bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the Liver Cytosol Antigen Type 1 Reacting With Autoantibodies in Chronic Active Hepatitis
Authors: Abuaf Nisen , Johanet Catherine , Chretien Pascale , Martini Eric , Soulier Emmanuelle , Laperche Syria , Homberg Jean Claude
Published: March 2007

ABSTRACT

An autoantibody to liver cytosol was previously described in childhood autoimmune chronic active hepatitis type 2. The antigen, liver cytosol antigen type 1, was for the first time partially purified using gel filtration and ion exchange chromatography, and it was characterized using immunodiffusion, immunoblot and sodium dodecyl sulfate—polyacrylamide gel electrophoresis analysis of the immunoprecipitate. Immunoblot detected a unique antigenic peptide at 62 kD from human cytosol and at 58 kD from rat cytosol. The same peptides were also detected when immuno–precipitates of liver cytosol antigen type 1 and autoantibodies to liver cytosol antigen were submitted to sodium dodecyl sulfate—polyacrylamide gel electrophoresis. A polymeric structure, probably a tetramer, is suggested for native liver cytosol antigen type 1 because in gel filtration chromatography liver cytosol antigen type 1 was eluted as a protein of a molecular weight between 240 and 290 kD when human liver cytosol was fractionated and between 220 and 270 kD from rat liver cytosol. Liver cytosol antigen type 1 is probably poor in carbohydrates because it was not stained by periodic acid—Schiff stain. The autoantibodies to liver cytosol were frequently found in association with antiliver kidney microsomal autoantibodies type 1, which are directed against the cytochrome P–450 of the IID6 subfamily. Antiliver kidney microsomal autoantibodies type 1 but not antiliver cytosol autoantibodies were found in association with antibodies to hepatitis C virus. Autoantibodies to liver cytosol antigen type 1 seem to be a more specific marker for autoimmune hepatitis type 2 than antiliver kidney microsomal antibodies type 1 autoantibodies. (HEPATOLOGY 1992;16:892-898.)
Postresection Recurrence of Hepatocellular Carcinoma Treated by Arterial Embolization: Analysis of Prognostic Factors
Authors: Takayasu Kenichi , Wakao Fumihiko , Moriyama Noriyuki , Muramatsu Yukio , Yamazaki Susumu , Kosuge Tomoo , Takayama Tadatoshi , Okada Shuichi , Okazaki Nobuo , Makuuchi Masatoshi
Published: March 2007

ABSTRACT

Of 270 consecutive patients with hepatocellular carcinoma who underwent surgery, 50 who had recurrence and were subsequently treated with transcatheter arterial embolization were analyzed. The longest interval between surgery and recurrence in the 50 patients who underwent transcatheter arterial embolization was 7 yr. Recurrence was initially found in the remnant liver in all patients but one; extrahepatic metastases were detected in 13 patients (26%) during follow–up. A “multiple” type was the most common (64%) hepatic recurrence pattern on angiography, followed by the “solitary” (16%) and “tumor thrombus” (12%) patterns. Hepatic recurrence was most frequently found in the ipsilateral lobe (48%) relative to the site of the primary hepatocellular carcinoma. Multivariate analysis of the factors affecting survival after transcatheter arterial embolization indicated that recurrence pattern (p = 0.025) and distant metastases (p = 0.011) were significant. Of 13 patients with distant metastases, 11 had the “multiple” pattern of hepatic recurrence. Survival rates for all 50 patients after initial surgery and after transcatheter arterial embolization were 90% and 64%, respectively, at 1 yr; 52% and 24%, respectively, at 3 yr; and 27% and 5%, respectively, at 5 yr. On analysis of survival rates after transcatheter arterial embolization in 37 patients with recurrence only in the liver and of the response of recurrent hepatocellular carcinoma to transcatheter arterial embolization, a significant difference was noted between those with “partial response” and “progressive disease” (p < 0.05) and between those with “no change” and “progressive disease” (p < 0.05). (HEPATOLOGY 1992;16:906-911.)
Does Elective Sclerotherapy Improve the Efficacy of Long–Term Propranolol for Prevention of Recurrent Bleeding in Patients With Severe Cirrhosis? A Prospective Multicenter, Randomized Trial
Authors: Ink Olivier , Martin Thierry , Poynard Thierry , Reville Marc , Anciaux Marie-Laure , Lenoir Claude , Marill Jean-Luc , Labadie Hélène , Masliah Claude , Perrin Daniel , Chaput Jean-Claude , Vetter Denis , Eugene Claude , Lebodic Louis , Licht Henri , Etienne Jean-Pierre
Published: March 2007

ABSTRACT

We conducted a prospective, multicenter, randomized trial to compare the efficacy of sclerotherapy plus propranolol with that of propranolol alone in the prevention of recurrent gastroesophageal bleeding in severely cirrhotic patients. For 2 yr (1987 to 1988) 131 patients (96% of whom were alcoholic) with Child–Pugh class B or C cirrhosis (56% were class B and 44% were class C) were randomly assigned to one of our two treatment groups after cessation of variceal bleeding, without hemostatic sclerosis, and were observed for at least 2 yr. Treatment observance was good in 89% of cases; alcohol withdrawal was observed in 62% of cases. Sclerotherapy was performed weekly with 1% polidocanol, and variceal obliteration was obtained in 83% of cases, in a mean number of four sessions. The cumulative percentages (expressed as mean ± S.D.) of recurrent bleeding at 2 yr were 42% ± 6% for propranolol plus sclerotherapy and 59% ± 6% for propranolol alone (a nonsignificant difference). Twentyeight patients from the propranolol group but only 12 patients from the propranolol–plus–sclerotherapy group had recurrent bleeding from esophageal variceal rupture (p < 0.01). The total number of blood units per patient with recurrent bleeding was slightly but not significantly more important in the propranolol group (8 ± 7) than in the propranolol–plus–sclerotherapy group (5 ± 5; p = 0.09). There were no statistical differences in the cumulative survival rate at 2 yr (propranolol plus sclerotherapy, 74% ± 6% and propranolol alone, 64% ± 6%) or in the number of patients who died of repeat bleeding (propranolol plus sclerotherapy, 13% ± 4% and propranolol alone, 17% ± 5%). Among the surviving patients, cirrhosis improved during the follow–up; Child–Pugh classification was the following at 1 mo: 35% for class A, 50% for class B and 15% for class C and the following at 2 yr: 58% for class A, 38% for class B and 4% for class C. In conclusion, elective sclerotherapy does not significantly decrease the rate of recurrent bleeding or death in severely cirrhotic patients who are treated with propranolol and who mainly abstain from drinking alcohol. (HEPATOLOGY 1992;16:912-919.)
Elevated Fibrin–Related and Fibrinogen–Related Antigens in Patients With Liver Disease
Authors: Kruskal Jonathan B. , Robson Simon C. , Franks John J. , Kirsch Ralph E.
Published: March 2007

ABSTRACT

Patients with liver disease have a variety of coagulation abnormalities. These derangements are of uncertain origin and do not always correlate with disease severity or activity. We have measured the levels and proportions of the total fibrin–related and fibrinogenrelated antigens, the principal fibrin (D–dimer) and fibrinogen (D–monomer) degradation fragments and intermediates of fibrin formation (fibrin monomers) in patients with a variety of acute and chronic liver diseases in whom all known other precipitating causes of disseminated intravascular coagulation had been excluded. Fibrin–related and fibrinogen–related antigens were extracted from serum using antihuman fibrinogen–IgG covalently bound to activated aminophenylthioether paper disks and were subjected to 4% to 11% sodium dodecyl sulfate—polyacrylamide gel electrophoresis under nonreducing conditions. Fibrinrelated and fibrinogen–related antigen proportions were determined by densitometry, and their levels were measured by radioimmunoassay. Levels of total fibrin–related and fibrinogen–related antigens (and D–dimer) were significantly elevated (p < 0.01) in patients with cirrhosis (121 to 641 ng/ml) and hepatocellular carcinoma (416 to 8,786 ng/ml) when compared with patients with acute viral hepatitis (84 to 322 ng/ml) and control subjects (38 to 186 ng/ml). In addition, D–monomer levels were elevated. These findings strongly suggest that disseminated intravascular coagulation is a component of the coagulopathy of certain liver diseases. Because fibrin–related and fibrinogen–related antigens have anticoagulant, vasoactive and immunosuppressive properties, their elevated presence may be biologically significant in these patients. (HEPATOLOGY 1992;16:920-923.)
Ursodeoxycholic Acid Therapy in Cystic Fibrosis—Associated Liver Disease: A Dose–Response Study
Authors: Colombo Carla , Crosignani Andrea , Assaisso Marisa , Battezzati Pier Maria , Podda Mauro , Giunta Annamaria , Zimmer-Nechemias Linda , Setchell Kenneth D.R.
Published: March 2007

ABSTRACT

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose–response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2–mo periods in a replicated Latinsquare design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% ± 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile. Our data indicate a need for doses of ursodeoxycholic acid of 20 mg/kg body wt/day or greater to obtain optimal improvement in biochemical indices of liver function and biliary ursodeoxycholic acid enrichment in cystic fibrosis patients with associated liver disease. (HEPATOLOGY 1992;16:924-930.)
Deficient Interleukin–2 Responsiveness of T Lymphocytes From Patients With Primary Biliary Cirrhosis
Authors: Menéndez José Luis , Girón José Antonio , Manzano Luis , Garrido Aurelio , Abreu Luis , Albillos Agustin , Durántez Alberto , Alvarez-Mon Melchor
Published: March 2007

ABSTRACT

There is increasing evidence that primary biliary cirrhosis is associated with an alteration of the immune system. Although the cause remains unknown, it has been suggested that the immune system of patients with primary biliary cirrhosis is involved in the pathogenesis of their disease. We have investigated the T–cell function in patients with primary biliary cirrhosis and have found defective phytohemagglutinin–induced T–cell mitogenesis. Likewise, their blastogenic response to CD3 monoclonal antibody was also depressed, although the DNA synthesis induced by stimulation with phorbol esters (12–O–tetradecanoilphorbol–13–acetate) plus ionophore (ionomycin) was normal. These alterations could not be ascribed either to a decreased synthesis of interleukin–2 or to a defective expression of interleukin–2 receptor after cellular activation. Moreover, this defective proliferative response of T lymphocytes was observed even in the presence of saturating concentrations of exogenous interleukin–2. These results represent evidence of the deficiency in the interleukin–2—dependent pathway found in T lymphocytes from patients with primary biliary cirrhosis. (HEPATOLOGY 1992;16:931-936.)
Effect of Loxiglumide and Atropine on Erythromycin–Induced Reduction in Gallbladder Volume in Human Subjects
Authors: Jebbink Max C.W. , Masclee Ad A.M. , van der Kleij Frank G.H. , Schipper Jaap , Rovati Lucio C. , Jansen Jan B.M.J. , Lamers Cornelis B.H.W.
Published: March 2007

ABSTRACT

This study was undertaken to investigate the effect of erythromycin, a motilin agonist with prokinetic activity, on fasting gallbladder volume. To evaluate the mechanism of action of erythromycin on gallbladder motility, erythromycin (3.5 mg/kg · 20 min, intravenously) was infused on three separate occasions: during cholinergic blockade with atropine (0.005 mg/kg · hr), during cholecystokinin receptor blockade with loxiglumide (10 mg/kg · hr) and during saline solution infusion (control). Atropine, loxiglumide and saline solution infusions were started 3 hr before administration of erythromycin and were continued for 3 hr thereafter. Gallbladder volumes (measured by ultrasonography), plasma cholecystokinin levels (radioimmunoassay) and plasma pancreatic polypeptide levels (radioimmunoassay) were determined at regular intervals for 6 hr in six healthy volunteers. During the 3–hr infusion before administration of erythromycin, both loxiglumide and atropine significantly increased gallbladder volumes—from 18 ± 2 to 37 ± 3 cm3 (p < 0.05) and from 17 ± 3 to 24 ± 2 cm3 (p < 0.05), respectively—whereas saline solution did not significantly affect gallbladder volume. During control saline solution infusion, erythromycin induced prolonged gallbladder contraction that was significant (p < 0.05) between 60 and 180 min and reached a maximum of 45% ± 8% at 150 min. Plasma cholecystokinin levels were not affected by erythromycin. Erythromycin induced a significant (p < 0.05) increase in plasma pancreatic polypeptide levels, from 12 ± 1 pmol/L to 34 ± 3 pmol/L. Loxiglumide did not prevent the erythromycininduced reduction in gallbladder volume. Atropine markedly reduced the effect of erythromycin, causing slight but significant (p < 0.05) gallbladder volume reductions (18% ± 4%) between 150 and 180 min. Atropine completely abolished the effect of erythromycin on pancreatic polypeptide secretion. In conclusion, both CCK and the cholinergic system are involved in the regulation of fasting gallbladder volume and erythromycin induces a significant reduction in gallbladder volume that is regulated by cholinergic mechanisms, whereas cholecystokinin is not involved. (HEPATOLOGY 1992;16:937-942.)
31P Magnetic Resonance Spectroscopy Detects A Functional Abnormality in Liver Metabolism After Acetaminophen Poisoning
Authors: Dixon Ruth M. , Angus Peter W. , Rajagopalan Bheeshma , Radda George K.
Published: March 2007

ABSTRACT

Eighteen patients with acetaminophen poisoning were studied with 31P magnetic resonance spectroscopy to measure phosphorus–containing metabolites in their livers. The concentrations of all magnetic resonance—detectable metabolites fell in parallel with a decrease in the synthetic ability of the liver, indicated by the prothrombin time ratio (international normalized ratio). In particular, ATP fell to about 20% of its normal concentration in severely affected patients, as did the phosphodiester signal, which is thought to arise mainly from the endoplasmic reticulum in the liver. The correlation between ATP levels and international normalized ratio suggests that the international normalized ratio is a more accurate measure of the number of viable hepatocytes than are other biochemical tests. (HEPATOLOGY 1992;16:943-948.)
Macroregenerative Nodules and Hepatocellular Carcinoma in Forty–Four Sequential Adult Liver Explants With Cirrhosis
Authors: Theise Neil D. , Schwartz Myron , Miller Charles , Thung Swan N.
Published: March 2007

ABSTRACT

Macroregenerative nodules, also called nodules of adenomatous hyperplasia, have been well documented in Japan. Extensive studies support the hypothesis that in the Japanese population these lesions represent a possible pathway for hepatocarcinogenesis. However, reporting of these lesions in non–Japanese populations has so far been rare. We examined 44 sequential cirrhotic hepatectomy specimens from adult patients who underwent orthotopic liver transplantation at our institution. All livers were serially sectioned every 0.5 cm. Macroregenerative nodules were defined as regenerative nodules at least 1 cm in diameter. Forty–eight macroregenerative nodules were found in 11 livers (25% of livers). The antecedent diseases in these livers included hepatitis C (3), alcoholism (2), primary biliary cirrhosis (2) (one with iron overload), cryptogenic cirrhosis (2), hepatitis B (1) and α1–antitrypsin deficiency (1). The macroregenerative nodules often differed from the surrounding nodular parenchyma in color, texture or the degree to which they bulged beyond the cut liver surface. Three livers contained grossly apparent hepatocellular carcinomas. Microscopically, macroregenerative nodules could be classified as those with (type 2) and without (type 1) dysplasia. Four livers had type 1 lesions, two had type 2 lesions and five had lesions of both types. We found 36 type 1 lesions in all and 12 type 2 lesions, 3 containing foci of microscopic carcinoma. All hepatocellular carcinomas arose in livers containing macroregenerative nodules (either type). Liver cell dysplasia, large–cell or small–cell, was observed in cirrhotic nodules of 27 livers. Microscopic or macroscopic hepatocellular carcinoma occurred in three livers with large–cell but not small–cell dysplasia and in one liver without dysplasia. We conclude that macroregenerative nodules are common in non–Japanese cirrhotic patients, occur in a wide range of chronic liver diseases and may represent precancerous lesions in this population. (HEPATOLOGY 1993;16:949-955.)
Saturability of Hepatic Iron Deposits in Genetic Hemochromatosis
Authors: Mandell Clara , Cesarini Lucia , Piperno Alberto , Fargion Silvia , Fracanzani Anna L. , Barisani Donatella , Conte Dario
Published: March 2007

ABSTRACT

The relationship of pretreatment serum ferritin and hepatic iron concentration to body iron removed by venesections was evaluated in 33 patients with genetic hemochromatosis. The median values of the three variables considered were 1,950 μg/L (range = 255 to 10,000), 1,175 μg/100 mg dry weight (range = 270 to 4,310) and 10 gm (range = 2 to 41), respectively. At basal liver biopsy 18 patients had cirrhosis, 6 patients had fibrosis and 9 patients had a normal pattern; siderosis was degree 3 in 6 patients and degree 4 in 27 patients. The results of fitting a polynomial regression of second degree showed that the curve of serum ferritin on iron removed was a straight line (R2 = 0.79, with a significant coefficient of linearity, p < 0.01, and a nonsignificant coefficient of curvature), whereas that of hepatic iron concentration on iron removed showed a curvature (R2 = 0.62, with significant coefficient of linearity and curvature, p < 0.01) and reached a plateau. The sigmoid model fit the curve of hepatic iron concentration on iron removed (R2 = 0.61), which suggested a saturation of hepatic iron storage capability; the asymptote corresponded to a hepatic iron concentration of about 2,000 μg/100 mg. In alcoholic patients (17 cases) the location of the sigmoid was greater than in nonalcoholic patients. Our results suggest that iron deposition occurs in the liver before other organs are involved and that with massive iron overload hepatic deposits reach saturation, after which hepatic iron concentration does not always reflect the amount of total stores. Alcohol consumption could slow the saturation of hepatic iron deposits. (HEPATOLOGY 1992;16:956-959)
Dietary N–3 Polyunsaturated Fatty Acids Decrease Biliary Cholesterol Saturation in Gallstone Disease
Authors: Berr Frieder , Holl Joseph , Jüngst Dieter , Fischer Sven , Richter Werner O. , Seifferth Bernd , Paumgartner Gustav
Published: March 2007

ABSTRACT

Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n–1 monounsaturated or n–6 polyunsaturated fatty acids with n–3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n–3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n–3 polyunsaturated fatty acids. Intake of n–3 polyunsaturated fatty acids increased (p < 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p < 0.001) and arachidonic acids (p < 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p < 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 ± 0.44 to 1.24 ± 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile. (HEPATOLOGY 1992;16:960-967.)
Acute Effects of Topical Methyl Tert–Butyl Ether or Ethyl Propionate on Gallbladder Histology in Animals: A Comparison of Two Solvents for Contact Dissolution of Cholesterol Gallstones
Authors: Esch Oliver , Spinosa John C. , Hamilton Ronald L. , Crombie Diane L. , Schteingart Claudio D. , Rondinone Joseph F. , D'Agostino Horacio B. , Lillienau Jan , Hofmann Alan F.
Published: March 2007

ABSTRACT

Experiments were performed in anesthetized rabbits and piglets to assess gallbladder mucosal injury during irrigation with methyl tert–butyl ether, a C5 ether, or ethyl propionate, a C5 ester—two organic solvents used in the contact dissolution of cholesterol gallstones. In 44 New Zealand White rabbits, the gallbladder was exposed to individual solvents or saline solution through a transhepatic catheter for 2 hr. Gallbladders were then harvested and fixed immediately or after a recovery period of 1, 4 or 8 days. Tissue sections were examined under light microscopy, and severity of injury was graded with predefined criteria by two pathologists blinded to the animals' treatment regimens. Histological assessment showed severe mucosal injury such as necrosis of the cells at the villus tips immediately after 2 hr of exposure to either solvent. After 4 days, injury had decreased significantly; after 8 days, complete mucosal healing had taken place. A similar study was performed in 32 piglets. Solvent or saline solution was oscillated in and out of the gallbladders of these piglets with a computer–controlled syringe pump at a pressure less than the leakage pressure of the gallbladder. Histological assessment was performed on tissue samples obtained immediately after the procedure or 8 days later. Both solvents caused severe mucosal injury; however, after 8 days complete mucosal healing had occurred, so that gallbladders exposed to solvent were indistinguishable from gallbladders exposed to saline solution, which was used as control. We conclude that both methyl tert–butyl ether and ethyl propionate cause moderate to severe epithelial injury but that the gallbladder epithelium regenerates within a few days. If these data apply to patients undergoing contact dissolution of gallstones, both methyl tert–butyl ether and ethyl propionate will cause severe but fully reversible mucosal injury. From the standpoint of toxicity to the gallbladder mucosa, ethyl propionate appears to qualify as an alternative to methyl tert–butyl ether for contact dissolution of cholesterol gallstones. (HEPATOLOGY 1992;16:984-991.)
Hepatic Accumulation of Lysosomes and Defective Transcytotic Vesicular Pathways in Cirrhotic Rat Liver
Authors: Dufour Jean-François , Gehr Peter , Reichen Jürg
Published: March 2007

ABSTRACT

To investigate the potential role of lysosomes in cirrhosis, we analyzed the activity of lysosomal enzymes in rats exposed long–term to phenobarbital and carbon tetrachloride. The activity of lysosomal enzymes was markedly increased in the homogenate of cirrhotic livers (e.g., arylsulfatase 9 ± S.D.2 vs. 16 ± 6 nmoles · min-1 · mg-1 in control rats and cirrhotic rats, respectively; p < 0.001). The corresponding plasma levels were also increased (7 ± 1 vs. 12 ± 3 nmoles · min-1 · mg-1; p < 0.01), whereas biliary excretion was diminished (16 ± 7 vs. 7 ± 2 pmol · min-1 · gm liver-1; p < 0.05) in cirrhotic rats. Stereological quantification of lysosomes visualized cytochemically revealed an increase of pericanalicular lysosomes averaging 1.5 ± 0.4 around a canaliculus in controls and 3.7 ± 1.0 in cirrhotic rats (p < 0.01). Because this suggested a defect in the transcellular vesicular pathway, we investigated the biliary excretion of horseradish peroxidase and epidermal growth factor in perfused livers. Bile flow and total horseradish peroxidase excretion were similar in control rats and cirrhotic rats. However, the early peak of biliary horseradish peroxidase excretion — usually taken as evidence of paracellular transport — was increased in cirrhotic rats (13 ± 7 vs. 57 ± 22%; p < 0.01), whereas the second peak—reflecting the transcellular vesicular pathway(s)—was markedly reduced (87 ± 7 vs. 43 ± 22%; p < 0.001). A similar reduction in the biliary excretion of intact epidermal growth factor and of its degradation products was found. These results demonstrate an increased number of lysosomes in hepatocytes of cirrhotic livers; this appears to be the result of accumulation rather than proliferation, in view of the reduced transcellular vesicular movement of different markers into bile. (HEPATOLOGY 1992;16:997-1006.)
Monitoring of Neurotransmitter Amino Acids by Means of An Indwelling Cisterna Magna Catheter: A Comparison of Two Rodent Models of Fulminant Liver Failure
Authors: Swain Margaret S. , Bergeron Marcelle , Audet Robert , Bleiz Andres T. , Butterworth Roger F.
Published: March 2007

ABSTRACT

Alterations of brain and cerebrospinal fluid amino acids have consistently been described in human and experimental fulminant liver failure. To evaluate the significance of such changes in the pathogenesis of hepatic encephalopathy in fulminant liver failure, brain and cerebrospinal fluid amino acids (glutamate, aspartate, GABA, glycine, taurine) were measured at various stages during the development of neurological dysfunction in rats after hepatic devascularization or thioacetamide treatment to induce acute liver failure. To facilitate repetitive removal of cerebrospinal fluid, a technique employing long–term implantation of cisterna magna catheters in conscious, freely moving rats was developed. Brain but not cerebrospinal fluid concentrations of the excitatory amino acids glutamate and aspartate were reduced in both animal models of fulminant liver failure in parallel with deterioration of neurological status. Brain and cerebrospinal fluid GABA levels were not significantly altered. Cerebrospinal fluid glycine levels were increased two to three times in parallel with increasing brain glycine content in the devascularized rat but were unchanged in thioacetamide–induced liver failure, suggesting distinct pathophysiological mechanisms in these two experimental situations. On the other hand, onset of coma in both animal models of fulminant liver failure was accompanied by significantly increased cerebrospinal fluid taurine levels. We suggest that such changes result from taurine release from astrocytes in brain into the extracellular fluid; this is consistent with taurine's role in the regulation of intracellular osmolarity in brain. Sequential measurements of amino acids in the cerebrospinal fluid of small rodents with indwelling cisterna magna catheters adds a useful new approach for exploring the neurobiology of hepatic encephalopathy in fulminant liver failure. (HEPATOLOGY 1992;16:1028-1035.)
Papaverine Inhibits Transcytotic Vesicle Transport and Lipid Excretion Into Bile in Isolated Perfused Rat Liver
Authors: Hayakawa Tomihiro , Katagiri Kenji , Hoshino Makoto , Nakai Tomio , Ohiwa Takayuki , Kumai Tomoyuki , Miyaji Makoto , Takeuchi Toshihiko , Corasanti James , Boyer James L.
Published: March 2007

ABSTRACT

Papaverine is a nonspecific smooth muscle relaxant and a phosphodiesterase inhibitor. Its effects on biliary excretion of lipids and horseradish peroxidase were investigated in a single–pass isolated perfused rat liver model. A constant infusion of papaverine (1.6 μmol/min; 40 μmol/L) significantly increased bile flow (microliters per minute per gram of liver) before (2.03 ± 0.09 vs. 1.0 ± 0.06) and after sodium taurocholate infusion (2.77 ± 0.10 vs. 1.88 ± 0.11). However, papaverine significantly and reversibly reduced biliary excretion of phospholipids and cholesterol (nanomoles per minute per gram of liver) after a 1.0 μmol/min sodium taurocholate infusion, from 7.45 ± 0.83 and 1.42 ± 0.15 to 1.75 ± 0.18 and 0.39 ± 0.06, respectively (p < 0.01), whereas secretion of bile acids was unaffected. When a 1–min pulse of horseradish peroxidase (25 mg) was infused in isolated perfused rat liver after a continuous infusion of N
6, O–2′–dibutyryladenosine 3′,5′–cyclic monophosphate (0.25 μmol/min; 6.25 μmol/L), horseradish peroxidase appeared in bile in an early (4 to 6 min) and late (20 to 25 min) peak. Papaverine significantly reduced the late peak, from 1.211 ± 0.264 to 0.498 ± 0.107 (p < 0.01). Papaverine had no significant effects on either cyclic AMP or cyclic GMP in the liver and bile, although it has been reported that papaverine is a phosphodiesterase inhibitor. These findings indicate that papaverine inhibits biliary excretion of lipids but not bile acids, and they suggest that papaverine has an inhibitory effect on transcytotic vesicle transport independent of an increase of cyclic nucleotides in hepatocytes. (HEPATOLOGY 1992;16:1036-1042.)
Lack of Control of Liver Gluconeogenesis in Cholestatic Rats With Reduced Portal Blood Flow
Authors: de Salles Roselino José Eduardo , de Castro-e-silva Orlando , Ceneviva Reginaldo
Published: March 2007

ABSTRACT

Previous studies indicated a role for ischemia in the metabolic changes induced by cholestasis. Liver pyruvate kinase is a key enzyme for the concurrent control of glycolysis and gluconeogenesis. In this experiment the control of pyruvate kinase activity was investigated in cholestatic rats. Pyruvate kinase kinetics changed from a sigmoidal type in sham–operated rats to a hyperbolic type in obstructed rats. The change in the enzymatic kinetics paralleled the reduction in the portal blood flow, which reached 50% of the control value 7 days after obstruction. Dibutyryl cyclic AMP (5 μmol/kg body wt) plus theophylline 0.1 mmol/L failed to inactivate the enzyme when injected into the portal veins of rats whose livers were obstructed 7 days before. Both the kinetics changes and the lack of phosphorylation control are compatible with ischemia. (HEPATOLOGY 1992;16:1055-1060.)
Regenerative Stimulus Increases Hepatocyte Tight Junctional Permeability
Authors: Poucell Siria , Hardison William G.M. , Miyai Katsumi
Published: March 2007

ABSTRACT

Experience with young animals, animals administered certain hepatotoxins and animals with two–thirds hepatectomy suggests that tight junctional permeability is increased in states characterized by architectural remodeling in the liver. In this work we correlate changes in tight junctional morphometry induced by two–thirds hepatectomy with changes in biliary permeability assessed by sucrose and horseradish peroxidase permeation and by alterations in biliary outputs of anionic and cationic cholephilic probes. By freeze–fracture examination tight junctional strand counts, density and orientation parallel to canaliculi were all reduced 24 hr after two–thirds hepatectomy. Occasionally, strands were perpendicular to the canaliculi, creating an unobstructed communication between bile and intercellular spaces. These morphological changes correlated with increased sucrose and paracellular horseradish peroxidase access into bile, with reduced biliary outputs of low molecular weight and especially with cationic cholephilic probes. The data support an increased but still charge–selective permeability of the biliary tree, which was induced by two–thirds hepatectomy 24 hr before. Presumably, fixed intercellular connections (tight junctions and gap junctions) must be loosened or lysed to allow the architectural reorganization required by the hepatocellular regenerative process. (HEPATOLOGY 1992;16:1061-1068.)
Elsewhere Reviews. Nitric Oxide and Hyperdynamic Circulation in Portal Hypertension
Authors: Häussinger Dieter
Published: March 2007

ABSTRACT

1 The effects of inhibiting endogenous nitric oxide (NO) synthesis with NG–monomethyl–L–arginine (L–NMMA) on the systemic and splanchnic circulation have been investigated in rats with experimental chronic portal hypertension, anaesthetized with ketamine.

2 Portal hypertension was induced by partial portal vein ligation, 2 weeks prior to study. This procedure induced a reduction in systemic arterial blood pressure (MAP), an increase in cardiac output as measured by radiolabelled microspheres, a reduction in peripheral and splanchnic vascular resistance and an increased portal venous inflow (PVI) and portal pressure, as compared to control non–ligated rats.

3 l–NMAA (6.25 and 50 mg kg-1, i.v.) dosedependently increased MAP, reduced cardiac output and PVI, and increased peripheral and splanchnic vascular resistance. With l–NMMA (50 mg kg-1), PVI and the vascular resistances returned to values comparable to those determined in control non–ligated anaesthetized rats under resting conditions.

4 Porto–collateral resistance was also increased by these doses of l–NMMA, whereas portal pressure was unchanged. The increase in renal blood flow and decrease in renal vascular resistance also seen in portal–hypertensive rats was reversed by l–NMMA (50 mg kg-1).

5 These effects of l–NMMA (50 mg kg-1) were inhibited by prior administration of l–arginine (300 mg kg-1, i.v.).

6 These findings indicate that the chronic hyperdynamic circulatory characteristics following portal vein stenosis can be attenuated by l–NMMA. Thus, the excessive formation of endogenous NO may be implicated in the pathogenesis of the haemodynamic disturbances and splanchnic vasodilatation associated with chronic portal hypertension.
Hepatology Elsewhere: Twenty Years After!
Authors: Blendis Laurence M.
Published: March 2007

ABSTRACT

Background.

Controlled trials have yielded inconsistent results with regard to the efficacy of corticosteroids in the treatment of alcoholic hepatitis. Three meta–analyses suggest that they may be effective in patients with encephalopathy who have severe liver disease.

Methods.

We conducted a randomized, double–blind trial comparing 28 days of prednisolone treatment (40 mg per day) with placebo in 61 patients with biopsyproved alcoholic hepatitis and either spontaneous hepatic encephalopathy (n = 19) or a discriminant–function value higher than 32. The discriminant function used was as follows: 4.6 (prothrombin time — control time [in seconds]) + serum bilirubin (in micromoles per liter)/17. Fifty–seven of the patients had evidence of cirrhosis on biopsy. The primary end point was death within two months.

Results .

One patient was lost to follow–up after 56 days. Treatment was discontinued in two patients because of drug toxicity. By the 66th day after randomization, 16 of 29 placebo recipients had died (mean [± SE] survival, 46 ± 8 percent), as compared with 4 of 32 preduieolone recipients (survival, 88 ± 5 percent) (log–rank test, 10.9; P = 0.001). The survival advantage for prednisolone persisted after stratification according to center and the presence of encephalopathy, and after adjustment for prognostic factors in a proportional–hazards model.

Conclusions .

Treatment with prednisolone improves the short–term survival of patients with severe biopsyproved alcoholic hepatitis.
Hepatitis A—New Information on An Old Virus
Authors: Dickinson Chris J.
Published: March 2007

ABSTRACT

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.
Hepatitis C Virus Infection in Medical Personnel After Needlestick Accident
Authors: Mitsui Takehiro , Iwano Keiko , Masuko Kazuo , Yamazaki Chikao , Okamoto Hiroaki , Tsuda Fumio , Tanaka Takeshi , Mishiro Shunji
Published: March 2007

ABSTRACT

Hepatitis C virus infections in medical personnel after needlestick accidents have been documented generally by detection of seroconversion to a hepatitis C virus nonstructural region antigen, c100–3 (a marker of infection). We tested for hepatitis C virus core–derived antibodies and genomic RNA in addition to c100–3 antibody in 159 cases of needlestick exposure that did not involve patients positive for HBsAg. Of these we found 68 cases with index patients positive for both hepatitis C virus RNA and antibodies and members negative for antibodies to HCV core or c100–3 before the needlestick accidents. Seven of these medical personnel became infected with hepatitis C virus after the accidents. Their hepatitis was generally subclinical or self–limited and transient, except for one patient in whom liver enzyme elevation persisted along with the antibodies. In our study, the risk of hepatitis C virus transmission from a single needlestick accident with hepatitis C virus RNA-positive blood was 10%, considerably higher than the 4% estimated in a previous study. We found that donor blood with antibody to an hepatitis C virus core–derived peptide with enzyme–linked immunosorbent assay optical densities greater than 2.0 carried a significant risk of transmitting hepatitis C virus to needlestick victims. No hepatitis C virus seroconversions occurred in medical personnel exposed to hepatitis C virus antibody- negative or hepatitis C virus RNA-negative blood; however, one such exposure resulted in a very mild non–A, non–B, non–C hepatitis. (Hepatology 1992;16:1109-1114.)
Therapy for Chronic Hepatitis B With Lymphoblastoid Interferon–α and Levamisole
Authors: Fattovich Giovanna , Giustina Giuliano , Brollo Lucio , Guido Maria , Pontisso Patrizia , Noventa Franco , Alberti Alfredo
Published: March 2007

ABSTRACT

About one third of patients with chronic hepatitis B show a sustained response when treated with interferon–α. Combining interferon–α with immunomodulators might be a way to increase response rate. The aim of this study was to compare the efficacy of lymphoblastoid interferon–α given alone with its efficacy when combined with levamisole in chronic hepatitis B. Forty–five patients with HBeAg–positive chronic hepatitis were randomly selected (with stratification for ALT levels) to receive a 6–mo course of combination therapy with lymphoblastoid interferon–α (5 million units/m2 three times per week) and levamisole (150 mg three times per week) or lymphoblastoid interferon at the same dose regimen and a matching placebo. Final evaluation 18 mo after randomization revealed a loss of both HBeAg and hepatitis B virus DNA with ALT normalization in 38% of patients treated with interferon–α alone and in 10% of patients receiving combination therapy. The higher response rate observed in patients treated with interferon–α alone was maintained after stratification for basal ALT levels (i.e., higher [45% vs. 10%] or lower [31% vs. 9%] than three times the upper normal value). The length of time to sustained HBeAg clearance was significantly (p < 0.05) shorter in patients receiving monotherapy than in patients receiving combination therapy. Blinded histological assessment revealed improvement in 44% of patients treated with interferon–α alone compared with improvement in 6% of patients receiving combination therapy. These results indicate that levamisole has no additive effects when combined with interferon–α in the treatment of HBeAg–positive chronic hepatitis. (Hepatology 1992;16:1115-1119.)
Expression and Localization of the Small and Large Delta Antigens During the Replication Cycle of Hepatitis D Virus
Authors: Wu Jaw-Ching , Chen Chih-Li , Lee Shou-Dong , Sheen I-Jane , Ting Ling-Pai
Published: March 2007

ABSTRACT

To study the expression and localization of delta antigen during the replication cycle of hepatitis D virus, we cotransfected HuH–7 hepatoma cells with a hepatitis B virus expression plasmid and plasmids expressing the small or large delta antigen or the entire HDV genome. The transfected cells and culture medium were analyzed on double immunofluorescence staining for delta antigen and HBsAg, on Western blotting and on Northern–blot hybridization from 4 hr to 9 days after transfection. In cells transfected with the expression plasmid carrying the small delta antigen open reading frame, only the small delta antigen was expressed; it was localized in the nucleolus and was not released into the medium during the culture period. In cells transfected with the large delta antigen expression plasmid, the large delta antigen expressed was localized in the nucleolus at the initial stage; this was followed by relocalization in nucleoplasm. Finally, large delta antigen was released in HBsAg–enveloped particles within 1 day of transfection. In cells cotransfected with hepatitis B virus and hepatitis D virus expression plasmids, the small delta antigen was expressed 4 hr after transfection, whereas the large form was expressed 3 days after transfection. Expression of the large delta antigen coincided with the localization changes from nucleolar to mixed stage and, finally, to nucleoplasm and release of the hepatitis D virus particles. The large delta antigen appears to play a key role in relocalization of the delta antigen and packaging of the hepatitis D virus virions. However, early expression of the large delta antigen suppressed hepatitis D virus replication, resulting in the release of defective particles containing an excess amount of the large delta antigen devoid of hepatitis D virus RNA. (Hepatology 1992;16:1120-1127.)
M4 and M9 Antibodies in the Overlap Syndrome of Primary Biliary Cirrhosis and Chronic Active Hepatitis: Epitopes or Epiphenomena?
Authors: Davis Paul A. , Leung Patrick , Manns Michael , Kaplan Marshall , Munoz Santiago J. , Gorin Frederic A. , Dickson Rolland E. , Krawitt Edward , Coppel Ross , Gershwin Eric M.
Published: March 2007

ABSTRACT

Before the identification of the major mitochondrial antigens of primary biliary cirrhosis as components of the 2–oxo–acid dehydrogenase enzyme family, mitochondrial autoantigens were believed to be extremely heterogeneous and were divided into nine subtypes termed M1 to M9. This classification was based on the data derived from the relatively nonspecific biochemical and immunological techniques that were available. After the cloning and definition of the major autoantigens, more than 95% of the sera of patients with primary biliary cirrhosis were found to react with components of the 2–oxo–dehydrogenase enzymes; these enzymes correspond to the old M2 classification. Two other “M” species, dubbed M4 and M9, have attracted significant attention because they have been postulated to be prognostic indicators and more recently have been tentatively identified respectively as sulfite oxidase (EC 1.8.3.1) and glycogen phosphorylase (EC 2.4.1.1). Indeed, patients with the “overlap syndrome” are reported to have antibodies to M4 and a poor prognosis, whereas patients with antibodies to M9 have a favorable prognosis. To address the significance and definition of M4 and M9, we performed in–depth studies of sera from 11 patients with the overlap syndrome, 75 patients with primary biliary cirrhosis, 19 chronic active hepatitis patients, 13 patients with primary sclerosing cholangitis, 10 patients with cholangiocarcinoma, 20 patients with systemic lupus erythematosus, 20 patients with alcoholic cirrhosis, 17 patients with scleroderma and 30 normal individuals, using techniques of ELISA, complement fixation, immunoblotting and enzyme inhibition. We report herein that we were unable to show any disease–specific reactivity toward the proposed M4 and M9 antigens. We offer potential explanations for false–positive readings and, most importantly, propose that the “M” nomenclature be discontinued and that autoantigens be designated by their proven and reproducible biochemical identity. (Hepatology 1992;16:1128-1136.)
Hepatitis C Virus Reinfection in Allografts After Orthotopic Liver Transplantation
Authors: König Volker , Bauditz Jürgen , Lobeck Hartmut , Lüsebrink Rainer , Neuhaus Peter , Blumhardt Gerhard , Bechstein Wolf Otto , Neuhaus Ruth , Steffen Rudolf , Hopf Uwe
Published: March 2007

ABSTRACT

From September 1988 to May 1991, 160 orthotopic liver transplantations were performed in our hospital. Twenty–four patients had end–stage cirrhosis caused by chronic non–A, non–B hepatitis. Antibodies against hepatitis C virus were documented before and after orthotopic liver transplantation in 13 patients. Studies using the polymerase chain reaction demonstrated hepatitis C virus RNA in the serum and liver tissue of 17 patients (10 of whom tested positive for hepatitis C virus antibodies) before orthotopic liver transplantation. Tissue samples taken from liver grafts during the operation were hepatitis C virus RNA negative in every case. Ten of these 17 patients had positive hepatitis C virus RNA findings in serum and liver biopsy specimens within the first month after surgery. One patient died of Mucor sepsis 2 mo after orthotopic liver transplantation. Another patient died of multiorgan failure 3 mo after a retransplantation. Two patients underwent retransplantation for graft rejection at 2 and 3 mo, respectively. One year after orthotopic liver transplantation, hepatitis C virus RNA was demonstrated in allograft biopsy specimens in 13 of 15 patients. Two patients remained hepatitis C virus RNA negative in repeated biopsies up to 12 mo. Mild portal and lobular hepatitis developed within 6 months of orthotopic liver transplantation in four patients and within 1 yr in five additional patients. The data suggest that persistent hepatitis C virus reinfects the allograft in most cases, but the risk of acute organ damage caused by hepatitis C virus reinfection is low. (Hepatology 1992;16:1137-1143.)