bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevation of chemotactic factor inactivator in alcoholic liver disease
Authors: Robbins Richard A. , Zetterman Rowen K. , Kendall Todd J. , Gossman Gail L. , Monsour Howard P. , Rennard Stephen I.
Published: March 2007

Defective regulation of neutrophil chemotaxis occurs in patients with alcoholic liver disease. One potent mediator of neutrophil chemotaxis is the complement-derived neutrophil chemoattractant, C5a, which can be inhibited by a serum protein, chemotactic factor inactivator. We hypothesized that chemotactic factor inactivator elevation might, in part, explain the defective neutrophil chemotaxis seen in patients with alcoholic hepatitis. To test this hypothesis, sera were collected from 22 patients with alcoholic hepatitis and 9 normal controls, and evaluated for the antigenic presence of chemotactic factor inactivator using an ELISA test. Chemotactic factor inactivator levels were found to be markedly elevated in patients with alcoholic hepatitis (162 ± 24 μg per ml) compared to normals (60 ± 3 μg per ml, p < 0.01). Subdividing the hepatitis patients revealed that the elevation of chemotactic factor inactivator was found to be greatest in those patients with mild alcoholic hepatitis (prothrombin time within normal limits and bilirubin ≤5 mg per dl, 256 ± 44 μg per ml, p < 0.001), while the group with the severest hepatic dysfunction (prolonged prothrombin time and bilirubin >5 mg per dl) did not differ significantly from controls (71 ± 11 μg/ml, p < 0.2). Importantly, the inhibition of C5a-induced chemotactic activity by partially purified chemotactic factor inactivator correlated with antigenic amounts of chemotactic factor inactivator in serum (r = 0.63, p < 0.05). The C5a inhibitory activity in sera obtained from patients with alcoholic hepatitis coprecipitated with chemotactic factor inactivator when serum was precipitated by ammonium sulfate precipitation (45 to 64% saturation). Depleting chemotactic factor inactivator by affinity chromatography resulted in a major loss of the ability of this partially purified chemotactic factor inactivator to inhibit C5a-induced chemotaxis (50 vs. 26% inhibition, p < 0.001), suggesting that chemotactic factor inactivator is a major inhibitor of C5a in these patients. These data suggest that elevations in chemotactic factor inactivator may explain impaired neutrophil chemotaxis in patients with alcoholic hepatitis.
The possible occurrence of “alcoholic hepatitis” in a patient with bulimia in the absence of diagnosable alcoholism
Authors: Cuellar Rafael E. , Tarter Ralph , Hays Amy , Van Thiel David H.
Published: March 2007

A case of a 20-yr-old female with possible “alcoholic hepatitis” and a mixed micro/macronodular cirrhosis occurring in association with overt bulimia and a history of anorexia nervosa, but without any objective evidence of either alcoholism or alcohol abuse, is reported. The possible factors that may have contributed, either alone or in combination, to produce this unusual occurrence are discussed.
Hepatic disease in patients with the acquired immune deficiency syndrome (AIDS)
Authors: Schneiderman David J. , Arenson David M. , Cello John P. , Margaretten William , Weber Thomas E.
Published: March 2007

The spectrum of liver disease in patients with acquired immune deficiency syndrome (AIDS) and the clinical impact of diagnostic percutaneous liver biopsy in this population were evaluated by a retrospective review of hepatic histology, clinical features and laboratory data in 85 patients (26 biopsies, 59 autopsies). Only 1 (3.8%) biopsy and 9 (15%) postmortem livers were histologically normal. Macrosteatosis and nonspecific portal inflammation were the most common histologic abnormalities. Intrahepatic AIDS-specific opportunistic infections or malignancies were detected in 42% of both biopsy and autopsy groups, with Mycobacterium avium-intracellulare the most frequent pathogen seen. Kaposi's sarcoma, although not detected on biopsy, was the most common postmortem AIDS-related hepatic finding. Intrahepatic lymphoma, cytomegalovirus hepatitis and hepatic mycoses were less frequently observed. In general, hepatic involvement represented part of a previously diagnosed, widely disseminated disease process, and liver biopsy led to new AIDS-specific diagnoses in only two patients. We conclude that while liver biopsy is a useful diagnostic tool in selected patients with AIDS, the information provided by biopsy rarely influences therapy or leads to improved survival.
Establishment and characterization of a diethylnitrosamine-initiated woodchuck hepatocyte cell line
Authors: Lee Gang-Hong , Kawaguchi Tokuichi , Nomura Kimie , Kitagawa Tomoyuki
Published: March 2007

Woodchucks free from woodchuck hepatitis virus were treated with diethylnitrosamine in vivo for 2 months, and then hepatocytes obtained by enzymatic perfusion were cultured with the hepatopromoter phenobarbital. This in vivo-in vitro procedure gave rise to proliferating epithelial cell foci, from one of which the presently described hepatocyte cell line (WLC-3) was established and characterized.

WLC-3 cells possess morphological and biochemical features of differentiated hepatocytes, including glucose-6-phosphatase activity and albumin production. Histopathological analysis of the tumor which developed transitorily in nude mouse subcutis after inoculation of the cell line revealed glandular structures comprising cells of hepatocellular-like morphology.

This is the first established woodchuck hepatocyte cell line free from woodchuck hepatitis virus and is therefore expected to be useful for studying the mode of gene expression and viral proliferation of woodchuck hepatitis virus and the mechanisms underlying woodchuck hepatitis virus-related hepatocarcinogenesis.
Chronic Delta Hepatitis: Detection of Hepatitis Delta Virus Antigen in Serum by Immunoblot and Correlation With Other Markers of Delta Viral Replication
Authors: Buti Maria , Esteban Rafael , Jardi Rosendo , Rodriguez-Frias Francisco , Casacuberta Jose , Esteban Juan Ignacio , Allende Elena , Guardia Jaime
Published: March 2007

To investigate the presence of serum hepatitis delta virus antigen by immunoblot and its correlation with other markers of active viral replication (intrahepatic hepatitis D antigen, IgM antibody to hepatitis D and serum hepatitis D virus RNA), we studied serum samples from 50 patients with chronic hepatitis D virus infection (38 with and 12 without intrahepatic hepatitis D antigen). Of the 38 patients with intrahepatic hepatitis D antigen, 27 (71%) had antigen detectable in seurm by immunoblot, whereas only two were reactive by conventional enzyme–linked immunosorbent assay. Thirty–one (82%) patients were also positive for serum hepatitis D virus RNA by spot hybridization and 33 (87%) were positive for IgM anti–hepatitis D virus. All markers were simultaneously present in 24 patients. Circulating hepatitis D antigen was detected in one (8%), IgM antihepatitis D in seven (58%) and hepatitis D virus RNA in two (17%) of the 12 patients who had anti–hepatitis D in serum but not detectable hepatitis D antigen in liver. Hepatitis D antigen was not detected in serum of any of the 15 control patients.

The results suggest that serum hepatitis D antigen as detected by immunoblot and serum hepatitis D virus RNA are similar in sensitivity for detection of active hepatitis D virus replication during chronic infection and constitute useful, sensitive and noninvasive tests for the diagnosis and monitoring of chronic hepatitis D virus infection.
High Levels of Acetaldehyde in Nonalcoholic Liver Injury After Threonine or Ethanol Administration
Authors: Ma Xiao-Li , Baraona Enrique , Hernández-Muñoz Rolando , Lieber Charles S.
Published: March 2007

Acetaldehyde, a product of ethanol oxidation which forms adducts with proteins, has been incriminated in the pathogenesis of alcoholic liver injury. High serum antibody titers against acetaldehyde–protein adducts have been found not only in alcoholics but also in patients with nonalcoholic liver disease, suggesting a contribution of acetaldehyde derived from sources other than exogenous ethanol. To investigate the effect of liver injury on the removal and the production of acetaldehyde, we produced fibrosis and cirrhosis (by chronic administration of carbon tetrachloride) and fatty liver (with very small doses of dimethylnitrosamine) in rats. Endogenous blood acetaldehyde levels increased by 38% in rats with severe liver injury (p < 0.005), but not significantly in rats with fatty liver. However, an i.v. load of threonine (a physiological source of acetaldehyde), in amounts equivalent to the daily intake of this amino acid, increased blood and hepatic acetaldehyde levels in the rats with both types of liver injury more than in controls. Threonine dehydrogenase and dehydratase activities, involved in the major pathways for threonine degradation in mitochondria and cytosol, respectively, were markedly decreased in rats with liver injury with a resulting increase in hepatic threonine concentration. Moreover, the threonine aldolase activity, which splits threonine into glycine and acetaldehyde, remained unaffected or even slightly increased. Liver injury was also associated with impaired mitochondrial functions, including a 10 to 23% decrease in acetaldehyde oxidation (depending upon the severity of the lesions). As a consequence, administration of ethanol (an exogenous source of acetaldehyde) resulted in striking elevations in the levels of acetaldehyde in carbon tetrachloride–treated rats. Thus, liver injury promotes the accumulation of acetaldehyde from either physiological sources or from ethanol by decreasing acetaldehyde oxidation and by enhancing its production from threonine.
Tumor Necrosis Factor–α Induces A K B Sequence–Specific Dna–Binding Protein in Human Hepatoblastoma Hepg2 Cells
Authors: Banerjee Ranjit , Karpen Saul , Siekevitz Miriam , Lengyel Gabriella , Bauer Joachim , Acs George
Published: March 2007

Tumor necrosis factor–α is an inducer of acute–phase protein synthesis in liver cells. The mechanism by which tumor necrosis factor–α alters gene expression in these cells is largely unknown. In this study, we demonstrate that tumor necrosis factor–α stimulates human immunodeficiency virus–1 long terminal repeat–promoted gene expression in the human hepatoblastoma HepG2 cell line and increased binding of trans–activating factors to kappa B (
k
B) DNA sequences. In contrast to lymphocytic cells where the nuclear factors recognizing the
k
B sequences are activated by both tumor necrosis factor–α and phorbol–12–myristate–13–acetate through a posttranslational mechanism, in HepG2 cells phorbol–12–myristate–13–acetate does not activate these factor(s), and de novo protein synthesis seems to be required in HepG2 cells for gene activation by tumor necrosis factor–α.
Gallstone Pancreatitis: When Is the Optimal Time for Intervention?
Authors: Elliott Dan W.
Published: March 2007

The correct timing of surgery in cases of gallstone pancreatitis is debatable. To delineate more clearly the influence of the timing of surgery in the treatment of the disease, a prospective randomized clinical study of early surgery (less than 48 hours after admission) and delayed surgery (more than 48 hours after admission) was conducted in 165 patients. Ranson's prognostic signs of severity of disease were used to classify the patients into two risk groups: mild pancreatitis (three or fewer positive signs) and severe pancreatitis (more than three positive signs). In patients with three or fewer positive Ranson's signs, the time of surgery appeared to have little effect on the outcome, whereas in patients with more than three positive signs, early surgery resulted in a significant increase in rates of morbidity and mortality. Controlled randomization showed that in patients with gallstone pancreatitis, edematous or hemorrhagic necrotizing pancreatitis can develop, with or without impacted stones, early or late in the progression of the disease, during early or delayed surgery. These findings suggest that (1) although a gallstone initiates a bout of pancreatitis, it does not cause the progression of the disease; (2) the fate of the progression of pancreatitis is decided early by the amount of digestive enzymes being activated; (3) early removal of an impacted stone does not ameliorate the progression of pancreatitis; and (4)surgery should be performed during the initial hospital admission after the pancreatitis has subsided.
Hormonal and enzymatic parameters of hepatic regeneration in patients undergoing major liver resections
Authors: Francavilla Antonio , Panella Carmine , Polimeno Lorenzo , Giangaspero Antonio , Mazzaferro Vincenzo , Pan Chen-En , Van Thiel David H. , Starzl Thomas E.
Published: March 2007

Thirteen patients who underwent 40% to 80% removal of their livers had blood samples drawn initially and daily on postoperative days 1 to 7. The enzyme marker of heightened polyamine metabolism, ornithine decarboxylase, and the indicator of DNA synthesis, thymidine kinase, were measured. In addition, the hormones (insulin, glucagon, estradiol and androgen), which in animals are known to reflect and possibly modulate regeneration, were measured. Changes in all these indices followed the same pattern as in rats, dogs and swine but at a slower rate. Ornithine decarboxylase and estradiol increased within 24 hr, but thymidine kinase and insulin rises did not become statistically significant until 3 to 5 days. Using these plasma or serum indices as surrogate measures of biochemical events in the liver itself, regeneration reached a maximum after 4 or 5 days. By computed tomography scan analysis, restoration of hepatic cell mass was not complete until 3 wk. (HEPATOLOGY 1990;12:1134-1138).
Metabolic actions of insulin-like growth factor-I in cultured hepatocytes from adult rats
Authors: Hartmann Heinz , Schmitz Frank , Christ Bruno , Jungermann Kurt , Creutzfeldt Werner
Published: March 2007

Short-term and long-term regulation of hepatic carbohydrate metabolism by insulinlike growth factor-I was studied in primary cultures of adult rat hepatocytes and compared with the metabolic potency of insulin. Insulinlike growth factor-I stimulated the formation of [14C]lactate from [14C]glucose up to three-fold with a half-maximally effective concentration of ˜50 nmol/L. Basal glycogenolysis was inhibited by about 20%, and glucagon-activated glycogenolysis was blocked completely by insulinlike growth factor-I with half-maximally effective concentrations of about 1.5 to 2 nmol/L. The activity of the key glycolytic enzymes glucokinase and pyruvate kinase were induced twofold. The glucagon-dependent induction of phosphoenolpyruvate carboxykinase—the key gluconeogenic enzyme—was antagonized with a half-maximally effective concentration of about 5 nmol/L. This inhibition of the glucagon-dependent induction of the enzyme was accompanied by a similar reduction of the increase in phosphoenolpyruvate carboxykinase—mRNA level as assessed by Northern blot analysis. The potency of insulinlike growth factor-I at half-maximally effective concentrations was approximately 2% to 4% that of insulin. Because binding studies demonstrated a comparably low affinity of insulinlike growth factor-I to the insulin receptor, it is suggested that in adult liver—in contrast to fetal and regenerating liver—insulinlike growth factor-I could exert short-term and long-term metabolic effects on parenchymal cells only through interaction with the insulin receptor. (HEPATOLOGY 1990;12:1139-1143).
Hepatic injury induced by bile salts: Correlation between biochemical and morphological events
Authors: Schmucker Douglas L. , Ohta Minoru , Kanai Setsuko , Sato Yuko , Kitani Kenichi
Published: March 2007

Continuous intravenous infusion of taurochenodeoxycholate at a rate of 0.4 μmol · min−1 · 100 gm−1 for only 30 min in rats caused threefold to tenfold greater release of proteins (alkaline phosphatase, lactate dehydrogenase and albumin) into bile in comparison with animals infused with tauroursodeoxycholate at much higher rates (1.8 μmol · min−1 · 100 gm−1) for 2 hr. The simultaneous infusion of tauroursodeoxycholate and taurochenodeoxycholate (0.6 and 0.4 μmol · min−1 · 100 gm−1, respectively) for 2 hr prevented the marked biochemical changes in the bile induced by taurochenodeoxycholate infusion alone. Livers infused with taurochenodeoxycholate for 15 to 60 min exhibited significantly more necrotic hepatocytes, especially in zone 1, in comparison with animals infused with tauroursodeoxycholate or a combination of taurochenodeoxycholate and tauroursodeoxycholate. A good correlation was observed between biochemical and morphological indices of bile acid—induced hepatocyte injury. These data suggest that (a) primary events induced by the acute infusion of toxic bile salts responsible for cholestasis include zone 1 hepatocellular necrosis and (b) this can be prevented by the simultaneous infusion of tauroursodeoxycholate (HEPATOLOGY 1990;12:1216-1221).
Characteristics of biliary lipid metabolism after liver transplantation
Authors: Ericzon Bo-Göran , Eusufzai Sharif , Kubota Keiichi , Einarsson Kurt , Angelin Bo
Published: March 2007

Biliary lipid metabolism was studied after 10 liver transplantations with continuous drainage of bile. Within 3 wk after transplantation, the new liver produced bile with concentrations of biliary lipids in agreement with those reported for T-tube bile in cholecystectolized nontransplanted subjects. Although changes in biliary lipid composition occurred swiftly in response to various forms of disturbed liver function, they did not provide substantially more information than did standard serum tests or simple measurements of bile flow in most patients. Secretion rates of phospholipids and cholesterol were found to be completely bile acid dependent. For each micromole of bile acids, 0.22 and 0.08 μmol of phospholipids and cholesterol were secreted, respectively. When bile flow was related to bile acid output, a linear relationship was found (r = 0.89), with a positive intercept indicating a bile acid-independent bile flow of approximately 44 μl/min. Analysis of individual bile acids showed almost exclusively primary bile acids. The relative proportion of chenodeoxycholic acid was more prominent during the first days after transplantation. Different explanations for this are discussed. (HEPATOLOGY 1990;12:1221-1228).
Cytokeratins for probing cell lineage relationships in developing liver
Authors: Desmet V. J. , van Eyken Peter , Sciot Raf
Published: March 2007

Immunohistochemistry with monoclonal anti-cytokeratin antibodies has revealed the presence of cytokeratin 19 in embryonic and early fetal hepatocytes. With the differentiation of bile ducts at about the 10th week, cytokeratin 19 disappears from liver cells but remains in bile duct cells. This marks an important step in the organogenesis of the liver.
Changes in interferon receptors on peripheral blood mononuclear cells from patients with chronic hepatitis B being treated with interferon
Authors: Nakajima Shinya , Kuroki Tetsuo , Shintani Machiko , Kurai Osamu , Takeda Tadashi , Nishiguchi Shuhei , Shiomi Susumu , Seki Shuichi , Kobayashi Kenzo
Published: March 2007

We studied the binding of 125I-labeled human interferon-α to peripheral blood mononuclear cells and the activity of 2′,5′-oligoadenylate synthetase in peripheral blood mononuclear cells obtained from 21 patients with chronic hepatitis B who were treated with human interferon-α or interferon-β. Fourteen patients were given interferon daily for 4 wk. Interferon receptors per cell decreased to about 50% of baseline but increased to baseline by 2 wk after therapy ended. The activity of 2′,5′-oligoadenylate synthetase rose about fivefold during therapy, decreasing to baseline by 1 wk after the end of therapy. The seven other patients were given interferon daily for 2 wk, no interferon for 2 wk and then interferon daily for 2 wk more. During both periods of therapy on this schedule, interferon receptors decreased to about 50% but returned to baseline 1 wk after the interferon was stopped. The activity of 2′,5′-oligoadenylate synthetase increased about fivefold during both the first and second periods of therapy and decreased to baseline 1 wk after interferon was stopped. Close negative correlation existed between the number of interferon receptors and the 2′,5′-oligoadenylate synthetase activity. The results of interferon therapy could not be predicted by either the numbers of interferon receptors before therapy or by the decrease in this number during therapy. (HEPATOLOGY 1990;12:1261-1265).
Interferon antibodies may negate the antiviral effects of recombinant α-interferon treatment in patients with chronic hepatitis B virus infection
Authors: Lok Anna Suk-Fong , Lai Ching-Lung , Leung Elsie Kit-Yee
Published: March 2007

In a randomized controlled trial of recombinant α-2a interferon for chronic hepatitis B, interferon antibodies developed in 21 (39%) of 54 Chinese adults who received IFN. No correlation was observed between sex, age, pretreatment serum ALT level or liver histological findings and the development of interferon antibodies. Antibodies were significantly more likely to develop in patients who received lower doses (2.5 or 5 MU/m2) of α-2a interferon than in those who received a higher dose (10 MU/m2): 53% vs. 11% (p = 0.006).

The development of interferon antibodies appeared to reverse the initial antiviral response to treatment, with reappearance of hepatitis B virus DNA in serum in 12 patients and HBeAg in three patients. Sustained clearance of HBeAg was achieved in only one (5%) patient but was achieved in seven (21%) patients without interferon antibodies. The mere presence of interferon antibodies did not preclude an antiviral response to interferon therapy, but patients with high titer neutralizing antibodies were less likely to respond.

These findings suggest that interferon antibodies may negate the antiviral effects of α-2a interferon. A higher incidence of interferon antibodies in Chinese vs. white patients with chronic hepatitis B may contribute to the poorer antiviral response in Chinese patients. (HEPATOLOGY 1990;12:1266-1270).
Hepatitis C virus antibodies in chronic alcoholic patients: Association with severity of liver injury
Authors: Parés Albert , Barrera Josep María , Caballería Joan , Ercilla Guadalupe , Bruguera Miquel , Caballería Llorenç , Castillo Ricardo , Rodés Joan
Published: March 2007

The prevalence of hepatitis C virus antibody and its relationship to the severity of liver disease in chronic alcoholic patients has been assessed, using a recently developed enzyme immunoassay and confirmed by a recombinant immunoblot assay, in 144 patients (mean age ± S.D. = 44.4 ± 11.3 yr) who had consumed >80 gm/day ethanol for >5 yr. Hepatic disease was evaluated by clinical and biochemical studies and by liver biopsy when appropriate. In addition, 76 liver biopsy specimens from these patients were analyzed to determine whether liver lesions were similar in alcoholic patients with and without hepatitis C virus antibodies.

According to clinical and histological features alcoholic patients were divided into five groups: normal liver (45 patients), fibrosteatosis (20 patients), alcoholic hepatitis (14 patients), cirrhosis (61 patients) and chronic hepatitis (4 patients). Hepatitis C virus antibodies were present in 35 alcoholic patients (24.3%). The prevalence of hepatitis C virus antibodies correlated with the severity of liver injury: 2.2% in patients without liver disease, 20% in those with fibrosteatosis, 21.4% in those with alcoholic hepatitis and 42.6% in those with cirrhosis. Hepatitis C virus antibodies were found in one of the four patients with chronic hepatitis (p < 0.001). Furthermore, patients positive for hepatitis C virus antibodies with normal liver or fibrosteatosis showed higher serum bilirubin and γ-globulin concentrations and lower aminopyrine breath test scores than did patients negative for hepatitis C virus antibodies with normal liver or fibrosteatosis. Similar differences between patients with and without hepatitis C virus antibodies were observed in patients with alcoholic hepatitis or cirrhosis. Histological features, except cells within sinusoids, were comparable in alcoholic patients with and without hepatitis C virus antibodies.

The increased prevalence of hepatitis C virus antibodies in alcoholic patients with severe liver injury and the impaired liver function in patients with these antibodies suggest that hepatitis C virus is involved in liver damage in chronic alcoholic patients (HEPATOLOGY 1990;12:1295-1299).
The human hepatic asialoglycoprotein receptor is a target antigen for liver-infiltrating T cells in autoimmune chronic active hepatitis and primary biliary cirrhosis
Authors: Löhr Hanns , Treichel Ulrich , Poralla Thomas , Manns Michael , Büschenfelde Karl-Hermann Meyer Zum , Fleischer Bernhard
Published: March 2007

Autoantibodies to the human hepatic asialoglycoprotein receptor have been found in nearly 50% of the sera of patients with autoimmune chronic active hepatitis and in 15% of patients with primary biliary cirrhosis. In this study we demonstrate that the human hepatic asialoglycoprotein receptor is also a target antigen for T cell—mediated immune responses. Peripheral blood lymphocytes of 37% (7 of 19) of patients with autoimmune chronic active hepatitis and 33% (2 of 6) of patients with primary biliary cirrhosis showed a proliferative response to highly purified human hepatic asialoglycoprotein receptor, whereas no proliferation was found with peripheral blood lymphocytes of patients with chronic viral hepatitis (0 of 13) and healthy blood donors (0 of 4). Moreover, we isolated T-cell clones from liver biopsy samples of two patients with autoimmune chronic active hepatitis and two patients with peripheral blood lymphocytes. Between 2.8% and 14.3% of these clones showed a specific proliferative response to purified human hepatic asialoglycoprotein receptor. The response was restricted to autologous antigen-presenting cells and could be blocked by monoclonal antibodies against human leukocyte antigen—DR molecules. The response of T cells to the human hepatic asialoglycoprotein receptor did not require the lectinlike activity of the asialoglycoprotein receptor. Thus the human hepatic asialoglycoprotein receptor could be identified as a major target antigen of humoral and cellular immune reactions in autoimmune-mediated liver diseases. (HEPATOLOGY 1990;12:1314-1320).
Electron microscopic observations on the accumulation of large granular lymphocytes (pit cells) and kupffer cells in the liver of rats treated with continuous infusion of interleukin-2
Authors: Bouwens Luc , Marinelli Andreas , Kuppen Peter J. K. , Eggermont Alex M. M. , van de Velde Cornelis J. H. , Wisse Eddie
Published: March 2007

Treatment schedules were investigated for in vivo induction of lymphokine-activated killer cells in the rat liver. Treatment of rats with continuous systemic or regional infusion of recombinant human interleukin-2 with a dose of 4 to 8 × 104 U/day during 7 days, resulted in an increase in number of large granular lymphocytes or pit cells in the liver up to 43 times normal. Kupffer cells, nongranular lymphocytes, monocytes and neutrophils also increased in number, but with a maximal fivefold increase this was much less pronounced than for large granular lymphocytes. Kupffer cells showed morphological signs of activation and were frequently seen in mitosis. Frequent mitoses were also observed for large granular lymphocytes, but not for other leukocytes. This indicates that the effect of interleukin-2 treatment on hepatic (sinusoidal) cells was primarily directed to large granular lymphocytes and Kupffer cells. The large granular lymphocyte accumulation occurred mainly intrasinusoidally, but they were also frequently observed in the space of Disse where they are not found in control rats. This may be explained partly by the observed damage or gaps in the endothelial lining. The intrasinusoidal large granular lymphocytes adhered to the endothelium and to Kupffer cells. Higher responses, for all cell types, were found when interleukin-2 was administered regionally, that is, through the hepatic artery rather than through the systemic route (jugular vein), although the differences were not statistically significant. Doses below 4 × 104 U/day did not result in significant increases of large granular lymphocytes in the liver. (HEPATOLOGY 1990;12:1365-1370).
Hepatocyte swelling stimulates macromolecular synthesis
Authors: Wondergem Robert
Published: March 2007

In hepatocytes from fasted rats, several amino acids are known to stimulate glycogen synthesis via activation of glycogen synthase. The hypothesis that an increase in cell volume resulting from amino acid uptake may be involved in the stimulation of glycogen synthesis is supported by the following observations. 1) The extent of stimulation of glycogen synthesis by both metabolizable and nonmetabolizable amino acids was directly proportional to their ability to increase cell volume, except for proline, which stimulated glycogen synthesis more than could be accounted for by the increase in cell volume. 2) Both cell swelling and stimulation of glycogen synthesis by amino acids were prevented when hepatocytes were incubated in hyperosmotic media containing sucrose or raffinose. 3) Increasing the cell volume by incubating hepatocytes in Na+-depleted media in the absence of amino acids also stimulated glycogen synthesis. 4) Stimulation of glycogen synthesis by Na+ depletion was prevented by restoring the normal osmolarity with sucrose, but not with choline chloride which, by itself, stimulated glycogen synthesis and increased cell volume.

It is concluded that stimulation of glycogen synthesis by amino acids is due, at least in part, to an increase in hepatocyte volume resulting from amino acid uptake, and that hepatocyte swelling per se stimulates glycogen synthesis.
Splanchnic vasodilation and renal vasoconstriction: A key to the hepatorenal syndrome?
Authors: Bosch Jaime
Published: March 2007

Systemic, femoral and renal hemodynamics were evaluated in 7 control subjects and 20 cirrhotic patients with ascites, 14 of them without (group A) and 6 with (group B) functional renal failure. Hyperdynamic systemic circulation, increased plasma volume, and hyperreninism were present in groups A and B. These changes were more severe in group B, which showed, as compared with group A, lower total vascular resistances and mean arterial pressure together with increased cardiac index and plasma renin activity. Significant differences in regional hemodynamics were also observed between groups. In group A, femoral and renal fractions of cardiac output were respectively increased and reduced as compared with controls. By contrast, in group B, both fractions of cardiac output were reduced when compared either with controls or with group A. In the entire patient group there was a close direct correlation between femoral and renal fractions of cardiac output (r = 0.88; p < 0.001) and both of them correlated independently with total vascular resistances (r = 0.79; p < 0.001 in both cases). These results indicate that, in nonazotemic cirrhotics with ascites, vasodilation in extrasplanchnic areas contributes to the genesis of the hyperdynamic circulation. The presence in group B of a reduced flow to extrasplanchnic territories, in association with an increase of the hyperdynamic circulatory status, suggests that exacerbation of splanchnic vasodilation is involved in the development of the hepatorenal syndrome. Finally, in cirrhosis, the changes that occur in systemic hemodynamics appear to influence renal function and renal blood flow.
Mechanism for binding of fatty acids to hepatocyte plasma membranes: Different interpretation
Authors: Storch Judith
Published: March 2007

The purpose of this study was to examine the interaction between fatty acids and plasma membranes from liver cells. We were unable to reproduce the reported effect of heating on the capacity of these membranes to bind [3H]oleate (Stremmel et al. Proc Natl Acad Sci USA, 1985;82:4-8). In fact, the distribution of [3H]oleate between plasma membranes and unilamellar vesicles of lipids extracted from these membranes was in favor of the lipids, indicating the absence of a detectable amount of binding to a putative fatty acid binding protein in plasma membranes. Radius of curvature of vesicles (125 Å vs 475 Å) had no effect on the partitioning of fatty acid. In addition, the distribution of [3H]oleate between plasma membranes and other phases had the properties of a partition coefficient over a 200-fold range of [3H]oleate. There was no evidence in this experiment for a binding isotherm, i.e., binding of [3H]oleate at a specific site, superimposed on the nonspecific partitioning of [3H]oleate into the lipids of the plasma membrane. There was no competition between [14C]oleate and [3H]palmitate for entry into plasma membranes. Finally, rates of uptake of [14C]oleate and [3H]palmitate by perfused rat liver were not affected by the presence of the other fatty acid in perfusates. These data indicate that the avidity of hepatocyte plasma membranes for [3H]oleate is a simple consequence of the physical chemical properties of oleate, lipids, and water. The data exclude the idea that the uptake of fatty acids into cells is the result of binding proteins and/or catalyzed reactions at the water-membrane interface of the cell or within the plane of the plasma membrane.
Levels of the human hepatocyte growth factor in serum of patients with various liver diseases determined by an enzyme-linked immunosorbent assay
Authors: Tsubouchi Hirohito , Niitani Yoshiyuki , Hirono Shuichi , Nakayama Hiroyuki , Gohda Eiichi , Arakaki Naokatu , Sakiyama Osami , Takahashi Kozo , Kimoto Masayoshi , Kawakami Shuichi , Setoguchi Minami , Tachikawa Tetsuya , Shin Sadahito , Arima Terukatsu , Daikuhara Yasushi
Published: March 2007

We have found a hepatotrophic factor in plasma or sera of patients with fulminant hepatic failure and have purified human hepatocyte growth factor from plasma of these patients. In this study we developed an enzyme-linked immunosorbent assay with high specificity and sensitivity for human hepatocyte growth factor in human serum. This assay for serum human hepatocyte growth factor is a sandwich method consisting of three steps. The standard curve for human hepatocyte growth factor appeared to be linear in the range of 0.20 to 12.50 ng purified human hepatocyte growth factor/ml (2.35 to 147 pmol/L). The assay took about 4 hr. Serum human hepatocyte growth factor values in patients with fulminant hepatic failure measured by enzyme-linked immunosorbent assay showed a strong positive correlation with that by bioassay using rat hepatocytes in primary culture. The mean value of serum human hepatocyte growth factor for 30 normal subjects was 0.24 ± 0.12 (S.D.) ng/ml that for 23 patients with fulminant hepatic failure was 8.06 ± 1.76 (S.E.M.) ng/ml - > 30 times greater than the mean value for normal subjects. Serum human hepatocyte growth factor levels in patients with acute hepatitis, chronic hepatitis and cirrhosis were found to be slightly higher than those in normal subjects, but only the increase in serum human hepatocyte growth factor of acute hepatitis patients was statistically significant. The enzyme-linked immunosorbent assay for serum human hepatocyte growth factor should prove useful for serum human hepatocyte growth factor level measurement in patients with various liver diseases. (HEPATOLOGY 1991;13:1-5).
Multiple cell cycles occur in rat hepatocytes cultured in the presence of nicotinamide and epidermal growth factor
Authors: Mitaka Toshihiro , Sattler Carol A. , Sattler Gerald L. , Sargent Linda M. , Pitot Henry C.
Published: March 2007

Multiple rounds of cell division were induced in primary cultures of rat hepatocytes in serum-free medium containing 10 mmol/L nicotinamide and 10 ng epidermal growth factor/ml. Cells per culture almost doubled between day 1 and day 5. The proliferating cells were predominantly mononucleate. The time course of DNA synthesis in cultured hepatocytes showed that peaks of the incorporation of 3Hthymidine were observed at 60 hr and 82 hr after plating. Labeling indices of the cells indicated that almost half the cells were labeled with 3H-thymidine in the periods 48 to 72 hr and 72 to 96 hr after plating. In addition, about 20% of the hepatocytes in culture initiated a second round of the cell cycle between 48 and 96 hr in culture, as demonstrated by the use of continuous treatments with 3H-thymidine and 5-bromo-2′-deoxyuridine. Furthermore, by day 4 of culture, about 40% and 15% of metaphases resulted from a second and third round of cell division, respectively. The cultured hepatocytes on day 5 stained with albumin immunocytochemically, and the activity of tyrosine aminotransferase was induced by dexamethasone and glucagon on day 3. In addition, electron micrographs revealed that dividing cells not only had many characteristics of liver mitochondria and bile canaliculus-like structures, but many also contained a few large peroxisomes with internal crystalline nucleoids. (Hepatology 1991;13:21-30).
Point mutation, allelic loss and increased methylation of c-Ha- Ras gene in human hepatocellular carcinoma
Authors: Ogata Norio , Kamimura Tomoteru , Asakura Hitoshi
Published: March 2007

Somatic alterations of the c-Ha-ras gene were examined in 21 Japanese patients with hepatocellular carcinoma. Restriction endonuclease analysis by double digestion with MspI and HpaII revealed that DNAs from two of 21 hepatocellular carcinoma tissues were affected by nucleotide substitution at the twelfth amino acid coding sequence of the c-Ha-ras gene. DNAs from cirrhotic noncancerous liver tissue, but not leukocytes, of one of these patients possessed the mutation, whereas DNAs from noncirrhotic liver tissue and leukocytes of the other patient did not. In one of the nine patients harboring heterozygosity for c-Ha-ras—related BamHI-fragments, the loss of one allele was demonstrated as a somatic change not only in DNA from the tumor tissue but also in DNA from the cirrhotic nontumorous tissue. In two of the 19 patients comparatively examined for digestion patterns of c-Ha-ras locus with HpaII and MspI, extensive methylation was observed as a somatic modification in both DNAs from the tumor and the cirrhotic nontumorous tissues. These results thus indicate that the genetic lesions affecting the c-Ha-ras gene do occur in human hepatocellular carcinoma and probably serve as one of the multiple steps in the process of hepatic carcinogenesis. (Hepatology 1991; 13:31-37).
Specificity of the hepatocyte Na+ -dependent taurocholate transporter: Influence of side chain length and charge
Authors: Hardison William G. M. , Heasley Victor L. , Shellhamer Dale F.
Published: March 2007

Trihydroxy bile acids with differing nonsterol chain length and charge were synthesized to define the effect of these parameters on the ability to competitively inhibit the Na+-dependent uptake of 14C taurocholate into isolated rat hepatocytes. Compounds with long side chains (≥ 0.8 nm) beyond carbon-17 of the sterol nucleus and carrying a negative charge or no charge were potent inhibitors. Introduction of a positive charge into the side chain weakened inhibition. When the length of the chain beyond carbon-17 fell below about 0.7 nm, charge still influenced inhibitory potency, but the effect was reversed and positively-charged chains yielded slightly greater inhibition than negatively-charged chains. From these results one may postulate a positively-charged cell surface domain extending outward from a point about 0.7 nm from the sterol nucleus receptor region. Up to about 0.7 nm from the sterol nucleus receptor region one might postulate a negative cell surface charge to account for the weaker inhibitory potency of compounds with short negatively-charged chains. Nonetheless, a short chain, regardless of charge, weakened inhibition, suggesting that a long negatively-charged side chain is necessary to orient the sterol moiety for optimal receptor fit. These data confirm that the Na+ -dependent taurocholate transport site is sensitive to alterations of side chain charge and length and emphasize the importance of structure when designing bile acid analogs to probe taurocholate transport mechanisms. (Hepatology 1991;13:68-72).
Prophylactic sclerotherapy for esophageal varices: Long-term results of a single-center trial
Authors: Triger David R. , Smart Howard L. , Hosking Shorland W. , Johnson Alan G.
Published: March 2007

Survival after prophylactic sclerotherapy was assessed in a single-center study involving 99 cirrhotic (41 alcoholic) patients enrolled over 8-yr. The wedged hepatic vein pressure gradient was measured; those with pressure ≥ 12 mm Hg were randomized to receive sclerotherapy or no treatment. The rest were not randomized. Patients in all three groups who bled were treated with emergency endoscopy and sclerotherapy. Stratification according to presence of ascites was also undertaken. Median follow-up was 61 mo (range = 14 to 107 mo). Survival among unrandomized patients was significantly longer than among randomized patients (p < 0.006), but there was no significant difference between those treated by sclerotherapy and the controls (p = 0.27). Alcoholic cirrhotic patients undergoing sclerotherapy had better 2-yr survival than did the controls (80% vs. 43%; p = 0.09), but this benefit was not sustained at 5 yr. Survival in the nonalcoholic patient groups was identical. Only 10 of 50 deaths were caused by variceal bleeding. Forty-eight percent of patients with large varices bled, compared with 20% of patients with small varices. Wedged hepatic vein pressure < 12 mm Hg accurately identified alcoholic patients at low risk of variceal bleeding but not nonalcoholic patients. Only four episodes of variceal bleeding were attributable to elective sclerotherapy.

We conclude that in our population, prophylactic sclerotherapy alone does not improve survival. The discrepancy in survival between alcoholic and nonalcoholic cirrhotic patients suggests that factors other than variceal hemorrhage may be responsible for the difference. (Hepatology 1991; 13:117-123).
Hemodynamic study during transdermal application of nitroglycerin tape in patients with cirrhosis
Authors: Iwao Tadashi , Toyonaga Atsushi , Sumino Michihiro , Takagi Kohsuke , Ohkubo Kazunori , Inoue Rintaroh , Tanikawa Kyuichi
Published: March 2007

We studied 14 patients with portal hypertension and cirrhosis using portal and hepatic vein catheterizations to determine the effects of transdermal application of nitroglycerin tape (containing 10 mg of nitroglycerin and capable of releasing 6 to 7 mg of nitroglycerin in 12 hr) on splanchnic hemodynamics. Patients randomly received nitroglycerin (n = 7) or a placebo (n = 7). No significant changes were observed after the administration of the placebo. In contrast, transdermal nitroglycerin caused a significant reduction in portal pressure, as evaluated by measurements of the portal venous pressure gradient (−22%, p < 0.01). The reduction of portal pressure was due to a decrease in the portal venous pressure, with no changes in the free hepatic venous pressure. Despite the fall in portal pressure, the hepatic blood flow was maintained. These findings suggest that transdermal nitroglycerin could be potentially useful in the treatment of portal hypertension associated with cirrhosis. (Hepatology 1991;13:124-128).
Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis
Authors: Donaldson Peter T. , Farrant Mark J. , Wilkinson Mark L. , Hayllar Karen , Portmann Bernard C. , Williams Roger
Published: March 2007

Human leukocyte antigen typing was performed in 81 patients with primary sclerosing cholangitis to investigate reported associations between human leukocyte antigen type and this disease. The results showed a significant increase in the frequency of the antigens B8 and DR3 compared with controls (53% vs. 23%, p < 0.0005, and 56% vs. 21%, p < 0.0005). This was caused by a significant rise in the frequency of the human leukocyte antigen A1 B8 DR3 haplotype (32 of 81 patients, 40% vs. 12 of 100 patients, 12%, p < 0.0005). By contrast, a significant reduction was seen in the frequency of the antigens B44 and DR4 (12% vs. 31%, p < 0.005, and 12% vs. 34%, p p < 0.001, pc p < 0.011) because of the complete absence of the B44 DR4 haplotype in the patient group (p = 0.027, Fisher's exact test). When all the DR3-positive individuals (including the DR2/DR3 heterozygotes) were eliminated, a significant secondary association with DR2 was noted, 25 (69%) of 36 remaining patients being DR2-positive compared with 27 (34%) of 79 DR3 negative controls (p < 0.0005, pc p < 0.006). Only 9% of the patients were DR2-positive and DR3-positive. Kaplan-Meier analysis demonstrated that survival was not influenced by the presence of either haplotype nor by the individual antigens. Patients who were DR3-positive were first seen at a significantly younger age than those who were DR2-positive (mean ages = 33 yr and 44 yr, respectively, p p < 0.002, Student's t test).

These data suggest that both human leukocyte antigen DR2 and the haplotype A1 B8 DR3 are independent factors that influence the initiation of PSC but do not determine the course of the disease. Furthermore, DR2 and DR3 may identify two etiological subsets of PSC. (Hepatology 1991;13:129-133).
Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to Pre-S- and S-encoded viral surface antigens
Authors: Gerken Guido , Paterlini Patricia , Manns Michael , Housset Chantal , Terre Sylvie , Dienes Hans-Peter , Hess Georg , Gerlich Wolfram H. , Berthelot Pierre , Büschenfelde Karl-Hermann Meyer Zum , Brechot Christian
Published: March 2007

The polymerase chain reaction was evaluated as a diagnostic tool in 72 chronic hepatitis B virus carriers. Hepatitis B virus DNA was detectable in the serum of HBsAg—positive virus carriers using aliquots as small as 100 al. The detection limit for cloned hepatitis B virus DNA was 100 ag. Primer pairs for different regions of the HBV genome resulted in different sensitivity. Detection of the amplified hepatitis B virus DNA by Southern blotting and subsequent scintillation counting or densitometry allowed a semiquantitative assay. Using several primer pairs in parallel for optimal detection, all HBeAg-positive HBsAg carriers, 80% of HBe antibody—positive symptomatic HBsAg carriers and 57% of asymptomatic HBe antibody—positive HBsAg carriers were found to have hepatitis B virus DNA in the serum. During antiviral therapy hepatitis B virus DNA disappeared by the polymerase chain reaction assay in patients who became HBeAg negative, but polymerase chain reaction detected a relapse earlier than did the conventional dot blot. Pre-S antigens were assayed in serum and liver samples from most chronic carriers by enzyme-linked immunosorbent assay and/or immunoblot. Although most viremic carriers were strongly positive for pre-S1 and pre-S2 antigens, some hepatitis B virus DNA—positive HBsAg carriers did not have detectable pre-S antigens, and vice versa. Our data show that assay of hepatitis B virus DNA in the serum by polymerase chain reaction is by far more proficient than by dot blot and that it cannot be replaced by serological assays of HBeAg or pre-S antigen. (Hepatology 1991;13:158-166).