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Carcinoma of the common bile duct with superficial spread to the intrahepatic segmental bile ducts: a case report.

A 54-year-old woman presented with jaundice. Percutaneous transhepatic biliary drainage, cholangiography via a percutaneous transhepatic biliary, drainage catheter, and percutaneous transhepatic cholangioscopy were performed to alleviate the jaundice and to evaluate her biliary system. A diffuse-type tumor was detected in the common bile duct. The tumor had spread superficially up to the right anterior segmental duct and the left hepatic duct and involved the caudate branches. Curative surgery, which included a right anterior segmentectomy, total caudate lobectomy, and pylorus-preserving pancreatoduodenectomy, was performed. The histopathologic diagnosis was moderately differentiated tubular adenocarcinoma originating at the common bile duct. The extent of the superficial spread of the tumor corresponded to our preoperative determination. Her postoperative recovery was uneventful. In this case report, we discuss the accurate preoperative diagnosis and rational surgical treatment of bile duct carcinoma with superficial spread.

Adenocarcinoma↗

Cholesterol crystallization in human gallbladder bile: relation to gallstone number, bile composition, and apolipoprotein E4 isoform.

Patients with multiple cholesterol gallstones are at increased risk of recurrence after nonsurgical therapy, possibly because of fast biliary cholesterol crystallization. Serum apolipoprotein E4 (apo E4) is a risk factor for primary cholesterol gallstone formation as well as recurrence. We examined potential effects of stone number and apolipoprotein E genotype on crystallization and on various crystallization-influencing factors in gallbladder biles of 36 cholesterol stone patients (25 multiple stones: 10 carrying the epsilon4 allele). Biliary cholesterol saturation, bile salt composition or concentrations of total protein, immunoglobulin (Ig)A, IgG, alpha1-acid glycoprotein, haptoglobin, or mucin--all crystallization promoters--did not differ between multiple and solitary stone patients, apparently not explaining different speed of crystallization (crystal observation time 3.5 +/- 0.6 days vs. 12.7 +/- 2.4 days, respectively; P = .0003). In contrast, biliary aminopeptidase-N activities (2,607 +/- 592 mU/mL vs. 947 +/- 185 mU/mL; P = .04) were higher and IgM levels (179 +/- 39 vs. 65 +/- 8 mg/L; P = .09) tended to be higher in the case of multiple stones. Although patients carrying the epsilon4 allele had similar stone numbers and crystallization as patients without the epsilon4 allele, their cholesterol saturation index (CSI) was lower (1.08 +/- 0.09 vs. 1.54 +/- 0.13; P = .01), whereas total protein and bile salt concentrations tended to be higher with preferential taurine-conjugation. In conclusion, fast cholesterol crystallization is associated with multiple stones but not with apolipoprotein E4. Whereas fast crystallization may contribute to high recurrence rates after nonsurgical therapy in case of multiple gallstones, the mechanism for increased risk of gallstone formation in patients carrying the epsilon4 allele remains unknown.

Apolipoprotein E4↗

The use of tandem mass spectrometry for the differentiation of bile acid isomers and for the identification of bile acids in biological extracts.

Tandem mass spectrometric (MS/MS) techniques hae been widely used for the differentiation of isomeric compounds, since their spectra may show differences sufficient to distinguish between them. There are several different ways by which the MS/MS data can be obtained depending on the energies of the ions and the collisions. In this paper MS/MS spectra have been obtained for a group of isomeric bile acids using: 1, low-energy ions and low-energy collisions in a triple quadrupole mass spectrometer by liquid chromatography/MS/MS; 2, high-energy ions and low-energy collisions in a hybrid mass spectrometer by fast-atom bombardment MS/MS. Liquid chromatography combined with tandem mass spectrometry (LC/MS/MS) has also been used to identify the bile acids present in biological matrices such as bile extracts.

Animals↗

Ionic flux and mucosal ultrastructure in the rat bile-pancreatic duct. Effect of bile salt perfusion on duct integrity.

The property of the pancreatic ductal system that restricts free ionic diffusion has been termed the "pancreatic duct mucosal barrier," damage to which may be important in the pathogenesis of acute gallstone pancreatitis. The bile-pancreatic duct of the rat (BPD) was perfused in situ with a standard ionic solution. The normal duct was permeable to both chloride and bicarbonate ions, and flux (JCl-, JHCO3-) appeared to occur by passive ionic diffusion. Measurement of absolute ionic flux and transductal potential difference (PD) gave control values of JCl-, +0.92 +/- 0.15 mumol/cm/hr; JHCO3-, -1.71 +/- 0.12 mumol/cm/hr; PD -2.3 +/- 0.20 mV. The preparation was stable over the experimental period, and the results obtained were reproducible between animals. Glycodeoxycholate compromised the integrity of the BPD with an increase in ionic flux and a reduction in PD with corresponding alterations in mucosal ultrastructure. Increasing concentrations of bile salt produced more severe damage to the BPD. The BPD of the rat is therefore analogous to the pancreatic duct of the cat in possessing a mucosal barrier, and the barrier is damaged by bile salts. This preparation may be useful for studying pancreatic duct integrity, a concept of importance in the pathogenesis of acute gallstone pancreatitis.

Animals↗

Bacteria in bile of patients with bile duct inflammation.

Bile samples taken intraoperatively from 100 patients with three different bile system diseases were subjected to bacteriological analysis. Statistically significant differences between the types of aerobic and anaerobic bacteria present in the bile were found.

Bacteria↗

Effect of 7-methylated bile acids and bile alcohols on cholesterol metabolism in hamsters.

The effect of 7-methyl substituted bile acid and bile alcohol analogues on cholesterol metabolism was studied in the hamster. Animals were fed chow plus 0.1% cholesterol supplemented with 0.1% of one of the following steroids: chenodeoxycholic acid, 7-methyl-chenodeoxycholic acid, 7 beta-methyl-24-nor-5 beta-cholestane-3 alpha, 7 alpha, 25-triol, cholic acid, 7-methyl-cholic acid, or 7 beta-methyl-24-nor-5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25-tetrol. Cholesterol absorption was determined from fecal analysis after feeding of radiolabeled cholesterol and beta-sitosterol. Of the six compounds studied, chenodeoxycholic acid and 7-methyl-chenodeoxycholic acid decreased intestinal cholesterol absorption (17% and 31% decrease, respectively). Only 7-methyl-chenodeoxycholic acid decreased serum cholesterol concentration (29% decrease), but there were no analogous changes of liver and biliary cholesterol concentration and cholesterol saturation of bile. Total fecal neutral sterol excretion was increased in the groups fed chenodeoxycholic acid and 7-methyl-chenodeoxycholic acid. In addition, the production of coprostanol was increased in both groups. These data suggest that 7-methyl-chenodeoxycholic acid resembles chenodeoxycholic acid in its effect on cholesterol metabolism and may be a potential candidate for further studies of its gallstone-dissolving properties.

Animals↗

Ursodeoxycholate further increases bile-duct cell proliferative response induced by partial bile-duct ligation in rats.

BACKGROUND: Bile salts (BSs) stimulate cholangiocyte proliferation in vitro and in vivo in normal rats. In this study, we evaluated the effects of BS-enriched diets on cholangiocyte proliferative activity already triggered by partial bile-duct ligation (pBDL), a surgical model that induces mild cholestatic conditions, focusing our attention on ursodeoxycholate (UDC). METHODS: Animals (n=45) were fed either a standard diet, or a 0.2% deoxycholate- or 0.2% UDC-enriched diet for 4 weeks. Then, in each group, ten animals underwent pBDL and five underwent sham operation. Serum and biliary BS levels, serum cholestasis and cytolysis indexes, as well as liver conventional histology, apoptosis and proliferative activity were evaluated 48 h after the operation. RESULTS: Animals that underwent pBDL showed sustained proliferative response compared with sham-operated rats. BS-enriched diets did not influence cholangiocyte proliferation in sham-operated rats. However, significantly increased proliferation was observed in pBDL rats fed a UDC-enriched diet. The evaluation of humoral and histological parameters excluded the possibility that the increased proliferation induced by UDC-enriched diet could be related to concomitant liver cell damage. CONCLUSION: A UDC-enriched diet is able to amplify the magnitude of the cholangiocyte hyperplastic process, which occurs by a stimulatory mechanism after partial bile-duct ligation.

Administration, Oral↗

Low conjunction of the cystic duct with the common bile duct: does it correlate with the formation of common bile duct stones?

BACKGROUND: This study aimed to evaluate the accuracy of magnetic resonance cholangiography (MRC) in detecting variants of low cystic duct conjunction, which can be a source of confusion during surgery when unrecognized. METHODS: All cases with both MRC and endoscopic retrograde cholangiography (ERC) indicating suspected common bile duct stones between January 1999 and January 2004 were retrospectively reviewed by investigators blinded to the final diagnosis. Assessment with ERC was regarded as the gold standard. The aim was to find a low conjunction of the cystic duct with the bile duct. The sensitivity and specificity of MRC were calculated in comparison with those for ERC. The cystic junction radial orientation was defined as lateral (insertion diagonally from the right), medial (insertion into the left side of the common hepatic duct), or posteroanterior (overlap of the junction with the bile duct in the posteroanterior view). A spiral cystic duct and a long parallel course were evaluated separately. RESULTS: Low insertion of the cystic duct was found on ERC in 66 of 622 patients (11%; 28 men and 38 women; mean age, 64.5 years). The sensitivity and specificity of MRC for detecting low cystic entrance were 100% (90.4% on an intention-to-diagnose basis and 100%, respectively). In 11 patients (16.6%), the radial orientation of the cysticohepatic junction could not be defined with MRC. The rate of correct MRC delineation was 95% for lateral (n = 21), 77% for medial (n = 26), and 74% for posteroanterior (n = 19) insertion of the cystic duct. CONCLUSION: The findings showed that MRC has good correlation with ERC with regard to the location and anatomic details of cystic duct insertion. Although this does not generate a separate indication for MRC before laparoscopic cholecystectomy, the anatomic information can be of additional use when MRC is clinically indicated in this setting.

Aged↗

Capillary gas chromatographic determinations of urinary bile acids and bile alcohols in CTX patients proving the ineffectivity of ursodeoxycholic acid treatment.

Urine samples and serum samples of a patient with cerebrotendinous xanthomatosis (CTX) were investigated by means of capillary gas chromatography, both before and during oral treatment with ursodeoxycholic acid (UDCA), and the results compared with those obtained during chenodeoxycholic acid (CDCA) therapy. The predominantly excreted bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and two abnormal bile acids, i.e. 23-norcholic acid and 23-hydroxycholic acid were determined. In addition, the serum cholestanol/cholesterol ratio was determined. Whereas previous experiments demonstrated that the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and the abnormal bile acids decreased within a few weeks during CDCA therapy, the present study shows that their urinary excretions remain essentially the same during UDCA treatment. In contrast to the decrease in the serum cholestanol/cholesterol ratio during CDCA therapy, this ratio remains essentially the same during UDCA therapy. It is therefore concluded that, in contrast to CDCA therapy, UDCA treatment is not effective in the treatment of CTX.

Bile Acids and Salts↗

Identification of bile alcohols in normal rabbit bile.

Rabbit bile was examined for bile alcohols. Using combined gas chromatography-mass spectrometry, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25,26-pentol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25--tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,24 beta-tetrol, 24-methyl-25-homo-5 beta-cholane-3 alpha, 7 alpha, 12 alpha, 24-tetrol, and 5 alpha-cholestane-3 alpha, 7 alpha, 12 alpha, 24 beta-tetrol were identified as the minor constituents of normal rabbit bile.

Animals↗

Bile acids, LXXIX. Synthesis and reduction of 1,4-dien-3-ones of various bile acids.

1,4-Dien-3-ones of various bile acids (IIa-d), their methyl esters (IIe-h), and their formylated derivatives (IIi-k) were synthesized and their reduction investigated by both catalytic and chemical methods as an alternative route to the synthesis of allo bile acids. Lithium-ammonia reduction proved to be the better method for the reduction of these 1,4-dien-3-ones producing the 3-keto- and 3 beta-hydroxy-allo bile acids (Vb-d) and (VIb-d) in 66-72% yields.

Ammonia↗

Development of bile acid metabolism: effect of glucocorticoids on bile acid metabolism in the neonatal rat.

The objective of this study was to examine the effect of glucocorticoid treatment in early neonatal life on plasma cholesterol and hepatic cholesterol 7 alpha-hydroxylase (CH-7A), the rate-limiting enzyme of bile acid biosynthesis from cholesterol, measured at weaning (Postnatal Day 20). Neonatal rat pups were injected subcutaneously with 5 micrograms of dexamethasone (DEXA) or vehicle (CON) for 5 days between Postnatal Days 4 and 8. On Postnatal Day 20, the animals were used for various studies. DEXA-treated pups weighed significantly less (P less than 0.001) than controls. Even though DEXA-treated animals had significantly smaller livers (P less than 0.001), microsomal protein per gram of liver was significantly greater (P less than 0.005) in the DEXA-treated animals. CH-7A activity (pmole/mg . min) was significantly lower (P less than 0.005) in the DEXA-treated animals (CON (4) 19.4 +/- 2.8; DEXA (4) 5.0 +/- 1.0). Plasma cholesterol (mg/100 ml) was significantly greater (P less than 0.005) in the DEXA-treated animals (CON (5) 179 +/- 7; DEXA (4) 223 +/- 5), a finding consistent with lower CH-7A activity in this group. Taurocholate absorption by in situ ileal loops in anesthetized rats was significantly greater in the DEXA-treated animals in agreement with the in vitro observations of Little and Lester. The basis for the reduced CH-7A activity in DEXA-treated pups is not known. It may be due in part to a new steady state in the enterohepatic circulation of bile acids resulting from a glucocorticoid-induced enhanced conservation of bile acids.

Animals↗

Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells.

Bile acids, which have been implicated in gastrointestinal-tract cell carcinogenesis, share properties with tumor promoters in that both affect signal transduction pathways responsible for cell proliferation and apoptosis. In the present study, we demonstrate that EGFR-ERK1/2 is activated following treatment of AGS human gastric carcinoma cells with bile acids. EGFR phosphoactivation is ligand-dependent, since treatment of cells with HB-EGF antisera or CM197 (a selective inhibitor of HB-EGF) markedly inhibits deoxycholate (DC)-promoted activation. Membrane-type bile acid receptor (M-BAR)/TGR5 is a recently identified G-protein-coupled receptor (GPCR). In AGS cells, siRNAs that target M-BAR suppress DC-induced phosphorylation of EGFR. Furthermore, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results suggest that in AGS cells, DC transactivates EGFR through M-BAR- and ADAM/HB-EGF-dependent mechanisms.

Adenocarcinoma↗

Bile duct of Luschka leading to bile leak after cholecystectomy--revisiting the biliary anatomy.

Bile ducts of Luschka (also called supravesicular ducts) are small bile ducts in the gallbladder bed. Although they do not drain any liver parenchyma, they can be a source of bile leak or biliary peritonitis after cholecystectomy in both adults and children, as shown in this case report. As a reminder, variations of biliary anatomy in the gallbladder bed and cholecysto-hepatic triangle of Calot, are reviewed.

Bile Ducts↗

Bile lithogenicity and gallbladder emptying in patients with microlithiasis: effect of bile acid therapy.

BACKGROUND & AIMS: Biliary cholesterol supersaturation, rapid nucleation of cholesterol, and altered gallbladder motility are prerequisite for gallstone formation. However, the pathogenesis of microlithiasis is not clear. The aim of this study was to determine the abnormalities of gallbladder emptying and bile composition in patients with microlithiasis. METHODS: Nucleation time, cholesterol saturation index (CSI), and gallbladder emptying were studied in patients with microlithiasis (n = 10), patients with gallstones (n = 10), and healthy volunteers (n = 10). Bile analysis was repeated in 6 patients with microlithiasis treated with ursodeoxycholic acid (UDCA) for 8 weeks. RESULTS: Nucleation time was shorter in patients with microlithiasis and those with gallstones than in healthy volunteers (P < 0.0001). Patients with microlithiasis had longer nucleation time than those with gallstones (P < 0.001). There was no difference in cholesterol levels and CSI in gallstone and microlithiasis patients. However, healthy volunteers had lower cholesterol levels (P < 0.01) and CSI (P < 0.01). Patients with microlithiasis had prolongation of nucleation time (P < 0.001) and lowering of CSI (P < 0.001) after UDCA therapy. Gallbladder ejection fraction was higher in microlithiasis patients than in gallstone patients (P < 0.01) but lower than in healthy volunteers (P < 0.01). CONCLUSIONS: Patients with microlithiasis have longer nucleation time and better gallbladder emptying than patients with gallstones. Bile abnormalities can be successfully corrected with UDCA therapy in patients with microlithiasis.

Adult↗

Studies of cholesterol and bile acid metabolism, and early atherogenesis in hamsters fed GT16-239, a novel bile acid sequestrant (BAS).

The purpose of this study was to compare the efficacy of GT16-239, an alkylated, cross-linked poly(allylamine) bile acid sequestrant with cholestyramine on cholesterol and bile acid metabolism, and early aortic atherosclerosis in hypercholesterolemic male F1B Golden Syrian hamsters. In this controlled study, 42 hamsters were divided into six groups and were fed a chow-based hypercholesterolemic diet supplemented with a 10% oil blend (55% coconut/45% corn), 0.1% cholesterol (w/w) (control) and either 0.9 or 1.2% cholestyramine or 0.2, 0.4 or 0.6% GT16-239 for 13 weeks. Laboratory analyses included evaluating plasma lipoprotein cholesterol and triglyceride concentrations, hepatic HMG-CoA reductase and 7 alpha-hydroxylase activities, fecal excretion of bile acids and neutral sterols, hepatic cholesterol concentrations, and early atherosclerosis (aortic fatty streak area). Relative to the control diet, the 0.6% GT16-239 versus the 1.2% cholestyramine significantly inhibited the elevation of plasma lipoprotein total cholesterol (TC) (-69% vs -40%), high density lipoprotein-cholesterol (HDL-C) (-49% vs -30%), and non-HDL-C (-81 vs -48%) concentrations; increased the activities of both HMG-CoA reductase (1492% vs 62%) and 7 alpha-hydroxylase (175% vs 86%); lowered the concentration of hepatic cholesteryl ester (-94% vs -59%); increased fecal cholesterol concentration (+28% vs -10%); and decreased aortic fatty streak area (-100% vs -86%). Unexpected findings of this comparison were increased fecal concentrations of cholic acid (533%) and chenodeoxycholic acid (400%) and the reduction in lithocholic acid (-50%) in the 0.6% GT16-239 compared to the 1.2% cholestyramine group. In summary, GT16-239 had a greater impact on cholesterol metabolism and early atherosclerosis in hypercholesterolemic hamsters than cholestyramine.

Allylamine↗

Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile acid transport system.

To increase hepatoselectivity of HMG-CoA reductase inhibitors by using the specific bile acid transport systems, deoxycholic acid-derived inhibitors 9 and 11 have been synthesized, on the basis of the concept of combining in one molecule structural requirements for specific inhibition of the HMG-CoA reductase and specific recognition by the ileal bile acid transport system. The 1-methyl-3-carboxylpropyl subunit of deoxycholic acid was replaced by the 3,5-dihydroxyheptanoic acid lactone of lovastatin, and position 12-OH was esterified with 2-methylbutyric acid. Compounds 9 and 11 were evaluated for their inhibitory activity on rat liver HMG-CoA reductase, cholesterol biosynthesis in HEP G2 cells, and [3H]taurocholate uptake in rabbit brush border membrane vesicles and compared with methyl derivatives 8 and 10. The steroidal 21-CH3 group affects both activity on HMG-CoA reductase and recognition by the ileal bile acid transport system.

Androstanols↗

Comparative studies of bile salts. 16-Deoxymyxinol, a second bile alcohol from hagfish.

1. Material containing the less polar sulphate previously noticed in hagfish bile salts gave, after dioxan-trichloroacetic acid cleavage, 16-deoxymyxinol [3beta,7alpha,-26(27)-trihydroxy-5alpha-cholestane]. 2. Anodic coupling of 3beta-hydroxy-5beta-cholanoic acid and the mixed half esters of dl-methylsuccinic acid, followed by lithium aluminium hydride reduction, yielded 3beta,26(27)-dihydroxy-5beta-cholestane. 3. 16-Deoxymyxinol, the third known bile alcohol having the 3beta-hydroxy-5alpha-hydrogen configuration, poses again the question of how the 3beta-hydroxyl group of cholesterol can be ;retained' in biosynthesis of primitive bile salts.

Alcohols↗