bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein kinase C agonists inhibit bile secretion independently of effects on the microcirculation in the isolated perfused rat liver
Authors: Corasanti James G. , Smith Neil D. , Gordon Ellen R. , Boyer James L.
Published: March 2007

The role of hormones in the regulation of bile secretion is not known; however vasoactive agents, which act via the phosphoinositide signal transduction pathway, may mediate changes in bile flow by altering the hepatic microvasculature. We therefore examined the effects of phorbol esters and diacylglycerol, agonists of the protein kinase C branch of the phosphoinositide cascade, on perfusion pressure and bile flow in a single-pass, hemoglobin-free, isolated perfused rat liver system with constant perfusate flow.

The active phorbol ester, 12,13-phorbol dibutyrate, produced a dose-dependent (maximal effect at 10−6
M), sustained and reversible decrease in bile flow from 1.09 ± 0.18 to 0.61 ± 0.09 μl per min per gm liver (37.2 ± 5.9%) while simultaneously increasing perfusion pressure from 12.3 ± 0.7 to 21.5 ± 2.5 cm H2O (74.0 ± 4.3%). Both effects were inhibited by the synthetic protein kinase C antagonist H-7. 1,2-Dioctanoyl-sn-glycerol, a diacylglycerol, produced changes in bile flow and perfusion pressure that were similar to, but more marked than, those caused by 12,13-phorbol dibutyrate, whereas the inactive phorbol ester 4α-phorbol didecanoate and the vehicle dimethyl sulfoxide had no effects on either parameter. 12,13-Phorbol dibutyrate infusion resulted in reversible decreases in oxygen consumption (23.3%) and a reversible vascular redistribution of trypan blue dye but did not alter hepatic venous effluent concentrations of K+. Increases in perfusion pressure produced by mechanical constrictions of the hepatic venous cannulae did not reproduce phorbol-induced changes in bile flow, suggesting that the cholestasis is not mediated by postsinusoidal increases in hepatic outflow resistance. Furthermore, the nonspecific vasodilators sodium nitroprusside (10−3
M) and papaverine (40 μM) prevented the phorbol-induced increases in perfusion pressure (p < 0.01) but did not block 12,13-phorbol dibutyrate’s cholestatic effects.

We conclude from this study that protein kinase C agonists have both vascular and nonvascular effects in the isolated perfused rat liver and that the cholestasis caused by these agents is independent of effects on the hepatic microcirculation.
Human ontogeny of the bile duct to portal space ratio
Authors: Kahn Ellen , Markowitz James , Aiges Harvey , Daum Fredric
Published: March 2007

Paucity of interlobular bile ducts is a common feature of cholestatic liver disease in premature infants. Whereas a bile duct to portal space ratio of 0.9 to 1.8 is cited by Alagille as the norm for children, there are no data regarding the normal bile duct to portal space ratio in preterm infants. In this study, by examining liver tissue obtained from autopsied fetuses and infants, we have determined that the bile duct to portal space ratio increases as a function of postconceptional age. After 38 weeks postconception, a ratio equal to or greater than 0.9 was seen in eight of nine subjects. Therefore, in evaluating premature infants for duct paucity, liver biopsies should be obtained only after 38 weeks. Prior to 38 weeks postconception, a bile duct to portal space ratio less than 0.9 may be physiologic.
Treatment of chronic type B hepatitis with recombinant α-interferon induces autoantibodies not specific for autoimmune chronic hepatitis
Authors: Mayet Werner-J. , Hess Georg , Gerken Guido , Rossol Siegbert , Voth Rita , Manns Michael , ZumBüschenfelde Karl-Hermann Meyer
Published: March 2007

Recombinant human α-interferon is now under intensive investigation as therapy for chronic Type B hepatitis. Recent reports have suggested that prolonged α-interferon therapy may induce autoimmune reactions. We have evaluated the problem of autoimmunity related to α-interferon therapy by testing for 15 different antibodies in the sera of 31 patients treated with α-interferon. No patient had autoantibodies before treatment; 27 (87%) of 31 patients developed at least one autoantibody. Eleven patients had antinuclear antibodies and 21 had smooth muscle antibodies, both of which usually developed during α-interferon therapy. In contrast, antibodies to endocrine organs such as thyroid microsomal, thyroglobulin and parietal cell antibodies arose in 12 patients, but usually several months after α-interferon treatment. The appearance of these autoantibodies did not correlate with disease activity or response to α-interferon. No patient developed autoantibodies specifically associated with autoimmune liver diseases such as liver kidney microsomal antibodies, autoantibodies to soluble liver antigen and the primary billiary cirrhosis-specific subtypes of antimitochondrial antibodies.

These results suggest that prolonged α-interferon therapy can induce autoantibody production and, in susceptible patients, may lead to autoimmune disorders.
Active and latent collagenase activity during reversal of hepatic fibrosis in murine schistosomiasis
Authors: Emonard Hervé , Grimaud Jean-Alexis
Published: March 2007

In schistosomiasis mansoni, eggs trapped in portal venules of the liver induce a granulomatous inflammatory reaction and subsequently fibrosis. Upon specific schistosomicidal treatment, however, fibrosis undergoes a marked reversal. The features of this process as regards collagen metabolism were examined in mice using praziquantel as the schistosomicidal drug, which was given 68 days after infection. It was found that collagenase activity in the liver, for both latent and active forms, increases rapidly until 5 days after treatment as compared to nontreated infected mice and then diminishes gradually. The hydroxyproline content in liver and (24-hr) urine are also modified, their values decreasing progressively up to 72 days after treatment without, however, reaching values observed in normal mice. Worm death appears to be the triggering stimulus of these events.
Disseminated intravascular coagulation in cirrhosis
Authors: Carr Justine Meehan
Published: March 2007

Hemorrhagic sequelae of liver disease were recognized and described over a century ago (1). Bleeding has been a common complication and a leading cause of death in patients with cirrhosis (2, 3). The coincidence of low clotting factor levels, hypofibrinogenemia and thrombo-cytopenia has prompted many investigators to ask whether disseminated intravascular coagulation (DIC) plays a role in the pathogenesis of hemorrhage in these patients (4-16). Despite an abundance of published investigations addressing this question, however, establishing the diagnosis of DIC in an individual patient with cirrhosis continues to pose a challenge for the clinician. In an attempt to reconcile the theoretical and the practical, the present review of the role of DIC in cirrhosis will address: (i) normal coagulation and the role of the liver; (ii) coagulation defects identified in DIC and in cirrhosis; (iii) role of DIC in cirrhosis, and (iv) new approaches to this question from the research, as well as from clinical, laboratories. Although some of the new techniques are still being evaluated, preliminary results appear promising in facilitating identification of DIC patients with cirrhosis.
The evolving spectrum of amiodarone hepatotoxicity
Authors: Rigas Basil
Published: March 2007

Amiodarone is believed to have caused acute hepatitis 24 hours after intravenous administration in two patients in whom no other alternative cause of hepatitis was found.
Antimitochondrial autoantibodies in primary biliary cirrhosis recognize cross-reactive epitope(s) on protein X and dihydrolipoamide acetyltransferase of pyruvate dehydrogenase complex
Authors: Surh Charles D. , Roche Thomas E. , Danner Dean J. , Ansari Aftab , Coppel Ross L. , Prindiville Thomas , Dickson Rolland E. , Gershwin Eric M.
Published: March 2007

Antimitochondrial autoantibodies are characteristically present in sera of patients with primary biliary cirrhosis. The antimitochondrial autoantibodies recognize four major antigens from beef heart mitochondria at relative molecular weights of 74, 56, 52 and 48 kD. In the present study, we report that the 56 kD antigen is the protein X of pyruvate dehydrogenase complex and that it possesses cross-reactive antimitochondrial autoantibody epitope(s) with the 74 kD antigen, the acetyltransferase (E2) of the pyruvate dehydrogenase complex. This was demonstrated by comparing the specificities of primary biliary cirrhosis sera with a protein X-specific rabbit antiserum and by absorbing primary biliary cirrhosis sera with recombinant pyruvate dehydrogenase-E2 fusion protein. In the two-dimensional gel analysis, primary biliary cirrhosis sera and protein X-specific rabbit antiserum reacted to the same two isoelectric point polypeptides at 56 kD molecular weight. The absorption of primary biliary cirrhosis sera with the human recombinant pyruvate dehydrogenase-E2 removed reactivity toward both the 74 and 56 kD antigens. Furthermore, analysis of 82 antimitochondrial autoantibody-positive primary biliary cirrhosis sera by immunoblotting did not reveal any sera which reacted solely against either the 74 or 56 kD antigen. Finally, primary biliary cirrhosis sera recognized protein X from human, bovine and porcine sources but not protein X from rat or mouse origin. The identification of protein X as another major target of the autoimmune response in primary biliary cirrhosis suggests that the pyruvate dehydrogenase complex may have a central role in the induction of this enigmatic disease.
Autoradiographic analysis of GABA-benzodiazepine receptors in an animal model of acute hepatic encephalopathy
Authors: Rössle Martin , Deckert Jürgen , Jones Anthony E.
Published: March 2007

To complement analogous studies using conventional ligand-membrane binding assays, the densities of γ-aminobutyric acid and benzodiazepine receptors in the brain have been assessed using an autoradiographic technique in an animal model of hepatic encephalopathy. Hepatic encephalopathy due to fulminant hepatic failure was induced in rabbits by the intravenous injection of galactosamine. The specific binding of three radiolabeled ligands was assessed densitometrically in several microregions of cerebral cortex, hippocampus and cerebellum. [3H]Muscimol was used to assess γ-aminobutyric acid receptor density and [3H]flunitrazepam or [3H]Ro 15-1788 was used to assess benzodiazepine receptor density. No significant differences were observed between the magnitude of binding of the three ligands to each of the microregions of brain from control rabbits and rabbits in Stage III or IV hepatic encephalopathy. These findings suggest that the behavioral expression of hepatic encephalopathy in the model studied is not dependent upon an increase in the number of γ-aminobutyric acid or benzodiazepine receptors, but do not conflict with the hypothesis that γ-aminobutyric acid-ergic tone is increased in hepatic encephalopathy.
Increased bioavailability of enzymes of eicosanoid synthesis in hepatic and extrahepatic tissues after portacaval shunting
Authors: Goerig Matthias , Wernze Heinrich , Kommerell Burkhard , Grün Martin
Published: March 2007

Metabolites of arachidonic acid have been attributed to severe circulatory, metabolic and hormonal alterations in patients with chronic liver disease. In order to study changes of the tissue-specific availability of enzymes of eicosanoid synthesis, we used portacavalshunted rats, as this model exhibits many clinical and biochemical similarities to patients suffering from cirrhosis of the liver. Microsomal mass and maximal velocity of prostaglandin H synthase, the initial enzyme of prostaglandin synthesis, were markedly and permanently increased after shunting in both hepatic and extrahepatic tissues as compared to those of sham-operated rats. Maximal velocity of thromboxane synthase and prostacyclin synthase, two more peripheral enzymes of the arachidonic acid cascade, were tissue-specifically enhanced, whereas the apparent affinities (Km) remained unchanged. Determination of 5-lipoxygenase activity in tissue preparations disclosed a preferential increase in the liver, lung and renal cortex after portacaval shunting. Furthermore, exposure to endotoxin closely mimicked the shunting-induced changes. These results suggest that after portacaval shunting and possibly in patients with advanced liver disease, profound abnormalities at the level of local enzyme expression might play a pathophysiologically important role in the control of eicosanoid synthesis.
Expression of blood group-related antigens in the intrahepatic biliary tree and hepatocytes in normal livers and various hepatobiliary diseases
Authors: Nakanuma Yasuni , Sasaki Motoko
Published: March 2007

The distribution of blood group-related antigens (A, B, H, Leb) in the intrahepatic biliary tree and hepatocytes was studied by immunoperoxidase techniques. In normal livers, large and septal bile ducts expressed A and B antigens in the cases with comparable blood groups and also expressed H antigen frequently in the cases with blood group O, A or B, and infrequently in the cases with AB. Lea and Leb were found in biliary cells at any level in secretors. In hepatobiliary diseases, A, B and H were neoexpressed in the interlobular bile ducts in addition to their expression in the large and septal bile ducts. Lea and Leb were found in almost all proliferated bile ductules and in some hepatocytes, especially those adjacent to ductules, in any of the hepatobiliary diseases, and their expression seemed parallel to the disease activity. H antigen was also neoexpressed in some hepatocytes and proliferated bile ductules. Extramural peribiliary glands expressed H, Lea, Leb and, to a lesser degree, A and B antigens in normal and pathologic conditions. This study disclosed that the normal biliary tree has a specific expression of blood group antigens at different levels and that this expression is altered in pathologic conditions. Periportal hepatocytes showed neoexpression of blood group antigens in pathologic conditions, and some of these hepatocytes may undergo ductular metaplasia.
Prolonged duck hepatitis B virus replication in duck hepatocytes cocultivated with rat epithelial cells: A useful system for antiviral testing
Authors: Fourel Isabelle , Gripon Philippe , Hantz Oliver , Cova Lucyna , Lambert Véronique , Jacquet Chantal , Watanabe Kyoichi , Fox Jack , Guillouzo Christiane , Trepo Christian
Published: March 2007

Duck cultured hepatocytes from Pekin ducks naturally infected by duck hepatitis B virus can remain functional twice longer if a coculture system with rat liver epithelial cells is used instead of ordinary primary culture. The use of a selective medium in which ornithine and lactate replaced arginine and glucose, respectively, allowed viral replication initiated in vivo to be maintained in the coculture for 2 months.

Several antiviral compounds including the pyrophosphate analog (phosphonoformic acid) or nucleoside analogs (9β-arabinofuranosyl AMP, 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodocytosine, 1,2′-deoxy-2′-fluoro-β-D-arabinofuranosyl-5-ethyluracil and 1,2′-deoxy-2′-fluoro-β-D-arabinofuranosyl thymine were studied in both culture systems for their ability to inhibit duck hepatitis B virus replication. Hepatocytes were treated for 7 days with 1,2′-deoxy-2′-fluoro-β-D-arabinofuranosyl-5-ethyluracil (10 μM) and 1,2′-deoxy-2′-fluoro-β-D-arabinofuranosyl thymine (0.5 μM) or for 14 days with 9β-arabinofuranosyl AMP (90 μM), phosphonoformic acid (100 μM) and 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodocytosine (6 μM). The effects of the drugs on viral replication were monitored by testing for duck hepatitis B virus DNA in the culture supernatant and in the cells by molecular hybridization. All the above-mentioned drugs demonstrated an inhibitory activity in both types of cultures which at the quite distinct doses used was greater for phosphonoformic acid and 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodocytosine than for 9β-arabinofuranosyl AMP, 1,2′-deoxy-2′-fluoro-β-D-arabinofuranosyl-5-ethyluracil or 1,2′-deoxy-2′-fluoro-β-D-arabinofuranosyl thymine. Viral replication, however, resumed following discontinuation of treatment.

More studies are needed to further confirm the relevance of this tissue culture system for the screening of new potential anti-hepatitis B virus agents.
Hepatitis during measles in young adults: Possible role of antipyretic drugs
Authors: Ackerman Zvi , Flugelman Moshe Y. , Wax Yohanan , Shouval Daniel , Levy Micha
Published: March 2007

Fifty-six per cent of 118 young adults observed during a recent measles epidemic had some disturbance on liver function tests. Five per cent developed overt jaundice. Patients treated for fever with paracetamol were found to have significantly higher rates of transaminase impairment compared to those treated with dipyrone. Sixty-five and 58% of patients given paracetamol had elevated ALT and AST levels, respectively. Only 15% of patients given dipyrone had elevated levels of these two enzymes (p < 0.01 for ALT and p < 0.02 for AST).

The mean levels of transaminases and bilirubin in the paracetamol-treated patients were significantly higher than those found in the dipyrone-treated patients [92 ± 86 vs. 42 ± 49 IU (p < 0.02) for AST and 12 ± 6.0 vs. 7.0 ± 2.0 μmoles per liter (p < 0.01) for bilirubin]. The cumulative dose of paracetamol in those who had impaired liver function was higher than that ingested by patients who did not develop liver damage, although still within the usual therapeutic range [11.6 ± 5.8 vs. 7.6 ± 4.2 gm (p = 0.02)]. The possible ways in which measles infection and paracetamol in combination can lead to hepatic damage are discussed.
Characterization of woodchuck hepatitis virus DNA and RNA in the hepatocellular carcinomas of woodchucks
Authors: Fuchs Klaus , Heberger Claudia , Weimer Thomas , Roggendorf Michael
Published: March 2007

Integration and transcription of woodchuck hepatitis virus DNA were studied by Southern and Northern blot analysis in 26 hepatocellular carcinomas and in adjacent nontumor tissue of woodchucks (Marmota monax). All liver tissue chronically infected with woodchuck hepatitis virus contained various amounts of episomal and replicative forms of woodchuck hepatitis virus DNA: episomal and replicative forms of woodchuck hepatitis virus DNA without integration were found in six tumors, episomal and integrated woodchuck hepatitis virus DNA was observed in 18 tumors and exclusively integrated woodchuck hepatitis virus DNA was found in two tumors. In most tumors and in all of the liver tissues chronically infected with woodchuck hepatitis virus, two major woodchuck hepatitis virus RNA species (3.7 and 2.1 kilobases) were detected. In tumors of two other animals (HW76 and HW89) with integrated wood-chuck hepatitis virus DNA, only single major transcripts of 3.5 and 2.5 kilobases, respectively, were detected. Hybridization with subcloned woodchuck hepatitis virus DNA probes showed that both aberrant transcripts lacked the C gene and a part of the pre-S1 gene; characterization of corresponding integrated woodchuck hepatitis virus DNA sequences revealed that the C gene was deleted in one tumor, although not in the other. In agreement with the nucleic acid data, we found expression of core protein by Western blotting only in chronically infected liver tissue of these animals, but not in the corresponding tumors. Deletion of the C gene in mRNA may be due to deletion of this gene in the integrated sequences or due to transcriptional regulation.
β-Blockade with propranolol and hepatic artery blood flow in patients with cirrhosis
Authors: Mastai Ricardo , Bosch Jaime , Bruix Jordi , Navasa Miguel , Kravetz David , Rodés Juan
Published: March 2007

In patients with cirrhosis and portal hypertension, propranolol administration reduces heart rate and cardiac output and diminishes portal pressure and collateral eral blood flow. However, there is little information on the possible effects of propranolol on hepatic artery blood flow. The present study addressed this question in 12 cirrhotic patients with end-to-side portacaval shunt, in whom all of the liver blood flow represents the hepatic artery blood flow. Hepatic artery blood flow (continuous infusion of indocyanine green), cardiac output (thermal dilution), heart rate and mean arterial pressure were measured before and 20 min after the intravenous infusion of 10 to 15 mg of propranolol. β-Adrenergic blockade caused a significant reduction of cardiac output (from 9.1 ± 2.1 to 7.1 ± 1.4 liters per min, p < 0.001) (mean ± S.D.) and heart rate (from 85 ± 10 to 71 ± 7 beats per min, p < 0.001), and a significant increase of systemic vascular resistance (from 9.0 ± 2.1 to 11.7 ± 2.7 mmHg per liter per min, p < 0.001), whereas mean arterial pressure did not change (77 vs. 78 mmHg). Propranolol significantly reduced hepatic artery blood flow (from 0.65 ± 0.20 to 0.55 ± 0.14 liters per min, p < 0.01). However, reduction of hepatic artery blood flow (-12.9 ± 7.3%) was significantly less than reduction of cardiac output (-21.1 ± 5.2%, p < 0.01). As a result, the fraction of the cardiac output delivered to the liver was significantly greater after propranolol (8.0 ± 1.7%) than before (7.3 ± 1.7%, p < 0.05). Similarly, increase in hepatic vascular resistance (14 ± 7%) was less pronounced than increase in systemic vascular resistance (27 ± 10%, p L< 0.05). Our results show that despite a redistribution of the cardiac output to the hepatic artery, propranolol causes a significant reduction of hepatic artery flow in cirrhosis.
Effects of propylthiouracil and methimazole on splanchnic hemodynamics in awake and unrestrained rats
Authors: Kawasaki Tsunehisa , Carmichael Frederick J. , Giles Gwynne , Saldivia Victor , Israel Yedy , Orrego Hector
Published: March 2007

The treatment of alcoholic liver disease with propylthiouracil is based on its effect of suppressing the ethanol-induced increase in hepatic oxygen consumption. It has been postulated that liver necrosis ensues when the increase in oxygen demand by the liver exceeds oxygen delivery to this organ. Data are now presented which show that propylthiouracil also increases portal blood flow in awake, unrestrained rats.

Liver blood flow was determined using the labeled microsphere technique in rats at various intervals (0.25, 0.5, 1.0, 3.0, 6.0 and 24 hr) after oral propylthiouracil (50 mg per kg). Administration of propylthiouracil (dose range: 6.25 to 100.0 mg per kg) produced a dose-dependent increase in portal blood flow when given either orally or intraarterially. Maximal flows were obtained with 50 mg per kg (controls = 37.8 ± 1.5, oral propylthiouracil = 50.7 ± 2.2 ml ± kg−1-min−1). This increase in portal blood flow was accompanied by a decrease in preportal vascular resistance (controls = 2.61 ± 0.16; propylthiouracil, 50 mg per kg = 1.79 ± 0.09 mmHg per ml ± kg−1 ± min−1). These effects were correlated with the plasma concentrations of propylthiouracil (r = 0.67, n = 68, p ≤ 0.001). The effect of oral propylthiouracil (50 mg per kg) on portal blood flow started at 0.5 hr and lasted for 6 hr after administration, whereas total liver blood flow was increased for 3 hr. Oral propylthiouracil (50 mg per kg) for 5 days resulted in a 53% increase in thyroid weight, an 85% reduction in 125I thyroid uptake and a 74% decrease in serum thyroxine concentration. This treatment, however, did not modify portal blood flow, nor the response to acute propylthiouracil. Oral administration of equipotent doses of another antithyroid drug, methimazole (10 and 20 mg per kg), had no effect on portal blood flow. Because of the rapid increase in portal blood flow following a single oral or parenteral dose of propylthiouracil and the lack of effect of methimazole, it is concluded that this response of propylthiouracil is independent of its effect on the thyroid gland and of intestinal absorption. The increase in portal blood flow can contribute to the protective effect of propylthiouracil against alcohol-induced liver necrosis by increasing oxygen delivery to the liver.
Sucralfate for the prevention of early rebleeding following injection sclerotherapy for esophageal varices
Authors: Polson Rex J. , Westaby David , Gimson Alexander E. S. , Hayes Peter C. , Stellon Anthony J. , Hayllar Karen , Williams Roger
Published: March 2007

One hundred eighty patients with variceal bleeding and treated by long-term sclerotherapy were randomized into a prospective randomized controlled clinical trial to assess the efficacy of sucralfate in reducing the frequency of rebleeding from esophageal ulceration prior to variceal obliteration. Overall, 29 (32%) of the 92 patients treated with the addition of sucralfate rebled, compared to 37 (42%) of 88 patients managed by sclerotherapy alone (p < 0.10), but when patients with well-compensated liver disease were considered, the respective figures were 14 (24%) and 25 (42%)--a statistically significant difference (p < 0.05). The frequency (˜70%), number (per patient) and extent of sclerotherapy-induced esophageal mucosal ulceration were not different for the two groups, although proven rebleeding from the ulceration occurred less frequently in those receiving sucralfate (10 and 20 occasions, respectively, p < 0.05). Mortality was not different for the two groups. Thus, use of sucralfate will reduce the frequency of rebleeding during long-term treatment by sclerotherapy, although benefit appears to be restricted to wellcompensated patients and without an endoscopic overt effect upon esophageal mucosal ulceration.
Lack of effects of isosorbide-5-mononitrate on hepatic hemodynamics in HBsAg-positive cirrhosis
Authors: Tsai Yang-Te , Lee Fa-Yauh , Lin Han-Chieh , Chang Ting-Tsung , Lay Chii-Shyan , Wang Sun-Sang , Kong Chi-Woon , Lee Shou-Dong , Lo Kwang-Juei
Published: March 2007

We conducted a randomized controlled hemodynamic study to evaluate the effect of placebo and 20 mg isosorbide-5-mononitrate, a long-acting organic nitrate, in 19 patients with HBsAg-positive cirrhosis by the simultaneous measurement of portal venous pressure and wedged hepatic venous pressure. Baseline values for the two groups were similar. One hour after oral administration of 20 mg isosorbide-5-mononitrate in 10 patients, mean arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure significantly decreased from 92 ± 13 (mean ± S.D.) to 82 ± 14 mmHg, from 12.9 ± 4.5 to 9.3 ± 2.4 mmHg and from 6.9 ± 3.4 to 4.3 ± 1.8 mmHg, respectively. However, both portal venous pressure gradient (from 18.1 ± 3.6 to 17.5 ± 3.0 mmHg) and hepatic venous pressure gradient (from 17.8 ± 5.2 to 16.6 ± 5.3 mmHg) remained unchanged during the study. In six patients who received 20 mg isosorbide-5-mononitrate twice daily for 7 days, hepatic venous pressure gradient remained unaltered as compared to basal and 1-hr values. There was no significant change in cardiac index, heart rate or systemic vascular resistance in either immediate (1-hr) or delayed (7-day) studies. Three patients (30%) developed mild headache or dizziness and two patients (20%) demonstrated systolic hypotension (<80 mmHg) during the immediate study. This study shows that isosorbide-5-mononitrate appears to have no effect in treating portal hypertension in patients with HBsAg-positive cirrhosis. In addition, the isosorbide-5-mononitrate may affect the systemic circulation more than the portal circulation.
Randomized controlled trial of adenine arabinoside 5′-monophosphate in chronic active hepatitis B: Comparison of the efficacy in heterosexual and homosexual patients
Authors: Marcellin Patrick , Ouzan Denis , Degos Françoise , Brechot Christian , Metman Etienne-Henri , Degott Claude , Chevalier Michelle , Berthelot Pierre , Trepo Christian , Benhamou Jean-Pierre
Published: March 2007

Twenty-two heterosexuals and 21 homosexuals with chronic active hepatitis B and who had HBsAg, HBeAg and hepatitis B virus DNA in serum were randomized separately to receive adenine arabinoside monophos-phate or placebo. In the 10 heterosexuals and nine homosexuals who received placebo, no change in hepatitis B virus DNA level and HBeAg was observed. Among the patients who received adenine arabinoside mono-phosphate, seven of the 12 heterosexuals and five of the 12 homosexuals lost hepatitis B virus DNA; five heterosexuals and three homosexuals also lost HBeAg; one homosexual lost HBsAg. There was no significant difference in response between heterosexual and homosexual patients. When results were pooled, there was a significant effect of adenine arabinoside monophosphate on hepatitis B virus replication. None of the 19 patients who received placebo but 50% of the 24 patients who received adenine arabinoside monophosphate were negative for serum hepatitis B virus DNA at 10 months after treatment (p < 0.001) and none of the 19 patients who received placebo and 33% of the 24 patients who received adenine arabinoside monophosphate were negative for HBeAg in serum (p < 0.005). Retrospective analysis showed that disappearance of hepatitis B virus DNA after administration of adenine arabinoside monophosphate was more common (i) in patients with a low pretreatment hepatitis B virus DNA level than in patients with a high pretreatment hepatitis B virus DNA level (8/11 vs. 4/13, p < 0.05); (ii) in patients with a high pretreatment ALT level than in patients with a low pretreatment ALT level (10/14 vs. 2/10, p < 0.05). Thus, homosexuals with chronic hepatitis B respond just as frequently as heterosexuals to adenine arabinoside monophosphate treatment, and the degree of hepatitis B virus replication, as reflected by serum HBV DNA level, and the degree of activity, as reflected by serum ALT level, are significant factors for predicting response to treatment.
Hepatitis delta virus infection in French male HBsAg-positive homosexuals
Authors: Pol Stanislas , Dubois Frédéric , Roingeard Philippe , Zignego Linda , Housset Chantal , Brechot Christian , Goudeau Alain , Berthelot Pierre
Published: March 2007

The prevalence and serological features of hepatitis delta virus infections were studied in a French population of chronic, non-drug addict, hepatitis B surface antigen carriers: 42 male homosexual patients were compared to 30 nonhomosexuals (20 who evidently had not been exposed to any of the usual hepatitis B virus-hepatitis delta virus risk factors and 10 hemodialyzed patients or kidney allograft recipients).

Six of the 42 male homosexuals (14.3%) had at least one serological marker of hepatitis delta virus infection (hepatitis delta antigen, total and/or IgM anti-hepatitis delta antibodies). Serological follow-up was obtained for five of these patients over several months and confirmed the chronicity of the delta infection in at least four of the five subjects. Hepatitis delta antigen and hepatitis delta virus RNA were found in the liver and in the serum, respectively, of four of the five tested patients.

Hepatitis B virus DNA was negative in the serum of five of the six hepatitis delta virus-positive homosexuals vs. only eight of 35 hepatitis delta virus-negative homosexuals (p < 0.02). Human immunodeficiency virus was negative in all of the nonhomosexuals; its prevalence did not differ between the hepatitis delta virus-positive and -negative homosexuals: three were human immunodeficiency virus-positive among the six former vs. 15 among the 36 latter. Human immunodeficiency virus positivity was without obvious influence on hepatitis B virus replication, since among 35 hepatitis delta virus-negative homosexuals hepatitis B virus DNA was found in 80% of the human immunodeficiency virus-positive individuals and 70% of those who were human immunodeficiency virus-negative.

Our results provide evidence for the following: French homosexual hepatitis B surface antigen chronic carriers are at particular risk of hepatitis delta virus infection, most often chronic, quite probably related to sexual transmission and characterized by a wide range of serological hepatitis delta virus profiles.
Effect of d-tryptophan-6-luteinizing hormone-releasing hormone on the tumoral growth and plasma sex steroid levels in cirrhotic patients with hepatocellular carcinoma
Authors: Guéchot Jérôme , Peigney Nicolas , Ballet François , Vaubourdolle Michel , Giboudeau Jacqueline , Poupon Raoul
Published: March 2007

Certain evidence suggests androgen dependence of hepatocellular carcinoma in cirrhotic patients. Consequently, it was postulated that antiandrogen therapy might be effective in the treatment of hepatocellular carcinoma. d-Tryptophan-6-luteinizing hormone-releasing hormone is a potent agonist analog of luteinizing hormone-releasing hormone which, when chronically administered, inhibits the pituitary gonadal axis and testicular androgen secretion in man. We studied the effects of d-tryptophan-6-luteinizing hormone-releasing hormone on tumoral growth in 17 male cirrhotic patients with hepatocellular carcinoma. After 3 to 6 months of therapy, no tumoral response was observed. Furthermore, measurements of plasma levels of testosterone, dihydrotestosterone, androstenedione, estradiol, estrone and sex hormone-binding globulin were performed before and 3 months after initiation of the antiandrogenic treatment. Before treatment, hypoandrogenism and hyperestrogenism were present; d-tryptophan-6-luteinizing hormone-releasing hormone induced a fall in plasma testosterone and dihydrotestosterone levels. Only a moderate decrease in estradiol and no modification of plasma estrone and sex hormone-binding globulin were found, indicating that the hyperestrogenemia of cirrhotic patients could be attributed to an increase in peripheral aromatization of androgens of adrenal origin.

The inability of d-tryptophan-6-luteinizing hormone-releasing hormone to reduce the growth of hepatocellular carcinoma is not totally in disagreement with the concept of androgen dependence of hepatocellular carcinoma since d-tryptophan-6-luteinizing hormone-releasing hormone does not inhibit the production of androgens of adrenal origin.
Mechanism of iron potentiation of hepatic uroporphyria: Studies in cultured chick embryo liver cells
Authors: Bonkovsky Herbert L.
Published: March 2007

Effects of iron were studied in cultured chick embryo liver cells to help elucidate the effect of hepatic iron in the human disease porphyria cutanea tarda and in toxic porphyria caused by chemicals. These cultures have proven useful because (a) phenobarbital and phenobarbital-like drugs induce a common form(s) of cytochrome P-450 (P-450-phenobarbital) in these cultures; (b) 20-methylcholanthrene and certain other polycyclic hydrocarbons induce a different form(s) (P-450-methylchol-anthrene), and (c) uroporphyria can be produced rapidly by exposure to suitable chemicals. In these cultures, treatment with iron alone did not produce porphyrin accumulation, and treatment with iron + 5-aminolevulinate caused accumulation of protoporphyrin, as did treatment with 5-aminolevulinate alone. However, treatment with phenobarbital-like drugs and iron, the latter at a concentration as low as 0.2 μM, led to accumulation of uro- and heptacarboxylporphyrins. Potentiation of uroporphyrin accumulation by iron began before there was a detectable synergistic increase in activity of 5-aminolevulinate synthase, the rate-controlling enzyme of heme synthesis. In contrast, treatment of cultures with 20-methylcholanthrene, in the presence or absence of iron, did not result in uroporphyrin accumulation or an increase in the activity of 5-aminolevulinate synthase. Uroporphyrinogen decarboxylase activity was unchanged by drug and iron treatments. Inhibitors of P-450-phenobarbital, SKF525A and piperonyl butoxide, as well as cadmium and cycloheximide prevented the porphyrin accumulation produced by glutethimide + iron, even though, except with cycloheximide, these substances further increased 5-amino-levulinate synthase activity. In vitro, uroporphyrin was oxidized autocatalytically by iron. In intact hepatocytes, even low concentrations of iron (0.2 to 20 γM), in the presence of a form of cytochrome P-450 induced by phenobarbital-like chemicals, produces uroporphyria primarily by enhancing uroporphyrinogen oxidation, not by inhibition of the decarboxylase. Induction of 5-aminolevulinate synthase amplifies the porphyrin overproduction.
Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin
Authors: Chernick Richard J. , Martasek Pavel , Levere Richard D. , Margreiter Raimund , Abraham Nader G.
Published: March 2007

Heme oxygenase, the rate-limiting enzyme for heme degradation, can be inhibited by several new synthetic metalloporphyrins. Under certain conditions, a depression in heme oxygenase activity has important clinical significance in the treatment of hyperbilirubinemia, and, in this regard, tin-protoporphyrin has been shown to decrease the production of bilirubin in vitro as well as in vivo. Similarly, our study was concerned with finding a new metalloporphyrin which will inhibit heme oxygenase. Many of the synthetic heme analogs that we analyzed were quite effective inhibitors of heme oxygenase, but the most powerful inhibitor was found to be zinc-deuteroporphyrin IX, 2,4-bisglycol. This metalloporphyrin almost completely inhibits liver heme oxygenase at concentrations as low as 0.5 μM. Its potency as an inhibitor was found to be greater than that of tin-protoporphyrin; the K
i
of zinc-deuteroporphyrin IX, 2,4-bisglycol was calculated to be 0.003 μM. In conclusion, we demonstrated that zinc-deuteroporphyrin IX, 2,4-bisglycol has potent inhibitory effects on human liver, kidney and brain heme oxygenase so that this metalloporphyrin can be considered as an alternative to tin-protoporphyrin in the treatment of hyperbilirubinemia.
Myeloproliferative disorders in portal vein thrombosis in adults
Authors: Knox Tasmin A. , Kaplan Marshal M.
Published: March 2007

In a prospective study of 33 adults with portal vein thrombosis unrelated to a liver tumor, we have assessed the prevalence of primary myeloproliferative disorders using conventional criteria and cultures of bone marrow progenitor cells. A primary myeloproliferative disorder was documented in 14 patients investigated at the time of recognition of portal vein thrombosis. Among these 14 patients, the main clue to the presence of the myeloproliferative disorder was (a) the observation of suggestive abnormalities of peripheral blood cell counts in 4 patients; (b) characteristic findings at bone marrow biopsy or determination of total red cell volume in 3 patients; and (c) formation of “spontaneous” erythroid colonies in cultures of bone marrow progenitor cells in erythro-poietin-poor medium in 7 patients. In 2 other patients, agnogenic myeloid metaplasia with myelosclerosis of apparently recent onset developed 5 yr after recognition of portal vein thrombosis. In conclusion, primary myeloproliferative disorders--in a full-blown or latent form, or at an early stage--are a major cause of portal vein thrombosis.
Taurocholate transport by basolateral plasma membrane vesicles isolated from human liver
Authors: Novak Donald A. , Ryckman Frederick C. , Suchy Frederick J.
Published: March 2007

Transport of taurocholate into the hepatocyte against unfavorable chemical and electrical gradients occurs via a sodium-dependent, carrier-mediated transport system. Although this cotransporter has been characterized in the rodent, it has not been demonstrated in man. Therefore, we utilized human liver, obtained via multiorgan donation but not used for transplantation, to prepare basolateral (sinusoidal) liver plasma membrane vesicles by a Percoll gradient method. Na+,K+ -ATPase, a marker enzyme for the basolateral domain, was enriched 28.9-fold in the final membrane fraction compared with homogenate, whereas the bile canalicular membrane enzymes Mg++ -ATPase and alkaline phosphatase were enriched only 3.4- and 6.4-fold, respectively. Marker enzyme activities for endoplasmic reticulum, lysosomes and mitochondria were not enriched compared with homogenate. Integrity of the membrane vesicles was confirmed by the demonstration of Na+ -dependent concentrative uptake of the amino acid L-alanine (estimated intravesicular volume of 0.59 μl per mg protein). An inwardly directed 100 mM Na+ gradient stimulated the initial rate of 2.5 μM taurocholate uptake and energized a transient 2-fold accumulation of the bile acid above equilibrium (“overshoot”). In contrast, uptake was slower and no overshoot occurred with a K+ gradient. A negative intravesicular potential, created by altering accompanying anions or by valinomycin-induced K+ diffusion potentials, did not enhance taurocholate uptake, suggesting an electroneutral cotransport mechanism. Chloride as the accompanying anion stimulated the initial rate of uptake compared with anions of lesser or greater lipid permeability. Na+ -dependent taurocholate (4 μM) uptake was significantly inhibited by 250 μM cholate, taurocholate, glycocholate, taurochenodeoxycholate and bromsulfophthalein. Conversely, in the presence of a K+ gradient, only taurochenodeoxycholate and bromsulfophthalein significantly inhibited taurocholate uptake. The initial rate (5 sec) of Na+ -dependent taurocholate uptake, measured as a function of extravesicular taurocholate concentration (1 to 200 μM), demonstrated Michaelis-Menten kinetics with a Km of 33.8 ± 4.4 μM and a Vmax of 1.25 ± 0.99 nmoles per mg protein per min. We conclude from these studies that taurocholate uptake by basolateral plasma membrane vesicles from human liver is sodium dependent, electroneutral, inhibitable by other bile acids and saturable, with an apparent Km near the concentration of taurocholate found in human portal blood.
Replication of duck hepatitis B virus in primary duck hepatocytes and its dependence on the state of differentiation of the host cell
Authors: Galle Peter R. , Schlicht Hans-jürgen , Kuhn Christa , Schaller Heinz
Published: March 2007

Primary duck hepatocytes obtained from Pekin ducks congenitally infected with duck hepatitis B virus were used to monitor expression of viral proteins and replication of viral DNA in cell culture. Duck hepatitis B virus core antigen, duck hepatitis B virus pre-surface antigen and duck hepatitis B virus DNA were detectable for at least 12 days after cell plating. Whereas expression of duck hepatitis B pre-surface antigen was constant during this time, expression of duck hepatitis B core antigen and of viral DNA rapidly declined. This diminished production of viral components in vitro was paralleled by a change of the hepatocytes toward a fibroblast-like morphology. Supplementation of cell culture medium with 2% dimethyl sulfoxide, a solvent known to maintain the differentiated state of cultured cells, retained competence of the cultured hepatocytes to express duck hepatitis B core antigen and duck hepatitis B virus DNA at high levels. In a second set of experiments, duck hepatitis B virus negative hepatocytes were infected with duck hepatitis B virus from serum of congenitally infected ducks. Dimethyl sulfoxide remarkably improved the competence of cultured duck hepatocytes to become productively infected. This function was maintained for at least 12 days postplating.
Enterically transmitted non-A, non-B hepatitis: Recovery of virus-like particles from an epidemic in south delhi and transmission studies in rhesus monkeys
Authors: Panda Subrat K. , Datta Rakesh , Kaur Jagjit , Zuckerman Arie J. , Nayak Nabeen C.
Published: March 2007

An epidemic of viral hepatitis, serologically characterized as due to non-A, non-B hepatitis, occurred in a village of South Delhi, India, in December, 1986, through January, 1987. Water contaminated with fecal matter was the apparent source of infection. Disease-associated virus-like particles were detected by immune electron microscopy in the feces of three patients within 5 days of illness. The virus-like particles were agglutinated by autologous acute-phase serum but not by convalescent serum. Rhesus monkeys inoculated with particle-containing fecal suspensions developed biochemical and morphologic features of acute, self-limited hepatitis. The findings in the present study and in earlier investigations of sporadic non-A, non-B hepatitis suggest that (i) the epidemic form and a proportion of sporadic cases of this infection in India may be related, both being enterically transmitted and associated with infection by a 27-to 32-nm virus-like particle, (ii) antibody responses to this virus occur early in disease and are transient and (iii) the rhesus monkey may prove to be a suitable model for studies of epidemic non-A, non-B hepatitis.
Experimental methods of ethanol administration
Authors: Lieber Charles S. , Decarli Leonore M. , Sorrell Michael F.
Published: March 2007

Techniques are reviewed for the experimental feeding of alcohol, including a liquid diet procedure invented 25 years ago. This technique results in much higher ethanol intake than with other approaches. As a consequence, various complications observed in alcoholics can be reproduced in animal models. These include fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared, and adequacy of nutrition in terms of minerals, vitamins, lipotropes, carbohydrates and proteins is discussed. The importance of selecting proper controls is emphasized. The respective advantages of three standardized basic rat formulas are reviewed: (i) an all-purpose (35% fat) diet, comparable to the diet previously referred to as the “Lieber-DeCarli formula” and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of hepatic changes characterized by a fatty liver; (ii) a low-fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes, and (iii) a high-protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e. pregnancy). Variations of this technique, including continuous intragastric infusion, are also discussed. It is concluded that, for most experimental studies of chronic alcohol consumption, the liquid diet technique provides one of the most efficient tools to study the effects of ethanol under controlled nutritional conditions because it allows for alcohol consumption of clinical relevance and offers flexibility to adjust to special experimental or physiologic needs by allowing for various substitutions required for a particular experimental design, including changes in lipids, proteins or other dietary constituents. The technique also facilitates the comparison with controls by simplifying the pair feeding and is the best procedure available for the study of the toxic effects of alcohol and their interactions with deficiency or excess of various nutrients.