bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenomatous Hyperplasia in the Vicinity of Small Hepatocellular Carcinoma
Authors: Eguchi Akira , Nakashima Osamu , Okudaira Sadayuki , Sugihara Shigetaka , Kojiro Masamichi
Published: March 2007

ABSTRPlCT

The nodular lesions seen in the noncancerous areas of the 80 consecutively resected small hepatocellular carcinoma associated with cirrhosis were pathomorphologically studied. A total of 51 nodular lesions were found, and they were classified into the following four groups: large regenerative nodule (30 nodules), adenomatous hyperplasia (12 nodules), atypical adenomatous hyperplasia (4 nodules) and adenomatous hyperplasia containing cancerous foci (5 nodules). Grossly, all large regenerative nodules were well demarcated, but some of the adenomatous hyperplasia group were vaguely nodular. Atypical adenomatous hyperplasia and adenomatous hyperplasia containing cancerous foci accounted for 43% of the adenomatous hyperplasia group found in the vicinity of the 16 resected hepatocellular carcinoma (20%) out of 80 cases. The mean size (±S.D.) of the adenomatous hyperplasias containing cancerous foci, 15.8 ± 2.2 mm, was significantly larger than 10.1 ± 2.6 mm of the adenomatous hyperplasias (p < 0.01). All adenomatous hyperplasias containing cancerous foci and 75% of the atypical adenomatous hyperplasias demonstrated a marked fatty change, but none of the large regenerative nodules were accompanied by any fatty changes.

This study demonstrated the morphological transition from adenomatous hyperplasia to hepatocellular carcinoma that was suggestive of multistep hepatocarcinogenesis. As a result, it is predicted that approximately 20% of all hepatocellular carcinomas may have the potential for being of multicentric origin and that approximately 40% of adenomatous hyperplasias may undergo malignant transformation, but it is difficult to estimate the exact number of incidences. The presence of varying degrees of fatty change may be one of the significant morphological markers for a malignant transformation from adenomatous hyperplasia to hepatocellular carcinoma. We should also be aware that adenomatous hyperplasias larger than 1.5 cm in size might already contain cancerous foci somewhere in the nodule. Accordingly, adenomatous hyperplasia should be treated as a premalignant lesion. (Hepatology 1992;15:843-848).
Changes in Bilirubin Pigments Secreted in Bile After Liver Transplantation
Authors: Goresky Carl A. , Gordon Ellen R. , Sanabria Juan-Ramon , Strasberg Steven M. , Flye Wayne M.
Published: March 2007

ABSTRPlCT

The species of bile pigments secreted in T–tube fistula bile after liver transplantation were ascertained by high–performance liquid chromatography in 15 patients for 10 days after liver transplant. Nine glycosidic conjugates and unconjugated bilirubin were resolved by the analytical procedure. The principal pigments in bile and their proportions in normal patients were the following: bilirubin diglucuronide = 83.0% ± bilirubin monoglucuronide = 9.7% ± 1.4% (S.D.); bilirubin monoglucuronide monoglucoside = 4.0% 2.8% (S.D.); and bilirubin monoglucuronide monoxyloside = 1.5% ± 1.8% (S.D.). All of the other possible glucuronide, glucose and xylose monoconjugates and diconjugates and unconjugated bilirubin were also found, but each was normally less than 1% of the total. In 13 of the 15 transplant patients, a significant depression in proportions of bilirubin diglucuronide and elevation in proportions of bilirubin monoglucuronide were found after the transplant, with an accompanying but generally small increase in the proportions of the minor conjugates. In two patients with rejection of the transplant, the changes were of larger magnitude, with improvement occurring only with recovery from the rejection. In one of these patients, kidney failure was present, and in addition to the diglucuronide and monoglucuronide conjugates diglucoside and monoglucoside monoxyloside conjugates were found in plasma. The underlying metabolic abnormalities are not clear but likely reflect underlying abnormal intracellular cofactor levels for conjugation. Glycogen depletion with reduction of UDP–glucuronate levels or reduced UDP–glucuronate formation from UDP–glucose, secondary to elevation of UDP–xylose, could potentially account for the changes in pigment excretion. (Hepatology 1992;15:849-857).
Serum and Hepatic Cholestanol, Squalene and Noncholesterol Sterols in Man: A Study on Liver Transplantation
Authors: Nikkilä Katriina , Höckerstedt Krister , Miettinen Tatu A.
Published: March 2007

ABSTRPlCT

Serum noncholesterol sterols indicate overall cholesterol metabolism in a variety of experimental and clinical conditions. In patients with advanced primary biliary cirrhosis serum cholestanol, a 5ä–derivative of cholesterol, is markedly increased, and cholesterol precursors, which are indicators of cholesterol synthesis, are clearly reduced, as is the ratio of plant sterols (campesterol/sitosterol). Therefore these variables were studied in the livers and sera of 23 patients undergoing liver transplantation (16 patients with chronic liver disease, 4 with acute liver failure and 3 receiving second liver) and in 10 healthy controls. A most striking finding was the markedly high liver and serum levels of cholestanol in patients with chronic end–stage liver disease, a finding specific for cholestanol but not for other sterols. Of the cholesterol precursor sterols, lathosterol exhibited low contents in both the serum and liver of the cirrhotic patient group, supposedly reflecting decreased cholesterol synthesis. In contrast to the largely similar levels of noncholesterol sterols in serum and liver and the positive correlations between the two sources, the serum squalene levels were markedly lower than the hepatic levels, with a negative correlation between the serum and the liver, suggesting that serum squalene content poorly reflects cholesterol synthesis. In contrast to campesterol, serum and liver sitosterol tended to show increases, and the serum and hepatic campesterol/sitosterol ratios were lower in the chronic liver disease patients than in the controls, probably because of the more consistently impaired biliary elimination of sitosterol in those patients. The findings show that cholestanol is markedly increased and that lathosterol and the campesterol/sitosterol ratio are decreased in both the serum and the liver of patients with chronic end–stage liver disease. Unlike squalene, serum noncholesterol sterols are quite evenly distributed with the respective hepatic sterols. Gas–liquid chromatographic quantitation of these sterols from nonsaponifiable serum lipids may offer a new means of determining the actual end stages of chronic liver diseases. (Hepatology 1992;15:863-870).
Combined Treatment of Portal Hypertension With Ritanserin and Propranolol in Conscious and Unrestrained Cirrhotic Rats
Authors: Pomier-Layrargues Gilles , Giroux Lise , Rocheleau Bernard , Huet Pierre-Michel
Published: March 2007

ABSTRPlCT

We recently reported that ritanserin, a 5–hydroxytryptamine receptor antagonist, induced significant reduction of portal pressure in cirrhotic rats. In this study, we investigated the hemodynamic effects of a combination of propranolol and ritanserin in conscious and unrestrained cirrhotic rats. Heparinized catheters exiting from the neck were placed into the portal vein, inferior vena cava, aorta and left ventricle. Cardiac output and regional blood flows were measured with radiolabeled microspheres and the reference–sample method. Serial hemodynamic studies were performed 4 hr after rats awakened (basal), 1 hr after administration of ritanserin (0.63 mg/kg body wt, intravenously) and after intravenous propranolol infusion (0.33 mg/kg/min for 15 min) in nine cirrhotic rats. Similar measurements were obtained in a control group of eight cirrhotic rats treated with the solvents of ritanserin and propranolol. Ritanserin caused significant reduction of portal pressure (-19%). Portal–venous inflow and splanchnic arteriolar resistances remained unchanged, whereas portal–venous resistances were slightly but significantly lowered (-17%); and ritanserin had no effects on systemic hemodynamics. The addition of propranolol resulted in further reduction of portal pressure (-24%); the final reduction after combined therapy was -38%. Propranolol induced a marked decrease in cardiac output (-31%) and portalvenous inflow (-30%). It also caused a significant increase in splanchnic arteriolar resistance (+39%), but did not magnify the ritanserin–induced decrease of portal–venous resistance. The combined therapy did not modify the mean arterial pressure. Our results show that the effects of ritanserin on portal pressure – probably mediated by a reduction of intrahepatic and/or portocollateral resistances – can be potentiated by propranolol, which lowers the portalvenous inflow. (Hepatology 1992;15:878-882).
Interaction of Ethanol With β–Carotene: Delayed Blood Clearance and Enhanced Hepatotoxicity
Authors: Leo Maria Anna , Kim Cho-Il , Lowe Nancy , Lieber Charles S.
Published: March 2007

ABSTRPlCT

Because we had found that ethanol interacts with retinol, we investigated whether it also affects its precursor, β–carotene. In 14 baboons fed ethanol (50% of total energy) for 2 to 5 yr with a standard amount of β–carotene (one 200–gm carrot/day), levels of β–carotene were much higher than in controls fed isocaloric carbohydrate, both in plasma (122.5 ± 30.9 nmol/dl vs. 6.3 ± 1.4 nmol/dl; p < 0.005) and in liver (7.9 ± 1.1 nmol/gm vs. 1.8 ± 0.5 nmol/gm; p < 0.001). Even 20 days after withdrawal of the carrots, plasma β–carotene levels remained higher in alcohol–fed baboons than in controls (10.1 ± 3.8 nmol/dl vs. < 0.1 nmol/dl). Next, the diet was supplemented with β–carotene beadlets: in four pairs of baboons given a low dose of β–carotene (3 mg/1,000 kcal), plasma levels were significantly higher in alcohol–fed animals than in controls, even when expressed per cholesterol (although the latter increased with alcohol intake). Seven pairs of animals were given a higher dose (30 mg/1,000 kcal) of β–carotene for 1 mo, followed, in four pairs, by 45 mg for another month. On cessation of β–carotene treatment, plasma levels decreased more slowly in the alcohol–fed baboons than in the controls. Percutaneous liver biopsy specimens revealed that liver concentrations of β–carotene correlated with plasma levels but were higher in the alcohol–fed baboons than in the control baboons, whereas the β–carotene–induced increase in liver retinoids was lower (p < 0.02). Furthermore, the ethanol–induced liver depletion of total retinoids (432 ± 103 nmol/gm vs. 1,711 ± 103 in controls; p < 0.001) was not corrected (637 ± 149 vs. 2,404 ± 74; p < 0.001), despite the massive supplementation with β–carotene. Moreover, in the animals fed alcohol with β–carotene, multiple ultrastructural lesions appeared, with autophagic vacuoles, abundant myelin figures, degenerated mitochondria and increased blood levels of the mitochondrial enzyme glutamic dehydrogenase. The histological changes were either absent or much less prominent in the baboons given β–carotene with the control diet or in animals fed the ethanol or control diets without β–carotene. Thus the combination of an increase in plasma and liver β–carotene after ethanol and a relative lack of a corresponding rise in retinol suggests interference with the conversion of β–carotene to vitamin A. Because of an associated exacerbation of the liver toxicity, we conclude that β–carotene must be administered cautiously in the presence of heavy alcohol consumption because the optimal human therapeutic dose remains to be defined. (Hepatology 1992;15:883-891).
Acute Ethanol Intoxication Stimulates Superoxide Anion Production By In Situ Perfused Rat Liver
Authors: Bautista Abraham P. , Spitzer John J.
Published: March 2007

ABSTRPlCT

This study examines the generation of superoxide anion by the perfused rat liver after ethanol intoxication and acute endotoxemia to assess the potential importance of oxygen–derived free radicals in the ethanol–induced hepatic pathological condition. Hepatic superoxide anion production of 0.65 ± 0.06 nmol/min/gm liver weight was measured 1 hr after ethanol infusion; it reached a peak value of 0.8 ± 0.07 at 3 hr and was reduced to 0.11 ± 0.01 by 7 hr. In a group of animals, 4–methylpyrazole was injected 5 min before the administration of ethanol to determine whether the metabolism of ethanol moiety is necessary for the observed effects. However, no significant inhibition of superoxide production was observed after 4–methylpyrazole administration. Introduction of ibuprofen into the perfused liver abolished superoxide anion production, suggesting that arachidonic acid metabolites may play an important role in superoxide generation under these conditions. Endotoxin, a potent activator of macrophages, has also been associated with increased superoxide release by the liver. Therefore the combined impact of ethanol and endotoxin on superoxide production by the liver was also examined. Acute ethanol intoxication inhibited the endotoxin–mediated superoxide anion generation by the perfused liver. These data indicate that the ethanol–mediated superoxide production and the ethanol–induced inhibition of the lipopolysaccharide–enhanced free–radical generation by the liver may have a pathophysiological significance in tissue injury and in resistance to infection. (Hepatology 1992;15?–898).
Effect of Cyclosporine on Colchicine Secretion by A Liver Canalicular Transporter Studied In Vivo
Authors: Speeg Vincent K. , Maldonado Alma L. , Liaci Julie , Muirhead Donna
Published: March 2007

ABSTRPlCT

The multidrug resistance transport protein is a normal constituent of the liver canalicular membrane, although its function has not been defined in vivo. Colchicine, a multidrug resistance substrate, is eliminated mainly by the liver. Cyclosporine reverses multidrug resistance in vitro, presumably by inhibiting the multidrug resistance transporter. This study assesses biliary colchicine elimination and the effect of cyclosporine on this process. After cyclosporine administration biliary colchicine clearance decreased from 11.6 ± 0.8 to 2.2 ± 0.4 ml/min ± kg (p < 0.05), and the colchicine bile/plasma ratio decreased from 166 ± 9 to 38 ± 5 (p < 0.05). Cremophor EL (a cyclosporine vehicle) transiently inhibited biliary colchicine clearance and colchicine bile/plasma ratio, but to a much smaller extent than cyclosporine in vehicle. Biliary cyclosporine clearance was 0.122 and 0.024 ml/min · kg after bolus doses of 2 or 10 mg/kg intravenously, respectively. Cyclosporine bile/plasma ratio was 1.3 to 5.2. When cyclosporine was given 16 hr before colchicine infusion, biliary colchicine clearance decreased 39% (p < 0.05), and colchicine bile/plasma ratio decreased 51% (p < 0.05). Thus colchicine is actively secreted into bile and will be useful in the study of the multidrug transporter in vivo. Cyclosporine profoundly inhibits colchicine secretion into bile but is itself mainly metabolized rather than secreted. If competition for a common carrier is the basis for the interaction, then cyclosporine represents a drug that binds to but is not transported by the canalicular transporter. (Hepatology 1992;15:899-903).
Liver Metabolic Zonation in Rat Biliary Cirrhosis: Distribution Is Reverse of That in Toxic Cirrhosis
Authors: Sokal Etienne M , Mostin Joelle , Buts Jean Paul
Published: March 2007

ABSTRPlCT

Liver cell functional heterogeneity has been shown to persist in toxic CCl4 cirrhosis in growing rats, but the zonation observed in cirrhotic nodules may be different in other types of cirrhosis. To investigate this possibility, we looked at the zonal activities of two microsomal enzymes, glucose–6–phosphatase and NADPH dehydrogenase, in cirrhotic nodules from growing rats with chronic cholestasis. Zonal activities were measured by quantitative cytochemistry and microdensitometry. Liver cell heterogeneity was demonstrated, and we confirmed that the metabolic zonation is the mirror image of that observed in toxic cirrhosis, with periportal activity at the nodule periphery and perivenular activity at the nodule centers. Glucose–6–phosphatase activity was 2.06 times higher at the peripheries of the nodules than at the centers, whereas NADPH dehydrogenase activity at the nodule periphery was 72% of the nodule center activity.

We conclude that a liver cell functional heterogeneity persists in biliary rat cirrhosis, with zonation the reverse of that previously found in toxic CCl4 cirrhosis. (Hepatology 1992;15:904-908).
Cocaine Hepatotoxicity: Influence of Hepatic Enzyme Inducing and Inhibiting Agents on the Site of Necrosis
Authors: Roth Lois , Harbison Raymond D. , James Robert C. , Tobin Thomas , Roberts Stephen M.
Published: March 2007

ABSTRPlCT

Cocaine–induced hepatotoxicity has been reported in human beings and is well documented in mice. One interesting feature of this toxicity that appears to be common to both species is an apparent shift in the intraacinar site of necrosis under circumstances known to alter cocaine metabolism. However, the evidence in human subjects is limited, and studies elucidating the mechanism of this phenomenon cannot be performed in human beings. Although future studies in mice may define the basis of this mechanism, the current evidence is a somewhat fragmented composite of studies using different mouse strains and enzyme–inducing agents. Therefore a comprehensive pathologic investigation was initiated for the purpose of identifying and establishing an animal model suitable for studying this phenomenon. In naive ICR mice a single 60 mg/kg dose of cocaine was found to produce midzonal (zone 2) coagulative necrosis. In mice whose oxidative metabolism had been increased with β–ionone or in which esterase metabolism had been inhibited by diazinon, the severity of the toxicity was increased but the intraacinar origin of the lesion did not change. However, when the oxidative microsomal metabolism of ICR mice was induced by phenobarbital or β–napthoflavone, the acinar zone affected was dramatically different. Phenobarbital induction produced zone 1 necrosis, whereas β–napthoflavone induction caused necrosis in zone 3. The site of necrosis corresponded with the distribution of cocaine, and its metabolites were identified with colloidal gold–conjugated antibody probes. The results of this study suggest that the agents shifting the location of cocaine–induced hepatic necrosis alter the intraacinar site of protein binding of cocaine and its metabolites. (Hepatology 1992;15:934-940).
Hepatitis C: Evaluating the Seropositive Blood Donor
Authors: Martin Paul
Published: March 2007

ABSTRPlCT

Objective:

To determine the epidemiologic, clinical, serologic, and histologic importance of antibodies to hepatitis C virus (anti–HCV) in blood donors.

Design:

Cross–sectional identification and prospective evaluation of seropositive donors; retrospective assessment of infectivity; and nested casecontrol study for risk factors.

Setting:

Liver unit of a referral–based university hospital.

Subjects:

Of 30 231 consecutive donors, 368 (1.2%) were found to be anti–HCV–reactive by enzyme–linked immunosorbent assay (ELISA). Two hundred and fifty–four of these 368 donors were evaluated for risk factors by comparison with 284 age– and sex–matched controls. Eighty–six spouses of seropositive donors were also evaluated.

Measurements and Main Results:

Twenty–four percent of the seropositive donors had a history of percutaneous exposure to blood. This rate increased to 45% when only those donors confirmed to be anti–HCV positive by a second–generation recombinant immunoblot assay (RIBA–2) were considered. A family history of liver disease (odds ratio, 2.8; 95% CI, 1.6 to 4.8), previous blood transfusion (odds ratio, 6.1; 95% CI, 3 to 12.5), and a history of tattooing or intravenous drug abuse (odds ratio, 8.4; 95% CI, 2.3 to 31) were associated with anti–HCV seropositivity. An elevated alanine aminotransferase (ALT) level was found in 58% of the seropositive donors. Of the 150 donors tested, 104 (69%; CI, 62% to 77%) were confirmed by RIBA–2 to be anti–HCV positive. Of the 105 donors who had a biopsy, 16% had normal histologic findings, 11% had minimal changes, 21% had chronic persistent hepatitis, 45% had chronic active hepatitis, and 7% had active cirrhosis. All 77 donors with RIBA–2–confirmed seropositivity had histologic abnormalities. Of 43 donors evaluated in an infectivity study, 82% were implicated in previous HCV transmission. Only 2.3% of the spouses were anti–HCV positive. The ELISA, RIBA–2, and ALT results correlated with infectivity and abnormal histologic findings.

Conclusions:

In our geographic area, almost 70% of donors who are anti–HCV positive by ELISA are confirmed to be positive by RIBA–2; most of these donors appear to be chronic carriers of HCV and have substantial liver disease.
Atp–Dependent Canalicular Bile Acid Transport: Another Piece of the Puzzle
Authors: Smith Daniel J.
Published: March 2007

ABSTRPlCT

The secretion of bile by the liver is primarily determined by the ability of the hepatocyte to transport bile acids into the bile canaliculus. A carrier–mediated process for the transport of taurocholate, the major bile acid in humans and rats, was previously demonstrated in canalicular membrane vesicles from rat liver. This process is driven by an outside–positive membrane potential that is, however, insufficient to explain the large bile acid concentration gradient between the hepatocyte and bile. In this study, we describe an ATP–dependent transport system for taurocholate in inside–out canalicular membrane vesicles from rat liver. The transport system is saturable, temperature–dependent, osmotically sensitive, specifically requires ATP, and does not function in sinusoidal membrane vesicles and right side–out canalicular membrane vesicles. Transport was inhibited by other bile acids but not by substrates for the previously demonstrated ATP–dependent canalicular transport systems for organic cations or nonbile acid organic anions. Defects in ATP–dependent canalicular transport of bile acids may contribute to reduced bile secretion (cholestasis) in various developmental, inheritable, and acquired disorders.

Direct photoaffinity labeling of liver plasma membrane subfractions enriched in sinusoidal and canalicular membranes using [35S]adenosine 5′–O–(thiotriphosphate) ([35S]ATPγS) allows the identification of ATP–binding proteins in these domains. Comparative photoaffinity labeling with [35S]ATPγS and with the photolabile bile salt derivative (7,7–azo–3α,12α–dihydroxy–5β–[3β–H]–cholan–24–oyl)–2′–aminethanesulfonate followed by immunoprecipitation with a monoclonal antibody (Be 9.2) revealed the identity of the ATP–binding and the bile salt–binding canalicular membrane glycoprotein with the apparent Mr
of 110,000 (gp110). The isoelectric point of this glycoprotein was 3.7.

Transport of bile salt was studied in vesicles enriched in canalicular and sinusoidal liver membranes. Incubation of canalicular membrane vesicles with [H] taurocholate in the presence of ATP resulted in an uptake of the bile salt into the vesicles which was sensitive to vanadate. ATP–dependent taurocholate transport was also observed in membrane vesicles from mutant rats deficient in the ATP–dependent transport of cysteinyl leukotrienes and related amphiphilic anions. Substrates of the P–glycoprotein (gp170), such as verapamil and doxorubicin, did not interfere with the ATP–dependent transport of taurocholate.

Reconstitution of purified gp 110 into liposomes resulted in an ATP–dependent uptake of [H]taurocholate. These results demonstrate that gp110 functions as carrier in the ATP–dependent transport of bile salts from the hepatocyte into bile. This export carrier is distinct from hitherto characterized ATP–dependent transport systems.
Hepatitis A: New Information on An Old Virus
Authors: Dickinson Chris J.
Published: March 2007

ABSTRPlCT

An outbreak of hepatitis A virus (HAV) infection in a neonatal intensive care unit (NICU) provided the opportunity to examine the duration of HAV excretion in infants and the mechanisms by which HAV epidemics are propagated in NICUs. The outbreak affected 13 NICU infants (20%), 22 NICU nurses (24%), 8 other staff caring for NICU infants, and 4 household contacts; 2 seropositive infants (primary cases) received blood transfusions from a donor with HAV infection. Risk factors for infection among nurses were care for a primary infant–case (relative risk [RR], 3.2), drinking beverages in the unit (odds ratio [OR], ∞), and not wearing gloves when taping an intravenous line (OR, 13.7). Among infants, risk factors were care by a nurse who cared for a primary infant–case during the same shift (RR, 6.1). Serial stool samples from infantcases were tested for HAV antigen (HAV–Ag) by enzyme immunoassay and HAV RNA by nucleic acid amplification using the polymerase chain reaction. Infantcases excreted HAV–Ag (n = 2) and HAV RNA (n = 3) 4-5 months after they were identified as being infected. Breaks in infection control procedures and possibly prolonged HAV shedding in infants propagated the epidemic in a critical care setting.
Significance of Igm Antibody to Hepatitis C Virus in Patients With Chronic Hepatitis C
Authors: Brillanti Stefano , Masci Caterina , Ricci Piero , Miglioli Mario , Barbara Luigi
Published: March 2007

We assessed the correlation between the positivity for serum IgM antibody to hepatitis C virus and the activity of liver disease in patients with chronic hepatitis C virus infection. Serum samples were taken from 10 antibody to hepatitis C virus–positive asymptomatic patients with normal serum ALT levels, from 14 untreated patients with clinically and histologically proven chronic hepatitis C and from 26 patients with clinically and histologically proven chronic hepatitis C assigned to receive recombinant interferon α–2a (6 million IU three times a week for 6 mo). Each serum specimen was tested for IgM antibody to hepatitis C virus–associated C 100–3 antigen by enzyme–linked immunosorbent assay. Patients were observed for at least 12 mo.

All 10 patients with normal ALT values tested negative for IgM antibody to hepatitis C virus. In contrast, 33 of 40 (82%) patients with chronic hepatitis C had IgM antibody to hepatitis C virus, and a positive correlation was seen between the ALT level and the level of IgM antibody to hepatitis C virus (r = 0.803, p < 0.001).

During interferon treatment, ALT levels declined into the normal range in 18 of 26 treated patients (69%) and remained normal after stopping treatment in 8 patients (31%). In untreated patients, in treated patients who did not respond to interferon treatment and in responder patients who relapsed, no significant changes in IgM antibody to hepatitis C virus levels were seen during the study period. In contrast, IgM antibody to hepatitis C virus became undetectable by the end of interferon treatment in seven of eight patients with a sustained response.

In conclusion, we found a positive correlation between the presence of serum IgM antibody to hepatitis C virus and the activity of the hepatitis C–induced liver disease. In patients with chronic hepatitis C showing a response to α–interferon treatment, the disappearance of IgM antibody to hepatitis C virus predicted that the response would be sustained. (Hepatology 1992;15:998-1001).
Hepatitis C Viremia in Patients With Hepatitis C Virus Infection
Authors: Lok Anna S.F. , Cheung Ramsey , Chan Rachel , Liu Vincent
Published: March 2007

Sera from 103 patients were tested for hepatitis C virus RNA by nested polymerase chain reaction assay. Using primers from the highly conserved 5′untranslated region, we detected hepatitis C virus RNA in 67 (88.2%) of 76 patients positive for antibody to hepatitis C virus by both second–generation and neutralization enzyme immunoassays. Hepatitis C virus RNA was detected in 93% of patients who had been infected for 10 yr or less and in 89% of those who had been infected for longer than 10 yr. Hepatitis C virus RNA was detected in all patients with chronic hepatitis, active cirrhosis or hepatocellular carcinoma and in 50% of those with nonspecific reactive hepatitis or inactive cirrhosis. Hepatitis C virus RNA was not detected in sera from 22 patients negative for antibody to hepatitis C virus or in 5 patients positive for antibody to hepatitis C virus by second–generation but not by neutralization enzyme immunoassay. Using primers from the less conserved nonstructural region 4, we detected hepatitis C virus RNA at a lower frequency, in 66% of patients who were positive for antibody to hepatitis C virus by both secondgeneration and neutralization enzyme immunoassays. The detection rate was higher in patients with frequent parenteral exposure.

Our study showed that hepatitis C viremia can be detected in most patients with hepatitis C virus infection, including those with long–standing infection or advanced liver disease. (Hepatology 1992;15:1007-1012).
Polymorphism of Alcohol Dehydrogenase, Alcohol and Aldehyde Dehydrogenase Activities: Implication in Alcoholic Cirrhosis in White Patients
Authors: Poupon Renee E. , Nalpas Bertrand , Coutelle Christiane , Fleury Benoit , Couzigou Patrice , Higueret Denise
Published: March 2007

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase—3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p<0.05 and p<0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p<0.001). Aldehyde dehydrogenase activity was not different between cirrhosis–free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p<0.01).

These results suggest that no phenotypic pattern of alcohol dehydrogenase—3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis. (Hepatology 1992;15:1017–1022).
Hemodynamic and Liver Function Predictors of Serum Hyaluronan in Alcoholic Liver Disease
Authors: Gibson Peter R. , Fraser Robert J.E. , Brown Tracey J. , Finch Caroline F. , Jones Penelope A. , Colman John C. , Dudley Francis J.
Published: March 2007

To define hepatic predictors of serum hyaluronan in patients with chronic liver disease, 62 patients with alcoholic liver disease were evaluated. In group 1, 30 patients had concurrent assessment of serum hyaluronan, liver function tests, Pugh grade and hemodynamic indices. A second, overlapping group of 42 patients (group 2) also had antipyrine clearance measured but without hemodynamic assessment. All but six patients had elevated serum hyaluronan levels. In both groups, serum hyaluronan levels differed between Pugh grades and, in each group, was significantly greater in Pugh grade C compared with those in Pugh grade A (p<0.05, Kruskal–Wallis test). When analyzed by correlation, serum hyaluronan was significantly associated with several indices in group 1, but on multivariate linear regression only three statistically independent predictors of serum hyaluronan were identified: serum albumin (p = 0.008), indocyanine green clearance (p = 0.024) and indocyanine green extraction (p = 0.036). The overall R2 for these correlates was 65%. In the second group, antipyrine clearance was not significantly associated with serum hyaluronan (r = 0.29, p = 0.06), but other associations were similar to the first group. On multivariate analysis, only serum albumin predicted serum hyaluronan (p<0.001; R2 = 43%). In conclusion, indices of hepatocyte synthetic function, sinusoidal blood flow and degree of intrahepatic shunting are independent predictors of serum hyaluronan in alcoholic liver disease. These data show the unique nature of serum hyaluronan and suggest its potential application to the assessment of acute hemodynamic changes in patients with liver disease. (Hepatology 1992;15:1054-1059).
Effect of Simvastatin, Ursodeoxycholic Acid and Simvastatin Plus Ursodeoxycholic Acid on Biliary Lipid Secretion and Cholic Acid Kinetics in Nonfamilial Hypercholesterolemia
Authors: Mazzella Giuseppe , Parini Paolo , Festi Davide , Bazzoli Franco , Aldini Rita , Roda Aldo , Tonelli Domenica , Cipolla Antonio , Salzetta Antonio , Roda Enrico
Published: March 2007

It has been recently shown that the newest hypocholesterolemic agent, simvastatin, lowers the biliary cholesterol saturation index and that its association with ursodeoxycholic acid renders it more effective. To determine the mechanism by which simvastatin decreases the biliary cholesterol saturation index, we evaluated hepatic secretion rates of cholesterol, bile acids and phospholipids, and cholic acid pool size, turnover and synthesis in eight hyperlipidemic patients (five women and three men, age range = 38 to 65 yr). These assessments were conducted before treatment, after 4 wk of simvastatin (40 mg/day), after 4 wk of ursodeoxycholic acid (600 mg/day) and after a further 4 wk of a combination therapy of simvastatin (40 mg/day) plus ursodeoxycholic acid (600 mg/day).

The cholesterol saturation index was significantly reduced with simvastatin (from 1.51 ± 0.10 to 0.94 ± 0.05, mean ± S.E.; p<0.02), with ursodeoxycholic acid (from 1.51 ± 0.10 to 0.86 ± 0.03, mean ± S.E.; p<0.02) and with the combination of simvastatin plus ursodeoxycholic acid (from 1.51 ± 0.01 to 0.70 ± 0.05, p<0.02). The cholesterol saturation index during combination therapy was significantly lower (p<0.02) than that reached during the use of simvastatin and ursodeoxycholic acid. Both simvastatin and ursodeoxycholic acid significantly reduced the hepatic secretion rate of cholesterol (from 130 ± 14 μmol/hr to 81 ± 12 μmol/hr, p<0.01, and 70 ± 9 μmol/hr, p<0.01) without affecting bile acid and phospholipid outputs. The combination induced a significantly greater decrease of biliary cholesterol output (from 130 ± 14 to 53 ± 5 μmol/hr). Cholic acid pool size, synthesis and turnover rate were not affected by simvastatin administration, but ursodeoxycholic acid and the combination therapy significantly increased (p<0.02) the turnover of cholic acid. Our study shows that simvastatin decreases the cholesterol saturation index by reducing the biliary cholesterol secretion rate and that a synergistic effect is obtained by the addition of ursodeoxycholic acid. (Hepatology 1992;15:1072-1078).
Isolation of A Calcium–Regulatory Protein From Black Pigment Gallstones: Similarity With A Protein From Cholesterol Gallstones
Authors: Okido Masayuki , Shimizu Shuji , Ostrow Donald J. , Nakayama Fumio
Published: March 2007

We have previously isolated from 13 cholesterol gallstones a low molecular weight acidic bili–protein that inhibited the precipitation of calcium carbonate in vitro. We now report the isolation of a similar protein from seven black pigment gallstones. Cholesterol was removed from the stones by Soxhlet apparatus with methyl t–butyl ether, and bile acids were extracted with methanol. The protein was purified by sodium dodecyl sulfate–polyacrylamide gel electrophoresis after demineralization of the stones with ethylenediaminetetraacetate. Structural and functional properties of the protein from the black stones that were similar to the protein from the cholesterol stones included the following: (a) an apparent molecular weight of about 5 kD; (b) a high content of acidic (19.8%) and hydrophobic (50.1%) amino acids with a low content of basic residues (8.4%) and little sulfide–containing amino acids (1.9%); (c) an inhibitory effect on both the initiation and growth of calcium carbonate crystals in vitro; and (d) very tight (possibly covalent) binding of a diazo–positive yellow pigment, presumably bilirubin, with maximum spectral absorbance at 410 nm. The structural and functional similarities of these bili–proteins from black pigment and cholesterol gallstones and their striking effects on calcium carbonate precipitation in vitro suggest that they play a common role in the regulation of precipitation of calcium salts during the formation of both types of gallstones. (Hepatology 1992;15:1079-1085).
Endocrine Mechanisms for the Formation of Sex–Related Differences in Hepatic Estrogen Receptor Content and Their Significance for the Realization of An Estrogen Effect on Angiotensinogen Blood Level in Rats
Authors: Ignatenko Lidia L. , Mataradze Guranda D. , Rozen Victor B.
Published: March 2007

The use of a modified, adequate method of quantification of estrogen receptors has permitted us to prove the existence of sex–specific peculiarities in rat liver estrogen reception and their significance for the realization of sex–dependent changes in angiotensinogen plasma level after estrogenization. Endocrine mechanisms for the formation of sex–related differences in hepatic estrogen receptor content in rats were investigated in detail. The investigation shows that androgens have negative regulatory influence on the hepatic estrogen receptor level in rats. Estrogens and adrenal and thyroid hormones do not take part in the regulation of hepatic estrogen receptor content in rats. It has been proven that the decisive role in keeping up a certain estrogen receptor concentration in hepatocytes belongs to pituitary growth hormone. It was shown for the first time that androgens are able to inhibit the stimulatory effect of growth hormone on hepatic estrogen receptors. (Hepatology 1992;15:1092-1098).
Inhibition of Superoxide and Nitric Oxide Release and Protection From Reoxygenation Injury by Ebselen in Rat Kupffer Cells
Authors: Wang Ji-Feng , Komarov Pavel , Sies Helmut , de Groot Herbert
Published: March 2007

Luminol chemiluminescence in phorbolesteractivated cultured rat liver Kupffer cells was strongly inhibited by the selenoorganic compound ebselen (IC50 = 2 μmol/L). Ebselen (2–phenyl–1,2–benzisoselenazol–3[2H]one) also diminished reduction of ferricytochrome c (IC50 = 10μmol/L), indicating a suppression of superoxide anion formation. Likewise, in lipopolysaccharide–pretreated Kupffer cells, ebselen proved to be a potent inhibitor of the conversion of oxyhemoglobin to methemoglobin (IC50 = 3 μmol/L) as a measure of nitric oxide formation. The sulfurcontaining analog (2–phenyl–1,2–benzisothiazol–3[2H]one) and the ebselen derivative, methylselenobenzanilide, were inactive. These results indicate that ebselen is a potent inhibitor of NADPH oxidase in Kupffer cells, as has been reported for other macrophages and granulocytes. In addition, they suggest a novel characteristic of ebselen, namely very effective inhibition of nitric oxide synthase of macrophages. In line with its inhibitory effects on the release of reactive oxygen species by macrophages, complemented by its antioxidant properties, ebselen was potent in the prevention of reoxygenation injury of Kupffer cells (IC50 ˜ 5 μmol/L). (Hepatology 1992;15:1112-1116).
Effect of Galactosamine on Hepatic Carbohydrate Metabolism: Protective Role of Fructose 1,6–Bisphosphate
Authors: de Oliveira Jarbas R. , Rosa Jose Luis , Ambrosio Santiago , Bartrons Ramon
Published: March 2007

Intraperitoneal administration of galactosamine (400 mg/kg body wt) to rats results in reversible liver cell injury that is related to a dose–dependent depletion of uridine phosphates by formation of UDP–sugar derivatives. This damage was monitored through changes in serum enzymatic activities that increased after the first 6 hr of drug administration. Glycemia and serum albumin remained stable during liver injury, whereas cholesterol and triglycerides decreased. To maintain plasma glucose concentration, the hepatic carbohydrate metabolism was greatly altered. Glycogen dropped during the first hours, remaining low for up to 48 hr. Fructose 2,6–bisphosphate and ATP levels decreased even faster than glycogen, with lactate following a similar diminution and being restored in parallel with both metabolites. The reduction in fructose 2,6–bisphosphate can be explained by changes in the substrates or modulators of the 6–phosphofructo–2–kinase/fructose 2,6–bisphosphatase, because neither the cyclic AMP levels nor the activity ratio of the enzyme were modified.

Simultaneous administration of galactosamine and fructose 1,6–bisphosphate (2 gm/kg) prevented liver cell death, as monitored by serum enzyme activities. Furthermore, the bisphosphorylated metabolite had protective effects on the changes in liver calcium content and ATP and fructose 2,6–bisphosphate concentrations. In contrast, fructose, fructose–1–phosphate and fructose–6–phosphate had no significant protection. Fructose 1,6–bisphosphate might decrease galactosamine toxicity by increasing fructose 2,6–bisphosphate and ATP levels, the changes in both metabolites probably being related. The significance of these findings with respect to the mechanism of galactosamine–induced liver injury is also discussed. (Hepatology 1992;15:1147-1153).
Intracellular Calcium As A Second Messenger for Human Hepatocyte Growth Factor in Hepatocytes
Authors: Kaneko Akira , Hayashi Norio , Tsubouchi Hirohito , Tanaka Yuji , Ito Toshifumi , Sasaki Yutaka , Fusamoto Hideyuki , Daikuhara Yasushi , Kamada Takenobu
Published: March 2007

Human hepatocyte growth factor is a newly discovered substance that stimulates DNA synthesis in vitro. In this study, we examined intracellular Ca2+ movement as one of the second messengers for human hepatocyte growth factor in primary–cultured hepatocytes. The addition of hHGF induced Ca2+ oscillation, but the frequency of oscillations varied from cell to cell. We also saw marked intercellular heterogeneity in the initial latent period for the Ca2+ response; the mean latent period was rather longer than those seen with phenylephrine and vasopressin. This difference in the initial latent period may be due to the difference in the pathways of Ca2+ elevation.

Duration of culture determined the number of human hepatocyte growth factor—responsive cells; their number peaked at 2 to 5 hours of confluent culture, whereas the peak was earlier in a low–density culture. These changes in responsiveness during culture can be explained by the cell cycle—dependent sensitivity to human hepatocyte growth factor of hepatocytes. The Ca2+ response to human hepatocyte growth factor was dose dependent; 10-10 mol/L hHGF gave the highest Ca2+ response, similar to the dose–response curve of DNA synthesis. We even observed the Ca2+ response in the Ca2+–free buffer, so the increase in Ca2+ was considered due to release from intracellular Ca2+ stores.

These results suggest that human hepatocyte growth factor causes the intracellular Ca2+ elevation in the early stage of the cell cycle and that it plays important roles in the signal transduction systems for human hepatocyte growth factor and the proliferation of hepatocytes. (Hepatology 1992;15:1173-1178).
Glucocorticoid Stimulates Hepatitis B Viral Gene Expression in Cultured Human Hepatoma Cells
Authors: Chou Chen-Kung , Wang Li-Hsien , Lin Hsing-Mei , Chi Chin-Wen
Published: March 2007

Glucocorticoids have been shown to influence the severity of hepatitis B virus-related chronic hepatitis in human. However, very little is known about the effects of glucocorticoids on hepatitis B virus replication in vitro. In this report, we used a welldifferentiated human hepatoma cell line, Hep3B, transfected with hepatitis B virus complementary DNA as a model to show that a glucocorticoid analog, dexamethasone, can directly stimulate the production of HBsAg and HBeAg. Elevation of 3.5–kb pregenomic RNA and all other viral RNAs in the transfected Hep3B cells after dexamethasone treatment supports the hypothesis that glucocorticoids directly stimulate hepatitis B virus gene expression in vitro. The concentration of dexamethasone for its half–maximal stimulatory activity toward HBsAg, HBeAg and all viral transcripts was approximately 10-8 mol/L, close to the affinity of glucocorticoid receptors to [3H]triamcinolone acetonide in Hep3B cells ( ± 10-8 mol/L). Specific glucocorticoid antagonist RU38486 completely blocked dexamethasone–induced HBV gene expression, suggesting that the stimulatory effect of dexamethasone was mediated through specific glucocorticoid receptors. (Hepatology 1992;16:13-18.)
Changes of Igg–Bearing Cell Populations in the Portal Tracts of Patients With Chronic Liver Disease of Viral Etiology: An Evaluation by Immunoperoxidase Method and Computerized Image Analysis
Authors: Torgano Giuseppe , Vecchi Maurizio , Arosio Eliana , Santambrogio Daniela , Ronchi Guido , Annoni Giorgio , Tomasini Maurizio , Contessini Ettore , De Franchis Roberto
Published: March 2007

Little is known about the distribution of IgG–bearing cell subpopulations in normal liver and their possible changes in disease conditions. We developed an immunohistochemical method that proved suitable and accurate for the identification and characterization of IgG–bearing cells and their subpopulations in liver specimens. The method uses specific monoclonal antibodies on serial mirror liver sections. We applied this method to four normal liver tissue specimens and 25 liver biopsy samples of chronic hepatitis of viral etiology. Only rare IgG–bearing cells could be observed in the portal tracts of normal liver specimens. In contrast, a dense infiltrate of such cells was seen in liver specimens from patients with chronic viral hepatitis. The density of IgG–bearing cells in such patients ranged from 6 to 20 cells × 10-4 μm2 in the different specimens (x- = 11 × 10-4 μm2). The increase in IgG–bearing cells did not appear to be related to the histological diagnosis, to the degree of histological inflammatory activity or to the type of viral infection. The major population of IgG–bearing cells consisted of IgG1–positive cells (68%); IgG2– (17%), IgG3– (8%) and IgG4 (7%)-bearing cells represented only minor fractions. The increased prevalence of IgG1–bearing cells observed in chronic hepatitis but not in normal liver specimens suggests that these findings may reflect an activation of antibody production directed toward viral antigens or antigenic structures of self. The identification of the antigenic specificities of the antibodies produced by IgG–bearing cells might provide important clues in understanding the pathogenesis of chronic viral hepatitis. (Hepatology 1992:16:19-23.)