Nonanastomotic Biliary Strictures Research Articles

Characteristics of fecal microbial communities in patients with non-anastomotic biliary strictures after liver transplantation.

AIMTo explore the possible relationship between fecal microbial communities and non-anastomotic stricture (NAS) after liver transplantation (LT).METHODSA total of 30 subjects including 10 patients with NAS, 10 patients with no complications after LT, and 10 non-LT healthy individuals were enrolled. Fecal microbial communities were assessed by the 16S rRNA gene sequencing technology.RESULTSDifferent from the uncomplicated and healthy groups, unbalanced fecal bacterium ratio existed in patients with NAS after LT. The results showed that NAS patients were associated with a decrease of Firmicutes and Bacteroidetes and an increase of Proteobacteria at the phylum level, with the proportion-ratio imbalance between potential pathogenic families including Enterococcaceae, Streptococcaceae, Enterobacteriaceae, Pseudomonadaceae and dominant families including Bacteroidaceae.CONCLUSIONThe compositional shifts of the increase of potential pathogenic bacteria as well as the decrease of dominant bacteria might contribute to the incidence of NAS.

Reply to “Reducing Nonanastomotic Biliary Strictures in Donation After Circulatory Death Liver Transplantation

Reply to “Reducing Nonanastomotic Biliary Strictures in Donation After Circulatory Death Liver Transplantation

Biliary Manometric Perfusion Test in Evaluating the Efficacy of Balloon Cholangioplasty for Non-Anastomotic Biliary Strictures after Orthotopic Liver Transplantation

Biliary Manometric Perfusion Test in Evaluating the Efficacy of Balloon Cholangioplasty for Non-Anastomotic Biliary Strictures after Orthotopic Liver Transplantation

Outcomes of Liver Transplantation Using Organ Donation After Brain Death (DBD) versus Organ Donation After Cardiac Death (DCD): A Single Center Experience

Introduction: Donation after cardiac death (DCD) liver allografts have been associated with primary nonfunction, ischemic cholangiopathy, hepatic artery stenosis and a higher re-transplantation rate when compared with donation after brain death (DBD) allografts. The number of liver transplantation (LT) with DCD allografts has increased in the recent years. We present our experience with using this extended criteria donor grafts. Primary objective: To compare patient and graft survival between DBD and DCD allografts. Secondary objective: To compare biliary and vascular rates of LT complications between both groups. Methods: We retrospectively reviewed all LTs performed at a major transplant center from January 2012 to April 2017. We included patients who received a combined liver and kidney transplant (n = 29), and excluded patients who received a split LT (n =4). DCD and DBD allografts were compared using Chisquare, Fischer exact test, log-rank tests and Kaplan-Meier plot analysis. Results: A total of 409 patients were analyzed, 100 patients received DCD grafts, and 309 patients received DBD grafts. There was no significant difference in the recipient age, gender, BMI or donor age, gender and BMI of both groups. The DBD recipients had a higher biological (p = 0.001) and match MELD scores, (p = 0.005) while the DCD donors had a higher donor risk index (p < 0.0001). Cholangiopathy in the DCD group was 12.2% and 3.6% in the DBD group, p = 0.001. Although, the rate of non-anastomotic biliary strictures, however, was significantly different between both groups (Table 1), cholangiopathy did not appear to be significant in predicting patient or graft survival in a sub-group analysis. Patient survival in DCD recipients was 92.7% at 1 year, and 80.3% at 4 years versus 96% at 1 year and 88.5% at 4 years in DBD recipients, p = 0.27. Graft survival in DCD recipients was 88% at 1 year, and 76.3% at 4 years versus 94.1% at 1 year and 78.8% at 4 years in DBD recipients, p = 0.34 (Figure 1).Figure: Patient and graft survival Kaplan-Meier curves.Conclusion: With careful selection, LT outcomes of DCD organs are comparable to DBD organs.Figure: Demographics and outcomes by donor relationship.

Long-term results after transplantation of pediatric liver grafts from donation after circulatory death donors.

BackgroundLiver grafts from donation after circulatory death (DCD) donors are increasingly accepted as an extension of the organ pool for transplantation. There is little data on the outcome of liver transplantation with DCD grafts from a pediatric donor. The objective of this study was to assess the outcome of liver transplantation with pediatric DCD grafts and to compare this with the outcome after transplantation of livers from pediatric donation after brain death (DBD) donors.MethodAll transplantations performed with a liver from a pediatric donor (≤16 years) in the Netherlands between 2002 and 2015 were included. Patient survival, graft survival, and complication rates were compared between DCD and DBD liver transplantation.ResultsIn total, 74 liver transplantations with pediatric grafts were performed; twenty (27%) DCD and 54 (73%) DBD. The median donor warm ischemia time (DWIT) was 24 min (range 15–43 min). Patient survival rate at 10 years was 78% for recipients of DCD grafts and 89% for DBD grafts (p = 0.32). Graft survival rate at 10 years was 65% in recipients of DCD versus 76% in DBD grafts (p = 0.20). If donor livers in this study would have been rejected for transplantation when the DWIT ≥30 min (n = 4), the 10-year graft survival rate would have been 81% after DCD transplantation. The rate of non-anastomotic biliary strictures was 5% in DCD and 4% in DBD grafts (p = 1.00). Other complication rates were also similar between both groups.ConclusionsTransplantation of livers from pediatric DCD donors results in good long-term outcome especially when the DWIT is kept ≤30 min. Patient and graft survival rates are not significantly different between recipients of a pediatric DCD or DBD liver. Moreover, the incidence of non-anastomotic biliary strictures after transplantation of pediatric DCD livers is remarkably low.

Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death.

BackgroundExperimental studies have suggested that end‐ischaemic dual hypothermic oxygenated machine perfusion (DHOPE) may restore hepatocellular energy status and reduce reperfusion injury in donation after circulatory death (DCD) liver grafts. The aim of this prospective case–control study was to assess the safety and feasibility of DHOPE in DCD liver transplantation.MethodsIn consecutive DCD liver transplantations, liver grafts were treated with end‐ischaemic DHOPE. Outcome was compared with that in a control group of DCD liver transplantations without DHOPE, matched for donor age, donor warm ischaemia time, and recipient Model for End‐stage Liver Disease (MELD) score. All patients were followed for 1 year.ResultsTen transplantations involving liver grafts treated with DHOPE were compared with 20 control procedures. There were no technical problems. All 6‐month and 1‐year graft and patient survival rates were 100 per cent in the DHOPE group. Six‐month graft survival and 1‐year graft and patient survival rates in the control group were 80, 67 and 85 per cent respectively. During DHOPE, median (i.q.r.) hepatic adenosine 5′‐triphosphate (ATP) content increased 11‐fold, from 6 (3–10) to 66 (42–87) µmol per g protein (P = 0·005). All DHOPE‐preserved livers showed excellent early function. At 1 week after transplantation peak serum alanine aminotransferase (ALT) and bilirubin levels were twofold lower in the DHOPE group than in the control group (ALT: median 966 versus 1858 units/l respectively, P = 0·006; bilirubin: median 1·0 (i.q.r. 0·7–1·4) versus 2·6 (0·9–5·1) mg/dl, P = 0·044). None of the ten DHOPE‐preserved livers required retransplantation for non‐anastomotic biliary stricture, compared with five of 20 in the control group (P = 0·140).ConclusionThis clinical study of end‐ischaemic DHOPE in DCD liver transplantation suggests that the technique restores hepatic ATP, reduces reperfusion injury, and is safe and feasible. RCTs with larger numbers of patients are warranted to assess the efficacy in reducing post‐transplant biliary complications.

Prognostic significance of hepatic arterial collaterals in liver transplant recipients with biliary strictures.

The aim of this study was to determine the prevalence of hepatic artery stenosis (HAS) and the prognostic implications of hepatic arterial collaterals in liver transplant (LT) recipients with biliary strictures. The 105 LT recipients transplanted between 2004 and 2015 at our center had documented biliary strictures. HAS and collaterals were assessed in high-quality imaging of the hepatic artery available from 66 recipients. Clinical, demographic, and biochemical recipient and donor data were retrospectively analyzed and tested for their association with biliary or arterial complications after LT. The prevalence of HAS was 68% (45 of 66) in LT recipients with biliary strictures. Seventy-six percent (37 of 49) of patients with nonanastomotic biliary strictures had HAS. This was significantly higher than in patients with anastomotic stricture, where 47% (8 of 17) of patients had a pathological hepatic arteriogram (P=.039). The location of bile duct strictures was not predictive for outcome. In contrast, arterial collaterals were associated with significantly better patient and graft survival. Impaired hepatic arterial perfusion is frequently associated with nonanastomotic strictures, but less closely correlated with anastomotic strictures. On survival analysis, hepatic arterial collaterals have a protective effect.

Feasibility and Midterm Results of Endovascular Treatment of Hepatic Artery Occlusion within 24 Hours after Living-Donor Liver Transplantation

PurposeTo evaluate the feasibility and midterm results of endovascular treatment of hepatic artery occlusion within 24 hours after living-donor liver transplantation (LDLT). Materials and MethodsFrom January 2012 to June 2014, 189 consecutive patients at a single institution underwent LDLT with right-lobe grafts. Among them, 10 were diagnosed with hepatic artery occlusion within 24 hours after LDLT. All 10 underwent endovascular treatment, including drug-eluting stent placement (n = 2), intraarterial thrombolysis (n = 5), or both (n = 3). Every patient received regular follow-up with multidetector computed tomography (CT). Data on primary technical success, primary and assisted primary patency, and biliary complications were analyzed. ResultsPrimary technical success was achieved in all 10 cases. Primary patency rates at 1 week, 3 months, and 6 months were all 70% (7 of 10), and the respective assisted primary patency rates were all 80% (8 of 10). Bleeding at the anastomotic site developed in 2 failed cases, prompting repeat liver transplantation. All 8 successfully recanalized cases showed hepatic artery patency on CT throughout follow-up (mean, 643.6 d; range, 236–1,081 d). Six of these cases had anastomotic biliary stricture, 4 of which were successfully treated by multisession biliary intervention. One patient had nonanastomotic biliary stricture and died of hepatic failure despite lifelong external drainage. ConclusionsEndovascular treatment could be an alternative therapeutic option for patients with hepatic artery occlusion within 24 hours after LDLT. It could help achieve long-term patency of the hepatic artery, but biliary stricture can potentially occur, and bleeding at the anastomotic site is a serious complication.

CD14 is associated with biliary stricture formation.

The pathogenesis of intrahepatic biliary stricture formation in patients with primary sclerosing cholangitis (PSC) or after liver transplantation (LTx) remains elusive. CD14 receptor signaling is a key mediator of the innate immune system; its common genetic variant is associated with alcoholic liver disease. PSC and LTx cohort patients and primary biliary cirrhosis (PBC) control patients were genotyped for the CD14 -260C>T (rs2569190) polymorphism, and genotypes were correlated with long-term clinical outcome. Biliary tissue, bile, and whole blood of PSC patients and healthy controls were screened for markers of the innate immune system and bacterial infection. In 121 PSC patients, the CD14 -260C>T genotype was associated with development of dominant bile duct strictures (P = 0.02). In 365 LTx patients, TT carriers (4.1%) were protected against the formation of nonanastomotic biliary strictures versus CC/CT patients (12.6%; P = 0.01). Chemokine ligand 8 (P = 0.04) and chemokine receptor 6 (P = 0.004) were up-regulated in biliary tissue of PSC patients with the TT versus the CC/CT genotype. Lipopolysaccharide whole-blood stimulation resulted in a significant change in interleukin (IL)-8 (P = 0.05) and IL-12p40 levels (P = 0.04) in healthy control subjects carrying the TT genotype. TT PSC patients were protected against Gram-negative bacterial biliary infection (TT: 0% vs. 22.5%; P = 0.02). Serum-soluble CD14 levels correlated with the CD14 -260C>T genotype (P = 0.02), representing an independent risk indicator of survival in PSC patients (hazard ratio, 0.40; 95% confidence interval, 0.19-0.86; P =0.01). The function of the innate immune response by CD14 is crucial during biliary infection and stricture formation. The benefits of CD14 signaling modification should be addressed in future studies. (Hepatology 2016;64:843-852).

Non-anastomotic biliary strictures are more severe after transplantation of donation after circulatory death, compared to donation after brain death livers

Non-anastomotic biliary strictures are more severe after transplantation of donation after circulatory death, compared to donation after brain death livers

Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures.

The aim of the present study was to assess whether flushing the donor liver with urokinase immediately before implantation reduces the incidence of nonanastomotic biliary strictures (NASs) after liver transplantation, without causing increased blood loss, analyzed as a historical cohort study. Between January 2005 and October 2012, all liver (re-)transplantations were included. Of the 185 liver transplant recipients included, 63 donor livers between January 2010 and October 2012 received urokinase (study group), whereas the donor liver of 122 consecutive recipients, who served as a historical control group, between January 2005 and January 2010 did not receive urokinase. Basic donor (Eurotransplant donor risk index) and recipient (age, body mass index, laboratory Model for End-Stage Liver Disease score) characteristics did not significantly differ in both groups. Thirty-three recipients developed NASs: 22 in the control group (18%) and 11 (17.5%) in the study group (P = 0.68). Analyzed separately for donation after circulatory death (P = 0.42) or donation after brain death (P = 0.89), there was no difference between the groups in incidence of NAS. Of all the recipients developing NAS, 7 (21%) needed retransplantation and all others were treated conservatively. Autologous blood transfusion requirements did not differ significantly between both groups (P = 0.91), whereas interestingly, more heterologous blood transfusions were needed in the control group (P < 0.001). This study has its limitations by its retrospective character. A multi-institutional prospective study could clarify this issue. In conclusion, arterial flushing of the liver with urokinase immediately before implantation did not lead to a lower incidence of NAS in this study, nor did it lead to increased blood loss.

Biliary complications following orthotopic liver transplantation: May contrast-enhanced MR Cholangiography provide additional information?

PurposeTo assess whether contrast-enhanced T1-weighted MR Cholangiography may provide additional information in the evaluation of biliary complications in orthotopic liver transplant recipients. Material and methodsEighty liver transplant patients with suspicion of biliary adverse events underwent MR imaging at 1.5T scanner. After acquisition of axial T1-/T2-weighted images and conventional T2-weighted MR Cholangiography (image set 1), 3D gradient-echo T1-weighted fat-suppressed LAVA (Liver Acquisition with Volume Acceleration) sequences were obtained about 30min after intravenous infusion of mangafodipir trisodium (Mn-DPDP,Teslascan®) (image set 2). The diagnostic value of mangafodipir trisodium-enhanced MR Cholangiography in the detection of biliary complications was tested by separate analysis results of image set 1 alone and image set 1 and 2 together. MRI results were correlated with direct cholangiography in 46 patients, surgery in 14 and/or clinical-radiological follow-up in the remaining 20 cases. ResultsThe level of confidence in the assessment of biliary adverse events was significantly increased by the administration of mangafodipir trisodium (p<0.05). Particularly, contrast-enhanced T1-weighted LAVA sequences tended to out-perform conventional T2-weighted MR Cholangiography in the delineation of anastomotic and non-anastomotic biliary strictures and in the diagnosis of biliary leak. ConclusionsContrast-enhanced T1-weighted MR Cholangiography may improve the level of diagnostic confidence provided by conventional T2-weighted MR Cholangiography in the evaluation of biliary complications after orthotopic liver transplantation.

Radiologic Characterization of Ischemic Cholangiopathy in Donation-After-Cardiac-Death Liver Transplants and Correlation With Clinical Outcomes.

The purpose of this study was to define the cholangiographic patterns of ischemic cholangiopathy and clinically silent nonanastomotic biliary strictures in donation-after-cardiac-death (DCD) liver grafts in a large single-institution series. We also examined the correlation of the radiologic findings with laboratory data and clinical outcomes. Data were collected for all DCD liver transplants at one institution from December 1998 to December 2011. Posttransplant cholangiograms were obtained during postoperative weeks 1 and 3 and when clinically indicated. Intrahepatic biliary strictures were classified by anatomic distribution and chronologic development. Radiologic findings were correlated with laboratory data and with 1-, 3-, and 5-year graft and patient survival rates. A total of 231 patients received DCD grafts. Cholangiograms were available for 184 of these patients. Postoperative cholangiographic findings were correlated with clinical data and divided into the following three groups: A, normal cholangiographic findings with normal laboratory values; B, radiologic abnormalities and cholangiopathy according to laboratory values; and C, radiologic abnormalities without laboratory abnormalities. Group B had four distinct abnormal cholangiographic patterns that were predictive of graft survival. Group C had mild nonprogressive multifocal stenoses and decreased graft and patient survival rates, although cholangiopathy was not detected in these patients according to laboratory data. Patterns and severity of nonanastomotic biliary abnormalities in DCD liver transplants can be defined radiologically and correlate with clinical outcomes. Postoperative cholangiography can depict the mild biliary abnormalities that occur in a subclinical manner yet cause a marked decrease in graft and patient survival rates in DCD liver transplants.

First experience of liver transplantation with type 2 donation after cardiac death in France

Organ donation after unexpected cardiac death [type 2 donation after cardiac death (DCD)] is currently authorized in France and has been since 2006. Following the Spanish experience, a national protocol was established to perform liver transplantation (LT) with type 2 DCD donors. After the declaration of death, abdominal normothermic oxygenated recirculation was used to perfuse and oxygenate the abdominal organs until harvesting and cold storage. Such grafts were proposed to consenting patients < 65 years old with liver cancer and without any hepatic insufficiency. Between 2010 and 2013, 13 LTs were performed in 3 French centers. Six patients had a rapid and uneventful postoperative recovery. However, primary nonfunction occurred in 3 patients, with each requiring urgent retransplantation, and 4 early allograft dysfunctions were observed. One patient developed a nonanastomotic biliary stricture after 3 months, whereas 8 patients showed no sign of ischemic cholangiopathy at their 1-year follow-up. In comparison with a control group of patients receiving grafts from brain-dead donors (n = 41), donor age and cold ischemia time were significantly lower in the type 2 DCD group. Time spent on the national organ wait list tended to be shorter in the type 2 DCD group: 7.5 months [interquartile range (IQR), 4.0-11.0 months] versus 12.0 months (IQR, 6.8-16.7 months; P = 0.08. The 1-year patient survival rates were similar (85% in the type 2 DCD group versus 93% in the control group), but the 1-year graft survival rate was significantly lower in the type 2 DCD group (69% versus 93%; P = 0.03). In conclusion, to treat borderline hepatocellular carcinoma, LT with type 2 DCD donors is possible as long as strict donor selection is observed.

Trps1 regulates biliary epithelial-mesenchymal transition and has roles during biliary fibrosis in liver grafts: a preliminary study.

ObjectiveTo investigate the role(s) of Trps1 in non-anastomotic biliary stricture (NABS) following liver transplantation.MethodsImmunohistochemical and histological techniques were used to detect Trps1, E-cadherin, CK19, vimentin, α-SMA, and collagen deposition. Human intrahepatic biliary epithelial cells (HIBECs) were infected with a Trps1 adenovirus, or transfected with Trps1 short-interfering RNAs (siRNAs). Reverse transcription polymerase chain reaction (RT-PCR) assays and western blotting were used to determine expression levels of epithelial and mesenchymal markers, and Trps1 in HIBECs.ResultsExpression of Trps1 and epithelial markers was down-regulated or absent in NABS liver samples. Mesenchymal markers were seen in biliary epithelial cells (BECs), with collagen deposited around the bile duct. Trps1 expression positively correlated with epithelial markers. Expression of epithelial marker mRNAs and proteins in HIBECs decreased with prolonged cold preservation (CP), while mesenchymal marker expression increased. A 12-h CP period led to increased Trps1 mRNA and protein levels. Expression of E-cadherin was increased in HIBECs following Trps1 adenovirus infection and CP/reperfusion injury (CPRI), with vimentin expression levels reduced and CPRI-mediated epithelial-mesenchymal transition (EMT) inhibited. Transfection of HIBECs with Trps1 siRNAs in conjunction with CPRI revealed that E-cadherin expression was decreased, vimentin expression was increased, and CPRI-mediated EMT was promoted.ConclusionTrps1 is involved in NABS pathogenesis following liver transplantation and negatively correlates with BEC EMT and biliary fibrosis in liver grafts. Trps1 demonstrates antagonistic effects that could reverse EMT.

Predictors of endoscopic treatment outcome in the management of biliary complications after orthotopic liver transplantation.

The most common complications after liver transplantation nowadays affect the biliary tract.We carried out a retrospective study to identify predictors of endoscopic treatment outcome in the management of post-transplantation biliary complications. Data from all patients with post-transplantation biliary complications subjected to endoscopic treatment at the University of Udine between 2000 and 2012 were extracted. To identify predictors of endoscopic treatment outcome, a logistic regression analysis was carried out. Cox modeling was used to identify factors associated with mortality. We identified 142 patients who developed biliary complications: 83 of these patients had a successful endoscopic therapy, whereas 45 had a failure. Fourteen patients, who developed nonanastomotic biliary stricture, were excluded from the analysis. Patients with biliary complications who had pretransplant Model for End-Stage Liver Disease score more than 10 [odds ratio (OR) 3.88; 95% confidence interval (CI) 1.16-12.95; P = 0.03] and stent retention time more than 12 months (OR 6.45; 95% CI 2.14-19.42; P < 0.01) were less likely to respond to endoscopic therapy. In contrast, both dilatation and stenting procedures (OR 0.10; 95% CI 0.03-0.30; P < 0.01) and 10 Fr diameter stent placement (OR 0.21; 95% CI 0.07-0.70; P = 0.01) predicted favorable endoscopic treatment outcome. Time to the occurrence of biliary complications of more than 3 months [hazard ratio (HR) 0.24; 95% CI 0.10-0.56] and placement of five or more stents (HR 0.31; 95% CI 0.12-0.79) were found to be protective against mortality, whereas hepatic artery thrombosis was a significant risk factor for mortality (HR 13.88; 95% CI 4.08-47.25). We found endoscopic treatment to be less effective in patients with pretransplant Model for End-Stage Liver Disease score more than 10 and stent retention time more than 12, whereas dilatation and stenting procedure and 10 Fr diameter stent placement predicted a favorable outcome.

High peak alanine aminotransferase determines extra risk for nonanastomotic biliary strictures after liver transplantation with donation after circulatory death.

Orthotopic liver transplantation (OLT) with donation after circulatory death (DCD) often leads to a higher first week peak alanine aminotransferase (ALT) and a higher rate of biliary nonanastomotic strictures (NAS) as compared to donation after brain death (DBD). This retrospective study was to evaluate whether an association exists between peak ALT and the development of NAS in OLT with livers from DBD (n=399) or DCD (n=97) from two transplantation centers. Optimal cutoff value of peak ALT for risk of development of NAS post-DCD-OLT was 1300IU/l. The 4-year cumulative incidence of NAS after DCD-OLT was 49.5% in patients with a high ALT peak post-OLT, compared with 11.3% in patients with a low ALT peak. (P<0.001). No relation between peak ALT and NAS was observed after DBD-OLT. Multivariate analysis revealed peak ALT ≥1300IU/l [adjusted hazard ratio (aHR)=3.71, confidence interval (CI) (1.26-10.91)] and donor age [aHR=1.04, CI 1.00-1.07] to be independently associated with development of NAS post-DCD-OLT. A peak ALT of <1300IU/l carries a risk for NAS similar to DBD-OLT. Thus, in DCD-OLT, but not in DBD-OLT, peak ALT discriminates patients at high or low risk for NAS.

Duodenal perforation secondary to migrated biliary stent in a liver transplant patient: successful endoscopic closure with an over-the-scope clip

Nonanastomotic biliary strictures after liver transplantation are common, occurring in as many as 16% of patients; they require serial ERCP for dilation and stenting. Although stent migration is not uncommon (6%-10% of patients), duodenal perforation from stent migration is rare but associated with a high mortality and often requires surgical intervention.

Fucosyltransferase-2 non-secretor status is associated with non-anastomotic biliary strictures after liver transplantation in recipients with primary sclerosing cholangitis

Fucosyltransferase-2 non-secretor status is associated with non-anastomotic biliary strictures after liver transplantation in recipients with primary sclerosing cholangitis

Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures

Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures