bluuebunny/crossref_metadata_2025 huggingface dataset:
Prophylactic β-blocker therapy: Clinical implications of an aggregate analysis
Authors: Gumucio Jorge J. , Imperiale Thomas F. , McCullough Arthur J.
Published: March 2007

Background.

The value of beta-adrenergic-antagonist drug therapy for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices is uncertain, both positive and negative study results having been reported.

Methods.

In this study, we analyzed data on individual patients from four randomized, controlled trials to assess the efficacy of this treatment. Of the 589 patients studied, 286 received a beta-adrenergic-antagonist drug (propranolol in 203 and nadolol in 83) and 303 received placebo.

Results.

After two years, the mean (± SE) percentage of patients who had had no upper gastrointestinal bleeding was 78 ± 3 percent in the beta-adrenergic-antagonist treatment group and 65 ± 3 percent in the control group (P = 0.002). The percentage of patients without fatal bleeding was 90 ± 2 percent in the treatment group and 82 ± 3 percent in the control group (P = 0.01). The percentage of patients surviving after two years was 71 ± 3 percent in the treatment group and 68 ± 3 percent in the control group (P = 0.34). After age and severity of cirrhosis were taken into account, the survival rate was better in the treatment group (P = 0.09). The percentage of surviving patients who had had no bleeding after two years was 62 ± 3 percent in the treatment group and 53 ± 3 percent in the control group (P = 0.04). Both propranolol and nadolol prevented a first episode of bleeding. Severe cirrhosis and especially the presence of ascites were associated with bleeding (P < 0.001) and death (P < 0.001) in both groups. The efficacy of beta-adrenergic-antagonist therapy in the prevention of bleeding (P < 0.001) and of fatal bleeding (P = 0.004) and in the prevention of bleeding or death (P = 0.005) was the same after adjustment for cause and severity of cirrhosis, ascites, and size of varices.

Conclusions.

Propranolol and nadolol are effective in preventing first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity.
Pulmonary dysfunction in advanced liver disease
Authors: Kim Sucha
Published: March 2007

PURPOSE: Abnormalities in pulmonary function have been reported in association with chronic liver disease of varied etiology. The aim of this study was to better define the frequency and nature of these abnormalities in patients who were being evaluated for liver transplantation.

PATIENTS AND METHODS: We performed a battery of pulmonary function tests and chest radiographs in 116 consecutive patients (50 men, 66 women; aged 19 to 70 years, mean 44.6 years) with severe advanced liver disease who were hospitalized specifically for evaluation for possible orthotopic liver transplantation and were able to perform technically satisfactory tests. In 17 patients, quantitative whole-body technetium-99m macroaggregated albumin perfusion scanning was also performed for assessment of possible right-to-left shunting through intrapulmonary vascular dilatations.
Use of designer recombinant mitochondrial antigens in the diagnosis of primary biliary cirrhosis
Authors: Leung Patrick S. C. , Iwayama Takashi , Prindiville Thomas , Chuang David T. , Ansari Aftab A. , Wynn Max R. , Dickson Rollie , Coppel Ross , Gershwin Eric M.
Published: March 2007

The appearance of autoantibodies against mitochondria in patients with primary biliary cirrhosis has been known for more than 25 yr. In the past, based on the biochemical complexity of the mitochondrion and the use of crude extracts for immunodiagnosis, a degree of nonspecificity in assaying for antibodies to mitochondria has been present. This problem has been largely circumvented by the cloning of the mitochondrial antigens and the identification of the E2 subunits of the pyruvate dehydrogenase complex and the branched chain 2-oxo-acid dehydrogenase complex as the major and immunodominant autoantigens of primary biliary cirrhosis. More than 90% of patients with primary biliary cirrhosis have been shown to react with one or both of these enzymes using either recombinant antigen or purified native protein. Approximately 10% of patients recognize only E2 subunits of branched chain 2-oxo-acid dehydrogenase complex and not pyruvate dehydrogenase complex. Such patients would be missed by diagnostic assay that has a low sensitivity to antibodies against E2 subunits of branched chain 2-oxo-acid dehydrogenase complex. The use of recombinant and biochemically pure antigens has permitted structural and conformational analysis of epitope mapping. We have taken advantage of the antigenic mapping studies of both primary biliary cirrhosis and branched chain 2-oxo-acid dehydrogenase complex E2 subunits and designed a molecule that expresses the immunodominant epitopes of both. Using this dual-headed molecule that coexpresses the epitope of two different antigens, we report herein a sensitive and reproducible assay for antibodies to mitochondria in patients with primary biliary cirrhosis. We believe that this recombinant protein is the first example of the use of designer molecules for immunodiagnosis. (Hepatology 1992; 15:367-372).
Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection
Authors: Hsu Hong-Yuan , Chang Mei-Hwei , Lee Chin-Yun , Chen Juei-San , Hsu Hey-Chi , Chen Ding-Shinn
Published: March 2007

Spontaneous loss of HBsAg is infrequent in adult HBV carriers. Little is known about this serological change in children. In a prospective study of 420 hepatitis B virus-carrier children who were observed for 1 to 12 yr (mean = 4.3 yr), spontaneous loss of HBsAg occurred in 10 patients, with an average incidence of 0.6%/yr. The HBsAg clearance rate was significantly higher in children who had anti-HBe; children who were at an older age on entry; children whose mothers were HBsAg-; or children with severe liver histological changes detected while they were HBeAg+. Children who seroconverted from HBeAg to anti-HBe before the age of 6 or who had a peak serum ALT level above 100 IU/L were more likely to clear HBsAg. In all 10 patients who became HBsAg-, serum hepatitis B virus DNA became undetectable by both spot hybridization and the polymerase chain reaction, suggesting a complete clearance of the virus from serum. After the loss of HBsAg, the anti-HBs levels were higher in the children born to carrier mothers than in those born to noncarrier mothers. These findings suggest that chronic hepatitis B virus-carrier children rarely lose HBsAg, especially if they have been infected during the perinatal period and have mild histological changes. The poor humoral immune response to HBsAg may be a contributing factor in the establishment of carrier status during horizontal infection but may not be primarily involved in the establishment of carrier status during perinatal infection. (Hepatology 1992;15:382-386).
Detection of the minus strand of hepatitis C virus RNA by reverse transcription and polymerase chain reaction: Implications for hepatitis C virus replication in infected tissue
Authors: Takehara Tetsuo , Hayashi Norio , Mita Eiji , Hagiwara Hideki , Ueda Keiji , Katayama Kazuhiro , Kasahara Akinori , Fusamoto Hideyuki , Kamada Takenobu
Published: March 2007

The combination of reverse transcription and polymerase chain reaction is a very powerful tool for the detection of hepatitis C virus RNA in sera of patients with hepatitis C virus infection. However, when studying the presence of this virus in tissue using polymerase chain reaction, it may be difficult to distinguish between blood viral particles adhering to the tissue and viral RNA contained within the tissue. Because hepatitis C virus has a single-stranded RNA of positive polarity, a minus-strand RNA is expected to be found in hepatitis C virus-replicating tissues as a template for the synthesis of genomic RNA. To see whether the detection of the minus strand of hepatitis C virus RNA by polymerase chain reaction can be used for the determination of hepatitis C virus-replicating tissues, we examined the presence of the minus strand of hepatitis C virus RNA in the plasma, peripheral blood mononuclear cells and liver specimens of patients with hepatitis C virus infection. The plus-strand RNA was detected in the plasma, peripheral blood mononuclear cells and the liver specimens, but the minus-strand RNA was only detected in the liver. These results suggest that hepatitis C virus replicates in the liver but not in peripheral blood mononuclear cells. This detection method for the minus strand of hepatitis C virus RNA should be useful for determining hepatitis C virus replication in tissues other than liver tissue. (Hepatology 1992;15:387-390).
Esophageal staple transection as a salvage procedure after failure of acute injection sclerotherapy
Authors: McCormick Aiden P. , Kaye Graham L. , Greenslade Lynda , Cardin Fabrizio , Hobbs Kenneth E. F. , McIntyre Neil , Burroughs Andrew K.
Published: March 2007

It is not clear which therapy should be used in patients with bleeding esophageal varices that are not controlled by emergency sclerotherapy. This is a high-risk group with reported mortality rates of between 70% and 90%. We report our 7-yr experience with staple transection of the esophagus in this patient group. Of 168 patients (280 bleeding episodes) treated with sclerotherapy, 22 had emergency staple transection for failure to control bleeding. Bleeding was controlled in 20 patients (90%), and 10 patients (45%) survived to leave the hospital, including 4 of 10 patients (40%) with Pugh grade C liver disease. We suggest that emergency staple transection is an effective salvage treatment for this high-risk group. (Hepatology 1992;15:403-406).
Orthotopic liver transplantation for urea cycle enzyme deficiency
Authors: Todo Satoru , Starzl Thomas E. , Tzakis Andreas , Benkov Keith J. , Kalousek Frantisek , Saheki Takeyori , Tanikawa Kyuichi , Fenton Wayne A.
Published: March 2007

Hyperammonemia, abnormalities in plasma amino acids and abnormalities of standard liver functions were corrected by orthotopic liver transplantation in a 14-day-old boy with carbamyl phosphate synthetase-I deficiency and in a 35-yr-old man with argininosuccinic acid synthetase deficiency. The first patient had high plasma glutamine levels and no measureable citrulline, whereas citrulline values were markedly increased in Patient 2. Enzyme analysis of the original livers showed undetectable activity of carbamyl phosphate synthetase-I in Patient 1 and arginosuccinic acid synthetase in Patient 2. Both patients were comatose before surgery. Intellectual recovery of patient 1 has been slightly retarded because of a brain abscess caused by Aspergillus infection after surgery. Both patients are well at 34 and 40 mo, respectively, after surgery. Our experience has shown that orthotopic liver transplantation corrects the life-threatening metabolic abnormalities caused by deficiencies in the urea cycle enzymes carbamyl phosphate synthetase-I and arginosuccinic acid synthetase. Seven other patients-six with ornithine transcarbamylase deficiency and another with carbamyl phosphate synthetase-I deficiency-are known to have been treated elsewhere with liver transplantation 1 1/2 yr or longer ago. Four of these seven recipients also are well, with follow-ups of 1 1/2 to 5 yr. Thus liver transplantation corrects the metabolic abnormalities of three of the six urea cycle enzyme deficiencies, and presumably would correct all. (Hepatology 1992;15:419-422).
Hepatic tissue oxygenation as a predictive indicator of ischemia-reperfusion liver injury
Authors: Goto Moritaka , Kawano Sunao , Yoshihara Harumasa , Takei Yoshiyuki , Hijioka Taizo , Fukui Hiroyuki , Matsunaga Takashi , Oshita Masahide , Kashiwagi Toru , Fusamoto Hideyuki , Kamada Takenobu , Sato Nobuhiro
Published: March 2007

The purpose of this study was to determine whether hepatic tissue oxygenation after ischemia-reperfusion procedures is an indicator for later liver injury. Partial ischemia in the liver was induced by ligating the left pedicles. Rats were divided into two groups according to duration of ischemia: group A (30-min ischemia) and group B (60-min ischemia). Indices of blood oxygenation and blood volume in regional hepatic tissue, serum ALT levels and histological appearance of livers were evaluated. Twenty-four hours after ischemia and reflow, all rats in group A were alive, whereas only 67% survived in group B. Blood-oxygenation index and blood-volume index in group A rats rebounded quickly after reperfusion. In group B, blood-oxygenation index and blood-volume index remained significantly lower than in group A after reperfusion. Serum ALT levels at 60 and 120 min after reperfusion in group B were significantly higher than those in group A. Bloodoxygenation index measured at 5 and 60 min of reperfusion showed significant correlation with serum ALT levels at, 120 min of reperfusion. When the percentage recovery of blood-oxygenation index at 5 and 60 min after reperfusion was more than 75%, all rats survived. No obvious signs of hepatocellular degeneration were observed histologically 5 min after reperfusion; however, substantial hepatocellular degeneration had occurred at 120 min of reperfusion in groups A and B. These data indicate that a decline in hepatic tissue oxygenation during the early phase of reperfusion (even when no obvious hepatocellular degeneration has been observed) can be a predictor of subsequent liver injury and prognosis. (Hepatology 1992;15:432-437).
Effect of complete sulfation of bile acids on bile formation: Role of conjugation and number of sulfate groups
Authors: Yousef Ibrahim , Mignault Diane , Tuchweber Beatriz
Published: March 2007

The effect of complete sulfation of conjugated cholic, chenodeoxycholic and deoxycholic acids on bile formation was investigated in rats. The sulfated bile acids were infused intravenously in stepwise increasing doses (1, 2, 3 and 4 μmol/min/100 gm body wt) in rats after 90 min of bile acid pool depletion. The effects of these bile acids on bile flow, bile salt, biliary phospholipid and cholesterol secretion rates were determined. In addition, their choleretic activity and their effect on biliary lipid secretion were calculated. Appropriate controls infused with nonsulfated bile were also performed. The sulfated bile acids increased bile flow with increasing the infusion doses, and the maximum bile flow was significantly higher than nonsulfated bile acids. Although cholestasis was developed during the infusion of nonsulfated bile acids, no cholestatic effect was observed for sulfated bile acids. With the exception of cholic acid, sulfation significantly increased the bile acid secretory rate maximum. The sulfates of chenodeoxycholic and deoxycholic acids were further hydroxylated. The choleretic activities for all the sulfated bile acids were significantly higher than the nonsulfated bile acids. All the sulfated bile acids significantly reduced the biliary lipid secretion, and a significant correlation was found between the choleretic activity and the phospholipid-dependent bile acid secretion. The data also showed that infusion of sulfated taurine-conjugated bile acids produced higher bile flow and bile acid secretion rate and was less effective when biliary lipid secretion rates were reduced compared with glycine conjugates. It is concluded that sulfated conjugated bile acids may have a role in protection during cholestasis either by stimulation of bile flow or by reduction of biliary lipid secretion, thus protecting cell membranes from the detergent properties of high concentrations of nonsulfated bile acids. (Hepatology 1992;15:438-445).
Treatment of hyperammonemia with carbamylglutamate in rats
Authors: Grau Eugenio , Felipo Vicente , Miñana María-Dolores , Grisolía Santiago
Published: March 2007

A protein-free diet causes a paradoxical increase of blood ammonia levels that seems to be due to decreased liver content of acetylglutamate, the physiological activator of carbamylphosphate synthetase. The purpose of this study was to assess whether oral administration to rats of carbamylglutamate, a metabolically stable activator of carbamylphosphate synthetase, could decrease the blood ammonia levels increased by the protein-free diet. We show that ingestion of moderate doses of carbamylglutamate increased about sixfold the liver content of carbamylphosphate synthetase activators and restores to normal values the blood ammonia levels. Excess ammonia is eliminated in urine as urea. These results indicate that carbamylglutamate, which is not toxic, could be useful in the treatment of hyperammonemia, especially in cirrhosis. (Hepatology 1991;15:446-448).
Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats
Authors: Swain Margaret , Butterworth Roger F. , Blei Andres T.
Published: March 2007

The pathogenesis of brain edema in acute liver failure is poorly understood. We have previously shown that rats with ischemic acute liver failure (portacaval anastomosis followed by hepatic artery ligation) exhibit brain edema and intracranial hypertension, with swelling of cortical astrocytes as the most prominent neuropathological abnormality. Because ammonia has been shown to induce swelling of astrocytes in vivo and in vitro, we examined the relationship between brain ammonia, amino acids generated from ammonia metabolism and brain water content in this model. Four groups of animals were studied: rats subjected to two sham operations, rats subjected to portacaval anastomosis and a sham operation, rats subjected to a sham operation and hepatic artery ligation and rats subjected to portacaval anastomosis and hepatic artery ligation. The last group of animals was studied at three progressive stages of encephalopathy. Cortical gray matter water increased from 80.26% ± 0.22% (sham + sham) to 82.46% ± 0.06% (last stage of devascularization). In cerebral cortex, brain ammonia increased to a maximum of 5.4 mmol/L. Glutamine, generated in glial cells from ammonia and glutamate, increased sixfold to 24 mmol/L and remained at this level throughout all stages of encephalopathy. Alanine, which may be generated from the transamination of glutamine, increased in parallel to the increase in water (r = 0.80, n = 15). In this model of fulminant liver failure and associated brain edema, brain ammonia increases to levels associated with in vitro swelling of brain slices and glial cells. The accumulation of osmogenic aminoacids such as glutamine and alanine may contribute to the selective astrocyte swelling seen in this condition. Ammonia, by its metabolically related amino acids, may play a role in the pathogenesis of brain edema in acute liver failure. (Hepatology 1992;15:449-453).
Enhancement in antioxidant-based hepatoprotective activity of trolox by its conjugation to lactosylphenylpyranoside
Authors: Wu Tai-Wing , Pristupa Zdenek B. , Zeng Ling-Hua , Au Jian-Xun , Wu Jun , Sugiyama Hiroshi , Carey Doug
Published: March 2007

When Trolox (a polar analog of vitamin E) is conjugated to p-aminophenyl-β-D-lactopyranoside, the resulting lactosylphenyl Trolox becomes a markedly more stable and effective hepatoprotector than Trolox. In primary rat hepatocytes exposed to xanthine oxidase-hypoxanthine, lactosylphenyl Trolox prolonged cell survival better than did Trolox, mannitol or ascorbate. In rats that underwent 80-min partial hepatic ischemia, infusion of lactosylphenyl Trolox at 2.9 to 5.7 μmol/kg body wt just before reoxygenation salvaged the organ more extensively than did Trolox. Mechanistically, we showed (a) that lactosylphenyl Trolox does not inhibit xanthine oxidase; (b) that lactosylphenyl Trolox effectively scavenges oxyradicals generated with xanthine oxidase and the peroxyl radicals produced with 2,2′-azo-bis(2-amidinopropane) HCl; (c) that both in hepatocytes and in vivo, lactosylphenyl Trolox is distinctly more cytoprotective than either or both of its precursors; and (d) that lactosylphenyl Trolox is amphipathic (i.e., it has both hydrophilic and hydrophobic properties), which enable it to better access and protect the lipid and aqueous milieus of the cell than the lipophile vitamin E and the moderately polar Trolox. Thus there are strong fundamental reasons for lactosylphenyl Trolox being an effective antioxidant-based hepatoprotector. (Hepatology 1992;15:454-458).
Hemodynamic effects of terbutaline, a β2-adrenoceptor agonist, in conscious rats with secondary biliary cirrhosis
Authors: Poo Jorge L. , Braillon Alain , Hadengue Antoine , Gaudin Christophe , Lebrec Didier
Published: March 2007

The hemodynamic responses to terbutaline - a selective β2-adrenoceptor agonist - were studied in conscious normal rats and in conscious rats with secondary biliary cirrhosis. Compared with those of normal rats, dose-response curves in cirrhotic rats indicated significantly decreased reactivity in arterial pressure and heart rate. Half-maximal effective dose was not significantly different between the two groups. Terbutaline induced significant, dose-dependent decreases in portal pressure in both normal rats (9.3%) and cirrhotic rats (13.8%). In normal rats, terbutaline administration (32 μg ± min−1 ± kg−1 body wt) increased both cardiac output and portal tributary blood flow, thus mimicking hemodynamic changes in cirrhotic rats. In cirrhotic rats, despite a significant increase in portal tributary blood flow (from 19.9 ± 1.7 ml/min to 22.7 ± 1.5 ml/min), terbutaline decreased portal pressure from 17.4 ± 1.0 mm Hg to 15.0 ± 0.8 mm Hg. This study indicates that increased β2-adrenoceptor stimulation in cirrhotic rats may be involved in hyperdynamic circulation. The association of a decreased portal pressure and increased splanchnic blood flow suggests that β2-adrenoceptor stimulation may modulate hepatic and portal collateral vascular resistance. (Hepatology 1992;15:459-463).
Metabolic and hemodynamic responses of bivascularly perfused rat liver to nerve stimulation, noradrenaline, acetylcholine and glucagon in thioacetamide-induced micronodular cirrhosis
Authors: Zimmermann Thomas , Gardemann Andreas , Machnik Georg , Dargel Rolf , Jungermann Kurt
Published: March 2007

Thioacetamide-induced rat cirrhosis was characterized by single-cell necroses, fibrosis, nodular parenchyma, decrease in parenchymal volume density and an increase in liver weight per body weight so that the total amount of parenchyma was not altered. The glycogen content was normal, and signs of decompensation were not found.

Isolated livers were single-pass perfused by way of both the hepatic artery and the portal vein. In the normal livers stimulation of the nerve plexuses around the hepatic artery or portal vein (7.5 Hz; 2 msec) and infusions of noradrenaline (1 μmol/L) by way of either vessel and of acetylcholine (10 μmoI/L) by way of the artery only increased glucose output, reduced both portal and arterial flow and increased the intravascular pressures. Glucagon (0.5 nmol/L) augmented glucose release and had no hemodynamic effects. In chronically thioacetamide-injured livers all stimuli caused smaller metabolic alterations per gram of liver weight and decreased portal flow more and arterial flow less with stronger enhancements of intravascular pressures than in the controls.

The lowered metabolic responsiveness per gram of cirrhotic liver was largely compensated by the increase in liver weight. Thus despite massive histological alterations and pronounced increases in stimulation-dependent resistances-predominantly in the portal system-cirrhotic rat livers responded in their glucose metabolism to nervous and hormonal stimuli in almost the same manner as normal livers. (Hepatology 1992;15:464-470).
Ethanol enhances ADP-ribosylation of protein in rat hepatocytes
Authors: Akinshola Emmanuel B. , Sharma Savitri , Potter James J. , Mezey Esteban
Published: March 2007

Decreases in hepatocyte NAD+ produced by ethanol are only partially explained by the increased conversion of NAD+ to NADH and NADP+. The purpose of this study was to determine whether a mechanism for the ethanol-induced decrease in NAD+ is its increased use in ADP-ribosylation. Exposure of hepatocytes in culture for 2 hr to 100 mmol/L ethanol increased the incorporation of 14C-ribose from prelabeled NAD+ into 14C-ribosylated proteins. Poly (ADP-ribose) polymerase activity was increased by exposure of isolated hepatocytes to 100 mmol/L ethanol for 10 min. In hepatocyte culture, increases in poly (ADP-ribose) polymerase were not detected after exposure to 100 mmol/L ethanol for 10 min or 2 hr but rather occurred at 24 hr. Ethanol exposure of hepatocytes in culture for 2 hr, however, decreased the K

m
for NAD+ of poly (ADP-ribose) polymerase. Both nicotinamide and 5-aminobenzamide, which are inhibitors of poly (ADP-ribose) polymerase, prevented the decrease in NAD+ produced by 2-hr exposure of hepatocytes in culture to 100 mmol/L ethanol. The effect of ethanol in decreasing DNA synthesis on days 3 and 4 of culture was not reversed by the inhibitors of poly (ADP-ribose) polymerase. These results indicate that increased ADP-ribosylation of hepatocyte proteins is a mechanism for the effect of ethanol in decreasing NAD+ (Hepatology 1992; 15:471-476).
Inhibition by noradrenaline and adrenaline of the increase in glucose and lactate output and decrease in flow after sympathetic nerve stimulation in perfused rat liver: Possible involvement of protein kinase C
Authors: Miura Hisayuki , Gardemann Andreas , Rosa Josip , Jungermann Kurt
Published: March 2007

In perfused rat liver stimulation of the hepatic nerve plexuses increased via α1-receptors glucose and lactate output decreased flow and caused an overflow of noradrenaline into the hepatic vein. Infusion of noradrenaline and adrenaline also elicited similar metabolic and hemodynamic alterations via α1-receptors, whereas infusion of isoproterenol via β2-receptors enhanced glucose output and slightly reduced lactate release without affecting flow. The influence of circulating catecholamines on the nerve stimulationdependent changes was investigated.

Noradrenaline (100 nmol/L) or adrenaline (40 nmol/L) but not isoproterenol (1 μmol/L), which themselves caused about half-maximal alterations, strongly inhibited the nerve stimulation-induced increase in glucose and lactate output and decrease in flow but had no effect on noradrenaline overflow.

The protein kinase C activator (4β)phorbol 12-myristate, 13-acetate (100 nmol/L) but not its analog (4α)phorbol 12,13-didecanoate (100 nmol/L) strongly inhibited the metabolic and hemodynamic changes caused by nerve stimulation or noradrenaline infusion. The protein kinase C inhibitor H7 (20 μmol/L) partially prevented the inhibition of the nerve actions by noradrenaline.

The results lead us to conclude that noradrenaline and adrenaline inhibited the metabolic and hemodynamic nerve actions by means of a mechanism involving protein kinase C rather than presynaptic α-receptors or β-receptors. The catecholamines apparently increased via α1-receptors inositol 1,4,5-trisphosphate, which in turn enhanced cytosolic Ca2+ and thus altered metabolism and in part hemodynamics, and diacylglycerol, which in turn activated protein kinase C and thus feedback inhibited the signal chain from α1-receptors via G proteins to phospholipase C. (Hepatology 1992;15:477-484).
Mitogenic effects of hepatic stimulator substance on cultured nonparenchymal liver epithelial cells
Authors: Gupta Sanjeev , LaBrecque Douglas R. , Shafritz David A.
Published: March 2007

We determined whether hepatic stimulator substance shares its mitogenic specificity for hepatocytes with nonparenchymal epithelial cells in the hepatocyte lineage. Cell lines designated HTC (derived from a rat hepatoma known to respond to hepatic stimulator substance) and FNRL, K-16 and K-22 (derived from rat liver nonparenchymal epithelial cells) were used. After exposure to hepatic stimulator substance, [3H]-thymidine incorporation into DNA was significantly increased (p < 0.001) in HTC, FNRL and K-16 cells, but not in K-22 cells. Fluorescence-activated cell sorting demonstrated that the mitogenic response to hepatic stimulator substance was associated with a greater proportion of cells entering the S phase. Epidermal growth factor, alone or in combination with hepatic stimulator substance, had no significant mitogenic effect on FNRL cells, but exposure of these cells to transforming growth factor-β1 inhibited [3H]-thymidine incorporation into DNA and reduced the proportion of cells in the S and G2/M phases. Simultaneous exposure of FNRL cells to hepatic stimulator substance and transforming growth factor-β1 abrogated the inhibitory effect of transforming growth factor-β1. Comparison of butyrate-synchronized HTC cells with hepatic stimulator substance-treated HTC cells showed that S-phase progression in these conditions was different, with no intervening cell cycle arrest after treatment with hepatic stimulator substance. Mitogenic stimulation of FNRL and K-16 cells with the liver-specific growth factor hepatic stimulator substance suggests that these cells are of hepatocyte lineage. These results strengthen the evidence for a possible link between hepatocytes and nonparenchymal liver epithelial cells during liver biogenesis and differentiation. (Hepatology 1992;15:485-491).
Fine-needle aspiration biopsy for the measurement of hepatic iron concentration
Authors: Olynyk John , Williams Phillip , Fudge Andrew , Pulbrook Steven , Kerr Rikki , MacKinnon Malcolm , Hall Pauline
Published: March 2007

The potential application of fine-needle aspiration liver biopsy in the documentation of hepatic iron overload has been assessed in iron-loaded rats. Fineneedle aspiration and standard liver biopsy specimens were obtained from three groups of animals supplemented with oral and parenteral iron for 2 to 6 mo. The mean dry weights of standard and fine-needle biopsy specimens were 7.41 ± 0.77 (± S.E.M.) and 0.57 ± 0.54 mg, respectively. Hepatic iron in fine-needle aspiration biopsy specimens correlated significantly with hepatic iron in standard liver biopsy specimens as measured by biochemical determination, computerized image analysis and histological grading (r > 0.9, p < 0.001). In conclusion, we have shown that fine-needle aspiration biopsy of the liver can obtain sufficient tissue for biochemical measurement of the hepatic iron concentration in an animal model of iron overload. The clinical applications of fine-needle aspiration liver biopsy in human beings with iron overload is currently being investigated.
Contribution of No-reflow phenomenon to hepatic injury after ischemia-reperfusion: Evidence for a role for superoxide anion
Authors: Koo Anthony , Komatsu Hirokazu , Tao Gongming , Inoue Masayashu , Guth Paul H. , Kaplowitz Neil
Published: March 2007

Controversy exists as to the role of oxygen-derived free radicals in tissue injury and the no-reflow phenomenon in reperfusion injury after ischemia. In this study using an experimental rat model, left hepatic lobar ischemia followed by reperfusion resulted in an increase of serum glutamic pyruvic transaminase at 30 min with concomitant histological evidence of hepatocellular necrosis at 24 hr. In the in vivo liver microcirculation, reperfusion after ischemia resulted in an initial transient return of blood flow, but stasis of blood flow later developed in the liver sinusoids. Thus a no-reflow phenomenon in the microcirculation was demonstrated. Intravenous administration of a longacting form of superoxide dismutase (half-life 6 hr, dose 4 or 8 mg/kg) significantly decreased the hepatocellular necrosis and reduced the microcirculatory stasis in the liver sinusoids. These studies established the important contribution of the no-reflow phenomenon in ischemia-reperfusion injury to the liver and the participation of superoxide anions in mediating the no-reflow phenomenon.
Presence of functionally active cytochrome P-450IIE1 in the plasma membrane of rat hepatocytes
Authors: Wu Defeng , Cederbaum Arthur I.
Published: March 2007

Recent experiments have described the presence of cytochrome P-450 and certain P-450 isozymes in the plasma membrane of rat liver. Experiments were carried out to evaluate whether cytochrome P-450IIE1 was present in the plasma membrane fraction of livers from control rats and rats treated with 4-methylpyrazole, which induces this isozyme. Using immunofluorescence, fluorescence was detected at the surface of intact hepatocytes that were initially incubated with anti-P-450IIE1 IgG, but not preimmune IgG, followed by incubating with goat antirabbit IgG conjugated with either fluorescein or rhodamine. The fluorescence appeared to be uniformly distributed across the entire surface. Intense intracellular staining could be observed when the hepatocytes were permeabilized by acetone treatment. Similar results were obtained with control hepatocytes; however, the fluorescence intensity was considerably less than that shown by the induced hepatocytes. Hepatocytes isolated from the pericentral zone of the liver acinus displayed more intense fluorescence at the surface than did hepatocytes from the periportal zone. Purified plasma membranes oxidized dimethylnitrosamine to formaldehyde at rates that were 14% to 30% that of the microsomes, which exceeds the 3% contamination of the plasma membranes by microsomes as assessed by glucose-6-phosphatase activity. Immunoblots of the plasma membranes revealed the presence of a single band, whose intensity of staining was 14% to 26% that of the microsomes. Oxidation of dimethylnitrosamine and immunoblot intensity were about twofold greater with plasma membrane fractions from 4-methylpyrazole-treated rats than controls. These results suggest the presence of inducible, functionally active P-450IIE1 in the plasma membrane, which may be of toxicological significance in view of the preferential metabolism of a variety of hepatotoxins and carcinogens and the elevated production of reactive oxygen intermediates by this isozyme. (Hepatology 1992;15:515-524).
The Pathology of Hepatitis C
Authors: Scheuer Peter J. , Ashrafzadeh Parvin , Sherlock Sheila , Brown David , Dusheiko Geoffrey M.
Published: March 2007

To determine the histologic pattern of hepatitis C, 54 liver biopsy specimens from 45 patients with a clinicopathological diagnosis of hepatitis C were studied. All patients were seropositive for antibody to hepatitis C virus by second–generation testing. Both transfusion–related and sporadic cases were included. More than half the samples showed chronic hepatitis without cirrhosis, whereas 44% showed developing or fully established cirrhosis. A histological pattern of mild chronic hepatitis with portal lymphoid follicles and varying degrees of lobular activity was found in many of the patients. Lymphoid aggregates or follicles were seen in 78% of biopsy specimens, but aggregates, less prominent than in hepatitis C, were also seen in 14 of 27 samples (52%) from patients with hepatitis B. We conclude that a characteristic histological pattern exists in chronic hepatitis C, that this pattern is not always found and that prominent lymphoid follicles, though not unique to hepatitis C, provide a useful diagnostic clue. (Hepatology 1992;15:567-571).
The Histological Features of Chronic Hepatitis C and Autoimmune Chronic Hepatitis: A Comparative Analysis
Authors: Bach Nancy , Thung Swan N. , Schaffner Fenton
Published: March 2007

Before the availability of serological markers for hepatitis C, the morphological features of this diagnosis, which represents most non–A, non–B hepatitis, could not be confirmed. We examined biopsy specimens from 50 patients with chronic hepatitis C and 21 patients with autoimmune chronic hepatitis. Each biopsy specimen was graded on 19 different histological features. The results indicated that at the time of biopsy, the average age of patients with chronic hepatitis C was 46 yr vs. 36 yr for autoimmune chronic hepatitis. Cirrhosis was seen more frequently in autoimmune chronic hepatitis (90%) than in hepatitis C (58%). Features more commonly observed in chronic hepatitis C were bile duct damage (91% vs. 40%), bile duct loss (91% vs. 20%), steatosis (72% vs. 19%) and lymphoid cell aggregation (follicles) within portal tracts (49% vs. 10%). Severe lobular necrosis and inflammation (76% vs. 38%), piecemeal necrosis (81% vs. 10%), multinucleated hepatocytes (29% vs. 6%) and broad areas of parenchymal collapse (76% vs. 6%) were seen more often in autoimmune chronic hepatitis. Exclusion of five patients with autoimmune chronic hepatitis who received immunosuppression before biopsy accentuated these differences. In conclusion, morphological criteria, in addition to serological data, may be useful for differentiating chronic hepatitis C from autoimmune chronic hepatitis, which histologically is a more aggressive disease. (Hepatology 1992;15:572-577).
A Randomized Controlled Trial of Lymphoblastoid Interferon–α in Patients With Chronic Hepatitis B Lacking Hbeag
Authors: Fattovich Giovanna , Farci Patrizia , Rugge Massimo , Brollo Lucio , Mandas Antonella , Pontisso Patrizia , Giustina Giuliano , Lai Eliana M. , Belussi Fabio , Busatto Graziella , Balestrieri Angelo , Ruol Arturo , Alberti Alfredo
Published: March 2007

Ongoing hepatitis B virus replication in the presence of antibody to HBeAg can be observed in patients with active liver disease. These forms of chronic hepatitis B have been described as having a poor prognosis. We have conducted a randomized controlled trial to assess the efficacy of lymphoblastoid interferon–α in 60 patients with antibody to HBeAg and hepatitis B virus DNA-positive chronic hepatitis. Patients received 5 million U/m2 interferon three times a week for 6 mo, or no treatment. Final evaluation 18 mo after randomization showed hepatitis B virus DNA negativity and ALT normalization in 53% of treated patients and in 17% of controls (p < 0.01). The probability of sustained hepatitis B virus DNA loss was significantly higher in treated patients than in controls (p < 0.005). Blinded histological assessment revealed improvement in 50% of treated patients compared with 33% of controls. Pretreatment hepatitis B virus DNA and aminotransferase levels and histological appearance were not predictive of response.

The results of this trial indicated that marked reduction of viral replication in serum and remission of liver damage can be obtained with lymphoblastoid interferon in about 50% of patients with HBeAg antibody- and HBV DNA-positive chronic hepatitis. This rate of response is higher than that reported previously. (Hepatology 1992;15:584-589).
Effect of Duration of Hepatitis B Virus Infection on the Association Between Human Immunodeficiency Virus Type–1 and Hepatitis B Viral Replication
Authors: Koblin Beryl A. , Taylor Patricia E. , Rubinstein Pablo , Stevens Cladd E.
Published: March 2007

This study examined the effect of duration of hepatitis B virus infection on the association between human immunodeficiency virus type–1 infection and hepatitis B viral replication. Twenty–five chronic HBsAg carriers were studied. Presence of hepatitis B virus DNA and expression of HBeAg were more frequent among 20 chronic HBsAg carriers positive for human immunodeficiency virus type–1 antibody compared with five chronic HBsAg carriers negative for human immunodeficiency virus type–1 antibody, but the associations were not statistically significant. Hepatitis B virus DNA and HBeAg were inversely related to duration of hepatitis B virus infection (p < 0.001). Stratifying for duration of hepatitis B virus infection, the presence of viral replication was similar among patients negative and positive for antibody to human immunodeficiency virus type–1. Hepatitis B virus DNA levels did not increase with the decline of cellular immunity over time. In conclusion, hepatitis B virus replication among chronic carriers may be a function of duration of hepatitis B virus infection rather than of an effect of human immunodeficiency virus type–1. (Hepatology 1992;15:590-592).
Liver Function in Acute Viral Hepatitis As Determined by A Hepatocyte–Specific Ligand: 99MTc–Galactosyl-Neoglycoalbumin
Authors: Virgolini Irene , Müller Christian , Höbart Josef , Scheithauer Werner , Angelberger Peter , Bergmann Helmar , O'Grady John , Sinzinger Helmut
Published: March 2007

Twelve patients with recently diagnosed acute viral hepatitis underwent serial 99mTc–galactosyl neoglycoalbumin scanning of the liver (for up to 8 mo). Injection of 99mTc–galactosyl neoglycoalbumin (150 mBq) at a rate of 3.5 mg (50 nmol; 1 ml) revealed that the liver is the exclusive site of tracer uptake. Simulation of 99mTc–galactosyl neoglycoalbumin kinetics allowed quantification of galactosyl neoglycoalbumin binding to human hepatic binding protein. Return of liver function test scores to normal values was associated in two patients with hepatitis A, in four patients with hepatitis B and in two patients with non–A, non–B hepatitis virus infection, with increases in hepatic binding protein concentration (up to three times the initial concentration), binding rate constant and hepatic blood flow. In the other four patients (three patients with hepatitis B and one patient with cytomegalovirus infection) a prolonged course of disease was monitored. In the mean, hepatic binding protein increased from 0.41 ± 0.11 μmol/L after onset of acute hepatitis (n = 12) to 0.78 ± 0.21 μmol/L after 6 mo of follow–up (n = 10) (p < 0.001). During this period, binding rate constant (72.4 ± 12.6 vs. 82 ± 11.5 μmol/L/sec; p < 0.05) and hepatic blood flow (0.027 ± 0.0051 vs. 0.031 ± 0.0083 L/sec; p < 0.05) increased. Hepatic binding protein concentration correlated highly with actual laboratory test results for liver function (r = 0.98; p = 0.0001). We conclude that scintigraphic evaluation of functional liver cell mass using the new receptor–tracer 99mTc–galactosyl neoglycoalbumin could provide an in vivo diagnostic means of quantifying liver function and assessing liver morphology. In addition, our findings suggest that changes in hepatic binding protein-receptor concentration are likely to occur in vivo. (Hepatology 1992;15:593-598).
Hydroxypyridinium Collagen Cross–Links in Human Liver Fibrosis: Study of Alveolar Echinococcosis
Authors: Ricard-Blum Sylvie , Bresson-Hadni Solange , Vuitton Dominique-Angèle , Ville Gerard , Grimaud Jean-Alexis
Published: March 2007

Liver samples from patients with three different types of liver diseases, alveolar echinococcosis (a dense and irreversible fibrosis), hepatocellular carcinoma and alcoholic cirrhosis, were analyzed for their content in hydroxypyridinium cross–links found in mature collagen. We demonstrated the presence of small amounts of pyridinoline in control livers (0.27 ± 0.06 pmol/pmol of collagen). Pyridinoline content was increased in fibrotic livers, with the highest values found in patients with alveolar echinococcosis (up to 1.33 pmol/pmol of collagen). The deoxy analogue of pyridinoline was not detected in either normal or fibrotic livers. Pyridinoline levels, expressed as picomoles per picomole of collagen, were similar in all patients with carcinoma (0.7 ± 0.05 pmol/pmol of collagen). They were heterogeneous in patients with alveolar echinococcosis and were particularly high in patients with alcoholic cirrhosis (1.04 ± 0.11 pmol/pmol of collagen). These results demonstrate for the first time the presence of an hydroxypyridinium cross–link in liver fibrosis and suggest that pyridinoline measurement might be an important criterion in assessing the irreversibility of human liver fibrosis. (Hepatology 1992;15:599-602).
Effect of Ursodeoxycholic Acid on the Kinetics of the Major Hydrophobic Bile Acids in Health and in Chronic Cholestatic Liver Disease
Authors: Beuers Ulrich , Spengler Ulrich , Zwiebel Franz M. , Pauletzki Juergen , Fischer Sven , Paumgartner Gustav
Published: March 2007

Beneficial effects of ursodeoxycholic acid in chronic cholestatic liver diseases have been attributed to displacement of hydrophobic bile acids from the endogenous bile acid pool. To test this hypothesis, we determined pool sizes, fractional turnover rates, synthesisiinput rates and serum levels of deoxycholic acid and chenodeoxycholic acid before and 1 mo after the start of treatment with ursodeoxycholic acid (13 to 15 mg/kg body wt/day) in four healthy volunteers and five patients with chronic cholestatic liver diseases (three with primary biliary cirrhosis and two with primary sclerosing cholangitis). Bile acid kinetics were determined by combined capillary gas chromatographyisotope ratio mass spectrometry in serum samples after administration of [2H4] deoxycholic acid and [13C]chenodeoxycholic acid. In healthy volunteers, deoxycholic acid pool sizes decreased during administration of ursodeoxycholic acid by 72%. In patients with cholestatic liver diseases, deoxycholic acid pool sizes before ursodeoxycholic acid treatment were only 13% of those in healthy volunteers and were unaffected by ursodeoxycholic acid treatment. Chenodeoxycholic acid pool sizes were not different in healthy volunteers and in patients with cholestatic liver disease, and were not altered by ursodeoxycholic acid treatment. In both healthy volunteers and patients with cholestatic liver disease, synthesidinput rates and serum levels of deoxycholic acid and chenodeoxycholic acid were not altered by ursodeoxycholic acid treatment. Because in our patients improvement of serum liver tests during short–term ursodeoxycholic acid treatment was noted without a decrease of the pool sizes of the major hydrophobic bile acids, we conclude that displacement of hydrophobic endogenous bile acids is not the mechanism of action of ursodeoxycholic acid in chronic cholestatic liver disease. (Hepatology 1992; 15603–608).
Value of Urinary Copper Excretion After Penicillamine Challenge in the Diagnosis of Wilson's Disease
Authors: Da Costa Claudia Martins , Baldwin Dianne , Portmann Bernard , Lolin Yvette , Mowat Alex P. , Mieli-Vergani Giorgina
Published: March 2007

To investigate the diagnostic value of 24–hr urinarycopper excretion testing after penicillamine challenge in the diagnosis of Wilson's disease, 75 consecutive children referred for a variety of liver problems and in whom parameters of copper metabolism had been investigated were analyzed retrospectively. Seventeen had Wilson's disease, 22 had autoimmune chronic active hepatitis, 6 had primary sclerosing cholangitis, 12 had chronic liver disease of various etiologies, 4 had cryptogenic acute liver failure, 6 had acute hepatitic illnesses and 8 had a variety of disorders featuring normal liver histological appearance. Serum ceruloplasmin and total copper levels were significantly lower in Wilson's disease patients compared with all other groups, but three children with Wilson's disease had normal ceruloplasmin levels and seven had normal total copper levels. No significant difference was found for free serum copper levels and liver copper content between Wilson's disease patients and the other groups. Baseline 24–hr urinary copper excretion was significantly higher in Wilson's disease patients compared with that of the other patients, but six children with Wilson's disease had levels just above the upper limit of normal, overlapping with values obtained in three children with liver failure, two with acute hepatitis, two with autoimmune chronic active hepatitis and three with primary sclerosing cholangitis. The 24–hr urinary copper excretion after penicillamine challenge proved the most accurate single diagnostic test; levels more than 25 μmol/24 hr were present in 15 of 17 patients with Wilson's disease, but in only 1 child with liver failure of the 58 with other disorders. The penicillamine challenge is a valuable aid in the diagnosis of Wilson's disease, particularly in children with no Kaiser–Fleischer rings. (Hepatology 1992; 15:609–615).