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G Paumgartner

Publications and source records attributed to G Paumgartner.

At least 19 recordsLinked to original sources
PubMed2001

Expression of hepatic transporters OATP-C and MRP2 in primary sclerosing cholangitis.

BACKGROUND/AIMS: In chronic cholestatic liver diseases, biliary excretion of organic anions from blood into bile is impaired. The aim of this study was to identify the underlying mechanism. METHODS: Expression of the basolateral organic anion transporting polypeptide OATP-C (SLC21A6) and the canalicular multidrug resistance protein 2 (MRP2) was studied in patients with primary sclerosing cholangitis (PSC) (n=4), a chronic cholestatic liver disease, and in non-cholestatic controls (n=4) (two with chronic hepatitis C, one with idiopathic liver cirrhosis and one with fatty liver). Total RNA was isolated from liver tissue, reverse transcribed and subjected to polymerase chain reaction (PCR) amplification using primers specific for OATP-C, MRP2 and beta-actin. PCR products were quantified densitometrically. RESULTS: When normalized for beta-actin expression, the level of OATP-C mRNA in liver tissue of patients with PSC was 49% of controls (OATP-C/beta-actin 1.60+/-0.25 vs. 3.24+/-0.69; p<0.05) and the level of MRP2 mRNA was 27% of controls (MRP2/beta-actin 0.70+/-0.36 vs. 2.54+/-0.56; p<0.01). CONCLUSIONS: Both OATP-C and MRP2 are decreased as measured by mRNA level in PSC. Downregulation of OATP-C might be the consequence of impaired canalicular secretion of organic anions and could serve to reduce the organic anion load of cholestatic hepatocytes.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.

Ursodeoxycholic acid (UDCA) exerts anticholestatic effects by undefined mechanisms. Previous work suggested that UDCA stimulates biliary exocytosis via Ca(++)- and protein kinase C (PKC)-dependent mechanisms. Therefore, the effect of taurine-conjugated UDCA (TUDCA) was studied in the experimental model of taurolithocholic acid (TLCA)-induced cholestasis on bile flow, hepatobiliary exocytosis, distribution of PKC isoforms, and density of the apical conjugate export pump, Mrp2, in canalicular membranes. Isolated perfused rat livers were preloaded with horseradish peroxidase (HRP), a marker of vesicular exocytosis, and were perfused with bile acids or dimethylsulfoxide (control) only. PKC isoform distribution and membrane density of Mrp2 were studied using immunoblotting and immunoelectron-microscopic techniques. Biliary secretion of the Mrp2 substrate, 2,4-dinitrophenyl-S-glutathione (GS-DNP), was studied in the presence or absence of the PKC inhibitor, bisindolylmaleimide I (BIM-I; 1 micromol/L). TLCA (10 micromol/L) impaired bile flow by 51%; biliary secretion of HRP and GS-DNP by 46% and 95%, respectively; membrane binding of the Ca(++)-sensitive alpha-isoform of PKC by 32%; and density of Mrp2 in the canalicular membrane by 79%. TUDCA (25 micromol/L) reversed the effects of TLCA on bile flow, secretion of HRP and GS-DNP, and distribution of alpha-PKC. TUDCA reduced membrane binding of epsilon-PKC and increased Mrp2 density 4-fold in canalicular membranes of cholestatic hepatocytes. BIM-I inhibited the effect of TUDCA on GS-DNP secretion in cholestatic livers by 49% without affecting secretion in controls. In conclusion, TUDCA may enhance the secretory capacity of cholestatic hepatocytes by stimulation of exocytosis and insertion of transport proteins into apical membranes via PKC-dependent mechanisms.

Animals↗
PubMed2001

Extracorporeal shock wave lithotripsy for clearance of bile duct stones resistant to endoscopic extraction.

BACKGROUND: Endoscopic extraction of bile duct stones after sphincterotomy has a success rate of up to 95%. Failures occur in patients with extremely large stones, intrahepatic stones, and bile duct strictures. This study examined the efficacy and the safety of extracorporeal shock-wave lithotripsy in a large cohort of patients in whom routine endoscopic measures including mechanical lithotripsy had failed to extract bile duct stones. METHODS: Out of 1587 consecutive patients, endoscopic stone extraction including mechanical lithotripsy was unsuccessful in 313 (20%). These 313 patients (64% women, median age, 73 years) underwent high-energy extracorporeal shock-wave lithotripsy. Stone targeting was performed fluoroscopically (99%) or by ultrasonography (1%). RESULTS: Complete clearance of bile duct calculi was achieved in 281 (90%) patients. In 80% of the patients, the fragments were extracted endoscopically after shock-wave therapy; spontaneous passage was observed in 10%. For patients with complete clearance compared with those without there were no differences with regard to size or number of the stones, intrahepatic or extrahepatic stone location, presence or absence of bile duct strictures, or type of lithotripter. Cholangitis (n = 4) and acute cholecystitis (n = 1) were the rare adverse effects. CONCLUSIONS: In patients with bile duct calculi that are difficult to extract endoscopically, high-energy extracorporeal shock-wave lithotripsy is a safe and effective therapy regardless of stone size, stone location, or the presence of bile duct stricture.

Adult↗
PubMed2000

Hepatobiliary transport.

The alterations of hepatobiliary transport that occur in cholestasis can be divided into primary defects, such as mutations of transporter genes or acquired dysfunctions of transport systems that cause defective canalicular or cholangiocellular secretion, and secondary defects, which result from biliary obstruction. The dysfunction of distinct biliary transport systems as a primary cause of cholestasis is exemplified by the genetic defects in progressive familial intrahepatic cholestasis or by the direct inhibition of transporter gene expression by cytokines. In both, the hepatocellular accumulation of toxic cholephilic compounds causes multiple alterations of hepatocellular transporter expression. In addition, lack of specific components of bile caused by a defective transporter, as in the case of mdr2/MDR3 deficiency, unmasks the toxic potential of other components. The production of bile is critically dependent upon the coordinated regulation and function of sinusoidal and canalicular transporters, for instance of Na+-taurocholate cotransporting polypeptide (NTCP) and bile salt export pump (BSEP). Whereas the downregulation of the unidirectional sinusoidal uptake system NTCP protects the hepatocyte from further intracellular accumulation of bile salts, the relative preservation of canalicular BSEP expression serves to uphold bile salt secretion, even in complete biliary obstruction. Conversely, the strong downregulation of canalicular MRP2 (MRP, multidrug resistance protein) in cholestasis forces the hepatocyte to upregulate basolateral efflux systems such as MRP3 and MRP1, indicating an inverse regulation of basolateral and apical transporters The regulation of hepatocellular transporters in cholestasis adheres to the law of parsimony, since many of the cellular mechanisms are pivotally governed by the effect of bile salts. The discovery that bile salts are the natural ligand of the farnesoid X receptor has shown us how the major bile component is able to regulate its own enterohepatic circulation by affecting transcription of the genes critically involved in transport and metabolism.

ATP-Binding Cassette Transporters↗
PubMed2000

Review article: defects in gall-bladder motor function--role in gallstone formation and recurrence.

The pathogenesis of cholesterol gallstones is now recognized as a multifactorial process, including saturation of bile with cholesterol, destabilization of bile leading to cholesterol crystals and hypomotility permitting crystal growth, and agglomeration and retention of microstones which then grow to macroscopic gallstones. In the last 15 years meticulous research has demonstrated convincing evidence that many patients with cholesterol gallstone disease have a distinct defect in gall-bladder motor function that is induced by bile saturated with cholesterol.

Cholelithiasis↗
PubMed2000

Effect of cholestyramine on bile acid pattern and synthesis during administration of ursodeoxycholic acid in man.

BACKGROUND: Cholestyramine is the first-line treatment for cholestasis-induced pruritus and is prescribed along with ursodeoxycholic acid (UDCA) in patients with cholestatic liver diseases. Impairment of the intestinal absorption of endogenous hydrophobic bile acids by cholestyramine is well known. It is unclear, however, whether cholestyramine also impairs the absorption of the hydrophilic bile acid, UDCA, in man. AIMS: To study serum levels of UDCA and endogenous bile acids as well as endogenous bile acid synthesis during simultaneous or separate administration of UDCA and cholestyramine in vivo; and absorption of UDCA both in the presence and absence of its hydrophobic epimer, chenodeoxycholic acid (CDCA), by cholestyramine in vitro. PATIENTS AND METHODS: Five healthy subjects received UDCA (12.5 +/- 0.5 mg kg-1 daily) as a single dose for periods of 14 days with or without cholestyramine (4 g daily). Fasting serum levels of bile acids and of 7alpha-hydroxy-4-cholesten-3-one (alpha-HC), a measure of endogenous bile acid synthesis, were determined by gas chromatography and high pressure liquid chromatography, respectively. In vitro, bile acid solutions were incubated for 24 h in the presence or absence of cholestyramine, and bile acid concentrations were determined in the supernatant. RESULTS: Simultaneous administration of UDCA and cholestyramine in man led to a decrease of fasting serum levels of UDCA by 60% when compared to UDCA serum levels during administration of UDCA alone. In contrast, serum levels of endogenous bile acids were not affected and alpha-HC serum levels were found increased 2. 7-fold indicating stimulation of endogenous bile acid synthesis by cholestyramine. Administration of cholestyramine and UDCA at an interval of 5 h tended to diminish the effect of cholestyramine on UDCA serum levels. In vitro, conjugated and unconjugated UDCA were effectively bound by cholestyramine both in the presence and absence of hydrophobic bile acids. CONCLUSIONS: The results strongly support the recommendation to administer UDCA and cholestyramine at different times of day.

Adult↗
PubMed2000

Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon.

BACKGROUND: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. METHODS: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. RESULTS: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. CONCLUSIONS: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

Adult↗
PubMed2000

Liver transplantation in primary biliary cirrhosis: risk assessment and 11-year follow-up.

BACKGROUND/AIMS: Liver transplantation (LTx) is the only established treatment in patients with end-stage primary biliary cirrhosis (PBC). Although short-term survival after LTx in this group of patients is usually good, few data exist on the long-term survival. The optimal timing of transplantation is difficult. Thus, the aims of this study were to assess the long-term survival of patients with PBC after LTx and to identify potential predictive factors for a positive outcome. METHODS: Survival of 28 patients with PBC who underwent LTx between 1985 and July 1999 in a single center was studied by Kaplan-Meier analysis and was compared to predicted survival without LTx using established prognostic models for PBC, the Mayo and European risk scores. Potential prognostic parameters obtained before LTx were tested for correlation to survival. Rates of bone fractures as markers of hepatic osteodystrophy were compared before and after LTx. RESULTS: Median follow-up after LTx was 90 months with a maximum of 140 months. Actuarial survival of patients with PBC was 89% after 1, 5, and 10 years and was significantly better than estimated survival without LTx after 1-7 years as calculated by the Mayo and European risk scores. Of several parameters tested, only serum bilirubin and the prognostic scores, but no other liver function tests obtained immediately prior to transplantation were significantly correlated with survival after LTx. The duration of intensive care after LTx was not associated with any parameters obtained before LTx. Bone fractures were diagnosed in 43% of patients of whom the vast majority were osteopenic before LTx as determined by osteodensitometry. CONCLUSION: Long-term survival of a well-defined group of patients with PBC was excellent after LTx and was inversely correlated with preoperative serum bilirubin levels as well as Mayo and European risk scores.

Adult↗
PubMed1999

Colonic mucosal proliferation is related to serum deoxycholic acid levels.

BACKGROUND: Hyperproliferation of the colorectal mucosa is regarded as an early step in colorectal carcinogenesis. Deoxycholic acid, a secondary bile acid, stimulates colorectal epithelial proliferation in animals and is considered a tumor promoter in human colorectal carcinogenesis. The aim of this study was to investigate the correlation between colorectal mucosal proliferation and the serum deoxycholic acid level. METHODS: From each of 19 patients (10 men and 9 women) with (n = 3) or without (n = 16) colorectal adenoma, 18 biopsy specimens were obtained by colonoscopy, 3 from each of the 6 colonic segments. A crude nuclei fraction was prepared, and DNA was stained by propidium iodide to determine the proliferative index (the percentage of cells in the S and G2/M phases of the cell cycle) by flow cytometry. Serum levels of deoxycholic acid were determined by gas-liquid chromatography. RESULTS: The colonic proliferation rates (median of the values obtained in all segments, 14.1%; range, 10.0-18.7%) and the fasting serum deoxycholic acid levels (median, 0.86 micromol/L; range, 0.28-1.58 micromol/L) showed a significant correlation (r = 0.51, P = 0.03). Serum lithocholic, cholic, chenodeoxycholic, and ursodeoxycholic acid levels were not correlated with the proliferation rates. CONCLUSIONS: Levels of deoxycholic acid in serum are correlated with the rates of the colorectal mucosa. These results are consistent with the concept that deoxycholic acid promotes colorectal carcinogenesis.

Adenoma↗
PubMed1999

Modulation of protein kinase C by taurolithocholic acid in isolated rat hepatocytes.

The protein kinase C (PKC) family of isoenzymes plays a key role in the regulation of hepatocellular secretion. The hydrophobic and cholestatic bile acid, taurolithocholic acid (TLCA), acts as a potent Ca++ agonist in isolated hepatocytes. However, its effect on PKC isoforms has not been elucidated. Here we investigate the effects of TLCA at low micromolar concentrations on the distribution of PKC isoforms and on membrane-associated PKC activity. The distribution of PKC isoforms was determined in isolated rat hepatocytes in short-term culture using Western blotting and immunofluorescence techniques. PKC activity was measured radiochemically. TLCA (10 micromol/L) induced selective translocation of epsilon-PKC by 47.9% +/- 20.5% (P <.02 vs. controls; n = 7), but not of alpha-, delta-, and zeta-PKC to the hepatocellular membranes, whereas the phorbol ester, phorbol 12-myristate 13-acetate (PMA) (1 micromol/L) caused translocation of all mobile isoforms, alpha-, delta-, and epsilon-PKC, as shown by immunoblotting. Immunofluorescence studies demonstrated selective translocation of epsilon-PKC to the canalicular membranes of isolated rat hepatocyte couplets by TLCA (10 micromol/L), but predominant translocation to intracellular and basolateral membranes by PMA (1 micromol/L). Both TLCA (10 micromol/L) and PMA (1 micromol/L) stimulated membrane-bound PKC activity by 60.5% +/- 45. 8% (P <.05 vs. controls; n = 5) and 72.4% +/- 37.2% (P <.05; n = 5), respectively. TLCA at lower concentrations (5 micromol/L) was less effective. Because activation of epsilon-PKC has been associated with impairment of vesicle-mediated targeting and insertion of membrane proteins in secretory cells, it is attractive to speculate that TLCA reduces bile secretory capacity of the liver cell by activation of epsilon-PKC at the canalicular membrane.

Animals↗
PubMed1999

Detection of colonic dysplasia by light-induced fluorescence endoscopy: a pilot study.

Light-induced fluorescence endoscopy (LIFE) has been shown to differentiate between normal mucosa and dysplastic lesions, and dysplastic lesions of the colon occult to routine white-light colonoscopy may thus be visualized by LIFE. We compared the sensitivity and specificity of LIFE to routine white-light colonoscopy in patients with colonic dysplasia. In a pilot study 20 patients with colonic adenoma, inflammatory bowel disease, or with a history of colon cancer were screened for colonic dysplasia during routine colonoscopy. Forty-two sites of mucosal abnormalities regarded as suspicious for dysplasia during white-light colonoscopy were additionally examined with a prototype LIFE system. Biopsies were taken from all 42 colonic sites. The LIFE images were classified as positive or negative for dysplasia. Sensitivity and specificity were calculated by correlating positive and negative findings to the histopathological results. Histopathology detected 21 adenomas with low-grade dysplasia and one with high-grade dysplasia. All dysplastic lesions were found by routine white-light endoscopy. The specificity of conventional white-light endoscopy was 80%. Of the 22 dysplastic lesions 20 were detected by LIFE (sensitivity 91%). The specificity of LIFE was 90% (two false-positive results). LIFE combined with conventional endoscopy may thus improve the detection of colonic dysplasia.

Adult↗
PubMed1999

Glutathione protects the rat liver against reperfusion injury after hypothermic preservation.

BACKGROUND & AIMS: The extracellular generation of reactive oxygen species (ROS) by Kupffer cells contributes to reperfusion injury of the liver allograft. The endogenous antioxidant glutathione (GSH) can detoxify these ROS; however, this effect might be limited by the low extracellular concentration of GSH. We therefore investigated whether an increase of extracellular GSH protects the liver against reperfusion injury after cold preservation. METHODS: Livers of male Sprague-Dawley rats subjected to 24 hours of cold ischemia in University of Wisconsin solution (4 degrees C) were reperfused for 2 hours in the absence (controls) or presence of 0.5, 1, 2, or 4 mmol/L GSH (n = 4-6 each). RESULTS: Two hours after starting reperfusion of control livers, the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase increased to 247 +/- 96 and 27 +/- 13 mU. min(-1). g liver(-1), respectively, but only to 76 +/- 43 and 10 +/- 4 mU. min(-1). g liver(-1) in the presence of 4 mmol/L GSH. This cytoprotective effect was confirmed histologically by a marked reduction of trypan blue staining of hepatocytes. Compared with control livers, postischemic bile flow was significantly enhanced by GSH (0.15 +/- 0.02 vs. 0.41 +/- 0.11 microL. min(-1). g liver(-1)), indicating improved liver function. During reperfusion of control livers, intracellular GSH content declined from 4.5 +/- 0.3 to 2.3 +/- 0.1 micromol/g liver, but only to 3.8 +/- 0.4 micromol/g liver in the presence of 4 mmol/L GSH. Reperfusion of untreated livers was accompanied by a prolonged increase of portal pressure to maximally 12.5 +/- 1.9 cm H2O, which was significantly attenuated by 4 mmol/L GSH (7.2 +/- 1.4 cm H2O). Similar cytoprotective and hemodynamic effects were observed with 2 mmol/L GSH, but not with 0.5 and 1 mmol/L GSH. CONCLUSIONS: Treatment of cold-preserved livers with GSH upon reperfusion prevents damage of hepatocytes, deterioration of the hepatic circulation, and loss of intracellular GSH. In view of these protective effects and its low toxicity in humans, GSH should be considered a candidate drug for prevention of ROS-related reperfusion injury of the liver allograft.

Animals↗
PubMed1999

Bile acid malabsorption as a cause of chronic diarrhea: diagnostic value of 7alpha-hydroxy-4-cholesten-3-one in serum.

To evaluate the usefulness of 7a-hydroxy-4-cholesten-3-one (HCO) serum concentrations as a diagnostic marker of bile acid malabsorption, we determined the reference range of HCO in 106 normal subjects (age 40.2+/-16.8 years; 55 women, 51 men) and conducted a utility study in 23 patients with chronic diarrhea of unknown origin (age 49.4+/-15.3 years, 13 women, 10 men). The diagnosis of bile acid malabsorption was made on the basis of a decreased retention of [75Se]homocholyltaurine after oral application (75SeHCAT test). HCO (reference range: 6-48 ng/ml) and the 75SeHCAT test yielded the same results in 19/23 (83%) patients. Bile acid malabsorption was identified by an increase of HCO in serum with a sensitivity of 90% and a specificity of 79%. Analysis of HCO in serum may serve as a novel, simple, and sensitive method for the detection of bile acid malabsorption in patients with chronic diarrhea of unknown origin.

Adult↗