bluuebunny/crossref_metadata_2025 huggingface dataset:
Occurrence of Oval–Type Cells in Hepatitis B Virus—Associated Human Hepatocarcinogenesis
Authors: Hsia Chu Chieh , Evarts Ritva P. , Nakatsukasa Harushige , Marsden Elizabeth R. , Thorgeirsson Snorri S.
Published: March 2007

Proliferation of a new population of epithelial cells with distinct structure, as well as cytokeratin and α–fetoprotein expression, was observed in nonneoplastic liver tissues from 14 cases (13 hepatitis B virus—positive) of human hepatocellular carcinoma. These cells were characterized by oval nuclei; scant, pale cytoplasm; small cell size; and cross–reaction with a monoclonal antibody against rat oval cells. These putative human oval cells were strongly positive for cytokeratin 19 and displayed considerable heterogeneity in α–fetoprotein and albumin expression. The oval cells were most prominent in actively regenerating nodules and in liver tissue surrounding the cancer. Oval cells and transitional types of cells appear to be the principal producers of α–fetoprotein in the regenerating liver. Cancer cells positive for cytokeratins 8, 18 and 19 were observed in half the hepatocellular carcinomas studied. The data suggest that a new cell population structurally similar to oval cells seen in early stages of chemical hepatocarcinogenesis in rats is consistently present in regenerating liver lesions associated with human hepatocellular carcinoma. Furthermore, it is possible that the proliferation of these oval–type cells may partly account for the elevation of serum α–fetoprotein frequently seen in precancerous stages of hepatitis B virus—associated human hepatocellular carcinoma.
Hepatitis B Virus Precore Mutants Are Identical in Carriers From Various Ethnic Origins and Are Associated With A Range of Liver Disease Severity
Authors: Tur-Kaspa Ran , Klein Athalia , Aharonson Shlomit
Published: March 2007

Hepatitis B virus carriers in Israel are mostly HBeAg negative, of whom 5% to 10% have circulating hepatitis B virus. Recently, a hepatitis B virus variant with a stop codon in the precore region was identified, and it was suggested that specific mutations are associated with fulminant or severe chronic active hepatitis. We have analyzed serum samples from HBeAg–positive and HBeAg–negative patients by polymerase chain reaction, using primers spanning the precore/core region. Nucleotide sequence analysis (by direct sequencing) from amplified hepatitis B virus DNA demonstrated that viral genomes from all HBeAg–negative patients contain G to A mutation (nucleotide 1896), leading to the formation of a stop codon. An additional G to A mutation was identified three nucleotides downstream (nucleotide 1899). These patients are of various ethnic origins, with no unique clinical characteristics and with normal liver histology, chronic hepatitis or cirrhosis. No mutation at the precore/core region was observed in the HBeAg–positive patients. In conclusion, the precore mutations identified in hepatitis B virus carriers in Israel are identical regardless of the carrier's ethnic origin and are associated with mild–to–severe liver disease.
Pulmonary Hemorrhage and Glomerulonephritis in Primary Biliary Cirrhosis
Authors: Bissuel François , Bizollon Thierry , Dijoud Frédérique , Bouletreau Paul , Cordier Jean François , Chazot Charles , Gouillat Christian , Trepo Christian
Published: March 2007

We observed life–threatening intrapulmonary hemorrhages and focal proliferative glomerulonephritis in a 41–yr–old woman with primary biliary cirrhosis. The severity of the symptoms necessitated blood transfusions and mechanical ventilation; the patient improved with the help of corticosteroid therapy. No formal evidence of either Goodpasture's syndrome or any other well–defined systemic vasculitis could be found. Neutrophil cytoplasmic antibodies were initially positive and became undetectable after 3 mo of immunosuppressive treatment without relapse. This association has not been described previously and may be added to the list of extrahepatic immune–mediated conditions associated with primary biliary cirrhosis.
Incidence and Diagnostic Features of Macroregenerative Nodules Vs. Small Hepatocellular Carcinoma in Cirrhotic Livers
Authors: Ferrell Linda , Wright Teresa , Lake John , Roberts John , Ascher Nancy
Published: March 2007

In Japan, the presence of a large regenerative nodule within a cirrhotic liver, referred to as a macroregenerative nodule or adenomatous hyperplasia, is thought to play a role in the pathogenesis of hepatocellular carcinoma. These lesions, however, have received little attention outside of Japan. We examined 110 sequentially explanted cirrhotic livers for the presence of such nodules. By gross examination, 19 livers (17.3%) had 40 nodules (10 livers had more than one nodule) between 0.8 and 3.5 cm in diameter. By histological examination, 28 of these were macroregenerative nodules and 12 were hepatocellular carcinomas. Three of these hepatocellular carcinomas, however, appeared to have arisen in association with a macroregenerative nodule. We found that the architectural features of thickened cell plates, formation of trabeculae and loss of reticulin were usually very helpful in differentiating benign macroregenerative nodules from hepatocellular carcinoma. The incidence of macroregenerative nodules in our series was similar to that seen in the Japanese studies, and although we feel that they may play a role in the pathogenesis of carcinoma, we do not believe their presence is necessary for the development of hepatocellular carcinoma.
Multiple Autoepitope Presentation for Specific Detection of Antibodies in Primary Biliary Cirrhosis
Authors: Briand Jean-Paul , Andre Chantal , Tuaillon Nadine , Herve Laurence , Neimark Jean , Muller Sylviane
Published: March 2007

Antimitochondrial autoantibodies are present in sera from close to 95% of patients with primary biliary cirrhosis. The so–called primary biliary cirrhosis–specific antigen, named M2, was found to be associated with an enzyme complex of the inner mitochondrial membrane and, more precisely, with the E2 component, dihydrolipoamide acetyltransferase, of the pyruvate dehydrogenase complex. We recently established that an immunodominant epitope recognized in direct enzyme–linked immunosorbent assay by primary biliary cirrhosis M2+ sera, but not by non—primary biliary cirrhosis M2+ sera, could be mimicked by a synthetic peptide encompassing residues 167-184 of the E2 component and associated with lipoic acid. This fragment is present in the natural inner lipoyl–binding site of the human enzyme, and the presence of lipoic acid located on Iysine 173 was found to be essential to allow IgG antibody binding. In this study we have improved the enzyme–linked immunosorbent assay test based on the synthetic peptide—lipoic acid conjugate by using a multiple antigen peptide system containing eight copies of the peptide as antigen. This approach avoids the use of a peptide conjugated to a carrier protein and was found to be particularly efficient because 23 of 27 primary biliary cirrhosis M2+ sera (85%) could be identified. A multiple antigen peptide without lipoic acid was not recognized by primary biliary cirrhosis antibodies. The peptide used in the multiple antigen peptide construction was a short 13–mer peptide encompassing a highly conserved sequence present in both the outer (residues 40-52) and the inner (residues 167-179) lipoyl–binding sites of the enzyme. Our results thus confirm that the highly conserved lipoate site, when associated with lipoic acid, constitutes a major conformational epitope of E2. The multiple antigen peptide construction with peptide—lipoic acid conjugate could be used as a valuable probe for primary biliary cirrhosis diagnosis.
Hepatic Mitochondrial Glutathione Depletion and Progression of Experimental Alcoholic Liver Disease in Rats
Authors: Hirano Akeshi , Kaplowitz Neil , Tsukamoto Hidekazu , Kamimura Seiichiro , Fernandez-Checa Jose C.
Published: March 2007

Long–term ethanol feeding has been shown to selectively reduce hepatic mitochondrial glutathione content by impairing mitochondrial uptake of this thiol. In this study, we assessed the role of this defect in evolution of alcoholic liver disease by examining the mitochondrial glutathione pool and lipid peroxidation during progression of experimental alcoholic liver disease to centrilobular liver necrosis and fibrosis. Male Wistar rats were intragastrically infused with a high–fat diet plus ethanol for 3,6 or 16 wk (the duration that resulted in induction of liver steatosis, necrosis and fibrosis, respectively). During this feeding period, the cytosolic pool of glutathione remained unchanged in the ethanol–fed animals compared with that in pair–fed controls. In contrast, the mitochondrial pool of glutathione selectively and progressively decreased in rats infused with ethanol for 3, 6 or 16 wk, by 39%, 31% and 85%, respectively. Renal mitochondrial glutathione level remained unaffected throughout the experiment. Serum ALT levels increased significantly in the ethanol–fed rats at 6 wk and remained elevated at 16 wk. In the mitochondria with severely depleted glutathione levels at 16 wk, enhanced lipid peroxidation was evidenced by increased malondialdehyde levels. Thus a progressive and selective depletion of mitochondrial glutathione is demonstrated in the liver in this experimental model of alcoholic liver disease and associated with mitochondrial lipid peroxidation and progression of liver damage.
Liver Regeneration and the Effect of Exogenous Putrescine on Regenerative Activity After Partial Hepatectomy in Cirrhotic Rats
Authors: Macintosh Ethel , Gauthier Tony , Pettigrew Norman , Minuk Gerald
Published: March 2007

There are conflicting data regarding the ability of the liver to regenerate after partial hepatectomy in animals and humans with cirrhosis. The purpose of this study was to document liver regeneration after partial hepatectomy in a carbon tetrachloride rat model of cirrhosis and to determine whether exogenous putrescine, a polyamine that has been reported to stimulate liver regeneration in animal models of acute liver failure, enhances regenerative activity in cirrhosis. Liver fibrosis and cirrhosis were produced by weekly intragastric gavage with carbon tetrachloride in 130 adult male rats. Vehicle–gavaged rats (n = 12) served as healthy controls. At surgery and at 4 and 8 hr after 70% hepatectomy, rats received normal saline solution or 1 or 10 mg/kg putrescine by intraperitoneal injection. Another group (n = 32) of carbon tetrachloride–treated rats was given putrescine (100 mg/kg) or normal saline solution twice daily for 10 days before partial hepatectomy and at 0, 4 and 8 hr after partial hepatectomy. Liver regeneration was documented 24 and 48 hr after partial hepatectomy on the basis of restitution of liver mass, ornithine decarboxylase activity and [3H]thymidine incorporation into liver DNA. Automated image analysis of the resected liver specimens separated carbon tetrachloride–treated rats into two subgroups: those with bridging fibrosis (fibrotic group) and those with micronodular cirrhosis (cirrhotic group). Restitution of liver mass and ornithine decarboxylase activity at 24 and 48 hr after partial hepatectomy were similar to carbon tetrachloride–treated rats (both fibrotic and cirrhotic) and vehicle–treated healthy controls. Hepatic DNA synthesis, however, was significantly impaired at 48 hr in fibrotic rats (42.1 ± 20.6 dpm/ng DNA; p < 0.05) and at 24 and 48 hr in cirrhotic rats (22.9 ± 9.6 and 27.0 ± 11.3 dpm/ng DNA, respectively; p < 0.005 and p <0.001) compared with vehicle–treated healthy controls (52.6 ± 9.2 and 78.3 ± 6.9 dpm/ng DNA at 24 and 48 hr, respectively). Putrescine therapy after or before and after partial hepatectomy did not alter restored liver mass, ornithine decarboxylase activity or DNA synthesis at 24 or 48 hr after partial hepatectomy in fibrotic or cirrhotic rats compared with their respective saline solution–treated controls. The results of this study indicate that hepatic DNA synthesis is impaired in rats with fibrosis and cirrhosis after partial hepatectomy and that exogenous putrescine does not enhance liver regeneration in this model of chronic liver disease.
Does Albumin Regulate Albumin?
Authors: Berkowitz Caryn M.
Published: March 2007

A novel feedback regulatory mechanism operating on transcription of the albumin gene is described in the rat. In 1946, it was proposed that circulating colloids, including serum albumin, may affect the synthesis and/or secretion of albumin in the liver. The molecular basis for this proposed regulation has now been inves tigated by adding oncotically active macromolecules to the circulation of normal or genetically albumin–deficient Nagase analbuminemic rats (NAR) and analyzing the hepatic expression of genes, including albumin after 24 h. The transcription rate of the albumin gene was higher in NAR than in normal rats and was dramatically reduced by raising serum albumin to 1.6 g/dl. Intravenous infusion of albumin into normal rats also decreased transcriptional activity of the albumin gene by 50-60%, and this decrease correlated with changes in serum colloid osmotic pressure after albumin infusion. Inhibition of albumin gene transcription was also observed upon intravenous infusion of other protein or nonprotein macromolecules, such as γ–globulin and dextran. This down–regulation appears to control the steady–state level of albumin mRNA in the liver. Aside from a concomitant decrease in apo E gene transcription after albumin or macromolecule infusion, there was no change in the transcription rate of other genes, including those exhibiting liver–preferred or –specific expression (e.g., tyrosine aminotransferase, cytochrome P–450, α1–antitrypsin, apolipoproteins A–I and B, and transferrin) or general cellular expression (e.g., α–tubulin, pro α2 collagen, and β–actin). Feedback regulation of albumin gene expression by serum colloids may serve as a specific homeostatic mechanism to maintain the steady–state level of total protein in the circulation.
Pregnancy and Cholelithiasis: Pathogenesis and Natural Course of Gallstones Diagnosed in Early Puerperium
Authors: Valdivieso Vicente , Covarrubias Carmen , Siegel Freddy , Cruz Francisco
Published: March 2007

Several recent reports have indicated an increased prevalence of gallstones in association with pregnancy. If these reports are true, the early puerperium should be a favorable time to detect the disease in its initial stages and follow its natural course. Accordingly, the gallbladder was examined by ultrasound in 980 women during the immediate postpartum period and in 150 nulliparous, age-matched healthy volunteers. Gallstones were detected in 12.2% of the puerperal women and in 1.3% of the control group.

In 70 patients who had stones in a functioning gallbladder, 22 (31%) had had attacks of biliary colic. The history of pain was more common in patients with stones greater than 10 mm in diameter. Forty-one women with small stones (<10 mm) were followed clinically and ultrasonographically for between 6 and 24 (mean = 8.7) mo. All remained pain-free, and in twelve subjects (29%) the stones disappeared.

Gallbladder bile was examined in 11 normal volunteers (controls) immediately after delivery and in 19 women with small stones 39 ± 6 days postpartum. Bile was saturated with cholesterol in the controls and was unsaturated in patients with gallstones.

We conclude that in our population pregnancy is a very important pathogenetic factor favoring gallstone formation. Attacks of biliary colic appear early and frequently in young Chilean women with this disease. Unexplained disappearance of small stones frequently occurs: in some cases it is likely to be the result of spontaneous dissolution because bile becomes unsaturated within a few weeks of delivery. (Hepatology 1993;17:1-4.)
Differentiation Between Heterozygotes and Homozygotes in Genetic Hemochromatosis by Means of a Histological Hepatic Iron Index: A Study of 192 Cases
Authors: Deugnier Yves M. , Turlin Bruno , Moirand Romain , Loréal Olivier , Brissot Pierre , Powell Lawrie W. , Summers Kim M. , Fletcher Linda , Halliday June W.
Published: March 2007

The biochemical hepatic iron index, defined as the ratio of hepatic iron concentration (expressed as micromoles per gram dry weight) to age permits accurate prediction of genetic status in patients with genetic hemochromatosis. However, the hepatic iron concentration is not always available. Therefore a histological hepatic iron index, defined as the ratio of total histological iron score (range = 0 to 60) to age, was evaluated in a total of 192 Australian and French patients with genetic hemochromatosis. These subjects had been classfied previously as heterozygotes (n = 18) or homozygotes (n = 174) according to clinical and familial data only. Biochemical hepatic iron index and histological hepatic iron index were well correlated (Spearman's test: rho = 0.75, p < 0.0001). Both were significantly (p < 0.0001) increased in homozygotes (respectively, 6.7 ± 3.8 [range = 1.2 to 22.6] and 0.62 ± 0.28 [range = 0.14 to 1.5]) compared with heterozygotes (respectively, 1 ± 0.4 [range = 0.45 to 1.6] and 0.08 ± 0.05 [range = 0 to 0.14]). The histological hepatic iron index was less than 0.15 in all heterozygotes and greater than 0.15 in all but two homozygotes. These data show that the age-dependent nature of iron accumulation can also be accommodated by calculating the histological hepatic iron index and that histological study is an accurate means of predicting the genetic status of hemochromatosis patients when hepatic iron concentration is not available. (Hepatology 1993;17:30-34.)
Oddi's Sphincter Motor Activity in Patients with Recurrent Pyogenic Cholangitis
Authors: Khuroo Mohammad Sultan , Zargar Showkat Ali , Yattoo Ghulam Nabi , Allai Mohammed Sultan , Khan Bashir Ahmad , Dar Mohammed Yousuf , Boda Mohammed Iqbal , Javid Gul
Published: March 2007

Oddi's sphincter motor activity was studied in 15 healthy subjects and 15 patients with recurrent pyogenic cholangitis. No significant difference was found in the common bile duct pressures, the Oddi's sphincter basal pressures or the amplitude, frequency and duration of phasic contractions between the controls and patients. However, a significant difference was found in the percentage of antegrade and retrograde phasic wave sequences between the two groups. In control patients 64.0% ± 5.3% of phasic wave sequences were antegrade, and 20% ± 3.6% were retrograde. In patients with recurrent pyogenic cholangitis, 37% ± 3.6% of phasic wave sequences were antegrade, and 42% ± 5.5% were retrograde. No significant difference was found in the percentage of simultaneous phasic wave sequences (16% ± 1.5% vs. 18.5% ± 2.8%, respectively) between the two groups. In all, five (33%) patients with recurrent pyogenic cholangitis had abnormal propagation of phasic contractions of Oddi's sphincter (retrograde phasic wave sequences greater than 50%), two (13%) patients had elevated Oddi's sphincter basal pressures (greater than 40 mm Hg) and one (7%) patient had increased frequency of Oddi's sphincter phasic contractions (more than 9/min). Six of the 15 patients had evidence of papillitis on duodenoscopy. We believe papillitis could induce motor abnormalities in these patients, thus resulting in delayed biliary drainage and recurrent attacks of cholangitis. (Hepatology 1993;17:53-58.)
Depression of Drug-metabolizing Activity in the Human Liver by Interferon-β
Authors: Okuno Hiroyasu , Takasu Masashi , Kano Haruhiko , Seki Toshihito , Shiozaki Yasuko , Inoue Kyoichi
Published: March 2007

The depressant effect of interferon beta on drugmetabolizing activity in the human liver was investigated. Seven patients with chronic hepatitis C were treated with interferon beta at doses of 3 × 106 to 9 × 106 IU/day for 8 wk. The activities of 7-methoxycoumarin O-demethylase and 7-ethoxycoumarin O-deethylase in specimens obtained by liver biopsy were examined before and after interferon treatment. Theophylline pharmacokinetics were also examined before and after interferon treatment. Interferon beta treatment reduced the activities of both O-dealkylases from 6.0 (100%) to 3.2 (53%) nmol/gm liver per minute and from 1.9 (100%) to 1.1 (58%) nmol/gm liver per minute, respectively (p < 0.05). The total body clearance of theophylline was also decreased (from 0.76 to 0.56 ml/kg/min; p < 0.05), and its elimination half-life was increased (from 8.4 to 11.7 hr; p < 0.05); however, the volume of distribution was not significantly affected. The magnitude of the decreases in enzyme activities and in theophylline clearance varied widely in individual patients and did not correlate with the dose of interferon administered. This study provides the first direct evidence that interferon beta can depress the activity of drugmetabolizing enzymes in the human liver. (Hepatology 1993;17:65-69.)
Hyperfibrinolysis Resulting from Clotting Activation in Patients with Different Degrees of Cirrhosis
Authors: Violi Francesco , Ferro Domenico , Quintarelli Claudio , Musca Antonio , Balsano Francesco , Cordova Corrado , Basili Stefania
Published: March 2007

This study explored the relationship between clotting activation and tissue plasminogen activator and its inhibitor in cirrhotic patients with different degrees of liver failure. Sixty-seven patients (40 men, 27 women; age = 31-77 yr) with cirrhosis diagnosed by liver biopsy were divided into three subgroups (A, B and C) on the basis of Child-Pugh classification. Tissue plasminogen activator antigen and activity, plasminogen activator inhibitor antigen and activity, fibrin/fibrinogen degradation products, and D-dimer were measured in each patient. Forty-two patients with normal levels of fibrin/fibrinogen degradation products and D-dimer showed significant progressive decreases of plasminogen activator inhibitor antigen levels (p < 0.01) and activity (p < 0.0001) from class A to class C. This decrease was significantly related to prothrombin time (p < 0.003). Tissue plasminogen activator values were not different in the three Child classes. Twenty-five patients (7 class B and 18 class C) with high circulating values of fibrin/fibrinogen degradation products and D-dimer had higher values of tissue plasminogen activator antigen (20.0 ± 10.1 ng/ml vs. 5.9 ± 3.0 ng/ml; p < 0.0001) and activity (6.9 ± 2.2 U/ml vs. 2.1 ± 1.3 U/ml;p < 0.0001) and lower values of plasminogen activator inhibitor antigen (6.9 ± 4.1 ng/ml vs. 14.8 ± 5.6 ng/ml; p < 0.0001) and activity (4.1 ± 2.8 U/ml vs. 9.8 ± 3.7 U/ml; p < 0.0001) than did patients with normal values of fibrin/fibrinogen degradation products and D-dimer. We conclude that cirrhotic patients without systemic signs of hyperfibrinolysis exhibited progressive decreases of plasminogen activator inhibitor levels, suggesting that its blood levels are strongly related to liver function. The clear-cut imbalance between tissue plasminogen activator and plasminogen activator inhibitor in patients with high circulating levels of D-dimer indicates that hyperfibrinolysis may be due mainly to clotting activation. (Hepatology 1993;17:78-83.)
Bile Acid Sulfonates Alter Cholesterol Gallstone Incidence in Hamsters
Authors: Cohen Bertram I. , Miki Shigeo , Mosbach Erwin H. , Ayyad Nariman , Stenger Richard J. , Mikami Takahiro , Yoshii Michiko , Kihira Kenji , Hoshita Takahiko
Published: March 2007

The prevention of cholesterol gallstone formation by three bile acid analogs, sodium 3α,7α-dihydroxy-5β-cholane-24-sulfonate, sodium 3α,7β-dihydroxy-5β-cholane-24-sulfonate and sodium 3α, 6α-dihydroxy-5β-cholane-24-sulfonate, was examined in a hamster model of cholesterol cholelithiasis. Sodium taurochenodeoxycholate, sodium tauroursodeoxycholate and sodium taurohyodeoxycholate were studied simultaneously for comparison. Gallstones and cholesterol crystals were induced in 14 of 15 hamsters fed a bile acid-free, semipurified lithogenic diet containing 0.3% cholesterol and 4% butterfat for 6 wk. The addition of 0.1% sodium taurochenodeoxycholate and sodium tauroursodeoxycholate to the lithogenic diet had little effect on the formation of gallstones or biliary cholesterol crystals. In contrast, sodium 3α,7β-dihydroxy-5β-cholane-24-sulfonate and sodium 3α,7β-dihydroxy-5β-cholane-24-sulfonate, when fed at the same dose, prevented cholesterol gallstone formation significantly. Sodium taurohyodeoxycholate and sodium 3α,6α-dihydroxy-5β-cholane-24-sulfonate inhibited cholesterol gallstone formation effectively. The cholesterol saturation index of bile was greater than 1.00 in all groups, with the exception of the group fed sodium 3α,7α-dihydroxy-5β-cholane-24-sulfonate. Liver and serum cholesterol levels tended to be lower in most of the groups that were fed bile acids. This effect was most pronounced in the animals receiving sodium taurohyodeoxycholate. At the end of the experiment, the administered sulfonate analogs were detected in gallbladder bile. Sodium 3α,7α-dihydroxy-5β-cholane-24-sulfonate (32.7%) became the major biliary bile acid; smaller percentages of the administered bile acid sulfonates were recovered in the bile of the groups fed sodium 3α,7β-dihydroxy-5β-cholane-24-sulfonate (12.3%) and sodium 3α, 6α-dihydroxy-5β-cholane-24-sulfonate (17.4%). The bile of the hamsters that were fed sodium taurochenodeoxycholate and sodium taurohyodeoxycholate contained considerable amounts of chenodeoxycholic acid (50.6%) and hyodeoxycholic acid (40.0%), respectively. On the other hand, in the bile of the group that was fed sodium tauroursodeoxycholate, ursodeoxycholic acid accounted for less than 1% of the total bile acids; the bile acid composition was similar to that of the group that was fed sodium taurochenodeoxycholate. We concluded that the sulfonate analogs of three dihydroxy bile acids suppressed the formation of cholesterol gallstones in a hamster model of cholesterol cholelithiasis. Their efficacy increased in the following order: sodium 3α,7α-dihydroxy-5β-cholane-24-sulfonate, sodium 3α, 6α-dihydroxy-5β-cholane-24-sulfonate, sodium 3α,7β-dihydroxy-5β-cholane-24-sulfonate; however, it was not directly related to their concentration in bile at the end of the feeding period (6 wk). (Hepatology 1993;17:103-110.)
Biliary Copper Excretion in Acutely and Chronically Copper-loaded Rats
Authors: Harada Masaru , Sakisaka Shotaro , Yoshitake Masao , Shakadoh Satoshi , Gondoh Kazuhisa , Sata Michio , Tanikawa Kyuichi
Published: March 2007

Biliary copper excretion was examined in rats with acute, continuous and chronic copper loads. Copper was excreted into bile, and the concentration peaked 40 min after a venous injection of copper sulfate (127 ng/gm body weight). The excretion was significantly inhibited by colchicine. Therefore some copper may be transported in hepatocytes by a vesicular pathway and excreted into bile. Biliary copper output increased over time and reached a plateau 180 min after a continuous venous infusion of copper sulfate (318 ng/gm body weight/hr) had started, when the concentration of copper in bile was much higher than that in plasma; the bile/plasma ratio of copper concentrations was 4.32 ± 0.46. These data support the idea that copper transport involves a specific uptake and transport system. In chronically copper-loaded rats, hepatic copper content was significantly increased compared with controls, and reaction products for copper were observed in hepatocyte granules by light microscopic examination with p-dimethylaminobenzylidene rhodanine stain. The number of lysosomes in hepatocytes increased and the shape changed. In chronically copper-loaded rats the number of tubular lysosomes was very high. However, other organelles appeared to be normal. In these rats biliary excretion of not only copper but also acid phosphatase, a Iysosomal enzyme, was significantly greater than the control. Therefore hepatocyte lysosomes may play an important role in biliary copper excretion. Furthermore, when biliary Iysosomal excretion increases, the tubular lysosomes actively participate in this excretion. (Hepatology 1993;17:111-117.)
The Clearance Rate of Chylomicron Retinyl Ester from Plasma Can Be Used to Distinguish Rats with Cirrhosis from Those with Portacaval Shunt
Authors: Kasai Tetsuhiro , Moriwaki Hisataka , Okuno Masataka , Numaguchi Satoshi , Murakami Nobuo , Seishima Mitsuru , Ohnishi Hiroo , Shidoji Yoshihiro , Muto Yasutoshi
Published: March 2007

Effects of carbon tetrachloride treatment and portacaval shunt surgery on exogenous chylomicron retinyl ester clearance from rat plasma were analyzed assuming three-compartment model kinetics. In rats with cirrhosis and in those with Eck fistulas, the relative pool size of compartment 2 decreased (0.20 and 0.36, respectively) compared with controls (0.82). The relative mass of compartment 3 significantly increased in rats with cirrhosis (1.55) or Eck fistula (0.19) compared with control rats (0.11). The cirrhotic and Eck fistula groups were indistinguishable on the basis of these parameters and on the basis of indocyanine green test values. However, the cirrhosis and Eck fistula groups differed clearly from each other with respect to fractional efflux rate constants (l
2,l
3), where the constant l
2 is from compartment 2 and the l
3 is from compartment 3. Both values decreased in cirrhotic rats, suggesting that the hepatic uptake of chylomicron retinyl esters was impaired by carbon tetrachloride. On the other hand, Eck fistula rats did experience dramatic increases in l
3, implying that the hepatic uptake of chylomicron retinyl esters from compartment 3 was enhanced by portacaval shunting. Elevation of the plasma estrogen level observed in Eck fistula rats may be responsible for the induction of low-density lipoprotein receptors on hepatocytes and for the subsequent enhancement of l
3. These results suggest that a three-compartment model of plasma retinyl ester disappearance kinetics gives important quantitative information about hepatic function. Clinical application of the chylomicron retinyl ester clearance test is discussed for estimating hepatic function reserves and for differential diagnosis of portal hypertension. (Hepatology 1993;17:125-130.)
Vasopressin Gene Expression in Rats with Experimental Cirrhosis
Authors: Kim Jin K. , Summer Sandra N. , Howard Randy L. , Schrier Robert W.
Published: March 2007

Impaired ability to excrete a water load occurs in a substantial number of patients with advanced cirrhosis and in animals with experimental cirrhosis. The nonosmotic stimulation of arginine vasopressin release from the pituitary has been implicated as an important factor in the abnormal water excretion in patients and animals with cirrhosis. In this study, arginine vasopressin hypothalamic gene expression was studied in cirrhotic rats. Cirrhosis was induced by a combination of phenobarbital treatment in drinking water and weekly intragastric administration of carbon tetrachloride for 13 to 15 wk. Severe cirrhosis was confirmed by morphological analysis and the presence of ascites. Plasma arginine vasopressin was also significantly higher in rats with cirrhosis (control = 1.77 ± 0.16 and cirrhotic rats = 4.14 ± 0.62 pg/ml, n = 9, p < 0.002). Hypothalamic arginine vasopressin messenger RNA was also significantly higher in cirrhotic rats (control = 762.1 ± 132.3 and cirrhotic rats = 1,834.2 ± 271.9 pg/hypothalamus, n = 9, p < 0.005). Pituitary arginine vasopressin content was significantly lowered in cirrhotic rats (control = 3.69 ± 0.98 and cirrhotic rats = 1.57 ± 0.09 μg/pituitary, n = 9, p < 0.05). No difference was seen in hypothalamic arginine vasopressin content between the two groups (control = 4.64 ± 0.34 and cirrhotic rats = 4.23 ± 0.33 ng/hypothalamus, n = 9, NS). Oxytocin messenger RNA in the hypothalamus was also not significantly different between the two groups (control = 8.61 ± 0.68 and cirrhotic rats = 9.33 ± 0.65 unit of density, n = 9, NS). No differences were seen in plasma sodium (control = 145.7 ± 1.62 and cirrhotic rats = 145.9 ± 1.09 mmol/L), plasma osmolality (control = 296.6 ± 2.6 and cirrhotic rats = 297.1 ± 4.2 mOsm/kg H2O), creatinine clearance and blood urea nitrogen between the two groups. These results therefore provide support for increased hypothalamic biosynthesis and pituitary release of arginine vasopressin in experimental cirrhosis in the rat. (Hepatology 1993;17:143-147.)
Persistence of systemic and splanchnic hyperkinetic circulation in liver transplant patients
Authors: Hadengue Antoine , Lebrec Didier , Moreau Richard , Sogni Philippe , Durand François , Gaudin Christophe , Bernuau Jacques , Belghiti Jacques , Gayet Brice , Erlinger Serge , Benhamou Jean-Pierre
Published: March 2007

Portal pressure and portal-systemic collateral circulation after orthotopic liver transplantation have not been investigated. We studied systemic and splanchnic hemodynamics in 17 patients with cirrhosis before and 205 ± 146 days after orthotopic liver transplantation. Among the 17 orthotopic liver transplantation patients, 12 had undergone hemodynamic study in the 6 mo before orthotopic liver transplantation. Controls were 50 patients with normal liver architecture. Cardiac index remained elevated in orthotopic liver transplantation patients compared with controls (3.6 ± 0.9 vs. 3.1 ± 0.4 L/min · m2; p < 0.05). Azygos blood flow, which was elevated before orthotopic liver transplantation (585 ± 402 ml/min), remained elevated after orthotopic liver transplantation (553 ± 343 ml/min). In transplant patients, hepatic blood flow was higher than it was in controls (2.26 ± 0.86 vs. 1.38 ± 0.57 L/min; p < 0.05). Elevated hepatic blood flow correlated with cardiac index (r = 0.647, p < 0.025). In patients with normal graft function, hepatic venous pressure gradient was normal (2 ± 1 mm Hg). In a patient with acute rejection, a sharp elevation in the hepatic venous pressure gradient was observed; it returned to normal 45 days after treatment. We conclude that despite normal portal pressure, portal-systemic collateral blood flow remains elevated after orthotopic liver transplantation. Possibly because of persistent collateral circulation, which may keep portal tributary blood flow elevated, hepatic blood flow is increased after orthotopic liver transplantation. Elevated splanchnic blood flow, in turn, contributes to the high cardiac index in liver recipients. Finally, a sharp elevation in portal pressure, which may be observed during acute rejection and subsides after treatment, merits further study. (Hepatology 1993;17:175-178.)
Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure
Authors: Rolando Nancy , Gimson Alexander , Wade Jim , Philpott-Howard John , Casewell Mark , Williams Roger
Published: March 2007

To compare the efficacy of a selective parenteral and enteral antimicrobial regimen in patients with fulminant liver failure, we classified 104 patients on reaching grade II encephalopathy as infected or noninfected. Patients who were infected were randomly assigned to receive IV cefuroxime (group 1) or selective parenteral and enteral antimicrobial regimen (group 2). Noninfected patients were randomly selected to receive either selective parenteral and enteral antimicrobial regimen (group 3) or no initial antimicrobials until clinically indicated (group 4). The four groups were comparable regarding age, sex, cause of disease, coma grade, international normalization ratio, presence of kidney failure and indicators of poor prognosis on admission to the study. Clinical parameters such as white cell count, temperature or changes in the chest radiograph, which were used to stratify patients into those infected or not, were not good predictors of infection because early infection rates were similar in the two groups. Three patients died within 24 hr and were excluded from the analysis. We found 42 microbiologically confirmed infections: group 1, 6 of 21; group 2, 8 of 21; group 3, 9 of 28; and group 4, 19 of 31. A reduction in infection was seen between groups 3 and 4 (p < 0.05). Patients receiving the selective parenteral and enteral antimicrobial regimen (groups 2 and 3) had fewer infections than the control group (group 4) (p < 0.005). Groups receiving early antimicrobial therapy (groups 1, 2 and 3) had a lower incidence of infection compared with group 4 (p < 0.0005). Overall, 55.5% survived, with no significant difference between the four groups. Of 36 patients who fulfilled criteria for liver transplantation, 15 of 24 patients who received early antimicrobials (groups 1, 2 and 3) and 3 of 12 control patients (group 4) underwent transplantation (p < 0.05). Selective parenteral and enteral antimicrobial regimen reduces the risk of infection in patients with fulminant liver failure, but this effect is probably related to the early administration of antimicrobials. No reduction in length of stay in the unit or in the cost of antimicrobials was found. (Hepatology 1993;17:196-201.)
Continuous increase of alcohol dehydrogenase activity along the liver plate in normal and cirrhotic human livers
Authors: Sokal Etienne Marc , Collette Elizabeth , Buts Jean Paul
Published: March 2007

To determine the zonal distribution of alcohol dehydrogenase in normal and cirrhotic human livers, we measured activities of this enzyme by quantitative cytochemical analysis along the liver cell plate in liver specimens from 10 normal organ donors and from 7 children with extrahepatic biliary atresia cirrhosis. In normal human liver samples, a continuous increase in alcohol dehydrogenase activity was observed along the sinusoid from the periportal to the perivenular hepatocytes (mean extinction units from 16.2 ± 10.0 to 58.0 ± 14.8). A similar observation was made in cirrhotic nodules, with activity increasing continuously from nodule periphery to center (7.6 ± 4.1 to 44.9 ± 13.3). This study demonstrates a heterogeneous pattern of alcohol dehydrogenase distribution along the sinusoid in normal human liver specimens. In addition, demonstration of this heterogeneity in human cirrhosis suggests that the cirrhotic liver is able to maintain a parenchymal functional organization, with persistence of metabolic zonation. (Hepatology 1993;17:202-205.)
Eosinophilic infiltration of the liver in primary biliary cirrhosis: A morphological study
Authors: Terasaki Shuichi , Nakanuma Yasuni , Yamazaki Masakazu , Unoura Masashi
Published: March 2007

Eosinophils and their secretory proteins are important in necroinflammatory processes. In this study we surveyed eosinophilic infiltration of the liver in 176 liver biopsy specimens from patients with primary biliary cirrhosis. A considerable number of eosinophils were found in the portal tracts in 51 of these specimens (29%), whereas this finding occurred in only 2 of 50 (4%) specimens from patients with viral chronic active hepatitis. Eosinophilic infiltration of the portal tracts was focal. These eosinophils were immunohistochemically shown to contain the secreted form of eosinophilic cationic protein. Grades of eosinophilic infiltration of the portal tracts were higher in those livers with higher grades of lymphoplasmacytic infiltration, granulomas and florid duct lesion in the portal tracts, and they were lower in those livers with higher grades of bile duct disappearance and orcein-positive granuoles in hepatocytes. In the livers of patients with primary biliary cirrhosis, eosinophils were abundant around the damaged bile ducts, around the portal vein branches and at the marginal regions, and they were scattered in the portal tracts, whereas only the last pattern was seen in viral chronic active hepatitis. Peripheral blood eosinophils tended to be increased in primary biliary cirrhosis patients with higher grades of eosinophilic infiltration of the portal tracts. Eosinophilic infiltration of the portal tracts may play a role in immunological injuries of the interlobular bile ducts in primary biliary cirrhosis. (Hepatology 1993;17:206-212.)
Effects of propranolol on gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy
Authors: Panés Julián , Bordas Josep M. , Piqué Josep M. , García-pagán Juan C. , Feu Faust , Terés Josep , Bosch Jaime , Rodés Joan
Published: March 2007

This study investigated the effects of the short-term administration of propranolol on gastric blood perfusion in cirrhotic patients with portal hypertensive gastropathy. Portal hypertensive gastropathy is a common cause of nonvariceal bleeding in cirrhosis, which is associated with increased gastric mucosal perfusion and is favorably influenced by propranolol therapy. Gastric mucosal perfusion was evaluated with laser-Doppler flowmetry and reflectance spectrophotometry. Measurements were performed under basal conditions and after the double-blind administration of propranolol (0.15 mg/kg intravenously) or placebo. Propranolol administration significantly reduced (p < 0.001) the laser-Doppler signal (2.93 ± 0.23 vs. 2.25 ± 0.22 V) and the hemoglobin content of the gastric mucosa (99.2 ± 3.8 vs. 89.3 ± 3.1 arbitrary units), whereas the oxygen content remained unchanged (37.4 ± 1.2 vs. 36.9 ± 1.0 arbitrary units). Placebo administration had no effect in any of these parameters. Changes in gastric perfusion after propranolol administration were associated with a significant decrease in hepatic venous pressure gradient and azygos blood flow. We conclude that short-term propranolol administration, in addition to lowering portal pressure, reduces the increased gastric blood perfusion in cirrhotic patients with portal hypertensive gastropathy, an effect that may contribute to prevention of bleeding from these lesions. (Hepatology 1993;17:213-218.)
Human hepatic stimulator substance: A product of gene expression of human fetal liver tissue
Authors: He Fuchu , Wu Chutse , Tu Qiang , Xing Guichun
Published: March 2007

Cloning of human hepatic stimulator substance requires clarification of whether the substance is the product of gene expression of liver cells. In this article the translation experiment in Xenopus laevis oocytes indicates that poly (A)+ messenger RNA of human fetal liver cells could conduct the biosynthesis of human hepatic stimulator substance. The translated human hepatic stimulator substance is a heat-, acid- and alkaline-resistant, but specific hepatic-stimulating, protein with a molecular weight in the range of 10 to 30 kD and with secreting ability. The characteristics of the translated human hepatic stimulator substance are consistent with those of biochemically purified human hepatic stimulator substance from human fetal liver cells. These results demonstrate that human hepatic stimulator substance is a product of gene expression of human fetal liver cells and that the complementary DNA of human hepatic stimulator substance could be screened from the complementary DNA library of human fetal liver tissue. (Hepatology 1993;17:225-229.)
Confocal microscopy immunofluorescence localization of desmin and other intermediate filament proteins in fetal rat livers
Authors: Vassy Jany , Rigaut Jean Paul , Briane Dominique , Kraemer Michel
Published: March 2007

Immunolocalization of desmin in fetal rat livers shows that on day 12 of gestation a high number of liver cells express desmin. This number decreases from day 14 onward. On day 20 about the same density of desmin-containing cells is found in fetal rat livers as is found in adult rat livers. Desmin-containing cells show two types of labeling patterns, especially on days 12 and 13 of gestation: (a) a basketlike network of intermediate filaments throughout the whole cell, similar to the labeling pattern of cytokeratin in hepatocytes; and (b) more strongly labeled intermediate filaments developing long and slender processes between adjacent cells, close to the labeling pattern of Ito cells in adult rats. From day 14 of gestation, the first type becomes rare, and from day 18 only the second type remains. Double-labeling experiments show that coexpression of desmin and cytokeratin is found in cells of the first type on days 12, 13 and 14 of gestation. Cells containing desmin with the labeling pattern of the second type never express cytokeratin. Coexpression of vimentin and cytokeratin is never found in fetal hepatocytes, even on day 12 of gestation. Numerous nonhepatocyte cells coexpress desmin and vimentin, but some cells contain vimentin or desmin alone. In desmincontaining cells the labeling pattern is of the first type (basketlike network). These results suggest that in early stages of fetal liver development, desmin is found in two different types of liver cells. Cells of the first type contain cytokeratin and desmin, and those of the second type contain desmin and vimentin, as Ito cells in adult liver tissue. Cells of the first type might represent a particular type of fetal hepatocyte. The existence of these two types of desmin immunolocalization is in convergence with electron microscopic data showing numerous lipid droplets both in fetal hepatocytes and in perisinusoidal cells. It is generally admitted that fetal liver differentiation is the result of the close association between endodermal and mesenchymal cells. Among the latter, desmin-containing cells (fetal Ito cells) might play a crucial role, especially because they are known to contain vitamin A and to express a hepatocyte growth factor in the normal adult liver. (Hepatology 1993;17:293-300.)
Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat
Authors: Fenyves Daphna , Gariépy Louise , Villeneuve Jean-Pierre
Published: March 2007

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio Vmax/Km) averaged 5,319 ± 1,193 ml/min; the extraction ratio in the perfused liver was close to 1.0 (0.97 ± 0.01). Important decreases of microsomal enzyme activity were observed in rats treated with chlorpromazine (30 ± 27 ml/min, p < 0.001) and in rats with acute liver injury (724 ± 401 ml/min, p < 0.001), accounting for the decrease in the hepatic extraction ratio by the perfused liver (0.33 ± 0.09 and 0.71 ± 0.04, respectively, p < 0.01). In cirrhotic livers, enzyme activity was not significantly different from that of controls (3,592 ± 1,857 ml/min) and could not account for the observed decrease in extraction (0.66 ± 0.14, p < 0.01). The extraction of antipyrine by the isolated perfused liver was also measured as an index of microsomal enzyme activity and related to propranolol extraction. Antipyrine extraction was decreased by 90% in acute liver injury, compared with 33% in cirrhosis, suggesting a much greater reduction of microsomal enzyme activity in the former group. Despite these differences, the extraction ratio of propranolol was reduced to a similar extent in rats with cirrhosis (0.64 ± 0.20) and in rats with acute liver injury (0.77 ± 0.10) compared with controls (0.97 ± 0.02). These results suggest that factors other than decreased enzyme activity (i.e., impaired uptake) contribute to lower propranolol extraction in cirrhosis. (Hepatology 1993;17:301-306.)