bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of treatments of bleeding varices: Effects of differences between treatment intended and treatment received
Authors: Rabeneck Linda
Published: March 2007

Ninety-seven patients with recent or active var-iceal bleeding were randomly assigned to oral pro-pranolol, endoscopic sclerotherapy plus oral pro-pranolol, or transhepatic sclerotherapy plus oral propranolol. The effects of treatment on the number of units transfused, rebleeding of any magnitude, major rebleeding, and death were assessed in these patients, 82% of whom were alcoholic and 81% Child’s Class C. After a minimum follow-up interval of 2 yr (range, 27-65 mo), major rebleeding rates were 65% for propranolol alone, 45% for endoscopic sclerotherapy plus propranolol, and 60% for transhepatic sclerotherapy plus propranolol. The corresponding death rates were 81% for propranolol alone, 55% for endoscopic sclerotherapy plus propranolol, and 66% for transhepatic sclerotherapy plus propranolol (p = 0.03). Thirty-three patients (34%) never received propranolol; 8 due to medical contraindications and 25 because they died or bled enough to meet the definition of treatment failure within 3 or 4 days of randomi- zations (no significant differences among treatment groups). Patients assigned to propranolol alone bled sooner, bled more units, and had a higher mortality rate than patients treated by endoscopic sclerotherapy plus propranolol. Patients treated with transhepatic sclerotherapy plus propranolol had intermediate results. Propranolol alone is inadequate treatment for esophageal var-iceal bleeding in patients with advanced liver disease.
The differentiation of cholesterol and pigment gallstones
Authors: Jüngst Dieter
Published: March 2007

Gallbladder biles and stones were obtained at 116 cholecystectomies for symptomatic gallstone disease. All 33 patients younger than 50 years had cholesterol stones, whereas 40% of the older patients had pigment stones. We compared the reliability of three different bile tests for the differentiation between cholesterol and pigment stone patients. Whereas both the presence of cholesterol monohydrate crystals in fresh gallbladder bile and a nucleation time ≤20 days in ultrafiltered gallbladder bile had a specificity of 100% for cholesterol gallstone disease, biliary supersaturation with cholesterol (cholesterol saturation index >1.0) had a low specificity. The sensitivity of nucleation time ≤20 days for cholesterol gallstone disease was 78% in concentrated gallbladder biles (biliary total lipid concentration ≥5 g/dl) but only 21% in dilute biles (biliary total lipid concentration <5 g/dl). In contrast, examination for the presence of cholesterol crystals in fresh bile was reasonably sensitive both in concentrated and diute gallbladder biles (sensitivity, 84% and 72%, respectively). In addition, duodenal bile obtained from 16 patients (10 cholesterol, 6 pigment) before cholecystectom showed cholesterol crystals in 7 of the cholesterol but in none of the pigment stone patients. We conclude that examination of fresh bile for cholesterol crystals is a specific and reasonably sensitive test for cholsterol gallstone disease.
γ–Interferon Treatment Inhibits Collagen Deposition in Murine Schistosomiasis
Authors: Czaja Mark J. , Weiner Francis R. , Takahashi Shizuko , Giambrone Marie-Adele , Der Van Meide Peter H. , Schellekens Huub , Biempica Luis , Zern Mark A.
Published: March 2007

Since interferons have been shown to affect the synthesis of matrix proteins such as collagen in several in vitro systems, the potential role of γ–interferon in inhibiting hepatic fibrosis was investigated. Hepatic cells, consisting primarily of hepatocytes, were treated with recombinant γ–interferon for 24 hr. Northern blot hybridization showed that γ–interferon treatment caused a profound decrease in pro–α2(I)collagen mRNA levels but an increase in β–actin mRNA content. The effects of γ–interferon were then studied in an in vivo model of hepatic fibrogenesis, murine schistosomiasis. Schistosoma–infected mice were treated with daily i.m. injections of γ–interferon for a 4–week period starting 4 weeks after the initial infection. γ–Interferon treatment decreased collagen deposition as determined by histologic evaluation and measurement of total liver collagen content. Northern blots showed Types I and III procollagen mRNA levels for treated, infected animals to be only 32 and 29% that of infected controls, but β–actin mRNA levels were significantly elevated. These results indicate a potential role for γ–interferon as an antifibrogenic agent in vivo.
Lipid Peroxidation and Antioxidant Defense Systems in Rat Liver After Chronic Ethanol Feeding
Authors: Kawase Tateo , Kato Shinzo , Lieber Charles S.
Published: March 2007

The effects of chronic ethanol feeding on hepatic lipid peroxidation, ascorbic acid, glutathione and vitamin E levels were investigated in rats fed low or adequate amounts of dietary vitamin E. Hepatic lipid peroxidation was significantly increased after chronic ethanol feeding in rats receiving a low–vitamin E diet, indicating that dietary vitamin E is an important determinant of hepatic lipid peroxidation induced by chronic ethanol feeding. No significant change was observed in hepatic non–heme iron content, but hepatic content of ascorbic acid and glutathione was increased by ethanol feeding. Both low dietary vitamin E and ethanol feeding significantly reduced hepatic α–tocopherol content, and the lowest hepatic α–tocopherol was found in rats receiving a combination of low vitamin E and ethanol. Plasma α–tocopherol was elevated after ethanol feeding, probably because of the associated hyperlipemia. Both the ratio of plasma α–tocopherol/plasma lipid and the red blood cell α–tocopherol were reduced by ethanol feeding. Furthermore, ethanol feeding caused a marked increase of hepatic α–tocopheryl quinone, a metabolite of α–tocopherol by free radical reactions. Ethanol feeding caused little changes of α–tocopherol and α–tocopheryl quinone content in mitochondria, whereas a striking increase in α–tocopheryl quinone was observed in microsomes. These data suggest that ethanol feeding causes a marked alteration of vitamin E metabolism in the liver and that the combination of ethanol with a low–vitamin E intake results in a decrease of hepatic α–tocopherol content which renders the liver more susceptible to free radical attack.
Effect of Orally Administered L–Carnitine on Blood Ammonia and L–Carnitine Concentrations in Portacaval–Shunted Rats
Authors: Hearn Timothy J. , Coleman Anton E. , Lai James C.K. , Griffith Owen W. , Cooper Arthur J.L.
Published: March 2007

l–Carnitine (16 mmoles per kg, injected intraperitoneally) is reported to protect mice against subsequent injection of ammonium acetate given at the unprotected LD100. The present studies in rats show a variable protective effect of l–carnitine (16 mmoles per kg) administered 1 hr prior to an LD100 dose of ammonium acetate. Survival ranged from 100% to 35%. In two experiments, protection was highly significant; in a third experiment, l–carnitine did not protect against death but did significantly prolong time to death. Although the cause of this variability is not known, the data establish the protective effect in rats of l–carnitine given 1 hr before ammonium acetate. d–Carnitine and deoxycarnitine, chemically related analogs unable to substitute for l–carnitine metabolically, are without protective effect. The protective effect of l–carnitine is short–lived and is, for example, completely lost if ammonium acetate is given 24 hr after l–carnitine administration. In contrast, the free carnitine content of brain rises slowly but continuously for at least 24 hr following a single dose of l–carnitine. The observation that protection from ammonia toxicity is not correlated with brain carnitine levels strongly suggests a major peripheral component to the protective effect. Chronically hyperammonemic (portacaval–shunted) rats were found to have significantly depressed total and free carnitine levels in blood compared to normal and sham–operated controls. The hypocarnitinemia, but not the hyperammonemia, was completely reversed in portacaval–shunted rats given drinking water containing 10 mM l–carnitine. No abnormal behavioral effects were noted in portacaval–shunted or control rats given l–carnitine for 16 weeks, and carnitine did not affect growth or fluid intake. Since carnitine levels are decreased in the serum of some patients with a variety of hyperammonemic syndromes, the present findings may be of clinical relevance to the long–term treatment of these diseases.
Estimation of the Fractional Catabolic Rate Constants for the Elimination of Cytosolic Liver Enzymes From Plasma
Authors: Peltenburg Henny G. , Hermens Wim T. , Willems George M. , Flendrig Guus J. , Schmidt Ellen
Published: March 2007

Pathological elevations of the plasma activities of liver enzymes are not simply related to the quantitative release of such enzymes from the liver. Several enzymatic indices, such as the well–known de Ritis quotient, may be determined by differences in the time course of hepatic enzyme release, rather than reflecting true differences in the released quantities of various enzymes. A more quantitative use of enzymatic data is hampered by the fact that the fractional catabolic rate constants for the elimination of enzyme activities from plasma are unknown. In the present study, three of these constants are estimated by comparison of the time–activity curves in plasma with the corresponding curve of a simultaneously released, more slowly eliminated reference enzyme. This method can be applied in patients with an acute short period of hepatic enzyme release. Values obtained for the cytosolic isoforms of lactate dehydrogenase, AST and ALT are: fractional catabolic rate constant (lactate dehydrogenase isoenzyme 5) = 0.13 ± 0.01 hr-1, fractional catabolic rate constant (cytosolic AST) = 0.088 ± 0.016 hr-1 and fractional catabolic rate constant (cytosolic ALT) = 0.034 ± 0.004 hr-1 (mean ± S.E., n = 10). These values are much higher than the apparent disappearance rate constants, because of extravascular return of activity and tailing release of enzymes during the major part of the elimination phase. It is shown that these results are consistent with earlier published data on the disappearance rates from plasma of lactate dehydrogenase, AST and ALT after acute liver injury. Cumulative release of various cytosolic enzymes occurred in proportion to the corresponding activities in human control livers.
Uptake of Bile Acids by Perfused Rat Liver: Evidence of A Structure–Activity Relationship
Authors: Aldini Rita , Roda Aldo , Simoni Patrizia , Lenzi Pierluigi , Roda Enrico
Published: March 2007

The hepatic extraction of unconjugated and taurineconjugated bile acids, provided with different hydrophilicity values, has been measured in the perfused rat liver, in order to evaluate the role of the bile acid structure and bile acid hydrophilicity on their uptake by the liver. Ursocholic, cholic, ursodeoxycholic and chenodeoxycholic acids, free and taurine–conjugated, were injected into the portal vein in dose response studies, using a nonrecirculating perfusion system.

For all of the bile acids, the uptake process showed saturation.

In addition, a nonsaturable component was apparent in bile acids provided with the lowest hydrophilicity values, as expressed by the lowest values of the water to octanol partition coefficient. The maximum uptake velocity increased with increasing values of the partition coefficient, which in turn were associated with 7–OH α to β epimerization, the presence of 12–OH in α position and taurine conjugation. The ratio of maximum uptake velocity to Km (Km being the half–saturation constant) appeared to be markedly increased by taurine conjugation and by 7–OH α to β epimerization, whereas it was reduced by the presence of 12–OH in α position.
Development and Evaluation of A System of Microencapsulation of Primary Rat Hepatocytes
Authors: Cai Zhuhui , Shi Zhiqing , Sherman Morris , Sun Anthony M.
Published: March 2007

To determine the in vitro function of microencapsulated hepatocytes, viable hepatocytes were isolated from rats and encapsulated within biocompatible alginatepolylysine membranes for in vitro studies. Urea formation, prothrombin and cholinesterase activity, the incorporation of tritiated leucine into intracellular proteins and the immunolocation of synthesized albumin were monitored in culture. Despite a decrease in some of these activities, the cultured hepatocytes continued to function throughout the 5–week observation period, producing and excreting urea, prothrombin and cholinesterase activity into the medium. In addition, albumin could be demonstrated within encapsulated hepatocytes for up to 5 weeks. Scanning and transmission electron microscopy showed the cells to be embedded within the alginate matrix and to retain a globular shape.
Liver Histology Abnormalities in the Morbidly Obese
Authors: Klain Joseph , Fraser Drora , Goldstein Jed , Peiser Jochanan , Avinoah Eliezer , Ovnat Amnon , Charuzi Ilan
Published: March 2007

A prospective study was undertaken in order to investigate the association between clinical and biochemical parameters and the histopathological findings in liver biopsies in the morbidly obese. Wedge liver biopsy specimens were taken at the beginning of the surgical procedure from 100 consecutive morbidly obese patients undergoing Roux–en–Y gastric bypass. Histological abnormalities were found in almost all of the examined material (98 of 100), which ranged from mild fatty infiltration through inflammatory change and alcoholic hepatitis–like change to fibrosis and cirrhosis. The patients with abnormalities were divided into two groups: those with a single abnormality (n = 56) and those with two or more histopathological findings (n = 42). Age, excess body weight, total cholesterol and triglyceride levels were significantly higher in the group with more than one histopathological finding. In a discriminant function analysis, it was found that the preoperatively available measures of age, sex and excess body weight, as well as ALT and triglyceride levels, could discriminate between the two patient groups. A model which uses these variables has been described which correctly assigns the patients to their histology groups in 73% of the cases. This model could provide a useful noninvasive clinical tool for the preoperative evaluation of possible hepatic damage in morbidly obese patients in whom there is no other known cause of possible liver disease.
Hepatic Drug Clearance in Chronic Liver Disease: Can We Expect to Find A Universal, Quantitative Marker of Hepatic Function?
Authors: Morgan Denis J. , Smallwood Richard A.
Published: March 2007

Blood clearance of antipyrine, indocyanine green, and galactose were measured to evaluate the alterations of effective hepatic blood flow and hepatic intrinsic clearances in chronic liver diseases. Galactose blood clearance, which may be taken as effective hepatic blood flow, decreased by approximately 30% in patients with cirrhosis (12.49 ± 0.76 ml/min/kg; mean ± SE; n = 17) compared with normal subjects (18.17 ± 1.03 ml/min/kg; n = 5). In patients with cirrhosis, intrinsic clearances of antipyrine (9.178 ± 0.14 ml/min/kg; n = 17) and indocyanine green (6.19 ± 1.38 ml/min/kg; n = 7) showed 61% and 85% reduction, respectively, compared with those of normal subjects (0.462 ± 0.048 ml/min/kg; n = 5; 41.72 ± 7.75 ml/min/kg; n = 5). Considering that indocyanine green and antipyrine are eliminated by different hepatic mechanisms, these mechanisms may not be equally sensitive to decrements in hepatic function. In addition, fractional reductions of intrinsic clearances for these compounds are thus much greater than that of effective hepatic blood flow.
Endogenous Opioid Peptides in the Pathogenesis of Ascites
Authors: Henriksen Jens H.
Published: March 2007

Methionine enkephalin and catecholamines were measured in carefully collected plasma samples from 25 patients with cirrhosis and ascites, and 25 with cirrhosis without ascites, 15 disease and 15 healthy controls. Methionine enkephalin was invariably raised in the ascites group, the median value being 4.6-6.9 times that of the other three groups. Similarly, in the ascites group, median noradrenaline was increased 2.5-4.2 and median adrenaline 1.8-2.5 times that of the other groups. Plasma methionine enkephalin is considerably raised in patients with cirrhotic ascites and has actions which could enable it to be an initiating factor of ascites formation.
Augmentation of the Natriuretic Response to Atrial Natriuretic Factor in Cirrhosis
Authors: Gerbes Alexander L.
Published: March 2007

The effects of atrial natriuretic factor (ANF) on splanchnic hemodynamics and renal function in portal hypertensive models are described incompletely. Furthermore, ANF–induced vasodilatation and hypotension may limit the assessment of its own renal physiological effects. We infused ANF (human ANF 102–126) to anesthetized portal vein–ligated rats, a model with prehepatic portal hypertension. Arterial pressure was reduced by 17%, but portal pressure was unaffected. Diuresis and natriuresis were explained in part by an increase in glomerular filtration rate; in addition, renal vascular resistance was significantly decreased. The natriuretic response to ANF was slightly, but significantly, decreased in portal hypertensive rats as compared to controls (fractional excretion of sodium, 1.8 ± 0.4 vs. 2.9 ± 0.3; P < .05). The addition of Phe–Ile–Orn–vasopressin, a V1 receptor agonist, normalized arterial pressure but induced a significant decrease in the portal pressure (15 ± 0.9 mm Hg base line vs. 12.8 ± 0.7 combination group; P < .01). Furthermore, the combination of both drugs markedly potentiated the natriuretic effects (0.4 ± 0.1 μEq/min of control vs. 10.0 ± 2.3 ANF vs. 32.2 ± 3.3 combination group; P < .001). The natriuretic potentiation resulted from increments in glomerular filtration rate and renal blood flow. Normalization of arterial pressure may enhance the renal physiological effects of ANF, in this portal hypertensive model.
Identification of Virus Components in Circulating Immune Complexes Isolated During Hepatitis A Virus Infection
Authors: Margolis Harold S. , Nainan Omana V.
Published: March 2007

Circulating immune complexes were isolated by conglutinin affinity chromatography during the course of hepatitis A virus infection in a chimpanzee. Characterization of circulating immune complexes showed that most of the hepatitis A virus–specific antibody was IgM, that IgG was present and that C3d and fibronectin were also present. Hepatitis A virus capsid polypeptides were identified in the circulating immune complexes and polypeptides in the molecular weight range of 63 to 67 kDa having immunological determinants common to both C3d and hepatitis A virus. Hepatitis A virus–RNA was detected in these circulating immune complexes using the polymerase chain reaction for in vitro amplification of nucleic acid and suggests the circulating immune complexes contain intact virus.
Quantitative Analysis of Pre–S1 and Pre–S2 in Relation to Hbsag Expression
Authors: Yuki Nobukazu , Hayashi Norio , Katayama Kazuhiro , Kasahara Akinori , Ueda Keiji , Fusamoto Hideyuki , Sato Nobuhiro , Kamada Takenobu
Published: March 2007

Sera from four patients with acute hepatitis B and 87 patients with chronic hepatitis B were examined quantitatively for pre–S1 and pre–S2 antigens by solid–phase enzyme immunoassays. Pre–S1 and pre–S2 antigens were detected in HBsAg–positive sera irrespective of the presence of viral replicative markers, and their titers correlated with those of HbsAg(r = 0.74, p < 0.01; r = 0.74, p < 0.01, respectively). Sera positive for HBeAg showed higher titers of pre–S1 (p < 0.01) and pre–S2 (p < 0.01) antigens than sera negative for HBeAg. The titers of pre–S1 and pre–S2 antigens also correlated with the levels of HBV–associated DNA polymerase activity (r = 0.51, p < 0.01; r = 0.59, p < 0.01, respectively) and HBV–DNA (r = 0.50, p < 0.01; r = 0.46, p < 0.01, respectively). However, the ratios between the titers of pre–S antigens and HBsAg had no significant relationships with those viral replicative markers. These findings suggest that the expression of pre–S antigens is intimately related to the expression of HBsAg and that they are not useful as markers of viral replication. The ratios between the titers of pre–S antigens and HBsAg tended to be high in patients with chronic active hepatitis and high aminotransferase levels. This finding may have been due to the hepatic release of pre–S antigens, overproduction of which may have some relationship to liver injury.
Reduction of Intrapulmonary Shunt and Resolution of Digital Clubbing Associated With Primary Biliary Cirrhosis After Liver Transplantation
Authors: Stoller James K. , Moodie Douglas , Schiavone William A. , Vogt David , Broughan Thomas , Winkelman Eugene , Rehm Patrice K. , Carey William D.
Published: March 2007

This report describes a patient with marked hypoxemia caused by intrapulmonary shunt associated with primary biliary cirrhosis. Liver transplantation resulted in resolution of digital clubbing and reduction of intrapulmonary shunt as demonstrated by normalization of room air arterial blood gases, reduction in shunt fraction and normalization of the indocyanin–enhanced echocardiogram and perfusion lung scan.

This patient's course challenges the conventional notion that intrapulmonary shunting associated with chronic liver disease does not reverse after liver transplantation. (HEPATOLOGY 1990; 11: 54-58.)
In Vivo Hepatic Energy Metabolism During the Progression of Alcoholic Liver Disease: A Noninvasive 31P Nuclear Magnetic Resonance Study in Rats
Authors: Takahashi Hisao , Geoffrion Yves , Butler Keith W. , French Samuel W.
Published: March 2007

We investigated serially in vivo the rations of phorylated metabolites and the intracellular PH in the livers of rats fed ethanol chronically to evaluate the relation between changes in energy metabolism and the progression of alcoholic liver disease with 31P nuclear magnetic resonance spectroscopy.

31P nuclear magnetic resonance spectra of the liver were acquired noninvasively from rats pair–fed a nutritionally adequate liquid diet containing ethanol or an isocaloric amount of dextrose with an implanted intragastric cannula of dextrose with an implanted intragastric cannula for up to 24 wk. A high blood alcohol level was constantly maintained. The spectra were obtained using a surface coil combined with a ferrite screen to eliminate nuclear magnetic resonance signals derived from the superficial muscles. Contaminating 31P nuclear magnetic resonance signals. Contaminating 31P nuclear magnetic resonance signals arising from abdominal tissues other than the liver were climinated from the spectra by digital subtraction.

Throughout the study the inorganic phosphate/β– ATP peak area ratio observed in alcohol–fed rats was found to be consistently elevated in comparison with the control rats ( at 3 to 5 wk alcohol–fed rats = 1.20 ± 0.10, control rats = 0.78 ± 0.04, p < 0.05,; at 22 to 24 wk alcohol–fed rats = 1.23 ± 0.10, control rats = 0.81 ± 0.06, p < 0.05.; mean ± S. E.). The phosphomonoesters/β–ATP ratio tended to be higher in alcohol–fed rats when compared with control rats. The intracellular pH measured by the chemical shift of the inorganic phosphate peak showed no significant differences between alcohol–fed rats and control rats. Steatosis, necrosis, inflammation and fibrosis were observed to be progressively more severe in the monthly liver biopsy speciments from alcohol–fed rats, so that the pathological score significantly increased with the duration of feeding (r = 0.623, p <0.001). The inorganic phosphate / β–ATP ratio was not significantly correlated with the changing pathological score, since the increased inorganci phosphate/β –ATP ratios remained constant over the duration of feeding.

This observation suggests that the increase in the inorganic phosphate/β–ATP rations is a primary effect of chronic ethanol feeding rather than a result of the workesening morphological changes observed in the liver. This low energy state in the liver may contribute to the pathogenesis of alcoholic liver disease. (HEPATOLOGY 1990; 11: 65-73.)
The Natural History of Nonalcoholic Steatohepatitis: A Follow–Up Study of Forty–Two Patients for Up to 21 Years
Authors: Powell Elizabeth E. , Cooksley Graham W.E. , Hanson Reginald , Searle Jeffrey , Halliday June W. , Powell Lawrie W.
Published: March 2007

Forty–two patients with nonalcoholic steatohepatitis were followed for a median of 4.5 yr (range = 1.5 to 21.5 yr). Except for two patients with lipodystrophy, all were obeser; 35 o f42 were women, 26 of 32 were hyperlipidemic and 15 were hyperglycemic. Upper abdominal pain was the most common reason for presentation. Inital liver biopsy specimens showed the presence of macrovesicular fatty infiltration, lobular (acinar) inflammation, apoptosis, Mallory bodies (in four cases) and fibrosis (in 18 cases). Cirrhosis was present at initial diagnosis in one subject and in another two subjects liver biopsy showed marked and in another two subjects liver biopsy showed marked fibrosis with distured architecture. Serial liver biopsy specimens revealed minimal or no apparent progression of the disorder in most of the patients, in keeping with their benign clinical course. However, one patient showed progression from fibrosis to cirrhosis during the 5–yr observation period, and in the patients with extensive fibrosis the the liver disease evolved from one of active inflammation to one of inactive cirrhosis without fat or inflammation. The patient with cirrhosis later died of hepatocellular carcinoma. The severity or type of hepatic change did not correlate with the degree of obesity, hyperlipidemia or hyperglycemia. However, in individual patients, poorly controlled diabetes and rapid weight loss preceded the onset of steatohepatitis.

We conclude that nonalcoholic steatohepatitis is a cause of hepatic inflammation histologically resembling that of alcohol–induced liver disease but usually slowly progressive and of low–grade severity. However, the disorder may ultimatley result in cirrhosis, Nonalcoholic steatohepatitis should be distinguished from alcoholic steatohepatitis and recognized as a further cause of “cryptogenic cirrhosis.” (HEPATOLOGY 1990; 11: 74-80.)
Elevation of Facilitated Glucose–Transporter Messenger Rna in Human Hepatocellular Carcinoma
Authors: Su Tsung-Sheng , Tsai Ting-Fen , Chi Chin-Wen , Han Shou-Hwa , Chou Chen-Kung
Published: March 2007

Complementary DNA of a rat brain glucose transporter gene was used to examine the expression of glucose–transporter messenger RNA in paired human hepatocellular carcinomas and adjacent nontumorous liver tissues, as well as in human hepatoma cell lines and human fetal liver samples. High expression of a major 2.8–kilobase glucose–transporter transcript was seen in all hepatoma cell lines and fetal liver samples examined, whereas a much lower level of expression was observed in liver tissues. When pairs of liver tissues were examined, elevation of glucose–transporter RNA levels was observed in most of the hepatocellular carcinoma tissues examined.
Alpha–1–Antitrypsin Distribution in Nodular Regenerative Hyperplasia of Liver
Authors: Thung Swan N.
Published: March 2007

Nodular regenerative hyperplasia, a disorder characterized by regenerative nodules scattered diffusely throughout the liver without associated fibrosis, is most often recognized at autopsy when the entire liver is available for inspection. Diagnosis by needle biopsy is much more subtle. Because alpha–1–antitrypsin expression by hepatocytes in a variety of liver diseases has suggested that it may represent a marker for regenerative or damaged hepatocytes, we elected to study the expression of alpha– 1 –antitrypsin by immunohisto chemical staining of paraffin–embedded tissue of biopsy material as a possible marker of this diagnosis. Seventeen liver biopsy specimens showing histological features consistent with nodular regenerative hyperplasia were selected and compared with 20 biopsy specimens of the liver without such features. Eight of the diseased cases showed periportal granular alpha– 1–antitrypsin staining as opposed to only one of the healthy biopsy specimens (p < 0.01; Fisher exact test). These results indicate that alpha–1–antitrypsin expression is increased in the regenerating compartment (as opposed to the presumably damaged atrophic portion) of the liver in nodular regenerative hyperplasia and suggest that alpha–1–antitrypsin staining may be useful in confirming the diagnosis of the disease by biopsy specimens.
Graft–Vs.–Host Disease After Liver Transplantation
Authors: Alexander Graeme , Portmann Bernard
Published: March 2007

Clinically evident, generalized graft–vs.–host disease is not thought to occur as a consequence of transplantation of most solid organs. The large inoculum of donor lymphoid cells required and the inability of the recipient to destroy these passenger cells are apparently rarely produced by solid–organ transplantation. However, there is a risk of graft–vs.–host disease when normal spleens are included in vascularized pancreas transplants.

We report on a case of severe, generalized acute graft–vs.–host disease in a recipient of a liver tranplant, involving documented transient chimerism of donor origin. This life–threatening complication was treated successfully with increase in the corticosteroid dosage and administration of anti–thymocyte globulin.
Defenestration of Hepatic Sinusoids in the Pathogenesis of Alcoholic Hyperlipoproteinemia
Authors: Scheig Robert
Published: March 2007

The hepatic sinusoidal endothelium separates sinusoidal blood from hepatocytes; changes in the porosity of this endothelium may affect the passage of chylomicrons into hepatocytes and influence lipid metabolism. Chronic exposure to ethanol reduces the porosity of the endothelium; this mechanism may underlie the hyperlipoprotelium; hyperlipoproteinaemia observed in some people who drink heavily.
Orthotopic Liver Transplantation for Alcoholic Liver Disease
Authors: Kumar Shashi , Stauber Rudolf E. , Gavaler Judith S. , Basista Michael H. , Dindzans Vincents J. , Schade Robert R. , Rabinovitz Mordechai , Tarter Ralph E. , Gordon Robert , Starzl Thomas E. , Van Thiel David H.
Published: March 2007

Alcohol abuse is the most common cause of end–stage liver disease in the United States, but many transplant centers are unwilling to accept alcoholic patients because of their supposed potential for recidivism, poor compliance with the required immunosuppression regimen and resulting failure of the allograft. There is also concern that alcohol–induced injury in other organs will preclude a good result. From July 1, 11982, to April 30, 1988, 73 patients received orthotopic liver transplants at the University of Pittsburgh for end–stage alcoholic liver disease. Fifty–two (71%) of these were alive at 25 ± 9 mo (mean ± S. D.) after transplantation, when a phone survey of these patients, their wives/husbands, and their physicians was performed to evaluate their subsequent use of alcohol, current medical condition and employment. Data obtained were compared with those for nonalcoholic patients selected as transplant controls. The recidivism rate has been 11.5%, with most patients drinking only socially. Fifty–four percent of the survivors are employed, 21% classify themselves as homemakers and only 11 (21%) are unable to work. Twenty–one patients died after transplantation; the most frequent cause of death was sepsis (43%), and intraoperative death was the next most common cause (28.6%). These data demonstrate that alcoholic patients can be transplanted successfully and achieve good health not significantly different from that of individuals transplanted for other causes. Thus orthotopic liver transplantation is a therapeutic option that should be considered for individuals with end–stage alcoholic liver disease who desire such therapy.
Sensitization of Hepatic Lipocytes by High–Fat Diet to Stimulatory Effects of Kupffer Cell–Derived Factors: Implication in Alcoholic Liver Fibrogenesis
Authors: Matsuoka Masaki , Zhang Martin Y. , Tsukamoto Hidekazu
Published: March 2007

A high–fat diet has previously been shown to be a key factor for induction of alcoholic liver fibrosis in a rat model of intragastric ethanol infusion. To explore a possible mechanism by which the high–fat diet facilitated such an effect, the present study examined how the high–fat diet with or without ethanol affected proliferation and collagen formation of hepatic lipocytes, perisinusoidal cells that have been suggested to be involved in liver fibrogenesis. We also evaluated effects of the high–fat diet on the sensitivity of lipocytes to stimulatory effects of Kupffer cell–derived factors. Intragastric infusion of ethanol and the high–fat diet for 9 to 10 wk resulted in induction of a varying degree of perivenular fibrosis in 75% of animals. Lipocytes isolated from these animals (A) had significantly higher basal rates of proliferation (three to four times) and collagen formation (1.5 times) than those isolated from control animals, which were isocalorically infused with the high–fat diet (H) or the low–fat diet (L), or those that were fed chow ad libitum (C). Lipocytes from the H group exhibited significantly higher relative production of collagen than those from the L group, but their net collagen production was not enhanced. The dialyzed Kupffer cell–conditioned medium from the A group markedly stimulated proliferation and collagen formation of lipocytes from the groups given the high–fat diet (A and H) but had minimal effects on those from the L and C groups, establishing the order of decreasing lipocyte sensitivity from the A, H, L to C group. Similarly, lipocytes from the H and A groups exhibited a more profound responsiveness to the stimulatory effect of transforming growth factor β 1 on collagen formation. These results demonstrate (a) that lipocytes isolated from the rats given the high–fat diet and ethanol are markedly proliferative and produce more collagen; and (b) that the Kupffer cells derived from these animals release factors that stimulate proliferation and collagen formation of lipocytes and (c) that the high–fat diet sensitizes lipocytes for stimulatory effects of the Kupffer cell–derived factors and transforming growth factor β1.
Role of Endotoxin–Responsive Macrophages in Hepatic Injury
Authors: Shiratori Yasushi , Tanaka Mitsugu , Hai1 Kenji , Kawase Tateo , Shiina Shuichiro , Sugimoto Tsuneaki
Published: March 2007

Although administration of 100 mg galactosamine caused severe hepatic injury in C3H/HeN mice, splenectomy reduced the grade of this hepatotoxicity. However, this hepatic injury was scarcely detected in the endotoxin–resistant C3H/HeJ mice. In addition, in contrast to high lethality in C3H/HeN mice with a combined administration of galactosamine and endotoxin, splenectomy rendered C3H/HeN mice slightly resistant to this treatment. Further resistance was demonstrated in C3H/HeJ mice. In an attempt to clarify the role of endotoxin–responsive spleen cells in the pathogenesis of hepatic injury, we investigated glactosamine–induced hepatic injury by transfer of lipopolysaccharide–treated C3H/HeN or C3H/HeJ spleen cells. Both oxygen–derived free radical production and the proportion of macrophages in spleen cells were markedly enhanced in C3H/HeN mice after an intraperitoneal injection of lipopolysaccharide. Further increase in oxidative free radical production was found in the dish–adherent cells (macrophages). These enhancements were not demonstrated in lipopolysaccharide–treated C3H/HeJ spleen cells. Athough hepatic injury was not demonstrated in both C3H/HeN and C3H/HeJ mice treated with 35 mg galactosamine alone, severe hepatotoxicity was found in these galactosamine–treated mice when they received lipopolysaccharide–activated C3H/HeN spleen cells, especially macrophages. Simultaneous administration of superoxide dismutase with the activated spleen cells reduced the grade of hepatic injury. On the other hand, hepatic injury was not demonstrated in the galactosamine–treated C3H/HeN or C3H/HeJ mice when they received lipopolysaccharide–treated C3H/HeJ spleen cells, although 3H–galactosamine incorporation into hepatocytes was nearly identical in both C3H/HeN and C3H/HeJ mice. These results suggest that oxidative free radicals of lipopolysaccharide responsive macrophages could contribute to the pathogenesis of galactosamine–induced hepatic injury.
Cryptic Na+, K+–Atpase Activity in Rat Liver Canalicular Plasma Membranes: Evidence for Its Basolateral Origin
Authors: Sellinger Marcus , Barrett Carolyn , Malle Phillipe , Gordon Ellen R. , Boyer James L.
Published: March 2007

Controversy exists concerning the localization of the enzyme Na+, K+–ATPase to canalicular membranes in hepatocytes. Most studies find enzyme activity only at the basolateral plasma membrane domain of the hepatocyte. However, Na+, K+–ATPase activity has been detected recently in a canalicular membrane fraction prepared by Mg++ precipitation, suggesting that differences in membrane domain fluidity account for these discrepancies. To reinvestigate this question, we used free–flow electrophoresis to further purify canalicular liver plasma membranes originally separated by sucrose density centrifugation. With this technique, canalicular membranes devoid of Na+, K+–ATPase activity by routine assay were separated into six subfractions. More than 80% of the activities of canalicular marker enzymes was recovered in two subfractions closest to the anode, which were totally devoid of Na+, K+–ATPase activity. However, Na+, K+–ATPase activity could now be detected in the four other fractions that contained only small amounts of canalicular marker enzymes. The basolateral marker enzyme, glucagonstimulated adenyl cyclase, comigrated with this cryptic Na+, K+–ATPase activity. Furthermore, addition of 6 μmol/L [12–(2–methoxyethoxy)–ethyl–8–(cis–2–noctylcyclopropyl)–octanoate], a membrane–fluidizing agent, to the original canalicular membrane preparation and to all subfractions did not stimulate or unmask latent Na+, K+–ATPase activity. Finally, when canalicular membranes isolated by Mg++ precipitation were subjected to free–flow electrophoresis, they could not be separated from the more positively charged Na+, K+–ATPase–containing fractions, probably because of alterations in surface charge. Together these findings suggest that Na+, K+–ATPase is a basolateral enzyme, that represents a small contaminant when present in canalicular liver plasma membranes and that methodological differences may account for previous discrepancies.
Volume Regulation in Liver: Further Characterization by Inhibitors and Ionic Substitutions
Authors: Häussinger Dieter , Stehle Thomas , Lang Florian
Published: March 2007

The present study has been performed to elucidate the mechanisms of volume regulation in isolated perfused liver. Reduction of extracellular osmolarity by 80 mOsm/L leads to a release of potassium and a sustained alkalinization of effluent. Reexposure to isotonic perfusate leads to reuptake of potassium by the liver and acidification of effluent. Part of the alkalinization could be due to release of bicarbonate parallel to potassium release. Carboanhydrase inhibition and replacement of bicarbonate/CO2 by HEPES buffer, however, do not significantly modify volume regulatory potassium release or reuptake. Reduction of perfusate chloride to 37 mmol/L by replacement of NaCI with raffinose leads to a decrease of liver weight indicative of shrinkage of liver cells. Subsequent omission of 180 mmol/L raffinose leads to potassium and chloride release and to alkalinization of effluent. Volume regulatory release of potassium is impaired in 1 mmol/L quinidine, 1 mmol/L SITS and 5 mmol/L barium. Volume regulatory reuptake of potassium is impaired by 1 mmol/L amiloride. Volume regulatory release of potassium is not appreciably affected by either; 1 mmol/L furosemide, 1 μmol/L verapamil, 1 mmol/L amiloride or 1 mmol/L barium and volume regulatory potassium reuptake proved insensitive to 1 mmol/L furosemide or 1 mmol/L barium. The data suggest that the cells release potassium and chloride during regulatory volume decrease by quinidine, SITS and weakly barium–sensitive transport systems and that regulatory volume increase is accomplished by activation of Na/H exchange.
Unusual Trihydroxy Bile Acids in the Urine of Patients Treated With Chenodeoxycholate, Ursodeoxycholate or Rifampicin and Those With Cirrhosis
Authors: Nakashima Toshiaki , Sano Atsushi , Seto Yoshifumi , Nakajima Toshikazu , Shima Toshihide , Sakamoto Yoshikuni , Okuno Tadao , Kashima Kei , Hasegawa Takeshi
Published: March 2007

Urinary bile acids from 20 patients treated with chenodeoxycholate, 18 treated with ursodeoxycholate, 15 treated with rifampicin and 8 patients with advanced cirrhosis were analyzed by gas–liquid chromatography and gas–liquid chromatography–mass spectrometry. Occurrence rates and amounts of three so–called unusual trihydroxy bile acids, hyocholate, ursocholate and ω–muricholate, were increased in patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and decreased in cirrhotic patients as compared with those in untreated healthy adults. These data suggest that chenodexycholate and ursodeoxycholate are hydroxylated to produce unusual trihydroxy bile acids in bile acid–loaded humans and that this metabolism may be related to the induction of hepatic microsomal enzymes by rifampicin. In contrast, the hydroxylation of chenodeoxycholate and ursodeoxycholate may be impaired by severe hepatic damage. Because the urine is a secretory pathway for internal bile acids, the occurrence of unusual trihydroxy bile acids in the urine may be used as an indicator of hepatic ability to metabolize “hydrophobic” dihydroxy bile acids their secretory forms.
Ascites in Cirrhosis: A Medical or Surgical Problem?
Authors: Shear Leroy
Published: March 2007

Fifty–seven cirrhotic patients with intractable ascites had a portosystemic shunt. In 35 patients, a peritoneovenous shunt had previously failed. Forty–six patients were in Pugh's class B and 11 were in class C. There were three operative deaths (5.3%). Fifty–three (98.2%) of the 54 survivors were cleared of ascites. In one patient, ascites persisted because of postshunt heart failure that resulted in a marked increase of caval pressure. Twenty–seven patients (50%) had late encephalopathy, which was severe and disabling in 12 (22%). One–and three–year survival rates were 72% and 36%, respectively. These results suggest that although portosystemic shunts are remarkably effective in dealing with ascites, the high rate of postoperative encephalopathy is a strong argument against their routine use in the management of intractable ascites in cirrhosis.
A Controlled Trial of Oral Propranolol Compared With Injection Sclerotherapy for the Long–Term Magnagement of Variceal Bleeding
Authors: Westaby David , Polson Rex J. , Gimson Alexander E.S. , Hayes Peter C. , Hayllar Karen , Williams Roger
Published: March 2007

This trial was carried out to assess the value of propranolo for the prevtion of recurrent variceal bleeding in patinets with well–compensated cirrhosis. We also compared porpranolol therapy to long–term injection sclerotherapy. One hundred and eight patients, in whom the orginal variceal hemorrhage stopped spontaneousley (before diagnostic endocopy) and without sclerotherpay or surgical intervention were included. All were pugh grade A or B; 55% had alcoholic cirrohosis. Patients were chosen randomly to receive oral propranolol (in a dosage to reduce resting pulse rate by 25%) or to undergo long–term injection sclerotherapy. In both groups, episodes of repeat bleeding that did not stop spontaneously were managed with sclerotherapy. Patients considered to have failed propranolol therapy were treated with long–term sclerothrapy. Follow –up ranged from 12 to 64 mo. In the propranolol group, 28 (54%) of the 52 patients had repeat bleeding from varices with a total of 57 episodes; 14 received long–term sclerotherapy. In the sclerotherapy group, 25 (45%) of the 56 patients had repeat bleeding, with a total of 40 episodes (P < 0.20). On an intetion–to–treat basis, the risk of bleedings expressed per patient–month of follow–up was similar for the two groups, at 0.05 and 0.037, respectitively. Survival as assessed by cumulative life analysis was also similar, with 55% and 66% alive at 3 yr (p <0.40). Stepwise regression analysis of possible factors prediciting further bleeding in patients taking propranolo selected only two variables — the pretreatment pulse rate and the extent of pulse–rate reduction in response to propranolol.

These data support propranolol as an alternative first–line measure to long–term injection for the management of variceal bleeding. The pretreatment pulse rate and subsequent response to propranolo may provide means of selecting those most likely to benefit. (Hepatology 1990;11:353-359.)
Reversal of the Behavioral and Electrophysiological Abnormalities of An Animal Model of Hepatic Encephalopathy by Benzodiazepine Receptor Ligands
Authors: Gammal Sergio H. , Basile Anthony S. , Geller David , Skolnick Phil , Jones Anthony E.
Published: March 2007

Behavioral and electrophysiological evidence implicating the GABA–benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy was obtained using an improved rat model of hepatic encephalopathy caused by thioacetamide–induced fulminant hepatic failure. After the administration of thioacetamide together with supportive therapy, acute hepatocellular failure developed in rats as a result of massive hepatocellular necrosis without evidence of renal failure or hypoglycemia. The evolution of hepatic encephalopthy in this model was sufficiently slow to readily permit the staging of the syndrome. Prominent features of the encephalopathy include a marked reduction in open field activity and an abnormal visual evoked response.

Both the deficits in spontaneous motor function and visual evoked response abnormalities of rats in stages III to IV hepatic encephalopathy were significantly improved after the administration of the benzodiazepine receptor ligands flumazenil or Ro 15–4513. Doses of flumazenil or Ro 15–4513 that produced these effects in rats with hepatic encephalopathy had no detectable action on either the behavior or the visual evoked responses of normal rats.

The ability of benzodiazepine receptor ligands to ameliorate both the behavioral depression and the visual evoked response abnormalities associated with hepatic encephalopathy in the thioacetamide–induced rat model suggest an involvement of the GABA/benzodiazepine receptor complex in the pathogenesis of hepatic encephalopathy. In addition, the similarity of these observations to those in rabbits with hepatic encephalopathy caused by galactosamine–induced fulminant hepatic failure is compatible with the hypothesis that the mechanisms of hepatic encephalopathy in these two distinct models share a common final pathway, the allosteric enhancement of GABAergic tone through the benzodiazepine receptor. These observations suggest that increased concentrations or availability of a ligand with agonist properties at the benzodiazepine receptor may be involved in the pathogenesis of hepatic encephalopathy and that administration of benzodiazepine receptor antagonists may be of value in the management of hepatic encephalopathy in man. (Hepatology 1990; 11: 371-378.)