bluuebunny/crossref_metadata_2025 huggingface dataset:
Ito–Cell Gene Expression and Collagen Regulation
Authors: Weiner Francis R. , Giambrone Marie-Adele , Czaja Mark J. , Shah Anish , Annoni Giorgio , Takahashi Shizuko , Eghbali Mahboubeh , Zern Mark A.
Published: March 2007

Ito cells are perisinusoidal cells thought to be a major source of collagen in normal and fibrotic livers. These cells appear to have features similar to several cell types but when cultured assume a fibroblast–like morphology. In this study we evaluated the phenotype of both freshly isolated and cultured Ito cells by examining their gene expression. To better define the modulators of Ito–cell collagen synthesis, we also examined the effect of transforming growth factor–β1, tumor necrosis factor–α and dexamethasone on collagen synthesis by these cells. Northern hybridization analysis revealed that cultured Ito cells expressed different types of procollagen mRNAs than did freshly isolated cells. Cultured cells contained large amounts of type I procollagen mRNA and lesser amounts of types III and IV, whereas freshly isolated cells contained more type IV procollagen mRNA than types I and III. Treatment of cultured cells with either transforming growth factor–β1 or tumor necrosis factor–α resulted in a greater than threefold increase in total collagen content, and the effects of these cytokines on Ito–cell collagen synthesis involved different levels of gene regulation. Transforming growth factor–β1–treated cells had an approximately threefold increase in their type I procollagen mRNA levels, whereas no increase in this mRNA level was found in tumor necrosis factor–α–treated cells. Transforming growth factor–β1 treatment induced a twofold increase in transforming growth factor–β1 mRNA content in cultured cells. In contrast to transforming growth factor–β1, dexamethasone inhibited type I procollagen and transforming growth factor–β1 mRNA content by at least twofold in cultured cells. These results suggest that cultured Ito cells alter their collagen gene expression such that they become phenotypically more fibroblast–like. Furthermore, transforming growth factor–β1's induction of its own mRNA in Ito cells suggests that these cells are capable of amplifying their collagen synthesis. Finally, the inhibition of transforming growth factor–β1 and procollagen type I gene expression by dexamethasone suggests another way steroids may be beneficial in the treatment of certain forms of chronic liver disease.
Absence of Growth–Hormone Receptor in Hepatocellular Carcinoma and Cirrhotic Liver
Authors: Chang Tien-Chun , Lin Jyh-Jian , Yu Shan-Chang , Chang Tien-Jye
Published: March 2007

Hepatocellular carcinoma is a hormone–sensitive tumor. It has been reported that thyroxine and prolactin significantly stimulated hepatoma growth, whereas growth hormone failed to do so. To learn whether the growth hormone receptor is present in human hepatocellular carcinoma, we used radioreceptor assays in samples of human hepatocellular carcinoma. The liver tissues adjacent to hepatocellular carcinoma (mostly cirrhotic) and control liver tissues (taken during various surgical procedures) were also studied. The study results showed that the affinity constant and capacity of high–affinity growth hormone receptor in normal liver tissues were 6.6 ± 2.0 × 1010 mol/L-1 (mean ± SE, n = 7) and 20.7 ± 11.5 fmol/mg protein, respectively. The affinity constant and capacity of low–affinity growth hormone receptor in normal liver tissues were 8.9 ± 3.3 × 109 mol/L-1 and 64.7 ± 32.1 fmol/mg protein, respectively. The absence of growth hormone receptor in human hepatocellular carcinoma and cirrhotic liver samples may explain the absence of growth hormone in the stimulation of hepatoma growth and the decrease of somatomedin levels in cirrhosis. (HEPATOLOGY 1990; 11: 123-126)
Purine Nucleoside Phosphorylase: A New Marker for Free Oxygen Radical Injury to the Endothelial Cell
Authors: Rao Prakash N. , Walsh Thomas R. , Makowka Leonard , Rubin Randy S. , Weber Thomas , Snyder James T. , Starzl Thomas E.
Published: March 2007

The effect of ischemia and reperfusion on purine nucleoside phosphorylase was studied in an isolated perfused rat liver model. This enzyme is localized primarily in the cytoplasm of the endothelial and Kupffer cells; some activity is associated with the parenchymal cells. Levels of this enzyme accurately predicted the extent of ischemia and reperfusion damage to the microvascular endothelial cell of the liver. Livers from Lewis rats were subjected to 30, 45 and 60 min of warm (37° C) no flow ischemia that was followed by a standard reperfusion period lasting 45 min. Purine nucleoside phosphorylase was measured at the end of the no flow ischemia and reperfusion periods as was superoxide generation (O2–). Bile production was monitored throughout the no flow ischemia and reperfusion periods. Control perfusions were carried out for 120 min. A significant rise in purine nucleoside phosphorylase levels as compared with controls was observed at the end of ischemia in all the three groups. The highest level, 203.5 ± 29.2 mU/ml, was observed after 60 min of ischemia. After the reperfusion period, levels of purine nucleoside phosphorylase decreased in the 30– and 45–min groups 58.17 ± 9.66 mU/ml and 67.5 ± 17.1 mU/ml, respectively. These levels were equal to control perfusions. In contrast, after 60 min of ischemia, levels of purine nucleoside phosphorylase decreased early in the reperfusion period and then rose to 127.8 ± 14.8 mU/ml by the end of reperfusion (p < 0.0001). Superoxide generation at the beginning of reperfusion was higher than in controls with similar values observed at the end of 30, 45 and 60 min of ischemia. During reperfusion, production of superoxide continued. Bile production was significantly lower at the end of 30 min (0.044 ± 0.026 μl/min/gm), 45 min (0.029 ± 0.0022 μ/min/gm) and 60 min of ischemia (0.022 ± 0.008 μ/min/gm) when compared with bile production by control livers during the corresponding time (0.680 ± 0.195, 0.562 ± 0.133 and 0.480 ± 0.100 μ/min/gm respectively; p < 0.001). During reperfusion, rates of bile production were normal after 30 and 45 min of ischemia. In contrast, significantly lower rates of bile production, 0.046 ± 0.36 μ/min/gm (p < 0.001) occurred during reperfusion after 60 min of ischemia. Control livers during the same period produced 0.330 ± 0.056 μl/min/gm of bile. The results indicate that purine nucleoside phosphorylase levels may be a good index of oxidative injury to the liver in ischemia reperfusion and reliably predict the functional state of the organ after reperfusion.
Role of Cholecystokinin and the Cholinergic System in Intestinal Stimulation of Gallbladder Contraction in Man
Authors: Hopman Wim P.M. , Jansen Jan B.M.J. , Rosenbusch Gerd , Lamers Cornelis B.H.W.
Published: March 2007

To determine the role of cholecystokinin and the cholinergic system in intestinal stimulation of gallbladder contraction, we studied the effects of atropine on plasma cholecystokinin and gallbladder contraction in six healthy volunteers (four men and two women aged 20 to 27 yr). Effects were noted after intraduodenal fat instillation and after dosage with exogenous cholecystokinin inducing plasma cholecystokinin concentrations similar to those after intraduodenal fat instillation. At regular intervals before and after administration of each stimulus, plasma cholecystokinin concentrations and gallbladder volumes were measured by radioimmunoassay and real–time ultrasonography, respectively. Intraduodenal infusion of 250 ml 20% Intralipid induced a peak plasma cholecystokinin increment of 10.2 ± 1.6 pmol/L compared with 10.7 ± 0.7 pmol/L during infusion of 1 Ivy dog unit per kilogram per hour of cholecystokinin. The increases in plasma cholecystokinin after fat and exogenous cholecystokinin administration were accompanied by similar decreases in gallbladder volume. Integrated gallbladder contraction after fat instillation was 3,939% ± 288%. min compared with 3,301% ± 359%. min during cholecystokinin infusion (NS). Atropine (0.015 mg/kg as bolus followed by 0.005 mg/kg/hr) did not change plasma cholecystokinin concentrations but induced similar inhibition of gallbladder contraction to 2,296% ± 511%. min (p < 0.05) after intraduodenal fat instillation and to 1,756% ± 456%. min (p < 0.05) during cholecystokinin infusion. We conclude that cholecystokinin is of major importance in intestinal stimulation of gallbladder contraction. Atropine inhibits the gallbladder response to intraduodenal fat. This inhibition is not due to a reduction in cholecystokinin secretion but to a diminished gallbladder response to cholecystokinin.
Therapy of Chronic Hepatitis B With Recombinant Human Alpha and Gamma Interferon
Authors: Di Bisceglie Adrian M. , Rustgi Vinod K. , Kassianides Chris , Lisker-Melman Mauricio , Park Yoon , Waggoner Jeanne G. , Hoofnagle Jay H.
Published: March 2007

Eight patients with chronic hepatitis B entered a pilot study of gamma interferon and alpha interferon in combination. Gamma interferon alone had minimal inhibitory effects on serum levels of hepatitis B virus as monitored by serum HBV DNA and DNA–polymerase activity. The drug also gave troublesome side effects. In contrast, alpha interferon had more potent inhibitory effects on serum HBV levels and fewer side effects. When combined, the two interferons showed no additive or synergistic effects in inhibiting serum levels of HBV DNA or DNA polymerase. These findings indicate that the addition of gamma interferon to alpha interferon provides no additional antiviral effects but contributes significantly to side effects.
Molecular Characterization of A New Variant of Hepatitis B Virus in A Persistently Infected Homosexual Man
Authors: Bhat Ramesh A. , Ulrich Paul P. , Vyas Girish N.
Published: March 2007

Based on the diversity of nucleotide sequences of cloned hepatitis B virus DNA genomes, we have predicted possible replication of genetic variants of human hepatitis B virus. This prediction is exemplified by studies of a chronic carrier of HBsAg/adw2, who lacked anti–HBc but carried exceedingly high levels of hepatitis B virus DNA in serum. Molecular characterization of a number of clones revealed a restriction map that deviated significantly from the typical pattern of the adw2 subtype, especially around the EcoRI site commonly used as a reference point. Mutations appearing consistently in the precore and core regions included (a) mutation in the precore region resulting in a termination codon after the initiation codon, (b) mutation of the core initiation codon and (c) an inframe insert of 36 nucleotides in the precore region with a new initiation site for the core protein.

The 36–nucleotide insertion resulted in a new core protein with 12 extra amino acids at its amino–terminal end. A few scattered point mutations were clustered in the amino–terminal half of the core gene. Although the core protein of this hepatitis B virus variant carried immunologically detectable HBcAg, the absence of a humoral immune response to HBcAg could have been caused by previous infection with human immunodeficiency virus. This naturally occurring human hepatitis B virus variant replicated efficiently without expressing the precore region, confirming previous observations made of the artificial mutants of duck hepatitis B virus.
Hepatis C Virus: A Giant Leap Forward
Authors: Zuckerman Arie J.
Published: March 2007

A random–primed complementary DNA library was constructed from plasma containing the uncharacterized non–A, non–B hepatitis (NANBH) agent and screened with serum from a patient diagnosed with NANBH. A complementary DNA clone was isolated that was shown to encode an antigen associated specifically with NANBH infections. This clone is not derived from host DNA but from an RNA molecule present in NANBH infections that consists of at least 10,000 nucleotides and that is positive–stranded with respect to the encoded NANBH antigen. These data indicate that this clone is derived from the genome of the NANBH agent and are consistent with the agent being similar to the togaviridae or flaviviridae. This molecular approach should be of great value in the isolation and characterization of other unidentified infectious agents.

A specific assay has been developed for a blood–borne non–A, non–B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post–transfusion NANBH (PT–NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.
Recurrence Factors Studied by Percutaneous Transpepatic Portography Before and After Endoscopic Sclerotherapy for Esophageal Varies
Authors: Takase Yasuhiro , Shibuya Susumu , Chikamori Fumio , Orii Kazuo , Iwasaki Yoji
Published: March 2007

High recurrence and rebleding rates have been reported when endocopic sclerotherapy has been performed on patients with esophageal varices. We studied the relationship between embolization range and recurrence rate in 26 patients in whom percutaneous transhepatic portography was carried out before and after sclerotherapy. Patients were divided into complete and incomplete embolization groups. The complete and incomplete embolization groups. The complete embolization group consisted of 16 patients whose esophageal varices had disappeared and in whom embolization of the feeders to the varices had occurred. The incomplete embolization group consisted of 10 patients whose esophageal varices had disappeared, but no embolization had occurred. Recurrence rates within 2 yr after the treatment were compared between complete and incomplete embolization groups. The recurence rates in the respective groups were 6.7% (1 of 15) and 70.0% (7 of 10), indicating a significant difference between the two groups (p < 0.05) and indicating that embolization of both esophageal varices and their feeders is essential to lower the recurrence rate after sclerotherapy. (Hepatology 1990;11:348-352.)
Energy Metabolism in Patients With Acute and Chronic Liver Disease
Authors: Schneeweiss Bruno , Graninger Wolfgang , Ferenci Peter , Eichinger Sabine , Grimm Georg , Schneider Barbara , Laggner Anton N. , Lenz Kurt , Kleinberger Gunter
Published: March 2007

Energy expenditure and substrate oxidation rate for fat, glucose and protein were evaluated by indirect calorimetry in 20 normal individuals, 35 patients with acute hepatitis and 22 patients with biopsyproven alcoholic cirrhosis in the postabsorptive state. Measurements were done in the resting state after an overnight fast (10 to 12 hr). Oxygen consumption (ml/min/1.73 m2) in normal subjects, in patients with acute hepatitis and in patients with cirrhosis was 206.5 ± 4.0 (mean ± S. E. M.), 216.4 ± 4.7 and 228.8 ± 7.1 (p < 0.05 vs. controls), respectively. When related to body surface area (Kcal/min/1.73 m2), resting energy expenditure did not differ between normal subjects (0.98 ± 0.02), patients with acute hepatitis (1.03 ± 0.02) and cirrhotic patients (1.06 ± 0.03). However, when related to 24–hr urinary creatinine excretion as an estimate of lean body mass, energy expenditure was in creased in cirrhosis (p < 0.0001). In cirrhosis an inverse association between the severity of liver disease according to Pugh and oxygen consumption and resting energy expenditure was found. In cirrhotic patients the percentages of total calories derived from fat (86% ± 5%), carbohydrate (2% ± 4%) and protein (12% ± 1%) were different from those of normal controls who metabolized 45% ± 4%, 38% ± 4%, 17% ± 1%, respectively. In acute hepatitis no alterations in metabolism could be found apart from a decreased protein oxidation rate.

In conclusion no appreciable changes in energy metabolism exist in acute hepatitis. The pattern of fuel use in cirrbosis resembles that in starvation. Data on resting energy expenditure depend on the calculations used. Resting energy expenditure was not increased in either group when related to body surface area. An inverse association between the severity of liver disease and energy expenditure was found in cirrhosis. (Hepatology 1990;11:387-393.)
Transferrin Receptor Expression in Rat Liver: Immunohistochemical and Biochemical Analysis of the Effect of Age and Iron Storage
Authors: Sciot Raf , Verhoeven Guido , van Eyken Peter , Cailleau Jean , Desmet Valeer J.
Published: March 2007

Hepatic transferrin receptors were studied in normal male rats at 1 to 59 wk after weaning, using immunohistochemical and biochemical techniques. The number of transferrin receptors measured and the intensity of the staining in situ decreased rapidly during the first 10 wk of life and more slowly thereafter. Immunohisto–chemistry further demonstrated changes in the topographical and (sub)cellular localization of the transferrin receptor. In the young rat livers, staining was almost exclusively present on hepatocytes in acinar zone 2 + 3 in a boneycomb to sinusoidal pattern. With aging, a panacinar heterogeneous and mainly sinusoidal staining of hepatocytes was more frequent. Kupffer cell positivity was more obvious as compared with the young rat livers. The observed changes in transferrin receptor expression may partly be explained by age–dependent alterations in DNA synthesis and proliferative potential of the liver cells. A series of rats were iron loaded with carbonyl iron up to 39 wk and “unloaded” by administration of a normal diet during 20 wk. In these animals, serial histochemical studies showed predominantly parenchymal (7 to 14 wk), mixed parenchmal and reticuloendothelial (39 wk) and almost exclusive reticuloendothelial siderosis (59 wk). In the siderotic livers transferrin receptor numbers tended to be lower than in the controls with significant differences after 14 and 39 wk. Immunohistochemistry showed decreased parenchymal but increased reticuloendothelial transferrin receptor expression with iron load. After the period of unloading, parenchymal transferrin receptors were virtually absent despite the negligible siderosis of these cells. In contrast, siderotic reticuloendothelial cells were intesely positive. These findings support down–regulation of parenchymal transferrin receptor resulting from iron storage. However, the positivity of siderotic reticuloendothelial cells and the absence of reemergence of parenchymal receptors in conditions of minimal parenchymal and prominent reticuloendothelial siderosis need further elucidation.(Hepatology 1990;11:416-427.)
The Hepatocyte Protein Synthesis Defect Induced by Galactosamine Involves Hypomethylation of Ribosomal Rna
Authors: Clawson Gary A. , Sesno Julie , Milam Kathy , Wang Yan-Fel , Gabriel Caroline
Published: March 2007

d–galactosamine produces an early defect in protein synthesis, independent of its effects on RNA synthcsis. Here we show that the defect in protein synthesis is inherent in purified ribosomal subunits in vitro. Furthere, galactosamine treatment is associated with an 85% decrease in methylation of ribosomal RNA, involving all sites (2′–0–ronpse and base positions), intact ribosomes from galactosamine–treated animals can be methylated to a greater extent than control ribosomes and in vitro methylation restores their funtional capacity. Statistical analyes of these data, along with those with a number of other hepatotoxins, reveal a correlation coefficent of r = 0.95 (p < 0.003) between protein synthetic capacity and ribosomal RNA methylaiton, and linear regression accounts for more than 90% of the observed variation. In contrast, no relationship was found between nucleolar RNA methylation and protein synthetic capacity. A relationship of borderline statistical significance was found between messenger RNA methylaiton and protein synthetic capacity, but it does not appear consistent with results obtained after CCI4 intoxication. These results lend strong support ot the notion that methylation status of ribosomal RNA is an important control for protein synthesis in quiscent hepatocytes and that net hypomethylation is a common responses to such divergent hepatotoxins as CCI4, ethionine and d–galactosamine. (Hepatology 1990;11:428-434.)
The Relevance of the Order of Revascularization in Liver Grafting
Authors: Hickman Rosemary , Innes Cath Rose
Published: March 2007

A study was conducted comparing the effects of initial arterialization vs. initial portal revascularization in unstored warm ischemic (for 30 min) livers, livers stored for 4 hr at 0° C in Collins solution and livers rendered warm ischemic for 1 hr before removal and replacement as autografts. All livers that received initial arterialization showed uniform diffuse perfusion, whereas those with initial portal perfusion were patchy and well perfused only in the right lobe. In the experimental animal, initial arterialization using an end–to–end method was much casier and required less retraction.

The energy charge and ATP levels dropped sharply during brief warm ischemia but returned rapidly to normal on revascularization. Although the decline in energy charge was less in stored livers, the return to normal was slower and incomplete. Plasma levels of AST indicated much greater damage in the stored livers and were lowest in recipients in unstored livers that were arterialized first. After longer warm ischemia, energy charge values declined and only completely returned to 60% of preoperative values within 2 hr of grafting. Despite this, the survival rate of these animals was very poor and only one survived overnight. Seven of the 12 survived the procedure, but in five death occurred within 30 min of full revascularization. In this group, AST levels rose sharply after revascularization to a mean level of 1,000 U. The resutls suggest that while initial arterizlization is beneficial if brief warm ischemia has occurred, it has no advantages other than improved subjective appearance of the liver and ease of performance after a 4–hr period of cold storage. Neither order of revascularization reversed the damage caused by 1 hr definitive warm ischemia. Although the advantages were limited, there were no appearent detrimental effects of primary arterialization and thus this order could be undertaken if so desired.(Hepatology 1990;11:471-476.)
Development of Colon Cancer After Liver Transplantation for Primary Sclerosing Cholangitis Associated With Ulcerative Colitis
Authors: Higashi Hidefumi , Yanaga Katsuhiko , Marsh Wallis J. , Tzakis Andreas , Kakizoe Saduro , Starzi Thomas E.
Published: March 2007

Between February 26, 1981, and July 30, 1987, 36 patients underwent orthotopic liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis. Three of the 36 recipients died within 3 mo because of graft nonfunction or surgical complications. The other 33 (92%) lived for at least 1 yr. Two of the 33 died after 12 and 14 mo, respectively, of recurrent cholangiocarcinoma that was not diagnosed before transplantation. Four other patients died of recurrent liver failure (three cases) or immunoblastic sarcoma (one case) after 14, 21, 36 and 44 mo. Twenty–seven (75%) of the patients are still alive 23 to 81 mo after transplantation. Two patients have been diagnosed as having colorectal cancer 11 and 21 mo respectively, after transplantation, for an overall incidence of 5.6% (2 of 36) and a corrected incidence of 6.5% (2 of 31) if the three early deaths and two later deaths caused by cholangiocarcinomas are excluded. It is not known whether colorectal malignancies were present but undetected at the time of transplantation or whether they developed afterward. It is clear that patients who undergo liver transplantation for primary sclerosing cholangitis associated with ulcerative colitis should have careful follow–up of the colon, including colonoscopy and multiple biopsies of the colorectal mucosa. Whether proctocolectomy should be considered prophylactically after liver transplantation is an unresolved issue.(Hepatology 1990;11:477-480.)
Liver Dissection in Hepatic Surgery: Ultrasound Vs Water Jet Vs Suction Knife
Authors: Jeppsson Bengt
Published: March 2007

A simple, inexpensive alternative method of blunt dissection for dividing liver parenchyma utilizing a suction knife is presented. The device, made from an ordinary suction tube, has been used successfully in six patients. Details of the device and method are discussed herein.
Hyperprolinemia and Lactatemia in Alcoholic Liver Disease: Relationships to Abstinence and Histological Findings
Authors: Rojking Marcos
Published: March 2007

It has not yet been established whether serum proline and blood lactate levels are increased in alcoholic liver disease. We measured serum proline and blood lactate in controls and in patients with different stages of alcoholic liver disease in the absence of hepatic failure. Samplings were done in both abstinent and drinking alcoholics. Compared to controls, there was a striking increase in serum proline levels in 52 abstinent alcoholics with little or no hepatic fibrosis by histological assessment (0.10 ± 0.01 vs. 0.155 ± 0.008; p < 0.005). Blood lactate levels were within the normal range and did not correlate with serum proline levels. On the other hand, serum proline and blood lactate levels were independent of hepatic necrosis and inflammation scores. In addition, in 10 patients with blood alcohol concentrations between 0.3 mg/ml and 7.8 mg/ml, serum lactate and proline were significantly elevated (2.42 ± 0.29 mg/ml and 0.275 ± 0.0026 mg/ml, respectively; p < 0.005). These results show that there is an association between serum proline levels and the abstinence period in alcoholic patients. They further suggest that in alcoholic patients neither serum proline nor blood lactate concentrations are reliable markers for liver histological activity (necrosis and Inflammation) or fibrosis.
Estrogen Induction of Hepatocellular Carcinomas in Armenian Hamsters
Authors: Coe John E. , Ishak Kamal G. , Ross Mary Jane
Published: March 2007

Liver tumors were found in most Armenian hamsters (Cricetulus migratorius) injected with on 15–mg pellet of diethylstilbestrol. The tumors were detectable as early as 1.5 mo after diethylstilbestrol administration and were usually present as multiple nodules that progressively increased in size. Histologically, the multicentric neoplasms were all hepatocellular carcinomas of varied degrees of differentiation and frequently (42.8%) contained Mallory bodies; preneoplastic lesions were not observed. This hepatocellular carcinoma hamster model is unique because estrogen alone without any other known mutagen is responsible for induction of hepatocellular carcinoma.(HEPATOLOGY 1990; 11:570:577.)
Autoantibodies to Human Asialoglycoprotein Receptor in Autoimmune–Type Chronic Hepatitis
Authors: Treichel Ulrich , Poralla Thomas , Hess Georg , Manns Michael , Büschenfelde Karl-Hermann Meyer Zum
Published: March 2007

Autoantibodies to the human asialoglycoprotein receptor (anti–h–ASGPR) were studied with a solid–phase ELISA in the sera of 421 patients with inflammatory liver diseases, 288 patients with various other disorders and 31 controls. Anti–h–ASGPR were found predominantly in autoimmune chronic active hepatitis (44 of 88, 50%) and were closely related to inflammatory activity. In a subpopulation of these patients with untreatd, biopsy–proven active disease or replase, 15 of 17 were positive (88%). In contrast, only 11 of 204 patients (5.3%) with viral hepatitis were Anti–h–ASGPR receptors–positive (x2 analysis; p < 0.001). We also compared the occurrence of Anti–h–ASGPR with antibodies to rabbit and rat asialoglycoprotein receptors in 352 sera. In contrast to the anti–human asialoglycoprotein receptor antibodies (3 of 107), anti–rabbit– or anti–rat–asialoglycoprotein receptor antibodies were found in 21 and 28 of 107 cases of viral hepatitis, indicating that different epitopes were recognized by these sera. In various other diseases anti–human asialoglycoprotein receptor antibodies were rarely found. Some sera from patients with connective–tissue diseases (8 of 73) and primary or secondary liver malignancies (6 of 55) exihibited Anti–h–ASGPR. In autoimmune chronic active hepatitis the presence of anti–human asialoglycoprotein receptors did not correlate to other established autoantibody systems. Thus we conclude that anti–human asialoglycoprotein receptor antibodies can serve as diagnostic markers for inflammatory active cases of autoimmune chronic active hepatitis. Immune reactions to the asialoglycoprotein receptor, which is expressed on the hepatocellular receptor, which is expressed on the hepatocellular membrane as a liver specific antigen, might contribute to the pathogenesis of autoimmune chronic active hepatitis.(HEPATOLOGY 1990; 11:606:612.)
Effects of Streptozotocin Diabetes in the Rat on Blood Levels of Ten Specific Plasma Proteins and on Their Net Biosynthesis by the Isolated Perfused Liver
Authors: Miller Leon L. , Treat Donna Eddy , Fridd Bruce , Wemett Drusilla
Published: March 2007

Adult male Sprague–Dawley rats with streptozotocin–induced diabetes (6 to 8 wk duration), treated or untreated with insulin, were studied with two aims: (a) to ascertain whether protracted diabetes in the rat is associated with changes in circulating plasma protein levels analogous to those reported in human diabetic patients with clinical evidence of complications; (b) to evaluate the effects of experimental diabetes on the net cumulative biosynthesis of 10 specific plasma proteins by the isolated liver, perfused for 24 hr.

Samples of liver donor plasma and samples of perfusate were analyzed by single radial immunodiffusion or by rocket immunoelectrophoresis for albumin, α1–macroglobulin and the acute phase glycoproteins: fibrinogen, α1–acid glycoprotein (Darcy), α1, acid glycoprotein (Kawasaki), haptoglobin, α2–(acute phase) globulin, hemopexin, C3–complement and ceruloplasmin.

Diabetes (6 to 8 wk), untreated with insulin, resulted in significantly increased liver donor plasma levels of α1–acid glycoprotein (Darcy) and α1–acid glycoprotein (Kawasaki); plasma levels of hemopexin and of C3 decreased to 75% and 30% of normal, respectively. Insulin treatment of diabetic liver donors for 6 to 8 wk prevented the increase in α1–acid glycoprotein (Darcy) and α1–acid glycoprotein (Kawasaki) and minimized the decrease in C3 to 75% of normal.

Perfused livers from untreated diabetic rats (6 to 8 wk) showed slightly decreased cumulative synthesis and secretion of α1–acid glycoprotein (Darcy); however, synthesis of albumin was reduced to 35% of normal and that of eight glycoproteins ranged from 25% of normal and that of eight glycoproteins renged from 25% of normal (fibrinogen) to 12% of normal (C3). The striking in vitro induction of increased synthesis of acute–phase proteins by cortisol plus insulin in the isolated perfused normalliver was in contrast to the severely attenuated induction in perfused livers of untreated diabetic rats, which ranges from 50% of normal for α1–acid glycoprotein (Darcy) to 5% of normal (C3).

Severely negative perfusate nitrogen balance and impaired glucose utilization by perfused untreated diabetic livers contrasted with positive nitrogen balance and good glucose utilization of normal livers in response to insulin plus cortisol. The plasma protein synthetic capacity and the in vitro response to insulin plus cortisol of perfused livers from insulin–treated diabetic rats were normal for seven of the proteins but moderately decreased for albumin, haptoglobin and C3.(HEPATOLOGY 1990; 11:635–645.)
Inhibition of Hbv Replication During Coinfection With Hbv and Hdv: Inhibition of the Inhibition by Coinfection With Hiv
Authors: Govindarajan Sugantha
Published: March 2007

The clinical course, changes in liver function tests and the behaviour of viral markers over the course of time have been examined in 45 patients with acute hepatitis B and 14 patients with acute hepatitis caused by B and D viruses coinfection. There were no significant differences, either in the clinical course or in the liver function tests, in the two groups. The changes in serum viral markers were as follows: HBV–DNA was the first marker to disappear; this was closely followed by HBeAg, and HBsAg was the last marker to become negative, during convalescence. This pattern was not altered by Delta coinfection. When we quentified serum HBV–DNA in both groups of patients, we found that Delta virus infection led to partial inhibition of HBV replication, so that serum HBV–DNA levels were significantly lower in those patients with acute hepatitis B who were simultaneously infected with Delta virus.
Endothelial Cell Transformation in Primary Biliary Cirrhosis: A Morphological and Biochemical Study
Authors: Babbs Christopher , Haboubi Najib Y. , Mellor Jonathan M. , Smith Alexander , Rowan Brenda P. , Warnes Thomas W.
Published: March 2007

There is increasing interest in the changes of the endothelial lining of the hepatic sinusoids during the development of chronic liver disease. In this study we looked for evidence of hepatic sinusoidal endothelial cell transformation and basement membrane production in patients with primary biliary cirrhosis.

Morphological transformation to vascular–type endothelial cells, as evidenced by the development of positive immunohistochemical staining for factor VIII–related antigen, was seen at the interface between portal tracts or fibrous septae and hepatic parenchyma; the most marked changes were observed in patients with established cirrhosis. Increased immunohistochemical staining for the basement membrane components type IV collagen and laminin was also found in a similar distribution. Raised serum levels of hyaluronic acid, a glycosaminoglycan metabolized by normal hepatic endothelial cells, were found in most patients and correlated strongly with advancing histological stage. Furthermore, significant positive correlations were found between serum hyaluronic acid and serum levels of laminin and type IV collagen.

The unique structure of the normal endothelial lining of the hepatic sinusoids is important in the maintenance of hepatic function. Our data show that significant changes in endothelial cell structure and function occur in primary biliary cirrhosis and appear to be a contributing factor to the progression of the disease. Further studies are needed to determine the extent and importance of these changes in other forms of chronic liver disease.(HEPATOLOGY 1990; 11:723–729.)
Sjögren's Syndrome in Patients With Primary Biliary Cirrhosis
Authors: Tsianos Epaminondas V. , Hoofnagle Jay H. , Fox Philip C. , Alspaugh Margaret , Jones Anthony E. , Schafer Daniel F. , Moutsopoulos Haralampos M.
Published: March 2007

Symptomatology and objective findings of Sjögren's syndrome were evaluated in 38 consecutive patients with primary biliary cirrhosis. Symptoms of Sjögren's syndrome were present in 18 (47.4%) patients, but were severe enough to warrant therapy in only four (10.5%). Nineteen patients consented to evaluation for Sjögren's syndrome, which included Schirmer's I test, measurement of parotid flow rate and serum autoantibodies, labial minor salivary gland biopsy and human leukocyte antigen typing. Histological changes diagnostic of Sjögren's syndrome were present in five patients (26.3%). All five patients had symptoms of Sjögren's syndrome and three had abnormal Schirmer's I tests, but none had corneal ulcerations or decreased parotid flow rates. Results of serological tests and human leukocyte antigen typing were not similar to those described in patients with primary Sjögren's syndrome but were similar to those described in patients with rheumatoid arthritis and Sjögren's syndrome associated with primary biliary cirrhosis is a form of secondary Sjögren's syndrome resembling that associated with rheumatoid arthritis.(HEPATOLOGY 1990; 11:730–734.)
Formation of Biliary Thrombi in Protoporphrin–Induced Cholestasis in Perfused Rat Liver
Authors: Berenson Malcolm M. , Gunther Cathy , Samowitz Wade S. , Bjorkman David J.
Published: March 2007

The effect of bile acids on the formation of biliary thrombi in protoporphyrin–induced cholestasis was determined by perfusing isolated rat livers with taurocholate, chenodeoxycholate and ursodeoxycholate with and without protoporphyrin. Protoporphyrin–induced reduction of bile flow was similar in the presence of each bile acid. The cholestasis was greater at high doses (2,000 to 10,885 nmol) than at low doses (1,500 nmol) of protoporphyrin, unrelated to the amount of lactate dehydrogenase released into the perfusate, and it was not altered by increasing bile acid infusions. Bile acid excretion was inhibited by high protoporphyrin doses. Periportal birefringent pigment deposits were seen in canaliculi and ductules when the biliary protoporphyrin concentration exceeded 161 nmol/ml, 345 nmol/ml and 1,036 nmol/ml for ursodeoxycholate, chenodeoxycholate and taurocholate, respectively; or, when the protoporphyrin (nanomole) to bile acid (micromole) ratio exceeded 3.23, 7.03 and 23.43, respectively. The maximal ratio of ductular deposits to portal tract deposits examined was 0.9. Electron microscopy showed these deposits were associated with canalicular thrombi. Thus, biliary thrombi were produced by infusion of bile acids and protoporphyrin. The occurrence of thrombi varied with bile acid structure. Explanations for this finding are speculative. The presence of periportal thrombi, however, did not influence the degree of functional cholestasis.(HEPATOLOGY 1990; 11:757–763.)
Cholesteryl Ester Storage Disease: Hepatopathology and Effects of Therapy With Lovastatin
Authors: Di Bisceglie Adrian M. , Ishak Kamal G. , Rabin Lionel , Hoeg Jeffrey M.
Published: March 2007

We describe three patients with cholesteryl ester storage disease. Diagnosis was confirmed by demonstrating a deficiency in lysosomal acid cholesteryl hydrolase activity in cultured skin fibroblasts from each of these patients. All had hepatomegaly, elevated serum aminotransferase activities and hyperlipoproteinemia. Histological examination of liver biopsy specimens before treatment revealed accumulation of fat within hepatocytes, bile duct epithelium and endothelial and Kupffer cells. Cholesterol crystals were recognized by their birefringence in frozen sections. A striking feature was the presence of markedly hypertrophied Kupffer cells and portal macrophages with foamy, tan–colored cytoplasm that stained readily with the periodic acid–Schiff reagent and aldehyde fuchsin. Periportal fibrosis was noted in all cases; incomplete cirrhosis was present in one case. Distinctive and hitherto undescribed lysosomal accumulations of triglyceride and cholesterol crystals were noted.

The patients were treated with lovastatin, a cholesterol–lowering agent, for at least 12 mo. No significant changes were seen in serum lipoprotein concentrations or liver histopathology after therapy. Thus lovastatin did not have an obviously beneficial effect on abnormal lipid metabolism in these patients.(HEPATOLOGY 1990; 11:764–772.)
Hepatic Ferritin Uptake and Hepatic Iron
Authors: Adams Paaul C. , Chau Luan A.
Published: March 2007

The effect of hepatic iron on the uptake of ferritin was studied by perfusing livers from normal, iron deficient and iron–loaded rats with 125I–labeled ferritin. Unlabeled ferritin with tracer doses of labeled ferritin in concentrations of 0.02 to 2,700 nmol/L were studied. Rats were made iron deficient by feeding an established iron–deficient diet for 3 wk. Rats were iron loaded by injection of iron dextran (50 mg/wk) for 3 wk. The mean percentage of uptake of ferritin was similar for doses ranging from 0.22 to 22.2 nmol/Lof 125I–labeled ferritin. Uptake was minimal at 4°C. The mean Percentage uptake of ferritin was 78% ± 10% in the iron–deficient rats (mean hepatic iron = 1.5μmol/gm), 79% ± 10% in the normal animals (mean hepatic iron = 9.2 μmol/gm) and 78% ± 8% in the iron–loaded animals (mean hepatic iron = 192 μmol/gm). In this experimental system, modulation of hepatic iron did not affect uptake of ferritin, suggesting that regulation of the hepatic ferrition, suggesting that regulation of the hepatic ferritin receptor may not depend on hepatic iron content. The rapid uptakee of ferritin by the liver despite iron noregulation of non–transferrin–bound iron by hepatic iron and may play a role in the progressive iron overload seen in hemochromatosis.(HEPATOLOGY 1990; 11:805–808.)
The Formation of Bile Canaliculi in Human Hepatoma Cell Lines
Authors: Chiu Jen-Hwey , Hu Cheng-Po , Lui Wing-Yiu , Lo Szecheng J. , Chang Chungming
Published: March 2007

Hepatocytes, known as polarized epithelial cells, are composed of sinusoid, basolateral and bile canalicular domains. Each domain contains proteins specific for it. Our studies indicate that the well–differentiated human hepatoma cell lines HepG2 and HuH–7 formed bile canaliculi in tissue culture, whereas the poorly differentiated hepatoma cell lines HA22T/VGH and SK–HEP–1 did not. We also used the 9B2 monoclonal antibody, previously shown to be specific for the human bile canalicular domain, to study formation of bile canaliculi in these human hepatoma cell lines. All four cell lines synthesize the 140–KD 9B2 antigen. Studies using peroxidase–antiperoxidase staining and immunoelectron microscopy revealed that the 9B2 antigen was first detected in cytoplasm and packaged in microvilli–lined vesicles, then vectorially transported to the cell surface and eventually fused with microvilli–lined vesicles from neighboring cells to form bile canaliculi in well–differentiated hepatoma cell lines. However, the 9B2 antigen of poorly differentiated lines was synthesized in cytoplasm, then transported directly to and evenly distributed on the cell membrane. These results lead us to conclude that human hepatoma cell lines could serve as a good in vitro model to study the formation of bile canaliculi in human hepatocytes. The bile canaliculi of human hepatocytes may be preformed and assembled in the intracellular, microvilli–lined vesicles, then vectorially transported to the cell surface, where they form the bile canaliculi through vesicles fusion. Finally, formation of bile canaliculi and transport of 9B2 antigen may be related to the differentiation of hepatocytes or progression stages of human hepatoma cells.(HEPATOLOGY 1990; 11:834–842.)
Presence of Functional Cytochrome P–450 on Isolated Rat Hepatocyte Plasma Membrane
Authors: Loeper Jacqueline , Descatoire Veronique , Maurice Michelle , Beaune Philippe , Feldmann Gerard , Larrey Dominique , Pessayre Dominique
Published: March 2007

Antibodies against cytochrome P–450 are found in some children with autoimmune hepatitis (antiliver/kidney microsome) and in patients with ticrynafen hepatitis (antiliver/kidney microsome2). For an immune reaction against cytochrome P–450 to possibly destroy the hepatocytes, one must assume that cytochrome P–450 is present on the plasma membrane surface of hepatocytes. In a first series of experiments, plasma membranes were prepared with a technique based on the electrostatic attachment of isolated hepatocytes to polyethyleneimine–coated beads. After vortexing, beads were coated with a very pure plasma membrane fraction. Microsomal contamination, judged from the specific activities of glucose–6–phosphatase or NADH–cytochrome c reductase, was less than 1%. Nevertheless, the specific content (permilligram of protein) of CO–binding cytochrome P–450 was 20% of that in microsomes; the specific benzo (a)pyrene hydroxylase activity was 25%, and ethoxycoumarin deethylase 11%, Immunoblots showed the presence of cytochromes P–450 UT–A, UT–H, PB–B, ISF–G and PCN–E, the last three isoenzymes being inducible by, respectively, phenobarbital, 3–methylcholanthrene and dexamethasone. In a second series of experiments, nonpermeabilized isolated hepatocytes from untreated rats were incubated with anticytochrome P–450 antibodies. Immunfluorescence and immunoperoxidase staining confirmed the presence of cytochromes P–450 UT–A, PB–B and ISF–G on the membrane. In a last series of experiments, human antiliver kidney microsomal1 antibodies were found to react specifically with rat liver plasma membrane cytochrome P–450 UT–H (IID subfamily). We conclude that several cytochrome P–450 isoenzymes are present, active and inducible on the plasma membrane surface of hepatocytes. It is therefore conceivable that immunization against plasma membrane cytochrome P–450 might lead to the immunological destruction of hepatocytes in some patients.(HEPATOLGOY 1990; 11: 850–858.)
Hypoxia and Cci4–Induced Liver Injury, But Not Acidosis, Impair Metabolism of Cysteinyl Leukotrienes in Perfused Rat Liver
Authors: Wettstein Matthias , Gerok Wolfgang , Häussinger Dieter
Published: March 2007

Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single–pass perfused rat liver. Hypoxia did not impair uptake of infused [3H] leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing ω–oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent ω–oxidation with subsequent slimination of the ω–oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H] leukotriene E4 addition because of an almost complete absence of ω–oxidation products in bile, whereas N–acetylleukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single–pass uptake of [3H] leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H] leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotriences. Thus, in leukotriene–induced shock syndromes, leukotriene elimination and inactivation may be imnpaired giving rise to a “vicious circle.”(HEPATOLOGY 1990; 11:866–873.)