bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Intravenous Amino Acid Infusion and Dietary Proteins on Kidney Function in Cirrhosis
Authors: Badalamenti Salvatore , Gines Pere , Arroyo Vicente , Llach Josep , Piera Carlos , Rimola Antoni , Jimenez Wladimiro , Gaya Joan , Casamitjana Roser , Rivera Francisca , Rodes Joan
Published: March 2007

Acute intravenous amino acid infusion or a highprotein diet increases renal plasma flow and the glomerular filtration rate in healthy subjects. Conversely, a low–protein diet reduces renal plasma flow and glomerular filtration rate. The aim of this study was to investigate the effect of intravenous amino acid infusion and dietary proteins on kidney function in cirrhosis. Protocol 1: renal plasma flow and glomerular filtration rate were measured before and during intravenous administration of a 10% amino acid solution (0.043 ml/kg/min) to eight compensated cirrhotic patients (group 1), nine nonazotemic cirrhotic patients with ascites (group 2) and seven cirrhotic patients with ascites and functional renal failure (group 3). Amino acid administration induced a significant increase in renal plasma flow and glomerular filtration rate in all groups studied. Renal plasma flow and glomerular filtration rate increased by 16% and 14%, and 21% in group 3. Protocol 2: Renal plasma flow and glomerular filtration rate were measured in nine cirrhotic patients with ascites after 11 days on a low–protein diet (0.5 gm/kg body weight/day) and also after the patients followed for 11 days a moderately high–protein diet (1.5 gm/kg body weight/day). The moderately high–protein diet was associated with a significant increase in renal plasma flow (12%) and glomerular filtration rate (13%) compared with values obtained while the patients followed the low–protein diet. Plasma glucagon levels increased markedly during the intravenous administration of amino acid and the intake of the moderately highprotein diet. However, no correlation existed between changes in renal plasma flow and glomerular filtration rate induced by intravenous amino acid or dietary proteins and changes in plasma glucagon levels. The renal effects of intravenous amino acid or dietary proteins were not associated with significant changes in plasma renin and norepinephrine levels and urinary excretion of 6–keto–prostaglandin–F1α. In conclusion, a moderately high–protein diet or intravenous amino acid administration increases renal plasma flow and glomerular filtration rate in cirrhosis. (Hepatology 1990; 11: 379-386.)
Formation of the 37–Kd Protein–Acetaldehyde Adduct in Primary Cultured Rat Hepatocytes Exposed to Alcohol
Authors: Lin Renee C. , Fillenwarth Michael J. , Minter Ronald , Lumeng Lawrence
Published: March 2007

We have previously reported that a 37–kD liver protein formed an adduct with acetaldehyde in vivo when rats were fed alcohol chronically. To understand the mechanism of the formation of this proteinacta ldehyde adduct, rat hepatocytes in primary culture were treated with ethanol in vitro for several days. When cultured in hormone–enriched and trac metalenriched Waymouth's medium, alcohol dehydrogenase activities in hepatocytes decreased only about 30% during 6 days of culture. At the end of the specified time, protein extracts of hepatocytes were immunotransbloted with rabbit immunoglobulin G that recognized acetaldehyde adduct as an epitope. The 37–kD protein, acetaldehyde adduct band could be detected within 3 days in cells that had been treated with alcohol at a steady–state concentration as low as 5 mmol/L. Although the maximal intensity was obtained at approximately 10 to 40 mmol/L ethanol, addition of cyanamide (an inhibitor of aldehyde dehydrogenase) further increased the intensity of this protein–acetaldehyde adduct band by more than twofold. A good correlation existed between acetaldehyde concentration in the medium and the intensity of the 37–kD protein acetaldehyde adduct band. Formation of the 37–kD liver protein–acetaldehyde adduct is thus dependent on acetaldehyde, and the 37–kD protein is apparently unusually susceptible to chemical modification by acetaldehyde.(Hepatology 1990;11:401-407.)
Role of Cytokeratin Intermediate Filaments in Transhepatic Transport and Canalicular Secretion
Authors: Kawahara Hiromu , Cadrin Monique , Perry George , Autilio-Gambetti Lucila , Swierenga Sabine H.H. , Metuzals Janis , Marceau Normand , French Samuel W.
Published: March 2007

The role of cytokeratin filaments in the function of hepatocytes was investigated using a nickel–treated hepatocyte in vitro model. Cytokeratin intermediate filaments were selectively dissociated from the cell cortex by nickel treatment. Cytokeratins and ubiquitin were observed using immunofluorescence and immunoelectrom microscopy. Hepatocytic function was assessed by visualizing uptake, transchepatic transport and secretion of fluorescein diacetate and horseradish peroxidase into the bile canaliculi. In control primary cultures, most of the bile canaliculi were surrounded by an inner layer of actin filaments and an outer pericanalicular sheath of cytokeratin filaments and microtubules. The cytoplasmic distribution of ubiquitin was diffuse and particulate. After treatment with NiC12 (150 μg/ml) for 24 hr, the cytokeratin filaments and desmoplakin became focally detached from the cell cortex and retracted to from an aggregate around the nucleus. These aggregates were associated with intense ubiquitin immunoreactivity. Only a few attachments of the cytokeratin filaments to the cell cortex remained. F–actin remained attached to the cell cortex in the areas where the cytokeratin filaments had become detached. The pericanalicular sheath of cytokeratin filaments and the bile canaliculi disappeared and actin was dispersed over the entire cell periphery. Fluorescein diacetate secretion and horseradish peroxidase uptake were almost completely absent in the hepatocytes treated with nickel. The effects of nickel persisted 24 hr after its removal from the medium. It is concluded that cytokeratin intermediate filaments play a critical role in the formation of the bile canaliculus, secretion of fluorescein diacetate and uptake of horseradish peroxidase. Further, our study indicates that cytokeratin ubiquitination occurs during collapse and aggregation of the cytokeratin filaments. The formation of cytokeratin–ubiquitin conjugates during aggregation suggests a role of ubiquitin in the control of cytokeratin organization in hepatocytes in the response to cell stress.(Hepatology 1990;11:335-348.)
Early Involvement of Hepatic Parenchymal Cells in Erythrohepatic Protoporphyria? An Ultrastructural Study of Patients With and Without Overt Liver Disease and the Effect of Chenodeoxycholic Acid Treatement
Authors: Raedemakers Louk H.P.M. , Cleton Maud I. , Kooliman Carole , de La Fajlle Harold Baart , van Hattum Jan
Published: March 2007

Liver biopsy specimens obtained from two groups of erythrohepatic protoporphyria patients were studied histopathologically and ultrastructurally. Group 1 comprised seven erythrohepatic protoporphyria patients with a normal liver histology; from two patients liver biopsy specimens were available before and after 1 yr of chenodeoxycholic acid treatment. Group 2 consisted of four patients with a history of liver disease and liver histopathology; three patients were observed before and after 1 yr of chenodeoxycholic acid treatment. Liver specimens of nine kidney transplant donors served as controls.

Unlike the morphology at the light microscopic level, the ultrastructure of hepatic parenchymal cells was affected in both groups of erythrohepatic protoporphyria patients. In both groups the nuclei, endoplasmic reticulum, lateral plasma membranes and bile canaliculi were altered. Collagen fibers were frequently present. In addition, in group 2 bile thrombi and intracytoplasmic protoporphyrin crystals were observed. After chenodeoxycholic acid administration, the latter feature had diminished.

It is concluded that (a) in erythrohepatic protoporphyria ultrastructural changes are present in the hepatic parenchymal cells even in early stages of the discase. Changes in bile canalicular ultrstructure suggest a defective hepatic excretory function, probably caused by the toxic effect of protoporphyrin. (b) Chenodeoxycholic acid administration causes no distinct improvement of the ultrastructure of organelles in the hepatic parenchymal cell or the bile canalicular system but may decrease crystalline protoporphyrin deposition in the liver.(Hepatology 1990;11:449-457.)
The Pathology of Liver Allograft Surving Longer Than One Year
Authors: Nakhleh Raouf E. , Schwarzenberg Sarah J. , Bloomer Joseph , Payne William , Snover Dale C.
Published: March 2007

Although prolonged survival after liver transplantation is now common, the condition of allografts after prolonged survival has not been widely discussed. We reviewed 86 biopsy samples from 38 patients. The samples were obtained between 366 and 1,622 days after transplant. Thirteen patients' biopsy samples were normal or showed minor changes. Six patients' samples showed rejection. Four patients, including two with rejection, demonstrated ischemic change. Three patients showed focal fibrosis, polymorphonuclear infiltration and bile duct proliferation simulating biliary obstruction, although biliary stones were found in only one patient. Three patients had acute hepatitis. Seven patients had a pattern of chronic persistent hepatitis; four had chronic active hepatitis. Follow–up biopsy samples were obtained in seven chronic hepatitis patients. Two of the patients with chronic active hepatitis have shown slight progression of the disease. None has progressed to cirrhosis, but neither has the chronic active hepatitis resolved. It is likely that some of these cases represent non–A, non–B hepatitis. Although histological abnormalities are common after successful transplantation, the clinical significance of many of the changes remains to be determined. Only patients with rejection or vascular thromboses required new transplants.(Hepatology 1990;11:465-470.)
Excision of Multiple Metastases: Better Designed Studies Are Needed
Authors: Adson Martin
Published: March 2007

Metastatic carcinoma to the liver is generally considered to be associated with a poor prognosis, with five year survival of only 20% to 30% after resection of solitary lesions. Ninety–eight consecutive patients underwent the surgical removal of one to 13 metastatic lesions from the liver. A rising carcinoembryonic antigen level was considered an indication for reexploration. All gross tumor was removed in every patient; 66 had more than one metastasis. Survival was unexpectedly high: 91 of 98 were alive at 12 months, 50 (70%) of 71 at 13 to 24 months, 23 (66%) of 36 at 25 to 36 months, 14 (74%) of 19 at 37 to 48 months, six (60%) of ten at 49 to 60 months, four (80%) of five at 61 to 72 months, and two (50%) of four 73 to 84 months after resection of multiple liver metastases. The procedure appears to be a safe and, in some patients, beneficial surgical technique for the removal of multiple hepatic metastases.
Isolation of A Potent Cholesterol Nucleation–Promoting Activity From Human Gallbladder Bile: Role in the Pathogenesis of Gallstone Disease
Authors: Groen Albert K. , Noordam Christa , Drapers Jan A.G. , Egbers Peter , Jansen Peter L.M. , Tytgat Guido N.J.
Published: March 2007

Gallbladder bile contains nucleation–promoting activity that binds to concanavalin A. The activity was found in gallbladder bile from cholesterol gallstone patients but also in gallbladder bile from patients without stones and patients with pigment stones. Bile from patients with multiple cholesterol gallstones contained high concanavalin A–binding nucleation–promoting activity. The activity was much lower in bile samples from pigment stone patients, patients without stones and patients with a solitary cholesterol stone. Serum contained very little activity and no concanavalin A–binding nucleation–promoting activity could be demonstrated in gallbladder mucosa. This suggests that concanavalin A–binding nucleation promoter is produced in the liver or bile duct epithelium. The activity was fully resistant to digestion with pronase but was heat labile and could be destroyed by prolonged incubation with a mixed gly cosidase preparation indicating that sugar residues are important for this activity. On a Superose 12 gel permeation column, promoting activity eluted in two major peaks at apparent molecular weights of 150 ± 30 kD (n = 5) and < 5 kD respectively. The mobility on the column was not int influenced by pronase digestion. The factor with the higher molecular weight could be isolated further by polyacrylamide gel electrophoresis under nondenaturing conditions. On sodium dodecyl sulfate–polyacrylamide gel electrophoresis, the apparent molecular weight of the glycoprotein was 130 kD. In conclusion, gallbladder bile contains nucleation–promoting activity that binds to concanavalin A. The activity is increased in bile from patients with multiple cholesterol gallstones and could therefore play an important role in the pathogenesis of gallstone disease.(HEPATOLOGY 1990; 11:525:533.)
Identification of the Bile Canalicular Cell Surface Molecule Gp110 As the Ectopeptidase Dipeptidyl Peptidase Iv: An Analysis by Tissue Distribution, Purification And N –Terminal Amino Acid Sequence
Authors: McCaughan Geoffrey W. , Wickson Julie E. , Creswick Paul F. , Gorrell Mark D.
Published: March 2007

This paper describes the tissue distribution, purification and N–terminal amino acid sequence of the bile canalicular cell surface molecule dipeptidyl peptidase IV. Immunoperoxidase staining of cryostat sections of rat liver with a monoclonal antibody, Medical Research Council OX–61, indicated specific binding to hepatocyte bile canalicular domains and brush borders of bile ducts. Additional staining was seen in other epithelial brush borders (small intestine, kidney, colon, pancreatic duct); acinar structures in salivary glands; endothelial structures and T cell areas in thymus, spleen and lymph node. The tissue distribution suggested that monoclonal antibody OX–61 binds to the ectoenzyme dipeptidyl peptidase IV. This was confirmed by depletion of dipeptidyl peptidase IV activity from tissue homogenates by monoclonal antibody OX–61 coupled to Sepharose. The molecule recognized by OX–61 was then purified from liver and kidney by monoclonal antibody affinity chromatography. The molecule had a molecular weight of 110 kD under reducing conditions. The purified molecule was subsequently analyzed for amino acid composition and N–terminal amino acid sequence. Thirty–one N–terminal amino acids were sequenced and indicated identity with part of the predicted N–terminus of the previously cloned bile canalicular molecule GP110. On review, other similarities between dipeptidyl peptidase IV and GP110 were detected: molecular weight, deglycosylated from and metabolic half–life. Finally, the recent cloning of dipeptidyl peptidase IV permitted a comparison between the molecule recognized by monoclonal antibody OX–61, GP110 and dipeptidyl peptidase IV. It is concluded that these three molecules are almost certainly identical.(HEPATOLOGY 1990; 11:534:544.)
Anesthesia and Pressor Responsiveness in Chronic Bile–Duct–Ligated Dogs
Authors: Bomzon Arieh , Monies-Chass Irka , Kamenetz Leonard , Blendis Laurence
Published: March 2007

Cardiovascular homeostasis is compromised under general anesthesia and in jaundice. Because surgery is often performed on jaundiced patients, it is not altogether surprising that the incidence of perioperative complications is higher in such patients than in nonjaundiced ones. In this study we assessed the potential synergistic effects of anesthesia and jaundice on cardiovascular responsiveness of chronic bile–ductligated dogs. Responsiveness to norepinephrine, angiotensin II and isoproterenol was determined before and after chronic bile–duct ligation or sham–operation while the dogs were conscious or under halothane, fentanyl or pentobarbital–sodium anesthesia. These data have shown that halothane– and barbiturate–induced anesthesia do not alter mean arterial blood pressure in unoperated dogs when compared with conscious dogs before laparoatomy. Furthermore, these two agents did not modify the pressor, dilator and positive inotropic responses to intravenous infusions of norepinephrine, angiotensin II and isoproterenol. Fentanyl, however, reduced mean arterial blood pressure and heart rate without influencing responsiveness to the three vasoactive agents. Blunted responsiveness in the chronic bile–duct–ligated dogs to the three vasoactive agents was observed without any marked changes in mean arterial blood pressure or heart rate. The same blunted responses observed in the conscious, chronic bile–duct–ligated dogs were also seen in the anesthetized, chronic bile–duct–ligated dogs. Halothane caused a marked hypotensive effect in the chronic bile–duct–ligated dogs that was not seen in the sham–operated dogs. Conscious and anesthetized sham–operated dogs responded in the same manner as the conscious and anesthetized dogs before ligation. Because we could not demonstrate any synergistic or antagonistic effects of anesthesia and jaundice on cardiovascular responsiveness, these results may be useful for researchers using animal models to investigate the pathogenesis of the cardiovascular complications of liver disease.(HEPATOLOGY 1990; 11:551:556.)
Functional Similarities of Hepatic Cystic and Biliary Epithelium: Studies of Fluid Constituents And In Vivo Secretion in Response to Secretin
Authors: Everson Gregory T. , Emmett Merrill , Brown William R. , Redmond Paul , Thickman David
Published: March 2007

Hepatic cysts are a frequent manifestation of autosomal dominant polycystic kidney disease, but little is known about their functional characteristics. The goals of our study were to define the composition of hepatic cyst fluid and to determine whether hepatic cysts secrete in response to intravenously administered secretin. We percutaneously punctured five hepatic cysts and one proximal renal cyst from six subjects with autosomal dominant polycystic kidney disease and one solitary hepatic cyst from a subject without autosomal dominant polycystic kidney disease. Most fluids had an electrolyte composition similar to serum. Fluid from all hepatic cysts had glutamyltranspeptidase concentrations above those found in serum ([cyst]/[serum] = 4.93 ± 5.92), contained secretory component (the epithelial receptor for polymeric IgA) and had glucose concentrations less than 15 mg/dl. Fluid from both hepatic and renal cysts of subjects with autosomal dominant polycystic kidney disease, but not from the subject with the solitary hepatic cyst, demonstrated extensive changes in the electrophoretic mobility of several serum proteins. Initial intracystic pressures ranged from 16 to 40 cm H2O, were reduced 57% to 97% after aspiration of a portion of cyst fluid and were held constant during the secretion study. Within 8 min of the intravenous administration of secretin, secretion of fluid increased in two of three hepatic cysts and in the renal cyst. The electrolyte composition of cyst fluids was not altered by secretin. These data suggest that hepatic cystic epithelium has functional characteristics of biliary epithelium and that secretion by both hepatic and renal cysts may be hormonally regulated.(HEPATOLOGY 1990; 11:557:565.)
Autoantibodies to Isolated Human Hepatocyte Plasma Membranes in Chronic Active Hepatitis. Ii. Specificity of Antibodies
Authors: Swanson Nigel R. , Reed William D. , Yarred Linda J. , Shilkin Keith B. , Joske Richard A.
Published: March 2007

The fine specificity of autoantibodies to human hepatocyte plasma membranes in autoimmune chronic active hepatitis was determined by one–dimensional immunoblotting. Sera from 12 patients with “classical” autoimmune chronic active hepatitis contained autoantibodies recognizing many human hepatocyte plasma membrane polypeptides in the 15 to 220 kD range. Many of these autoantibodies titrated beyond 1:80,000 and some may be potentially “pathological.” In particular, one band with and apparent molecular weight of 60 kD was a dominant and consistent finding in all patients with autoimmune chronic active hepatitis by immunoblotting. Serum absorption studies showed this band to be predominantly liver–specific. Control sera from patients with chronic persistent hepatitis, nonhepatic autoimmune disease and normal healthy subjects possessed low titer reactivity that most likely represented “natural” autoantibodies. Anti–human hepatocyte plasma membranes in autoimmune chronic active hepatitis consisted of all three immunoglobulin isotypes (G, M and A) and their presence was not caused by nonspecific reactions as a consequence of hypergammaglobulinemia. Autoantibodies were shown to be specific by virtue of their absorption and exhaustion on titration. Many were directed at species nonspecific determinants, however, some autoantibodies recognized human–specific polypeptides. The majority of anti–human hepatocyte plasma membranes appeared to be organ–specific as sera from patients with autoimmune chronic active hepatitis reacted only weakly with polypeptides of kidney plasma membranes. Of the activity detected, few bands corresponded with those obtained using polypeptides of human hepatocyte plasma membranes. Our results show that patients with autoimmune chronic active hepatitis possess and array of liver–specific autoantibodies to polypeptide subunits of human hepatocyte plasma membranes. Those with highest affinity, avidity and serum titer (for example the 60 kD band) hold the greatest potential in future studies to define the candidate target autoantigen(s) involved in the pathogenesis of autoimmune chronic active hepatitis.(HEPATOLOGY 1990; 11:613:621.)
Cocaine–Induced Liver Cell Injury: Comparison of Morphological Features in Man and in Experimental Models
Authors: Kanel Gary C. , Cassidy William , Shuster Louis , Reynolds Telfer B.
Published: March 2007

Although investigative research of animal models in cocaine metabolism and associated liver cell injury has been fairly extensive during the past 10 yr, little evidence of hepatotoxicity has been documented in man. We report a case of fulminant hepatic failure and acute rhabdomyolysis resulting from cocaine use. Coagulative–type perivenular and midzonal necrosis and periportal microvesicular fatty change were the predominant morphological features throughout all lobules of the liver, in contrast to periportal necrosis described in the only previous case report with biopsy. Differences in zonal necrosis caused by the same drug are not typically seen in man experiencing direct or indirect intrinsic hepatotoxicity. However, experimental models have shown cocaine to have this ability, dependent on enzyme induction or inhibition, sex and dose. Therapeutic approaches for prevention of possible liver cell injury by cocaine toxicity are discussed.(HEPATOLOGY 1990; 11:646–651.)
Single, Total Paracentesis for Tense Ascites: Sequential Hemodynamic Changes and Right Atrial Size
Authors: Panos Marios Z. , Moore Kevin , Vlavianos Panayiotis , Chambers John B. , Anderson John V. , Gimson Alexander E.S. , Slater Jeremy D.H. , Rees Lesley H. , Westaby David , Williams Roger
Published: March 2007

Hemodynamic changes induced by a single, total paracentesis were evaluated in 21 patients with tense ascites from whom 4 to 16 L of ascites were drained over 2 to 8 hr with no serious complications. At 60 min, compared to baseline, there was an increase in cardiac output (7.7 ± 0.5 to 8.5 ± 0.6 L/min, p < 0.02) and a tendency for right atrial pressure to decrease (9.3 ± 0.8 to 7.50 ± 0.8 mm Hg, NS), with no change in pulmonary capillary wedge pressure (10.9 ± 0.9 to 10.7 ± 0.9 mm Hg). Between 3 and 12 hr later, there was a drop in right atrial pressure, pulmonary capillary wedge pressure and cardiac output to 5.6 ± 0.6 (p < 0.02), 7.2 ± 0.8 mm Hg (p < 0.002) and 7.2 ± 0.6 L/min (NS) respectively, indicative of the development of relative hypovolemia and suggesting that therapeutic plasma expansion is appropriate at this time. Two–dimensional echocardiography before paracentesis (n = 8) showed a reduction in the right to left atrium area ratio as compared with values in patients with minimal ascites (0.54 ± 0.04 vs. 0.82 ± 0.02, p < 0.0001). This technique may help in identifying patients with right atrial compression caused by tensea ascites.(HEPATOLOGY 1990; 11:662–667.)
The Effects of Ethanol Administration on Portal Pressure and Gastroesophageal Collateral Blood Flow in Patients With Alcoholic Cirrhosis
Authors: Ready Joanna B. , Hossack Kenneth F. , Rector William G.
Published: March 2007

The pathogenesis of variceal hemorrhage is not well understood. Portal pressure and gastroesophageal collateral (azygous) blood flow are similar in patients with cirrhosis with or without a history of variceal bleeding. However, acute increases in these parameters in individual patients might predispose them to variceal rupture.

Fifteen patients with alcoholic cirrhosis and portal hypertension were evaluated to test the hypothesis that ethanol intake acutely increases portal pressure or gastroesophageal blood flow and is a possible risk factor in variceal hemorrhage. A 10% solution of ethanol in 5% dextrose in water was infused intravenously at a rate sufficient to raise the blood–alcohol level to 100 mg/dl over 30 min. Eight patients received ethanol 5% dextrose in water; seven patients received a placebo (5% dextrose in water alone). Ethanol did not produce a significant change in wedged hepatic–vein pressure, free hepatic–vein pressure, azygous blood flow, mean arterial pressure or heart rate compared with the effects of 5% dextrose in water alone.

Acute administration of ethanol does not increase portal pressure or gastroesophageal blood flow. It is unlikely that acute ethanol ingestion is a risk factor for variceal hemorrhage.(HEPATOLOGY 1990; 11:674–677.)
A Randomized Trial of Terlipressin Plus Nitroglycerin Vs. Balloon Tamponade in the Control of Acute Variceal Hemorrhage
Authors: Fort Eric , Sautereau Denis , Silvain Christine , Ingrand Pierre , Pillegand Bernard , Beauchant Michel
Published: March 2007

A randomized trial was undertaken to determine the efficacy of nitroglycerin in addition to terlipressin infusion to improve the control of acute variceal hemorrhage compared with balloon tamponade. Fortyseven bleeding episodes in 34 cirrhotic patients were included, with terlipressin plus sublingual nitroglycerin in 23 episodes (group I) and balloon tamponade in 24 episodes (group II). At the end of the 12–hr period, hemorrhage had been equally controlled in both groups (18 of 23; 78% in group I and 19 of 24; 79% in group II). When attempted, balloon tamponade appeared more efficient in the failures of group I (4 of 4) than did terlipressin plus nitroglycerin in the failures of group II (0 of 3), although this difference was not significant. Major complications were rare (one in each group) and never required cessation of therapy. Thus terlipressin and nitroglycerin were as effective as balloon tamponade in controlling variceal hemorrhage and were associated with few minor complications.(HEPATOLOGY 1990; 11:678–681.)
Methanethiol Metabolism and Its Role in the Pathogenesis of Hepatic Encephalopathy in Rats and Dogs
Authors: Blom Henk J. , Chamuleau Robert A.F.M. , Rothuizen Jan , Deutz Nicolaas E.P. , Tangerman Albert
Published: March 2007

The metabolism of methanethiol was studied in rats. Administration of a noncomatogenic dose of methanethiol through inspired air or injection into the upper colon resulted in an elevation of the concentrations of methanethiol mixed disulfides in serum (protein-S-S-CH3 and X-S-S-CH3, × yet unknown) and in urine (X-S-S-CH3. The concentrations of methanethiol mixed disulfides proved to be a relative measure of exposure to methanethiol. The levels of volatile sulfur compounds methanethiol, dimethylsulfide and dimethyldisulfide in the air expired by rats exposed to a noncomatogenic dose of methanethiol through the colon were also elevated. Rats with acute hepatic encephalopathy caused by liver ischemia also showed elevation of methanethiol mixed disulfide levels on challenge of methanethiol through the colon or inspired air, but to a significantly smaller extent than did the corresponding sham–operated rats. This suggests that the liver is at least partly responsible for formation of methanethiol mixed disulfides. No additional toxic effects were observed in the rats with ischemic livers on methanethiol exposition when compared with normal rats, suggesting that the liver does not play an essential role in methanethiol detoxification. Metabolism of methanethiol by blood to sulfate, for example, might be more important.

In rats with acute hepatic encephalopathy caused by liver ischemia and in dogs suffering from hepatic encephalopathy resulting from chronic liver disease, large and significant increases in ammonia levels were measured. However, the mean levels of methanethiol mixed disulfides in rats and dogs with hepatic encephalopathy were not different from the mean normal levels in these animals. It is concluded that in these animal models of liver failure the role of methanethiol in the pathogenesis of hepatic encephalopathy is probably minor or insignificant.(HEPATOLOGY 1990; 11:682–689.)
Serum Ferritin Levels and Hepatocellular Carcinoma: the Cart or the Horse?
Authors: Powell Lawrie W. , Halliday June W.
Published: March 2007

Previous studies from this laboratory support the view that increased serum ferritin levels are associated with an increased risk of primary hepatocellular carcinoma (PHC). We have tested this hypothesis in a population of Korean patients with chronic liver disease followed for development of PHC. Serum ferritin levels were measured over time in 249 patients with liver diseases (mostly chronic) followed for 2 to 17 years in Seoul, Korea. Most of the patients were chronically infected with hepatitis B virus. During the first 8 months of follow–up, there were no cases of PHC and no deaths. During this same period, no patient had a serum ferritin level initially below 300 ng/ml and rising above 300 ng/ml, but some patients with ferritin levels above 300 ng/ml experienced decreases to below 300 ng/ml. Therefore, patients were grouped by ferritin level during the first 8 months of follow–up into 3 categories according to the above criteria. Multivariate analysis showed that consistently elevated ferritin levels (category 3) were significantly associated with the development of PHC. Men were more likely to have elevated ferritin levels than women and were at higher risk of developing PHC. Men who were chronically infected with HBV and had ferritin levels above 300 ng/ml had a 50% chance of developing PHC during the follow–up period, compared with a 20% risk of PHC for men with lower ferritin levels (categories 1 and 2). This elevated risk of PHC in men with elevated ferritin levels was confined to the first 3 years of follow–up.
Increased Endogenous Neuropeptide Ligand for Benzodiazepine Receptors in Hepatic Encephalopathy
Authors: Butterworth Roger F.
Published: March 2007

The neuropeptide diazepam binding inhibitor (DBI) is an endogeneous allosteric modulator of gammaaminobutyric acid (GABA) receptors at the benzodiazepine recognition site. Recent theories on the neurochemical cause for hepatic encephalopathy have implicated activation of inhibitory neurotransmitter GABA systems. In 20 patients with hepatic disease, blood and cerebrospinal fluid (CSF) levels of ammonia and amino acids were measured. As in previous studies there was a selective elevation of CSF amino acids as well as a correlation between CSF glutamine levels and encephalopathy. CSF DBI levels were maximally elevated 5–fold in patients with hepatic encephalopathy, but they were normal in those patients with liver disease not associated with changes in mental status and in patients with nonhepatic encephalopathy. Levels of DBI correlated with the clinical staging of hepatic encephalopathy. These data suggest that DBI may participate in the modulation of cerebral function in hepatic encephalopathy.
The Relative Affinity of Recombinant Dihydrolipoamide Transacetylase for Autoantibodies in Primary Biliary Cirrhosis
Authors: Robertson Craig A. , Coppel Ross L. , Prindiville Thomas , Fregeau David , Kaplan Marshall , Dickson Rolland E. , Gershwin Eric M.
Published: March 2007

In normal individuals there is an adaptive immune response to a foreign antigen in which antibodies of increasing affinity are produced with time. This is not always true of an autoimmune response. However, because only a limited number of autoantigens have been cloned or purified, this issue has not been studied well. In primary biliary cirrhosis the predominant manifestation of autoimmunity is antimitochondrial antibodies that react with dihydrolipoamide transacetylase. The availability of recombinant dihydrolipoamide transacetylase and the develoopment of a rapid and reproducible enzyme–linked immunosorbent assay for autoantibodies has allowed us to address the affinity of autoantibodies using thiocyanate inhibition. Thiocyanate is a chaotropic compound known to inhibit antigen–antibody binding in a concentration–dependent manner. We used this property to inhibit the binding by enzyme–linked immunosorbent assay of human recombinant dihydrolipoamide transacetylase with serum autoantibodies from 55 patients with primary biliary cirrhosis. The relative affinity and serum autoantibody titers were then compared with the histological stage of the liver biopsy sample. Interestingly, we found a considerable heterogeneity of relative affinities. These relative affinities did not correlate with the histological stage or the serum titer of antimitochondrial antibodies. However, the ability of serum autoantibodies to inhibit intact primary biliary cirrhosis enzyme activity was found to correlate highly (R2 = 0.751) with the relative affinity. Thus there are profound differences between patients with respect to qualitative expression of autoantibodies. The significance of this data will be unclear until more is determined regarding the nature of the epitope that drives T cells and leads to B–cell responses.(HEPATOLOGY 1990; 11:717–722.)
Estradiol–17β–D–Glucuronide (E–17G) Cholestasis in Perfused Rat Liver: Fate of E–17G and Choleretic Responses to Bile Salts
Authors: Utili Riccardo , Tripodi Marie F. , Adinolfi Luigi E. , Gaeta Giovanni B. , Abernathy Charles O. , Zimmerman Hyman J.
Published: March 2007

This study was designed to test the hypothesis that increasing the infusion rate of bile salts could overcome drug–induced cholestasis. Cholestasis was induced by administration of 17.5 μmol/L estradiol–17β–d–glucuronide during the infusion of taurocholate, tauroursodeoxycholate or dehydrocholate at 20 nmol/min/gm liver. After 30 min, a bolus of 10 μmol of the bile salts was added to the perfusate, and the infusion rate of each bile salt was increased. Taurocholate at a rate of 62 or 125 nmol/min/gm liver, caused a prompt dose–dependent increase of the depressed bile flow and bile salt excretion. A higher rate of taurocholate infusion (180 nmol/min/gm liver) was less effective than either the 62 or 125 rate in increasing bile flow. Infusion of tauroursodeoxycholate at 250 or 390 nmol/min/gm liver also led to a dose–dependent recovery. Further increase of tauroursodeoxycholate infusion rate to 580 nmol/min/gm liver did not provide any additional recovery in bile flow. Dehydrocholate, at rates of 62 or 125 nmol/min/gm liver, gave only a slight enhancement of bile flow. Both taurocholate and tauroursodeoxycholate caused a marked removal of the estradio–17β–D–glucuronide, which had accumulated in the liver. At lower taurocholate infusion rates, the estradiol–17β–d–glucuronide was excreted mainly in the bile. At the highest rate, however, biliary excretion of estradiol–17β–d–glucuronide declined significantly, and a marked back–efflux of the estrogen into the perfusate was noted. In contrast, tauroursodeoxycholate led to enhanced biliary estradiol–17β–d–glucuronide excretion at all increased tauroursodeoxycholate infusion rates and to only a small increase in back–efflux of estradiol–17β–D–glucuronide at the two highest tauroursodeoxycholate infusion rates. Dehydrocholate, at higher infusion rates, did not enhance estradiol–17β–d–glucuronide biliary transport or regurgitation. The effects of taurocholate, tauroursodeoxycholate and dehydrocholate on bile flow, bile salt secretion and estrogen excretion during estradiol–17β–d–glucuronide cholestasis paralleled their relative hydrophobicity and detergent effect. Taurocholate infusion also decreased the adverse effect of estradiol–17β–d–glucuronide on sucrose clearance. Among the bile salts used, taurocholate was the most effective in increasing bile flow during estradiol–17β–D–glucuronide cholestasis but showed some toxicity. Although less effective, tauroursodeoxycholate did not exert adverse effects. Accordingly, tauroursodeoxycholate has a higher therapeutic index that might be relevant in efforts to treat estrogen–induced cholestasis by administration of bile salts.(HEPATOLOGY 1990; 11:735–742.)
The Ursodeoxycholate Dose–Dependent Formation of Ursodeoxycholate–Glucuronide in the Rat and the Choleretic Potencies
Authors: Takikawa Hajime , Sano Naoyo , Narita Tohru , Yamanaka Masami
Published: March 2007

The reason for the discrepancy between bile flow and biliary bile acid excretion during ursodeoxycholate infusion in rats is unknown. We found that ursodeoxycholate–glucuronide is formed during ursodeoxycholate infusion at higher doses. Ursodeoxycholate infusion (1 to 3 μmol/min/100 gm body weight) for 90 min caused marked hypercholeresis, and the previously reported discrepancy between bile flow and biliary bile acid excretion was observed when bile acid concentrations were measured by regular enzymatic methods. However, the appearance of ursodeoxycholate–glucuronide was observed on thin–layer chromatography analysis and up to 30% of the ursodeoxycholate in bile was found to be glucuronidated when determined by the enzymatic method after β–glucuronidase treatment. The choleretic activity of ursodeoxycholate–glucuronide (25.2 μI/μmol) was about 3 times higher than that of ursodeoxycholate (8.9 μl/μmol) when infused at 0.25 μmol/min/100 gm body weight and ursodeoxycholate–glucuronide also stimulated higher biliary bicarbonate excretion than ursodeoxycholate. These results indicate that the discrepancy between bile flow and biliary bile acid excretion caused by high–dose infusion of ursodeoxycholate into rats can be explained by glucuronide conjugation of ursodeoxycholate that cannot be detected by the regular enzymatic method. The glucuronidation of ursodeoxycholate might also be important in the ursodeoxycholate induced increase in biliary bicarbonate excretion.(HEPATOLOGY 1990; 11:743–749.)
Kinetics of Taurocholate Efflux From Freshly Isolated Suspensions and Primary Cultures of Rat Hepatocytes
Authors: Kukongviriyapan Veerapol , Stacey Neill H.
Published: March 2007

Isolated rat hepatocytes have been advocated as a model to study aspects of mechanism of chemicalinduced interference with biliary excretory function. Some technical problems do exist in studying efflux, such as the reuptake of the previously excreted substrate. Another concern is the loss of liver–specific functions in hepatocytes with continuing time in culture. It is important to address such technical aspects and to determine whether the process of efflux is compromised in primary cultures of hepatocytes. In the presence of Na + the apparent efflux of taurocholate from hepatocytes was shown to be significantly confounded by reuptake of substrate. The unidirectional efflux was best demonstrated in buffer where choline replaced Na +. A comparison of efflux kinetics for cultured cells to those in suspension showed that both apparent affinity for transport carriers and transport capacity were greater in the former. The simple diffusion component for efflux increased with the time in culture, but affinity for transport carriers and transport capacity remained unchanged over 6 to 24 hr. However, it was not possible to determine meaningful kinetic constants after 24 hr in culture because the uptake of taurocholate was so low. Primary cultured hepatocytes may therefore be of limited value in the study of efflux of bile salts in the longer term, mainly because of the inability of cells to take up and accumulate a sufficiently high level of bile salts.
The Onset of Sodium Retention in Experimental Cirrhosis in Rat Is Related to A Critical Threshold of Liver Function
Authors: Wensing Georg , Sabra Ramzi , Branch Robert A.
Published: March 2007

Although sodium retention is a common coplication in advanced liver disease, the relationship between liver and kidney function in cirrhosis has not been well established. The objective of this study was to investigate this relationship in an experimental model of cirrhosis induced in phenobarbital–treated rats by weekly intragatric adminstration of carbon terachloride. Liver function, measured by the aminopyrine breath test, and urinary sodium excretion on a constant salt diet, were measured weekly. Administation of carbon tetrachloride led to cirrhosis, sodium retention, ascites and a reduction in liver function as measured by the amino pyrine breath test in all 15 rats surviving the first 8 wk. The time to develop sodium retention (defined as a decridese in urinary sodium excretion rate to less than 0.3 mmol/24 hr) varied from 9 to 19 wk. The aminopyrine breath test rate constant of elimination was reduced from 24 × 10-3 min -2 2 × 10-3 at the start of carbon tetrachloride administration by 61% ± 10% at the time sodium retention occurrred. A linear decrease was seen in aminopyrine breath test rate constant of elimination in the weeks preceding the onset of sodium retention. Sodium retention occurred when aminopyrine breath test rate contant of elimination was reduced to a critical threshold of 10 × 10-3 ± 1 × 10-3 min-1, and then permitted to recover above this level by withdrawal of carbon tetrachloride. Sodium retention occurred when the aminopyrine breath test rate constant of elimination fell below the threshold; this was followed by spontaneous diuresis when aminopyrine breath test rate constant of elimnation in the weeks preceding the onset of sodium retention. Sodium retention occurred when aminopyrine breath test rate contant of elimination was reduced to a critical threshold of 10 × 10-3 ± 1 × 10-3 min-1, and then permitted to recover above this level by withdrawal of carbon tetrachloride. Sodium retention occurred when the aminopyrine breath test rate constant of elimination fell below the treshold: this was followed by spontaneous diuresiss when aminopyrine breath test rate constant of elimination improved above 10 × 10-3 ± 1 × 10-3 min-1. the onset of sodium retention preceded the onset of ascites in all rats. Theses results indicate a critical threshold of hepatic function in the phenobarbital, carbon terachloride model of cirrhosis, below which sodium retention followed by ascites formation occurs.(HEPATOLOGY 1990; 11:779–786.)
Variable Expression of Pres1 Antigen in Serum During Chronic Hepatitis B Virus Infection: An Accurate Marker for the Level of Hepatitis B Virus Replication
Authors: Petit Marie-Anne , Zoulim Fabien , Caipel Francis , Dubanchet Sylvie , Dauguet Charles , Trepo Christina
Published: March 2007

The expression of the preSl antigen of hepatitis B virus in sera from chronic HBsAg carriers was studied using a specific monoclonal antibody F35.25 in an original, double–immunoradiometric assay. The antibody F35.25 recognized an epitope located between amino–acid residues 32 and 53 on the preSl sequence of the large HBsAg protein. This domain could be involved in the recognition of hepatitis B virus by hepatocyte receptors. PreS1 antigen detection by monoclonal antibody F36.25 closely correlated with the presence of complete virions in the serum of HBsAg carriers, as demonstrated by ultracentrifugation– gradient experiments and electron–microscopical ex–amination. Of the 19 HBsAg carriers with chronic liver disease, preSl antigen was detected in 17 (90%): all of the 11 HBeAg– and hepatitis B virus–DNA–positive cases (group 1) and six of eight anti–HBe–positive cases with low levels of hepatitis B virus replication (group 2). PreSl antigen/HBsAg ratios parallel to preS1 antigen titers were significantly higher in the HBeAg–positive group (34% and 1:106) than in the anti–HBe–positive group (18% and l:lO2). In contrast, preSl antigen was not detected in 18 (90%) of the 20 HBsAg healthy carriers positive for anti–HBe and negative for serum hepatitis B virus–DNA (group 3). Our results show that in chronic HBsAg carriers the serum expression of preSl antigen correlates well with the level of hepatitis B virus replication (serum hepa–titis B virus–DNA and/or liver HBcAg) and that it may be useful in assessing the clinical importance of the chronic viral infection.(HEPATOLOGY 1990; 11:809–814.)
Long–Term Results of Resection for Large Hepatocellular Carcinoma: A Multivariate Analysis of Clinicopathological Features
Authors: Lai Edward Cheuck-Seen , Ng Irene Oi-Lin , Ng Mathew Ma-Tai , Lok Anna Shuk-Fong , Tam Po-Chor , Fan Sheung-Tat , Cho Tat-Kuen , Wong John
Published: March 2007

Recurrent or metastatic disease is frequently en–countered among patients who have had resection of their primary hepatocellular carcinoma. A retro–spective study on 117 patients (104 men, 13 women; mean age ± standard deviation: 53.8 ± 12.4 yr) who had hepatectomy for large hepatocellular carcinoma (diameter ≥ 5 cm) was conducted to identify an at–risk population for tumor recurrence. Disease–free survival was correlated with 22 clinical (n = 5), serological (n = 2), gross pathological (n = 3) and histological (n = 12) features of the resected specimens using Cox's multivariate regression analysis. Recurrent hepatocel–lular carcinoma was detected in 74 patients within a median follow–up period of 13.7 mo. Although 17 patients had extrahepatic disease alone, recurrence was confined to the hepatic remnant in 40 patients. Disease–free survival rates at 1, 3 and 5 yr were 40%, 19% and 12%, respectively. Two of the five histological parameters isolated, negative resection margin (p <0.01) and encapsulation (p < 0.006), were identified as favorable independent prognostic predictors. When patients with positive margins were excluded from the analysis, repeated calculation showed that encapsu–lation was the only important determinant. From this analysis, detailed histological study of the resected tumor is seen to be the only satisfactory means for assessing long–term prognosis. An aggressive approach is warranted among patients with encapsulated tu–mors. Even with a clear resection margin, adjuvant treatment should be considered for those patients who have unencapsulated lesions.(HEPATOLOGY 1990; 11:815–818.)
Promoting Effect of Citrulline in Hepatocarconogenesis: Possbile Mechanism in Hypercitrullinemia
Authors: Nakayama Maski , Okamoto Yasuyki , Morita Tomofumi , Matsumoto Makoto , Fukui Hiroshi , Nakano Hiroshi , Tsujii Tadasu
Published: March 2007

Hypercitrullinemia (adult type), believed to be one of the hereditary urea cycle disorders, is known to be complicated by hepatocellular carcinoma at a high incidence (approximately 14%). Weinvestigated the relationship between this hypercitrullinemia and he–patocarcinogenesis. After the addition of citrulline, incorporation of tritiated thymidine into primary cultured hepatocytes of adult rat increased in a dose–dependent fashion in the range of 0.1 to 5 mmol/L. The citrulline–added group also showed significant in–crease in ornithine and polyamine contents in hepatpcytes. The incidence of epithelial cell foci in the in vivo–in vitro tumor promotion analyzing system significantly rose in the group maintained with mmol/L citrulline and in the group maintained with 1.5 mmol/L phenobarbital. These findings suggest the possiblility that citrulline has a promotion effect on hepatocyte proliferation and that at high concentra–tions it plays the role of a hepatocarcinogenesis pro–moter.(HEPATOLOGY 1990; 11:819–823.)