bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in chinese patients
Authors: Chao You-Chen , Liou Shian-Ren , Chung Ying-Ying , Tang Hung-Shang , Hsu Chung-Te , Li Ting-Kai , Yin Shih-Jiun
Published: March 2007

Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the principal enzymes responsible for the oxidation of ethanol, are polymorphic at the ADH2, ADH3 and ALDH2 loci in human beings. Our previous studies have shown that, compared with nonalcoholic individuals, Chinese alcoholic patients without liver disease had significantly lower frequencies of the ADH2*2 and ADH3*1 alleles, which encode high maximum velocity β2- and γ1-ADH subunits, respectively, as well as a lower frequency of the ALDH2*2 allele, which encodes an enzymatically inactive subunit. The data strongly suggest that genetic variation in both ADH and ALDH may influence drinking behavior and the risk of alcoholism developing through acetaldehyde formation. To further investigate the possible role of acetaldehyde in the pathogenesis of alcoholic liver disease, we determined the ADH and ALDH genotype frequencies in patients with alcohol-related cirrhosis (n = 27), viral hepatitis-related cirrhosis (n = 29) and gastric and duodenal ulcer without relevance to alcohol (n = 30). We developed a new restriction fragment length polymorphism method to genotype the mutant and normal ALDH2 alleles by using polymerase chain reaction-directed mutagenesis, which proved to be simpler and faster than the conventional detection methods that use hybridization with allele-specific oligonucleotide probes. We found that the frequencies of the alleles ADH2*2 (57), ADH3*1 (78) and ALDH2*2 (9) in the alcoholic cirrhotic patients were significantly lower than those in the healthy controls and in the patients with cirrhosis from viral hepatitis and with gastric and duodenal ulcer. No significant differences in the allele frequencies of these three genes between the alcoholic cirrhotic patients and the alcohol-dependent subjects without severe liver injury were found, although the alcoholic cirrhosis group tended to have a higher incidence of ALDH2*1/*2 heterozygotes (5 of 27) than did the alcohol-dependent group (6 of 50). The results confirm previous studies that the ADH2*2, ADH3*1 and ALDH2*2 genes can affect predisposition to alcoholism in Chinese patients and suggest that the mutant ALDH2*2 gene may influence susceptibility to alcoholic cirrhosis. (Hepatology 1994;19:360-366).
Augmentation of portal blood flow improves function of human cirrhotic liver
Authors: Cardoso Jorge E. , Gautreau Chantal , Jeyaraj Prema Raj , Patrzalek Dariusz , Cherruau Brigitte , Vaubourdolle Michel , Legendre Claire , Wroblewski Tadeusz , Houssin Didier
Published: March 2007

In cirrhotic livers, the intrahepatic resistance is increased and drug elimination and portal transhepatic flow are decreased. The aim of our work was to study the effect of a twofold increase in portal blood flow during 2 hr on the hemodynamic parameters, drug elimination and hepatic viability in eight isolated perfused human cirrhotic livers. Using an oxygenated recirculating system with independent arterial and portal flows, we perfused livers with Kreb’s buffer bicarbonate solution, bovine serum albumin (20 gm·L−1) and human red blood cells (hematocrit 20). The flow was maintained at a basal level of 0.713 ± 0.19 L/min for 1 hr and then increased and maintained for 2 hr at twice the basal flow. Portal pressure-portal flow curve slopes were linear (27.04 ± 21.06 mm Hg·L−1·min; range = 6.43 to 60.8) and correlated with intrahepatic resistance during the basal-flow period (r = 0.87, p < 0.01). Parameters registered during the basal- and high-flow periods were compared by use of Student’s t test: portal pressure increased from 23.5 ± 7 to 37.3 ± 16.7 mm Hg (p < 0.05); arterial pressure increased from 80.3 ± 19 to 103.5 ± 26 mm Hg (p < 0.005); hepatic artery flow resistance increased 31.9 (from 690.1 ± 218 to 899.4 ± 269 mm Hg·L−1·min; p < 0.005); indocyanine green clearance increased by 28.2 (from 86.0 ± 58.3 to 109.2 ± 74.8 ml·min−1·kg liver−1; p < 0.04). No significant differences were observed in enzyme release, biliary flow (n = 5) and oxygen consumption. Histological examinations demonstrated sinusoidal dilatations in six of eight cases. These results suggest that better liver perfusion and function of cirrhotic nodules might be obtained by increasing portal flow and perfusion pressure. (Hepatology 1994;19:375-380).
Gender-dependent reduction of spontaneous motor activity and growth in rats subjected to portacaval shunt
Authors: Conjeevaram Hari S. , Mullen Kevin D. , May Elizabeth J. , McCullough Arthur J.
Published: March 2007

Alterations in behavior are frequently described in rats subjected to portacaval shunt. Previous work has reported reduced spontaneous motor activity in various settings (nighttime, red light, decreased illumination) in this animal model. We investigated this phenomenon in rats of both genders subjected to portacaval shunt to determine whether our previously observed divergent growth patterns (males reduced, females unchanged) had any impact on the alterations in spontaneous motor activity in this model. Dietary intake, growth, motor activity and serum ammonia and amino acid concentrations were measured, in addition to final liver and spleen weights, in each animal after 3 to 4 wk of observation. Our results reconfirm the differential impact of portacaval shunt on growth in male (35 reduction p < 0.01) but not female rats (5 reduction, NS) compared with their respective-gender sham-operated controls. In addition, spontaneous motor activity was significantly reduced in male (≃ 50, p = 0.01) but not female rats subjected to portacaval shunt. The reduction of activity in male rats subjected to portacaval shunt did not correlate with any of the measured biochemical data or calculated nutritional/growth parameters. Thus we observed gender-dependent reduction in spontaneous motor activity after portacaval shunt in the rat. The mechanism for this phenomenon is unknown, but it is easily investigated with this reproducible model. (Hepatology 1994;19:381-388).
Hepatocarcinogenesis is the sequel to hepatitis in Z#2 α1-antitrypsin transgenic mice: Histopathological and DNA ploidy studies
Authors: Geller Stephen A. , Nichols Stephen W. , Kim Sungsook , Tolmachoff Tanya , Lee Stephen , Dycaico Mark J. , Felts Katherine , Sorge Joseph A.
Published: March 2007

Z mutant-associated α1-antitrypsin deficiency in human beings leads to hepatitis and, in some cases, hepatocellular carcinoma. To begin to delineate the molecular basis for the development of hepatocellular carcinoma in α1-antitrypsin deficiency, we previously developed transgenic mice using human α1-antitrypsin M and Z genomic clones. High-copy Z lineage mice (12 gene copies/haploid mouse genome; “Z#2”) had hepatocytes distended with human α1-antitrypsin deficiency globules. Hepatitis was present, and the morphological changes mimicked those observed in human α1-antitrypsin deficiency-related liver disease. The numbers of hepatocytes containing α1-antitrypsin globules decreased with age, and α1-antitrypsin-negative nodular aggregates of hepatocytes increased in number and size. Hepatocytic dysplasia occurred as early as 6 wk and was almost universally present at 1 yr. Nodules of dysplastic cells demonstrating aneuploidy were seen as early as 10 wks. These became persistent, proliferative lesions. Dysplasia and aneuploidy distinctly increased with time and advancing microscopic stage as lesions progressed to malignancy. Tumors were seen after 1 yr as adenomas, which are aneuploid and most likely well-differentiated hepatocellular carcinoma, and borderline malignant lesions; and, in 82 of Z#2 mice 16 to 20 mo old, as invasive hepatocellular carcinoma. These observations suggest but do not conclusively prove that hepatocellular carcinoma in α1-antitrypsin deficiency and other hepatic disorders arises as a result of a common, endogenously stimulated pathway for hepatocellular carcinogenesis. (Hepatology 1994;19:389-397).
Characterization of the antiviral effects of 2′ carbodeoxyguanosine in ducks chronically infected with duck hepatitis B virus
Authors: Mason William S. , Cullen John , Saputelli Jeff , Wu Tsung-Teh , Liu Chen , London Thomas W. , Lustbader Edward , Schaffer Priscilla , O’Connell Anna P. , Fourel Isabelle , Aldrich Carol E. , Jilbert Allison R.
Published: March 2007

This study was carried out to evaluate benefits and limitations of long-term therapy of hepatitis B virus infections with a nucleoside analog inhibitor of virus replication. The model we used was the domestic duck chronically infected with duck hepatitis B virus by in ovo infection. 2′ Carbodeoxyguanosine was used as an inhibitor of viral DNA synthesis. In all animals examined there was a reduction in virus production during therapy. A dose of 2′ carbodeoxyguanosine of 10 μg/kg every other day reduced the number of infected hepatocytes from greater than 95 to 25 to 50 in less than 3 mo, whereas a 10-fold higher dose produced a decline to less than 10. Histological evaluation revealed mild to moderate liver injury in ducks receiving the higher dose of 2′ carbodeoxyguanosine, suggesting that disappearance of infected hepatocytes may have been accelerated by a toxic effect of the drug. Drug treatment did not completely eliminate duck hepatitis B virus from any duck, and replication was restored in all hepatocytes within a few weeks to several months after antiviral therapy was terminated. Our results suggest that elimination of a chronic infection with a single inhibitor of replication may be difficult in a host that lacks an antiviral immune response capable of eliminating at least a portion of the infected hepatocytes and of ultimately producing antibodies capable of neutralizing residual virus. (Hepatology 1994; 19:398-411).
Transforming growth factor-β1 and mannose 6-phosphate/insulin-like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat
Authors: Saperstein Lawrence A. , Jirtle Randy L. , Farouk Marwan , Thompson Hugh J. , Chung Kyung S. , Meyers William C.
Published: March 2007

These studies investigate the role of transforming growth factor-β1, a potent inhibitor of epithelial cell proliferation and stimulator of extracellular matrix biosynthesis, during intrahepatic bile duct hyperplasia and biliary fibrosis. These pathogenic responses were induced in rats by common bile duct ligation. Bile duct cell replication, measured by the bromodeoxyuridine labeling index, was significantly increased 24 hr after common bile duct ligation. This response diminished to baseline by 1 wk. Liver collagen content, determined by quantification of hydroxyproline, was increased significantly after 1 wk of common bile duct ligation, and by 4 wk was increased by a factor of 4. Immunohistochem-istry revealed low levels of TGF-β1 in normal intrahepatic bile duct epithelium. In contrast, the bile duct epithelium in bile duct-ligated rats stained strongly positive for transforming growth factor-β1 at 1 and 4 wk after ligation. These results suggest that transforming growth factor-β1 may play a role in both the termination of the bile duct epithelial cell proliferative response and the induction of fibrogenesis after common bile duct ligation. In addition, the mannose 6-phosphate/insulin-like growth factor II receptor was up-regulated in hyperplastic bile duct epithelium 1 and 4 wk after ligation. Because the mannose 6-phosphate/insulin-like growth factor-II receptor has been shown to facilitate the proteolytic activation of transforming growth factor-β1, these results suggest that the bile duct epithelium may also be involved in the activation of transforming growth factor-β1. (Hepatology 1994;19:412-417).
Inflammatory cytokines up-regulate intercellular adhesion molecule-1 expression on primary cultured mouse hepatocytes and T-lymphocyte adhesion
Authors: Morita Masahiko , Watanabe Yoshifumi , Akaike Toshihiro
Published: March 2007

We investigated the effect of inflammatory cytokines on the intercellular adhesion molecule-1 expression on primary cultured murine hepatocytes. Tumor necrosis factor-α, interferon-γ and interleukin-1α up-regulated the intercellular adhesion molecule-1 expression on hepatocytes in a dose-dependent fashion; however, interleukin-6 did not. On the basis of kinetic analysis, the expression level reached a peak 24 hr after stimulation, and both cycloheximide and actinomycin D inhibited the expression. Furthermore, T lymphocytes bind more to interferon-γ-stimulated hepatocytes than to unstimulated hepatocytes. The binding was dependent on the concentration of interferon-γ. The binding was also up-regulated by stimulating T lymphocytes with phorbol myristate acetate. Tumor necrosis factor-α and interleukin-1α demonstrated the same effect as interferon-γ, whereas interleukin-6 did not increase T-lymphocyte adhesion to the hepatocytes. The adhesion induced by interferon-γ or tumor necrosis factor-α was inhibited by antibody against either intercellular adhesion molecule-1 or lymphocyte function-associated antigen-1, a ligand for intercellular adhesion molecule-1, but was not inhibited by CD44 antibodies. These results demonstrate that inflammatory lymphokines enhance the T-lymphocyte adhesion to primary cultured hepatocytes by up-regulating the intercellular adhesion molecule-1 expression on the stimulated hepatocytes by activating the de novo pathway. This mechanism may play an important role in the pathogenesis of hepatitis. (Hepatology 1994;19:426-431).
Modulation of the asialoglycoprotein receptor in human hepatoma cells: Effect of glucose
Authors: Weiss Peretz , Ashwell Gilbert , Morell Anatol G. , Stockert Richard J.
Published: March 2007

The hepatic receptor for asialoglycoproteins was found to be modulated by the glucose concentration in the medium of the human hepatoma cell line HepG2. The surface binding of asialoorosomucoid, a well-documented ligand for this receptor, increased from 20 ng/mg of cellular protein to about 40 ng/mg as the glucose concentration was increased from 10 to 50 mg/dl. The up-modulating effect of glucose was mimicked by pyruvate, a product of glucose metabolism, and abolished by both 2-deoxyglucose, an inhibitor of glucose metabolism, and by cycloheximide, an inhibitor of protein synthesis. Scatchard plot analysis indicated a rise in the number of binding sites and a twofold increase in binding affinity. In contrast, the binding of antibody remained unchanged with respect to alterations in glucose concentration, an indication that the actual number of receptors remained constant in face of an increased number of binding sites. Specificity of the glucose effect was shown by the binding of insulin and transferrin to their respective receptors, which was unaffected by the high glucose concentration that increased asialoorosomucoid binding. The repression of receptor binding seen with cells grown in biotin-deprived medium was reversed by increasing the glucose concentration of the medium. In this case, binding was restored to a level sixfold to sevenfold higher than that of the control cells grown in dialyzed serum. The stimulatory effect of glucose was shown to be independent of and significantly greater than that of cyclic GMP, a known regulator of receptor expression of biotin-deficient HepG2 cells. These results suggest that increasing glucose concentrations effect an activation of either silent or nonfunctional receptors or increase the stoichiometry of ligand binding per receptor complex. The data provided here are interpreted as suggesting a potential role of glucose in maintaining hepatic homeostasis through regulation of the asialoglycoprotein receptor. (Hepatology 1994;19:432-439).
Ito cell heterogeneity: Desmin-negative ito cells in normal rat liver
Authors: Ballardini Giorgio , Groff Paolo , de Giorgi Lucilla Badiali , Schuppan Detlef , Bianchi Francesco B.
Published: March 2007

The presence of desmin is used to identify Ito cells in rat liver and to evaluate the purity of separated and cultured Ito cells. Heterogeneity of the normal Ito cell population has been suggested; this could include variations in the content of cytoskeletal components. For these reasons we decided to reevaluate the use of desmin staining as a phenotypical marker of Ito cells in normal rat liver. Our approach was to combine desmin staining with identification of vitamin A (autofluorescence), lipid droplets (Sudan III), vimentin, laminin and tenascin, using cryostat sections: Immunofluorescence, double-immunofluorescence or immunoperoxidase techniques were used. All the techniques described corroborate the existence of desmin-negative Ito cells, mainly located in pericentral areas. In fact, lobular desmin-positive cells showed uneven distribution because they were more frequent in periportal than in pericentral areas. On the contrary, Ito cells identified on the basis of morphological criteria or positivity for laminin were evenly distributed. Double immunofluorescence confirmed this observation, showing nearly complete codistribution of laminin and desmin in periportal areas. Outside this area, positivity for desmin was observed only in about 50 of lamininpositive cells. Our observations suggest that desmin cannot be viewed as a phenotypical marker but rather is a differentiation marker of Ito cells, possibly indicating a specific functional state. (Hepatology 1994;19:440-446).
Effects of bile duct ligation on calcium excretion in the rat†
Authors: Vakil Nimish , Sharma Anil , Yagil Yoram
Published: March 2007

In an earlier study we showed that bile duct-ligated rats were highly susceptible to gentamicin nephrotoxicity and that oral calcium administration had a pronounced protective effect. The mechanism by which this occurs is unclear. Because cations compete with gentamicin for tubule binding sites, it has been suggested that the increased susceptibility of the kidney to gentamicin after bile duct ligation might result from decreased cation excretion. The aim of this study was to determine the effect of bile duct ligation on calcium excretion in relation to overall renal function. Male Sprague-Dawley rats underwent bile duct ligation and division. Pair-fed sham-operated rats served as controls. Metabolic and clearance studies were carried out at 3, 5, 7, 14 and 21 days after surgery. Urine output was higher in bile duct-ligated rats, and they excreted more calcium at 3, 5, 7 and 14 days, while excreting less sodium than controls. We conclude that after bile duct ligation, there is increased calcium excretion, which is independent of the abnormality in sodium excretion. Enhanced nephrotoxicity with aminoglycosides in the bile duct-ligated rat model cannot be explained by decreased calcium excretion. (Hepatology 1994;19:457-463).
Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria
Authors: Krähenbühl Stephan , Talos Christine , Fischer Sven , Reichen Jürg
Published: March 2007

The toxicity of hydrophilic (cholate) and lipophilic (deoxycholate, chenodeoxycholate, and lithocholate) bile acids on the function of the electron transport chain was investigated in intact and disrupted rat liver mitochondria. In intact mitochondria, lipophilic bile acids used at a concentration of 100 μmol/L (0.1 μmol/mg protein) inhibited state 3 and state 3u (dinitrophenol-uncoupled) oxidation rates for L-glutamate, succinate, duroquinol or ascorbate/N, N, N′, N′-tetramethyl-p-phenylenediamine as substrates. In contrast, state 4 oxidation rates and ADP/oxygen ratios were not significantly affected. At a bile acid concentration of 10 μmol/L (0.01 μmol/mg protein), the state 3 oxidation rate for L-glutamate was decreased in the presence of deoxycholate, chenodeoxycholate or lithocholate, whereas only lithocholate inhibited state 3 oxidation for succinate or duroquinol. In broken mitochondria, inhibition of oxidative metabolism was found for NADH or duroquinol as substrate in the presence of 100 μmol/L lithocholate (0.2 μmol/mg protein) and for duroquinol in the presence of 100 μmol/L chenodeoxycholate. Direct assessment of the activities of the enzyme complexes of the electron transport chain revealed decreased activities of complex I and complex III in the presence of 100 μmol/L deoxycholate or chenodeoxycholate or 10 μmol/L lithocholate. Inhibition of complex IV required higher bile acid concentrations (300 μmol/L for chenodeoxycholate or 30 μmol/L for lithocholate), and complex II was not affected. Both chenodeoxycholate and lithocholate were incorporated into mitochondrial membranes. The phospholipid content of mitochondrial membranes decreased in incubations containing 100 μmol/L (0.1 μmol/mg protein) chenodeoxycholate but was not affected in the presence of 100 μmol/L lithocholate. The studies show that lipophilic bile acids impair the function of the electron transport chain in isolated rat liver mitochondria. The inhibitory effect of lipophilic bile acids on the electron transport chain can be explained by an unspecific effect on the inner mitochondrial membrane of intact mitochondria at high concentrations (100 μmol/L) and by a specific impairment of complex I and complex III in broken mitochondria or in intact mitochondria incubated with low bile acid concentrations (10 μmol/L). The impairment of mitochondrial function by bile acids may be clinically relevant in patients or animals with chronic cholestasis. (Hepatology 1994;19:471-479).
Pathways of intracellular trafficking and release of ferritin by the liver in vivo: The effect of chloroquine and cytochalasin D
Authors: Ramm Grant A. , Powell Lawrie W. , Halliday June W.
Published: March 2007

We have previously shown that the clearance of exogenous ferritin and the release of endogenous ferritin into both serum and bile are altered by the microtubular inhibitor colchicine. In this study we further examined the role of the lysosome-endosome pathway in ferritin metabolism. We examined the effect of the lysosomotropic agent chloroquine and the microtubular inhibitor cytochalasin D on the uptake and release of ferritin by normal and iron-loaded rats under basal conditions and in the presence of an exogenous tissue ferritin load. Either chloroquine (50 mg/kg body wt) or cytochalasin D (0.9 μg/100 gm body wt/min) was administered to normal and iron-loaded rats at zero time. Rats were also infused with either saline solution or rat liver ferritin containing a trace amount of 125I-ferritin. The clearance of 125I-ferritin from the circulation was not affected by chloroquine or cytochalasin D either in normal or in iron-loaded rats; however, both chloroquine and cytochalasin D decreased the serum ferritin concentration in normal rats to 39 ± 9 and 22 ± 7 of the baseline serum ferritin levels, respectively, implying that both drugs inhibited the release of endogenous ferritin in normal rats. In iron-loaded rats both chloroquine and cytochalasin D decreased the biliary ferritin concentration to 11 ± 1 and 37 ± 4 of the baseline ferritin levels, respectively, and the 125I protein-bound counts per minute in the bile to 50 of the control result. This finding is consistent with an inhibitory effect of both drugs on the biliary excretion of endogenous ferritin and the intracellular transport of exogenous ferritin, respectively. In the presence of an exogenous tissue ferritin load, there was no detectable inhibitory effect of either drug on the biliary excretion of either endogenous or exogenous ferritin. These results provide the following evidence: (a) the receptor-mediated endocytosis of ferritin is not dependent on functioning lysosomes or microfilaments; (b) the release of endogenous ferritin into the serum of normal rats and the bile of iron-loaded rats is a chloroquine-sensitive, microfilament-dependent process; (c) the biliary excretion of trace amounts of exogenous ferritin is dependent on both chloroquine-sensitive vesicles and microfilaments; and (d) increased levels of exogenous ferritin are excreted directly into the bile by way of a second microfilament-independent, chloroquine-insensitive pathway. This study provides support for a physiological mechanism for the release of ferritin from the liver. (Hepatology 1994;19:504-513).
Spontaneous Ca2+ release from a caffeine and ryanodine-sensitive intracellular Ca2+ store in freshly prepared hepatocytes
Authors: Osada Shinji , Okano Yukio , Saji Shigetoyo , Nozawa Yoshinori
Published: March 2007

A considerable fraction of freshly prepared hepatocytes loaded with the fluorescent [Ca2+]i indicator fura-2 exhibited spontaneous rhythmic fluctuations that tended to decrease with increasing length of incubation after isolation. These oscillations were dependent on the external Ca2+. They could no longer be observed when a Ca2+ chelator-(ethylenebis [oxyethylenenitrilo]) tetraacetic acid-was added to medium. Addition of thapsigargin, which is known to release Ca2+ from inositol 1,4,5-trisphosphate-sensitive and -insensitive Ca2+ stores, induced a large transient increase in [Ca2+]i and abolished the fluctuations. When the cells were treated with 2 mmol/L caffeine, frequency was increased, whereas 10 mmol/L caffeine induced a single large peak followed by a persistent plateau. Moreover, addition of dibutyryl cAMP led to decreased frequency of fluctuations. Ryanodine caused larger fluctuations; thereafter the [Ca2+]i level became much higher and the spikes ceased. These results suggest that spontaneous rhythmic fluctuations in freshly prepared hepatocytes are driven by Ca2+ release from a caffeine- and ryanodine-sensitive calcium-induced calcium release pool. (Hepatology 1994;19:514-517).
Liver glut-1 expression: An enigma deepens
Authors: Rhoads David B.
Published: March 2007

The basal hepatocyte phenotype is conferred by the expression of liver-specific genes. In the adult liver, the basal hepatocyte phenotype is further modified by transcriptional and post-transcriptional regulation of genes which result in the appearance of specific proteins in selected hepatocytes. One of these proteins is the erythroid/brain or GLUT-1 glucose transporter. The GLUT-1 protein is detected in the plasma membrane of only one or two hepatocytes located at the end of the liver cell plate, contiguous to the hepatic venule. The objective of this study was to define the molecular mechanisms responsible for the restricted expression of the GLUT-1 protein in rat liver. Hepatocytes were isolated from either the proximal (“periportal”) or the distal (“perivenular”) half of the liver cell plate. The GLUT-1 mRNA as well as the GLUT-1 protein content and intracellular distribution were defined after subcellular fractionation of each hepatocyte population. In addition, the location of the GLUT-1 protein in liver tissue was determined by confocal microscopy. We propose that the GLUT-1 gene is transcribed and the mRNA is translated by both “periportal” and “perivenular” hepatocytes. However, insertion of the GLUT-1 protein into the plasma membrane occurs only in the last two hepatocytes contiguous to the hepatic venule. In other hepatocytes, the protein remains in a different cellular compartment characterized here as a “low density microsomal” fraction.
…And the bands play on
Authors: Schapiro Robert H.
Published: March 2007

Injection sclerotherapy of bleeding oesophageal varices is undoubtedly beneficial but it is associated with a substantial complication rate, and variceal rebleeding is common during the treatment period before variceal obliteration is achieved. We aimed to find out whether endoscopic variceal banding ligation is safer and more effective. The two methods were compared in a randomised controlled trial of 103 patients (54 assigned to banding ligation, and 49 to injection sclerotherapy) of whom 21 (39) and 23 (47), respectively, had active bleeding at index endoscopy. Both treatments were highly effective in controlling active haemorrhage (91 and 92 respectively). Variceal obliteration was not achieved for 22 patients in each group, but among those whose varices were eradicated, banding ligation achieved obliteration more quickly than did sclerotherapy (mean 39 [SD 4] vs 72 [7] days, p = 0.004) and in fewer endoscopy sessions (3.4 [2.2] vs 4.9 [3.5], p = 0.006). Rebleeding was less common in the banding ligation group than in the sclerotherapy group (16 [30] vs 26 [53], p < 0.05). There was no difference in outcome between the groups, but 14 sclerotherapy patients were withdrawn from the trial (7 for orthotopic liver transplantation) compared with only 5 (1 for liver transplantation) in the banding ligation group (p < 0.05). Complication rates were similar in the two groups.

Variceal banding ligation is a safe and effective technique, which obliterates varices more quickly and with a lower rebleeding rate than injection sclerotherapy.
Predicting cholangiocarcinoma in patients with primary sclerosing cholangitis: An analysis of the serological marker CA 19-9
Authors: Rogers Steven A. , Podolsky Daniel K.
Published: March 2007

Primary sclerosing cholangitis (PSC) predisposes to the development of cholangiocarcinoma, a usually fatal complication that is difficult to diagnose. Serum concentrations of CA 19-9, a tumor-associated antigen, are frequently increased in patients with only cholangiocarcinoma. The aim of this study was to assess the value of an increased serum CA 19-9 level for the diagnosis of cholangiocarcinoma in patients with preexisting PSC. We analyzed serum samples from 9 patients with PSC and superimposed cholangiocarcinoma and from 28 patients with only PSC. Serum concentrations of CA 19-9 were measured in a blinded manner with use of an immunoradiometric assay. The serum CA 19-9 concentrations were increased in 8 of 9 patients (89) with PSC and cholangiocarcinoma (mean±SE, 391 ± 86 U/ml; range, 4 to 677), whereas they were increased in only 4 of 28 patients (14) with only PSC (mean ± SE, 61 ± 16 U/ml; range, 2 to 370). The sensitivity of a CA 19-9 value greater than 100 U/ml for cholangiocarcinoma in PSC was 89, and the specificity was 86. The measurement of serum concentrations of CA 19-9 is a promising test for detecting cholangiocarcinoma in patients with PSC.
Conservation of hepatitis C virus 5′ untranslated sequences in hepatocellular carcinoma and the surrounding liver
Authors: Sullivan Deborah E. , Gerber Michael A.
Published: March 2007

Persistent infection by hepatitis C virus is a major risk factor for the development of hepatocellular carcinoma, but the mechanism of hepatocarcinogenesis is unknown. To study the association of hepatitis C virus with hepatocellular carcinoma, we sequenced part of the 5′ untranslated region of hepatitis C virus from the tumor tissue and the surrounding nontumorous liver of three patients with hepatocellular carcinoma. No sequence differences between tumor-derived and liver-derived hepatitis C virus isolates were detected. The conservation of the 5′ untranslated region of hepatitis C virus-not only in infected hepatocytes, but also in neoplastic cells-suggests that the regulatory elements at the 5′ terminus of the viral genome play an important role in the pathobiology of hepatitis C virus. (Hepatology 1994;19:551-553).
Clinical significance of concomitant hepatitis C infection in patients with alcoholic liver disease
Authors: Fong Tse-Ling , Kanel Gary C. , Conrad Andrew , Valinluck Boontar , Charboneau Francine , Adkins Rodney H.
Published: March 2007

The significance of antibodies to hepatitis C virus in patients with chronic alcoholic liver disease is unclear. Prior studies have utilized the first-generation enzyme-linked immunosorbent assay, which is limited by problems with sensitivity and specificity. Hepatitis C virus infection in 137 patients with biopsy-proven alcoholic liver disease was assessed with second-generation hepatitis C virus antibody assays and reverse transcription-polymerase chain reaction for detection of hepatitis C virus RNA in the serum. The patients were categorized into three groups according to results of serological testing. Discriminant-function analysis was used to determine which factors (risk, biochemical and histological) could best differentiate the three groups. Thirty-three patients were reactive on secondgeneration enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay and RNA positive (group 1). Twelve were reactive on second-generation enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay but RNA negative (group 2). Eighty-six were nonreactive on second-generation enzyme-linked immunosorbent assay, and six were reactive on second-generation enzyme-linked immunosorbent assay but negative on second-generation recombinant immunoblot assay and negative for hepatitis C virus RNA (group 3). Seventy-six percent of patients in group 1 and 58 in group 2 had parenteral risk factors, compared with only 1 in group 3 (p < 0.00001). The mean ALT level was higher in group 1 patients (p < 0.05). The mean histologic activity index was significantly higher in group 1 (p = 0.0007). Periportal and bridging necrosis and portal inflammation were significantly increased in group 1 (p = 0.0004 and p = 0.002, respectively). We found no significant difference in intralobular degeneration and focal necrosis or fibrosis among the three groups. The histological and biochemical features of groups 2 and 3 were similar. Most patients with alcoholic liver disease with concomitant hepatitis C infection have an identifiable parenteral risk factor. Patients with viremia have histological evidence of chronic hepatitis superimposed on alcoholic liver disease. The histological features of hepatitis C virus antibody-reactive patients without viremia resemble those of patients without serological evidence of hepatitis C virus infection. (Hepatology 1994;19:554-557).
Pathogenesis of posttransfusion viral hepatitis in children with β-thalassemia
Authors: Feitelson Mark , Lega Laura , Guo Juanhui , Resti Massimo , Rossi Maria E. , Azzari Chiara , Blumberg Baruch S. , Vierucci Alberto
Published: March 2007

The pathogenesis of posttransfusion hepatitis was determined in 14 children with β-thalassemia. All had blood samples obtained in 1980 or 1981, were vaccinated against hepatitis B virus in 1983 and had another serum sample collected in 1989. Seven children had detectable antibodies against hepatitis C virus before vaccination, and all were positive in 1989. With specific solid-phase enzyme immunoassays, all children had antibodies against hepatitis B virus, X and polymerase antigens in 1981, and six had one or both antibodies in 1989. Hepatitis B virus infection was confirmed by means of polymerase chain reaction, which demonstrated virus DNA in 13 of the 14 children. The amplification products spanning the X/precore region were smaller than expected, suggesting mutations in this region. Cloning and sequencing of these products revealed deletions spanning part or all of the X gene. The results show that these children were infected with hepatitis B virus even without other markers in serum, that hepatitis B persists years after vaccination and that such infections are associated with the presence of X deletion mutants. Coinfection with hepatitis B and C viruses, the former containing a new class of variants, is common in children with β-thalassemia. (Hepatology 1994;19:558-568).
Coinfection study of precore mutant and wild-type hepatitis B-like virus in ducklings
Authors: Chuang Wan-Long , Omata Masao , Ehata Toshiki , Yokosuka Osamu , Hosoda Kazuhiko , Imazeki Fumio , Ohto Masao
Published: March 2007

The precore mutant hepatitis B virus often emerges from a mixed infection with combined wild-type and precore mutant viruses. Nevertheless, the precore mutant does not seem to be an evolutionarily favored strain. To investigate the interaction between wildtype and precore mutant hepadnaviruses in an animal model of perinatal transmission, we used an e antigendefective mutant duck hepatitis B virus with mutations inside the stem-loop structure of precore messenger RNA for this coinfection study. Thirty 1-day-old ducklings were infected with wild-type duck hepatitis B virus, precore mutant virus or both viruses. The amounts of viremia and the distribution of viruses were analyzed by spot hybridization, polymerase chain reaction, restriction fragment length polymorphism, cloning and sequencing. We found that all the ducklings became chronic carriers of duck hepatitis B virus. The precore mutant replicate was less active than wild-type duck hepatitis B virus, and it could be overgrown by wild-type virus during the course of coinfection. These results demonstrated that wild-type duck hepatitis B virus might become the predominant species in a situation similar to the perinatal cotransmission in human beings. This might at least in part explain why the prototype virus could prevail for years. (Hepatology 1994;19:569-576).
“Inapparent” hepatitis B virus infection and hepatitis C virus replication in alcoholic subjects with and without liver disease
Authors: Zignego Anna Linda , Foschi Marco , Laffi Giacomo , Monti Monica , Careccia Grazia , Romanelli Roberto Giulio , de Majo Enrichetta , Mazzanti Roberto , Buzzelli Giampiero , la Villa Giorgio , Gentilini Paolo
Published: March 2007

We evaluated hepatitis B virus DNA and hepatitis C virus RNA in sera from 110 HBsAg and IgM HBc antibody-negative heavy drinkers (50 cirrhosis, 13 chronic active hepatitis, 25 fatty liver with or without mild to moderate fibrosis, alcoholic hepatitis or both and 22 healthy alcoholic subjects) with polymerase chain reaction. Results of hepatitis C virus polymerase chain reaction were compared with those obtained with two tests (second generation recombinant immunoblot assay and enzyme-linked immunosorbent assay) used to detect hepatitis C virus antibodies. Hepatitis B virus DNA was found in three (2.7) patients. Hepatitis C virus RNA was detected in 29 (29.8) of the 97 subjects whose sera were well preserved for RNA extraction (42.5 cirrhosis, 83.3 chronic active hepatitis, 8 fatty liver and 0 healthy alcoholic subjects). Results obtained with second-generation recombinant immunoblot assay and enzyme-linked immunosorbent assay had a high degree of agreement with polymerase chain reaction as expected, the K indexes being 0.76 and 0.61, respectively. Nevertheless, five hepatitis C virus RNA-positive patients had negative recombinant immunoblot assay results, whereas all hepatitis C virus RNA-positive patients had positive or borderline enzyme-linked immunosorbent assay results. We conclude that, in Italian HBsAg-negative alcoholic patients, “inapparent” hepatitis B virus infection is rare. On the contrary, hepatitis C virus infection, as detected on hepatitis C virus polymerase chain reaction, is quite frequent, especially in patients who have cirrhosis and chronic active hepatitis. Second-generation enzyme-linked immunosorbent assay can be reliably used as initial test for the detection of hepatitis C virus infection in alcoholic patients; clearly positive results are very likely to correspond to viremia. Borderline results necessitate confirmation with polymerase chain reaction analysis. (Hepatology 1994;19:577-582).
Circadian variations of portal pressure and variceal hemorrhage in patients with cirrhosis
Authors: García-Pagán Joan C. , Feu Faust , Castells Antoni , Luca Angelo , Hermida Ramón C. , Rivera Francisca , Bosch Jaume , Rodés Joan
Published: March 2007

This study was aimed at investigating whether portal pressure, which is usually measured in the morning, is subject to circadian variations in patients with cirrhosis. Furthermore, a possible circadian variation for the occurrence of variceal bleeding was also investigated. Ten patients with alcoholic cirrhosis and portal hypertension had serial measurements of portal pressure, evaluated by the hepatic venous pressure gradient (the difference between wedged and free hepatic venous pressures), during a 24-hr period. In addition, a survey of the hour of occurrence of variceal hemorrhage was performed in 101 consecutive cirrhotic patients with hematemesis, in whom the precise moment of onset of bleeding could be determined, and the origin of bleeding was confirmed by emergency endoscopy. Statistical evaluation with the population-mean cosinor method allowed detection of a circadian variation in portal pressure. Portal pressure progressively declined during the afternoon and evening (from 17.9 ± 5.3 mm Hg at 12 PM to a nadir of 16.8 ± 4.9 mm Hg at 7 PM (p < 0.05). Thereafter, portal pressure increased during the night, returning to baseline values at 9 AM (18.1 ± 5.1 mm Hg). The acrophase was at 8:32 AM (± 100 min) with an amplitude of 3.45 ± 1.1 (% of mean ± S.E.) (rhythm detection: p < 0.03). Similarly, the analysis of the time of occurrence of variceal hemorrhage with the use of a multiple-components rhythmometry test disclosed two peaks in the prevalence of esophageal bleeding. The more pronounced peak (orthophase) occurred at 10:44 PM, when portal pressure started to increase, and the second peak occurred at 9:12 AM, close to the acrophase value of portal pressure. This study shows that in patients with cirrhosis, portal pressure exhibits a circadian variation. This may influence the moment of occurrence of variceal bleeding, which also showed a circadian variation. (Hepatology 1994;19:595-601).
Influence of paraesophageal venous collaterals on efficacy of endoscopic sclerotherapy for esophageal varices
Authors: Lin Ching-Yih , Lin Pin-Wen , Tsai Hong-Ming , Lin Xi-Zhang , Chang Ting-Tsung , Shin Jeng-Shiann
Published: March 2007

To determine the diagnostic accuracy of computer tomography in the detection of venous collaterals surrounding the esophagus in patients with portal hypertension, preoperative computer tomography interpretations of these veins in 15 patients who were candidates for the Sugiura procedure for treatment of esophageal varices were correlated with those of the intraoperative assessment. Laparotomy revealed severe paraesophageal varices in five patients; four of them were found to have paraesophageal varices in computer tomography films. The sensitivity and specificity of computer tomography in diagnosing severe paraesophageal varices were 80% and 100%, respectively. A second assessment was performed in 59 additional patients with esophageal variceal hemorrhage to investigate the influence of paraesophageal varices on the efficacy of endoscopic sclerotherapy in the treatment of varices. The patients were divided into two groups: Group A included 17 patients with and group B 42 patients without paraesophageal varices on presclerotherapy computer tomography. All patients underwent elective sclerotherapy after being deemed hemodynamically stable. Patients in group A required more treatment sessions, more sclerosant and longer periods to obliterate varices completely than did group B patients. Eight patients in group A and six in group B (57% vs. 16%, p < 0.05) had variceal recurrence after obliteration during mean follow-ups of 20.8 and 19.9 mo, respectively. The mean time elapsed before variceal reappearance was shorter for group A than for group B (4.1 ± 3.3 vs. 11.8 ± 2.7 mo, p < 0.05). Among patients who developed new varices, five patients in group A and one in group B experienced repeat bleeding. The repeat bleeding rate was higher for group A than for group B (29% vs. 3%, p < 0.05). In conclusion, computer tomography proved a reliable diagnostic procedure in detecting severe paraesophageal varices in patients with portal hypertension. Endoscopic injection sclerotherapy is less effective in treating patients with esophageal variceal hemor rhage who have severe paraesophageal collaterals. (Hepatology 1994;19:602-608).
Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis†
Authors: Doherty Derek G. , Donaldson Peter T. , Underhill James A. , Farrant Mark J. , Duthie Ann , Mieli-Vergani Giorgina , McFarlane Ian G. , Johnson Philip J. , Eddleston Adrian L. W. F. , Mowat Alex P. , Williams Roger
Published: March 2007

Susceptibility to autoimmune hepatitis in white patients is associated with the human leukocyte antigen class II antigens DR3 and DR4. To analyze the molecular basis of these associations, we used oligonucleotide probes to determine the DRB, DQA and DQB hypervariable nucleotide sequences in 119 patients with autoimmune hepatitis and 177 matched controls. DRB3*0101, which encodes DR52a, predisposed patients most strongly to the disease. It was present in 58% of patients and 25% of controls (corrected P < 0.000005), whereas DQA1*0101 and 0102 conferred protection in males only. The DR4 subtype, DRB1*0401, was raised in the DRB3*0101-negative patients; 81% possessed either DRB3*0101 or DRB1*0401, compared with 42 of controls (corrected P < 0.0000001). These alleles encode the amino acid sequence Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the DRβ polypeptide, which was present in 94% of patients and 64% of controls (corrected P < 0.000001) and in all patients who tested positive for autoantibodies to the hepatic asialoglycoprotein receptor. The patients with DRB1*0401 had less severe disease, relapsed less frequently and were first seen significantly later in life than those patients with DRB3*0101; and whereas a single copy of DRB1*0401 predisposed to autoimmune hepatitis, DRB3*0101-associated susceptibility had a dose-related effect. These data provide evidence that specific residues in the DRβ polypeptides predispose to autoimmune hepatitis in white patients and genes linked to DRB3*0101 and DRB1*0401 may determine two clinically distinct disease patterns. (Hepatology 1994;19:609-615).
Clinical significance of the evaluation of hepatic reticuloendothelial removal capacity in patients with cirrhosis
Authors: Bolognesi Massimo , Merkel Carlo , Bianco Simone , Angeli Paolo , Sacerdoti David , Amodio Piero , Gatta Angelo
Published: March 2007

The reticuloendothelial system plays an important role in the prevention of bacterial infection in patients with cirrhosis. Few data are available, however, on its activity in such patients. The aim of this study was to evaluate the maximum removal capacity of hepatic reticuloendothelial system in patients with cirrhosis on the basis of study of the removal kinetics of increasing amounts of 99mTc millimicrospheres and to verify its value as a prognostic factor for death and development of spontaneous bacterial peritonitis. Common clinical and biochemical parameters, Pugh score, maximum removal capacity, aminopyrine metabolic capacity and galactose elimination capacity were measured in 43 patients with cirrhosis (33 with alcoholic cirrhosis, 8 with posthepatitic cirrhosis and 2 with cryptogenic cirrhosis). Hepatic plasma flow and indocyanine green plasma clearance were also measured in 16 of these patients. Reference range of maximum removal capacity was determined in seven normal subjects. Maximal removal capacity below the normal range was found in 24 patients (56%). In the whole series maximum removal capacity averaged 16 ± 12 μg/kg body wt/min (mean ± S.D.). Maximal removal capacity was significantly correlated with serum albumin, prothrombin index, Pugh score, aminopyrine breath test, galactose elimination capacity and indocyanine green plasma clearance but not with hepatic plasma flow. During follow-up of up to 48 mo, spontaneous bacterial peritonitis developed in six patients, all with impaired maximum uptake capacity, and 11 patients died. Survival was significantly shorter in patients with impaired maximum removal capacity than in those with normal maximum removal capacity (log-rank test: p = 0.024). Moreover, impaired maximum removal capacity was associated with increased risk of spontaneous bacterial peritonitis (log-rank test: p = 0.037); it was also found to be an independent prognostic factor when total ascitic fluid protein concentration was taken into account. We conclude that a decrease in maximum removal capacity is often present in patients with cirrhosis, particularly in those with advanced disease. The impairment in maximum removal capacity is associated with increased risk of spontaneous bacterial peritonitis. (Hepatology 1994;19:628-634).