bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Effects of Chenodeoxycholic and Ursodeoxycholic Acids on Interleukin 1, Interleukin 6 and Tumor Necrosis Factor-α Production by Monocytes
Authors: Calmus Yvon , Guechot Jerome , Podevin Philippe , Bonnefis Marie-Therese , Giboudeau Jacqueline , Poupon Raoul
Published: March 2007

Cell–mediated immunity and macrophage activity, especially that of Kupffer cells, are impaired during cholestasis. Some evidence exists that bile acids play a role in these immune defects. The purpose of this study was to evaluate the effects of individual bile acids on immunity and to determine whether monocytes could be a target. We assessed the effects of chenodeoxycholic acid, an endogenous bile acid, ursodeoxycholic acid, which has been shown to partially correct the immunological abnormalities observed in primary biliary cirrhosis, and their tauroconjugates on the production of interleukin–1, interleukin–6 and tumor necrosis factor-α. Chenodeoxycholic acid had a dose–dependent inhibitory effect on interleukin–1 (inhibitory concentration 50% = 60 m¨mol/L), interleukin–6 (inhibitory concentration 50% = 80 m¨mol/L) and tumor necrosis factor-α (inhibitory concentration 50% = 80 m¨mol/L) production; inhibition was almost complete at 250 m¨mol/L. In contrast, ursodeoxycholic acid had lesser or minimal inhibitory effects (inhibitory concentration 50% = 100 m¨mol/L for interleukin–1 and above 200 m¨mol/L for interleukin–6 and tumor necrosis factor-α). The inhibitory effects of taurochenodeoxycholic acid and tauroursodeoxycholic acid were similar to those of chenodeoxycholic acid and ursodeoxycholic acid, respectively. Ursodeoxycholic acid did not reverse the chenodeoxycholic acid-induced inhibition of interleukin–6 or tumor necrosis factor-α production. In conclusion, chenodeoxycholic acid exerts strong inhibitory effects on monocyte activity in vitro, whereas the effects of ursodeoxycholic acid are minor. (Hepatology 1992;16:719-723.)
Fraternal Concordance of Types of Abnormal Hepatocellular Mitochondria in Wilson's Disease
Authors: Sternlieb Irmin
Published: March 2007

Three distinct patterns of structural abnormalities of mitochondria, indicated as types I, II and III and associated with steatosis, were identified in the hepatocytes of 40 of 42 asymptomatic and 8 of 22 symptomatic patients with documented Wilson's disease before treatment. No correlation was seen between the type of mitochondrial abnormality and the patient's age, hepatic copper concentration, degree of hepatic steatosis or serum aminotransferase level. However, comparison of the types of abnormal hepatocellular mitochondria displayed by five pairs and one trio of asymptomatic siblings revealed remarkably similar types of abnormalities in each family. The variety of mitochondrial types encountered in different families and the high degree of type identity in sibling relationships indicate that the structural changes are genetically determined. (Hepatology 1992;16:728-732).
Inhibition of Rat Hepatic Lipocyte Activation in Culture by Interferon–γ
Authors: Rockey Don C. , Maher Jacquelyn J. , Jarnagin William R. , Gabbiani Giulio , Friedman Scott L.
Published: March 2007

Hepatic lipocytes (perisinusoidal, Ito cells) are the primary matrix–producing cells in liver fibrosis. During liver injury they undergo activation, a process characterized by cell proliferation and increased fibrogenesis. We and others have established a culture model in which in vivo features of lipocyte activation can be mimicked by cells grown on plastic. Additionally, we recently showed that activation is associated with new expression of smooth muscle-specific α–actin both in vivo and in culture. Although interferon–γ is known to inhibit collagen production in some systems, its action as a general modulator of lipocyte activation has not been examined; this issue forms the basis for our study.

In culture–activated lipocytes, interferon–γ (1,000 U/ml) significantly inhibited lipocyte proliferation as assessed by [3H]thymidine incorporation assay and nuclear autoradiography. In time–course studies of activation, it also markedly reduced expression of smooth muscle-specific α–actin and its messenger RNA. In dose–response experiments, maximal inhibitory effects on smooth muscle-specific α–actin mRNA gene expression were achieved with as little as 10 U interferon–γ/ml. Inhibition of cellular activation was reversible; after interferon–γ withdrawal, messenger RNA levels of smooth muscle-specific α–actin returned to untreated control levels. The effect of interferon–γ extended to extracellular matrix gene expression, with reduction of type I collagen, type IV collagen and total fibronectin messenger RNAs to 3%, 24% and 15% of untreated control levels, respectively. In contrast to the marked effects on smooth muscle–specific α–actin and extracellular matrix gene expression, interferon–γ reduced total protein synthesis by only 17.7%. Moreover, maximal doses of interferon–γ had no effect on cell viability as determined by exclusion of propidium iodide. In summary, interferon–γ is a potent inhibitor of lipocyte activation and may prove useful in the treatment of fibrotic liver injury. (Hepatology 1992;16:776-784.)
Fat–Storing Cells of the Rat Liver Synthesize and Secrete C1–Esterase Inhibitor; Modulation by Cytokines
Authors: Schwögler Stefan , Odenthal Margarete , Knittel Thomas , zum Büschenfelde Karl-Hermann Meyer , Ramadori Giuliano
Published: March 2007

During liver fibrogenesis, fat–storing cells transform into myofibroblast–like cells and produce increasing amounts of extracellular matrix proteins. Because fat–storing cells produce α2–macroglobulin, an important serine protease inhibitor (serpin), we investigated whether fat–storing cells also synthesize C1–esterase inhibitor, another important serpin. C1–esterase inhibitor synthesis was studied in rat fatstoring cells at day 0, 3 and 7 after isolation by biosynthetic labeling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Messenger RNA was examined by Northern–blot analysis. C1–esterase inhibitor gene expression and synthesis were detectable in freshly isolated fat–storing cells and increased distinctly during the time in culture. The cellular source of C1–esterase inhibitor in fat–storing cell cultures was also identified by in situ hybridization of cells at different times after isolation. By inhibition of the N–glycosylation using tunicamycin, rat C1–esterase inhibitor was identified as a glycoprotein. The time course of C1–esterase inhibitor secretion was determined by pulse–chase experiments. C1–esterase inhibitor synthesis was increased 6–fold to 10–fold by interferon–γ. Specific messenger RNA levels were also raised distinctly by this cytokine. In contrast, interferon–α and dexamethasone did not alter C1–esterase inhibitor gene expression. Because C1–esterase inhibitor synthesis is increased by advancing culture time and by the inflammatory mediator interferon–γ, we suggest that fat–storing cells may enhance the deposition of extracellular matrix proteins by inhibiting their degradation. (Hepatology 1992;16:794-802.)
Detection of Circulating Intercellular Adhesion Molecule-1 in Chronic Liver Diseases
Authors: Adams David H. , Mainolfi Elizabeth , Burra Patrizia , Neuberger James M. , Ayres Reuben , Elias Elwyn , Rothlein Robert
Published: March 2007

The leucocyte adhesion molecule intercellular adhesion molecule-1 is induced on bile ducts in patients with primary biliary cirrhosis and primary sclerosing cholangitis and may be involved in targeting immune damage to these structures. It has recently been reported that, when activated, in vitro lymphocytes release a soluble form of intercellular adhesion molecule-1 that can also be detected in human serum. Because it is functionally active, this circulating intercellular adhesion molecule-1 might play a role in regulating inflammation by blocking adhesion. We used an enzyme–linked immunosorbent assay to detect circulating intercellular adhesion molecule–1 in the serum of patients with primary biliary cirrhosis and primary sclerosing cholangitis. Levels of circulating intercellular adhesion molecule-1 were markedly elevated in primary biliary cirrhosis and primary sclerosing cholangitis when compared with other chronic liver diseases. Circulating intercellular adhesion molecule-1 is probably derived from activated lymphocytes rather than from bile ducts because biliary epithelial cells from patients with primary biliary cirrhosis did not release circulating intercellular adhesion molecule-1 when stimulated to express the membrane–bound molecule in vitro. These studies are the first to demonstrate circulating intercellular adhesion molecule-1 in chronic inflammatory diseases that are characterized by strong tissue expression of intercellular adhesion molecule-1 and as such suggest a potential immunoregulatory role for circulating adhesion molecules. The very high levels detected in primary biliary cirrhosis and primary sclerosing cholangitis probably reflect lymphocyte activation, which is further evidence of immune pathogeneses for these diseases. (Hepatology 1992;16:810-814.)
Hepatitis C Virus Rna and Antibody Response in the Clinical Course of Acute Hepatitis C Virus Infection
Authors: Puoti Massimo , Zonaro Antonella , Ravaggi Antonella , Marin Maria Grazia , Castelnuovo Filippo , Cariani Elisabetta
Published: March 2007

ABSTRACT

Hepatitis C virus RNA, anti—hepatitis C virus immune response and biochemical markers of liver injury were investigated in 17 patients with acute non–A, non–B hepatitis. At the first observation, 1 to 3 wk from the clinical onset, all patients had hepatitis C virus RNA in their serum, and most (15 of 17) were positive for second–generation anti—hepatitis C virus enzyme immunoassay. Follow–up serum samples were available for 10 patients. The rate of recombinant immunoblot assay—confirmed anti—hepatitis C virus enzyme immunoassay reactivities increased from 67% in the first 3 wk to 86% after 21 wk. Elevated ALT levels were associated with hepatitis C virus RNA positivity in most of cases, but the viral nucleic acid was also detected in sera with normal or slightly increased enzyme values. None of the single antibodies tested were related to hepatitis C virus RNA positivity or to the clinical phase of the infection. Therefore hepatitis C virus RNA determination might provide important additional information as compared with anti—hepatitis C virus markers, allowing earlier diagnosis, discrimination of active infection and, possibly, prognostic evaluation. (HEPATOLOGY 1992;16:877-881.)
Treatment of Children With Chronic Hepatitis C With Recombinant Interferon–α: A Pilot Study
Authors: Ruiz-Moreno Mercedes , Rua Maria José , Castillo Inmaculada , García-Novo Maria Dolores , Santos Maravillas , Navas Sonia , Carreño Vicente
Published: March 2007

ABSTRACT

Twelve children with chronic non–A, non–B hepatitis were entered in a pilot trial of recombinant interferon–α. Although all the children had hepatitis C virus RNA in serum, only five had antibodies against this virus. Children received 3 MU/m2 body surface area interferon–α 3 times/wk for 6 mo; they were followed for 24 mo, including the therapy period. One child was dropped from the study, so the results are from the 11 children who completed the study. At the end of the therapy period, 36% of the children had normal ALT levels; this percentage increased to 90% at mo 15 of follow–up. Thereafter, relapse occurred in five children; thus ALT normalization was observed in 5 of 11 children at the 24th month. Moreover, two different ALT patterns were found: HCV antibody—negative children had significant peaks of ALT levels with respect to the basal samples (p < 0.05) until the third month of the therapy; these levels later decreased. In contrast, HCV antibody—positive children had slight fluctuations of ALT until normal levels were reached. At the end of treatment, three children had HCV RNA; one demonstrated a rebound in ALT levels. Finally, histological activity had decreased significantly in the second liver biopsy specimen in all children. In summary, interferon treatment in children with chronic hepatitis C may be helpful, although these results should be confirmed in controlled trials. (HEPATOLOGY 1992;16:882-885.)
Two Distinct Subtypes of Hepatitis C Virus Defined by Antibodies Directed to the Putative Core Protein
Authors: Machida Atsuhiko , Ohnuma Hitoshi , Tsuda Fumio , Munekata Eisuke , Tanaka Takeshi , Akahane Yoshihiro , Okamoto Hiroaki , Mishiro Shunji
Published: March 2007

ABSTRACT

Four distinct genotypes of hepatitis C virus types I, II, III and IV have been identified by comparison of nucleotide sequences of isolates from different areas of the world. We examined the possibility that hepatitis C virus may have serologically definable subtypes. Enzyme–linked immunosorbent assay systems were prepared by use of two synthetic peptides deduced from the putative core protein of hepatitis C virus. The following are the two peptides that were used: (a) IPKARRPEGRTWAQPGY (subtype–1) conserved in hepatitis C virus isolates with type I and type II genotypes; and (b) IPKDRRSTGKSWGKPGY (subtype–2) conserved in type III and type IV genotypes. With the enzyme–linked immunosorbent assays, the subtype–1 antibodies were detected in 26 (68%) of 38 subjects whose hepatitis C virus RNA had been genotyped as type I or type II, whereas subtype–2 antibodies were not detected. Inversely, the subtype–2 antibodies were detected in 10 (56%) of 18 subjects with hepatitis C virus RNA genotypes III or IV, whereas subtype–1 antibodies were detected in none of them. These results suggest that hepatitis C virus has two serologically distinguishable core antigen subtypes, corresponding to either genotype I/II or genotype III/IV. Subtyping of HCV by serological methods would contribute to tracking transmission routes of the virus, especially in cases where serum samples were not stored under conditions to preserve RNA or in infected hosts who have cleared the virus and therefore have only antibodies remaining to identify the infection. (HEPATOLOGY 1992;16:886-891.)
Antimitochondrial Antibodies in Kindreds of Patients With Primary Biliary Cirrhosis: Antimitochondrial Antibodies Are Unique to Clinical Disease and Are Absent in Asymptomatic Family Members
Authors: Caldwell Stephen H. , Leung Patrick S.C. , Spivey James R. , Prindiville Thomas , de Medina Maria , Saicheur Theparat , Rowley Merrill , Reddy Rajender K. , Coppel Ross , Jeffers Lennox J. , MacKay Ian R. , Schiff Eugene R. , Gershwin Eric M.
Published: March 2007

ABSTRACT

The 2–oxo–acid dehydrogenase family of enzymes have been identified as the major mitochondrial autoantigens of primary biliary cirrhosis. Using immunoblotting, enzyme–linked immunosorbent assay and enzyme inhibition with both purified mitochondrial proteins and recombinant autoantigens, we have studied family members and spouses of patients with primary biliary cirrhosis for the presence of antimitochondrial antibodies. Antimitochondrial antibodies and other common autoantigens were also tested for by indirect immunofluorescence. This study included 27 index patients with primary biliary cirrhosis, 15 spouses and 48 first– and second–degree relatives. Overall, 7 relatives (11%) were positive for autoantibodies to nuclear and cytoplasmic antigens by indirect immunofluorescence against mouse liver and stomach sections. However, with immunofluorescence, the reactivity strictly paralleled that of antimitochondrial antibodies in only one of these (1:640)—a sibling with mild pruritus and a liver biopsy specimen diagnostic of primary biliary cirrhosis despite normal levels of serum alkaline phosphatase. In addition, one of the mothers, who had a history of sarcoidosis, was positive by immunoblotting for antibodies to the E2 subunit of the pyruvate dehydrogenase complex and protein X. All other relatives were negative for all of the assays. Antibodies to neither the 2–oxo–acid dehydrogenase enzymes nor the recently proposed family of naturally occurring mitochondrial antibodies were found in spouses or healthy relatives. Three other first–degree relatives suffered from liver disease: two died (one from primary biliary cirrhosis and the other from an unknown type of liver disease) and one (a sibling with primary biliary cirrhosis) was unavailable for testing. Our results are consistent with a familial predisposition to primary biliary cirrhosis. These data do not support a deficiency of naturally occurring mitochondrial antibodies as an explanation for an inherited basis of the disease because none of our samples, patients or relatives, were positive for these putative autoantibodies. Among blood relatives, antimitochondrial antibodies were not detected in the absence of proved or suspected primary biliary cirrhosis. Within primary biliary cirrhosis kindreds, the presence of antimitochondrial antibodies should arouse suspicion of primary biliary cirrhosis even without overt clinical or biochemical disease markers. (HEPATOLOGY 1992;16:899-905.)
Analysis of Hepatocellular Proliferation: Study of Archival Liver Tissue Is Facilitated by An Endogenous Marker of Dna Replication
Authors: Vemuru Ravikumar P. , Aragona Emma , Gupta Sanjeev
Published: March 2007

ABSTRACT

Assessment of liver regeneration with endogenous genes that are expressed during DNA replication is physiological, specific and direct. To determine whether H3 histone messenger RNA expression (which is tightly coupled with DNA synthesis) could be used for this purpose, we initially examined liver regeneration in a mouse model. After partial hepatectomy, RNA transblot studies showed induction of H3 histone messenger RNA expression in regenerating mouse livers. In situ molecular hybridization demonstrated that the overall pattern of H3 histone messenger RNA expression correlated with [3H]thymidine labeling of hepatocytes. After partial hepatectomy, H3 histone messenger RNA expression in hepatocytes peaked at 48 hr (>60 times greater than at 24 hr; p < 0.001) and then rapidly declined. Although hepatocyte labeling with [3H]thymidine showed similar kinetics of liver regeneration, use of this parameter resulted in overestimation of the proliferative compartment when it was compared with H3 histone messenger RNA expression. Next we determined whether H3 histone messenger RNA expression could be used to study hepatocellular proliferation in archival human material. H3 histone messenger RNA—expressing hepatocytes were identified on in situ hybridization in patients with acute or chronic active hepatitis and active cirrhosis, but not inactive cirrhosis. These studies demonstrate that H3 histone messenger RNA is expressed in a phasic manner during liver regeneration. Use of H3 histone messenger RNA expression to evaluate hepatocellular proliferation should facilitate clinical studies and greatly advance our understanding of the pathophysiology of liver regeneration. (HEPATOLOGY 1992;16:968-973.)
Metabolic Clearance Rate of Arginine Vasopressin in Patients With Cirrhosi
Authors: Solis-Herruzo José A. , Gonzalez-Gamarra Amelia , Castellano Gregorio , Muñoz-yagüe Maria Teresa
Published: March 2007

ABSTRACT

Metabolic clearance rate and half–time of arginine vasopressin were measured in 43 cirrhotic patients and 10 control subjects. Synthetic arginine vasopressin was infused intravenously at a rate of 500 pg/min/kg of body weight for 75 min. The metabolic clearance rate was significantly reduced, and the half–time of arginine vasopressin after stopping the infusion was significantly increased in patients with cirrhosis, particularly in those with ascites and in those with moderate or severe liver dysfunction. Changes in metabolic clearance rate and half–time of arginine vasopressin correlated with the score of the liver dysfunction, prothrombin activity and levels of serum albumin and bilirubin but not with parameters of kidney function (serum creatinine levels and clearance of creatinine). We conclude that reduced metabolic clearance rate and prolonged half–time of vasopressin in plasma are frequent findings in cirrhotic patients with poor liver function. This impaired catabolism of antidiuretic hormone may contribute to maintaining elevated plasma levels of this hormone in these patients and may be an additional factor leading to fluid retention and to dilutional hyponatremia. (HEPATOLOGY 1992;16:974-979.)
Evidence for Normal Nitric Oxide—Mediated Vasodilator Tone in Conscious Rats With Cirrhosis
Authors: Sogni Philippe , Moreau Richard , Ohsuga Masaru , Cailmail Stephane , Oberti Frederic , Hadengue Antoine , Pussard Eric , Lebrec Didier
Published: March 2007

ABSTRACT

Because it has been hypothesized that the hyperkinetic circulation in portal hypertension is the result of increased synthesis of nitric oxide, we compared the hemodynamic effects of nitric oxide synthesis—specific agonist (L–arginine) and antagonist between normal and cirrhotic conscious rats. The dose–response curves showed that L–arginine significantly decreased arterial pressure and increased heart rate. These changes started at the 200 mg/kg dose and were similar in both groups of rats. In both groups of rats NG–monomethyl—L–arginine (25 mg/kg) significantly decreased cardiac output by 35%. In cirrhotic rats, NG–monomethyl—Larginine decreased portal pressure from 15.3 ± 0.9 mm Hg to 13.6 ± 0.7 mm Hg and portal tributary blood flow from 7.8 ± 0.7 ml · min-1 · 100 gm-1 to 5.9 ± 0.7 ml · min-1 · 100 gm-; it significantly increased portal territory vascular resistance from 950 ± 108 dyn · sec · cm-5 · 100 gm-1 × 103 to 1,579 ± 258 dyn · sec · cm-5 · 100 gm-1 × 103. In normal rats, portal tributary blood flow decreased similarly, by 27%, and portal territory vascular resistance increased by 55%. In neither group was hepatic arterial blood flow altered. Before and after NG–monomethyl–L–arginine administration, arterial cyclic GMP concentrations were not significantly different between normal and cirrhotic rats. In conclusion, this study shows evidence of a normal role for nitric oxide—mediated vasodilatation in rats with cirrhosis and that inhibition of nitric oxide synthesis reduces portal hypertension. These results did not support the hypothesis that nitric oxide synthesis is increased in cirrhosis. (HEPATOLOGY 1992;16:980-983.)
Role of Cytochrome P–450 2E1 in Ethanol–, Carbon Tetrachloride— and Iron–Dependent Microsomal Lipid Peroxidation
Authors: Castillo Tirso , Koop Dennis R. , Kamimura Seiichiro , Triadafilopoulos George , Tsukamoto Hidekazu
Published: March 2007

ABSTRACT

This study investigated the role of cytochrome P–450 2E1 in enhanced microsomal lipid peroxidation in experimental alcoholic liver disease. We also examined the contribution of this isoform to the increased microsomal injury in alcoholic liver disease caused by carbon tetrachloride—induced or iron–induced oxidant stress. Adult male Wistar rats were intragastrically infused with a high–fat diet and ethanol or glucose for 16 wk; this resulted in hepatic lipid peroxidation and fibrogenesis in the ethanol–fed animals. Microsomes were isolated by differential centrifugation in the presence of 100 μmol/L deferoxamine, washed twice in buffer without deferoxamine and incubated in the absence or presence of ethanol (50 mmol/L), carbon tetrachloride (150 μmol/L), ferric citrate (50 μmol/L) or ferric citrate plus ethanol at 37° C for 30 min in an NADPH–generating system. The basal rate of lipid peroxidation in microsomes isolated from ethanol–fed rats was increased by 52% compared with that in microsomes from controls. Carbon tetrachloride—induced and ferric citrate—induced lipid peroxidation were also accentuated in microsomes from ethanol–fed rats, by 76% and 108%, respectively. Ethanol added in vitro significantly reduced basal (-58%) and ferric citrate—induced (-48%) lipid peroxidation in microsomes from ethanol–fed rats, whereas it had an insignificant effect on that in control microsomes. In fact, this protective effect of ethanol on microsomes from ethanol–fed rats resulted in attenuation of the difference in the level of microsomal lipid peroxidation between the two groups. P–450 2E1 IgG antibody added to the incubation completely blocked the enhanced lipid peroxidation observed in microsomes from ethanol–fed rats under the basal, ferric citrate—induced and carbon tetrachloride—induced conditions. Immunoblot analysis of microsomal proteins with P–450 2E1 IgG antibody demonstrated a large increase in the level of this cytochrome in microsomes from ethanol–fed rats. The catalytic activity of P–450 2E1, measured by antibody–inhibitable p–nitrophenol hydroxylation, was increased 20–fold over control levels by the ethanol feeding. These results demonstrate (a) induction of P–450 2E1 at an advanced stage of experimental ALD, (b) a major role of this cytochrome in the enhanced basal lipid peroxidation of microsomes obtained from livers with ALD; (c) a major contribution of P–450 2E1 to the increased vulnerability of these microsomes to ferric citrate and carbon tetrachloride—induced peroxidation and (d) the possible implication of ethanol withdrawal in further peroxidative injury caused by the absence of the protective effect of ethanol. (HEPATOLOGY 1992;16:992-996.)
Ethanol–Induced Vasoconstriction Causes Focal Hepatocellular Injury in the Isolated Perfused Rat Liver
Authors: Oshita Masahide , Sato Nobuhiro , Yoshihara Harumasa , Takei Yoshiyuki , Hijioka Taizo , Fukui Hiroyuki , Goto Moritaka , Matsunaga Takashi , Kashiwagi Toru , Kawano Sunao , Fusamoto Hideyuki , Kamada Takenobu
Published: March 2007

ABSTRACT

The role of microcirculation in the pathogenesis of alcoholic liver injury was investigated in isolated perfused livers from fed rats. Infusion of ethanol into the portal vein at concentrations ranging from 25 to 200 mmol/L increased portal pressure, which is an indicator of hepatic vasoconstriction, in a concentration–dependent fashion. Portal pressure started to rise immediately on initiation of ethanol load and remained at higher than basal levels throughout the period of ethanol infusion. Release of lactate dehydrogenase, an indicator of cell injury, into the effluent perfusate began to increase after 20 to 30 min of ethanol infusion and continued to increase until the end of the experiment (60 min after the initiation of ethanol infusion). The lactate dehydrogenase level in the effluent perfusate at 60 min was dependent on the ethanol concentration (0 mmol/L, 8 ± 3 IU/L; 25 mmol/L, 22 ± 3 IU/L; 50 mmol/L, 51 ± 11 IU/L; 100 mmol/L, 60 ± 7 IU/L; 200 mmol/L, 120 ± 7 IU/L). Simultaneous infusion of sodium nitroprusside (100 μmol/L), a known vasodilator, inhibited significantly the ethanol–induced increases in portal pressure and lactate dehydrogenase release by abolishing hepatic vasoconstriction. In histological examinations focal hepatocellular necrosis, evidenced by trypan blue staining of cell nuclei, was detected predominantly in midzonal and pericentral areas of the liver lobule after 60 min of ethanol infusion. Change in portal pressure during 60 min of ethanol infusion correlated significantly with levels of lactate dehydrogenase after ethanol infusion (r = 0.82; p < 0.001). These data indicate that ethanol in the portal blood at concentrations higher than 25 mmol/L causes focal hepatocellular necrosis, at least in part because of hepatic vasoconstriction. Therefore this ethanol–induced microcirculatory disturbance might be involved in the pathogenesis of alcoholic liver disease. (HEPATOLOGY 1992;16:1007-1013.)
Vitamin E Dietary Supplementation Protects Against Carbon Tetrachloride—Induced Chronic Liver Damage and Cirrhosis
Authors: Parola Maurizio , Leonarduzzi Gabriella , Biasi Fiorella , Albano Emanuele , Biocca Maria E. , Poli Giuseppe , Dianzani Mario U.
Published: March 2007

ABSTRACT

Previous studies have shown that α–tocopherol (vitamin E) pretreatment of experimental animals can protect against acute liver necrosis induced by carbon tetrachloride. In this study we investigated whether the increase of vitamin E liver content by dietary supplementation influences chronic liver damage and cirrhosis induced by carbon tetrachloride in the rat. Our data indicate that vitamin E supplementation did not interfere with the growth rate of the animals and increased about threefold the liver's content of the vitamin. Vitamin E supplementation significantly reduced oxidative liver damage, but it was not effective in protecting against development of fatty liver and did not interfere with metabolic activation of carbon tetrachloride. Moreover, vitamin E—fed animals showed incomplete but significant prevention of liver necrosis and cirrhosis induced by carbon tetrachloride. This has been shown by means of histological examination, analysis of serum parameters and biochemical evaluation of collagen content. These results show that an increased liver content of vitamin E can afford a significant degree of protection against carbon tetrachloride-induced chronic liver damage and cirrhosis. (HEPATOLOGY 1992;16:1014-1021)
S –Adenosylmethionine Treatment Prevents Carbon Tetrachloride—Induced S –Adenosylmethionine Synthetase Inactivation and Attenuates Liver Injury
Authors: Corrales Fernando , Giménez América , Alvarez Luis , Caballería Joan , Pajares María A. , Andreu Hernán , Parés Albert , Mato José M. , Rodés Joan
Published: March 2007

ABSTRACT

Administration of carbon tetrachloride to rats resulted in induction of hepatic fibrosis and a 60% reduction of hepatic S–adenosylmethionine synthetase activity without producing any significant modification of hepatic levels of S–adenosylmethionine synthetase messenger RNA. The reduction of S–adenosylmethionine synthetase activity was corrected by treatment with S–adenosylmethionine (3 mg/kg/day, intramuscularly). Administration of carbon tetrachloride also produced a 45% depletion of liver glutathione (reduced form) that was corrected by S–adenosylmethionine treatment. After the rats received carbon tetrachloride, a 2.3–fold increase in liver collagen was observed; prolyl hydroxylase activity was 2.5 times greater than that seen in controls. These increases were attenuated in animals treated with carbon tetrachloride and S–adenosylmethionine. The attenuation by S–adenosylmethionine treatment of the fibrogenic effect of carbon tetrachloride was associated with a decrease in the number of rats in which cirrhosis developed. (HEPATOLOGY 1992;16:1022-1027.)
The Role of Nitric Oxide in the Vascular Hyporesponsiveness to Methoxamine in Portal Hypertensive Rats
Authors: Lee Fa-Yauh , Albillos Agustin , Colombato Luis A. , Groszmann Roberto J.
Published: March 2007

ABSTRACT

This study examined whether an increased activity of the endothelium–derived relaxing factor, nitric oxide, may account for the hyporesponsiveness to vasoconstrictors in portal hypertension. We performed dose–response curves to methoxamine, an α–adrenoceptor agonist, with and without Nω–nitro–L–arginine, a specific inhibitor of nitric oxide synthesis, in experimental portal hypertension. Partial portal vein—ligated or sham–operated rats were pretreated with a continuous intravenous infusion of either Nω–nitro–L–arginine (50 μg · kg-1 · min-1) or saline. Thirty minutes after starting the infusion of Nω–nitro–L–arginine or saline an infusion of methoxamine (10, 30 and 100 μg · kg-1 · min-1) was added. Total peripheral resistance was calculated from mean arterial pressure and cardiac index. Repeated measurements of cardiac index were performed by a thermodilution technique. In portal vein—ligated rats pretreated with saline, the increase in total peripheral resistance after methoxamine infusion was significantly less than that of sham–operated rats (0.2 ± 0.1 vs. 1.0 ± 0.3, 0.6 ± 0.1 vs. 1.6 ± 0.3 and 3.7 ± 0.5 vs. 6.1 ± 0.7 mm Hg · ml-1 · min · 100 gm, p < 0.05, methoxamine 10, 30 and 100 μg · kg-1 · min-1, respectively). In the presence of Nω–nitro–L–arginine, the change in total peripheral resistance after methoxamine infusion was similar in both groups (p > 0.05). In conclusion, this study demonstrates that a vascular hyporesponsiveness to methoxamine is present in portal vein—ligated rats and that this hyporesponsiveness is reversed by blockade of nitric oxide. This suggests that nitric oxide plays an important role in the arterial vasodilation observed in portal hypertensive states. (HEPATOLOGY 1992;16:1043-1048.)
The Perfused Liver Is Capable of Producing All Transferrin Glycan Variants Found in the Sera of Intact Rats
Authors: Hu Wei-Li , Chindemi Paul A. , Regoeczi Erwin
Published: March 2007

ABSTRACT

The single oligosaccharide attachment in rat transferrin exhibits marked structural microheterogeneity. In this study we examined whether all microheterogeneous forms of rat transferrin found in plasma are derived from a single organ, such as the liver. To this end we analyzed the glycans of rat transferrin synthesized by the isolated perfused rat liver by a method established earlier for rat transferrin isolated from rat plasma.

Our observations provide evidence that the liver can and does produce all variant rat transferrin glycans present in plasma. However, this discovery does not preclude the possibility that extrahepatic sources with an active rat transferrin gene may contribute to the circulation rat transferrin molecules, which bear glycan variants identical to those made by the liver. The glycan spectra of rat transferrin in plasma and in liver perfusate compared closely with each other in a quantitative sense. Nevertheless, rat transferrin in the perfusate was sialylated to a lesser extent and fucosylated to a greater extent than rat transferrin in plasma. These differences could not be eliminated by supplementation of the medium with insulin, dexamethasone, pyruvate and adenine or adenosine either alone or in combinations, nor could it be eliminated by use of a fluorocarbon O2 carrier. In contrast, epidermal growth factor normalized both parameters. The pH of the perfusing medium also influenced sialylation and fucosylation in such a way that higher pH brought these parameters closer to their values in plasma rat transferrin. Lower pH, on the other hand, reduced sialylation and left the fucosylation index unchanged. (HEPATOLOGY 1992;16:1049-1054.)
The P53 “Knockout”: Gone But Not Forgotten
Authors: Carbone David
Published: March 2007

ABSTRACT

Mutations in the p53 tumour–suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
Estimated Central Blood Volume in Cirrhosis: Relationship to Sympathetic Nervous Activity, β–Adrenergic Blockade and Atrial Natriuretic Factor
Authors: Henriksen Jens H. , Bendtsen Flemming , Gerbes Alexander L. , Christensen Niels Juel , Ring-Larsen Helmer , Sørensen Thorkild I.A.
Published: March 2007

ABSTRACT

The estimated central blood volume (i.e., blood volume in the heart cavities, lungs and central arterial tree) was determined by multiplying cardiac output by circulatory mean transit time in 19 patients with cirrhosis and compared with sympathetic nervous activity and circulating level of atrial natriuretic factor. Arterial norepinephrine level, an index of overall sympathetic nervous activity (3.08 nmol/L in patients vs. 1.36 nmol/L in controls; p < 0.01) was negatively correlated (r = -0.54, p < 0.01) with estimated central blood volume (mean = 23 ml/kg in patients vs. 27 ml/kg in controls; p < 0.05). Similarly, renal venous norepinephrine level (an index of renal sympathetic tone; 4.26 nmol/L in patients vs. 1.78 nmol/L in controls; p < 0.01) was inversely correlated with estimated central blood volume (r = -0.53, n = 18, p < 0.02). No significant correlation could be established between arterial atrial natriuretic factor level (8.9 pmol/L in patients vs. 9.6 pmol/L in controls; not significant) and estimated central blood volume. Hemodynamic values were subsequently modified with oral propranolol (80 mg). During β–adrenergic blockade, the mean estimated central blood volume was not altered significantly, except in six patients who exhibited decreases in mean arterial blood pressure (85 to 69 mm Hg; n = 6) and decreases in mean estimated central blood volume (23.2 to 20.6 ml/kg; n = 6, p < 0.05). Slight increases were observed in mean right atrial pressure (2.2 to 3.7 mm Hg; n = 14, p < 0.05); this change was positively correlated with the change in estimated central blood volume (r = 0.44, n = 14, p = 0.06). In conclusion, reduced estimated central blood volume probably “unloads” volume receptors and baroreceptors, thus provoking enhanced overall and renal sympathetic nervous activity and thereby contributing to increased water and salt retention in cirrhosis. During β–adrenergic blockade estimated central blood volume changes correlated with alterations in preload and afterload. These findings indicate that central circulatory and arterial underfilling is a key element of the hemodynamic derangement observed in cirrhosis. (Hepatology 1992;5:1163-1170.)
Human Cholecystitis Is Associated With Increased Gallbladder Prostaglandin I2 and Prostaglandin E2 Synthesis
Authors: Myers Stuart I. , Bartula Lori
Published: March 2007

ABSTRACT

Microsomal prostanoid synthesis was compared in normal gallbladders removed during organ donation and inflamed gallbladders removed at cholecystectomy. Normal human gallbladder microsomes demonstrated low rates of conversion of [14C]arachidonic acid to total labeled prostanoids, which increased during 1 to 30 min of incubation. Normal human gallbladder microsomes converted labeled substrate to all primary prostaglandins without demonstration of a major product. Inflamed human gallbladder microsomes increased the rate of conversion of [14C]arachidonic acid to total labeled prostanoids two or three times over the levels demonstrated by normal gallbladder microsomes at all times of incubation (p < 0.01). The main prostanoids synthesized by the inflamed human gallbladder microsomes were prostaglandin E2 and 6–keto–prostaglandin F1α, which were increased four times over the levels demonstrated by normal gallbladder microsomes (p < 0.01). These data showed that inflammation of the human gallbladder was associated with increased synthesis of gallbladder 6–keto–prostaglandin F1α, and prostaglandin E2. (Hepatology 1992;16:1176-1179.)
Octreotide Inhibits the Meal–Induced Increases in the Portal Venous Pressure of Cirrhotic Patients With Portal Hypertension: A Double–Blind, Placebo–Controlled Study
Authors: McCormick Aiden P. , Biagini Maria Rosa , Dick Robert , Greenslade Lynda , Chin Jason , Cardin Fabrizio , Wagstaff Donald , McIntyre Neil , Burroughs Andrew K.
Published: March 2007

ABSTRACT

The aim of this study was to determine the effects of the long–acting somatostatin analog, octreotide, on portal venous pressure and collateral blood flow in cirrhotic patients with portal hypertension during fasting and postprandial states. In a double–blind, placebo–controlled study, we investigated the effects of octreotide on the hepatic venous pressures and azygos blood flow of 21 patients before and after a standard liquid meal containing 40 gm of protein in 250 ml. Octreotide significantly reduced azygos blood flow from a mean of 499 ± 65 ml/min to a mean of 355 ± 47 ml/min (p < 0.01), but it had no effect on the hepatic venous pressure gradient. The hepatic venous pressure gradient of patients in the placebo group increased significantly, from a fasting mean of 16.4 ± 1.6 mm Hg to a mean of 20.0 ± 1.7 mm Hg 30 min after the meal (p < 0.01). In a second protocol hepatic venous pressures were measured in 20 patients at 30–min intervals for 2 hr after ingestion of the mixed meal. Again the placebo group showed a significant increase in the hepatic venous pressure gradient 30 min after the meal (20.4 ± 1.5 mm Hg vs. 18.2 ± 1.2 mm Hg; p < 0.05), but the group receiving octreotide showed no significant changes during the 2 hr of observation. We conclude that octreotide significantly reduces azygos blood flow, with little effect on portal venous pressure, and that it appears to inhibit postprandial increases in portal pressure in cirrhotic patients with portal hypertension. (Hepatology 1992;16:1180-1186.)
Failure of Simple Biochemical Indexes to Reliably Differentiate Fulminant Wilson's Disease From Other Causes of Fulminant Liver Failure
Authors: Sallie Richard , Katsiyiannakis Leah , Baldwin Dianne , Davies Sue , O'Grady John , Mowat Alex , Mieli-Vergani Giorgina , Williams Roger
Published: March 2007

ABSTRACT

Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non–Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (<0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (χ2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis. Massively elevated hepatic copper stores with normal serum copper concentrations were seen in some patients; in others tissue copper concentration from different regions of the same liver varied up to 7–fold. Treatment with D–penicillamine in five patients had no observable beneficial effect. (Hepatology 1992;16:1206-1211.)
Effect on the Canine Eck Fistula Liver of Intraportal Tgf–β Alone or With Hepatic Growth Factors
Authors: Francavilla Antonio , Azzarone Alessandro , Carrieri Guiseppe , Scotti-Fogueni Carlo , Zeng Qia-Hua , Cillo Umberto , Porter Kendrick , Starzl Thomas E.
Published: March 2007

ABSTRACT

Transforming growth factor–β canceled the hepatocyte proliferation caused by transforming growth factor–α when the two substances were mixed and administered through a disconnected central portal vein branch after creation of an Eck fistula. In contrast, transforming growth factor–β had no antidotal action on the stimulatory effects of insulin or full test doses of insulinlike factor–2, hepatocyte growth factor, epidermal growth factor or triiodothymanine. A minor antidotal effect on hepatic stimulatory substance activity could be detected, but only with hepatic stimulatory substance was given in doses smaller than those known to cause maximum stimulatory response. These results suggest a highly specific pharmacological and physiological interaction between transforming growth factor–α and transforming growth factor–α in the modulation of liver growth control. (Hepatology 1992;16:1267-1270.)
Rapid Donor Liver Nutritional Enhancement in A Large Animal Model
Authors: Cywes Robert , Greig Paul D. , Morgan Glynn R. , Sanabria Juan R. , Clavien Pierre-Alain , Harvey Robert P.C. , Strasberg Steven M.
Published: March 2007

ABSTRACT

Organ donors are typically subject to acute hyponutrition that might affect postpreservation liver function. Livers from nutritionally supplemented rats function better after preservation than livers from fasted rats. We have developed a method to glycogenate the liver of large animals in the temporal context of a human donor liver operation and have studied the fate of glycogen stores during preservation. Starved anesthetized pigs were infused with a hexose solution (glucose, fructose or galactose) by way of the superior mesenteric vein for 3 hr. Regular porcine insulin was infused to maintain a hyperglycemic hyperinsulinemic arterial glucose clamp at 12 to 16 mmol/L. Liver biopsy specimens and blood samples were taken before infusion and hourly. At 3 hr the liver was excised, stored for 24 hr at 1°C in University of Wisconsin solution and biopsied. It was then placed at 20° C for 1 hr to simulate the reimplantation stage of transplantation. Glycogen and nucleotide levels were measured, and results were corrected for starch in the University of Wisconsin solution. A 20% glucose infusion produced rapid hepatic glycogenation without side effects. Greater glycogenation was obtained with 20% fructose but at the cost of lactic acidosis and a fall in pH. A combination of 15% glucose and 5% fructose produced intermediary glycogenation without significant side effects. Galactose (20%) was less efficient than glucose alone. The addition of alanine and glutamine (20 mmol/L) did not significantly improve glycogenation. Metabolism of glycogen at 1° C did occur. Glycogen content fell 0.15% ± 0.05% dry weight liver per hour during cold preservation and 5.49% ± 2.15% per hour during ischemic rewarming. The rate of glycogen depletion during rewarming was dependent on the amount of glycogen available at the start of the period. Phosphorylated nucleotide levels were maintained at significantly higher levels in glycogenated livers. Periodic acid-Schiff staining showed a clear gradient of glycogenation maximal in zone 1 and minimal in zone 3. Rapid hepatic glycogenation is possible and beneficial in terms of maintaining adenine nucleotide levels in a large animal model. (Hepatology 1992;16:1271-1279.)
Surgical Management of the Budd–Chiari Syndrome: No Place for A Procrustean Bed
Authors: Langnas Alan N. , Sorrell Michael F. , Donovan Jeremiah P. , Shaw Byers W.
Published: March 2007

ABSTRACT

Over 12 years, 22 patients with the Budd–Chiari syndrome were treated surgically. Eighteen underwent a mesenterico–caval shunt (MCS); two, a side–to–side portacaval shunt; one, a mesentericoatrial shunt (MAS); and one, a liver transplantation (OLT). One patient died after operation from the precipitating condition, and two MCS grafts that thrombosed were restored. All 21 surviving patients remain well, free from ascites, and all shunts are patent after a mean follow–up of 5.6 ± 1 years, five patients with more than 10 years' follow–up. This long–term survival achieved by portasystemic shunts suggests that they have a major role in the treatment of the Budd–Chiari syndrome. The authors prefer the mesenterico–caval shunt using a jugular graft. This ensures a total portasystemic shunt, avoids subhepatic surgery, and reduces the long–term risk of prosthetic graft thrombosis. The MAS was reserved for cases with complete caval thrombosis. Patients with significant degrees of caval compression were satisfactorily decompressed by MCS. In patients not promptly treated, the disease progresses to cirrhosis and such patients must be evaluated for transplantation similarly to those with other hepatopathies.