bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative Metabolism in Cirrhotic Patients With and Without Hepatocellular Carcinoma: Effects of Malnutrition
Authors: Guglielmi Francesco William , Mastronuzzi Tecla , de Marco Maria , Laddaga Lucia , Panella Carmine , Francavilla Antonio
Published: March 2007

ABSTRACT

Progressive degrees of metabolic alterations are frequent in cirrhosis impairing peripheral tissue and body composition. Hepatocellular carcinoma worsens protein wasting and malnutrition. A normal energy production rate and an abnormal substrate oxidation rate are well–known findings in cirrhosis; however, no data are available on cirrhotic patients with hepatocellular carcinoma. The aim of this study was to measure oxidative metabolism in cirrhotic patients with and without hepatocellular carcinoma and to investigate the correlation between energy production rate, respiratory quotient and nutritional state. Thirteen male cirrhotic patients with hepatocellular carcinoma (8 well–nourished and 5 malnourished) were compared with 17 cirrhotic patients without hepatocellular carcinoma (11 well–nourished and 6 malnourished) and six controls who were age and sex matched. A diagnosis of malnutrition was made if the fat mass percentage was reduced to less than 20% of the patient's body weight. Indirect calorimetry was performed between 8 and 10 AM, after a 12–hr fast, for 30 min (with a 10–min steady–state period), and measured energy production rate was calculated according to Weir's formula. Body composition was assessed by means of the Durnin and Womersley formula. Anthropometry and bioelectric impedance analysis showed no variations in kilograms of fat–free mass in our malnourished patients. Our data show that, when the energy production rate is measured while the patient is at rest and corrected for fat–free mass, the energy requirements of cirrhotic patients and cirrhotic patients with hepatocellular carcinoma matched that of the controls, regardless of nutritional state. A significant reduction (p < 0.01) of respiratory quotient was documented in the presence of malnutrition both in cirrhotic patients and cirrhotic patients with hepatocellular carcinoma. Well–nourished cirrhotic patients and well–nourished cirrhotic patients with hepatocellular carcinoma had normal oxidative patterns. (Hepatology 1992;16:1144-1149.)
Aflatoxin B1 Dna Adducts in Smeared Tumor Tissue From Patients With Hepatocellular Carcinoma
Authors: Chen Chien-Jen , Zhang Yu-Jing , Lu Sheng-Nan , Santella Regina M.
Published: March 2007

ABSTRACT

Aflatoxins are well–known animal hepatocarcinogens, but the association between aflatoxins and human hepatocellular carcinoma remains to be elucidated. A study method consisting of indirect immunofluorescence assay combined with densitometry was developed to quantitate aflatoxin B1 DNA adducts in smeared liver tissue obtained at the time of biopsy for diagnosis in 50 hepatocellular carcinoma patients in Taiwan. Monoclonal antibody 6A10, generated against the persistent form of the major N7 guanine adduct of aflatoxin B1, was used for detection of adduct. Thirty–five (70%) of the hepatocellular carcinoma samples had detectable levels of aflatoxin B1 DNA adducts (≥ 1/106 nucleotides). The detection rate was slightly lower in men (69%) than in women (75%), and younger patients had a significantly higher rate of adducts (83%) than did older ones (58%). Carriers of both HBsAg and HBeAg, carriers of HBsAg only and noncarriers had different rates of detection: 29%, 74% and 82%, respectively. Patients with family histories of hepatocellular carcinoma had a higher detection rate (100%) than did those patients without such histories (67%). No association was found between aflatoxin B1 DNA adducts in liver tissue and Child's score for severity of liver disease. The results suggest that aflatoxin B1 may be involved in the pathogenesis of hepatocellular carcinoma in Taiwan. Our immunohistochemical method for analysis of adducts in small numbers of cells from the target organ should improve results of monitoring for the biologically effective dose of aflatoxin. Hepatology 1992;16:1150-1155.
Emergency Liver Transplantation for Fulminant Liver Failure in Infants and Children
Authors: Devictor Denis , Desplanques Laurence , Debray Dominique , Ozier Yves , Dubousset Anne-Marie , Valayer Jacques , Houssin Didier , Bernard Olivier , Huault Gilbert
Published: March 2007

ABSTRACT

We report our results with orthotopic liver transplantation in children with fulminant liver failure. Thirty–five children with fulminant liver failure were evaluated for liver transplantation. The main causes of liver failure were viral hepatitis (54.2%), drug–induced liver injury (14.2%) and Wilson's disease (11.4%). Children were considered as candidates for liver transplantation only if hepatic encephalopathy was associated with a decrease in the level of factor V to below 25%. Seven children (20%) did not meet this criterion and recovered spontaneously. Six children (17.1%) had contraindications for liver transplantation and died. In three of these six children, contraindications included irreversible brain damage at the time of admission. Twenty–two children (62.8%) met the criteria for liver transplantation and were placed on the emergency transplant list. Three of them died awaiting grafts. Nineteen children underwent liver transplantation; 13 of them (68.4%) are alive without sequelae, after 6 mo to 4 yr of follow–up, at this writing. Four of the children who died after surgery had severe encephalopathy on admission that did not improve after liver transplantation. In conclusion, emergency liver transplantation appears to be an effective treatment for children with fulminant liver failure. Nevertheless, irreversible brain damage developed in 10 patients, and they died before or after surgery. We postulate that many of these deaths could have been avoided if children had been transferred to a liver transplantation facility and had undergone transplantation earlier. We emphasize that children with acute liver failure should be transferred to a center that performs liver transplantation before the development of hepatic encephalopathy. (Hepatology 1992;16:1156-1162.)
Overexpression of P53: A Rare Event in A Large Series of White Patients With Hepatocellular Carcinoma
Authors: Laurent-Puig Pierre , Flejou Jean-François , Fabre Monique , Bedossa Pierre , Belghiti Jacques , Gayral François , Franco Dominique
Published: March 2007

ABSTRACT

Mutant p53 has been found in a wide variety of human malignancies including carcinomas of the lung, breast and colon. Because of the controversial mutational rate of the p53 gene in hepatocellular carcinoma, a large series of liver tumors from white patients with different risk factors was examined immunohistochemically for expression of the p53 mutant to assess its prevalence and the relationships between p53 overexpression and clinicopathological data. Nine of 58 specimens were found to have detectable evidence of p53 gene mutation by virtue of the immunohistochemical detection of mutant p53 protein. The p53 mutation was more frequent in patients with serological hepatitis B and C markers than in patients without these markers (p = 0.046). The prevalence of p53–positive tumors was also significantly higher in the group of tumors with invaded portal branches than in the group without (p = 0.02). Our results showed that p53–positive hepatocellular carcinoma is a rare finding in patients exposed to a low dietary aflatoxin intake and that p53 mutation seems to occur at a late stage of the tumoral process and could contribute to an aggressive tumoral phenotype. (Hepatology 1992;16:1171-1175.)
Characterization of Sodium–Dependent Amino Acid Transport Activity During Liver Regeneration
Authors: Fowler Fred C. , Banks Robert K. , Mailliard Mark E.
Published: March 2007

ABSTRACT

Liver regeneration occurs after removal of or damage to a portion of the liver; it leads to restoration of the original liver mass. The activities of three sodium–dependent amino acid transporters–system A, system N and system ASC–were determined during a 5–day period of liver regeneration in the rat. Seventy–percent hepatectomy or laparotomy was performed in pairs of rats; these rats' livers were removed at different time points after surgery. Transport activity was determined through measurement of the Na+–dependent uptake of tritiated amino acids by isolated hepatic plasma membrane vesicles. System A activity, as measured by the Na+ –dependent uptake of 2–aminoisobutyric acid, is increased in the regenerating liver 2 to 24 hr after surgery compared with that of controls. Kinetic analysis of 2–(methylamino)isobutyric acid uptake showed a 100% increase in the maximum velocity of system A transport in the hepatectomized animals with no change in the Michaelis constant, suggesting an increase in the number of system A transport proteins in the plasma membrane of regenerating liver. During liver regeneration, no changes were noted in the transport activities of system N and system ASC as measured by the uptake of glutamine and cysteine, respectively, in the presence of 2–(methylamino)isobutyric acid. Our work suggests that system A performs a unique role in the secondary active transport of its substrate neutral amino acids to meet the metabolic demands of regenerating liver. (Hepatology 1992;16;1187-1194.)
The Incidence of Portal Vein Thrombosis At Liver Transplantation
Authors: Nonami Toshiaki , Yokoyama Itsuo , Iwatsuki Shunzaburo , Starzl Thomas E.
Published: March 2007

ABSTRACT

The incidence of portal vein thrombosis was examined in 885 patients who received orthotopic liver transplantations for various end–stage liver diseases between 1989 and 1990. The thrombosis was classified into four grades. Grade 1 was thrombosis of intrahepatic portal vein branches, grade 2 was thrombosis of the right or left portal branch or at the bifurcation, grade 3 was partial obstruction of the portal vein trunk, and grade 4 was complete obstruction of the portal vein trunk. Among the 849 patients without previous portosystemic shunt, 14 patients (1.6%) had grade 1, 27 patients (3.2%) had grade 2, 27 patients (3.2%) had grade 3 and 49 patients (5.8%) had grade 4 portal vein thrombosis. The incidence of portal vein thrombosis was highest (34.8%) in the patients with hepatic malignancy in the cirrhotic liver, followed by those with Budd–Chiari syndrome (22.2%) and postnecrotic cirrhosis of various causes (15.7%). The patients with encephalopathy, ascites, variceal bleeding, previous splenectomy and small liver had significantly higher incidences of portal vein thrombosis than the others. The total incidence of portal vein thrombosis among the 36 patients with previous portosystemic shunt was 38.9%, which was significantly higher than that (13.8%) of those without shunt. (Hepatology 1992;16;1195-1198.)
Appearance of Hepatocytelike Cells in the Interlobular Bile Ducts of Human Liver in Various Liver Disease States
Authors: Nomoto Minoru , Uchikosi Yasurou , Kajikazawa Natumi , Tanaka Yasuki , Asakura Hitosi
Published: March 2007

ABSTRACT

Among 1,098 liver biopsy specimens obtained from patients with various liver diseases characterized by liver injury, 58 epithelial cells whose cytoplasms stained positively by the periodic acid-Schiff stain (digested with diastase) were recognized in the interlobular bile ducts of 37 specimens from 36 patients. Light microscopic study revealed that the cytoplasms of these cells were clear or stained weakly eosinophilic on hematoxylin and eosin staining and that the cell limits were distinct. From their reaction with periodic acid-Schiff stain and from electron microscopic observation it was clear that these cells contained an abundance of glycogen and were located among the normal bile duct cells surrounded by basement membrane. On electron microscopy, these cells had microvilli of equal sizes on their luminal surfaces and many irregularly sized microvilluslike cell membrane projections on their basal surfaces. They rested on basement membrane with basal spaces. These cells varied in size from 25.0 to 452.2 μm2 (mean = 212.2 μm2). In contrast, the sizes of normal bile duct cells and hepatocytes ranged from 20.0 to 69.3 μm2 (mean = 34.2 μm2) and from 113.0 to 860.3 μm2 (mean = 447.0 μm2), respectively. Immunohistochemical study with antiserum to cytokeratin 19, albumin and α1–antitrypsin on serially cut frozen sections showed that some of these cells expressed markers of bile duct cells and hepatocytes. Some cells expressed only the markers of hepatocytes. Computer graphic three–dimensional reconstruction clearly demonstrated that these cells were located sparsely (but sometimes in groups) among normal interlobular bile duct cells, without any connection to the surrounding parenchymal hepatocytes. This pathognomonic significance of these cells is unknown, but they may represent the transformation or metaplasia of bile duct cells to hepatocytes. (Hepatology 1992;16:1199-1205.)
Chronic Ethanol Consumption Disturbs G–Protein Expression and Inhibits Cyclic Amp-Dependent Signaling in Regenerating Rat Liver
Authors: Diehl Anna Mae , Yang Shi Qi , Cote Piera , Wand Gary S.
Published: March 2007

ABSTRACT

Evidence suggests that ethanol desensitizes hepatocytes to the trophic effects of hormones. Cyclic AMP-dependent signals are important regulators of intermediary metabolism, cellular proliferation and differentiation, and modulate liver growth during hepatic regeneration. The events leading to cyclic AMP accumulation after partial hepatectomy were characterized in rats consistently fed ethanol–containing diets and compared with results in rats fed isocaloric amounts of nonethanol diet to determine whether altered cyclic AMP-dependent signal transduction contributes to ethanol–associated aberrations in hepatic growth regulation. Ethanol treatment significantly inhibited hepatic accumulation of cyclic AMP after partial hepatectomy. This was most likely the result of decreased synthesis of cyclic AMP because activation of adenylyl cyclase by agents acting through receptors (e.g., glucagon or isoproterenol), GTP–binding proteins (GTP–γ–S) and directly on adenylyl cyclase (e.g., forskolin) was significantly inhibited in ethanol–fed rats. Both homologous and heterologous desensitization contributed to this effect. β1–Adrenergic receptors were relatively down–regulated 6 hr after partial hepatectomy in ethanol–fed rats, whereas glucagon receptor kinetics were similar in the two groups. Liver membrane expression of GTP–binding proteins differed markedly after partial hepatectomy in ethanol–fed and pair–fed rats. Ethanol significantly inhibited post-partial hepatectomy induction of the stimulatory G protein, GSα but led to overexpression of the inhibitory, G12α, subunit. Steadystate messenger RNA levels of these G proteins were similar in ethanol–fed and pair–fed rats, suggesting that ethanol inhibits G protein expression posttranscriptionally. Differences in hepatic expression of the cyclic AMP-regulated gene, phosphoenolpyruvate carboxykinase, were sought to screen for potential functional implications of altered cyclic AMP-dependent signaling. Post-partial hepatectomy induction of phosphoenolpyruvate carboxykinase expression was inhibited in ethanol–fed animals. Ethanol–induced desensitization of signaling by way of cyclic AMP-dependent paths may constitute a major obstacle to the orderly process of liver regeneration. (Hepatology 1992;16:1212-1219.)
Sequential Appearance of Intestinal Mucosal Cell Types in the Right and Caudate Liver Lobes of Furan–Treated Rats
Authors: Elmore Lynne W. , Sirica Alphonse E.
Published: March 2007

ABSTRACT

Furan rapidly induces in rat liver a unique, lobespecific pattern of development of intestinal metaplasia and associated cholangiofibrosis. To establish early cell–precursor relationships in the genesis of this cholangiofibrosis, a time–course study was conducted in which young adult male Fisher 344 rats received furan by gavage at a daily dose of 45 mg/kg body wt over a 32–day treatment period. An analysis of individual liver lobes obtained at different time points from these animals during furan treatment revealed the following sequence of histopathological changes, which were located mainly in the right and, to a lesser extent, the caudate liver lobes: day 1, severe hepatonecrosis in zone 3 extending into zone 2 of the liver acini; days 3 to 5, presence of a diffuse inflammatory cell infiltrate in hepatonecrotic areas, which gradually resolved; day 7, prominent bile ductule hyperplasia in tissue sections exhibiting marked loss of normal liver parenchyma; day 9, continued replacement of injured liver by hyperplastic bile ductule tissue, which now contained occasional metaplastic glandular structures composed of columnar basophilic epithelial cells; days 12 to 16, increasing cell diversity in the developing metaplastic glands, with the sequential appearance of goblet cells, Paneth cells and serotonin–positive neuroendocrine cells; and day 32, typical cholangiofibrosis defined by hyperplastic bile ductule-type structures in association with an increased number of metaplastic intestinal glands and progressively more dense fibrotic stroma. Interestingly, at 16 and 32 days the cellular composition of the newly formed metaplastic intestinal glands in liver closely resembled that of the crypts of Lieberkühn in the normal adult rat small intestine. These results strongly suggest that hyperplastic bile ductule cells differentiate preferentially along the small–intestinal mucosa lineage in the right and caudate liver lobes of the furan–treated rats. In addition, they support the view that small intestinal metaplasia is an important intermediate in the development of cholangiofibrosis in liver. (Hepatology 1992;16:1220-1226.)
Direct Evidence That Hepatocyte Growth Factor Is A Hepatotrophic Factor for Liver Regeneration and Has A Potent Antihepatitis Effect In Vivo
Authors: Ishiki Yoshihide , Ohnishi Hiroo , Muto Yasutoshi , Matsumoto Kunio , Nakamura Toshikazu
Published: March 2007

ABSTRACT

Hepatocyte growth factor, a potent mitogen for mature hepatocytes in vitro, seems to function as a hepatotrophic factor for liver regeneration. We examined the mitogenic effect of hepatocyte growth factor on mouse liver in vivo. The labeling index of hepatocytes was markedly increased when recombinant human hepatocyte growth factor was injected intravenously into mice subjected to 30% hepatectomy (control, 1.7% ± 0.1%; 1 μg hepatocyte growth factor, 6.4% ± 1.3%; 5 μg hepatocyte growth factor, 18.3% ± 0.2%) and into mice administered carbon tetrachloride (control, 12.7% ± 1.0%; 1 μg hepatocyte growth factor, 26.3% ± 2.8%) or α–naphthylisothiocyanate (control, 0.4% ± 0.1%; 1 μg hepatocyte growth factor, 3.8% ± 1.1%; 5 μg hepatocyte growth factor, 14.2% ± 2.0%). In addition, weights of the remnant livers in mice given hepatocyte growth factor 60 hr after 30% hepatectomy were significantly greater than those of untreated control mice (control, 0.93 ± 0.04 gm; 5 μg hepatocyte growth factor, 1.06 ± 0.04 gm). Hepatocyte growth factor prevented any marked increase in the serum levels of liver enzymes and bilirubin when it was administered to mice also treated with α–naphthylisothiocyanate (control: ALT, 394 ± 278 IU/L; lactate dehydrogenase, 2,644 ± 1,109 IU/L; bilirubin, 9.6 ± 2.6 mg/dl; and 5 μg hepatocyte growth factor: ALT, 135 ± 7.9 IU/L; lactate dehydrogenase, 1,672 ± 626 IU/L; bilirubin, 1.0 ± 0.8 mg/dl). Our findings show that intravenously injected hepatocyte growth factor stimulates the growth of hepatocytes in mouse liver and protects the integrity of hepatocytes in vivo against hepatitis caused by hepatotoxin. Thus hepatocyte growth factor may prove to be useful as a treatment for liver diseases as it is a hepatotrophic factor with a potent antihepatitis effect. (Hepatology 1992;16:1227-1235.)
Inflammation and Platelet–Activating Factor Production During Hepatic Ischemia/Reperfusion
Authors: Zhou Weiguo , McCollum Mark O. , Levine Barry A. , Olson Merle S.
Published: March 2007

ABSTRACT

The role of platelet–activating factor as a potential mediator of hepatic inflammatory injury associated with liver ischemia/reperfusion was investigated using a partial no–flow model in rats in vivo. Plateletactivating factor levels of livers from sham–operated rats and from animals experiencing hepatic reperfusion for less than 6 hr were very low. They were observed to increase significantly after 12 hr of reperfusion and reached peak levels after a 24–hr reperfusion period, a time when maximal hepatic injury and inflammation occurred. Treatment of experimental rats with WEB2170, a platelet–activating factor receptor antagonist, attenuated the hepatic injury and inflammation, as evidenced by decreases in plasma ALT and in hepatocyte necrosis and neutrophil infiltration. Both inactivation of Kupffer cells with gadolinium chloride and inhibition of the formation of reactive oxygen species with allopurinol reduced platelet–activating factor production in the liver, whereas induction of neutropenia had no effect, suggesting that interaction of Kupffer cells with oxygenderived free radicals may be a plausible mechanism for hepatic platelet–activating factor accumulation. It is concluded that platelet–activating factor contributes to the inflammatory consequences of ischemia/reperfusion underlying late–phase hepatic injury. (Hepatology 1992;16:1236-1240.)
Differential Expression of Hepatocyte Growth Factor, Transforming Growth Factor–α and Transforming Growth Factor–β1 Messenger Rnas in Two Experimental Models of Liver Cell Proliferation
Authors: Masuhara Masaaki , Katyal Sikandar L. , Nakamura Toshikazu , Shinozuka Hisashi
Published: March 2007

ABSTRACT

Hepatocyte growth factor, a potent hepatocyte mitogen in vitro, appears to trigger hepatocyte regeneration after partial hepatectomy and after acute liver cell necrosis. Transforming growth factor–α and transforming growth factor–β may also be involved in the control of liver regeneration. In this study we assessed possible roles of hepatocyte growth factor, transforming growth factor–α and transforming growth factor–β1 on liver cell proliferation in vivo, using a model of choline deficiency that is associated with liver cell necrosis and a model of a hypolipidemic agent (4–chloro–6–(2,3 xylidino)–2–pyrimidinylthio (N–β–hydroxyethyl) acetamide) without liver necrosis. Male F344 rats were fed a choline–deficient diet or 0.16% 4–chloro–6–(2,3 xylidino)–2–pyrimidinylthio (N–β–hydroxyethyl) acetamide diet for 6 and 4 wk, respectively. Rats were killed periodically, and the expression of hepatocyte growth factor messenger RNA in the liver, lung and kidney was determined by Northern–blot analysis. The levels of transforming growth factor–α and transforming growth factor–β1 messenger RNAs in the liver were also determined. Feeding a choline–deficient diet for 1 to 6 wk led to gradual increases in the levels of hepatocyte growth factor, transforming growth factor–α and transforming growth factor–β1 messenger RNAs in the liver. Feeding a 4–chloro–6–(2,3 xylidino)–2–pyrimidinylthio (N–β–hydroxyethyl) acetamide diet for 3 days and 2 wk induced marked enhancement of liver cell proliferation as judged by hepatocyte 5–bromo–2–deoxyuridine incorporation. In contrast to the choline–deficient diet–induced liver cell proliferation, 4–chloro–6–(2,3 xylidino)–2–pyrimidinylthio (N–β–hydroxyethyl) acetamide–induced liver cell proliferation was associated with decreased levels of hepatocyte growth factor and transforming growth factor–β1 messenger RNAs. Feeding of a cholinedeficient diet or 4–chloro–6–(2,3 xylidino)–2–pyrimidinylthio (N–β–hydroxyethyl) acetamide had no apparent effects on the levels of hepatocyte growth factor messenger RNA in the lung and kidney. The results suggest that distinct patterns of messenger RNA expression exist for the growth factors in the liver undergoing compensatory hyperplasia and mitogenic stimulation of liver cell proliferation and that the role of hepatocyte growth factor in liver cell proliferation in vivo depends on the nature of the proliferative stimuli. (Hepatology 1992;16:1241-1249.)
Interaction of Bile Salts With Calcium Hydroxyapatite: Inhibitors of Apatite Formation Exhibit High-Affinity Premicellar Binding
Authors: Qiu Sui-Min , Soloway Roger D. , Crowther Roger S.
Published: March 2007

ABSTRACT

Of the major human bile salts, only the glycineconjugated dihydroxy species prevent the transformation of amorphous calcium phosphate to calcium hydroxyapatite, a component of gallstones; we have proposed that this inhibition occurs by competition between the bile salt and HPO4
2- anions for binding site on the apatite crystal embryo. Now we show that the binding affinity of bile salts to fully mature hydroxyapatite has the following order: glycineconjugated dihydroxy salts > taurine–conjugated dihydroxy salts > glycocholate ˜ taurocholate. Glycine–conjugated dihydroxy bile salts bound with high affinity as “premicellar” aggregates, but the remaining species appeared to bind as a wider range of aggregate sizes. Glycochenodeoxycholate binding was decreased as the pH increased from 6.6 to 9.8 and the apatite surface charge reversed from net positive to net negative. Binding was competitively inhibited by HPO4
2-, but not by H2PO4
-. Ca2+ promoted the binding of glycochenodeoxycholate, taurochenodeoxycholate and glycocholate, and for the latter two bile salts the increase was associated with enhanced “premicellar” binding. The binding of taurocholate was not influenced by Ca2+. When either glycocholate or taurocholate was mixed with glycochenodeoxycholate, mixed aggregates were formed that had a lower affinity for apatite than had pure glycochenodeoxycholate aggregates. Because only glycine–conjugated dihydroxy bile salts inhibit apatite formation, these results suggest that inhibition depends on high–affinity “premicellar” bile salt-apatite binding. (Hepatology 1992;16:1280-1289.)
Cholangitis and Endoscopic Drainage
Authors: Barnett Jeffrey L.
Published: March 2007

ABSTRACT

Background.

Emergency surgery for patients with severe acute cholangitis due to choledocholithiasis is associated with substantial morbidity and mortality. Because recent results suggested that emergency endoscopic drainage could improve the outcome of such patients, we undertook a prospective study to determine the role of this procedure as initial treatment.

Methods.

During a 43–month period, 82 patients with severe acute cholangitis due to choledocholithiasis were randomly assigned to undergo surgical decompression of the biliary tract (41 patients) or endoscopic biliary drainage (41 patients), followed by definitive treatment. Hospital mortality was analyzed with respect to the use of endoscopic biliary drainage and other clinical and laboratory findings. Prognostic determinants were studied by linear discriminant analysis.

Results.

Complications related to biliary tract decompression and subsequent definitive treatment developed in 14 patients treated with endoscopic biliary drainage and 27 treated with surgery (34 vs. 66 percent, P > 0.05). The time required for normalization of temperature and stabilization of blood pressure was similar in the two groups, but more patients in the surgery group required ventilatory support. The hospital mortality rate was significantly lower for the patients who underwent endoscopy (4 deaths) than for those treated surgically (13 deaths) (10 vs. 32 percent, P < 0.03). The presence of concomitant medical problems, a low platelet count, a high serum urea nitrogen concentration, and a low serum albumin concentration before biliary decompression were the other independent determinants of mortality in both groups.

Conclusions.

Endoscopic biliary drainage is a safe and effective measure for the initial control of severe acute cholangitis due to choledocholithiasis and to reduce the mortality associated with the condition.
Chronic Graft–Vs.–Host Disease of the Liver: Another Indication of Ursodeoxycholic Acid?
Authors: Erlinger Serge
Published: March 2007

ABSTRACT

Objective:

To determine the safety and efficacy of ursodeoxycholic acid treatment in patients with chronic graft–versus–host disease (GVHD) of the liver.

Design:

Open–label study in which each patient served as his or her own control.

Setting:

Private practice and a university bone marrow transplant center.

Patients:

Twelve patients with refractory chronic GVHD of the liver were studied after allogeneic bone marrow transplantation.

Interventions:

After baseline data collection, patients were given ursodeoxycholic acid (UDCA, 10 to 15 mg/kg body weight per day) for 6 weeks. After discontinuation of the drug, patients were followed for an additional 6 weeks. Doses of immunosuppressive drugs were unchanged for these 12 weeks.

Measurements:

Signs, symptoms, Karnofsky performance scores, hematocrit, total leukocyte count, absolute neutrophil count, platelet count, alanine aminotransferase (ALT), aspartate aminotrasferase (AST), alkaline phosphatase, gamma–glutamyltransferase (GGT), total serum bilirubin, prothrombin time.(Text missing).
A Calcium–Binding Protein in Bile and Gallstones
Authors: Kestell Michael F. , Sekijima John , Lee Sum P. , Park Han Z. , Long Michelle , Kaler Eric W.
Published: March 2007

Calcium salts are often present in the center of all types of gallstones. Matrix proteins are known to be essential for biomineralization and may therefore also be important in the formation and growth of gallstones. Other researchers have described an anionic peptide fraction of a biliary lipoprotein complex in bile and a low—molecular weight acidic glycoprotein present in gallstones. Our goal was to determine whether such a protein was present in bile and whether this protein has any calcium–binding properties. We identified a pigment–associated, highly acidic protein that precipitates from bile on addition of CaCl2 0.5 mol/L. In addition, the protein is selectively concentrated in cholesterol and pigment stones. We have, therefore, confirmed the findings of these other researchers, and we have extended the study of this protein's interactions with calcium. Sodium dodecylsulfate—polyacrylamide gel electrophoresis demonstrates a single band (molecular weight ≤ 14 kD) that reacts positively with cationic stains. The protein was shown to inhibit the precipitation of CaCO3 from a supersaturated solution. The capacity to bind calcium was further confirmed by autoradiography with 45Ca++ and by a membrane adsorption—binding assay. Calcium–induced aggregation was demonstrated by equilibrium dialysis and by quasielastic light scattering studies. Protein measured by Lowry's assay method and amino acid analysis constitutes only 2% to 4% of the harvested material. We speculate that a substantial lipid component may also be present. The presence of this material in bile, its ability to bind pigment and calcium, its presumed lipid content, its self–aggregation in the presence of calcium and its selective incorporation into gallstones suggest that it may play a functional role in the pathogenesis of gallstones.
Hepatitis C Virus and Porphyria Cutanea Tarda: Evidence of A Strong Association
Authors: Fargion Silvia , Piperno Alberto , Cappellini Maria Domenica , Sampietro Maurizio , Fracanzani Anna Ludovica , Romano Riccardo , Caldarelli Rita , Marcelli Rosaria , Vecchi Luisa , Fiorelli Gemino
Published: March 2007

Porphyria cutanea tarda in human beings is believed to be due to reduced hepatic uroporphyrinogen decarboxylase activity. However, extrinsic factors such as alcohol abuse and drug intake are required for clinical manifestation of the disease. In addition to typical cutaneous lesions, patients with porphyria cutanea tarda usually have chronic liver disease and moderate iron overload. Of 74 Italian patients with porphyria cutanea tarda, hepatitis C virus antibodies were detected in 76% by enzyme–linked immunoassay and in 82% by recombinant immunoblot assay. Viral genome, studied with nested polymerase chain reaction, was found in the sera of 49 subjects—47 positive and 2 indeterminate on recombinant immunoblot assay. Five percent of the patients were HBsAg–positive, and about 40% had had past hepatitis B contacts. Alcohol abuse was present in 38%. Liver biopsies performed in 42 patients showed chronic persistent hepatitis in 7 patients, chronic active hepatitis in 22 patients, fibrosis in three patients and cirrhosis in 10 patients. Hepatitis C virus antibody was detected in 100% of patients with chronic active hepatitis and in about 80% of all other groups. Alcohol abuse was more frequent in patients with cirrhosis (80%) than in the other groups. In Italian patients with porphyria cutanea tarda, the prevalence of hepatitis C virus infection was very high, comparable to that in non–A, non–B hepatitis and high–risk patient groups. Hepatitis C virus is probably the main pothogenetic factor of the liver disease of patients with porphyria cutanea tarda.
Clearance of Hbsag in Seven Patients With Chronic Hepatitis B
Authors: Adachi Hiroshi , Kaneko Shuichi , Matsushita Eiki , Inagaki Yutaka , Unoura Masashi , Kobayashi Kenichi
Published: March 2007

The natural history of chronic hepatitis B patients who spontaneously cleared serum HBsAg was investigated. A total of 351 patients with chronic hepatitis B were observed in our hospital for at least 3 yr. Seven of these patients became HBsAg negative during the follow–up period. HBsAg disappeared within 6 mo (range = 11 to 169 days, mean = 70 days) after acute elevation of ALT. ALT levels as high as 500 IU were found in three patients, whereas such elevation was not demonstrated in the other four patients. After the disappearance of HBsAg, ALT levels returned to normal in all patients. With one exception, all patients seroconverted to antibody to HBsAg; however, hepatitis B virus DNA remained detectable in serum using the polymerase chain reaction in five patients. The titer of percent inhibition of antibody to HBcAg gradually decreased to less than 70% when a 1:200 dilution of the serum of six patients was used. Four of the patients had active liver disease develop: two had chronic active hepatitis and two had cirrhosis. Three of these four patients subsequently had hepatocellular carcinoma develop. These findings suggest that patients may suffer complications of chronic hepatitis even after normalization of transaminase activities and after the clearance of HBsAg. Thus hepatitis B virus should be considered as a possible factor associated with hepatocellular carcinoma even in the absence of HBsAg, particularly if serum hepatitis B virus DNA persists.
Prevalence, Classification and Natural History of Gastric Varices: A Long–Term Follow–Up Study in 568 Portal Hypertension Patients
Authors: Sarin Shiv K. , Lahoti Deepak , Saxena Sanjay P. , Murthy Nandguri S. , Makwana Uday K.
Published: March 2007

To determine the prevalence and natural history of gastric varices, we prospectively studied 568 patients (393 bleeders and 175 nonbleeders) with portal hypertension (cirrhosis in 301 patients, noncirrhotic portal fibrosis in 115 patients, extrahepatic portal vein obstruction in 117 patients and hepatic venous outflow obstruction in 35 patients). Primary (present at initial examination) gastric varices were seen in 114 (20%) patients more were present in bleeders than in nonbleeders (27% vs. 4%, respectively; p < 0.001). Secondary (occurring after obliteration of esophageal varices) gastric varices developed in 33 (9%) patients during follow–up of 24.6 ± 5.3 mo. Gastric varices (compared with esophageal varices) bled in significantly fewer patients (25% vs. 64%, respectively). Gastric varices had a lower bleeding risk factor than did esophageal varices (2.0 ± 0.5 vs. 4.3 ± 0.4, respectively) but bled more severely (4.8 ± 0.6 vs. 2.9 ± 0.3 transfusion units per patient, respectively). Once a varix bled, mortality was more likely (45%) in gastric varix patients. Gastric varices were classified as gastroesophageal or isolated gastric varices. Type 1 gastroesophageal varices (lesser curve varices) were the most common (75%). After obliteration of esophageal varices, type 1 gastroesophageal varices disappeared in 59% of pateints and persisted in the remainder; bleeding from perisistent gastroesophageal varices was more common than it was from gastroesophageal varices that were obliterated (28% vs. 2%, respectively; p < 0.001). Type 2 gastroesophageal varices, which extend to greater curvature, bled often (55%) and were associated with high mortality. Type 1 isolated gastric varices patients had only fundal varices, with a high (78%) incidence of bleeding. Type 2 isolated gastric varices were mainly (86%) ectopic, secondary gastric varices that bled only rarely (9%). Sclerotherapy was more effective in controlling acute bleeding and obliterating varices in gastroesophagael varices than in isolated gastric varices; the latter often required surgery. In conclusion, gastric varices are a common and serious complication of portal hypertension. Our classification was helpful in understanding the natural history and management of gastric varices.
The Effect of Oral–Administered Lactulose on Colonic Nitrogen Metabolism and Excretion
Authors: Mortensen Per Brøbech
Published: March 2007

The influence of lactulose on organic acid fermentation, nitrogen metabolism and excretion in the colonassociated with its mechanism of action on hepatic encephalopathy was investigated. Orally administered lactulose in increasing amounts (0 to 20 to 40 to 80 to 160 gm/day) to 12 healthy volunteers decreased ammonia production in 16.6% fecal homogenates incubated 6 hr and 24 hr at 37° C (mean ± S.E.M.:from 7 ± 1 to 0 ± 0 and from 13 ± 2 to 0 ± 0 mmol/L, respectively). Every dose of lactulose was given for 3 days with intervals of 1 to 2 wk, and 24–hr stools were collected on day 3. Fecal concentrations of ammonia decreased (from 50 ± 9 to 11 ± 3 mmol/L), but ammonia excretions increased (from 6 ± 2 to 17 ± 4 mmol/24 hr). Total fecal concentrations of nitrogen decreased (from 1,043 ± 78 to 300 ± 136 mmol/L), but excretions of nitrogen increased fourfold (from 111 ± 21 to 457 ± 113 mmoL/24 hr) because of the increase in stool mass. Fecal pH declined (from 6.9 ± 0.1 to 4.9 ± 0.1), but total organic acids (short–chain fatty acids and DL–lactate; range = 105 to 148 mmol/L) and osmolality in feces (417 to 450 mOsm/L) did not change, although the colonic fermentation of lactulose had a major impact on the proportions between the nontoxic acetate (increased from 65% ± 2% to 89% ± 3%) and the potentially neurotoxic 3–6–carbon fatty acids (decreased from 35% ± 2% to 11% ± 2%). The effects of lactulose on bacterial ammonia assimilation, protein degradation and fermentation in the colonic contents in vivo are central in the mechanism of action for the increased excretion of nitrogen. However, ammonia excretion per se is not important because it only constitutes 4% to 5% of fecal nitrogen.
Analysis of the P53 Tumor–Suppressor Gene in Hepatocellular Carcinomas From Britain
Authors: Challen Christine , Lunec John , Warren William , Collier Jane , Bassendine Margaret F.
Published: March 2007

Human hepatocellular carcinomas from patients in Britain, an area of low prevalence of hepatocellular carcinoma and low dietary exposure to aflatoxin B1, were analyzed for mutations in the p53 tumorsuppressor gene. Abnormalities in the p53 gene were detected in 2 of 19 hepatocellular carcinomas by polymerase chain reaction—single–stranded conformation polymorphism. Direct sequencing of the evolutionarily conserved regions of p53 (exons 5,6,7 and 8), where mutations have been commonly found in a variety of tumors, confirmed that only two hepatocellular carcinomas had mutations in p53, one a 6–bp deletion of codons 158 and 159 (exon 5) and the other a G to A transition at codon 286 (exon 8). No mutations were found in any hepatocellular carcinoma in exons 6 and 7; in particular all tumors had wild–type sequence at codon 249, which has been reported to be a mutational hot spot in the p53 gene in hepatocellular carcinomas from high incidence areas such as China and southern Africa. Abnormalities in p53 expression were examined by immunohistochemistry and found in 1 of the 19 hepatocellular carcinomas. These findings show that p53 mutations are infrequently involved in the malignant transformation of hepatocytes in an area of low hepatocellular carcinoma prevalence. They support the suggestion of a possible link between dietary exposure to aflatoxin and selective G to T mutations at codon 249 of the p53 gene. Our observations also indicate that hepatitis B virus infection alone, present in six of the hepatocellular carcinomas examined, does not account for the specificity for codon 249 mutations reported from endemic areas.
Risk Factors Linked to Tumor Recurrence of Human Hepatocellular Carcinoma After Hepatic Resection
Authors: Jwo Shyh-Chuan , Chiu Jen-Hwey , Chau Gar-Yang , Loong Che-Chuan , Lui Wing-Yu
Published: March 2007

A total of 238 patients who received curative hepatic resections during the last 10 yr were observed to search for the risk factors linked to early tumor recurrence of human hepatocellular carcinoma after hepatectomy. The results revealed that tumor size, tumor appearance and DNA ploidy were the factors in predicting tumor recurrence after resection for hepatocellular carcinoma. Patients with a tumor size less than or equal to 5 cm or a tumor appearance of the solitary type had better disease–free survival than did those with a tumor size greater than 5 cm or a tumor appearance of multiple/daughter nodule types (p < 0.05). Although patients with pattern III (aneuploid with ≥ 2 G0/G1 peaks) hepatoma had fewer statistically significant differences (p = 019) than did those with pattern I (diploid) or pattern II (aneuploid with single G0/G1 peak) tumors in predicting tumor recurrence, they did have poorer results in terms of the overall survival rate (p < 0.05). We conclude that patients with hepatocellular carcinoma having the aforementioned risk factors should be observed closely.
Pallidal Hyperintensity on Magnetic Resonance Imaging in Cirrhotic Patients: Clinical Correlations
Authors: Kulisevsky Jaime , Pujol Jesús , Balanzó Joaquín , Junqué Carme , Deus Joan , Capdevilla Antoni , Villanueva Cándido
Published: March 2007

Patients with cirrhosis show increased signal intensity in the globus pallidus on T1–weighted magnetic resonance imaging of the brain. This abnormal appearance of the basal ganglia has been related to the severity of liver failure and to the presence of portalsystemic shunting, although its cause and clinical significance remain unknown. We prospectively assessed the metabolic, neurological and neuropsychological statuses of 30 stable cirrhotic patients and correlated these clinical variables with computed measurements of globus pallidus signals. Some metabolic variables denoting disease severity appeared to be significantly related to image changes, although the strongest association was found with plasma ammonia levels. After adjustment for ammonia level, on multiple regression analysis, the other variables were not significant. Furthermore, pallidal changes were associated with specific neurological symptoms and neurological functions, symptoms and functions that also had a significant correlation with ammonia levels. Our findings suggest that globus pallidus signal abnormality could arise as a marker of brain impairment related to hyperammonemia.
Variability of Atrial Natriuretic Peptide Plasma Levels in Ascitic Cirrhotics: Pathophysiological and Clinical Implications
Authors: Angeli Paolo , Caregaro Lorenza , Menon Francesca , Sacerdoti David , de Toni Renzo , Merkel Carlo , Gatta Angelo
Published: March 2007

Ascitic cirrhotic patients are a heterogenous population with respect to factors that may affect plasma human atrial natriuretic peptide levels (such as degree of plasma volume and plasma levels of angiotensin II, vasopressin and norepinephrine). Thus the proven variability of plasma human atrial natriuretic peptide values in ascitic cirrhotic patients may be due also to the selection of patients, not only to the study conditions. The response to standardized stepped–care medical treatment of ascites makes it possible to characterize ascitic cirrhotic patients with different patterns of renal sodium excretion, intrarenal sodium handling, plasma renin activity, plasma aldosterone and thus, probably, effective circulating volume. Consequently, we evaluated human atrial natriuretic peptide plasma levels in controls (n = 23), in ascitic cirrhotic patients who underwent spontaneous diuresis (group A, n = 7) and in cirrhotic patients who required diuretic treatment (group B, n = 44). The last group was then divided into two subgroups. Subgroup B–R (n = 25) included patients who responded to spironolactone alone, whereas subgroup B–NR (n = 19) included patients who did not respond to 500 mg/day spironolactone. All patients were maintained on identical normocaloric restricted sodium intake (80 mEq/day) throughout the study. Ascitic cirrhotic patients, as a whole, had higher values of human atrial natriuretic peptide than did controls (70.8 ± 46.6 pg/ml vs. 41.7 ± 16.3 pg/ml, p < 0.025). No difference was found in human atrial natriuretic peptide/plasma renin activity between the two groups (87 ± 160 pg/ng/hr vs. 44 ± 73 pg/ng/hr, p = NS). Human atrial natriuretic peptide values in group A (n = 7) and those in group B (n = 44) were greater than those in controls (113.3 ± 63.3 pg/ml, p < 0.001, and 64.9 ± 41.4 pg/ml, p < 0.025), but they were quite different between themselves (p < 0.05). Human atrial natriuretic peptide/plasma renin activity values in group A were significantly higher than those of controls (213 ± 194 pg/ng/hr, p < 0.01) but not significantly higher than those of group B (72 ± 41 pg/ng/hr, p = NS). A significant difference was found between human atrial natriuretic peptide and human atrial natriuretic peptide/plasma renin activity values in subgroups B–R and B–NR (76.1 ± 49.4 pg/ml vs. 50.8 ± 19.4 pg/ml, p < 0.05, and 113 ± 189 pg/ng/hr vs. 20 ± 49 pg/ng/hr, p < 0.05, respectively). We concluded that plasma human atrial natriuretic peptide values may reflect different pathophysiological features in ascitic cirrhotic patients. In particular, as patients require more diuretic drugs human atrial natriuretic peptide and human atrial natriuretic peptide/plasma renin activity levels progressively fall, suggesting that patients become progressively “underfilled” and that the antinatriuretic factors predominate.
Susceptibility to Primary Biliary Cirrhosis Is Associated With the Hla–Dr8–Dqb1*0402 Haplotype
Authors: Underhill James , Donaldson Peter , Bray Gary , Doherty Derek , Portmann Bernard , Williams Roger
Published: March 2007

In studies to date seeking associations between human leukocyte antigens (HLA) and primary biliary cirrhosis, no class I association but several different class II associations have been described. The aims of this study were to reassess the DR associations in primary biliary cirrhosis and to examine for the first time the role of DQB. DRB genotypes were determined on standard Taq1 restriction–fragment–length polymorphism analysis in 159 white northern European patients with the disease and 162 racially matched local controls. Polymerase chain reaction gene amplification and sequence–specific oligonucleotide analysis were used to determine DQB genotypes in 89 patients and 181 controls. An increased frequency of human leukocyte antigen DR8 was observed in the patient group (11% vs 4%; relative risk = 3.3; p < 0.01). Although we saw an increased frequency of the DQB1*0402 allele (11% vs. 3%; relative risk = 3.5; p < 0.025), this was not significant after correction for multiple testing. The strongest association was with the two–locus haplotype DR8–DQB1*0402 (11% vs. 2.2%; relative risk 5.5; p < 0.001). The DRB data reported here confirm the findings of previous studies, although the described association with DR8 is considerably weaker. The weak genetic contribution of human leukocyte antigen in the susceptibility to primary biliary cirrhosis is in contrast to its role in other autoimmune liver diseases.