have a high incidence of ischemic-type biliary lesions.

Biliary Complications After Liver Transplantation From Maastricht Category-2 Non-Heart-Beating Donors

There are unresolved issues regarding the security of liver transplantation with non-heart-beating donors (NHBDs). Recently, an increased incidence of biliary complications, mainly intrahepatic ischemic-type biliary strictures, has been described after controlled NHBDs. We studied the incidence and risk factors for biliary complications among uncontrolled NHBDs recipients compared with a large population of HBD recipients. Overall, 16.8% of patients in the HBD group and 41.7% of patients in the NHBD group suffered any type of biliary complication (P=0.66). However, the incidence of nonanastomotic biliary strictures was significantly greater in the NHBD group (P<0.001). Multivariate analysis showed that independent risk factors for nonanastomotic strictures were hepatic artery thrombosis (relative risk; 98.7) and receiving a liver from a NHBD (relative risk; 47.1). If this type of donors is accepted as a source of liver organs, the high incidence of biliary complications should be considered and efforts should be made to decrease ischemic injury.

The Impact of Donor Variables on the Outcome of Orthotopic Liver Transplantation for Hepatitis C

Morphologic characteristics of the graft have been proposed as a major contributor to the long-term outcomes in orthotopic liver transplantation (OLT). Our objective was to determine the impact of donor variables, including donor age, donor-recipient HLA match, and type of donation (DCD vs donation after brain death [DBD]), on the outcome of OLT in 192 patients with hepatitis C virus (HCV). Fourteen patients underwent OLT from donation after cardiac death (DCD) donors and 188 from DBD donors. Mean donor age, warm ischemia time at recovery, and cold ischemia time were similar between the groups. Overall graft survival rate at 1 year (55% DCD vs 85% DBD) and 5 years (46% DCD vs 78% DBD) was significantly lower in the DCD group ( P = .0003). Similarly, patient survival rate at 1 year (62% DCD vs 93% DBD) and 5 years (62% DCD vs 82% DBD) was significantly lower in the DCD group ( P = .0295). Incidences of hepatic artery thrombosis, portal vein thrombosis, and primary nonfunction were similar between the DCD and DBD groups. The incidence of liver abscess with ischemic-type biliary stricture was higher in recipients from DCD as compared with DBD (42% vs 2%). A trend toward lower graft survival was noted in recipients from donors older than 60 years of age in the HCV population ( P = .07), with statistically lower patient survival ( P = .02). Donor- recipient HLA matching did not appear to correlate with OLT outcome in patients with HCV. DCD donors and donors older than 60 years of age significantly impact patient and graft survival. Lower graft and patient survival in recipients from DCD donors does not appear to be related to early disease recurrence.

Using livers from donation after cardiac death donors—A proposal to protect the true Achilles heel

As the waiting list for organ transplant continues to increase (over 90,000 candidates as of May 30, 2007), the pressure to increase the number of donor organs is the impetus to expand the use of organs from donation after cardiac death (DCD) donors. The focus on DCD, previously referred to as non–heart-beating donor (NHBD), has led to significant increases in its utilization (Table 1), although the contribution to the donor pool remains only 7% in the United States and is disproportionately reflected in increased kidney transplants (Table 2). Prior to the acceptance of brain death, donors were required to have cessation of heart function in order to procure organs for transplantation. In some areas where brain death legislation has not been widely adopted, such as Asia, DCD represents a significant source of organs for transplantation. Although the Maastricht Conference on DCD in 1994 identified 4 categories of DCD [Category I: dead on arrival; Category II: unsuccessful resuscitation; Category III: waiting cardiac death; and Category IV: cardiac death in a braindead donor], it is easier to envision DCD based on two distinct populations, one following uncontrolled cardiopulmonary arrest (Categories I and II) and the other under conditions of controlled removal from life support, without the criteria for brain death being fulfilled. In 1995, the University of Pittsburgh provided one of the earliest comparisons between controlled and uncontrolled DCD. There were 24 DCD livers, 14 in the uncontrolled group (Group 1) and 10 in the group in which controlled termination of life support was performed in the operating room (Group 2). Of the liver grafts that were used, the immediate graft function rate was 50% (3/6) in Group 1 and 100% (6/6) in Group 2; however, the overall 2-year patient and graft survival was only 58% and 33%, respectively. In order to improve outcomes with DCD donors, the decision was made to avoid using uncontrolled DCD livers and, with further experience, to more carefully control risk factors [e.g., avoidance of old ( 60 year old) DCD donors, avoidance of donors with long ( 60 minutes) warm ischemic times during procurement, avoidance of confounding factors in the DCD donors, and minimization of cold ischemic times]. While patient survival and graft survival have improved in more recent eras, the impact of DCD on liver transplantation, as assessed from the Scientific Registry of Transplant Recipients (SRTR) database, shows that DCD graft survival was significantly lower than that of donation after brain death (DBD) grafts, with 1and 3-year graft survival of 70.2% and 63.3% for DCD recipients versus 80.4% and 72.1% for recipients of livers from conventional DBD donors. Recipients of a DCD graft had a greater incidence of primary nonfunction (11.8 versus 6.4%) and retransplantation (13.9% versus 8.3%) compared with DBD recipients. Similar findings have also been reported at single centers 12,13 The mandated period of warm ischemia imposed during the process of certifying death in controlled DCD leads to stagnation of blood in the microcirculation.

Donation After Cardiac Death

To determine whether the outcomes of liver transplantation (LTx) from donation after cardiac death (DCD) donors are equivalent to those from donation after brain death (DBD) donors. Because of the significant donor organ shortage, more transplant centers are using livers recovered from DCD donors. However, long-term, single-center outcomes of liver transplantation from DCD donors are limited. From January 1, 1993, to July 31, 2002, 553 liver transplants were performed from DBD donors and 36 were performed from DCD donors. Differences in event rates between the groups were compared with Kaplan-Meier estimates and the log-rank test. Differences in proportion and differences of means between the groups were compared with Fisher exact test and the Wilcoxon rank sum test, respectively. Mean warm ischemic time at recovery in the DCD group was 17.8 +/- 10.6 minutes. The overall rate of biliary strictures was greater in the DCD group at 1 year (33% versus 10%) and 3 years (37% versus 12%; P = 0.0001). The incidence of hepatic artery thrombosis, portal vein stenosis/thrombosis, ischemic-type biliary stricture (ITBS), and primary nonfunction were similar between groups. However, the incidence of both hepatic artery stenosis (16.6% versus 5.4%; P = 0.001) and hepatic abscess and biloma formation (16.7% versus 8.3%; P = 0.04) were greater in the DCD group. Trends toward worse patient and graft survival and increased incidence of ITBS were seen in DCD donors greater than 40 years compared with DCD donors less than 40 years. Overall patient survival at 1 year (DCD, 80%; versus DBD, 91%) and 3 years (DCD, 68%; versus DBD, 84%) was significantly less in the DCD group (P = 0.002). Similarly, graft survival at 1 year (DCD, 67%; versus DBD, 86%) and 3 years (DCD, 56%; versus DBD, 80%) were significantly less in the DCD group (P = 0.0001). Despite similar rates of primary nonfunction, LTx after controlled DCD resulted in worse patient and graft survival compared with LTx after DBD and increased incidence of biliary complications and hepatic artery stenosis. However, overall results of LTx after controlled DCD are encouraging; and with careful donor and recipient selection, LTx after DCD may successfully increase the donor liver pool.

Reconstructive surgery for ischemic-type lesions at the bile duct bifurcation after liver transplantation.

To assess the feasibility, morbidity, mortality, and clinical success rate of surgical reconstruction of the biliary system in patients with ischemic-type biliary lesions in their liver graft. After liver transplantation, strictures in the biliary tree with secondary sludge formation can occur in the absence of vascular problems. Jaundice, pruritus, and recurrent cholangitis are predominant clinical features leading to considerable morbidity. Interventional measures are the first-line treatment but are frequently only of transient success. Retransplantation is usually considered when interventional treatment is not effective. Surgical exploration and reconstruction was performed in 17 patients with ischemic-type biliary strictures at a median of 2 years after liver transplantation. Findings during surgery, surgical strategies, and postsurgical courses are described. Clinical symptoms and biochemical parameters of cholestasis and liver function were analyzed in the postsurgical course. During surgery, all 17 patients were found to have strictures or sclerotic changes involving the hepatic bifurcation and extrahepatic bile duct. Sludge or stones were present in nine patients. In 14 patients with viable bile ducts proximal to the bifurcation, surgical reconstruction was performed by resection of the bifurcation and hepaticojejunostomy. In three patients with more extensive biliary destruction, portoenterostomy with or without peripheral hepatojejunostomy was performed. The prevalence rate of biliary infection at surgery was 93%; the predominant organisms were Candida and enterococci. The perioperative mortality rate was 0%. Clinical symptoms and biochemical parameters became normal or were considerably improved in 14 of 16 patients (88%). The hepatic bifurcation seems to be a predominant site for ischemic-type biliary changes after liver transplantation. Surgical treatment by resection of the bifurcation and reconstruction by high hepaticojejunostomy is a safe and highly effective approach leading to cure or persistent major improvement in most patients.

USE OF FATTY DONOR LIVER IS ASSOCIATED WITH DIMINISHED EARLY PATIENT AND GRAFT SURVIVAL

It is well known that implantation of donor livers with severe fatty infiltration (>60%) is frequently associated with early hepatic dysfunction and an increased incidence of primary nonfunction after liver transplantation. The outcome of donor livers with less fatty infiltration has not been well defined. We, therefore, studied the outcome of 59 liver transplantations in which donor livers with up to 30% fat were used. Patient outcome was compared to a time-matched control group of 57 patients. The two groups were similar in terms of age, gender, preservation time, primary diagnosis, and UNOS status. We compared both groups with regard to 4-month and 2-year patient and graft survival. We also assessed the incidence of ischemic type biliary strictures and hepatic artery thrombosis, and evaluated the causes of graft loss in both groups. We found that use of donor livers with up to 30% fatty infiltration was associated with a significant decrease in 4-month graft survival (76% vs. 89%, P<0.05) and in 2-year patient survival (77% vs. 91%, P<0.05). Primary nonfunction and primary dysfunction formed the main cause of graft loss and mortality. Multivariate analysis showed that fatty infiltration is an independent predictive factor for outcome after transplantation. We conclude that liver allografts with up to 30% fat lead to diminished outcome after liver transplantation. However, this diminished outcome should be viewed with respect to the increasing mortality on the national waiting list.

A positively lymphocytotoxic crossmatch is a risk factor for ischemic type biliary strictures: [formula omitted] Division of Transplantation, Transfusion Medicine, Mayo Clinic, Rochester, MN

A positively lymphocytotoxic crossmatch is a risk factor for ischemic type biliary strictures: [formula omitted] Division of Transplantation, Transfusion Medicine, Mayo Clinic, Rochester, MN

Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation.

The clinical significance and outcome of nonanastomotic strictures and dilatations involving only the biliary tree of the graft with a radiological appearance of biliary ischemia is unknown. Therefore we analyzed the grafts of 128 patients to evaluate the biochemical, radiological and histological features that prompted the diagnosis of ischemic-type biliary stricture and the clinical outcome of this complication. Ischemic-type biliary strictures were diagnosed in 25 patients (19%). Initial graft function was similar in all patients, whether or not this complication developed. Most ischemic-type biliary strictures occurred between 1 and 4 mo after orthotopic liver transplantation. However, the appearance of ischemic-type biliary stricture in the month after transplantation was predictive for a poor outcome in all six grafts with early onset of ischemic-type biliary strictures. Eighteen patients (72%) were treated with biliary stents and repeated dilatations. Long-term patency was achieved in 88% of these patients. Repeat transplantation was performed in six patients (24%); five survived. Finally, patients with ischemic-type biliary strictures spent more time in the hospital during the first year after orthotopic liver transplantation than did patients without the complication (62 +/- 27 days vs. 37 +/- 20 days; p < or = 0.001). This was due to repeated hospitalizations and a higher incidence of retransplantation. One-year graft survival was lower in patients with ischemic-type biliary strictures than in patients without ischemic-type biliary strictures (69% vs. 88%; p = 0.006). However, 1-yr patient survival was similar in the two groups (91% vs. 89%). In conclusion, early appearance of ischemic-type biliary stricture features is associated with poor graft prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)