Risk Factors for Infectious Complications following Endoscopic Retrograde Cholangiopancreatography in Liver Transplant Patients: A Single-Center Study.

Background: Liver transplant recipients often require endoscopic retrograde cholangiopancreatography (ERCP) for biliary complications, which can lead to infections. This retrospective single-center study aimed to identify risk factors for infectious complications following ERCP in liver transplant patients. Methods: A retrospective analysis was conducted on 285 elective ERCP interventions performed in 88 liver transplant patients at a tertiary care center. The primary endpoint was the occurrence of an infection following ERCP. Univariable and multivariable regression analyses, Cox regression, and log-rank tests were employed to assess the influence of various factors on the incidence of infectious complications. Results: Among the 285 ERCP interventions, isolated anastomotic stenosis was found in 175 cases, ischemic type biliary lesion (ITBL) in 103 cases, and choledocholithiasis in seven cases. Bile duct interventions were performed in 96.9% of all ERCPs. Infections after ERCP occurred in 46 cases (16.1%). Independent risk factors for infection included male sex (OR 24.19), prednisolone therapy (OR 4.5), ITBL (OR 4.51), sphincterotomy (OR 2.44), cholangioscopy (OR 3.22), dilatation therapy of the bile ducts (OR 9.48), and delayed prophylactic antibiotic therapy (>1 h after ERCP) (OR 2.93). Additionally, infections following previous ERCP interventions were associated with an increased incidence of infections following future ERCP interventions (p < 0.0001). Conclusion: In liver transplant patients undergoing ERCP, male sex, prednisolone therapy, and complex bile duct interventions independently raised infection risks. Delayed antibiotic treatment further increased this risk. Patients with ITBL were notably susceptible due to incomplete drainage. Additionally, a history of post-ERCP infections signaled higher future risks, necessitating close monitoring and timely antibiotic prophylaxis.

The biliary microbiome in ischaemic-type biliary lesions can be shaped by stenting but is resilient to antibiotic treatment.

This study aims to characterize the biliary microbiome as neglected factor in patients with ischaemic-type biliary lesions (ITBL) after liver transplantation. Therefore, the V1-V2 region of the 16S rRNA gene was sequenced in 175 bile samples. Samples from patients with anastomotic strictures (AS) served as controls. Multivariate analysis and in silico metagenomics were applied cross-sectionally and longitudinally. The microbial community differed significantly between ITBL and AS in terms of alpha and beta diversity. Both, antibiotic treatment and stenting were associated independently with differences in the microbial community structure. In contrast to AS, in ITBL stenting was associated with pronounced differences in the biliary microbiome, whereas no differences associated with antibiotic treatment could be observed in ITBL contrasting the pronounced differences found in AS. Bacterial pathways involved in the production of antibacterial metabolites were increased in ITBL with antibiotic treatment. After liver transplantation, the biliary tract harbours a complex microbial community with significant differences between ITBL and AS. Fundamental changes in the microbial community in ITBL can be achieved with biliary stenting. However, the effect of antibiotic treatment in ITBL was minimal. Therefore, antibiotics should be administered wisely in order to reduce emerging resistance of the biliary microbiome towards external antibiotics.

Research progress on the role of bile salts in ischemic-type biliary lesion after liver transplantation / 器官移植

Ischemic-type biliary lesion (ITBL) refers to biliary tract injury caused by insufficient blood supply of hepatic artery, which is one of the main factors affecting the long-term survival and quality of life of liver transplant recipients. The incidence of ITBL is associated with cold and warm ischemia, acute and chronic rejection, cytomegalovirus infection and the bile effect, etc. The occurrence of ITBL is a complicated process involving with multiple factors and steps. The therapeutic option of ITBL is extremely limited. A large proportion of ITBL patients should undergo repeated liver transplantation. ITBL has become one of the most critical factors preventing further advancement of liver transplantation. Hence, it is of significance to strengthen prevention and explore more effective modalities. Recent studies have found that toxic injury of bile salts plays a central role in ITBL. Active regulation of bile components, regulation of bile acid-related receptor expression and blockage or activation of bile acid-related signaling pathways probably have potentials in the prevention and treatment of ITBL. In this article, the cytotoxicity of bile salts and the mechanism of bicarbonate umbrella in the incidence and progression of ITBL after liver transplantation were reviewed, aiming to provide reference for the diagnosis and treatment of ITBL.

Association between indocyanine green clearance test and ischemic type biliary lesions within one year after orthotopic liver transplantation / Asociación entre la prueba de clearance verde de indocianina y las lesiones biliares de tipo isquémico dentro de un año después del trasplante ortotópico de hígado

Background: Ischemic type biliary lesions (ITBLs), a particular subset of non-anastomotic biliary strictures (NAS), are characterized by intra and extrahepatic strictures that occur in the absence of either hepatic artery thrombosis or stenosis. When they occur within the first year after liver transplantation their development is mostly related to ischemia–reperfusion injury (IRI). The indocyanine green plasma disappearance rate (ICG-PDR) might be able to predict the probability of IRI-induced graft damage after liver transplantation. Objective: Our aim was to evaluate the association between ICG-PDR and the occurrence of ITBLs. Secondly, we searched for evidence of IRI in patients presenting ITBLs. Methods: This retrospective single-center observational study assessed a cohort of 60 liver transplant patients. Each patient underwent ICG-PDR on the 1st postoperative day. ITBLs were identified by means of either cholangiography or magnetic resonance imaging evidence of a deformity and narrowing of the biliary tree in the absence of hepatic artery thrombosis/stenosis. Results: ITBLs were discovered in 10 patients out of 60 liver recipients (16.67%) within one year after transplantation. A low ICG-PDR value was found to be a significant predictive factor for ITBL development, with an OR of 0.87 and a 95% CI of 0.77–0.97. Liver biopsies were performed in 56 patients presenting unexplained abnormal liver function test results. A statistically significant association was found between the development of ITBLs and anatomopathological evidence of IRI. Limitations: Retrospective, single-center study. Conclusions: The findings from this study show a relationship between low ICG-PDR values on first post-operative-day and the occurrence of ITBLs within 1 year after transplantation.(AU)

Antecedentes: Las lesiones biliares de tipo isquémico (ITBL) representan un subconjunto de estenosis biliares no anastomóticas, caracterizadas por estenosis intra y extrahepáticas, que ocurren en ausencia de trombosis o estenosis de la arteria hepática. Cuando ocurren dentro del primer año después del trasplante de hígado, están relacionadas principalmente con la lesión por isquemia-reperfusión (IRI). La tasa de desaparición del plasma con verde de indocianina (ICG-PDR) podría estimar el daño del injerto inducido por IRI después de un trasplante. Objetivo: Nuestro objetivo es evaluar la asociación entre ICG-PDR y la aparición de ITBL. También investigamos la evidencia de IRI entre los pacientes que presentaron ITBL. Métodos: Estudio observacional, retrospectivo, unicéntrico, realizado en una cohorte de 60 receptores trasplantados con determinacion del ICG-PDR el primer día posoperatorio. Las ITBL se definieron mediante colangiografía o evidencia por resonancia magnética de deformidad del árbol biliar en ausencia de trombosis/estenosis de la arteria hepática. Resultados: De 60 receptores, se descubrieron ITBL en 10 pacientes (16,67%) en el primer año. El valor bajo de ICG-PDR es un factor predictivo significativo para ITBL, con OR=0,87 y un IC (95%)=0,77-0,97. Se analizaron 56 biopsias hepáticas para la presencia de IRI, si los receptores presentaban una prueba de función hepática anormal inexplicable, encontrando asociación significativa entre ITBL y evidencia anatomopatológica de IRI. Limitaciones: Estudio retrospectivo, unicéntrico.(AU)

Association between indocyanine green clearance test and ischemic type biliary lesions within one year after orthotopic liver transplantation.

BACKGROUND: Ischemic type biliary lesions (ITBLs), a particular subset of non-anastomotic biliary strictures (NAS), are characterized by intra and extrahepatic strictures that occur in the absence of either hepatic artery thrombosis or stenosis. When they occur within the first year after liver transplantation their development is mostly related to ischemia-reperfusion injury (IRI). The indocyanine green plasma disappearance rate (ICG-PDR) might be able to predict the probability of IRI-induced graft damage after liver transplantation. OBJECTIVE: Our aim was to evaluate the association between ICG-PDR and the occurrence of ITBLs. Secondly, we searched for evidence of IRI in patients presenting ITBLs. METHODS: This retrospective single-center observational study assessed a cohort of 60 liver transplant patients. Each patient underwent ICG-PDR on the 1st postoperative day. ITBLs were identified by means of either cholangiography or magnetic resonance imaging evidence of a deformity and narrowing of the biliary tree in the absence of hepatic artery thrombosis/stenosis. RESULTS: ITBLs were discovered in 10 patients out of 60 liver recipients (16.67%) within one year after transplantation. A low ICG-PDR value was found to be a significant predictive factor for ITBL development, with an OR of 0.87 and a 95% CI of 0.77-0.97. Liver biopsies were performed in 56 patients presenting unexplained abnormal liver function test results. A statistically significant association was found between the development of ITBLs and anatomopathological evidence of IRI. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: The findings from this study show a relationship between low ICG-PDR values on first post-operative-day and the occurrence of ITBLs within 1 year after transplantation.

Research progress on mesenchymal stem cell in treatment of ischemic-type biliary lesion / 器官移植

At present, surgical and endoscopic interventions are mainly employed to treat ischemic-type biliary lesion (ITBL). Due to the disadvantages of single therapeutic strategy, high difficulty and expensive medical cost, it is urgent to identify a novel treatment option. Mesenchymal stem cell (MSC) has become potential seed cell for tissue and organ repair in regenerative medicine due to its high self-renewal capability, multi-directional differentiation potential, low immunogenicity and immunoregulatory effects, etc. Recent studies have demonstrated that MSC transplantation into ITBL animal models may not only home to the injured area, but also promote the repair of injured biliary tract tissues through anti-apoptotic and pro-angiogenic effect, which indicates that MSC transplantation is expected to become a new strategy for the treatment of ITBL. In this article, the biological characteristics of MSC, the mechanism and clinical application of MSC transplantation for ITBL were reviewed.

Serum proteomic predicts effectiveness and reveals potential biomarkers for complications in liver transplant patients.

Sophisticated postoperative complications limit the long-term clinical success of liver transplantation. Hence, early identification of biomarkers is essential for graft and patient survival. High-throughput serum proteomics technologies provide an opportunity to identify diagnostic and prognostic biomarkers. This study is aimed to identify serum diagnosis biomarkers for complications and monitor effectiveness. Serum samples from 10 paired pre- and post-liver transplant patients, 10 acute rejection (AR) patients, 9 ischemic-type biliary lesion (ITBL) patients, and 10 healthy controls were screened using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to explore divergence in polypeptide. Then, we used ELISA and western blot analysis to validate the expression of these potential biomarkers, and studied the correlation of proteomic profiles with clinical parameters. ACLY, FGA, and APOA1 were significantly lower in pre-operative patients compared with healthy controls, and these patients had modest recovery after transplantation. Downregulation of both, ACLY and FGA, was also observed in AR and ITBL patients. Furthermore, bioinformatics analysis was performed and the results suggested that the identified proteins were involved in glucolipid metabolism and the clotting cascade. Together, these findings suggest that ACLY, FGA, and APOA1 could be novel non-invasive and early biomarkers to detect complications and predict effectiveness of liver transplantation.

Clinical analysis of classification and prognosis of ischemic-type of biliary lesions after liver transplantation / 中华器官移植杂志

Objective To classify the ischemic-type of biliary lesions (TTBL) after liver transplantation based on the imaging findings and the severity of the clinical manifestations,and analyze the relationship between the grading and prognosis of ITBL.Methods 886 liver transplantation recipients were divided into 2 groups:ITBL group (124 cases),and non-ITBL group (762 cases).The prognosis of the recipients was compared between the two groups.According to the severity of ITBL,ITBL patients were divided into three grades,and the prognosis was compared among the three grades.Results The survival rate,graft survival rate and adverse prognosis rate between ITBL group and non-ITBL group were statistically significant (P＜0.001).There was no significant difference in survival rate among mild,moderate and severe ITBL groups.There was very significant difference in graft survival between mild and moderate group versus severe group (P＜0.05).There was no significant difference between mild and moderate groups in graft survival.There was significant difference in the incidence of adverse outcomes between mild group versus moderate and severe groups (P＜0.04),but there was no significant difference between the moderate and severe groups.Conclusion The ITBL classification based on the imaging severity of the biliary tract and the level of bilirubin can predict the prognosis of ITBL.

Biliary complications after liver transplantation.

UNLABELLED: Biliary complications (BCs) remain one of the most outstanding factors influencing long-term results after orthotopic liver transplantation. The authors carried out a systematic overview of 1720 papers since 2008, and focused on 45 relevant ones. Among 14,411 transplanted patients the incidence of BCs was 23%. Biliary leakage occurred in 8.5%, biliary stricture in 14.7%, mortality rate was 1-3%. RISK FACTORS: preoperative sodium level; p = 0.037, model of end-stage liver disease score >25; p = 0.048, primary sclerosing cholangitis; p = 0.001, malignancy; p = 0.026, donor age >60, macrovesicular graft steatosis; p = 0.001, duct-to-duct anastomosis; p = 0.004, long anhepatic phase; p = 0.04, cold ischemic time >12 h; p = 0.043, use of T-tube; p = 0.032, insufficient flush of bile ducts; p = 0.001, acute rejection; p = 0.003, cytomegalovirus infection; p = 0.004 and hepatic artery thrombosis; p = 0.001. The management was surgical in case of biliary leakage, and interventional radiology or endoscopic retrograde cholangiopancreatography in case of biliary stricture. Mapping of miRNA profile is a new field of research. Nemes-Doros score is a useful tool in the estimation of hepatic artery thrombosis. Management of BCs requires a multidisciplinary expert team.

Pathogenesis of Portal Cavernoma Cholangiopathy: Is it Compression by Collaterals or Ischemic Injury to Bile Ducts During Portal Vein Thrombosis?

The pathogenesis of portal cavernoma cholangiopathy (PCC) is important as it can impact the choice of treatment modalities. PCC consists of a reversible component, which resolves by decompression of collaterals as well as a fixed component, which persists despite the decompression of collaterals. The reversible component is due to compression by large collaterals located adjacent to the bile duct as well as possibly intracholedochal varices. The fixed component is likely to be due to ischemia at the time of portal vein thrombosis, local ischemia by compression as well as encasement by a solid tumor-like cavernoma comprising of fibrous hilar mass containing multiple tiny collateral veins rather than markedly enlarged portal collaterals. Although cholangiographic abnormalities in portal hypertension are common, the prevalence of symptomatic PCC is low. This is likely to be related to the cause of portal hypertension, the duration of portal hypertension and possibly the pattern of occlusion of the splenoportal axis. There may possibly be higher prevalence of symptomatic PCC in extension of the thrombosis to the splenomesentric veins.

MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation.

BACKGROUND & AIMS: Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though the exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive of the development of ITBL after liver transplantation. METHODS: Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222, and CDmiR-296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n=20) and grafts without biliary strictures (n=37) were compared. RESULTS: MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (p<0.01) and were identified as an independent risk factor by multivariate analysis (p<0.01, HR: 6.89). The discriminative power of HDmiRs/CDmiRs in perfusates was validated by analysis of separate brain death- (DBD) and cardiac death donors (DBD; p ≤ 0.016) and was superior to expression in liver biopsies (C=0.77 in perfusates vs. C<0.50 in biopsies). CONCLUSIONS: This study demonstrates that differential release of CDmiRs during graft preservation is predictive of the development of ITBL after liver transplantation. This provides new evidence for the link between graft-related bile duct injury and the risk for later development of ITBL.