Diagnosis and Management of Biliary Strictures after Deceased-Donor Liver Transplantation Based on Clinical Practice

Biliary complications are still the main complications for liver transplantation recipients. Biliary strictures comprise the major part of all biliary complications after deceased-donor liver transplantation (LT). Biliary strictures following LT are divided into anastomotic strictures (AS) and non-anastomotic strictures (NAS). A Limitation of current published researches is that most studies aren’t based on clinical practice. The aim of this review is to summarize risk factors, clinical presentation, diagnosis and management in post-LT biliary strictures.

Still elusive: Developments in the accurate diagnosis of indeterminate biliary strictures

Indeterminate biliary strictures pose a significant diagnostic dilemma for gastroenterologists.Despite advances in endoscopic techniques and instruments,it is difficult to differentiate between benign and malignant pathology.A positive histological diagnosis is always preferred prior to high risk hepatobiliary surgery,or to inform other types of therapy.Endoscopic retrograde cholangiopancreato-graphy with brushings has low sensitivity and despite significant improvements in instruments there is still an unacceptably high false negative rate.Other methods such as endoscopic ultrasound and cholangioscopy have improved diagnostic quality.In this review we explore the techniques available to aid accurate diagnosis of indeterminate biliary strictures and obtain accurate histology to facilitate clinical management.

Clinical approach to indeterminate biliary strictures:Clinical presentation,diagnosis,and workup

Despite advances in cross-sectional imaging and endoscopic technology,bile duct strictures remain a challenging clinical entity.It is crucial to make an early determination of benign or malignant nature of biliary strictures.Early diagnosis not only helps with further management but also minimizes mortality and morbidity associated with delayed diagnosis.Conventional imaging and endoscopic techniques,particularly endoscopic retrograde cholangiopancreatography(ERCP)and tissue sampling techniques play a key in establishing a diagnosis.Indeterminate biliary strictures(IDBSs)have no definite mass on imaging or absolute histopathological diagnosis and often warrant utilization of multiple diagnostics to ascertain an etiology.In this review,we discuss possible etiologies,clinical presentation,diagnosis,and management of IDBSs.Based on available data and expert opinion,we depict an evidence based diagnostic algorithm for management of IDBSs.Areas of focus include use of traditional tissue sampling techniques such as ERCP with brush cytology,intraductal biopsies,fluorescence in situ hybridization and flow cytometry.We also describe the role of endoscopic ultrasound(EUS)-guided fine needle aspiration and biopsies,cholangioscopy,confocal laser endomicroscopy,and intraductal EUS in management of IDBSs.

Endoscopic management of benign biliary strictures:Looking for the best stent to place

Benign biliary strictures(BBS)might occur due to different pancreaticobiliary conditions.The etiology and location of biliary strictures are responsible of a wide array of clinical manifestations.The endoscopic approach endoscopic retrograde cholangiopancreatography represents the first-line treatment for BBS,considering interventional radiology and surgery when endoscopic treatment fails or it is not suitable.The purpose of this review is to provide an overview of possible endoscopic treatments for the optimal management of this subset of patients.

Diagnosis of biliary strictures after liver transplantation:Which is the best tool?

AIM: To evaluate the diagnostic value of different indirect methods like biochemical parameters, ultrasound (US) analysis, CT-scan and MRI/MRCP in comparison with endoscopic retrograde cholangiography (ERC), for diagnosis of biliary complications after liver transplantation. METHODS: In 75 patients after liver transplantation, who received ERC due to suspected biliary complications, the result of the cholangiography was compared to the results of indirect imaging methods performed prior to ERC. The cholangiography showed no biliary stenosis (NoST) in 25 patients, AST in 27 and ITBL in 23 patients. RESULTS: Biliary congestion as a result of AST was detected with a sensitivity of 68.4% in US analysis (specificity 91%), of 71% in MRI (specificity 25%) and of 40% in CT (specificity 57.1%). In ITBL, biliary congestion was detected with a sensitivity of 58.8% in the US, 88.9%in MRI and of 83.3% in CT. However, as anastomotic or ischemic stenoses were the underlying cause of biliary congestion, the sensitivity of detection was very low. InMRI detected the dominant stenosis at a correct localization in 22% and CT in 10%, while US failed completely. The biochemical parameters, showed no significant difference in bilirubin (median 5.7; 4,1; 2.5 mg/dL), alkaline phosphatase (median 360; 339; 527 U/L) or gamma glutamyl transferase (median 277; 220; 239 U/L) levels between NoST, AST and ITBL.CONCLUSION: Our data confirm that indirect imaging methods to date cannot replace direct cholangiography for diagnosis of post transplant biliary stenoses. However MRI may have the potential to complement or precede imaging by cholangiography. Optimized MRCP-processing might further improve the diagnostic impact of this method.

Management issues in post living donor liver transplant biliary strictures

Biliary complications are common after living donor liver transplant(LDLT) although with advancements in surgical understanding and techniques, the incidence is decreasing. Biliary strictures are more common than leaks. Endoscopic retrograde cholangiopancreatography(ERCP) is the first line modality of treatment of post LDLT biliary strictures with a technical success rate of 75%-80%. Most of ERCP failures are successfully treated by percutaneous transhepatic biliary drainage(PTBD) and rendezvous technique. A minority of patients may require surgical correction. ERCP for these strictures is technically more challenging than routine as well post deceased donor strictures. Biliary strictures may increase the morbidity of a liver transplant recipient, but the mortality is similar to those with or without strictures. Post transplant strictures are short segment and soft, requiring only a few session of ERCP before complete dilatation. Long-term outcome of patients with biliary stricture is similar to those without stricture. With the introduction of new generation cholangioscopes, ERCP success rate may increase, obviating the need for PTBD and surgery in these patients.

Endoscopic therapy for biliary strictures complicating living donor liver transplantation: Factors predicting better outcome

AIM To identify factors predicting outcome of endoscopic therapy in bile duct strictures(BDS) post living donor liver transplantation(LDLT).METHODS Patients referred with BDS post LDLT, were retrospectively studied. Patient demographics, symptoms(Pruritus, Jaundice, cholangitis), intra-op variables(cold ischemia time, blood transfusions, number of ducts used, etc.), peri-op complications [hepatic artery thrombosis(HAT), bile leak, infections], stricture morphology(length, donor and recipient duct diameters) and relevant laboratory data both pre-and post-endotherapy were studied. Favourable response to endotherapy was defined as symptomatic relief with > 80% reduction in total bilirubin/serum gamma glutamyl transferase. Statistical analysis was performed using SPSS 20.0.RESULTS Forty-one patients were included(age: 8-63 years). All had right lobe LDLT with duct-to-duct anastomosis. Twenty patients(48.7%) had favourable response to endotherapy. Patients with single duct anastomosis, aggressive stent therapy(multiple endoscopic retrogradecholagiography, upsizing of stents, dilatation and longer duration of stents) and an initial favourable response to endotherapy were independent predictors of good outcome(P < 0.05). Older donor age, HAT, multiple ductal anastomosis and persistent bile leak(> 4 wk post LT) were found to be significant predictors of poor response on multivariate analysis(P < 0.05). CONCLUSION Endoscopic therapy with aggressive stent therapy especially in patients with single duct-to-duct anastomosis was associated with a better outcome. Multiple ductal anastomosis, older donor age, shorter duration of stent therapy, early bile leak and HAT were predictors of poor outcome with endotherapy in these patients.

Update of cholangioscopy and biliary strictures

Cholangioscopy remains another modality in the investigation of biliary strictures. At cholangioscopy, the"tumour vessel" sign is considered a specific sign formalignancy. Through its ability to not only visualisemucosa, but to take targeted biopsies, it has a greater accuracy, sensitivity and specificity for malignant strictures than endoscopic retrograde cholangiopancreatography guided cytopathological acquisition. Cholangioscopy however, is time consuming and costly, requires greater technical expertise, and should be reserved for the investigation of undifferentiated strictures after standard investigations have failed.

Percutaneous interventional therapy for anastomotic biliary strictures after orthotopic liver transplantation

Objective To describe the technique,efficacy, and safety of percutaneous interventional therapy for anastomotic biliary strictures after orthotopic liver transplantation ( OLT) . Methods From May 2004 to December 2009,25 patients with anastomotic biliary stric-

Endoscopic therapy of benign biliary strictures

Benign biliary strictures are being increasingly treated with endoscopic techniques. The benign nature of the stricture should be first confirmed in order to ensure appropriate therapy. Surgery has been the traditional treatment, but there is increasing desire for minimally invasive endoscopic therapy. At present, endoscopy has become the first line approach for the therapy of post- liver transplant anastomotic strictures and distal （Bismuth ! and I） post-operative strictures. Strictures related to chronic pancreatitis have proven more difficult to treat, and endoscopic therapy is reserved for patients who are not surgical candidates. The preferred endoscopic approach is aggressive treatment with gradual dilation of the stricture and insertion of multiple plastic stents. The use of uncovered self expandable metal stents should be discouraged due to poor long-term results. Treatment with covered metal stents or bioabsorbable stents warrants further evaluation. This area of therapeutic endoscopy provides an ongoing opportunity for fresh research and innovation.

Hepatobiliary scintigraphy for detecting biliary strictures after living donor liver transplantation

AIM:To investigate the diagnostic accuracy of hepatobiliary scintigraphy(HBS) in detecting biliary strictures in living donor liver transplantation(LDLT) patients.METHODS:We retrospectively reviewed 104 adult LDLT recipients of the right hepatic lobe with duct-toduct anastomosis,who underwent HBS and cholangiography.The HBS results were categorized as normal,parenchymal dysfunction,biliary obstruction,or bile leakage without re-interpretation.The presence of biliary strictures was determined by percutaneous cholangiography or endoscopic retrograde cholangiopancreatography(ERCP).RESULTS:In 89 patients with biliary strictures,HBS showed biliary obstruction in 50 and no obstruction in 39,for a sensitivity of 56.2%.Of 15 patients with no biliary strictures,HBS showed no obstruction in 11,for a specificity of 73.3%.The positive predictive value(PPV) was 92.6%(50/54) and the negative predictive value(NPV) was 22%(11/50).We also analyzed the diagnostic accuracy of the change in bile duct size.The sensitivity,NPV,specificity,and PPV were 65.2%,27.9%,80% and 95%,respectively.CONCLUSION:The absence of biliary obstruction on HBS is not reliable.Thus,when post-LDLT biliary strictures are suspected,early ERCP may be considered.

Endoscopic ultrasonography can diagnose distal biliary strictures without a mass on computed tomography

AIM:To assess the diagnostic ability of endoscopic ultrasonography(EUS)for evaluating causes of dista biliary strictures shown on endoscopic retrograde chol angiopancreatography(ERCP)or magnetic resonance cholangiopancreatography(MRCP),even without iden tifiable mass on computed tomography(CT). METHODS:The diagnostic ability of EUS was retro spectively analyzed and compared with that of routine cytology(RC)and tumor markers in 34 patients with distal biliary strictures detected by ERCP or MRCP a Dokkyo Medical School Hospital from December 2005 to December 2008,without any adjacent mass or ec centric thickening of the bile duct on CT that could cause biliary strictures.Findings considered as benign strictures on EUS included preservation of the normasonographic layers of the bile duct wall,irrespective of the presence of a mass lesion.Other strictures were considered malignant.Final diagnosis of underlying diseases was made by pathological examination in 18 cases after surgical removal of the samples,and by clinical follow-up for>10 mo in 16 cases. RESULTS:Seventeen patients(50%)were finally di- agnosed with benign conditions,including 6"normal" subjects,while 17 patients(50%)were diagnosed with malignant disease.In terms of diagnostic ability,EUS showed 94.1%sensitivity,82.3%specificity,84.2% positive predictive value,93.3%negative predictive value(NPV)and 88.2%accuracy for identifying ma- lignant and benign strictures.EUS was more sensi- tive than RC(94.1%vs 62.5%,P=0.039).NPV was also better for EUS than for RC(93.3%vs 57.5%,P= 0.035).In addition,EUS provided significantly higher sensitivity than tumor markers using 100 U/mL as the cutoff level of carbohydrate antigen 19-9(94.1%vs 53%,P=0.017).On EUS,biliary stricture that was fi- nally diagnosed as malignant showed as a hypoechoic, irregular mass,with obstruction of the biliary duct and invasion to surrounding tissues. CONCLUSION:EUS can diagnose biliary strictures caused by malignant tumors that are undetectable on CT.Earlier detection by EUS would provide more therapeutic options for patients with early-stage pancreaticobiliary cancer.

Efficacy of multiple biliary stenting for refractory benign biliary strictures due to chronic calcifying pancreatitis

AIMTo investigate endoscopic therapy efficacy for refractory benign biliary strictures (BBS) with multiple biliary stenting and clarify predictors. METHODSTen consecutive patients with stones in the pancreatic head and BBS due to chronic pancreatitis who underwent endoscopic therapy were evaluated. Endoscopic insertion of a single stent failed in all patients. We used plastic stents (7F, 8.5F, and 10F) and increased stents at intervals of 2 or 3 mo. Stents were removed approximately 1 year after initial stenting. BBS and common bile duct (CBD) diameter were evaluated using cholangiography. Patients were followed for &ge; 6 mo after therapy, interviewed for cholestasis symptoms, and underwent liver function testing every visit. Patients with complete and incomplete stricture dilations were compared. RESULTSEndoscopic therapy was completed in 8 (80%) patients, whereas 2 (20%) patients could not continue therapy because of severe acute cholangitis and abdominal abscess, respectively. The mean number of stents was 4.1 &plusmn; 1.2. In two (20%) patients, BBS did not improve; thus, a biliary stent was inserted. BBS improved in six (60%) patients. CBD diameter improved more significantly in the complete group than in the incomplete group (6.1 &plusmn; 1.8 mm vs 13.7 &plusmn; 2.2 mm, respectively, P = 0.010). Stricture length was significantly associated with complete stricture dilation (complete group; 20.5 &plusmn; 3.0 mm, incomplete group; 29.0 &plusmn; 5.1 mm, P = 0.011). Acute cholangitis did not recur during the mean follow-up period of 20.6 &plusmn; 7.3 mo. CONCLUSIONSequential endoscopic insertion of multiple stents is effective for refractory BBS caused by chronic calcifying pancreatitis. BBS length calculation can improve patient selection procedure for therapy.

Current endoscopic approach to indeterminate biliary strictures

Biliary strictures are considered indeterminate when basic work-up, including transabdominal imaging and endoscopic retrograde cholangiopancreatography with routine cytologic brushing, are non-diagnostic. Indeterminate biliary strictures can easily be mischaracterized which may dramatically affect patient's outcome. Early and accurate diagnosis of malignancy impacts not only a patient's candidacy for surgery, but also potential timely targeted chemotherapies. A significant portion of patients with indeterminate biliary strictures have benign disease and accurate diagnosis is, thus, paramount to avoid unnecessary surgery. Current sampling strategies have suboptimal accuracy for the diagnosis of malignancy. Emerging data on other diagnostic modalities, such as ancillary cytology techniques, single operator cholangioscopy, and endoscopic ultrasonography-guided fine needle aspiration, revealed promising results with much improved sensitivity.

Common controversies in management of biliary strictures

Biliary strictures are caused by a heterogeneous group of benign and malignant conditions, each requiring a specific treatment approach. Management of biliary strictures often involves endoscopy either for definite treatment, as a bridge to surgery or for palliative purposes. Endoscopic treatment of various types of biliary strictures is not standardized and there are multiple areas of controversy regarding the best treatment options. These controversies are mainly due to lack of well-designed comparative studies to support a specific therapy. This paper reviews three common areas of controversy in the endoscopic management of biliary strictures. The areas discussed in this editorial include the role of biliary drainage in resectable malignant strictures and whether such drainage should be performed routinely prior to surgery, the best endoscopic palliation for unresectable hilar strictures and whether unilateral or bilateral stenting should be attempted, and the optimal endoscopic management for dominant strictures in patients with primary sclerosing cholangitis. The goal of this editorial is twofold. The first is to review the current literature on management of the aforementioned strictures and offer recommendations based on available evidence. The second goal is to highlight the gaps in our knowledge which in turn can encourage future research on these topics.

New anti-reflux plastic stent to reduce the risk of stent-related cholangitis in the treatment of biliary strictures

BACKGROUND There is little data available on the role of new anti-reflux plastic stents(ARPSs).AIM To compare the use of ARPSs with that of traditional plastic stents(TPSs)for patients with biliary strictures.METHODS Consecutive patients with biliary strictures who underwent first endoscopic biliary stenting between February 2016 and May 2019 were included.The onset of stent-related cholangitis,stent patency,clinical success,and other adverse events were evaluated.RESULTS Sixty-seven patients in the ARPS group and 66 patients in the TPS group were included in the final analyses.Fewer patients experienced stent-related cholangitis in the ARPS group than that in the TPS group(8 patients vs 18 patients;P=0.030).The median time till the onset of first stent-related cholangitis was later in the ARPS group than that in the TPS group(128.5 d vs 76 d;P=0.039).The cumulative median stent patency in the ARPS group was 185 d,which was significantly longer than that in the TPS group(133 d;P=0.001).The clinical success rates and other adverse events did not significantly differ between both groups.CONCLUSION Placement of new ARPS might be a safe and effective optional therapeutic strategy to reduce the risk of stent-related cholangitis and prolong stent patency.

Enhancing diagnostic strategies for biliary strictures:an evolving landscape

The diagnosis of patients with biliary strictures of undetermined etiology remains a significant challenge.Biliary strictures,whether benign or malignant,often present with similar clinical features and imaging findings.For patients,this uncertainty can lead to repeated laboratory and radiological tests,invasive procedures,as well as delayed treatment and considerable anxiety.The complexity of these cases necessitates the integration of multiple diagnostic modalities to enhance accuracy while balancing patient safety and resource utilization.

Guidelines on cholangioscopy for indeterminate biliary strictures:one step closer to consensus

Described as early as the 1950s(1),cholangioscopy has evolved from a burdensome intra-operative maneuver performed during open surgery,to a minimally-invasive,widely-available tool that can be utilized on demand during endoscopic retrograde cholangiopancreatography(ERCP).The advent of the latest generation digital cholangioscopes with improved image quality,maneuverability,and the ability to pass tools through a dedicated instrument channel has revolutionized the modern approach to a wide variety of biliary disorders(2).

New rabbit model for benign biliary stricture formation with repeatable administration

BACKGROUND The treatment of benign biliary strictures(BBS)is a challenging clinical problem.At present,there is a lack of ideal models for the study of BBS treatment.AIM To develop a novel animal model of BBS to simulate studies on the processes and mechanisms in the human condition.METHODS A rabbit model of benign bile duct stricture was established by surgical injury of the bile duct.After removal of the gallbladder,a drainage tube was placed th-rough the cystic duct at the stump,and a BBS model was induced by surgical injury at the lower end of the common bile duct.RESULTS Compared with the control group,the model rabbits showed gross jaundice,increased serum bilirubin,and decreased liver function.Cholangiography showed segmental bile duct stenosis in the model rabbits.Pathological staining showed inflammatory cell infiltration and fibrosis in the biliary tract of rabbits in the model group.This was consistent with the clinical manifestations of BBS.This model provided serology,imaging,pathology,and other aspects of BBS.CONCLUSION We have successfully established an animal model of benign stricture of the lower bile duct with repeatable administration,which is consistent with the clinical manifestations of BBS.

Post-transplant biliary complications using liver grafts from deceased donors older than 70 years:Retrospective case-control study

BACKGROUND The shortage of liver grafts and subsequent waitlist mortality led us to expand the donor pool using liver grafts from older donors.AIM To determine the incidence,outcomes,and risk factors for biliary complications(BC)in liver transplantation(LT)using liver grafts from donors aged>70 years.METHODS Between January 1994 and December 31,2019,297 LTs were performed using donors older than 70 years.After excluding 47 LT for several reasons,we divided 250 LTs into two groups,namely post-LT BC(n=21)and without BC(n=229).This retrospective case-control study compared both groups.RESULTS Choledocho-choledochostomy without T-tube was the most frequent technique(76.2%in the BC group vs 92.6%in the non-BC group).Twenty-one patients(8.4%)developed BC(13 anastomotic strictures,7 biliary leakages,and 1 nonanastomotic biliary stricture).Nine patients underwent percutaneous balloon dilation and nine required a Rouxen-Y hepaticojejunostomy because of dilation failure.The incidence of post-LT complications(graft dysfunction,rejection,renal failure,and non-BC reoperations)was similar in both groups.There were no significant differences in the patient and graft survival between the groups.Moreover,only three deaths were attributed to BC.While female donors were protective factors for BC,donor cardiac arrest was a risk factor.CONCLUSION The incidence of BC was relatively low on using liver grafts>70 years.It could be managed in most cases by percutaneous dilation or Roux-en-Y hepaticojejunostomy,without significant differences in the patient or graft survival between the groups.