Osteopontin induces ductular reaction contributing to liver fibrosis.

OBJECTIVE: In human chronic liver disease, there is association between ductular reaction (DR) and fibrosis; yet, the mechanism triggering its onset and its role in scar formation remains unknown. Since we previously showed that osteopontin (OPN) is highly induced during drug-induced liver fibrosis, we hypothesised that OPN could drive oval cells (OC) expansion and DR and signal to hepatic stellate cells (HSC) to promote scarring. RESULTS: In vivo studies demonstrated increased OPN expression in biliary epithelial cells (BEC) and in OC in thioacetamide (TAA)-treated mice. OPN ablation protected mice from TAA and bile duct ligation-induced liver injury, DR and scarring. This was associated with greater hepatocyte proliferation, lower OC expansion and DR along with less fibrosis, suggesting that OPN could activate the OC compartment to differentiate into BEC, which could then signal to HSC to enhance scarring. Since TAA-treated wild-type mice and cirrhotic patients showed TGF-ß(+) BEC, which were lacking in TAA-treated Opn(-/-) mice and in healthy human explants, this suggested that OPN could regulate TGF-ß, a profibrogenic factor. In vitro experiments confirmed that recombinant OPN (rOPN) decreases hepatocyte proliferation and increases OC and BEC proliferation. To evaluate how BEC regulate collagen-I production in HSC, co-cultures were established. Co-cultured BEC upregulated OPN and TGF-ß expression and enhanced collagen-I synthesis by HSC. Lastly, recombinant TGF-ß (rTGFß) and rOPN promoted BEC proliferation and neutralisation of OPN and TGF-ß reduced collagen-I expression in co-cultured HSC. CONCLUSIONS: OPN emerges as a key matricellular protein driving DR and contributing to scarring and liver fibrosis via TGF-ß.

Effects of tegaserod on bile composition and hepatic secretion in Richardson ground squirrels on an enriched cholesterol diet.

BACKGROUND: Tegaserod is effective in treating IBS patients with constipation, and does not alter gallbladder motility in healthy individuals or in patients with IBS. However, it is not known if tegaserod affects the biliary tract in gallstone disease, so to this end the effects of tegaserod on bile composition and hepatic secretion of Richardson ground squirrels maintained on an enriched cholesterol diet were examined. RESULTS: Animals were fed either a control (0.03%) or enriched (1%) cholesterol diet for 28 days, and treated s.c. with tegaserod (0.1 mg/kg BID) or vehicle. Bile flow, bile acid, phospholipids and cholesterol secretion were measured with standard methods. Tegaserod treatment or enriched cholesterol diet, alone or combination, did not alter body or liver weights. The enriched cholesterol diet increased cholesterol saturation index (CSI), cholesterol concentrations in gallbladder and hepatic duct bile by approximately 50% and decreased bile acids in gallbladder bile by 17%. Tegaserod treatment reversed these cholesterol-induced changes. None of the treatments, drug or diet, altered fasting gallbladder volume, bile flow and bile salts or phospholipid secretion in normal diet and cholesterol-fed animals. However, tegaserod treatment prevented the decreases in bile acid pool size and cycling frequency caused by the enriched cholesterol diet, consequent to re-establishing normal bile acid to concentrations in the gall bladder. Tegaserod had no effect on these parameters with normal diet animals. CONCLUSION: Tegaserod treatment results in increased enterohepatic cycling and lowers cholesterol saturation in the bile of cholesterol-fed animals. These effects would decrease conditions favorable to cholesterol gallstone formation.

Tegaserod does not alter fasting or meal-induced biliary tract motility.

OBJECTIVE: Tegaserod is a 5-HT(4) receptor partial agonist that increases peristaltic activity of the intestinal tract. It is approved for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). IBS is a chronic gastrointestinal disorder of function that is reported to be associated with an increased incidence of abdominal surgery including cholecystectomy. The effect of tegaserod on nongut digestive organs, such as the gallbladder and biliary tract, has not been previously investigated. Therefore, this study aimed to evaluate the effects of tegaserod on gallbladder contractility and on functional status of the sphincter of Oddi during both the interdigestive and the digestive periods in healthy female subjects and in female patients with IBS-C. METHODS: During a 6-wk, double-blind, placebo-controlled crossover study, gallbladder contractility and concomitant change in luminal diameter of the common hepatic duct (CHD) and the common bile duct (CBD, both proximal and distal) in response to a standard liquid meal were quantified using real-time ultrasonography. Changes in luminal diameter of the CHD and the CBD were used as a surrogate marker for sphincter of Oddi function. Ultrasound measurements were conducted every 15 min from 45 min before, to 60 min after the test meal to observe the impact of tegaserod on gallbladder volume and any concomitant change in the diameters of the CHD and the CBD that developed in response to gallbladder contraction. The ultrasound measurements of gallbladder contractility, along with the CHD and the CBD diameters, were repeated after each of the two 2-wk periods of treatment with tegaserod or placebo. The recommended dose of tegaserod (6 mg b.i.d.) for IBS-C patients was used in healthy female subjects (n = 13) and female patients with IBS-C (n = 20). Twice this dose (12 mg b.i.d.) was also evaluated in an additional 20 female patients with IBS-C. Statistical evaluations were conducted using a two-sided analysis of variance (ANOVA). RESULTS: Gallbladder contractility variables including ejection fraction, ejection rate and ejection period, fasting and residual volume, and maximal emptying, were similar after 2 wk of treatment with tegaserod 6 mg b.i.d. and placebo in healthy female subjects and female patients with IBS-C. There were no significant changes in the luminal diameters of the CHD or the CBD after tegaserod compared to placebo in any cohort. Additionally, no significant dilation (> or =7 mm in diameter) of the CHD or CBD was observed during maximal gallbladder emptying. Similar results were also observed when tegaserod was given at 12 mg b.i.d. in patients with IBS-C. Tegaserod treatment had no significant effect on plasma CCK concentration in response to the test meal. No significant abdominal pain or unexpected adverse events were reported during the study. CONCLUSIONS: This study showed no significant pharmacodynamic effect of tegaserod on gallbladder contractility or on CBD and CHD diameters as a surrogate marker of sphincter of Oddi function during both the interdigestive (fasting) and the digestive (postprandial) periods in healthy female subjects and female patients with IBS-C.

Combined external beam and intraluminal radiotherapy for irresectable Klatskin tumors.

BACKGROUND: In most cases of proximal cholangiocarcinoma, curative surgery is not possible. Radiotherapy can be used for palliative treatment. We report our experience with combined external beam and intraluminal radiotherapy of advanced Klatskin's tumors. PATIENTS AND METHODS: 30 patients were treated for extrahepatic proximal bile duct cancer. Our schedule consisted of external beam radiotherapy (median dose 30 Gy) and a high-dose-rate brachytherapy boost (median dose 40 Gy) delivered in four of five fractions, which could be applied completely in twelve of our patients. 15 patients in the brachytherapy and nine patients in the non-brachytherapy group received additional low-dose chemotherapy with 5-fluorouracil. RESULTS: The brachytherapy boost dose improved the effect of external beam radiotherapy by increasing survival from a median of 3.9 months in the non-brachytherapy group to 9.1 months in the brachytherapy group. The effect was obvious in patients receiving a brachytherapy dose above 30 Gy, and in those without jaundice at the beginning of radiotherapy (p < 0.05). CONCLUSIONS: The poor prognosis in patients with advanced Klatskin's tumors may be improved by combination therapy, with the role of brachytherapy and chemotherapy still to be defined. Our results suggest that patients without jaundice should be offered brachytherapy, and that a full dose of more than 30 Gy should be applied.

Influence of indomethacin on effects of endothelin-1 on guinea pig isolated rings of common bile duct and sphincter of Oddi.

The effects of endothelin-1 on motility of guinea pig extra-hepatic biliary tract portions were studied. Endothelin-1 (< or =100 nM) failed to contract rings of hepatic, cystic, proximal or distal common bile ducts, or choledochal or papillary halves of sphincter of Oddi. At 100 nM, endothelin-1 or sarafotoxin S6c (selective endothelin ET(B) receptor agonist) inhibited contractions of choledochal (but not papillary) sphincter of Oddi to carbachol (1 microM) by 63+/-5 and 45+/-9%, respectively. In distal common bile duct, indomethacin (5.6 microM) unmasked potent contractile effects of endothelin-1 [EC(50) 7.8 (5.5-11.1) nM; E(MAX) 80+/-6% of response to 80 mM KCl] and enhanced the contractile potency of carbachol (585-fold at EC(50) level), but not cholecystokinin C-terminal octapeptide. Inhibition of cholinergic responsiveness of the choledochal sphincter of Oddi by endothelin-1 was reduced by BQ-123 (1 microM; endothelin ET(A) receptor antagonist; cyclo[DTrp-DAsp-Pro-DVal-Leu]) and abolished by either BQ-123 plus BQ-788 (1 microM; endothelin ET(B) receptor antagonist; N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-D-norleucine) or indomethacin. Thus, eicosanoids of the cyclo-oxygenase pathway (i.e. prostanoids) suppress endothelin-1-induced contractions of distal common bile duct and mediate endothelin ET(A) and ET(B) receptor-dependent inhibition of cholinergic responsiveness of the choledochal portion of the sphincter of Oddi.

Inhibition of the cholinergic twitch response in guinea-pig common bile duct: an evaluation of the effects of noradrenaline, clonidine and fentanyl.

Presynaptic inhibitory effects of noradrenaline, clonidine and fentanyl on twitch contractions evoked by transmural electrical stimulation were investigated in guinea-pig common bile duct (CBD). Antagonism of the response to fentanyl by naloxone and to noradrenaline and clonidine by yohimbine confirmed the involvement of presynaptic opiate and alpha 2-adrenoceptors respectively. Clonidine caused desensitization of presynaptic alpha 2-adrenoceptors. No cross desensitization between clonidine and fentanyl was observed. Furthermore, partial agonistic activity of clonidine at presynaptic alpha 2-adrenoceptors was also observed by the antagonism of noradrenaline response in this preparation.

D-600 sensitive and insensitive spontaneous contractions in the guinea-pig hepatic duct.

The mechanical properties of the longitudinally cut preparations of the guinea-pig hepatic duct were studied. About 42% of the preparations (18 of 43 preparations) showed spontaneous phasic contractions which were unaffected by either tetrodotoxin, guanethidine or atropine. About 60% of them exhibited phasic contractions which appeared at irregular frequencies in the same tissue and varied in size. This sort of contractions usually accompanied small contractions. In about 20%, contractions occurred constantly in frequency (about 6-14 every 10 min) and in size. The remaining 20% showed twitch-like contractions which occurred sporadically. These contractions were classified into two types depending upon the susceptibility to the Ca2+ entry blocker, D-600. D-600 (1-100 microM) strongly suppressed both regularly occurring contractions and twitch-like ones. On the other hand, the drug was ineffective on irregularly occurring contractions. The Ca2+ sources underlying these contractions were discussed.

Iatrogenic sclerosing cholangitis following hepatic arterial chemotherapy infusion.

A case of common hepatic duct stricture secondary to hepatic artery chemotherapy infusion is described. CT and endoscopic retrograde cholangiopancreatography (ERCP) may be used in concert to differentiate this entity from other causes of jaundice--namely, hepatic replacement by tumor, porta hepatis adenopathy, and chemotherapy hepatotoxicity.

Cholangitis complicating intraarterial chemotherapy in liver metastasis.

In the past 2 years at our institution, 87 patients with hepatic metastasis from colorectal carcinoma have undergone surgical implantation of an arterial pump for the direct infusion of chemotherapeutic agents into the liver. We report six cases of cholangitis complicating the course of these patients.

Puncture of the gallbladder during peritoneoscopy - technique and diagnostic relevance (author's transl). / Die laparoskopische Gallenblasenpunktion - Technik und diagnostische Möglichkeiten

Peritoneoscopic puncture of the gallbladder for transvesical cholecysto-cholangiography and for aspiration of bile for chemical and bacteriological analysis is performed rather rarely because of a seemingly high rate of complications. The risk however is low if an appropriate technique is used. In our series the gallbladder was punctured in 110 cases; a local peritonitis subsiding under conservative treatment occured as a complication in only one case. Peritoneoscopic puncture of the gallbladder is indicated in the following conditions: extrahepatic occlusion of the bile duct system of unknown origin, nonvisualization of the gallbladder during cholangiography, biliary dyskinesia, typical biliary colics with normal X-ray findings. In addition, gallbladder puncture should be done if any suspicion of gallbladder disease arises during peritoneoscopy. The procedure as well as technical variations for cholecysto-cholangiography and for X-ray investigation of the pancreatic duct system are described.