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ABSTRACT: Hepatocellular apoptosis plays a major role in the pathogenesis of chronic hepatitis C. It can be measured noninvasively by determining the circulating levels of cytokeratin-18 fragments. We hypothesized that the effect of antiviral therapy on this parameter will be different in patients with a sustained virological response, relapse (REL) and nonresponse (NR). We quantified cytokeratin-18 fragments in plasma of patients participating in the Swiss Hepatitis C cohort, who received antiviral therapy without stopping because of sides effects. A total of 315 patients were included, 183 with a sustained response, 64 with NR and 68 who relapsed. Mean levels ±SD of circulating cytokeratin-18 fragments before therapy were 174 ± 172 U/L for responsders, 188 ± 145 for nonresponders and 269 ± 158 U/L for patients who relapsed. The values were significantly higher in the REL group (ANOVA P < 0.006). A sustained response was associated with a significant improvement of the plasma levels (94 ± 92 U/L, paired test P < 0.000001), whereas there was no improvement in the nonresponder group (183 ± 158 U/L) and in the relapser group (158 ± 148 U/L). There was a weak correlation between alanine aminotransferase (ALT) and cytokeratin-18 fragment levels (r² = 0.35, P < 0.000001) before therapy but not after therapy and none with hepatitis C virus (HCV) viremia. Successful antiviral therapy results in a significant decrease in circulating levels of cytokeratin-18 fragments arguing for a reduction in hepatocellular apoptosis after clearance of the HCV. Baseline cytokeratin-18 fragment levels are higher in relapsers. Correlations with ALT are weak, suggesting that these two tests measure different but related processes.
Journal of Viral Hepatitis 12/2010; 17(12):845-50. · 4.09 Impact Factor
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K Overbeck, J F Dufour,
B Müllhaupt,
B Helbling,
J Borovicka,
R Malinverni,
M Heim,
D Moradpur,
A Cerny,
M Rickenbach,
F Negro
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ABSTRACT: AIM OF THE STUDY: To assess the impact of international consensus conference guidelines on the attitude of Swiss specialists when facing the decision to treat chronic hepatitis C patients. METHODS: Questionnaires focusing on the personal situation and treatment decisions were mailed to 165 patients who were newly diagnosed with hepatitis C virus (HCV) infection and enrolled into the Swiss Hepatitis C Cohort Study during the years 2002-2004. RESULTS: Survey respondents (n = 86, 52.1%) were comparable to non-respondents with respect to severity of liver disease, history of substance abuse and psychiatric co-morbidities. Seventy percent of survey respondents reported having been offered antiviral treatment. Patients deferred from treatment had less advanced liver fibrosis, were more frequently infected with HCV genotypes 1 or 4 and presented more often with a history of depression. There were no differences regarding age, socio-economic background, alcohol abuse, intravenous drug abuse or methadone treatment when compared with patients to whom treatment was proposed. Ninety percent of eligible patients agreed to undergo treatment. Overall, 54.6% of respondents and 78.3% of those considered eligible had actually received antiviral therapy by 2007. Ninety-five percent of patients reported high satisfaction with their own hepatitis C management. CONCLUSIONS: Consistent with latest international consensus guidelines, patients enrolled in the Swiss Hepatitis C Cohort with a history of substance abuse were not withheld antiviral treatment. A multidisciplinary approach is warranted to provide antiviral treatment to patients suffering from depression.
Schweizerische medizinische Wochenschrift 02/2010; · 1.68 Impact Factor
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ABSTRACT: Transaminases, gamma-GT and alcalic phosphatase are classically termed as liver enzymes, however they can be found in almost every organ. Elevated levels of the transaminases ALAT (alanin-aminotransferase) and ASAT (aspartat-aminotransferase) are signs of disturbed permeability of the cells, in which these enzymes can be found. In contrast to ALAT, which is mainly liver-specific, the ASAT is found in other organs as well, e.g. heart and skeletal muscle. At a mild elevation of these enzymes a reevaluation is recommended, however if an elevation persists and is suspicious for a liver disease, a specific work up is necessary. In this manuscript, we discuss often overlooked problems and provide a diagnostic algorithm for the workup of elevated liver enzymes.
Praxis 04/2009; 98(6):330-4.
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ABSTRACT: Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), leading to significant morbidity and mortality. Although the combination of pegylated interferon-alpha (IFN-alpha)/ribavirin is the preferred treatment for these patients, the optimal schedule remains undetermined. In an uncontrolled trial, 19 patients with HCV infection recurring after LT received pegylated IFN-alpha(2a), 180 mug weekly, and ribavirin, 10 mg/kg body weight daily, for 48 weeks. The proportion of patients with undetectable HCV RNA in their serum after 12 weeks of treatment was 53%. Five patients (26%) dropped out of the study due to intolerance (in 2 cases), depression (in 1), or infectious complications (in 2). A sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/19 patients (47%). SVR was associated with an early virological response after 12 weeks of therapy (P<0.001) and a treatment duration >80% (P=0.02), but not with baseline HCV RNA level or a cumulative dose of pegylated IFN-alpha(2a) or ribavirin >80% of the scheduled dose. All 4 patients with genotype 2 or 3 reached SVR, as compared with 33% of patients with genotype 1 or 4 (P=0.03). A 48-week course of pegylated IFN-alpha(2a)/ribavirin therapy is effective in patients with recurrent HCV infection after LT.
Transplant Infectious Disease 12/2008; 11(1):33-9. · 2.22 Impact Factor
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ABSTRACT: Physiological cholestasis linked to immature hepatobiliary transport systems for organic anions occurs in rat and human neonates. In utero, the placenta facilitates vectorial transfer of certain fetal-derived solutes to the maternal circulation for elimination. We compared the ontogenesis of organic anion transporters in the placenta and the fetal liver of the rat to assess their relative abundance throughout gestation and to determine whether the placenta compensates for the late maturation of transporters in the developing liver. The mRNA of members of the organic anion transporting polypeptide (Oatp) superfamily, the multidrug resistance protein (Mrp) family, one organic anion transporter (OAT), and the bile acid carriers Na(+)-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) was quantified by real-time PCR. The most abundant placental transporters were Oatp4a1, whose mRNA increased 10-fold during gestation, and Mrp1. Mrp1 immunolocalized predominantly to epithelial cells of the endoplacental yolk sac, suggesting an excretory role that sequesters fetal-derived solutes in the yolk sac cavity, and faintly to the basal syncytiotrophoblast surface. The mRNA levels of Oatp2b1, Mrp3, and Bsep in the placenta exceeded those in the fetal liver until day 20 of gestation, suggesting that the fetus relies on placental clearance of substrates when expression in the developing liver is low. Mrp3 immunolocalized to the epithelium of the endoplacental yolk sac and less abundantly in the labyrinth zone and endothelium of the maternal arteries. The placental expression of Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, Oat, Ntcp, Mrp2, and Mrp6 was low.
AJP Regulatory Integrative and Comparative Physiology 01/2005; 287(6):R1505-16. · 3.34 Impact Factor
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ABSTRACT: Chronic aethylism has always been a major social as well as health problem. It may lead, at least in some patients, to steatohepatitis (ASH) which is known to progress to cirrhosis more rapidly. Because of the fact that the prevalence of obesity in association with the metabolic syndrome (insulin resistance) is strikingly increasing in the Western world, we will more and more often be faced with a second form of steatohepatitis, the so called non-alcoholic steatohepatitis (NASH). Clinical differentiation between these two entities may often be difficult. The use of the CAGE-questions as well as interviewing family members can help to indentify hidden alcohol abuse. Clinically, the presence of both diseases can only be speculated. To get the diagnosis, liver biopsy must be performed to show the typical histologic feature of fatty liver with hepatocyte necrosis as well as infiltration of polymorphcellular leukocytes. Histology cannot differentiate between ASH and NASH. Therefore, similar pathogenetic mechanisms are supposed. However, therapeutic approaches are different. Treatment of choice in ASH is alcohol abstinence, that of NASH the reduction of insulin resistance, primarily by weight loss.
Therapeutische Umschau 09/2004; 61(8):505-12.
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ABSTRACT: More and more patients are trying out herbal medicine. It is estimated that half of the population have used alternative products at least once in their live. Gastrointestinal diseases often require long-lasting treatments involving many side-effects that can impair the patient's motivation. The majority of persons with symptoms of the irritable bowel syndrome or chronic liver disease resort to non-conventional therapies. However, potential hepatotoxicity of herbal products should not be underestimated. In this article, we discuss herbal preparations in specific gastrointestinal and hepatological indications, concentrating on products that have been tested in randomized, controlled clinical trials. Effective symptomatic treatment of obstipation, irritable bowel and inflammatory bowel disease has been demonstrated with plant-derived preparations. On the other hand phytotherapeutic preparations can not be recommended at present for the treatment of cirrhosis or chronic viral hepatitis based on the available data.
Therapeutische Umschau 07/2002; 59(6):313-6.
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ABSTRACT: Vitamin D(3) affects the immuno response and improves experimental autoimmune diseases. We investigated the effect of 1,25-dihydroxycholecalciferol (1,25[OH](2)D(3)) Rocaltrol as a single immunosuppressive agent and in combination with low-dose cyclosporin A (CsA) in vascularized liver allografts in rats in a high-responder strain combination (ACI-->Lewis). Recipients were placed on a low-calcium diet 7 days before transplantation and were treated with 0.1 or 1 microg/kg/d 1,25(OH)(2)D(3) intraperitoneally beginning 3 days before transplantation. Treatment combining 1,25(OH)(2)D(3) with CsA (2 mg/kg/d) was also tested. Graft function and survival, histologic rejection, and concentrations of interleukin (IL)-2, -4, -10, and -12 in serum and in grafts were measured. 1,25(OH)(2)D(3) increased allograft survival in a dose-dependent manner when compared with controls (P <.05 for both groups). Serum bilirubin, aspartate transaminase (AST), and lactate dehydrogenase (LDH) activities were significantly lower in 1,25(OH)(2)D(3)-treated animals. Vitamin D reduced the concentration of IL-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity index 10 days after transplantation was significantly lower in low- and high-dose 1,25(OH)(2)D(3)-treated rats compared with vehicle-treated controls (P <.0001 for both groups). The combination of either low-dose or high-dose vitamin D(3) and CsA prolonged graft survival when compared with low-dose CsA only (P <.05 for both groups). After 3 weeks, hypercalcemia developed in high-dose 1,25(OH)(2)D(3)-treated rats. It is concluded that 1,25(OH)(2)D(3) prolongs survival of liver allografts in rats by decreasing the severity of acute rejection. Analogues of vitamin D with fewer hypercalcemic effects may have potential as immunosuppressive drugs in liver transplantation.
Hepatology 12/2001; 34(5):926-34. · 11.66 Impact Factor
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ABSTRACT: In response to stimulation at the plasma membrane, hepatocellular Ca(2+) signals are fast and precise and lead to rapid local changes in cytoplasmic free Ca(2+) concentration. These changes result from the opening of the inositol 1,4,5-trisphosphate receptor (InsP(3)R), which is a four-subunit intracellular InsP(3)-gated channel that releases Ca(2+) from the stores. To investigate the molecular mechanism underlying interactions between the InsP(3)R subunits, we cloned the predominant hepatocellular isoform, InsP(3)R isoform 2 (InsP(3)R2), and screened for interactions using the yeast two-hybrid assay. We found that the C-terminal domain of rat InsP(3)R2 interacts with itself, and that the cytoplasmic part preceding the first transmembrane domain, a region near a Ca(2+)-binding site, also interacts with itself. These interactions were confirmed by pull-down experiments. The C-terminal domain of InsP(3)R2 is also able to interact with the C-termini of rat InsP(3)R1 and InsP(3)R3. These results advance our understanding of the molecular mechanisms that underlie the oligomerization and interactions of the InsP(3)R subunits during the opening/closing of the Ca(2+) channel.
European Journal of Biochemistry 12/2001; 268(22):5981-8. · 3.58 Impact Factor
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ABSTRACT: Alagille syndrome is a rare inherited condition, which typically manifests during the first year of life as an episode of prolonged cholestasis. Although the pattern of inheritance is autosomal dominant with almost complete penetrance, highly variable expression may delay the diagnosis, and with passing time the clinical findings may be more difficult to recognize. This has clinical implications, as patients with Alagille syndrome are at risk for late complications such as hepatocellular carcinoma. We report a case of a 35-yr-old patient with Alagille syndrome who was diagnosed with colonic polyposis raising the possibility of an association between the two.
The American Journal of Gastroenterology 10/2001; 96(9):2775-7. · 7.28 Impact Factor
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The Lancet 02/2001; 357(9249):72. · 38.28 Impact Factor
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ABSTRACT: The molecular basis of capacitative (or store-operated) Ca2+ entry is still subject to debate. The transient receptor potential proteins have been hypothesized to be structural components of store-operated Ca2+ channels and recent evidence suggests that Trp3 and its closely related homolog Trp6 are gated by the N-terminal region of the inositol 1,4,5-triphosphate receptors (InsP3R). In this study, we report the existence of two isoforms of the human Trp4 protein, referred to as alpha-hTrp4 and beta-hTrp4. The shorter variant beta-hTrp4 is generated through alternative splicing and lacks the C-terminal amino acids G785-S868. Using a yeast two-hybrid assay and glutathione-S-transferase-pulldown experiments, we found that the C-terminus of alpha-hTrp4, but not of beta-hTrp4, associates in vitro with the C-terminal domain of the InsP(3) receptors type 1, 2 and 3. Thus, we describe a novel interaction between Trp proteins and InsP3R and we provide evidence suggesting that the formation of hTrp4-InsP3R complexes may be regulated by alternative splicing.
FEBS Letters 02/2001; 487(3):377-83. · 3.54 Impact Factor
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ABSTRACT: Ca(2+) signals regulate many cellular functions, including proliferation. They are governed by the inositol 1,4,5-trisphosphate receptor (IP(3)R), the only intracellular hepatic Ca(2+) channel and by the endoplasmic reticulum Ca(2+) pumps, SERCA. To characterise their role in regeneration, expression of their isoforms was studied after 2/3 hepatectomy by real-time quantitative PCR, Western blot and binding studies. We found an early increase in the expression of the IP(3)R isoform 1 which contrasted with the decrease of the expression of the IP(3)R isoforms 2 and 3 and of SERCA3. This results in a transient switch between IP(3)R isoforms 1 and 2, IP(3)R isoform 1 becoming predominant before the first round of mitosis. Binding studies detected a 30% diminution of the IP(3)R population at 24 h. In conclusion, the Ca(2+) signalling machinery is regulated, after hepatectomy, by changes in expression of the IP(3)R and SERCA isoforms to adapt Ca(2+) signals to the regenerative state.
Molecular Cell Biology Research Communications 07/2000; 3(6):374-9.
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ABSTRACT: Ca(2+) signals mediate the hepatic effects of numerous hormones and growth factors. Hepatic Ca(2+) signals are elicited by the inositol trisphosphate receptor, an intracellular Ca(2+) channel. Three isoforms of this receptor have been identified; they are expressed and regulated differently. We investigated the effect of liver fibrosis and cirrhosis on the hepatic expression of the inositol trisphosphate receptor isoforms. Two different rat models were used: bile duct ligation (fibrosis) and chronic exposure to CCl(4)/phenobarbital (cirrhosis). Messenger RNA levels were determined by ribonuclease protection assay (RPA), competitive polymerase chain reaction (PCR) followed by Southern blotting, and real-time quantitative PCR. Protein expression was assessed by Western blotting; tissue distribution was assessed by immunohistology. In control animals, isoform 2 was the predominant isoform, isoform 1 represented less than one third, and isoform 3 less than 1%. After bile duct ligation, expression of types 1 and 3 increased 1.9- and 5.7-fold, and expression of type 2 decreased 2. 5-fold at the protein level. After exposure to CCl(4)/phenobarbital, expression of types 1, 2, and 3 were 2.4-, 0.9-, and 4.2-fold their expression in control animals. Type 2 was localized to the apical domain of hepatocytes, consistent with a role for Ca(2+) signals in canalicular function. Type 3 was detectable in intrahepatic bile duct epithelial cells and not in hepatocytes, suggesting that Ca(2+) signals may be regulated differently in these cells. Signaling through inositol trisphosphate receptor participates in the pathogenesis of cirrhosis, because this process affects the expression of its isoforms.
Hepatology 11/1999; 30(4):1018-26. · 11.66 Impact Factor
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ABSTRACT: Graft rejection and infection remain major problems following liver transplantation; both are heavily influenced by the immunosuppressive regimen. Despite the disparity in the primary disease leading to transplantation, all patients receive the same posttransplant immunosuppressive treatment in a given center. The aim of this study is to detect a possible effect of the underlying disease on the incidence of early acute rejection episodes after orthotopic liver transplantation (OLT).
Retrospective analysis on all 101 consecutive liver transplants performed in 95 patients between 1983 and March 1998; five of these patients, surviving less than 30 days, were not included. The immunosuppressive regimen was based on conventional triple therapy during the whole study period. The diagnosis and treatment of acute rejection within the first 30 days post-OLT was uniform throughout the whole study period.
Though there were no differences with respect to patients' characteristics [age, child classification, number of HLA-mismatches or cytomegalovirus (CMV)-serocompatibility], patients with primary biliary cirrhosis (PBC) showed a significant increase of acute rejection after OLT compared with the other patients transplanted for other liver diseases (P = 0.024). The incidence of infection was not elevated in patients transplanted for PBC when compared with other diagnoses.
Our results indicate that primary liver disease may be a determinant for acute graft rejection in PBC. Furthermore, these results suggest that immunosuppressive regimens based on the underlying disease should be considered.
Langenbeck s Archives of Surgery 07/1999; 384(3):259-63. · 1.81 Impact Factor
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ABSTRACT: Cirrhosis occurs in 20-50% of patients with hepatitis C and is thought to be irreversible. We describe two patients with cirrhosis secondary to hepatitis C in whom the extensive fibrosis and cirrhosis appeared to regress in response to treatment with interferon-alpha (IFN-alpha). Both patients were in the early stages of cirrhosis, class A in the Child-Pugh classification, total score 5 for each patient. Both responded fully to IFN-alpha and had normalization of all liver function tests and disappearance of hepatitis C viral RNA. Liver biopsies, performed before and after treatment, were coded unpaired by patient, combined with 21 liver biopsies from eight other patients with chronic hepatitis, and read independently by two pathologists using the Knodell scoring system. Knodell scores decreased from 14 to 3.5 and from 13.5 to 4 in these two patients. Cirrhosis and extensive fibrosis, present at baseline, were not present on follow-up liver biopsies, which were of sufficient size to reduce the likelihood of sampling error. We conclude that hepatic fibrosis and clinically early cirrhosis may be reversible in some patients with hepatitis C who respond to treatment with IFN-alpha.
Digestive Diseases and Sciences 01/1999; 43(12):2573-6. · 2.12 Impact Factor
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ABSTRACT: Guanosine 3',5'-cyclic monophosphate (cGMP), whose production is stimulated by the interaction of nitric oxide, natriuretic peptides, and guanylin with their respective guanylate cyclases, activates secretion through ion channels in several epithelia. Cl- channels have been identified in the apical membrane of biliary epithelial cells. The aim of this study was to investigate the production of cGMP and its effects on Cl- permeability in biliary epithelial cells.
Halide efflux measurement, whole-cell patch clamp recording, radioimmunoassay, and reverse-transcription polymerase chain reaction using two human biliary cell lines (H69 and Mz-ChA-1) were performed.
In cells equilibrated with 125I, bromo-cGMP stimulated halide efflux by 22%. In whole-cell patch clamp recordings, the addition of cGMP intracellularly, or of atrial natriuretic peptide extracellularly, stimulated inward currents at negative membrane potentials, consistent with Cl- efflux through open channels. In H69 cells, atrial and C-type natriuretic peptides stimulated production of cGMP. Mz-ChA-1 responded only to atrial natriuretic peptide. Both cell lines expressed messenger RNA for the guanylate cyclase type A receptor and the guanylate cyclase free-clearance receptor.
These data suggest that natriuretic peptide stimulates cGMP production in human biliary epithelial cells, which in turn may regulate ductular bile formation through the opening of Cl- channels.
Gastroenterology 04/1998; 114(4):782-90. · 11.68 Impact Factor
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ABSTRACT: Hepatic fibrosis and cirrhosis occur in many types of chronic liver injury and generally seem to be irreversible.
To determine whether cirrhosis caused by autoimmune hepatitis can be reversible.
Retrospective study.
Eight patients with autoimmune hepatitis and cirrhosis who responded to medical therapy and had follow-up liver biopsy while in clinical and biochemical remission.
Biopsy specimens were randomly coded in an unpaired manner according to patient and were read independently by two pathologists using the Knodell scoring system.
The median alanine aminotransferase level decreased from 10.30 mukat/L to 0.37 mukat/L, the median serum bilirubin level decreased from 70 mumol/L to 10 mumol/L, and the median serum albumin level increased from 34 g/L to 43 g/L. Cirrhosis, extensive fibrosis, or both were present in all patients at diagnosis but were not present on follow-up liver biopsy. The median Knodell score decreased from 14.0 to 1.3, and the median fibrosis score decreased from 3.3 to 0.8.
Hepatic fibrosis and cirrhosis may be reversible in some patients in whom autoimmune hepatitis responds to treatment.
Annals of internal medicine 01/1998; 127(11):981-5. · 16.73 Impact Factor
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ABSTRACT: The bile canaliculi of hepatocytes contract spontaneously, and it is hypothesized that this canalicular motility provides a propulsive force for normal intrahepatic bile flow. Cytochalasin disrupts actin polymerization, inhibits contraction, and decreases bile flow. We investigated whether this cholestasis was associated with impaired canalicular secretion. Isolated rat hepatocyte doublets, with and without incubation with 2 mumol/L cytochalasin D (cytD), were superfused, under first-order conditions, to steady state with fluorescein isothiocyanate-labeled glycocholic acid (FITC-GC) and carboxy-4',5'-dimethylfluorescein diacetate (CMFD), which are fluorescent substrates for the bile acid and the nonbile acid organic anion transport pathways, respectively. Fluorescent microscopic images were quantified and the data analyzed by noncompartmental and compartmental kinetic methods. cytD dilated the canalicular spaces fivefold but did not change the proportion of doublets that secreted either probe. Cytochalasin did not affect the mean cellular transit times of FITC-GC (2.8 and 2.5 minutes for control and cytochalasin-treated groups, respectively) and of carboxy-4',5'-dimethylfluorescein (3.8 and 3.7 minutes, respectively). Analysis with a three-compartment model gave estimates of the rate constants for canalicular secretion: 0.21 +/- 0.04 and 0.22 +/- 0.03 min-1 in control and treated cells, respectively, for FITC-GC, and 0.14 +/- 0.01 and 0.16 +/- 0.02 min-1, respectively, for carboxy-dimethylfluorescein. When kinetics are first-order, the canalicular secretion of organic anions is not altered by actin disruptive agents, suggesting that actin filaments do not modulate the function or distribution of these transporters. This suggests that impaired contractility rather than impaired canalicular secretion is the mechanism of cytD-induced cholestasis.
Hepatology 05/1997; 25(4):970-5. · 11.66 Impact Factor
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ABSTRACT: The second messenger, cyclic guanosine monophosphate (cGMP), mediates the actions of nitric oxide, natriuretic peptides, and microbial toxins on cellular contractility and electrolyte movement. Because both hepatocellular contractility and electrolyte secretion participate in bile formation, we investigated the actions of cGMP on this process in intact liver. In rat liver perfused with 8-bromo-cyclic GMP (bcGMP) at 0.5 and 3 micromol/min, bile flow increased by 5% and 31%, respectively. The biliary excretion of the bile acid, taurocholate ([3H]-labeled; 1 micromol/min) and of the organic anion, bromosulfophthalein ([35S]-labeled; tracer dose), was unchanged. The paracellular and transcytotic pathways of biliary excretion, assessed by horseradish peroxidase (HRP), were unaffected. BcGMP was concentratively secreted into bile and the accompanying 30% increase in the biliary clearance of erythritol suggested that the choleresis was primarily osmotic in nature. Unlike cyclic adenosine monophosphate (cAMP), which stimulates bile acid dependent bile flow and transcytosis, bcGMP increased bile acid independent bile flow mainly as a result of its concentrative biliary secretion.
Hepatology 01/1997; 24(6):1487-91. · 11.66 Impact Factor
