bluuebunny/crossref_metadata_2025 huggingface dataset:
Renin and angiotensinogen mRNA expression in the kidneys of rats subjected to long-term bile duct ligation
Authors: Ubeda Mariano , Matzilevich Marion M. , Atucha Noemí M. , García-Estañ Joaquín , Quesada Tomás , Tang Shiow-Shih , Ingelfinger Julie R.
Published: March 2007

Activation of antinatriuretic systems such as the renin-angiotensin system, is of major importance in the pathogenesis of sodium retention in cirrhosis. In this study, we studied the intrarenal renin-angiotensin system by measuring renin and angiotensinogen mRNA expression in the kidney of rats subjected to long-term bile duct ligation in a phase before the development of ascites, when sodium retention is already present. Experiments were performed in sham-operated and bile duct-ligated rats 3 wk after surgery. Balance studies showed lower sodium excretion and greater sodium retention in the bile duct-ligated rats compared with the control animals. Plasma renin activity (4.41 ± 1.01 ng Angiotensin I/ml/hr in the bile duct-ligated group vs. 4.20 ± 0.74 in the controls) and plasma renin concentration were not different between the two groups. However, plasma renin substrate was significantly decreased in bile duct-ligated animals. Total kidney renin mRNA was significantly higher in the bile duct-ligated animals (0.83 ± 0.14 densitometric units vs. 0.44 ± 0.04 in the controls), as determined on Northern-blot analysis and densitometric quantitation. Angiotensinogen mRNA expression in the kidneys of bile duct-ligated rats was significantly decreased (0.09 ± 0.01 densitometric units) compared with that of the controls (0.21 ± 0.03). These results indicate that sodium-retaining, nonascitic bile duct-ligated rats show abnormalities of the intrarenal renin angiotensin system that precede changes in plasma renin activity. Our data suggest that the intrarenal renin angiotensin system may participate in the initiation of the renal pathophysiological abnormalities present in bile duct-ligated rats. (Hepatology 1994;19:1431-1436.)
Suppression of lipopolysaccharide-stimulated release of tumor necrosis factor by adenosine: Evidence for A2 receptors on rat kupffer cells†
Authors: Reinstein Leon J. , Lichtman Steven N. , Currin Robert T. , Wang Jian , Thurman Ronald G. , Lemasters John J.
Published: March 2007

In liver grafts that will fail as a result of storage injury, reperfusion activates Kupffer cells. Overproduction of tumor necrosis factor by activated Kupffer cells may cause primary graft nonfunction, multiple organ failure and, eventually, death of graft recipients. Carolina rinse solution, adenosine, nisoldipine, pentoxifylline and prostaglandin E1 reduce graft failure from storage/reperfusion injury. To test the hypothesis that these agents act by suppressing cytokine release by activated Kupffer cells, we assessed the effect of each drug on tumor necrosis factor released from cultured rat Kupffer cells stimulated with lipopolysaccharide. Adenosine, nisoldipine and prostaglandin E1 each suppressed lipopolysaccharide-stimulated tumor necrosis factor release. The adenosine A2 receptor agonists. 5-n-ethylcarboxamidadenosine, 2-chloro-adenosine and R-phenylisopropyl adenosine also blocked tumor necrosis factor release in a potency suggestive of A2 receptor activity. Xanthine amine congener, a specific A1 receptor antagonist, failed to reverse the suppression by adenosine of tumor necrosis factor release, whereas CGS15943A, an A2 receptor antagonist, did reverse suppression by adenosine and 5-n-ethylcarboxamidadenosine. CGS15943A had no effect on suppression of lipopolysaccharide-stimulated tumor necrosis factor release by nisoldipine or prostaglandin E1. Dibutyryl-cyclicAMP also suppressed tumor necrosis factor release. Adenosine, 5-n-ethylcarboxamidadenosine, prostaglandin E1 and pentoxifylline increased cyclicAMP levels in cultured Kupffer cells, but nisoldipine did not. We conclude that (a) adenosine A2 receptors exist on Kupffer cells, (b) the suppression of tumor necrosis factor release by adenosine occurs by way of a cyclicAMP-dependent adenosine A2 receptor mechanism, (c) prostaglandin E1 and nisoldipine also suppress tumor necrosis factor release but do not act through adenosine receptors and (d) because agents that suppress tumor necrosis factor release by Kupffer cells also reduce graft failure after liver transplantation, activation of Kupffer cells and release of tumor necrosis factor may be involved in storage/reperfusion injury to liver grafts. (Hepatology 1994;19:1445-1452.)
Cholesteryl esters from oxidized low-density lipoproteins are in vivo rapidly hydrolyzed in rat kupffer cells and transported to liver parenchymal cells and bile
Authors: Pieters Moniek N. , Esbach Sebastiaan , Schouten Donald , Brouwer Adriaan , Knook Dick L. , Van Berkel Theo J. C.
Published: March 2007

Human low-density lipoprotein was labeled in its cholesteryl ester moiety with [3H]cholesteryl oleate or [3H]cholesteryl oleoyl ether and oxidized by exposure to 10 μmol/L of cupric sulfate. The in vivo metabolism of cholesteryl esters of oxidized low-density lipoprotein was determined after injection into rats. When oxidized low-density lipoprotein was labeled with [3H]cholesteryl oleoyl ether, a nonhydrolyzable analog of cholesteryl oleate, Kupffer cells contributed to 55.1% ± 4.1% of the total liver uptake 10 min after injection. When [3H]cholesteryl oleate-labeled oxidized low-density lipoprotein was injected, the radiolabeled cholesterol esters were nearly completely hydrolyzed within 1 hr of injection. Within this time, the Kupffer cell-associated radioactivity declined to 32% of the maximal uptake value. In serum, the highest specific resecreted [3H]cholesteryl (esters) were associated with the serum high-density lipoprotein fraction, suggesting role for high-density lipoprotein as an in vivo cholesterol acceptor. The kinetics of biliary secretion were studied in rats equipped with catheters in the bile duct, duodenum and heart. One hour after injection of [3H]cholesteryl oleate-labeled oxidized low-density lipoprotein, 4.15% ± 0.67% of the injected dose was secreted in the bile, mainly as bile acids. Six hours after injection, this value was 19.2% ± 1.2%. These values are three times higher than those for injected [3H]cholesteryl oleate-labeled acetylated low-density lipoprotein, which is initially mainly taken up by liver endothelial cells. The rapid processing of cholesteryl esters derived from oxidized low-density lipoprotein to bile acids indicates that Kupffer cells form an efficient protection system against the atherogenic action of oxidized low-density lipoprotein in the blood compartment. (Hepatology 1994;19:1459-1467.)
Transport of lactoferrin from blood to bile in the rat
Authors: Regoeczi Erwin , Chindemi Paul A. , Hu Wei-Li
Published: March 2007

The bile contains small quantities of lactoferrin, the origin of which is uncertain. For this reason, we studied the liver’s capability of transferring lactoferrin from the plasma to the bile by injecting a dose (10 to 20 μg/100 gm) of labeled bovine lactoferrin intravenously and following its appearance in bile over 3 hr. Whether diferric or iron free, lactoferrin peaked in the bile 35 min after administration (i.e., the same time as bovine lactoperoxidase and diferric rat transferrin). However, only a small portion of the lactoferrin dose (approximately 1%) was recovered with the bile in 3 hr. On the basis of autoradiographic evidence, the excreted lactoferrin appeared intact. The biliary excretion profile of albumin, a protein thought to reach the canaliculus by paracellular diffusion, was notably devoid of a peak. This, together with competition observed between lactoferrin and lactoperoxidase on one hand and 2Fe-transferrin and lactoferrin on the other for transfer to bile, suggests that lactoferrin is routed through the hepatocyte in vesicles. The process is initiated by binding to a plasma membrane component to which lactoperoxidase and 2Fe-transferrin can also bind. Most 59Fe bound to lactoferrin accompanied the protein carrier to the bile. We conclude that under normal circumstances (i.e., when concentration of lactoferrin in the plasma is very low), lactoferrin transferred from plasma by the liver is probably not the major source of this protein in bile. (Hepatology 1994;19:1476-1482.)
Use of reverse transcription-polymerase chain reaction to evaluate in vivo cytokine gene expression in rats fed ethanol for long periods
Authors: Nanji Amin A. , Zhao Shuping , Sadrzadeh Hossein S.M. , Waxman David J.
Published: March 2007

We evaluated the expression of interleukin-1α, interleukin-1β, tumor necrosis factor-α and transforming growth factor-β mRNAs in the intragastric-feeding rat model of alcoholic liver disease. Rats were fed different diets for periods of 2 or 4 wk. Animals fed saturated fat and ethanol and the corn oil-dextrose control group had no liver injury, whereas animals fed corn oil and ethanol showed pathologic changes. RNA was extracted from the livers at the time of killing, reverse-transcribed and amplified; polymerase chain reaction products were subjected to electrophoresis on agarose gel. Interleukin-1α mRNA was present in all groups at 2 and 4 wk; interleukin-1β and transforming growth factor-β mRNAs were present in all groups at 4 wk. Tumor necrosis factor-α mRNA was absent in all groups at 2 wk but was present in the corn oil-ethanol group only at 4 wk. Because pathological liver injury was evident in the corn oil-ethanol group by 4 wk, the presence of tumor necrosis factor-α mRNA at this time suggests a pathogenetic role for tumor necrosis factor-α in alcohol-induced liver injury. (Hepatology 1994;19:1483-1487.)
Collagenase pretreatment and the mitogenic effects of hepatocyte growth factor and transforming growth factor-α in adult rat liver
Authors: Liu Meng-Lun , Mars Wendy M. , Zarnegar Reza , Michalopoulos George K.
Published: March 2007

Hepatocyte growth factor and transforming growth factor-α are two well-known hepatomitogens for primary hepatocyte cultures. Here we report that these two growth factors also stimulate in vivo DNA syntheses in normal, unoperated, adult rat liver after 24-hr continuous intraportal infusion. As determined by an immunohistochemical staining technique, 5-bromo-2′-deoxyuridine incorporation was increased in a dose-dependent fashion after infusion of up to 10 μg of growth factor/100 gm body weight in the rat. Stimulation of DNA synthesis was seen in the periportal area. Pretreatment using intraportal infusion of collagenase (1 U/kg body weight) for 4 hr before administration of growth factor increased the labeling by 2- to 4-fold to a labeling index range of 48% to 52%. These results suggest that collagenases and possibly other proteases are involved in making hepatocytes competent to respond to growth factors at very early stages of liver regeneration. (Hepatology 1994;19:1521-1527.)
Mdr 2 Knockout mice link biliary phospholipid deficiency with small bile duct destruction
Authors: Leveille-Webster Cynthia R. , Arias Irwin M.
Published: March 2007

Two types of P-glyeoprotein have been found in mammals: the drug-transporting P-glycoproteins and a second type, unable to transport hydrophobic anti-cancer drugs. The latter is encoded by the human MDR3 (also called MDR2) and the mouse mdr2 genes, and its tissue distribution (bile canalicular membrane of hepatocytes, B cells, heart, and muscle) suggests a specialized metabolic function. We have generated mice homozygous for a disruption of the mdr2 gene. These mice develop a liver disease that appears to be caused by the complete inability of the liver to secrete phospholipid into the bile. Mice heterozygous for the disrupted allele had no detectable liver pathology, but half the level of phospholipid in bile. We conclude that the mdr2 P-glycoprotein has an essential role in the secretion of phosphatidylcholine into bile and hypothesize that it may be a phospholipid transport protein or phospholipid flippase.
Cholecystectomy protects against extrahepatic bile duct cancer: Is this a result of the removal of gallstones?
Authors: Walden David T. , Soloway Roger D. , Crowther Roger S.
Published: March 2007

The aetiology of cancer of the extrahepatic bile duct is unknown. Gallstones have been proposed to be a risk factor on the basis of ecological and epidemiological evidence. As gallstones are formed in the gallbladder, the occurrence of extrahepatic bileduct cancer in patients after cholecystectomy is of interest.

All patients (62 734) who had had a cholecystectomy during 1965-1983 within the Uppsala Health Care Region, Sweden, were followed up to the end of 1987. Excluding the first year of follow-up, 23 cancers of the extrahepatic bileduct occurred vs 26.3 expected for a standardised incidence ratio (SIR) of 0.88 (95% confidence interval [CI] 0.56-1.31). Ten years or more after operation there was a greater reduction of risk (SIR=0.27; 95% CI 0.06-0.80). Similar patterns were observed for men and women, and among patients who had undergone cholecystectomy only compared with those who had had their common bileducts explored. To assess surveillance bias the incidence of primary liver cancer was also analysed: SIR=1.15; 95% CI 0.91-1.44 overall, and 10 years or more after cholecystectomy SIR=0.98; 95% CI 0.66-1.40.

This study shows a reduced risk of extrahepatic bileduct cancer 10 or more years after cholecystectomy, indicating that gallstones may be a cause of cancer.
Changes in the Prevalence of Hbeag–Negative Mutant Hepatitis B Virus During the Course of Chronic Hepatitis B
Authors: Hamasaki Keisuke , Nakata Keisuke , Nagayama Yuji , Ohtsuru Akira , Daikoku Manabu , Taniguchi Kenji , Tsutsumi Takuya , Sato Yoshiaki , Kato Yuji , Nagataki Shigenobu
Published: March 2007

ABSTRACT

Hepatitis B virus with a G–to–A point mutation at nucleotide 83 in the precore region (mutant hepatitis B virus 83), which cannot produce HBeAg, is commonly found in HBe antibody–positive hepatitis B virus carriers. We analyzed the consecutive changes in the prevalence of mutant hepatitis B virus 83 during the course of chronic hepatitis B virus infection. Forty–five patients with chronic hepatitis B who were followed up for more than 2 yr in our hospital were studied by polymerase chain reaction in combination with a restriction fragment length polymorphism assay. Mutant hepatitis B virus 83 was found in 14 of 18 (78%) HBe antibody–positive patients and in 8 of 27 (30%) HBeAg–positive patients at baseline. Eighteen of the 22 patients who had mutant hepatitis B virus 83 (82%) showed mixed viral populations of wild–type hepatitis B virus and mutant hepatitis B virus 83, whereas 4 (18%) had only mutant hepatitis B virus 83 and were positive for HBe antibody. During a 2 yr follow–up period, mutant hepatitis B virus 83 was newly detected in 9 of 23 (39%) patients who had wild–type hepatitis B virus alone at baseline. The proportion of mutant hepatitis B virus 83 to whole hepatitis B virus in the serum of 18 patients with mixed viral populations at baseline fluctuated during follow–up. In contrast, wild–type hepatitis B virus was never detected throughout the study in all four patients who had only mutant hepatitis B virus 83 at baseline. These results suggest that mutant hepatitis B virus 83 is prevalent even in HBeAg–positive patients with chronic hepatitis B. The presence of mutant hepatitis B virus 83 leads to complete and irreversible displacement of wild–type virus in some cases. (Hepatology 1994;20:8-14.)
Dna Ploidy Analysis of Hepatic Preneoplastic and Neoplastic Lesions in Woodchucks Experimentally Infected With Woodchuck Hepatitis Virus
Authors: Mi Li-Jun , Patil Jaygonda , Hornbuckle William E. , Cote Paul J. , Gerin John L. , Tennant Bud C. , Paronetto Fiorenzo
Published: March 2007

ABSTRACT

We analyzed the DNA ploidy and the nuclear size of hepatocytes within hepatocellular carcinoma, putative preneoplastic (clear cell and basophilic foci) and adjacent non–neoplastic liver in 30 woodchucks neonatally infected with the woodchuck hepatitis virus. In livers from control woodchucks, in clear cell foci and in most chronic portal hepatitis, the hepatocytes were diploid, with less than 10% tetraploid cells. Aneuploid peaks were found in 50% of the livers with chronic active hepatitis, in 63% of basophilic foci and in 90% of hepatocellular carcinoma. Within the same tumor, aneuploid peaks with different DNA indices were observed frequently, indicating heterogeneity of tumor. S–phase was always elevated, indicating an increased rate of proliferation. Aneuploid cells had nuclei that were larger than those of control liver cells. In some basophilic foci and in some livers with chronic active hepatitis, abnormal DNA was demonstrated before the development of hepatocellular carcinoma, suggesting that these may be populations of hepatocytes at risk of neoplastic transformation. (Hepatology 1994;20:21-29.)
Favorable Effects of Total Paracentesis on Splanchnic Hemodynamics in Cirrhotic Patients With Tense Ascites
Authors: Luca Angelo , Feu Fausto , García-Pagán Juan Carlos , Jiménez Wladimiro , Arroyo Vicente , Bosch Jaime , Rodés Juan
Published: March 2007

ABSTRACT

Total paracentesis is widely used in the treatment of patients with cirrhosis and tense ascites. However, very little information is available regarding its consequences on splanchnic circulation, and its effects on portocollateral blood flow have not been investigated. Ten cirrhotic patients admitted because of tense ascites had measurements of hepatic and systemic hemodynamics, renal function and endogenous vasoactive neurohumoral systems at baseline, just after total paracentesis and 1 hr later. Total paracentesis caused a significant increase in cardiac output (+11%; 95% confidence interval, +4% to +19%) and a rapid fall in portal pressure, as shown by significant decreases in both the wedged hepatic venous pressure (-27% ± 8%; p<0.005) and the hepatic venous pressure gradient (-10%; 95% confidence interval, -3% to -18%). This was accompanied by a marked decrease in azygos blood flow (-28%; 95% confidence interval, -13% to -43%). These favorable hemodynamic effects were associated with a fall of the elevated levels of plasma renin activity (-47% ± 9%; p<0.05), plasma aldosterone (-31% ± 21%; p<0.05) and plasma norepinephrine and by a decrease in levels of serum creatinine (-24% ± 15%; p<0.05) and blood urea nitrogen (-4% ± 3%; p<0.05). These changes were maintained 1 hr later. This study indicates that in patients with cirrhosis and tense ascites total paracentesis favorably influences the systemic hemodynamics, portocollateral blood flow and portal pressure. (Hepatology 1994;20:30–33.)
Systemic Antibiotic Therapy Prevents Bacterial Infection in Cirrhotic Patients With Gastrointestinal Hemorrhage
Authors: Blaise Marcel , Pateron Dominique , Trinchet Jean-Claude , Levacher Serge , Beaugrand Michel , Pourriat Jean-Louis
Published: March 2007

ABSTRACT

This randomized prospective study was aimed at assessing the efficiency of a systemic antibiotic therapy for the prevention of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage by ruptured esophageal varices. For 15 mo, all patients hospitalized with no infection on admission, were included in the study. Starting on admission day, patients in group A received ofloxacin (400 mg/day) for 10 days, first intravenously then orally. They also received an intravenous bolus of amoxicillin plus clavulanic acid (1 g) before each endoscopy performed during hemorrhage. Patients in group B received antibiotic therapy only in cases of established or suspected infection. Chest X–ray, blood culture, urine culture and sputum and ascitic fluid culture were performed every day for 7 days, then every other day for the next 7 days. A bronchial sampling was performed with the Wimberley technique on patients with endotracheal intubation. Ninety–one patients (55 men, 54 ± 11 years, 78% Child Pugh class C) were included in the study (46 in group A, 45 in group B). Group A showed a lower incidence of bacterial infections than group B (20% vs. 66%; p<0.001). Breakdown of positive bacteriological sampling was as follows: blood (6 vs. 17), ascites (3 vs. 7), lungs (2 vs. 18), urine (1 vs. 10). The 2–wk mortality rate was 24% in group A and 35% in group B. (Hepatology 1994;20:34–38.)
Portosystemic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt: Results of A Prospective Controlled Study
Authors: Sanyal Arun J. , Freedman Arthur M. , Shiffman Mitchell L. , Purdum Preston P. , Luketic Velimir A. , Cheatham Andrea K.
Published: March 2007

ABSTRACT

Portosystemic encephalopathy is a common complication of surgical portacaval shunts. Recently, transjugular intrahepatic portosystemic shunts have been proposed to produce portal decompression in a manner analogous to a side–to–side portacaval shunt, but with less morbidity. The incidence and clinical spectrum of portosystemic encephalopathy after transjugular intrahepatic portosystemic shunts, however, had not been previously prospectively defined. We therefore prospectively studied portosystemic encephalopathy in 30 patients undergoing transjugular intrahepatic portosystemic shunts and compared these findings with 25 patients concurrently undergoing sclerotherapy (controls). At entry, both study groups were comparable. Portosystemic encephalopathy was assessed by examining and grading mental status, asterixis, plasma ammonia and trail making tests. The portosystemic encephalopathy index was calculated from these parameters. Nine of 30 patients with transjugular intrahepatic portosystemic shunts experienced 24 episodes of acute portosystemic encephalopathy during follow–up; 6 of 9 had a history of portosystemic encephalopathy before transjugular intrahepatic portosystemic shunts and 5 of these 6 patients had Child C cirrhosis. Mental status and asterixis scores as well as portosystemic encephalopathy index worsened significantly in the first month after transjugular intrahepatic portosystemic shunts but showed some improvement thereafter. Increasing age, a medical history of portosystemic encephalopathy and trail scores for part B greater than 100 sec were predictors of portosystemic encephalopathy after transjugular intrahepatic portosystemic shunts. Portosystemic encephalopathy could be managed medically in all but one patient who underwent liver transplant. In contrast, there were no significant changes in mental status, asterixis, ammonia or trail scores over time in sclerotherapy controls. Only six episodes of encephalopathy occurred in endoscopic sclerotherapy patients over the duration of the study. Thus, overall risk of portosystemic encephalopathy after transjugular intrahepatic portosystemic shunts was higher than during sclerotherapy. (Hepatology 1994;20:46-55.)
Psoriatic Lesions in Patients With Chronic Liver Disease Are Distinct From Psoriasis Vulgaris Lesions, As Judged on Basis of Integrin Adhesion Receptors
Authors: Giannelli Gianluigi , Savoia Paola , Schiraldi Oronzo , Lospalluti Mario , De Luca Michele , Marchisio Pier Carlo , Quaranta Vito
Published: March 2007

ABSTRACT

Psoriatic lesions are relatively frequent in patients with chronic liver disease. Furthermore, therapy with interferons tends to exacerbate the symptoms. The pathogenesis of psoriatic lesions is unclear. An important question is whether such lesions may be linked to the underlying chronic liver disease in these patients, or whether they are incidental manifestations of psoriasis vulgaris. We collected biopsy specimens from involved and uninvolved skin areas of chronic liver disease patients with psoriatic manifestations, as well as from psoriasis vulgaris patients, and investigated the patterns of integrin adhesion receptors by means of immunohistochemical methods. Integrin expression is known to be characteristically altered in psoriasis vulgaris. We found some of these changes in chronic liver disease psoriatic lesions — namely pericellular redistribution and suprabasal expression of the basement membrane receptor α6β4 and of the intercellular integrins α2β1 and α3β1. However, psoriasis vulgaris causes two other typical changes: One is the induction of the prototype fibronectin receptor α5β1, and the other is the alteration of integrin expression in areas of the epidermis that are macroscopically normal. These two changes were not found in chronic liver disease psoriasis biopsy specimens in 14 patients investigated. Thus integrin expression may be useful in differentiating chronic liver disease psoriatic lesions from psoriasis vulgaris lesions. Even though the two types of lesions are indistinguishable on inspection or by their histological features, they may be caused by distinct pathogenetic mechanisms. It remains to be seen whether the underlying chronic liver disease has a role, albeit indirect, in such mechanisms. (Hepatology 1994;20:56-65.)
Timing of the First Variceal Hemorrhage in Cirrhotic Patients: Prospective Evaluation of Doppler Flowmetry, Endoscopy and Clinical Parameters
Authors: Siringo Sebastiano , Bolondi Luigi , Gaiani Stefano , Sofia Soccorsa , Zironi Gianni , Rigamonti Alessandra , Febo Giulio Di , Miglioli Mario , Cavalli Giancarlo , Barbara Luigi
Published: March 2007

ABSTRACT

We followed 87 cirrhotic patients with esophageal varices and without previous hemorrhage for a mean period of 24 mo to prospectively evaluate the occurrence of variceal bleeding within (early) or after (late) 6 mo from entry and the contribution of portal Doppler ultrasound parameters to the prediction of early and late hemorrhage. Clinical, biochemical, endoscopic and portal Doppler ultrasound parameters were recorded at entry. Variceal bleeding occurred in 22 patients (25.3%). Nine (40.9%) bled within the first 6 mo. Cox regression analysis identified variceal size, cherry–red spots, serum bilirubin and congestion index of the portal vein (the ratio of portal vein [cross–sectional area] and portal blood flow velocity) as the only independent predictors of first variceal hemorrhage. Discriminant analysis was used to find the prognostic index cut off points to identify patients who bled within 6 mo (prognostic group 1) or after 6 mo (prognostic group 2) or remained free of bleeding (prognostic group 3). The cumulative proportion of patients correctly classified was 73% in prognostic group 1,47% in prognostic group 2 and more than 80% in prognostic group 3. The addition of Doppler ultrasound flowmetry to clinical, biochemical and endoscopic parameter only improved the classification of patients with early bleeding. (Hepatology 1994;20:66-73.)
Establishment of A Cell Line From A Hepatocellular Carcinoma From A Patient With Hemochromatosis
Authors: Sing Garwin K. , Pace Raymond , Prior Sharon , Scott Janet S.D. , Shield Paul , Martin Nicole , Searle Jeffrey , Battersby Cameron , Powell Lawrie W. , Cooksley Graham W.E.
Published: March 2007

ABSTRACT

We describe the establishment and characterization of a novel hepatoma cell line. This cell line, designated RBHF–1, was established from a hepatocellular carcinoma of a 67–yr–old man with a history of genetic hemochromatosis. At this writing, the cells have been maintained in RPMI–1640 tissue–culture medium and fetal calf serum without any additional supplements for 30 mo. The cells form colonies on soft agar and are not tumorigenic in nude mice. The cell line is polymorphic and displays characteristics of mature hepatocytes by synthesizing albumin, α2–macroglobulin, fibronectin and α–fetoprotein. Cytogenetic analysis shows multiple chromosomal aberrations, with a consistent deletion in the long arm and deletions or rearrangements in the short arm of chromosome 1. There is no evidence for hepatitis B or hepatitis C virus infection of the cell line. The cells contain no detectable intracellular iron after staining with Perls' stain. Unlike other hepatoma cell lines, there is no detectable binding of epidermal growth factor to RBHF–1 cells. This is the first cell line to be established from a patient with hemochromatosis, and it provides a potentially important model for the study of hepatocyte transformation in association with iron overload. (Hepatology 1994;20:74-81.)
Imaging Diagnosis of Small Hepatocellular Carcinoma
Authors: Ikeda Kenji , Saitoh Satoshi , Koida Isao , Tsubota Akihito , Arase Yasuji , Chayama Kazuaki , Kumada Hiromitsu
Published: March 2007

ABSTRACT

To elucidate the detectability of small hepatocellular carcinoma by various imaging modalities, we performed digital subtraction angiography, computed tomographic arterioportography and carbon dioxide–enhanced ultrasonography. Of 76 patients with a small hepatocellular carcinoma of 2 cm or less in maximum diameter, 61 underwent digital subtraction angiography, computed tomographic arterioportography and enhanced ultrasonography at the same time. Concerning the 61 patients undergoing all the procedures, the characteristics of hepatocellular carcinoma were found in 57.4% (35 of 61) by digital subtraction angiography, 75.4% (46 of 61) by computed tomographic arterioportography and 72.1% (44 of 61) by enhanced ultrasonography. Among them, four hepatocellular carcinomas were detected only by enhanced ultrasonography, three were diagnosed only by computed tomographic arterioportography and two were diagnosed by both of them. Except for six hemangioma nodules that were easily diagnosed only with angiography, four of 55 benign hepatic nodules (7.3%) showed false–positive findings suggestive of hepatocellular carcinoma with either computed tomographic arterioportography or enhanced ultrasonography. In conclusion, computed tomographic arterioportography and enhanced ultrasonography could complementarily detect a small hepatocellular carcinoma more sensitively than digital subtraction angiography. (Hepatology 1994;20:82-87.)
Serum 7α-Hydroxycholesterol Reflects Hepatic Bile Acid Synthesis in Patients With Obstructive Jaundice After External Biliary Drainage
Authors: Okamoto Shuichiro , Fukushima Kazuhisa , Higashijima Hidetaka , Makino Ichiro , Kishinaka Masanori , Oda Hitoshi , Yamashita Hiroyuki , Ichimiya Hitoshi , Chijiiwa Kazuo , Kuroki Syoji
Published: March 2007

ABSTRACT

To examine the hypothesis that serum levels of 7α–hydroxycholesterol reflect bile acid synthesis in the liver, we analyzed serum 7α–hydroxycholesterol and bile acid output in 13 patients with obstructive jaundice after relief of biliary obstruction. Before biliary drainage, the serum level of 7α–hydroxycholesterol was 92 ± 12 pmol/ml (mean ± S.E.M.) and was significantly lower than the control value (226 ± 26 pmol/ml, p<0.01). After biliary drainage, serum 7α–hydroxycholesterol level and biliary bile acid outputs began to rise in some patients, indicating reversible liver dysfunction. In other patients, serum 7α–hydroxycholesterol levels and bile acid outputs did not increase, suggesting severe or irreversible liver dysfunction. On and after the third day of biliary decompression, serum 7α–hydroxycholesterol levels correlated well with bile acid excretion (p<0.01, r=0.93). Other liver function parameters, such as serum bilirubin, serum bile acids, albumin, and bile flow, also revealed significant correlation with serum 7α–hydroxycholesterol levels. We conclude that the serum 7α–hydroxycholesterol level clearly reflects bile acid synthesis in the liver and that it may serve as a useful parameter for the assessment of hepatic functional recovery in patients with obstructive jaundice after biliary drainage. (Hepatology 1994;20:95-100.)
Predicting Recidivism After Orthotopic Liver Transplantation for Alcoholic Liver Disease
Authors: Osorio Robert W. , Ascher Nancy L. , Avery Mark , Bacchetti Peter , Roberts John P. , Lake John R.
Published: March 2007

ABSTRACT

With appropriate selection criteria, patients with end–stage alcoholic liver disease who undergo orthotopic liver transplantation have similar graft and patient survivals as patients undergoing transplantation for other causes. However, because of the possibility of recidivism after orthotopic liver transplantation there is still reluctance to transplant alcoholic patients. This study examined the association between pretransplant psychosocial variables and the risk of recidivism after orthotopic liver transplantation. At our institution, 43 patients received orthotopic liver transplantation for the referral diagnosis of alcoholic liver disease from February 1, 1988 to May 1, 1991. This represented 17% of all first transplants (43 of 257) performed during this period. Patients were interviewed before orthotopic liver transplantation by a single psychiatrist and responses to a defined set of questions were entered into a clinical database. All 43 patients diagnosed with alcoholic liver disease and a comparison group of patients transplanted for diagnoses other than alcoholic liver disease received a postoperative questionnaire regarding past and present alcohol use. Patients enrolled in the study all had at least 7 mo of follow–up, with the median follow–up being 21 mo. Eighty–six percent of alcoholic liver disease patients (37 of 43) and 86% of patients in the comparison group (37 of 43) of ALD patients agreed to participate in the study. Nineteen percent of alcoholic liver disease patients (7 of 37) and 24% of patients in the comparison group (9 of 37) admitted to having used alcohol after orthotopic liver transplantation, with 8% (3 of 37) and 11% (4 of 37) currently using alcohol, respectively. No association between amount or duration of alcohol used before liver transplantation and recidivism was found in patients with alcoholic liver disease. Binge use of alcohol, history of driving under the influence of alcohol, history of alcohol withdrawal, and other drug use also were not associated with recidivism in alcoholic liver disease patients. Patients who participated in in–patient or out–patient rehabilitation programs before or after transplantation, or who admitted they were alcoholics, had similar rates of recidivism. Being married, employed or having a history of psychiatric symptoms requiring treatment were not associated with recidivism rates in alcoholic liver disease patients. Finally, after multivariate analysis only one variable was associated with recidivism in alcoholic liver disease patients, sobriety less than 6 mo. These findings support the selection criterion of abstinence from alcohol for>6 mo before alcoholic liver disease patients undergo orthotopic liver transplantation. (Hepatology 1994;20:105-110.)
Collagen–Acetaldehyde Adducts in Alcoholic and Nonalcoholic Liver Diseases
Authors: Svegliati-Baroni Gianluca , Baraona Enrique , Rosman Alan S. , Lieber Charles S.
Published: March 2007

ABSTRACT

Alcoholic and, to a lesser extent, nonalcoholic patients with liver disease have serum antibodies to acetaldehyde–protein adducts produced

in vitro.

These antibodies presumably reflect the presence of adducts in the liver, but the protein that triggers this immune response has not been identified. To study this, we measured the reactivity of cytosolic proteins to rabbit IgG developed against a P–450 2E1—acetaldehyde adduct, isolated from alcohol–fed rats, that recognizes acetaldehyde–modified epitopes in proteins. Adducts were determined on Western blots by scanning densitometry of antibody–linked alkaline phosphatase activity in 4 normal livers and in needle biopsy specimens from subjects with liver disease, 17 alcoholic and 14 nonalcoholic. In all livers, except for a normal one, we found a reactive protein of at least 200 kD, similar to the collagen–acetaldehyde adduct we reported to be markedly increased in rats with experimentally induced cirrhosis. The immunostaining intensity in the alcoholic patients with liver disease was eightfold (p<0.01) and that in nonalcoholic patients with liver disease was fourfold, greater (p<0.02) than the weak staining in normal livers; it correlated with the degree of inflammation and serum AST or γ–glutamyl transpeptidase activities. The adduct was reproduced on incubation of normal cytosolic proteins with 2.5 mmol/L acetaldehyde, whereas higher concentrations yielded many additional adducts; the adduct also reacted with IgG antibody to rat collagen type I and disappeared after digestion with collagenase, suggesting that the target protein is a form of collagen. The association of this collagen–acetaldehyde adduct with parameters of liver disease activity suggests that the adduct reflects the liver injury and may even contribute to its development, both in alcoholic and in nonalcoholic subjects. (Hepatology 1994;20:111-118.)
Prognostic Significance of Diabetes in Patients With Cirrhosis
Authors: Bianchi Giampaolo , Marchesini Giulio , Zoli Marco , Bugianesi Elisabetta , Fabbri Andrea , Pisi Emilio
Published: March 2007

ABSTRACT

Alterations in carbohydrate metabolism are frequently observed in cirrhosis, and approximately 15% to 30% of patients have overt diabetes. In a retrospective and prospective study in cirrhosis, we analyzed the prognostic significance of diabetes, which was defined as the presence of hyperglycemia and overt glycosuria that in most cases required dietary restrictions or active treatment. The clinical records of all patients with cirrhosis admitted to our department for the period 1980 to 1985 were reviewed in 1985 and 1986, and surviving patients were prospectively followed up until December 1991. Final status could be obtained in 354 (98 with diabetes) of 382 eligible patients; 110 were alive at the end of follow–up. Prognostic factors were identified by Kaplan–Meier analysis, followed by Cox's stepwise regression. The model identified, in sequence, albumin, ascites, age, encephalopathy, bilirubin, diabetes, and platelets as prognostic factors. The larger mortality rate in patients with diabetes was not due to complications of diabetes but to an increased risk of hepatocellular failure. Diabetes was no longer a risk factor as a covariate in a subgroup of 271 patients when varices were added but was again significant when patients who died of gastrointestinal bleeding were excluded. The presence of diabetes, clinically detectable and often requiring adequate treatment, is a risk factor for long–term survival in cirrhosis. (Hepatology 1994;20:119-125.)
Primary Biliary Cirrhosis: Prediction of Short–Term Survival Based on Repeated Patient Visits
Authors: Murtaugh Paul A. , Dickson Rolland E. , Van Dam Gooitzen M. , Malinchoc Michael , Grambsch Patricia M. , Langworthy Alice L. , Gips Chris H.
Published: March 2007

ABSTRACT

The progression of primary biliary cirrhosis was studied in 312 patients who were seen at the Mayo Clinic between January 1974 and May 1984. Follow–up was extended to April 30, 1988, by which time 140 of the patients had died and 29 had undergone orthotopic liver transplantation. These patients generated 1,945 patient visits that enabled us to study the change in the prognostic variables of primary biliary cirrhosis (age, bilirubin value, albumin value, prothrombin time and edema) from the time of referral. Also, using this database and the Cox proportional–hazards regression model, we developed an updated model for primary biliary cirrhosis that can be used to predict short–term survival at any time in the course of the disease. This model uses the values of the prognostic variables measured at the latest patient visit. Comparison of predicted survival from the update model and the natural history model of primary biliary cirrhosis showed that the updated model was superior to the original model for predicting short–term survival. This finding applied to both the Mayo Clinic patients and an independent set of 83 Dutch patients. The Mayo updated model is recommended for improving the accuracy of predictions of survival during the 2 yr after a patient visit. (Hepatology 1994;20:126-134.
Skeletal Muscle Glycogen Content in Patients With Cirrhosis
Authors: Selberg Oliver , Radoch Eva , Walter Gerhard Franz , Müller Manfred James
Published: March 2007

ABSTRACT

We investigated stable cirrhotic patients for muscle glycogen content. Muscle biopsy samples were taken of 14 patients after overnight fasting. Electron microscopy showed normal intracellular distribution of glycogen (n=8). Muscle glycogen concentration was 16.5 ± 7.1 gm/kg wet muscle weight (normal range, 10 to 20 gm/kg). Basal, early postabsorptive, exerciseinduced and insulin–induced respiratory quotients as well as insulin sensitivity (euglycemic clamp technique, 7.2 pmol insulin/kg body weight/min) and glucose tolerance were assessed. The glucose disposal rate was 23.0 ± 10.1 μmol/kg/min (mean ± S.D.), indicating moderate insulin resistance in these patients. We found no association between basal muscle glycogen content and basal or postprandial respiratory quotient, insulin sensitivity, nutritional status or glucose tolerance. However, there was a positive correlation between muscle glycogen content and exercise, as well as insulin–induced respiratory quotient (r=0.651, p<0.03 and r=0.587, p<0.03, respectively). We conclude that postabsorptive muscle glycogen stores, which are effectively maintained in patients with cirrhosis, are one determinant of exercise–induced and insulin–induced whole body fuel metabolism in these patients. (Hepatology 1994;20:135-141.)
Prostaglandin F2α and D2 Release From Primary Ito Cell Cultures After Stimulation With Noradrenaline and Atp But Not Adenosine
Authors: Athari Annette , Hänecke Kristina , Jungermann Kurt
Published: March 2007

ABSTRACT

Rat liver Ito cells were cultured for 24 hr with 20% newborn calf serum. Stimulation with the sympathetic neurotransmitter noradrenaline (0.1 μmol/L to 1 mmol/L) led to a dose–dependent increase in prostaglandin F2α release and a slightly smaller enhancement of prostaglandin D2 production. Prostaglandin F2α and prostaglandin D2 release strongly. The relase was highest again during the first 30 sec. stimulation. Stimulation with the possible cotransmitter ATP (10 μmol/L and 1 mmol/L ATP) also enhanced both prostaglandin F2α and prostaglandin D2 release strongly. The release was highest again during the first 30 sec. Stimulation with noradrenaline and ATP simultaneously did not increase the effects of noradrenaline or ATP alone. Adenosine had no effect on prostaglandin production. The effects of noradrenaline were inhibited specifically by the α1–adrenoreceptor antagonist prazosin but not by the p1–purinoreceptor antagonist 8–phenyltheophylline. The effects of ATP were not antagonized by the inhibitors. Because the metabolic actions of sympathetic hepatic nerves can be inhibited by inhibitors of prostanoid synthesis and mimicked by prostaglandins F2α and D2, and because the Ito cells are well innervated, our results permit the conclusion that Ito cells could be involved in the nervous signal chain: During sympathetic nerve action the neurotransmitter noradrenaline and the cotransmitter ATP cause increases in prostaglandin F2α and prostaglandin D2 release from Ito cells within 30 to 60 sec by way of α1 and p2 receptors, respectively. The released prostaglandins then activate glycogenolysis in the hepatocytes proper. (Hepatology 1994;20:142-148.)
Reduced Expression of Glutathione S–Transferase Yb2 During Progression of Chemically Induced Hepatocellular Carcinomas in Fischer 344 Rats
Authors: Stalker Margaret J. , Kocal Trudy E. , Quinn Bette Anne , Gordon Sonya G. , Hayes Anthony M.
Published: March 2007

ABSTRACT

We followed the expression of several glutathione S–transferase subunits in altered foci, liver neoplasms and metastases produced in male Fischer 344 rats by a modified Solt–Farber protocol, to determine whether components of the resistant phenotype are lost during neoplastic progression. At 6 mo after initiation, altered foci and persistent nodules displayed increased immunohistochemical expression of glutathione S–transferase subunits Yf (π–class), Ya (α–class) and Yb1 (μ–class) in comparison with normal or surrounding liver tissue. However, although most altered foci exhibited little change in glutathione S–transferase Yb2 (μ–class) subunit expression, 5% of Yf–positive foci and nodules were partially or completely deficient in Yb2 expression. At 12 and 18 mo after initiation, most grossly visible hepatocellular tumors retained induced expression of glutathione S–transferase subunits Yf, Ya and Yb1, but 63% of the carcinomas, 88% of the primary metastatic carcinomas and 94% of the pulmonary metastases were deficient in Yb2 expression. These differences in glutathione S–transferase subunit expression were confirmed by quantitative analysis by reverse–phase HPLC of S–hexylglutathione affinity–purified glutathione S–transferases from advanced tumors. Cytosolic glutathione S–transferase activity for

trans

–4–phenyl–3–buten–2–one in advanced tumors ranged from 42% to 66% of the activity in matched surrounding liver, whereas glutathione S–transferase activities for 1–chloro–2,4–dinitrobenzene were increased by 140% to 161%. These studies demonstrate that progression of hepatocellular carcinomas in the resistant hepatocyte model of carcinogenesis in which several glutathione S–transferase subunits are induced is associated with the loss of a major constitutive μ–class hepatic glutathione S–transferase. Although the mechanism and role of the reduction or loss of glutathione S–transferase Yb2 during malignant progression are unknown, we propose that loss of glutathione S–transferase Yb2 in some preneoplastic populations of hepatocytes might be conducive to further DNA damage by presently unknown environmental or endogenous compounds that are normally detoxified preferentially by glutathione S–transferase isoenzymes containing this subunit. (Hepatology 1994;20:149–158.)
Beneficial or Adverse Effects of Hepatectomy Vs. Ethanol Injection Therapy in Rbt–1 Carcinoma of the Rat Liver
Authors: Ikeda Yasuharu , Matsumata Takashi , Hayashi Hiroshi , Taketomi Akinobu , Yamamoto Kazuharu , Sugimachi Keizo
Published: March 2007

ABSTRACT

In an attempt to ascertain the possible beneficial or adverse effects of ethanol injection into a hepatic malignant tumor, we carried out a series of experiments using the RBT–1 carcinoma. Ten days after the inoculation of RBT–1 carcinoma into the rat livers, the animals were separated into four groups: group A received a sham operation, group B had ethanol injections directly into the hepatic tumor, group C underwent tumor removal and group D underwent tumor removal 20 min after ethanol injection. When a comparison was made with all groups, survival time was significantly longer in group B than in A (p<0.01), group C than A (p<0.01) and group C than B (p<0.01). The incidence of vascular permeation of liver tumor cells into the hepatic vein was significantly higher in group D than C (p<0.05). Twenty days after initial injection of RBT–1 tumor, 10 rats in each group were killed, and their lungs were assessed for evidence of metastatic spread of tumor. The number of metastatic nodules in the lungs was significantly increased in those rats that had undergone intrahepatic ethanol injection vs. those that had not (group B vs. A [p<0.05] and group D vs. C [p<0.05]). The number of metastatic nodules in the lungs differed significantly in those rats that had undergone hepatectomy vs. those that had not. These results are taken to mean that hepatectomy and ethanol injection into a tumor was an effective therapy. However, we believe ethanol injection into hepatic tumors may increase the risk of metastasis and should not, at present, be recommended in those patients who have operable liver cancer. (Hepatology 1994;20:166-169.)