bluuebunny/crossref_metadata_2025 huggingface dataset:
Complications of liver biopsy in liver transplant patients: Increased sepsis associated with choledochojejunostomy
Authors: Bubak Mark E. , Porayko Michael K. , Krom Ruud A. F. , Wiesner Russell H.
Published: March 2007

We investigated the incidence and types of liver biopsy complications in our first 160 consecutive liver transplantations. A significant complication was identified by the need for therapeutic intervention (for example, hospitalization, transfusion, intravenous fluids, chest tube, surgery or antibiotic therapy). A total of 950 percutaneous hepatic allograft biopsies were performed in 136 patients (mean = 6.9 biopsies/graft; range = 1 to 29). A significant complication was reported after 17 (1.8%) liver biopsies in 13 (9.6%) patients. Bleeding complications occurred in 11 patients and serious infection developed in 6 patients, but all patients recovered with appropriate therapy. Of special interest was that five of six patients with infectious complications had undergone Roux-en-Y choledochojejunostomy as part of the transplantation operation. The incidence of infectious complications related to a series of biopsies was significantly greater in patients who underwent choledochojejunostomy (12.5%) than in patients who underwent duct-to-duct biliary anastomosis (1%) (p < 0.01). Furthermore, all septic events in patients who underwent choledochojejunostomy were related to enteric organisms. This investigation reaffirms the safety and low incidence of complications related to percutaneous liver biopsy even in this unique patient population. However, we did identify a subgroup of patients with biliary-enteric anastomoses who appear to be at increased risk of septic complications after liver biopsy. Antibiotic prophylaxis at the time of liver biopsy may be appropriate in this high-risk subgroup to decrease the frequency of infectious complications. (Hepatology 1991;14:1063-1065.)
IgG is associated with the asialoglycoprotein receptor in the human liver
Authors: Inamoto Takashi , Brown William R.
Published: March 2007

Various pathophysiological relationships between IgA and the asialoglycoprotein receptor on hepatocytes have been proposed. As a step toward defining these relationships, we purified the receptor from human livers by means of p-aminophenyl β-D-thiogalactopyranoside-agarose affinity chromatography. Unexpectedly, we found the asialoglycoprotein receptor to be associated specifically with IgG. Evidence for the specific association included the following: (a) IgG, but little IgA or IgM, was associated with asialoglycoprotein receptor that had been bound to asialoorosomucoid in an enzyme-linked immunosorbent assay; (b) the asialoglycoprotein receptor-associated IgG was predominantly IgG2 and IgG4 subclasses, whereas serum IgG is predominantly IgG1; and (c) some asialoglycoprotein receptor was specifically recovered together with IgG from an anti-IgG affinity column. The association of IgG with asialoglycoprotein receptor was not mediated by receptor recognition of carbohydrate moieties because IgG neither bound directly to asialoglycoprotein receptor nor inhibited binding of asialoglycoprotein receptor to asialoorosomucoid in vitro. The association could not be attributed to antigen-antibody interaction either. We conclude that IgG is associated in vitro with the asialoglycoprotein receptor by a mechanism not yet fully defined and speculate that the IgG serves an immunological function. (Hepatology 1991;14:1070-1075.)
Growth of normal human hepatocytes in primary culture: Effect of hormones and growth factors on DNA synthesis
Authors: Ismail Tariq , Howl John , Wheatley Mark , McMaster Paul , Neuberger James M. , Strain Alastair J.
Published: March 2007

Although the ability of hormones and growth factors to stimulate DNA synthesis in rat hepatocytes has been investigated extensively, no such study of human hepatocytes has been reported. Here we describe a series of experiments to identify those factors that regulate human hepatocyte DNA synthesis in vitro and which therefore may play a role in the control of human liver regeneration.

Human hepatocytes were isolated from normal liver tissue obtained after graft reduction for transplantation into pediatric recipients. Cells were maintained in culture for up to 5 days, and DNA synthesis was determined. Hydroxyurea reduced [3H]thymidine incorporation into DNA by 95%, indicating replicative DNA synthesis. As previously found with rat hepatocytes, epidermal growth factor and transforming growth factor-α stimulated DNA synthesis at low nanomolar concentrations; transforming growth factor-α was slightly more potent. Although the overall rate of thymidine incorporation was lower than that for rodent cells, human hepatocytes were sensitive to lower concentrations of these growth factors, and the degree of stimulation was similar. Conversely, transforming growth factor-β inhibited DNA synthesis at low picomolar levels. By contrast (unlike rat hepatocytes), arginine-vasopressin failed to initiate or potentiate DNA synthesis in human cells.

These data indicate that normal human hepatocytes can respond to low concentrations of growth promoters or inhibitors, previously shown to have activity on rat hepatocytes. These factors may then play a role in control of human liver growth. However, important species differences are apparent, highlighting the limitations of extrapolating from animal studies to humans. (Hepatology 1991;14:1076-1082.)
Regulation of hepatic transferrin, transferrin receptor and ferritin genes in human siderosis
Authors: Pietrangelo Antonello , Rocchi Emilio , Ferrari Alberto , Ventura Ezio , Cairo Gaetano
Published: March 2007

Although many studies have examined the regulation of transferrin, transferrin receptor and ferritin subunit gene expression in experimental systems, no molecular biological data in humans have been documented to date. In this study we simultaneously analyzed the hepatic content of transferrin, transferrin receptor and heavy and light ferritin subunit messenger RNAs in tissue samples obtained from subjects with normal iron balance and patients with primary or secondary iron overload. Steady-state levels of transferrin messenger RNA were not depressed by iron overload. On the contrary, they were increased (p < 0.001) in patients with severe hepatic siderosis (liver iron content > 200 μmol/gm dry wt) as compared with the control group. This indicates that, as already suggested by our previous data in experimental siderosis, iron maintains the ability to induce transferrin gene activity even when cellular iron content is significantly increased. Transferrin receptor gene expression was found to respond in the same manner to any cause of iron-tissue load, regardless of the cause. In fact, a lower signal for transferrin receptor messenger RNA was consistently detected in iron-overloaded patients vs. control subjects, particularly in patients with thalassemia major and idiopathic hemochromatosis (p < 0.001). Ferritin light-subunit messenger RNA accumulation was significantly increased in those patients with severe siderosis (idiopathic hemochromatosis and thalassemia major = liver iron between 200 and 600 μmol/gm dry wt). The fact that no significant change in hepatic ferritin heavy-subunit gene expression was detected in iron-loaded patients confirms preferential production of light-subunit-enriched ferritins in long-term iron overload. In addition, our data indicate that, in conditions where liver-specific abnormalities of iron-regulated proteins have been suggested (i.e., idiopathic hemochromatosis and sporadic porphyria cutanea tarda), the hepatic control of human iron metabolism, as inferred by the activity of transferrin, transferrin receptor and ferritin genes, is normal. (Hepatology 1991;14:1083-1089.)
Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: A randomized controlled trial
Authors: Mezey Esteban , Caballería Joan , Mitchell Mack C. , Parés Albert , Herlong Franklin H. , Rodés Joan
Published: March 2007

The effect of parenteral amino acid administration on nutritional state, liver function and mortality was assessed in patients with severe alcoholic hepatitis. Twenty-eight patients received 2 1/day of a solution of dextrose (65 gm/L) and amino acids (25.8 gm/L) for 1 mo, whereas 26 received only the dextrose solution. All patients were allowed to eat a standard hospital diet. During the month in the hospital, there were six deaths in the treatment group and five deaths in the control group. Nitrogen balance improved in the treated group, but not in the control group. Creatinine-height index, triceps skin fold measurement and levels of serum albumin and prealbumin increased similarly in both groups. Serum retinol binding protein increased more in the treatment group than it did in the control group, and transferrin was increased only in the treatment group. Serum bilirubin, type III aminoterminal procollagen peptide and aminopyrine clearance improved more in the treatment group than in the control group, whereas serum AST and prothrombin time improved in the treatment group but not in the control group. Cumulative 2-yr survival rates from the day of entry into the study were 42% and 38% in the treatment and control groups, respectively. Patients who survived 2 yr and patients in the treatment group who died during the 2-yr follow-up had continued improvement in serum retinol binding protein, transferrin, bilirubin and prothrombin time. These parameters were unchanged in patients in the control group who died during follow-up. We conclude that parenteral amino acid administration for 1 mo in patients with severe alcoholic hepatitis does not affect mortality, but results in improvement in biochemical, metabolic and nutritional parameters; this continues after completion of amino acid administration. (Hepatology 1991;14:1090-1096.)
Kupffer cell-derived cytokines induce the synthesis of a leukocyte chemotactic peptide, interleukin-8, in human hepatoma and primary hepatocyte cultures
Authors: Thornton Amanda J. , Ham John , Kunkel Steven L.
Published: March 2007

Communication circuits operating between activated monocytes/macrophages and adjacent hepatocytes in the liver effect important alterations in hepatocyte function. We demonstrate here that primary human hepatocytes and hepatoma cells are able to function as effector cells in the recruitment of inflammatory cells in hepatic disease and inflammatory states by synthesizing a neutrophil/lymphocyte chemotactic factor, interleukin-8. We have further investigated the possibility that endogenous factors elaborated by activated peripheral blood monocytes and Kupffer cells in the liver are mediators of hepatocytederived interleukin-8 expression. Twenty-four-hour conditioned medium from lipopolysaccharidestimulated peripheral blood monocytes and nonparenchymal human liver cells enriched for Kupffer cells induced a time-dependent increase in interleukin-8 messenger RNA levels in SK-hepatoma cells over a 24-hr period, similar to that seen for tumor necrosis factor-α or interleukin-1β induction of interleukin-8 in primary hepatocytes. Exogenously added lipopolysaccharide or recombinant interleukin-6 had no effect. Cell-associated interleukin-8 antigen was present in SK-hepatoma and primary hepatocytes that had been incubated with macrophage-conditioned medium, tumor necrosis factor or interleukin-1β. Similarly, neutrophil chemotactic activity was secreted by SKhepatoma cells, a significant proportion of which could be blocked with interleukin-8-specific antiserum. Preincubation of macrophage-conditioned medium with neutralizing antibodies to tumor necrosis factor-α or interleukin-1β reduced its interleukin-8 messenger RNA-inducing capacity. Exposure of SK-hepatoma to conditioned medium followed by removal of the stimulus resulted in a rapid down-regulation of interleukin-8 messenger RNA to 50% of the maximum level within the first hour. These data suggest that products derived from activated Kupffer cells can modulate hepatoma cells and primary hepatocyte interleukin-8 gene expression. In addition, macrophage/monocyte-derived tumor necrosis factor-α and interleukin-1β have major roles in the positive regulatory component of this modulation. (Hepatology 1992;15:1112-1122.)
Serum factor from patients with cirrhosis and hepatocellular carcinoma enhances production of prostaglandin E2 by U937 cells
Authors: Iwamoto Hiroaki , Sakamoto Shigeru , Nawata Hajime
Published: March 2007

The effect of serum from patients with cirrhosis and hepatocellular carcinoma on the release of prostaglandin E2 by the human histiocytic lymphoma cell line U937 was investigated to explain the mechanism underlying the immunoregulatory dysfunction of monocytes in cirrhosis and hepatocellular carcinoma. Prostaglandin E2 production by U937 cells cultured with serum from cirrhosis patients (5.9 ± 2.7 ng/ml, p < 0.01) and hepatocellular carcinoma patients (5.4 ± 2.6 ng/ml, p < 0.01) was significantly higher than that of control cultures (2.0 ± 1.0 ng/ml). This activity was decreased after heating and after freezing and thawing. By size exclusion fast protein liquid chromatography, the probable factor was eluted in the fraction with a molecular weight of 150 kD. By anion exchange chromatography with a stepwise increase of the NaCl concentration, the peak activity augmenting prostaglandin E2 production by U937 cells was eluted in the 0.05 to 0.1 mol/L NaCl fraction. The high level of this factor (monocyte-regulating factor) in patient serum might be one cause of abnormal monocyte immunoregulatory function in cirrhosis and hepatocellular carcinoma. (Hepatology 1991;14:1123-1128.)
Efficacy and safety of ursodeoxycholic acid for dissolution of gallstone fragments: Comparison with the combination of ursodeoxycholic acid and chenodeoxycholic acid
Authors: Sackmann Michael , Pauletzki Juergen , Aydemir Uelker , Holl Joseph , Sauerbruch Tilman , Hasford Joerg , Paumgartner Gustav
Published: March 2007

A prospective, double-blind, randomized, single-center study was conducted to compare ursodeoxycholic acid alone with the combination of ursodeoxycholic acid and chenodeoxycholic acid for dissolution therapy of gallstone fragments after shock wave lithotripsy. Patients with single radiolucent gallstones up to 30 mm in diameter or up to three stones of similar total volume received either 750 mg ursodeoxycholic acid alone (group A, n = 138) or the combination of 500 mg ursodeoxycholic acid and 500 mg chenodeoxycholic acid (group B, n = 144) in a single bedtime dose. The bile acids were administered from 2 wk before electrohydraulic lithotripsy until 3 mo beyond complete disappearance of all fragments. Patient’s characteristics, stones (group A, 82% single stones, maximum diameter 19 ± 5 mm, mean ± S.D.; group B, 82% single stones, 18 ± 5 mm), lithotripsy treatment and follow-up period were not different between the two groups.

Between the two groups, no statistically significant difference was found in the time required for complete clearance of the fragments (group A, median time = 15 mo; group B, median time = 13 mo; p = 0.7). At 12 mo after lithotripsy, the probability of complete clearance was 46% ± 5% in group A and 49% ± 5% in group B. Diarrhea occurred significantly more often in group B than in group A (p < 0.001) and was the main reason for withdrawal of randomized medication. Severe adverse effects of the bile acids were not observed.

It is concluded that monotherapy with ursodeoxycholic acid is as efficient as the combination of ursodeoxycholic acid and chenodeoxycholic acid for fragment dissolution after lithotripsy. Therapy with ursodeoxycholic acid alone causes diarrhea less frequently and has to be withdrawn less often than the combination of ursodeoxycholic and chenodeoxycholic acid. (Hepatology 1991;14:1136-1141.)
Physicochemical and bacteriological analysis of the contents of occluded biliary endoprostheses
Authors: Moesch Christian , Sautereau Denis , Cessot Franclois , Berry Pascal , Mounier Marcelle , Gainant Alain , Pillegand Bernard
Published: March 2007

The deposits obstructing 12 biliary endoprostheses were examined by scanning electron microscopy and analyzed quantitatively by Fourier transform infrared spectroscopy. Calcium palmitate and bilirubinate associated with proteins were found in all the deposits. Apart from the small amount of cholesterol, this composition closely resembled that of brown pigment gallstones and suggested an infectious cause. Facultative aero-anaerobic organisms were found on bacteriological investigation. β-Glucuronidase activity was only detected in one sample, suggesting that the calcium bilirubinate may have been formed through tissue glucuronidases. In our study, deposit formation was thought to have been caused by the action of bacterial phospholipases (although not measured) rather than β-glucuronidases. (Hepatology 1991;14:1142-1146.)
Effects of anesthetic agents and abdominal surgery on liver blood flow
Authors: Cowan Russell E. , Jackson Barry T. , Grainger Stephen L. , Thompson Richard P. H.
Published: March 2007

The cause of postoperative liver dysfunction is often unclear, but a decrease in liver blood flow during anesthesia and/or major surgery may be important. Plasma half-life and clearance of indocyanine green were therefore measured in 42 patients before, during and after anesthesia and abdominal surgery. In 13 patients, liver blood flow was also estimated from indocyanine green extraction using hepatic vein catheterization. The major finding was an early decrease in estimated liver blood flow after induction of anesthesia, but not later during or after surgery. Mean indocyanine green half-life increased by 26% (p < 0.005), mean indocyanine green plasma clearance decreased by 19% (p < 0.01) and mean estimated hepatic blood flow decreased by 36% (p < 0.005) during the first 30 min of anesthesia. These changes were greater in males and in patients older than 55 yr, but changes were similar with each of three anesthetic groups. Half-life, but not indocyanine green clearance, was also significantly prolonged by mid-operation in the older (>55 yr) patients and in those undergoing lower abdominal surgery. We suggest that this period of reduced liver blood flow during anesthesia is caused by the effects of neuromuscular blocking agents and may contribute to postoperative liver damage. (Hepatology 1991;14:1161-1166.)
Effects of ritanserin, a selective and specific S2-serotonergic antagonist, on portal pressure and splanchnic hemodynamics in portal hypertensive rats
Authors: Nevens Frederik , Pizcueta Pilar M. , Fernández Mercedes , Bosch Jaime , Rodés Joan
Published: March 2007

Serotonergic mechanisms have recently been implicated in the pathogenesis of portal hypertension; this suggests that blockade of serotonin S2 receptors may be a new approach for the pharmacological therapy of portal hypertension.

This study was aimed at investigating the effects of ritanserin, a selective S2-serotonergic antagonist, in portal-hypertensive rats whose condition was due to partial portal vein ligation. The animals were randomized under double-blind conditions into two groups: the first received ritanserin (0.7 mg/kg body wt, intravenously), and the second received the same volume of placebo (isotonic saline solution). The hemodynamic studies were performed using radiolabeled microspheres 60 min after drug administration.

Ritanserin administration significantly reduced portal pressure (from 11.8 ± 0.8 mm Hg to 9.4 ± 0.6 mm Hg; p < 0.05). This was associated with lower portocollateral resistance (1.8 ± 0.2 mm Hg/ml/min 100 gm in the ritanserin group vs. 2.3 ± 0.2 mm Hg/ml/min 100 gm in rats receiving placebo; not significant), but we saw no changes in portal-vein inflow (5.5 ± 0.7 ml/min 100 gm vs. 5.4 ± 0.5 ml/min 100 gm), mean arterial pressure (95.9 ± 3.5 mm Hg vs. 94.0 ± 4.0 mm Hg) and cardiac index (31.9 ± 3.5 ml/min 100 gm vs. 28.5 ± 2.6 ml/min 100 gm). Hepatic arterial and kidney blood flows were not modified by ritanserin.

In summary, our results demonstrate that ritanserin infusion decreases portal pressure without causing systemic hemodynamic changes. This effect is probably due to a decrease in portocollateral resistance in portal-hypertensive rats.

These results provide further for a role of serotonin in the pathogenesis of portal hypertension. (Hepatology 1991;14:1174-1178.)
Decreased hepatic glycogen content and accelerated response to starvation in rats with carbon tetrachloride-induced cirrhosis
Authors: Krahenbuhl Stephan , Weber Fred L. , Brass Eric P.
Published: March 2007

Glucose homeostasis and fatty acid metabolism are abnormal in patients with cirrhosis. To assess the metabolic response to starvation in an animal model of cirrhosis, glycogen and fuel metabolism were characterized in rats with CCl4-induced cirrhosis studied 2 wk after 10 weekly doses of CCl4. Plasma concentrations of glucose and β-hydroxybutyrate were not different between fed CCl4-treated and control rats, but plasma nonesterified fatty acid concentrations were higher in cirrhotic animals (0.25 ± 0.01 vs. 0.39 ± 0.04 mmol/L; p < 0.05). After 12 hr of starvation, the plasma nonesterified fatty acid concentration had reached 0.58 ± 0.04 mmol/L in CCl4-treated rats, compared with 0.38 ± 0.04 mmol/L in control rats (p < 0.05). The redistribution of the hepatic carnitine pool toward acylcarnitines, which is characteristic of starvation, was complete after fasting for 12 hr in the CCl4-treated rats, compared with the 24 hr required in control rats. In fed cirrhotic rats, liver glycogen content per gram liver was decreased by 64% compared with control rats (30.0 ± 5.1 vs. 10.8 ± 1.1 mg/gm liver wet wt; p < 0.05). After 12-hr fasting, hepatic glycogen content had fallen to 14.3 ± 3.9 and 4.8 ± 0.4 mg/gm liver wet wt (p < 0.05) in control and cirrhotic animals, respectively. To further characterize the status of glycogen metabolism in cirrhotic livers, activities of glycogen synthase and glycogen phosphorylase were determined. Hepatic active and total glycogen phosphorylase activities normalized to hepatocellular content were unaffected by CCl4 treatment, whereas total glycogen synthase activity was increased by 45%. In conclusion, hepatic glycogen content in fed animals with CCl4-induced cirrhosis is decreased, and cirrhotic animals have accelerated transition from the fed to the fasted state, as evidenced by hepatic glycogen depletion, increased plasma nonesterified fatty acid concentrations and redistribution of the hepatic carnitine pool. Rats with CCl4-induced liver cirrhosis provide a useful animal model to study changes in energy metabolism induced by chronic liver disease. (Hepatology 1991;14:1189-1195.)
A scanning electron microscopic study of postnatal development of rat peribiliary plexus
Authors: Haratake Joji , Hisaoka Masanori , Furuta Akiko , Horie Akio , Yamamoto Osamu
Published: March 2007

Hepatic microcirculation in the developing stages is not fully clarified. This study aimed at clarifying the development of hepatic microcirculation, especially peribiliary vascular plexuses, in neonatal rats by corrosion cast procedures and scanning electron microscopy. Peribiliary vascular plexuses of large bile ducts at the hilus of 1-day-old rats showed a simple capillary network that directly poured into the portal vein. The hepatic artery promptly tapered down into many small branches and ended in sinusoids or capillary plexuses around portal vein branches near the hilus. Neither apparent hepatic artery branches nor peribiliary vascular plexuses were found in the peripheral areas of the liver. On the seventh day, very loose peribiliary vascular plexuses and small hepatic artery branches appeared up to the peripheral portal tracts, and the peribiliary vascular plexuses of large bile ducts were still capillary networks. After the seventh day, peribiliary vascular plexuses of large and medium-sized portal tracts often poured into side branches of the portal vein rather than directly into the portal vein as shown in the rats from the first day mentioned above. Peribiliary vascular plexuses of the large bile duct in 2-week-old rats showed a double layer, that is, an outer layer composed of arteries and veins and an inner layer of capillary vessels, that resembled peribiliary vascular plexuses of adult livers. After nearly 4 wk, hepatic microcirculations had almost fully developed into those of adult rats. It was concluded that the gradual postnatal development of the hepatic arterial system and the peribiliary vascular plexuses occurred in parallel with the maturation of the intrahepatic biliary trees. (Hepatology 1991;14:1196-1200.)
3,3′,4,4′-Tetrabromobiphenyl sensitizes rats to the hepatotoxic effects of endotoxin by a mechanism that involves more than tumor necrosis factor
Authors: Shedlofsky Steven I. , Hoglen Niel C. , Rodman Larry E. , Honchel Ron , Robinson Farrel R. , Swim Alice T. , McClain Craig J. , Robertson Larry W.
Published: March 2007

To determine whether the cytokine tumor necrosis factor/cachectin might be a mediator of hepatotoxicity seen after exposure to polyhalogenated aromatic hydrocarbons, rats treated with a single dose of 3,3′,4,4′-tetrabromobiphenyl (150 μmol/kg intraperitoneally) or corn oil vehicle were studied. The 3,3′,4,4′-tetrabromobiphenyl caused the expected anorexia, alterations in organ weights and changes in cytochromes P-450 over 21 days. Although tumor necrosis factor could not be detected in the serum of rats at any time after 3,3′,4,4′-tetrabromobiphenyl treatment alone (from 90 min to 21 days), 3,3′,4,4′-tetrabromobiphenyl treatment significantly increased peak serum tumor necrosis factor concentrations after intravenous bacterial endotoxin (lipopolysaccharide, 1 mg/kg). This effect was seen with lipopolysaccharide given 24 hr, 48 hr, and 20 days after 3,3′,4,4′-tetrabromobiphenyl treatment and increases in peak serum tumor necrosis factor levels ranged from threefold to eightfold over controls in various experiments with no significant differences between the three time points. However, a synergistic increase in hepatic damage (assessed by serum enzymes and liver histological findings 24 hr after lipopolysaccharide injection) was seen in rats given lipopolysaccharide 24 hr and 48 hr after 3,3′,4,4′-tetrabromobiphenyl administration, with 75% and 25% lethality, respectively. There was no lethality with lipopolysaccharide given 20 days after 3,3′,4,4′-tetrabromobiphenyl administration or with simultaneous administration. A lower dose of lipopolysaccharide (0.1 mg/kg) given 24 hr after 3,3′,4,4′-tetrabromobiphenyl also enhanced hepatotoxicity and serum tumor necrosis factor but without lethality. Lipopolysaccharide decreased cytochromes P-450 concentrations and activities to similar extents at all time points tested in both control and 3,3′,4,4′-tetrabromobiphenyl-treated rats. In conclusion, 3,3′,4,4′-tetrabromobiphenyl treatment increases the amount of tumor necrosis factor released into the serum after lipopolysaccharide exposure and sensitizes animals to lipopolysaccharide hepatotoxicity and lethality 1 to 2 days after 3,3′,4,4′-tetrabromobiphenyl administration. However, the enhancement of endotoxicity does not correlate with increased serum tumor necrosis factor or altered activities of cytochromes P-450. (Hepatology 1991;14:1201-1208.)
Hepatic biochemical changes as a result of acute cocaine administration in the mouse
Authors: Boyer Scott C. , Petersen Dennis R.
Published: March 2007

The biochemical mechanism of cocaine hepatotoxicity is thought to involve enzymatic formation of reactive metabolites. The exact hepatocellular effects of these metabolites have yet to be established. This study was designed to monitor, in a time course after an acute cocaine dose, biochemical parameters that are important in cellular defense and homeostasis in vivo. The hepatic parameters measured were ATP as an indicator of cellular energetic status, reduced and oxidized glutathione, NADH and NADPH as measures of redox changes, and thiobarbituric acid-reactive products and microsomal conjugated dienes to determine the extent of lipid peroxidation. In addition, serum ALT levels were determined at each time point to assess the extent of toxicity. Inbred mouse strains selected for their relative sensitivity (male DBA/2Ibg) and resistance (male C57BL/6Ibg) to cocaine-mediated hepatotoxicity were used in this study. Animals were given an acute 50 mg/kg intraperitoneal dose of cocaine, and at various times after administration the hepatic and serum determinations were made. The results of this study confirm the strain difference in cocaine-induced hepatotoxicity and also indicate that there are changes in the biochemistry of the liver that are brought about by acute cocaine administration. In particular, depletions of hepatic GSH, NADH, NADPH and ATP coupled with significant increases in oxidized glutathione were observed in the DBA mouse. C57BL mice showed similar decreases in reduced glutathione, NADH and NADPH but exhibited no significant depletion of hepatic ATP. A similar extent of lipid peroxidation was seen in both mouse strains after cocaine administration. Differences in oxidized glutathione levels after cocaine administration were observed, indicating that an oxidative stress may occur in the DBA mouse to a significantly greater extent than the C57BL mouse. In addition, differences in the extent of ATP depletion suggest that cocaine-mediated disruption of cellular bioenergetics may be an important determinant of hepatotoxicity. (Hepatology 1991;14:1209-1216.)
Organic anion transport in HepG2 cells: Absence of the high-affinity, chloride-dependent transporter
Authors: Min Albert D. , Goeser Tobias , Liu Rui , Campbell Celeste G. , Novikoff Phyllis M. , Wolkoff Allan W.
Published: March 2007

In previous studies, we identified a 55 kD organic anion-binding protein in liver cell sinusoidal plasma membrane subfractions. Other investigators identified another 55 kD bromosulfophthalein/bilirubin binding protein on the surface of rat hepatocytes and HepG2 cells and suggested that this protein served as a transporter for these ligands. In this study, transport of 35S-sulfobromophthalein by the human hepatoma cell line, HepG2, was quantified in the presence and absence of bovine serum albumin to further clarify the possible function of these plasma membrane binding proteins. In contrast to results in normal rat hepatocytes, virtually no uptake of 35S-sulfobromophthalein by HepG2 cells in the presence of bovine serum albumin was found. In the absence of albumin, HepG2 cells expressed temperature-dependent uptake of 35S-sulfobromophthalein. However, the high-affinity CI−-dependent sulfobromophthalein transport that characterizes normal rat hepatocytes was absent, as indicated by an approximately 95-fold lower affinity and 170-fold higher capacity of HepG2 cells for sulfobromophthalein compared with previous results with rat hepatocytes. These results suggest that 55 kD sulfobromophthalein/bilirubin-binding protein on the liver cell surface differs from organic anion-binding protein and is not responsible for sulfobromophthalein extraction in the presence of albumin, although it may play some role in lower affinity transport by cells. Immunoblot analysis and metabolic labeling of HepG2 cells demonstrated synthesis of organic anion-binding protein. However, light microscopic immunocytochemistry and immunoprecipitation of surface iodinated rat hepatocytes and HepG2 cells with antibody to a recombinant organic anion-binding protein fusion protein indicated absence of organic anion-binding protein on the surface of HepG2 cells. Because cell surface organic anion-binding protein and the mitochondrial F1-ATPase β-subunit are immunologically highly cross-reactive, the presence of intracellular but not cell surface organic anion-binding protein immunoreactivity in HepG2 cells suggests that the mitochondrial and cell surface forms of this protein are independently regulated. These studies also indicate that demonstration of sulfobromophthalein transport alone cannot be used as evidence for the presence of the high-affinity transporter. (Hepatology 1991;14:1217-1223.)
Cell cycle-dependent uptake of putrescine and its importance in regulating cell cycle phase transition in cultured adult mouse hepatocytes
Authors: Martin Roger L. , Ilett Kenneth F. , Minchin Rodney F.
Published: March 2007

Previous studies in which investigators have induced the rate of polyamine uptake in vitro have used either inhibitors of polyamine biosynthesis or growth factors that induce cell proliferation. Recently, however, we have described the induction of putrescine uptake in cultured adult mouse hepatocytes and have shown that uptake is independent of both intracellular polyamine levels and proliferation. Although proliferation was not apparent in those studies, data suggested that, after isolation, the cells entered G1 of the cell cycle. In this study, we have examined whether the induction of putrescine uptake is a function of entry into the cell cycle and whether uptake activity is essential for optimal progression into the S phase. Using ribonuclease reductase subunit M1 as a marker of entry into the cell cycle, we have shown that hepatocytes enter G1 during the first 4 hr of culture. Both putrescine uptake and ornithine decarboxylase activity increased as the cells entered G1. Treatment of the cells with retinoic acid (10 to 33 μmol/L) prevented them from entering G1 and also inhibited the induction of the putrescine transporter by up to 90%. In contrast, initiation of G1 to S phase transition markedly down-regulated the activity of the transporter. Thus induction of the putrescine transporter in isolated hepatocytes appears to be a G1-specific event. Culturing the hepatocytes in the presence of 1,1′-bis[3-(1′-methyl-[4,4′-bipyridinium]-1-yl)-propyl]-4,4′-bipyridinium, a potent competitive inhibitor of putrescine uptake, resulted in a 47% decrease in intracellular putrescine. Measurement of the distribution of tracer 3H polyamines showed a loss of intracellular polyamines and an accumulation of extracellular polyamines when cells were treated with 1,1′-bis[3-(1′-methyl-[4,4′-bipyridinium]-1-yl)-propyl]-4,4′-bipyridinium, indicating that the re-uptake of effluxed polyamines contributes to intracellular polyamine homeostasis in cultured hepatocytes. DNA synthesis was significantly inhibited in 1,1′-bis[3-(1′-methyl-[4,4′-bipyridinium]-1-yl)-propyl]-4,4′-bipyridinium-treated cells, and this effect was completely reversed by the addition of 200 μmol/L extracellular putrescine. We concluded that putrescine uptake is important for maintaining high intracellular putrescine levels required for optimal G1 to S phase transition in isolated mouse hepatocytes. (Hepatology 1991;14:1243-1250.)
Bilirubin diglucuronide transport by rat liver canalicular membrane vesicles: Stimulation by bicarbonate ion
Authors: Adachi Yukihiko , Kobayashi Hiroaki , Kurumi Yoshiaki , Shouji Mika , Kitano Motokazu , Yamamoto Toshio
Published: March 2007

The purpose of this study was to provide further insight into the mechanism of bilirubin diglucuronide excretion through the hepatocyte canalicular membrane by investigating the uptake of (3H)bilirubin diglucuronide by purified canalicular membrane vesicles of rat liver. The uptake was analyzed by a rapid filtration technique. The difference between vesicle-associated (3H)bilirubin diglucuronide at 37° C and at 0° C during the initial 1 min was regarded as uptake. Twenty second uptake was saturated by increasing the (3H)bilirubin diglucuronide concentration at a vesicle-inside-directed 100 mmol/L KCl gradient (Km = 75 μmol/L, Vmax = 320 pmol/mg protein 20 sec at 37° C). No sodium dependency was observed. When canalicular membrane vesicles were preincubated with nonlabeled bilirubin diglucuronide, the uptake increased 1.3-fold (transstimulation). Vesicle-inside-positive potential induced by valinomycin and potassium caused a 1.4-fold increase in the uptake. When Cl− was replaced by equivalent ion concentrations of SO4
2-, HCO3
−, NO3
− and SCN−, the uptake was 78%, 244%, 68% and 50%, respectively, and specific stimulation by HCO3
− was observed (Km = 75 μmol/L, Vmax = 700 pmol/mg protein 20 sec at a vesicle-inside-directed 100 mmol/L KHCO3 gradient at 37° C). The uptake was inhibited in a dose-dependent manner by the addition of 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid. The uptake was ATP independent. From these results, it was concluded that bilirubin diglucuronide transport through the canalicular membrane is carrier mediated, electrogenic and stimulated by HCO3
−. (Hepatology 1991;14:1251-1258.)
Excellent prognosis in wilsonian chronic active hepatitis: New data or an article of faith?
Authors: Johnson Philip J. , Williams Roger
Published: March 2007

Twenty of 320 patients with Wilson’s disease initially presented with chemical and laboratory features of chronic active hepatitis, confirmed histologically in 17. When first seen, cirrhosis was present in all 20 and was complicated by ascites and/orjaundice in 11. Within 1 week to 8 years of the onset of overt liver disease the diagnosis of Wilson’s disease was established, and treatment with d-penicillamine was promptly initiated in 19 patients. One man refused treatment and died 4 months later. Treated patients received d-penicillamine or trientine for a total of 264 patient-years (median, 14 patient-years). Abnormal water retention, for which salt restriction and diuretics were added to penicillamine or trientine, disappeared in all but 1 of the patients so affected. Symptomatic improvement and virtually normal levels of serum albumin, bilirubin, aspartate aminotransferase, and alanine aminotransferase followed within 1 year in the majority of subjects. One woman died after 9 months of treatment. Two patients, who became noncompliant with the therapeutic regimen after 9 and 17 years of successful pharmacological treatment, required liver transplants. These results indicate that the prognosis of specifically treated Wilsonian chronic active hepatitis is very good in spite of the presence of cirrhosis.
In search of abnormal enzyme activities of hepatic cholesterol metabolism in patients with cholesterol gallstone disease
Authors: Rigotti Attilio , Nervi Flavio
Published: March 2007

Hepatic cholesterol metabolism was examined in 27 Swedish patients with cholesterol gallstone disease and in 13 patients free of gallstones operated for roentgenographically suspect polyps in the gallbladder. All 40 patients underwent cholecystectomy, and a liver biopsy and gallbladder bile were obtained at surgery. The cholesterol saturation of gallbladder bile was significantly higher in patients with gallstones compared to the gallstone-free controls (131 ± 13 vs. 75 ± 5%, P < 0.001). Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase activity, governing cholesterol synthesis, did not differ between gallstone and gallstone-free patients (104 ± 11 vs. and 109 ± 22 pmol/min per mg protein, respectively). The activity of cholesterol 7 α-hydroxylase, catalyzing the catabolism of cholesterol to bile acids, was not significantly decreased in gallstone patients (6.2 ± 1.1 vs. 8.0 ± 2.0 pmol/min per mg protein). The capacity to esterify cholesterol, judged by the activity of acyl coenzyme A: cholesterol acyltransferase (ACAT), was similar in gallstone and gallstone-free patients (5.4 ± 0.4 vs. 6.7 ± 1.1 pmol/min per mg protein). In the presence of exogenous cholesterol, ACAT activity increased by more than fourfold in both groups. No correlation was found between the saturation of gallbladder bile and any of the mentioned enzyme activities in gallstone patients. It is concluded that distinct abnormalities in cholesterol metabolizing enzymes are not of major importance for development of gallstones in Swedish patients with cholesterol gallstone disease. The results support the contention that the etiology of cholesterol gallstones is multifactorial.
Significance of serum human hepatocyte growth factor levels in patients with hepatic failure
Authors: Tomiya Tomoaki , Nagoshi Sumiko , Fujiwara Kenji
Published: March 2007

Serum human hepatocyte growth factor levels were measured using a newly developed enzyme-linked immunosorbent assay kit in patients with liver diseases. Serum human hepatocyte growth factor levels were increased in correlation with derangements of prothrombin time, total bilirubin and other parameters reflecting hepatocellular dysfunction in 112 patients with chronic liver disease. The levels were positively correlated with serum AST and ALT levels in 59 of these patients whose prothrombin times were within the normal range. Abnormally increased serum human hepatocyte growth factor levels were found in 100% of the determinations in 16 patients with fulminant hepatic failure and in 80% of the determinations in 16 patients with chronic hepatic failure. The levels greater than 1 ng/ml, however, were found in 94% of determinations in the former group, but only in 16% of the determinations in the latter group. This difference was seen irrespective of prothrombin time or hepatic coma grades. In patients with fulminant hepatic failure serum human hepatocyte growth factor levels were increased immediately after plasma exchange using heparin as the anticoagulant in 71% of the determinations. This increase disappeared 12 hr after discontinuation of plasma exchange. In 17 of 39 patients with chronic renal failure who had no liver disease, serum human hepatocyte growth factor levels were abnormally increased before hemodialysis using heparin, and the levels were elevated immediately after hemodialysis in all the patients. The increase of serum human hepatocyte growth factor levels in hepatic failure may be the result of hepatocellular dysfunction and necrosis. Renal failure and extracorporeal circulation may also increase serum human hepatocyte growth factor levels. The determination of the levels may be useful to differentiate fulminant and chronic types of hepatic failure. (Hepatology 1992;15: 1-4).
Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells
Authors: Schirmacher Peter , Geerts Albert , Pietrangelo Antonello , Dienes Hans P. , Rogler Charles E.
Published: March 2007

Hepatocyte growth factor/hepatopoietin A is a complete mitogen for parenchymal liver cells, and its expression is increased as an early response to acute liver injury. To identify the liver cell population responsible for hepatocyte growth factor gene expression, we investigated tissue sections and isolated and purified cell fractions from normal rat liver by in situ and Northern blot hybridization. Hepatocyte growth factor transcripts were present in sinusoidal liver cells, which were preferentially located in the periportal parenchyma. Northern hybridization analysis of RNA isolated from purified liver cell fractions demonstrated that HGF messenger RNA is present only in fat-storing cells. No specific hepatocyte growth factor gene expression was detected in parenchymal cells, endothelial cells and Kupffer cells. Myofibroblast-like transition of fat-storing cells, which is linked to fibrogenesis in chronic liver disease, results in the loss of hepatocyte growth factor expression. Hepatocyte growth factor gene expression in the normal liver, a new function of fat-storing cells, suggests that this growth factor may play a role in the physiological balance between cell death and replacement in the liver and that hepatocyte growth factor may also act in a paracrine manner. Furthermore, loss of hepatocyte growth factor expression in myofibroblast-like cells derived from fat-storing cells may be responsible for reduced parenchymal cell regeneration in chronic liver disease. (Hepatology 1992;15:5-11).
Intrasplenic hepatocellular transplantation corrects hepatic encephalopathy in portacaval-shunted rats
Authors: Ribeiro Joaquim , Nordlinger Bernard , Ballet François , Cynober Luc , Coudray-Lucas Colette , Baudrimont Marielle , Legendre Claire , Delelo Roland , Panis Yves
Published: March 2007

The aim of this work was to evaluate the effect of intrasplenic hepatocellular transplantation on hepatic encephalopathy in an experimental model of chronic liver failure induced by end-to-side portacaval shunt in the rat. Inbred male Wistar Furth rats were divided into three groups: rats subjected to portacaval shunt (n = 10), rats subjected to portacaval shunt and intrasplenic hepatocellular transplantation of 107 hepatocytes isolated from livers of syngeneic rats (n = 10) and sham-operated rats (n = 10). Behavior tests were performed in a blind fashion at 3 wk, at 2 mo and at 3 mo after surgery. Spontaneous activity and nose-poke exploration by individual rats were studied in automated open field boxes equipped with infrared cells. Each cell beam interruption was automatically recorded on a microcomputer and transformed into a score index (counts/hour). Plasma levels of amino acids, ammonia and total biliary acids were measured. Portacaval shunt rats showed reduced spontaneous activity and nose-poke exploration scores. Intrasplenic hepatocellular transplantation significantly increased spontaneous activity after 2 mo and improved nose-poke exploration after 3 wk. At 3 mo, spontaneous activity and nose-poke exploration in portacaval shunt/intrasplenic hepatocellular transplantation rats were not significantly different from those of sham rats. Increases in plasma ammonia levels after portacaval shunt were not corrected. Amino acid imbalance and bile acid concentration in plasma were partially corrected by intrasplenic hepatocellular transplantation. These data show that intrasplenic hepatocellular transplantation can correct the neurological symptoms of hepatic encephalopathy in an experimental model of chronic liver failure and suggest that intrasplenic hepatocellular transplantation might be of therapeutic interest in chronic liver failure. (Heratology 1992;15:12-18).
Improved detection of hepatitis c virus antibodies in high-risk populations
Authors: McHutchison John G. , Person John L. , Govindarajan Sugantha , Valinluck Boontar , Gore Tessie , Lee Steven R. , Nelles Mitchell , Polito Alan , Chien David , DiNello Robert , Quan Stella , Kuo George , Redeker Allan G.
Published: March 2007

Sera from 483 patients at high (group 1, n = 313) and lower (group 2, n = 170) risk for exposure to hepatitis C were tested for antibodies to hepatitis C using first-generation (c100-3) and second-generation enzyme-linked immunosorbent assays and four-antigen recombinant immunoblot assay. The second-generation enzyme-linked immunosorbent assay and nitrocellulose-based immunoblot assay differ from c100-3-based systems in the addition of expression products from the NS3/NS4 (c33c, c200) and putative nucleocapsid (c22-3) region of the hepatitis C genome. In group 1, the sensitivity of detection of hepatitis C antibodies was 45%, 55% and 46% by the first- and second-generation enzyme-linked immunosorbent assays and recombinant immunoblot assay, respectively. In group 2, antibodies were detected by each test system in 26%, 32% and 7% of patients, respectively. Most sera (99%) reactive with the first-generation enzyme-linked immunosorbent assay were reactive with the second-generation enzyme-linked immunosorbent assay (in group 1, 89% of these specimens demonstrated reactivity to at least one antigen with the immunoblot assay, compared with only 31% in group 2). An additional 12% (group 1) and 6% (group 2) of specimens demonstrated reactivity with the second-generation enzyme-linked immunosorbent assay only (of these, 75% [group 1] and 9% [group 2] demonstrated reactivity to at least one antigen with the immunoblot assay). Ninety-eight percent of specimens not reactive with both enzyme-linked immunosorbent assay test systems were also nonreactive by recombinant immunoblot assay. Antibodies to c22-3 and c33c were more frequently detected in chronic hepatitis C virus infection and appeared earlier in acute hepatitis C virus infection, compared with 5-1-1 and c100-3. These results indicate that the addition of structural and nonstructural hepatitis C virus antigens in the second-generation enzyme-linked immunosorbent assay improves the sensitivity of detection of hepatitis C antibodies. (Hepatology 1992;15:19-25).