bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatotoxicity Due to Allyl Alcohol in Deermice Depends on Alcohol Dehydrogenase
Authors: Belinsky Steven A. , Bradford Blair U. , Forman Donald T. , Glassman Edward B. , Felder Michael R. , Thurman Ronald G.
Published: March 2007

The role of alcohol dehydrogenase in the hepatic necrosis due to allyl alcohol was studied in two strains of the deermouse, Peromyscus maniculatus. Mice of the alcohol dehydrogenase–negative (Adh
N) strain which lack alcohol dehydrogenase activity were resistant to allyl alcohol toxicity. In contrast, dose–dependent necrosis of periportal regions of the liver and increases in plasma levels of lactate dehydrogenase, sorbitol dehydrogenase and SGOT were observed in plasma from alcohol dehydrogenase–positive deermice (Adh
F) 24 hr following administration of allyl alcohol (21 to 84 mg per kg). Half–maximal damage to periportal areas was observed with about 52 mg per kg allyl alcohol. Thus, these data demonstrate that metabolism of allyl alcohol to acrolein by alcohol dehydrogenase is obligatory for the hepatotoxicity of allyl alcohol.
Effects of Hypoxia and Phenobarbital Treatment on the Metabolism of Mitomycin C in Experimental Animals
Authors: Nomura Fumio , Ohnishi Kunihiko , Koen Hirofumi , Iida Shinji , Tanabe Yuichi , Hatano Hitoshi , Okuda Kunio
Published: March 2007

To evaluate the effects of anaerobic conditions and inducers for the mixed–function oxidase system on the metabolism of mitomycin C, a bioreductive alkylating agent widely used for the treatment of hepatocellular carcinoma, experiments so designed were performed in rats and mice. Metabolism of mitomycin C by microsomes from normal rat liver and diethyl–nitrosamine–induced mouse hepatocellular carcinoma tissue was assessed from the disappearance of the quinone portion of mitomycin C and by measurement of alkylating metabolites using 4–(p–nitrobenzyl)pyridine as a trapping agent. The metabolism of mitomycin C measured by the two independent methods was strikingly increased under anaerobic conditions in both intact and tumor tissues. Since involvement of cytochrome P–450 in the metabolic activation of mitomycin C was shown recently, effects of representative inducers for the mixed–function oxidase system on the metabolism of mitomycin C were also studied. Phenobarbital treatment resulted in a significant increase in the metabolism of mitomycin C in both intact and tumor tissues under anaerobic conditions. The markedly enhanced formation of active metabolites of mitomycin C under anaerobic conditions may explain on a metabolic basis, at least in part, our recent clinical observations that chemoembolizations with microcapsular forms of mitomycin C is more effective than conventional bolus administration of this agent in the treatment of hepatocellular carcinoma. Combination of anaerobic conditions and induction of the mixed–function oxidase system may be applicable to chemotherapy of hepatic malignancy.
Effect of Glycoursodeoxycholate on Precipitation of Calcium Carbonate
Authors: Marteau Chantal , Portugal Henri , Pauli Anne-Marie , Gerolami André
Published: March 2007

The potential role of bile salts in preventing calcium carbonate precipitation was investigated by studying their interaction of Ca2 and their inhibitory effects on calcium carbonate formation.

Glycochenodeoxycholate micelles bound more calcium than did glycocholate. At bile salt concentrations exceeding 12.5 mM, glycoursodeoxycholate bound calcium as well as glycochenodexycholate did. Similar results for calcium binding were observed in mixed micelles of bile salts and lecithin. In bicarbonate (25 or 50 mM) and CaCl2 (10 mM) solutions, calcium carbonate formation was inhibited by the bile salts. Glycoursodeoxycholate and glycochenodeoxycholate (25 mM) prevented calcium carbonate formation which was delayed by glycocholate. This effect is not due to differences between both series of bile salts for calcium binding since glycoursodeoxycholate or glycochenodeoxycholate (25 mM) more efficiently prevented calcium carbonate precipitation than did 35 mM glycocholate in spite of the same Ca2+ binding.

These results suggest that some bile salts may have a specific role in preventing calcium precipitation in bile. The mechanism is unknown. The physical properties of glycoursodeoxycholate and glycochenodeoxycholate do not support a role for CaCO3 precipitation in gallstone calcification during litholytic therapy.
High Density Lipoprotein Subpopulations in Chronic Liver Disease
Authors: Chang Linus , Clifton Peter , Barter Philip , Mackinnon Malcolm
Published: March 2007

Severe liver disease may be associated with a reduction in plasma concentration of high density lipoprotein and an impairment of plasma cholesterol esterification. These changes were confirmed in two patients with severe acute on chronic alcoholic liver disease. In five additional patients with biopsy–proven clinically compensated cirrhosis, there wasminimal reduction in concentration of plasma cholesteryl esters; there was, however a reduction of the plasma high density lipoprotein concentration to only 48 to 66% of normal. The particle size distribution of high density lipoprotein in these five patients was determined by gradient gel electrophoresis. The high density lipoprotein2 subfraction was preserved. The high density lipoprotein3 subfraction, however, was markedly changed with a reduction in the normal particles of radius 4.3 m and an accentuation of smaller particles of radius 3.9 m; in two patients, these smaller particles were the major high density lipoprotein subpopulation. Further investigations of this finding of a distinctive distribution of high density lipoprotein subpopulations in patient with chronic liver disease may provide new insights into high density lipoprotein metabolism.
Hepatic Hemodynamics and Oxygen Consumption in Alcoholic Fatty Liver Assessed by Organ–Reflectance Spectrophotometry and the Hydrogen Clearance Method
Authors: Kasahara Akinori , Hayashi Norio , Kurosawa Kazuhei , Sasaki Yutaka , Sato Nobuhiro , Kamada Takenobu
Published: March 2007

Hepatic blood flow and estimated hepatic oxygen consumption were studied in rats treated chronically with ethanol by organ–reflectance spectrophotometry and the hydrogen clearance method.

In the withdrawal state from ethanol, the concentration of hemoglobin in the hepatic tissue (ΔEr569—650), the estimated hepatic oxygen consumption (estimated VO2) and the regional liver blood flow decreased significantly in rats treated chronically with ethanol in comparison with their controls. On the other hand, there was no significant difference in the estimated oxygen saturation of the hepatic blood hemoglobin (estimated SO2) between both groups. That is, an increase in oxygen extraction, which was exhibited by a decrease in the estimated SO2, did not occur in rats treated chronically with ethanol in spite of a decrease in blood supply.

Thus, in the withdrawal state from ethanol, both oxygen delivery to the liver and oxygen utilization in the liver weredisturbed at the stage of alcoholic fatty liver.
Short–Term Effects of Propranolol on Portal Venous Pressure
Authors: Garcia-Tsao Guadalupe , Grace Norman D. , Groszmann Roberto J. , Conn Harold O. , Bermann Max M. , Patrick Michael J.C. , Morse Steven S. , Alberts Jeanne L.
Published: March 2007

The present study was designed to investigate the effect of propranolol on portal pressure of patients with alcoholic cirrhosis and portal hypertension and to correlate these effects with clinical and laboratory parameters. The mean baseline hepatic venous pressure gradient in the 50 patients studied was of 18.2 ± 4.1 mm Hg. It decreased significantly2 hr after the oral administration of 40 mg of propranolol to 15.7 ± 4.2 mm Hg (a mean reduction of 13.4 ± 17%). This reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure. There was no correlation between the decrease in hepatic venous pressure gradient and the decrease in heart rate. When results were analyzed individually, only 15 (30%) showed a large decrease in hepatic venous pressure gradient (>20%), 15 (30%) showed a moderate decrease (10 to 19%), and in 20 patients (40%) there was no reduction or an increase in hepatic venous pressure gradient. Comparison of “responders” (those that reduced hepatic venous pressure gradient >10%) and “nonresponders” (hepatic venous pressure gradient reduction <10%) showed no significant differences in baseline laboratory and hemodynamic parameters, in the severity of the liver disease, in theheart rate and blood pressure response to propranolol, nor in the propranolol plasma levels achieved 2 hr after propranolol administration. Propranolol plasma levels correlated with the reduction in heart rate but not with the reduction in hepatic venous pressure gradient. Of 14 nonresponders to 40 mg of propranolol who received additional doses, six showed a reduction inhepatic venous pressure gradient.

We conclude that, although propranolol reduces the mean portal pressure in patients with alcoholic cirrhosis and portal hypertension, this response is not uniform. Twenty percent of cirrhotic patients do not show any reduction in portal pressure even after maximal doses of propranolol. There is no clear explanation for this variable response; pharmacologic and/or hemodynamic factors may be involved. Neither the heart rate response to propranolol nor the propranolol plasma concentrations were found to be useful in assessing the portal pressure response to propranolol.
Substrates and Products of Purified Rat Liver Bilirubin Udp – Glucuronosyltransferase
Authors: Chowdhury Namita Roy , Arias Irwin M. , Lederstein Mitchell , Chowdhury Jayanta Roy
Published: March 2007

To determine whether the isoform of UDP–glucuronosyltransferase which catalyzes the formation of bilirubin monoglucuronide also mediates the formation of bilirubin diglucuronide and other specific sugar conjugates of bilirubin, Wistar rats were treated with clofibrate (300 mg per kg i.p. × 7 days); this resulted in a 200% increase in hepatic transferase specific activity for bilirubin. Proteins from hepatic microsomal fractions were solubilized, and the transferase isoform with activity toward bilirubin was purified by a combination of chromatofocusing, affinity chromatography and hydrophobic chromatography, to apparent homogeneity as judged by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The purified isoform catalyzed the formation of monoglucuronide and diglucuronide (with UDP–glucuronic acid as a cosubstrate), and glucoside and xyloside (with UDP–glucose and UDP–xylose as respective cosubstrates) of bilirubin and glucuronidation of the carcinogen metabolite 4′–hydroxydimethylaminoazobenzene. It also catalyzed the conversion of bilirubin monoglucuronide to diglucuronide (with UDP–glucuronic acid as cosubstrate, pH optimum 7.8), to mixed glucuronide–glucoside conjugate (with UDP–glucose as a cosubstrate) and to unconjugated bilirubin (with UDP as a cosubstrate, pH optimum 5.5). Each transferase activity was copurified at each purification step. Results of enzyme kinetic studies suggest that UDP–glucuronic acid, UDP–glucose and UDP–xylose recognize a common site. Transferase activities toward bilirubin were not detectable in homozygous Gunn rats liver microsomal fractions; in heterozygous Gunn rats, these activities were reduced by 40 to 60%. The results suggest that conjugation of bilirubin with glucuronic acid, glucose or xylose is catalyzed by a single transferase isoform.
Branched Chain Amino Acids in Hepatic Encephalopathy
Authors: Fb Cerra , Nk Cheung , Je Fischer , Conn Harold O.
Published: March 2007

Seventy–five patients with acute hepatic decompensation superimposed on chronic alcoholic cirrhosis were prospectively randomized for a blinded trial of the treatment of hepatic.
Epidemiology of Hepatitis B E Antigen and Antibody in Mentally Retarded Hbsag Carriers
Authors: Lohiya Ghanshyam , Lohiya Sunita , Ngo Vinh Trong , Crinella Ramona
Published: March 2007

Screening for HBeAg and anti–HBe was performed on 133 carriers of HBsAg in aninstitution for the mentally retarded. By radioimmunoassay, the prevalences of HBeAg and anti–HBe were determined to be 16 and 78%, respectively. HBeAg prevalence was significantly different in the following pairs of carriers: 70% in blacks, 10% in whites, and 35% incarriers with Down's syndrome, 8% in carriers without Down's syndrome. Mean age of HBeAg–positive carriers (25.7 years) was lower than HBeAg–negative carriers (29.6 years, p < 0.05). SGPT levels were abnormal in 66% of HBeAg–positive and 25% of HBeAg–negative carriers (p < 0.01). This suggests an association between HBeAg positivity andfunctional liver impairment.
Detection of Pre–S1 Proteins in Serum and Liver of Hbsag–Positive Patients: A New Marker for Hepatitis B Virus Infection
Authors: Theilmann Lorenz , Klinkert Mo-Quen , Gmelin Karl , Salfeld Jochen , Schaller Heinz , Pfaff Eberhard
Published: March 2007

The presence of pre–S1 proteins in serum and liver of individuals with acuteand chronic hepatitis B virus infection was investigated in Western blots using antibodies against a fusion protein, containing amino acids 20—120 of the pre–S region. Pre–S1 proteins were present in 20 of 38 HBsAg–positive sera. All sera positive for pre–S1 proteins were also positive for hepatitis B virus DNA indicating the presence of hepatitis B virions, and 16 of these sera were also positive for HBeAg. In five sera positive for hepatitis B virus DNA, pre–S1 proteins werenot found. In an additional study, pre–S1 proteins could be detected in 4 of 6 patients with acute hepatitis B virus infection during the first 2 weeks after admissionto the hospital. The presence of pre–S1 proteins showed a good correlation with the detection of hepatitis B virus DNA. After seroconversion from HBeAg to anti–HBe, both hepatitis B virus DNA and pre–S1 proteins were no longer detectable. Pre–1 proteins were present in three liver tissue specimens from two patients with acute hepatitis B virus infection and from one patient with cirrhosis of the liver. The proteins were not found in the liver of two HBsAg–positive patients with hepatocellular carcinoma (primary liver carcinoma), negative for HBeAg. Pre–S1 proteins can be detected in serum, positive for hepatitis B virus DNA and in liver tissue ofhepatitis B virus–infected individuals. The presence of these proteins appears to correspond with the presence of hepatitis B virus DNA, both markers indicating hepatitis B virus replication.
Differential Distribution of Hepatitis B Core and E Antigens in Hepatocytes: Analysis by Monoclonal Antibodies
Authors: Mondelli Mario , Tedder Richard S. , Ferns Bridget , Pontisso Patrizia , Realdi Giuseppe , Alberti Alfredo
Published: March 2007

Current knowledge on the expression of HBeAg in hepatocytes is incomplete because of difficulties in obtaining monospecific antisera devoid of anti–HBc reactivity. In this study, we have examined by immunofluorescence the expression of HBcAg and HBeAgin cryostat liver sections from 25 chronic carriers of HBsAg using monoclonal antibodies.

Although virtually all liver biopsies displayed concordance for HBeAg and HBcAg expression, the pattern of fluorescence differed markedly. Thus, monoclonal anti–HBcgave nuclear staining in all 13 reactive biopsies, while cytoplasmic staining was observed in only two of these. In contrast, monoclonal anti–HBe showed cytoplasmic reactivity coexisting with nuclear reactivity in 10 of 13 reactive biopsies. Hepatitis B virus DNA polymerase activity in the serum appeared to correlate better with the presence of HBcAg in hepatocytes rather than HBeAg.

These results provide further evidence that HBeAg is expressed both in the nuclei and in the cytoplasm of infected hepatocytes. The observation that the number of cells expressing HBeAg exceeds those expressing HBcAg in carriers with active virus replication would suggest that assembly of core particles occurs in only a proportion of infectedhepatocytes expressing HBeAg.
The Risk of Hepatitis B Transmission From Health Care Workers to Patients in A Hospital Setting—A Prospective Study
Authors: Labrecque Douglas R. , Muhs Joan M. , Lutwick Larry I. , Woolson Robert F. , Hierholzer Walter R.
Published: March 2007

A prospective study was designed to determine the risk of hepatitis B transmission from health care deliverers to patients in the hospital setting. Six chronic carriers of hepatitis B were identified: 2 surgeons, 1 dialysis nurse, 1 pediatric ICU nurse, 1 pharmacist and 1 orderly. Three of the six were HBeAg–positive. Two of the HBeAG–positive chronic carriers also had circulating hepatitis B virus DNA and accounted for approximately two–thirds of the total patient contacts. Two hundred thirteen patients were exposed 450 times to these six hepatitis B carrier staff without evidence of hepatitis B acquisition over a 6–month follow up. One–hundred nineteen control patients, exposed 789 times to noncarrier health care deliverers, were also negative. Another 33 patients were exposed to three additional individuals who were in the prodrome of acute hepatitis B: an intensive care nurse, a dental hygienist and amedical student. These patients showed no evidence of hepatitis B during 6 months of follow–up, nor did 25 separate control patients. Thus, 246 patients were exposed atotal of 483 times to nine health care personnel who had either acute or chronic hepatitis B. No evidence of hepatitis B transmission was found. One–hundred forty–four controls revealed similar results after 814 exposures. Based on the number of exposures to chronic carriers alone, the risk of hepatitis B transmission is estimated to be less than 1%. Our data suggest that, with observation of appropriate hospital technique, the risk of hepatitis B transmission by health care workers is relatively low, even in the high risk settings of surgery or renal dialysis performed by an HBeAg–positive hepatitis B virus DNA–positive carrier. Available accumulated data do not support the automatic exclusion of chronic HBsAg carrier health care workers from any area of primary patient care.
Pyridoxal–5′–Phosphate and Alkaline Phosphatase
Authors: Lumeng Lawrence
Published: March 2007

Markedly increased circulating concentrations of pyridoxal–5′–phosphate (PLP) were found in each of 14 patients representing all clinical forms of hypophosphatasia, an inborn error characterized by deficient activity of the tissue–nonspecific (bone/liver/kidney) isoenzyme of alkaline phosphatase (AP). The mean PLP concentration in plasma was 1,174 nM (range, 214 to 3,839 nM) in the patients and 57 ± 26 nM (mean ± S.D.) in 38 control subjects. In four affected children, urinary excretion of the PLP degradation product, 4–pyridoxic acid, was unremarkable during consumption of normal quantities of dietary vitamin B6.

Our findings identify increased circulating PLP concentration as a marker for hypophosphatasia and provide further evidence that tissue–nonspecific AP acts in vitamin B6 metabolism. Tissue–nonspecific AP appears to function as an ectoenzyme to regulate extracellular but not intracellular levels of PLP substrate. Performing assays of circulating PLP concentrations alone to assess vitamin B6 nutrition may be misleading in disorders associated with altered AP activity.
Antibody to the receptor for polymerized human serum albumin in acute and persistent infection with hepatitis B virus
Authors: Okamoto Hiroaki , Usuda Sadakazu , Imai Mitsunobu , Tachibana Katsumi , Tanaka Eiji , Kumakura Tomoko , Itabashi Masako , Takai Emiko , Tsuda Fumio , Nakamura Tetsuo , Miyakawa Yuzo , Mayumi Makoto
Published: March 2007

The antibody against the receptor for polymerized human serum albumin was determined by radioimmunoassay. The method involved the inhibition by the test serum, absorbed with HBsAg particles without the receptor, on the binding of polymerized human serum albumin to HBsAg particles with the receptor fixed on a solid support. The amount of polymerized human serum albumin captured by the receptor on HBsAg was then determined by the radiolabeled monoclonal antibody directed to an epitope specific for polymerized human serum albumin. In acute infection, the antibody to the receptor for polymerized human serum albumin appeared in the early recovery phase while HBs antigenemia and elevated transaminase levels were still present, preceding the antibody to HBsAg (anti-HBs). The antibody was detected in 4 (1%) of 358 sera from asymptomatic carriers of HBsAg containing antibody to HBeAg, and in none of 67 sera containing HBeAg. Although the antibody was found in as many as 111 (74%) of 150 sera from blood donors who had presumably acquired anti-HBs after natural infection, it was not detected in any sera from 77 recipients of hepatitis B vaccine who had seroconverted for anti-HBs. On the basis of these observations, the determination of antibody to the receptor for polymerized human serum albumin helps in further understanding the immunity to hepatitis B virus.
Effects of a new loop diuretic (muzolimine) in cirrhosis with ascites: Comparison with furosemide
Authors: Bernardi Mauro , De Palma Rossana , Trevisani Franco , Santini Costanza , Patrono Daniela , Motta Roberto , Servadei Donatella , Gasbarrini Govanni
Published: March 2007

Muzolimine is a loop diuretic with both the dosedepend increasing effectiveness of loop diurexctics and the long-lasting effect of thiazides. This is a potential advantage in the treatment of ascites in advanced cirrhosis since these patients have a low tolerance to sudden reductions of blood volume.

Equivalent single, oral doses of furosemide (40 mg) and muzolimine (30 mg) were given to 10 cirrhotic patients with ascites and reduced renal perfusion (glomerular filtration rate=30 to 75 ml per min). The study was preceded by 4 days of equilibration (dietary sodium 40 mmoles per day), and the drugs were alternated via a single-blind, cross-over protocol after a wash-out period of 3 days. Renal function was monitored under basal conditions and after diuretic administration through 4-hr clearance periods for 24 hr. The reninaldosterone axis was evaluated before diuretic administration and after 8 and 24 hr. Muzolimine led to a 12-hr cumulative diuresis [AUC0−2=2.52 ± 0.42 (S.E.) ml per min] and natriuresis (5.14 ± 1.05 mmoles per hr), which were comparable to those of furosemide (2.85 ± 0.29 ml per min and 6.75 ± 1.63 mmoles per hr). Its effect, however, was distributed over a longer period (8 hr) than furosemide (4 hr). Muzolimine activity mainly-differed from furosemide because of: significantly lower 12-hr potassium excretion (AUC0−2=0.28 ± 0.82 vs. 2.69 ± 0.46 mmoles per hr; p<0.005); greater sodium/ chloride excretion ratio (0.45 ± 0.08 vs. 0.26 ± 0.06; p<0.025), and absence of rebound phenomena. These were clearly evident with furosemide, involving both the glomerular filtration rate and renal ion excretions from the third clearance period. Finally, plasma renin activity significantly increased 24 hr after furosemide (from 1.66 ± 0.40 to 2.35 ± 0.60 ng per ml per hr; p<0.05), whereas it was not affected by muzolimine administration. These findings suggest that muzolimine use in the treatment of ascites in cirrhosis may be followed less easily by complications, such as diureticinduced uremia and metabolic alkalosis, as compared to other loop diuretics.
Frequency and significance of tumor thrombi in esophageal varices in hepatocellular carcinoma associated with cirrhosis
Authors: Arakawa Masahiro , Kage Masayoshi , Matsumoto Shin-Ichi , Akagi Yasuhisa , Noda Takemi , Fukuda Kazunori , Nakashima Toshiro , Okuda Kunio
Published: March 2007

Histological examination of the wall of the stomach and esophagus in patients with hepatocellular carcinoma associated with cirrhosis demonstrated intravariceal tumor thrombi in 13 (23.6%) of 55 cases studied. There were distant hematogenous metastases in 31 of them, of whom 12 (38.7%) had variceal tumor thrombi. Tumor thrombi were of varying sizes, and tumor cells appeared either intact, degenerated or necrotic. In seven cases, there was a firm adhesion of thrombi onto the vascular wall suggesting possible mural infiltration, but no extravascular metastases were noted grossly. These findings suggest a possibility of metastasis of hepatocellular carcinoma to the stomach and esophagus via the portal vein. It is also suggested that the degree of varices is not increased by tumor thrombus formation per se, and that both varices and tumor thrombi are due to extensive hepatofugal collateral circulation. Considering that 12 of 13 cases of intravariceal tumor thrombi had lung metastases, a portal vein—varices—lung route is possible for lung metastasis beside the established route through the hepatic vein in hepatocellular carcinoma.
The ontogeny of liver copper metabolism in the guinea pig: Clues to the etiology of Wilson's disease
Authors: Srai Surjit K. S. , Burroughs Andrew K. , Wood Bernard , Epstein Owen
Published: March 2007

The normal human neonate has a copper profile indistinguishable from Wilson's disease, and we have previously postulated that this disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism. This study validates the developing guinea pig as a suitable animal in which to study copper ontogeny. At birth, liver copper concentrations are 7 times higher than in adults and serum copper and ceruloplasmin are 27 and 21% of adult values, respectively. A 53% fall in liver copper occurs in the 4 days after birth. This is associated with a marked increase in bile copper output, which does not parallel increasing bile flow. Liver copper falls, and serum copper and ceruloplasmin increase to near adult levels in the 30 days after birth. Until the sixtieth day of gestation, liver copper was significantly increased in copper-stressed littermates, although paradoxically at birth, concentrations were significantly lower. In copper-stressed fetal animals, bile copper output increased markedly before birth.

Metallothionein was the dominant copper-binding protein in the fetal liver but a minor component in the adult. Superoxide dismutase activity only developed after birth. We conclude that the postnatal switch from the fetal to adult mode of copper metabolism involves activation of biliary excretion and ceruloplasmin export as well as changes in the association of copper with hepatic copper proteins. Similarities between the fetus and Wilson's disease suggest that this disease is caused by failure of this postnatal adaptation process.
Relationships between 34 HLA-A, HLA-B and HLA-DR antigens and three serological markers of viral infections in alcoholic cirrhosis
Authors: Doffoel Michel , Tongio Marie M. , Gut Jean-Pierre , Ventre Guy , Charrault Alain , Vetter Denis , Ledig Marc , North Marie L. , Mayer Simone , Bockel René
Published: March 2007

In order to study the genetic risk of alcoholic cirrhosis, the frequency of 26 HLA-A and -B antigens was compared in 184 normal controls, 175 alcoholic cirrhotic patients and 83 alcoholic patients with hepatic steatosis of carefully selected ethnic origin. Eight HLA-DR antigens were also determined in 95 subjects of the normal control group and 63 patients of the alcoholic cirrhosis group. The incidence of hepatitis B virus antibodies (anti-HBc and anti-HBs) was defined in 74 patients of the alcoholic steatosis group, 170 patients of the alcoholic cirrhosis group and 111 normal controls different from the previously mentioned normal control group. The incidence and the titers of cytomegalovirus and rubella antibodies were also determined in 93 patients of the alcoholic cirrhosis group and the 111 normal controls. Serum immunoglobulin concentrations were measured in the same 93 cirrhotic patients. Compared with the controls, the alcoholic cirrhosis group revealed a significantly higher frequency of HLA-B15 (21.7 vs. 9.8%, p<0.00025, corrected p<0.050) and HLA-DR4 (38.1 vs. 17.9%, p<0.005, corrected p<0.050) and a significantly lower frequency of HLA-B13 (2.9 vs. 11.4%, p<0.025, corrected p<0.050). As for the frequency of all other HLA antigens, there was no significant difference between the three groups (normal controls, alcoholic cirrhosis and alcoholic steatosis). In the alcoholic cirrhosis group, the incidence of hepatitis B virus antibodies was higher in B15(+) patients (41.6%) than in B15(−) ones (19.4%, p<0.010) and in DR4(+) patients (50%) than in DR4(−) ones (15.4%, p<0.005). In the control and steatosis groups, there was no significant difference. In the alcoholic cirrhosis group, a significantly higher incidence of anticytomegalovirus was also observed in B15(+) patients (95.0%) than in B15(−) patients (69.9%, p <0.050), as well as significantly higher titers (p<0.050) of anticytomegalovirus and rubella and significantly higher IgG concentrations (p<0.025). All of these significant differences were not found in the control group. These results suggest that: (i) there is a genetic predisposition in alcoholic cirrhosis which may be associated with the presence of HLA-B 15 and DR4 antigens, and (ii) the higher incidence of hepatitis B virus antibodies in B15(+) and DR4(+) cirrhotic patients may be the result of differences in their immune responsiveness when compared to B15(−) and DR4(−) patients.
Bile infection documented as initial event in the pathogenesis of brown pigment biliary stones
Authors: Cetta Francesco M.
Published: March 2007

Findings in two patients having brown pigment bile stones, recurrent 18 and 36 months after cholecystectomy, are reported. Present data suggest that bile infection precedes rather than follows the formation of brown stones. The present data are part of a prospective study of 600 consecutive patients who underwent operation for gallstones and in whom clinical and laboratory findings, intra- and postoperative bile culture and bile pH were related to the analysis of stone composition by X-ray diffractometry and infrared spectroscopy.

Both patients during the first operation underwent cholecystectomy, sphincterotomy and T-tube drainage. Bile culture was negative both at operation and in the first 3 to 5 samples obtained from the T-tube every 2 days, while Escherichia coli was found, starting from the tenth and fourteenth postoperative days, respectively. At the second operation, typical recurrent “earthy” brown stones, easily crushed with the fingers, with no central nucleus of a different structure were found. Previous sphincterotomy became stenotic, and E. coli was found in the operative bile in a concentration higher than 106 per ml. It is suggested that bile infection by E. coli, in addition to bile stasis, plays a crucial role in the pathogenesis of brown pigment stones.
Intrahepatic cholangiectases and large-duct obliteration in primary sclerosing cholangitis
Authors: Ludwig Jurgen , Maccarty Robert L. , Larusso Nicholas F. , Krom Ruud A. F. , Wiesner Russell H.
Published: March 2007

We studied intrahepatic bile ducts of five patients with chronic ulcerative colitis and primary sclerosing cholangitis. The livers had been obtained at the time of orthotopic liver transplantation. After specimen cholangiography and perfusion fixation, sequential blocks and sections from portal tracts were studied, combining light microscopy with scanning electron microscopy. In vivo cholangiograms were studied also. The specimens revealed: (i) absence of normal bile ducts; (ii) presence of thin-walled tubular or saccular cholangiectases with semicircular and annular fibrous crests, without evidence of superinfection; (iii) cholangiectases with secondary acute or chronic-cellular cholangitis, with or without cholangitic abscesses; (iv) fibrous cholangitis without ductal dilatation; (v) transformation of bile ducts into fibrous cords which were either solid or contained remnants of bile duct epithelium, and (vi) complete loss of bile ducts. The shape and distribution of the cholangiectases suggested that these lesions were manifestations of the disease process and not passively dilated normal ducts. Fibrous-obliterative cholangitis with formation of fibrous cords was found not only at the level of interlobular and adjacent septal bile ducts but also at the level of segmental bile ducts that normally would have been demonstrable in cholangiograms. The “pruned-tree” appearance in cholangiograms appears to result from the transition between patent and often cholangiectatic ducts, and duct obliteration. At present, intrahepatic cholangiectases in association with duct obliteration can be considered pathognomonic morphologic features of primary sclerosing cholangitis.
Mechanisms of secretion of proteins into bile: Studies in the perfused rat liver
Authors: Kloppel Thomas M. , Brown William R. , Reichen Juerg
Published: March 2007

Employing the in situ perfused rat liver, we examined the origins and mechanisms of transport of proteins into bile. First, utilizing polyacrylamide gels, we noted that many biliary proteins co-migrated with dominant serum proteins. Upon liver perfusion with serum-free medium, most proteins disappeared from the biliary profile; one major biliary protein that was not present in serum, identified as secretory component, remained. Kinetic analysis of the disappearance half-lives of the biliary proteins suggested that some serum proteins enter bile by a slow (20 to 30 min; transcellular) route, while others utilize both slow and rapid (5 min; paracellular) routes. In biosynthetic labeling experiments, secretion of newly synthesized proteins into bile was delayed about 20 min when compared with secretion of proteins into the perfusion medium and comprised less than 1% of the total secreted proteins. When a new liver was inserted into the perfusion medium containing newly synthesized secreted proteins, only two proteins, hemopexin and an unidentified protein, were transported into the bile from the perfusion medium; other biliary proteins were presumed to come directly from the hepatocyte. This latter group included some proteins that were secreted into the perfusion medium as well as into bile, and others, e.g., secretory component, that were secreted only into bile. Based on our results we have defined six pathways for entry of proteins into bile.
Liver DNA synthesis promoter activity detected in human plasma from subjects with hepatitis
Authors: Díaz-Gil Juan J. , Sánchez Gonzalo , Santamaría Luis , Trilla Carolina , Esteban Paloma , Escartín Pedro
Published: March 2007

A liver DNA synthesis promoter activity was detected in human plasma from subjects with hepatitis. The assay procedure consisted of intraperitoneal injection into mice of aliquots of plasma, previously chromatographed on Sephadex G-25. After 24 hr, [3H]thymidine was injected and its incorporation into liver DNA measured. The increase in [3H]thymidine uptake of injected mice was not detected in those administered plasma from normal subjects (basal [3H]thymidine incorporation was that corresponding to saline-injected mouse values). At a maximal effective dose (0.3 mg protein per mouse), plasma from subjects with hepatitis increased the mitotic index of mouse liver hepatocytes; at the same dose, plasma from normal subjects had no effect. This DNA synthesis promoter activity appears to be a protein, as it is sensitive to trypsin digestion and heat.
Hepatitis B virus infection and liver disease in ethiopian immigrants to Israel
Authors: Ben-Porath Edna , Hornstein Lea , Zeldis Jerome , Nahmias Jacob , Gruia Mignon , Bilgoray Batia , Satinger Yehudit
Published: March 2007

We assessed infection with hepatitis B virus in 357 Ethiopians who immigrated to Israel. Hepatitis B virus infection, as measured by the presence in the serum of HBsAg, anti-HBs, or anti-HBc, started at an early age (35% at the age of 1 to 4 years) and reached an overall rate of 98% in individuals over 40 years old. A high rate of HBsAg antigenemia in the young age group (19% at the age of 1 to 8 years) was associated with HBeAg and serum hepatitis B virus DNA. However, hepatitis B virus DNA was rarely detected in HBsAg-positive serum of older individuals who were anti-HBe-positive. No hepatitis B virus DNA sequences were detected in the serum of individuals who had anti-HBs. Despite the extremely high rate of hepatitis B virus infection that occurred at an early age, no clinical evidence of chronic liver disease in this population was detected.
Acetone potentiation of chronic liver injury induced by repetitive administration of carbon tetrachloride
Authors: Charbonneau Michel , Tuchweber Beatriz , Plaa Gabriel L.
Published: March 2007

The ability of ketonic compounds to modify the chronic liver injury (cirrhosis) induced by haloalkanes is unknown. To investigate this problem, male Sprague-Dawley rats were treated p.o. twice weekly for 12 weeks with acetone (25 mmoles per kg in corn oil) or corn oil alone (10 ml per kg). The rats were treated p.o. with corn oil (10 ml per kg) or CCl4 (5 mmoles per kg in corn oil) 18 hr after each pretreatment. Animals were killed after 4, 8, 10 or 12 weeks of treatment. Liver-kidney/body weight ratios were computed; biochemical analyses were performed on plasma (ALT, bilirubin and blood urea nitrogen) and liver (collagen) samples. For the 10-week group, liver injury was assessed by a morphometric analysis. Body weight gain was slower in acetone-treated rats given CCl4;35% died. Compared to corn oil + CCl4-treated rats, acetone + CCl4-treated animals showed significantly lower liver weight/body weight ratios and higher kidney weight/body weight ratio values at all four times. Significantly higher levels occurred at all four times for bilirubin concentrations, and at 4, 8 and 10 weeks for collagen contents. No significant differences were observed in ALT activities between corn oil- and acetone-treated rats challenged with CCl4. Light microscopy revealed that after 10 weeks of treatment, acetone + CCl4-treated animals showed a fully developed cirrhosis, whereas a much less severe lesion was observed in corn oil + CCl4-treated rats. Evidence of nephrotoxicity was observed in the acetone + CCl4 group as exemplified by significantly elevated blood urea nitrogen values. We conclude that acetone treatment increases the extent of fibrosis and accelerates the appearance of cirrhosis induced by CCl4.
Blood level of mitochondrial aspartate aminotransferase as an indicator of the extent of ischemic necrosis of the rat liver
Authors: Nishimura Tadashi , Yoshida Yukuo , Watanabe Fusao , Koseki Masato , Nishida Toshiro , Tagawa Kunio , Kawashima Yasunaru
Published: March 2007

To assess the severity of ischemic liver injury, we examined release of mitochondrial aspartate aminotransferase (EC 2.6.1.1) and its cytoplasmic isozyme from the ischemic rat liver into the circulation. Their patterns of leakage were quite different: the level of cytoplasmic aspartate aminotransferase reached a peak soon after the circulation to the ischemic liver was restored, while that of mitochondrial aspartate aminotransferase increased slowly, reaching a maximum after more than 10 hr. On anoxic incubation of mitochondria isolated from the normal liver, oxidative phosphorylation capacity was lost within 2 hr, at which time no leakage of matrix enzymes was observed: more than 10 hr after-loss-of-oxidative phosphorylation were needed for the matrix enzymes to leak out of the mitochondrial membrane. Since the viability of cells is considered to depend on the capacity of oxidative phosphorylation, it is highly likely that the delayed appearance of mitochondrial aspartate aminotransferase in blood indicates the postmortem changes of injured cells. In fact, the cumulative activity of mitochondrial aspartate aminotransferase but not cytoplasmic aspartate aminotransferase in circulation after ischemic liver injury correlated fairly well with the decrease of total adenine nucleotides which were monitored to measure viable cells. The difference between mitochondrial aspartate aminotransferase and cytoplasmic aspartate aminotransferase as quantitative indices of hepatic necrosis may be due to the relative stability of the former and significant inactivation of the latter during hepatic ischemia. Therefore, the determination of mitochondrial aspartate aminotransferase in blood may be useful in the assessment of liver necrosis after ischemic injury.
Quantitation, tissue distribution and proliferation kinetics of kupffer cells in normal rat liver
Authors: Bouwens Luc , Baekeland Marijke , de Zanger Ronald , Wisse Eddie
Published: March 2007

In normal rat liver, Kupffer cells were unequivocally identified using peroxidase cytochemistry by light microscopy in semithin plastic sections. The Kupffer cell population was found to constitute 31% of the sinusoidal cells and by morphometry and serial sectioning, a mean absolute number of 14 to 20 × 106 Kupffer cells per g liver was calculated. The mean distribution of Kupffer cells in the liver lobules was 43% in the periportal, 28% in the midzonal and 29% in the central area of the lobule. Administration of latex particles labeled only 64% of all Kupffer cells, and in particular centrally located cells, showed a lower activity of latex uptake, even at overloading doses. Furthermore, the latter cells were of smaller size than periportal Kupffer cell profiles.

The mean number and distribution of latex-labeled Kupffer cells did not change over a period of 3 months, indicating a long lifetime for these resident macrophages. This slow population turnover was supported by the observed small mitotic index, 0.06% after a 6 hr arrest by vinblastine, and by the small [3H]thymidine labeling index which did not change over a period of 3 weeks after administration of the label. It is proposed that the Kupffer cell population, under physiologic conditions, is a long-living and self-renewing population, the kinetics of which substantially differ from those of other sinusoidal cell types.
Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?
Authors: van der Sluijs Peter , Bootsma Hans P. , Postema Bart , Moolenaar Frits , Meijer Dirk K. F.
Published: March 2007

The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drugcarrier conjugate fluorescein-lactosylated albumin (F-LnHSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytosed neoglycoprotein. Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L7HSA and F-L25HSA could not completely be inhibited by a dose of 10 mg asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactoseterminated glycoproteins. Clearance experiments with fluoresceinated 125I-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (˜90%) inhibition of hepatic uptake, while also a pronounced effect was obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein permole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neoglycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of “inversed targeting” could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.
Diagnostic tests in jaundice: WHO is to choose, the doctor or the computer?
Authors: O'Connor K. W.
Published: March 2007

A model has been developed for ordering diagnostic tests in jaundiced patients. The system proceeds in two steps: (i) diagnostic hypotheses are calculated for each patient from the results of physical examination and routine biological investigations; (ii) given these hypotheses, the most efficient test (out of 22) for reaching the final diagnosis is selected using four criteria: diagnostic value, risk, financial cost, and time in obtaining the result. This model was tested in 62 patients. In 43 of them (69%), the selected test was sufficient for reaching a diagnostic accuracy of 100%. In this group of patients, a mean of 3.7 (range 1-6) tests per patient was ordered by physicians. In the 19 remaining patients, the selected test was not sufficient for the final diagnosis, thus requiring a multiple choice process. It is suggested that such a system could help physicians to improve the care of patients by more efficient ordering of diagnostic tests.
Hepatic lesions induced by alcohol sensitizing drugs: Two lesions for the price of one
Authors: Vazquez Jaime J.
Published: March 2007

Two cases of disulfiram-induced hepatitis are presented. Both cases had prompt recurrence of abnormal liver function tests after rechallenge with small doses of the drug. All cases of disulfiram-induced hepatotoxicity reported in the English literature are reviewed.
Low serum alkaline phosphatase activity in Wilson's disease
Authors: Shaver William A. , Bhatt Harshika , Combes Burton
Published: March 2007

Low values for serum alkaline phosphatase activity were observed early in the course of two patients with Wilson's disease presenting with the combination of severe liver disease and Coombs' negative acute hemolytic anemia. A review of other cases of Wilson's disease revealed that 11 of 12 patients presenting with hemolytic anemia had values for serum alkaline phosphatase less than their respective sex- and age-adjusted mean values; in eight, serum alkaline phosphatase activity was less than the lower value for the normal range of the test. Low values for serum alkaline phosphatase were much less common in Wilson's disease patients with more chronic forms of presentation. Copper added in high concentration to serum in vitro did not have an important effect on serum alkaline phosphatase activity. The mechanism responsible for the decrease in serum alkaline phosphatase activity in patients is uncertain.
Metabolism of 24-norlithocholic acid in the rat: Formation of hydroxyl- and carboxyl-linked glucuronides and effect on bile flow
Authors: Shattuck Karen E. , Radominska-Pyrek Anna , Zimniak Piotr , Adcock Eugene W. , Lester Roger , St. Pyrek Jan
Published: March 2007

24-Norlithocholic (3α-hydroxy-24-nor-5β-cholan-23-oic) acid is the lower homologue of lithocholic acid, a potent cholestatic agent. In order to characterize its cholestatic potential and metabolic fate, 3β-tritiated 24-norlithocholate was infused intravenously into adult male Sprague-Dawley rats prepared with an external biliary fistula. The results demonstrate that 24-norlithocholate does not induce cholestasis in rats when administered in doses in excess of those necessary for lithocholate to produce cholestasis. Hydroxyl- and carboxyl-linked glucuronides were identified as major metabolites secreted in the bile. Especially noteworthy is the identification of carboxyl-linked glucuronides of mono-, di- and trihydroxylated C23 bile acids. Their total amount (25% of recovered radioactive products) is comparable to that of the hydroxyl-linked glucuronide of 24-norlithocholic acid (41%). In this study, for the first time, a bile acid diglucuronide, substituted both at 3-hydroxyl and carboxyl groups, was detected (11%).