Clinical use of uncovered balloon-expandable metallic biliary stents for treatment of extrahepatic biliary tract obstructions in cats and dogs: 11 cases (2012-2022).

OBJECTIVE: To describe the application of uncovered balloon-expandable metallic biliary stents for treatment of extrahepatic biliary obstructions (EHBOs) and the outcomes for dogs and cats treated for EHBO with this technique. STUDY DESIGN: Retrospective single institutional study. ANIMALS: Eight dogs and three cats treated at the Veterinary Specialty Hospital of San Diego for EHBO between January 2012 and February 2022. METHODS: Data collected from the medical records included signalment, presenting complaint, laboratory and imaging findings, surgical findings, hospitalization time, complications, and follow-up information. RESULTS: Median duration of short-term follow up was 16 days (6-45 days). Improved biochemical abnormalities and resolution of clinical signs were recorded in 10/11 cases. Two dogs died within 2 weeks of surgery. One dog developed systemic inflammatory response syndrome 5 days postoperatively and was euthanized; the cause of death in the second case was unknown. Long-term follow up was available in seven cases, with a median duration of 307.5 days (62-2268 days). Bile-duct patency was maintained for at least 356-622 days (median: 446 days) in three cats and 62-2268 days (median: 650.5 days) in four dogs with long-term follow up available. One cat had recurrent obstruction with choledocholiths 446 days postoperatively. One stent was removed 614 days postoperatively due to recurrent cholangiohepatitis. CONCLUSION: Uncovered balloon-expandable metallic biliary stents were placed successfully and relieved EHBO in all cases that survived to discharge. CLINICAL SIGNIFICANCE: Use of uncovered balloon-expandable metallic biliary stents should be considered as an alternative to temporary choledochal luminal stenting or cholecystoenterostomy to manage EHBO.

Predictive factors in the differential diagnosis of benign and malignant causes in patients undergoing endoscopic retrograde cholangiopancreatography for extrahepatic cholestasis.

OBJECTIVE: Diagnosing benign vs. malignant extrahepatic cholestasis is challenging despite the currently available advanced imaging and endoscopic techniques. This study aims to determine the predictive accuracy of initial biochemical data and bile duct dilatation findings in transabdominal ultrasound (US) to differentiate between benign and malignant disease in patients with extrahepatic cholestasis. PATIENTS AND METHODS: We reviewed the case records of 814 patients who had undergone endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (in cases of unsuccessful ERCP) for extrahepatic cholestasis. The etiology of biliary obstruction was determined based on ERCP, endoscopic ultrasonography, radiology, cytology, biopsy, and/or clinical follow-up at one year. The patients were divided into benign and malignant groups according to the underlying etiology of biliary obstruction. A complete biochemical profile, transabdominal ultrasonography at presentation, and other demographic data were recorded. RESULTS: Alkaline phosphatase (p = 0.002), aspartate aminotransferase (p = 0.038), and bilirubin levels were significantly higher in malignant patients. The mean age of patients with malignancy was 69.5 years, vs. 60.6 years in benign patients (p < 0.001). The likelihood of malignancy increased with the increased bilirubin levels (> 200 µmol/l: 30.0% sensitivity, 97.6% specificity). The total bilirubin level predicting malignancy as the best cut-off value was 111 mmol/L with optimum sensitivity and specificity (61.8% and 83.8%, respectively) and area under the curve = 0.756, (p < 0.001). Intrahepatic bile duct (IHBD) dilatation was significantly higher in malignant patients (p < 0.001). CONCLUSIONS: A serum bilirubin level of 111 µmol/L or higher and the detection of IHBD dilatation on abdominal ultrasonography are important predictors in the differential diagnosis of benign and malignant causes of extrahepatic cholestasis.

Evaluation of renal arterial resistive index in patients with extrahepatic cholestasis.

OBJECTIVE: Biliary obstruction has been shown to cause acute renal failure. The Renal Resistive Index (RRI) has been recognized to be an important index for evaluating changes in renal plasma flow and renal damage in cholestatic patients. We aimed to investigate the effects of cholestasis on renal hemodynamics in patients with extrahepatic cholestasis by RRI. PATIENTS AND METHODS: The prospective study included patients with extrahepatic cholestasis due to benign biliary stricture, choledocholithiasis, or periampullary tumor between January 1, 2022, and December 31, 2022. Renal and liver function tests, as well as renal doppler ultrasound for RRIs, were conducted before and after cholestasis treatment. RESULTS: Patients who experienced cholestasis resolution after treatment showed lower cholestasis enzymes and bilirubin values and higher glomerular filtration rates compared to pre-treatment values. RRI values significantly decreased in patients with resolved cholestasis compared to pre-treatment levels (p=0.009). Patients with malignant cholestasis had higher RRI values than those with benign cholestasis (p=0.006). Bilirubin levels were higher (p=0.001), and glomerular filtration rates were lower (p=0.046) in patients with malignant cholestasis compared to those with benign cholestasis. CONCLUSIONS: Acute renal injury in cholestatic patients can be demonstrated non-invasively by RRI and is reversible once cholestasis has resolved. Patients with benign cholestasis had lower RRI values than those with cholestasis due to periampullary tumors.

An unusual cause of extrahepatic cholestasis associated with solid liver lesions: a case report.

IgG4-related sclerosing cholangitis is a special type of cholangiopathy often associated with autoimmune pancreatitis. In this article, we report an unusual case of IgG4-SC limited to the common hepatic duct and associated with pseudo tumoral liver lesions, but without evidence of pancreatic involvement. Corticosteroid therapy was rapidly effective and allowed normalization of liver tests.

Does lithium attenuate the liver damage due to oxidative stress and liver glycogen depletion in experimental common bile duct obstruction?

In extrahepatic cholestasis, the molecular mechanisms of liver damage due to bile acid accumulation remain elusive. In this study, the activation of glutamatergic receptors was hypothesized to be responsible for bile acid-induced oxidative stress and liver damage. Recent evidence showed that lithium, as an N-methyl-d-aspartate receptor (NMDAR) GluN2B subunit inhibitor, may act on the glutamate/NMDAR signaling axis. Guinea pigs were assigned to four groups, as sham laparotomy (SL), bile duct ligated (BDL), lithium-treated SL (SL + Li) and lithium-treated BDL (BDL + Li) groups. Cholestasis-induced liver injury was evaluated by aspartate aminotransferase (AST), alanine transaminase (ALT), interleukin-6 (IL-6), tissue malondialdehyde (MDA), copper­zinc superoxide dismutase and reduced glutathione levels. The liability of glutamate/NMDAR signaling axis was clarified by glutamate levels in both plasma and liver samples, with the production of nitric oxide (NO), as well as with the serum calcium concentrations. Blood glucose, glucagon, insulin levels and glucose consumption rates, in addition to tissue glycogen were measured to evaluate the liver glucose-glycogen metabolism. A high liver damage index (AST/ALT) was calculated in BDL animals in comparison to SL group. In the BDL animals, lithium reduced plasma NO and glutamate in addition to tissue glutamate concentrations, while serum calcium increased. The antioxidant capacities and liver glycogen contents significantly increased, whereas blood glucose levels unchanged and tissue MDA levels decreased 3-fold in lithium-treated cholestatic animals. It was concluded that lithium largely protects the cholestatic hepatocyte from bile acid-mediated damage by blocking the NMDAR-GluN2B subunit.

Covered versus uncovered double bare self-expandable metal stent for palliation of unresectable extrahepatic malignant biliary obstruction: a randomized controlled multicenter trial.

BACKGROUND AND AIMS: In a recent randomized controlled trial, a double bare metal stent (DBS) showed better stent patency than single-layer metal stents. However, clear evidence comparing the efficacy of uncovered (UCDBS) and partially covered (PCDBS) DBSs for distal malignant biliary obstruction (MBO) is lacking. Therefore, we compared the clinical outcomes including stent patency of UCDBSs versus PCDBSs. METHODS: A multicenter, randomized study was performed in patients with distal MBO. The primary endpoint was stent patency. Secondary endpoints were the proportion of patients with patent stents at 6 months, risk factors for stent dysfunction, overall survival, technical and clinical success rates of stent placement, and other adverse events (AEs). RESULTS: Among 258 included patients, 130 were randomly assigned to the PCDBS group and 128 to the UCDBS group. The mean duration of stent patency of the PCDBS (421.2 days; 95% confidence interval [CI], 346.7-495.7) was longer than that of the UCDBS (377.4 days; 95% CI, 299.7-455.0), although total stent dysfunction and stent dysfunction within 6 months were not different between groups. Multivariate analysis indicated that chemotherapy after stent placement was a significant factor for overall survival (hazard ratio, .570; 95% CI, .408-.796) and had a marginal impact on stent patency (hazard ratio, 1.569; 95% CI, .923-2.667). There were no remarkable differences in AEs, including pancreatitis, cholecystitis, and stent migration, between the 2 groups. CONCLUSIONS: The use of PCDBSs compared with UCDBSs in patients with distal MBO has unclear benefits regarding stent patency and overall survival, although PCDBSs have a lower rate of tumor ingrowth. (Clinical trial registration number: NCT02937246.).

An infrequent cause of cholestasis: morphine-induced cholestasis / [Una causa infrecuente de colestasis extrahepática: colestasis inducida por morfina.]

Introduction: Extrahepatic cholestasis by opiates is a very rare entity of which only case reports are recorded in the literature. Methods: We present the case of a patient who developed abdominal pain and cholestasis after consumption of high doses of morphine for pain management of her underlying disease, treated by laparoscopic surgery. Results: The patient evolved favorably in the postoperative period without bilirrhage and was discharged on the fifth day with bilirubin values ​​within normal parameters. Conclusion: Sphincter of Oddi dysfunction syndrome secondary to long-term use of opioids is a very rare entity. However, it should be suspected in cases of extrahepatic cholestasis in which no stones or tumors are observed and in patients with long-term use of high-dose opiates either due to addiction or chronic pain treatment.

Introducción: La colestasis extrahepática producida por opiáceos es una entidad sumamente infrecuente de la cual solo se registran reportes de casos en la literatura. Métodos: Se presenta el caso clínico de una paciente que desarrolló dolor abdominal y colestasis luego del consumo prolongado de morfina a altas dosis, tratada por cirugía laparoscópica. Resultados: La paciente evoluciona favorablemente en el postoperatorio sin bilirragia y es dada de alta al quinto día con valores de bilirrubina dentro de los parámetros normales. Conclusión: El síndrome de disfunción del esfínter de Oddi secundario a consumo por tiempo prolongado de opioides es una entidad muy infrecuente. Sin embargo, debe sospecharse ante cuadros de colestasis extrahepáticas en los que no se observe litiasis ni tumores y en pacientes con consumo de opiáceos a altas dosis por tiempo prolongado ya sea por adicción o por tratamiento del dolor crónico.

Development and validation of a risk score for predicting clinical success after endobiliary stenting for malignant biliary obstruction.

BACKGROUND: Endoscopic drainage is the primary treatment for unresectable malignant biliary obstruction (MBO). This study developed and validated a pre-endoscopic predictive score for clinical success after stent placement. METHODS: Patients with unresectable MBO undergoing ERCP-guided endobiliary stent placement between 2007 and 2017 were randomly divided into derivation (n = 383) and validation (n = 128) cohorts. To develop the risk score, clinical parameters were built by logistic regression to predict (1) ≥ 50% total bilirubin (TB) resolution within 2 weeks and (2) bilirubin normalization (TB level <1.2 mg/dL) within 6 weeks following stenting. The scoring scheme was applied to the validation cohort to test its performance. RESULTS: A ≥ 50% TB resolution within 2 weeks was shown in 70.5% of cases. The risk scoring scheme had areas under the receiver operating characteristic curve (AUROC) of 0.70 (95% CI, 0.64-0.76) and 0.67 (95% CI, 0.57-0.77) in the derivation and validation cohorts, respectively. Thirty-one percent had TB normalization within 6 weeks after stenting. Significant predictors for TB normalization were extrahepatic biliary obstruction (odds ratio [OR] = 2.35), pre-endoscopic TB level (OR = 0.88), and stent type (OR = 0.42). The AUROC of a risk score for predicting TB normalization within 6 weeks was 0.78 (95% CI, 0.72-0.83) and 0.76 (95% CI, 0.67-0.86) in the derivation and validation cohorts, respectively. A score > 1.30 yielded a specificity of 98% and a positive predictive value of 84% for predicting TB normalization. A score of < -4.18 provided a sensitivity of 80%-90% and a negative predictive value of 90%-93% for predicting the absence of TB normalization. CONCLUSIONS: The pre-endoscopic scoring system comprising biliary obstruction level, liver biochemistry, and type of stent provides prediction indices for TB normalization within 6 weeks after stenting. This scheme may help endoscopists identify patients with unresectable MBO suited for palliative stenting.

Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model.

The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. We evaluated whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. As cholestasis progressed to day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and tumor necrosis factor-like weak induced apoptosis receptor (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. We revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis.

Features of Ductular Reaction in Rats with Extrahepatic Cholestasis.

Ductular reaction develops during liver regeneration, fibrosis, and carcinogenesis. However, the types, stages of formation, and topography of ductular profiles in various pathologies remain insufficiently studied. Using the model of common bile duct occlusion, we showed that the number and topography of ductular profiles are closely related to the duration of biliary obstruction. The ductular profiles can be located inside the portal tract, along the existing bile ducts, and/or intramurally, around the portal vein, periportally, inside the lobules, in the portocaval fibrous connections, in the adventitia of the hepatic veins, in the septs connecting the portal tracts, and also in the "portal plate" of the liver. The ductular profiles can be formed as a result of expansion of existing bile ducts, cholangiocyte proliferation, as well as transdifferentiation of hepatocytes and activation of mesenchymal stem cells.

Enteral extended biliary stents versus conventional plastic biliary stents for the treatment of extrahepatic malignant biliary obstruction: a single-center prospective randomized controlled study.

BACKGROUND AND AIMS: The main limitation of plastic stents is the relatively short stent patency due to occlusion. We designed enteral extended biliary stents with lengths of 26 cm (EEBS-26 cm) and 30 cm (EEBS-30 cm) to prolong stent patency. This study aimed to compare patency among EEBS-26 cm, EEBS-30 cm, and conventional plastic biliary stent (CPBS). METHODS: A single-center prospective randomized controlled study was conducted. Eligible patients were randomized into the EEBS-26 cm, EEBS-30 cm, and CPBS groups, respectively. All patients were followed up every 3 months until stent occlusion, patient death, or at 12-month follow-up. The primary outcome was stent patency. The secondary outcomes included stent occlusion rate, patient survival, mortality, the rate of technical success, and adverse events. RESULTS: Totally 117 patients were randomized into the three groups. There were no significant differences among the three groups in technical success rate, hospital stay, mortality, patient survival, and adverse events (P = 1.000, 0.553, 0.965, 0.302, and 0.427, respectively). Median stent patency durations in the EEBS-26 cm, EEBS-30 cm, and CPBS groups were 156.0 (95% CI 81.6-230.4) days, 81.0 (95% CI 67.9-94.1) days, and 68.0 (95% CI 20.0-116.0) days, respectively (P = 0.002). The EEBS-26 cm group had longer stent patency compared with the CPBS (P = 0.007) and EEBS-30 cm (P < 0.001) groups. The EEBS-26 cm group had lower stent occlusion rates compared with the other groups at 6 months (48.1% vs. 90.5% vs. 82.8%, P = 0.001) and 9 months (75.0% vs. 100.0% vs. 92.9%, P = 0.022). CONCLUSION: EEBS-26 cm has prolonged stent patency and is safe and effective for the alleviation of unresectable extrahepatic malignant biliary obstruction.

Cholecystectomy in 23 cats (2005-2021).

OBJECTIVE: To describe the clinical presentation, treatments, and long-term outcomes following cholecystectomy in cats. STUDY DESIGN: Clinical retrospective study. ANIMALS: Twenty-three client-owned cats. METHODS: Medical records of all cats undergoing cholecystectomy between 2005 and 2021 at a single referral hospital were retrospectively reviewed. No cats were excluded. An owner questionnaire assessed long-term outcomes. RESULTS: Vomiting, jaundice, and abdominal pain were the most common clinical signs; median duration of signs was 4 days (range 1-21). Cholelithiasis was the major indication for cholecystectomy followed by cholecystitis. Intraoperative hypotension and postoperative anemia were commonly encountered. Nine cats required a postoperative blood product transfusion. Cardiopulmonary arrest and death occurred in five cats. Eighteen cats (78.3%) survived to discharge. Long-term follow up (>60 days) was available for 16 cats at a median of 1003 days (range 81-4995). Fifteen cats survived over 6 months with eight cats (44.4%) surviving over 3 years. The most common short-term and long-term postoperative complication was vomiting. Owners assessed postoperative outcome as excellent in all cats and quality of life as excellent or good. CONCLUSION: The most common indication for cholecystectomy was cholelithiasis. Perioperative complications were commonly encountered. Perioperative mortality rate was 21.7%. Long-term owner evaluation of clinical outcome was considered excellent. CLINICAL SIGNIFICANCE: Cats undergoing cholecystectomy for non-neoplastic causes can have a favorable prognosis for recovery and quality of life. Concurrent extrahepatic biliary duct obstruction is not a contraindication for cholecystectomy provided that patency of the common bile duct is restored.

Percutaneous transhepatic drainage is safe and effective in biliary obstruction-A single-center experience of 599 patients.

BACKGROUND: Historically, surgical bilioenteric bypass was the only treatment option for extrahepatic bile duct obstruction, but with technological advancements, percutaneous transhepatic drainage (PTD) and endoscopic solutions were introduced as a less invasive alternative. Endoscopic methods may lead to a decreasing indication of PTD in the future, but today it is still the standard treatment method, especially in hilar obstructions. METHODS: In our retrospective data analysis, we assessed technical success rate, reintervention rate, morbidity, mortality, and the learning curve of patients treated with PTD over 12 years in a tertiary referral center. RESULTS: 599 patients were treated with 615 percutaneous interventions. 94.5% (566/599) technical success rate; 2.7% (16/599) reintervention rate were achieved. 111 minor and 22 major complications occurred including 1 case of death. In perihilar obstruction, cholangitis were significantly more frequent in cases where endoscopic retrograde cholangiopancreatography had also been performed prior to PTD compared to PTD alone, with 39 (18.2%) and 15 (10.5%) occurrences, respectively. DISCUSSION: The results and especially the excellent success rates demonstrate that PTD is safe and effective, and it is appropriate for first choice in the treatment algorithm of perihilar stenosis. Ultimately, we concluded that PTD should be performed in experienced centers to achieve low mortality, morbidity, and high success rates.

Choledochal stenting for treatment of extrahepatic biliary obstruction in cats.

BACKGROUND: Limited information currently exists regarding the clinical progression and outcomes of cats that undergo choledochal stenting as a treatment for extrahepatic biliary obstruction (EHBO). HYPOTHESIS/OBJECTIVES: Describe clinical characteristics, indications for choledochal stent placement, procedure, and outcomes in a cohort of cats undergoing choledochal stenting and evaluate risk factors associated with survival as well as recurrence of EHBO in affected cats. ANIMALS: Twenty-three client-owned cats undergoing choledochal stent placement. METHODS: Retrospective study. Medical records from 6 academic institutions were reviewed, and data were extracted and analyzed statistically. RESULTS: Median age of cats was 10.1 years (range, 2-16), and all cats had at least 2 clinical signs. Most common clinical signs were vomiting in 20/22 (90.9%), inappetence in 19/22 (86.4%), and lethargy in 19/23 (82.6%). Procedural complications were uncommon and rarely related to the stenting procedure. Clinical signs improved postoperatively in 15/20 (75.0%) cats and serum total bilirubin concentration decreased postoperatively in 13/19 (68.4%) cats. Eighteen (78.3%) cats survived to discharge. Recurrence of EHBO was documented in 7/18 (38.9%) cats that survived to discharge. Cholelithiasis was associated with recurrence of EHBO. Median survival time for cats that survived to discharge was 931 days (range, 19-3034). Absence of peritoneal effusion was associated with survival to discharge. CONCLUSIONS AND CLINICAL IMPORTANCE: Choledochal stenting was an effective treatment modality in cats with EHBO with few procedural complications and potential for prolonged survival, but substantial risk for recurrence of EHBO was identified.

Hypoplasia of Extrahepatic Biliary Tree and Intrahepatic Cholangiolopathy in Cystic Fibrosis Imperfectly Mimic Biliary Atresia in 4 Infants With Cystic Fibrosis and Kasai Portoenterostomy.

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed. Microscopic differences between the gallbladder and extrahepatic bile ducts in cystic fibrosis and sporadic biliary atresia were unequivocal, despite some histologic overlap; no erosive or fibro-obliterative lesions typical of biliary atresia were seen. Common in liver, biopsies were small duct cholangiopathy with intense focal cholangiolitis and massive accumulation of ceroid pigment within damaged cholangiocytes, and in portal macrophages, portal fibrosis, and unequivocal features of large duct obstruction were inconspicuous compared with biliary atresia. Plugs of bile in small ducts tended to be pale and strongly periodic acid-Schiff-reactive in cystic fibrosis. Distinguishing the liver lesion from that of biliary atresia is challenging but possible. Liver biopsies from 2 additional infants with cystic fibrosis and prolonged jaundice that spontaneously resolved showed a similar small duct cholangiopathy. Small gallbladders and extrahepatic ducts challenge surgical judgment as findings in liver biopsies challenge the pathologist. The decision to perform a Kasai procedure is reasonable when mimicry of biliary atresia is grossly complete. We hypothesize that a disorder of bile volume/flow during development and/or early infancy linked to the CFTR mutation alone or in combination with the stresses of neonatal intensive care causes destructive cholangiolitis and intrahepatic reduction of bile flow with secondary hypoplasia of extrahepatic biliary structures.