Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2.
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We have proposed previously that the evaluation of transcellular transport across the double-transfected Madin-Darby canine kidney II (MDCK II) monolayer that expresses both human organic anion transporting polypeptide 4 (OATP2/SLC21A6) and multidrug resistance associated protein 2 (MRP2/ABCC2) on the basal and apical membranes, respectively, may be useful in characterizing human biliary excretion (J Biol Chem 277: 6497-6503, 2002). However, to demonstrate that this in vitro system represents in vivo biliary excretion, it is essential to compare in vitro data with in vivo biliary excretion. The problem is that we cannot determine the human biliary excretion for many ligands. In the present study, we have established a double-transfected MDCK II monolayer that expresses both rat Oatp4/Slc21a10 and Mrp2/Abcc2 on the basal and apical membranes, respectively, for the purpose of quantitatively comparing the clearance for transcellular transport with that for in vivo biliary excretion. The basal-to-apical transport of 17beta-estradiol-17beta-d-glucuronide, pravastatin, leukotriene C(4), cyclo-[D-Asp-Pro-d-Val-Leu-d-Trp] (BQ123), temocaprilat, and taurolithocholate 3-sulfate was significantly higher than that in the opposite direction in the double transfectant. Kinetic analysis suggested that that the rate-determining step of these compounds is the uptake process. The extent of the transcellular transport across the rat double-transfectant correlated well with that across the double-transfectant for human OATP2/SLC21A6 and MRP2/ABCC2. Moreover, considering the scaling factor, the clearance values for in vitro transcellular transport correlated well with those for in vivo biliary clearance. The double-transfected MDCK II monolayer may be useful in analyzing the hepatic vectorial transport of organic anions and in predicting in vivo biliary clearance. (+info)
Ursodeoxycholic acid-augmented hepatobiliary scintigraphy in the evaluation of neonatal jaundice.
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Early differentiation of extrahepatic biliary atresia from intrahepatic cholestasis is important. Hepatobiliary scintigraphy is an excellent noninvasive investigation for ruling out extrahepatic biliary atresia. This study aimed at identifying the role of ursodeoxycholic acid (UDCA), a choleretic agent, in conjunction with hepatobiliary scintigraphy in differentiating extrahepatic biliary atresia from neonatal hepatitis. METHODS: Fifty-one infants (42 male, 9 female) aged 0.3-5.5 mo (mean, 2.9 mo) presenting with neonatal jaundice underwent 99mTc-mebrofenin hepatobiliary scintigraphy. For patients who did not show any excretion of tracer into the intestine till 24 h, the study was repeated after oral administration of UDCA (20 mg/kg every 12 h) for 48-72 h. Ultrasonography and, if required, liver biopsy and intraoperative cholangiography were used with clinical data such as stool color and serologic and other etiologic investigations to form a final diagnosis. RESULTS: Of 51 patients, 19 showed biliary excretion in the first study, ruling out extrahepatic biliary atresia. Neonatal hepatitis was the final diagnosis in these. Of the remaining 32 patients, 12 nonexcretors converted to excretors after UDCA treatment, whereas 20 still showed no biliary drainage. Four nonexcretors on scintigraphy had a final diagnosis of neonatal hepatitis with galactosemia; the remaining 16 had extrahepatic biliary atresia. The specificity of hepatobiliary scintigraphy in ruling out extrahepatic biliary atresia improved from 54.3% to 88.6% (P < 0.001) after UDCA treatment. None of the patients experienced any ill effects from UDCA administration. CONCLUSION: Pretreatment with UDCA significantly improves the specificity of hepatobiliary scintigraphy in ruling out extrahepatic biliary atresia as a cause of prolonged neonatal jaundice. (+info)
Liver transplant donor candidates: associations between vascular and biliary anatomic variants.
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Our objective was to investigate the coexistence of vascular and biliary anatomic variants, the latter of which are known to increase the risk of biliary complications in living liver donor transplantation. A total of 108 consecutive liver donor candidates were examined by magnetic resonance (MR) imaging that included 2 MR cholangiography methods, T2-weighted MR cholangiography and mangofodipir-enhanced T1-weighted three-dimensional (3D) MR cholangiography, as well as gadolinium-enhanced MR angiography and venography of the liver. Images were interpreted by at least 2 investigators in consensus for definition of hepatic arterial, portal venous, and biliary anatomy. A subset of 51 subjects underwent laparotomy for right hepatectomy. Of the 108 subjects examined, 50 (46%) demonstrated normal hepatic artery, portal vein, and biliary anatomy. Variants of the hepatic artery were found in 27 of 108 (25%) subjects, of the portal vein in 12 of 108 (11%) subjects, and of the bile ducts in 30 of 108 (28%) subjects. Of the 27 subjects with hepatic arterial variants, 8 (30%) also had variant biliary anatomy. The association between hepatic arterial variants and biliary variants was not statistically significant (P >.5). However, of the 12 subjects with portal vein variants, 7 (58%) had biliary variants, and in 6 of 7 cases, the right posterior hepatic duct was anomalous. By chi-square analysis, the association between portal venous and biliary variants was significant (P =.012). In conclusion, over half of subjects with portal vein variants were found to have anomalous biliary anatomy, which always involved the hepatic ducts of the right lobe. The association between portal venous and biliary variants is statistically significant, while there is no significant association between hepatic arterial and biliary variants. (+info)
Use of CT cholangiography to evaluate the biliary tract after liver transplantation: initial experience.
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Evaluation of the biliary tract after liver transplantation, particularly when a Roux-en-Y hepatojejunostomy precludes endoscopic retrograde cholangiography, may be challenging. We present five cases of suspected biliary obstruction after liver transplantation in which multidetector-row computed tomography (CT) cholangiography was used. In conclusion, it was determined that multidetector-row CT cholangiography may be a useful modality for demonstrating patent biliary-enteric anastomoses and excluding flow-limiting biliary anastomotic strictures. (+info)
Cholangiography following common duct drainage.
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In a series of 197 patients with extrahepatic biliary disease, 65 who had symptoms that met certain established criteria were operated upon to explore the common bile duct for stones. Stones or debris were found in 34 cases. Certain phases of the procedure used are being reevaluated.Because of unsatisfactory results with immediate cholangiograms, they were made only in selected cases in which the anticipated advantages outweighed the known disadvantages. Delayed cholangiography (10 or 12 days postoperatively) is considered a "must," however, for determination of the presence of remaining stones. If residual stones are shown, they are removed as soon as possible. (+info)
Biliary dysgenesis in the PCK rat, an orthologous model of autosomal recessive polycystic kidney disease.
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Hepatic polycystic disease occurs alone or in combination with polycystic kidney disease (PKD). In autosomal recessive PKD (ARPKD), liver lesions are the major cause of morbidity and mortality in older patients. ARPKD is caused by a mutation to PKHD1 and the PCK rat is an orthologous model of disease. Recently, we showed that fibrocystin, Pkhd1 protein, is localized to primary cilia in rat cholangiocytes and that disruption of its ciliary expression results in biliary cystogenesis. This study describes biliary phenotype in the PCK rat using micro-computed tomography scanning and three-dimensional reconstruction, and light, scanning, and transmission microscopy. Our results show that the biliary tree undergoes extensive remodeling resulting in bile duct dilatation, focal budding, and formation of cysts that are initially connected to bile ducts, but throughout time separate from them. Progressive liver enlargement results from massive cyst formation while liver parenchymal volume remains unchanged. Cilia in cystic cells are abnormal consistent with the notion that the primary defect in ARPKD resulting in cystogenesis may be linked to ciliary dysfunction. Our results suggest that the PCK rat is a useful model for studies of biliary cystogenesis and treatment options of inherited cystic liver disease. (+info)
Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy.
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The Alagille Syndrome (AGS) is a heritable disorder affecting the liver and other organs. Causative dominant mutations in human Jagged 1 have been identified in most AGS patients. Related organ defects occur in mice that carry jagged 1 and notch 2 mutations. Multiple jagged and notch genes are expressed in the developing zebrafish liver. Compound jagged and notch gene knockdowns alter zebrafish biliary, kidney, pancreatic, cardiac and craniofacial development in a manner compatible with an AGS phenocopy. These data confirm an evolutionarily conserved role for Notch signaling in vertebrate liver development, and support the zebrafish as a model system for diseases of the human biliary system. (+info)
Multiple transport systems mediate the hepatic uptake and biliary excretion of the metabolically stable opioid peptide [D-penicillamine2,5]enkephalin.
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Rapid and extensive biliary excretion of [D-penicillamine2,5]enkephalin (DPDPE) in rats as the unchanged peptide suggests that multiple transport proteins may be involved in the hepatobiliary disposition of this zwitterionic peptide. Although DPDPE is a P-glycoprotein substrate, the role of other transport proteins in the hepatic clearance of DPDPE has not been established. Furthermore, the ability of various experimental approaches to quantitate the contribution of a specific hepatic uptake or excretion process when multiple transport systems are involved has not been addressed. 3H-DPDPE uptake in suspended Wistar rat hepatocytes was primarily (>95%) due to temperature-dependent transport mechanisms; similar results were obtained in suspended hepatocytes from Mrp2-deficient (TR-) rats. Pharmacokinetic modeling revealed that saturable and linear processes were involved in 3H-DPDPE uptake in hepatocytes. The use of transport modulators suggested that hepatic uptake of 3H-DPDPE was mediated by Oatp1a1, Oatp1a4, and likely Oatp1b2. Accumulation of 3H-DPDPE in sandwich-cultured (SC) hepatocytes was rapid; uptake of 3H-DPDPE in SC rat hepatocytes from control and TR- rats was similar. However, the biliary excretion index and biliary clearance decreased by 83 and 85%, respectively, in TR- SC rat hepatocytes, indicating that DPDPE is an Mrp2 substrate. Rate constants for uptake and excretion of 3H-DPDPE in SC rat hepatocytes were determined by pharmacokinetic modeling; data were consistent with basolateral excretion of 3H-DPDPE from the hepatocyte. These results demonstrate the complexities of hepatobiliary disposition when multiple transport mechanisms are involved for a given substrate and emphasize the necessity of multi-experimental approaches for the comprehensive resolution of these processes. (+info)