bluuebunny/crossref_metadata_2025 huggingface dataset:
Fulminant Hepatitis Related to Transmission of Hepatitis B Variants With Precore Mutations Between Spouses
Authors: Yotsumoto Shigeru , Kojima Mineo , Shoji Isao , Yamamoto Kayoko , Okamoto Hiroaki , Mishiro Shunji
Published: March 2007

A precore defective variant of hepatitis B virus has been indicated to cause fulminant hepatitis in various instances such as intrahospital outbreaks or motherto–child transmission of hepatitis B virus. To learn whether similar variants are involved in interspouse transmission, we analyzed three cases of fulminant hepatitis B that developed in formerly healthy subjects whose only exposure to hepatitis B virus was contact with their longtime spouses, who were carriers of HBV and positive for antibody to HBe. The DNA clones for precore and S genes were propagated from patients and spouses and sequenced. Because of the conservation of S–gene sequences and the identity of subtypes between patient and spouse, it was suggested that patients were infected with hepatitis B virus from their spouses, not from other sources. A TGG–to–TAG mutation at the 28th codon of the precore gene of hepatitis B virus was commonly observed in all DNA clones from patients with fulminant hepatitis and from their spouses. A 29th–codon GGC–to–GAC mutation was additionally evident in DNAs from one patient–and–spouse couple. A significant rise in the circulating hepatitis B virus concentration was transiently observed in the index spouse of this case just before development of fulminant hepatitis in her husband. The increase in circulating HBV DNA was associated with a rise in abundancy of variants with mutations at both the 28th and 29th codons, compared with variants with only a 28th–codon mutation. The double mutation in hepatitis B virus DNA may either help the virus escape immune surveillance or replicate at a higher rate than before. (Hepatology 1992;16:31-35.)
Ischemic–Type Biliary Complications After Orthotopic Liver Transplantation
Authors: Sanchez-Urdazpal Luis , Gores Gregory J. , Ward Ellen M. , Maus Timothy P. , Wahlstrom Erik H. , Moore Breanndan S. , Wiesner Russell H. , Krom Ruud A.F.
Published: March 2007

Nonanastomotic biliary strictures that involve only the biliary tree of the graft occur after orthotopic liver transplantation in patients with hepatic artery thrombosis, chronic ductopenic rejection and ABO blood group incompatibility. This complication may also occur in the absence of these known risk factors. The major focus of our study was to evaluate the risk factors for nonanastomotic biliary stricturing of unknown cause after orthotopic liver transplantation. Results demonstrate that the development of biliary strictures is strongly associated with the duration of cold ischemic storage of allografts in both Euro–Collins solution and University of Wisconsin solution. Results also demonstrate that strictures are not associated with the type of biliary reconstruction, the primary liver disease, cytomegalovirus infection, allograft rejection or the presence of a positive lymphocytotoxic crossmatch. More recently, we have markedly reduced the occurrence of nonanastomotic biliary stricturing by decreasing the ischemia time of our allografts. Thus nonanastomotic biliary strictures appear to be the result of the ischemia/reperfusion-induced tissue injury associated with the harvest and implantation of allografts. (Hepatology 1992;16:49-53.)
Isolation and Characterization of the Mannose Receptor From Human Liver Potentially Involved in the Plasma Clearance of Tissue–Type Plasminogen Activator
Authors: Otter Marlies , Žočková PETRA , Kuiper Johan , Van Berkel Theo J.C. , Barrett-Bergshoeff Marrie M. , Rijken Dingeman C.
Published: March 2007

Various studies have shown that mannose receptors rapidly eliminate glycoproteins and microorganisms bearing high mannose-type carbohydrate chains from the blood circulation. The purpose of this study was to characterize the mannose receptor in the liver, which in vivo is involved in the rapid clearance of tissue–type plasminogen activator from the circulation.

Human liver membranes were solubilized in Triton X–100, and the solution was applied to a tissue–type plasminogen activator Sepharose column. Bound proteins were eluted with ethylenediaminetetraacetate (10 mmol/L). A second, similar purification step rendered a single liver protein of 175,000 daltons. A combination of ligand blotting and a chromogenic assay for tissue–type plasminogen activator demonstrated that the identified liver protein is a mannose receptor because it bound tissue–type plasminogen activator, this tissue–type plasminogen activator binding being fully inhibited by 0.2 mol/L D–mannose. Western–blot analysis revealed that the isolated liver protein is immunologically identical to the human mannose receptor from placenta. Treatment of the liver protein and the placenta mannose receptor with trypsin yielded the same pattern of proteolytic degradation products as identified on sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

We conclude that the physiologically relevant mannose receptor for tissue–type plasminogen activator clearance isolated from human liver is immunologically and structurally similar to or identical with the human mannose receptor isolated from placenta. (Hepatology 1992;16:54-59.)
Plasma Atrial Natriuretic Peptide and Renin–Aldosterone in Patients With Cirrhosis and Ascites: Basal Levels, Changes During Daily Activity and Nocturnal Diuresis
Authors: Panos Marios Z. , Anderson John V. , Payne Nadia , Langley Peter , Slater Jeremy D.H. , Rees Lesley , Williams Roger
Published: March 2007

Measurements of plasma atrial natriuretic peptide concentrations at 8 AM showed raised levels in 21 patients with cirrhosis and ascites (10.5 ± 0.8 pmol/L) compared with levels in 10 age–matched controls (4.1 ± 0.64 pmol/L; p < 0.0001). In eight patients and 10 controls, atrial natriuretic peptide, plasma renin activity, plasma aldosterone and urinary sodium excretion were measured every 4 hr for 24 hr. Subjects were mobile between 8 AM and 11 PM and supine from 11 PM to 8 AM. In controls, urinary sodium excretion was highest between 4PM and 11 PM (19.34 ± 3.74 μmol/min) and lowest between midnight and 8 AM (7.06 ± 1.23 μmol/min; p < 0.001). In patients, urinary sodium excretion was 0.63 ± 0.14 μmol/min between 4 PM and midnight and 1.85 ± 0.71 μmol/min (p < 0.08) between midnight and 8 AM. In patients during the day, mean plasma atrial natriuretic peptide concentration did not change despite large individual variation, but large, sustained rises in plasma renin activity and plasma aldosterone were seen. Correlations were noted between atrial natriuretic peptide and urinary sodium excretion between midnight and 8 AM (r = 0.65; p < 0.02) and 4 PM and midnight (r = 0.54; p < 0.05) but not between 8 AM and 4 PM. Plasma renin activity dropped from 12.54 ± 2.49 at midnight to 7.41 ± 0.88 pmol/hr/ml at 8 AM (p < 0.05); plasma aldosterone decreased from 1,032 ± 101 to 798 ± 56 pmol/L (p < 0.05). These findings are consistent with the hypothesis that atrial natriuretic peptide contributes to the nocturnal natriuresis of cirrhosis; it is possible that reduction in the activity of the renin–aldosterone system in recumbency may allow the natriuretic effect of this substance to become manifest. (Hepatology 1992;16:82-88.)
A Prospective Randomized Trial Comparing Repeated Endoscopic Sclerotherapy and Propranolol in Decompensated (Child Class B and C) Cirrhotic Patients
Authors: Dasarathy S. , Dwivedi Manisha , Bhargava Dinesh K. , Sundaram K. R. , Ramachandran K.
Published: March 2007

A prospective randomized study was conducted to compare the efficacy of long–term endoscopic sclerotherapy vs. propranolol in Child class B and C patients with variceal bleeds within the 30 days before the study. Forty–five and 46 patients were randomized to receive sclerotherapy and propranolol, respectively, after preentry stratification for Child scores. Sclerotherapy was administered with 1% polidocanol at 10–day intervals until obliteration of varices was achieved. Propranolol was administered to achieve a reduction in resting pulse rate of 25%. Rebleeding occurred in 19 patients undergoing sclerotherapy and in 31 receiving propranolol (p < 0.05). The number of episodes of rebleeding was higher (p < 0.05) in the propranolol group (n = 64) than in the sclerotherapy group (n = 35). The mean bleeding risk factor, number of hospitalizations for rebleeding and blood transfusion requirement were also significantly higher in the propranolol–treated patients. The median bleed–free period was more than 36 mo in the sclerotherapy group and 2.5 mo in the propranolol group (p < 0.01). The median survival time was significantly longer in the sclerotherapy group (>36 mo) than in the propranolol group (>24 mo). We conclude that in decompensated cirrhotic patients, long–term endoscopic sclerotherapy is superior to propranolol in preventing rebleeding and improving survival. (Hepatology 1992;16:89-94.)
Clinical Significance of Elevated Plasma Endothelin Concentration in Patients With Cirrhosis
Authors: Uchihara Masakatsu , Izumi Namiki , Sato Chifumi , Marumo Fumiaki
Published: March 2007

Endothelin is a newly discovered potent vasoconstrictor peptide. To explain the clinical significance of endothelin in patients with chronic liver diseases, we measured the plasma concentration of endothelin in patients with chronic hepatitis (n = 15), cirrhosis with ascites (n = 8) and cirrhosis without ascites (n = 12), and we compared the findings with the plasma concentration of endothelin in normal controls (n = 14). The plasma endothelin concentration was significantly higher in patients with cirrhosis with ascites than in normal controls (8.3 ± 2.3 pg/ml vs. 3.3 ± 1.4 pg/ml, mean ± S.D., p < 0.001), whereas no significant difference was observed between normal controls and the other groups of patients (cirrhosis without ascites = 5.0 ± 1.3 pg/ml; chronic hepatitis = 3.8 ± 1.2 pg/ml). In patients with cirrhosis, the plasma endothelin concentration showed a significant negative correlation with creatinine clearance (r = -0.73, p < 0.01), but no significant correlation was observed between plasma endothelin concentration and fractional excretion of filtered sodium. Furthermore, plasma endothelin levels were significantly higher in patients with endotoxemia than in those without (10.1 ± 2.1 pg/ml vs. 4.9 ± 1.2 pg/ml, p < 0.001). From these results, elevated plasma endothelin, which has a close relation to endotoxemia, may play a contributory role in kidney dysfunction in patients with cirrhosis. (Hepatology 1992;16:95-99.)
Prognostic Factors in Patients With Hepatocellular Carcinoma Receiving Systemic Chemotherapy
Authors: Okada Shuichi , Okazaki Nobuo , Nose Haruhiko , Yoshimori Masayoshi , Aoki Kazunori
Published: March 2007

A total of 71 consecutive patients with unresectable hepatocellular carcinoma were analyzed retrospectively to determine the significant prognostic factors. All the patients received systemic chemotherapy in a phase 2 study from 1980 to 1990, with no other anticancer treatment. Median survival time and 1–yr and 2–yr survival rates were 5.6 mo, 23% and 5%, respectively. By the univariate analysis, a performance status of 0-1 and tumor size less than 50% of the liver cross–sectional area were shown to be the factors most significantly favoring a better prognosis. By the multivariate analysis using the Cox proportional hazards model, a performance status of 0-1 (p < 0.001), absence of tumor thrombus in the main portal trunk (p = 0.003) and age less than 60 yr (p = 0.036) were independent favorable prognostic factors. A prognostic index was calculated from these three factors according to the following equation: 1.8109 × (0 = performance status of 0-1 and 1 = performance status of 2-3) + 0.9322 × (0 = tumor thrombus absent in the main portal trunk and 1 = present) + 0.6996 × (0 = age < 60 yr and 1 = age ± 60 yr). This index was used to classify the patients into three groups with a good, intermediate and poor prognosis. The median survival times for these three groups were 9.8, 3.8 and 1.9 mo, respectively (p < 0.01). The results of this study may be useful in the design and analysis of future clinical trials of systemic therapy for hepatocellular carcinoma. (Hepatology 1992;16:112-117.)
Natural History of Small Untreated Hepatocellular Carcinoma in Cirrhosis: A Multivariate Analysis of Prognostic Factors of Tumor Growth Rate and Patient Survival
Authors: Barbara Luigi , Benzi Giovanna , Gaiani Stefano , Fusconi Fabio , Zironi Gianni , Siringo Sebastiano , Rigamonti Alessandra , Barbara Carlotta , Grigioni Walter , Mazziotti Alighieri , Bolondi Luigi
Published: March 2007

We analyzed the growth pattern of tumor masses and the survival of 39 asymptomatic Italian patients with a total of 59 small (≤ 5 cm in diameter) hepatocellular carcinomas arising from cirrhosis. The total length of the observation period ranged from 90 to 962 days, with an average of 364 ± 229 (mean ± S.D.). Doubling time ranged from 27.2 to 605.6 days (mean ± S.D., 204.2 ± 135; median = 171.6 days). Three different growth patterns were recognized: (a) tumors with no or very slow initial growth pattern (doubling time > 200 days), 10 cases (37%); (b) tumors with declining growth rate over time, 9 cases (33.4%); and (c) tumors with almost constant growth rate, 8 cases (29.6%). Using the stepwise discriminant analysis, we found a score based on albumin, alcohol intake, number of nodules, echo pattern and histological type that allowed a correct prediction of short doubling time (≤ 150 days) in 55.6%, medium doubling time (151 to 300 days) in 60% and long doubling time (>300 days) in 100% of cases. The estimated survival rate of the 39 patients, calculated by the Kaplan–Meier method was 81% at 1 yr, 55.7% at 2 yr and 21% at 3 yr. Stepwise discriminant analysis showed that a score based on sex, HBsAg status, alcohol consumption, ascites, γ–glutamyltranspeptidase, prothrombin time, Child–Pugh class and all the sonographical parameters could predict 2–yr survival in 100% of cases. We conclude that great variability of growth patterns exists among and within small hepatocellular carcinomas. Prediction of subsequent growth rate is unreliable in most cases. The sonographical characteristics, together with the histological features, can, however, help in identifying cases with long doubling time (>300 days). The discriminant analysis on survival of cirrhotic patients with small hepatocellular carcinomas demonstrates that the underlying liver disease plays a key role in the long–term survival probability. (Hepatology 1992;16:132-137.)
Isoenzymes of Carbohydrate Metabolism in Primary Cultures of Hepatocytes From Thioacetamide–Induced Rat Liver Necrosis: Responses to Growth Factors
Authors: Cascales Maria , Martin-Sanz Paloma , Alvarez Alberto , Sanchez-Pérez Miguel , Fernández Carmen Diez , Boscá Lisardo
Published: March 2007

Hepatocytes isolated from the liver of rats after a necrotizing dose of thioacetamide (6.6 mmol/kg) were used to study the postnecrotic process of liver regeneration. Flow cytometry analysis revealed populations of dedifferentiated hepatocytes exhibiting physical properties (size and fluorescence emission at 530 nm) similar to those found in fetal (22 days old) liver cells. The percentage of these cells increased progressively from 24 to 48 and 72 hr after thioacetamide administration. In primary cultures of hepatocytes the effects of phorbol 12–myristate 13–acetate, bombesin and insulin were investigated on the 6–phosphofructo 2–kinase/fructose 2,6 bisphosphate system. Bombesin and insulin stimulated 6–phosphofructo 2–kinase activity and fructose 2,6–bisphosphate content both in control and in thioacetamide–treated hepatocytes. However, phorbol 12–myristate 13–acetate stimulated 6–phosphofructo 2–kinase activity and increased fructose 2,6–bisphosphate concentration in thioacetamide–treated liver cells, whereas no similar response was found in hepatocytes from control rats. The response of postnecrotic thioacetamide–treated hepatocytes to phorbol 12–myristate 13–acetate was similar to that obtained from 22–day–old fetal liver cells, which reveals that different methods might control fructose 2,6–bisphosphate content and therefore the mechanisms of glycolysis and gluconeogenesis at this regulatory step. The lack of response to glucagon of glycogen phosphorylase a and 6–phosphofructo 2–kinase from thioacetamide–treated hepatocytes may indicate that the expression of specific enzymes of carbohydrate metabolism undergoes transitions to lessdifferentiated isoenzymatic forms. Moreover, the isoenzyme pattern of hexokinases elicits a complete disturbance in glucokinase and hexokinases activities. These results led us to conclude that the characteristics and behavior of thioacetamide–induced postnecrotic hepatocytes are closely related to those found in fetal liver cells. (Hepatology 1992;16:232-240.)
Role of Cellular Superoxide Dismutase Against Reactive Oxygen Metabolite-Induced Cell Damage in Cultured Rat Hepatocytes
Authors: Ito Yasuaki , Hiraishi Hideyuki , Razandi Mahnaz , Terano Akira , Harada Takashi , Ivey Kevin J.
Published: March 2007

Reactive oxygen metabolites have been reported to be important in the pathogenesis of ischemia/reperfusion–induced and alcohol–and druginduced liver injuries. We investigated the role of superoxide dismutase, cellular and extracellular, in preventing reactive oxygen metabolite-induced cytotoxicity in cultured rat hepatocytes. Cells were exposed to reactive oxygen metabolites enzymatically generated by hypoxanthine–xanthine oxidase. Cytotoxicity was quantified by measuring51Cr release from prelabeled cells and lactate dehydrogenase release. Reactive oxygen metabolites caused dose–dependent cytotoxicity. Good correlation was found between the values for51Cr and lactate dehydrogenase release. Reactive oxygen metabolite-induced cell damage was reduced by catalase but not by superoxide dismutase. Cellular superoxide dismutase and catalase activities were not increased after incubation with exogenous superoxide dismutase and catalase for up to 5 hr. Pretreatment with diethyldithiocarbamate inhibited cellular superoxide dismutase activity without inhibiting other antioxidants such as catalase, glutathione, glutathione reductase and glutathione peroxidase and sensitized cells to reactive oxygen metabolite-induced cytotoxicity. We conclude that hydrogen peroxide is an important mediator in hypoxanthine–xanthine oxidase-induced cell damage and that superoxide dismutase plays a critical role in cellular antioxidant defenses against hypoxanthine–xanthine oxidase-induced cytotoxicity in cultured rat hepatocytes in vitro. (Hepatology 1992;16:247-254.)
Cholesterol Metabolism in Human Gallbladder Mucosa: Relationship to Cholesterol Gallstone Disease and Effects of Chenodeoxycholic Acid and Ursodeoxycholic Acid Treatment
Authors: Sahlin Staffan , Ahlberg Jon , Reihnér Eva , Starhlberg Dagny , Einarsson Kurt
Published: March 2007

The objective of this study was to investigate cholesterol metabolism in human gallbladder mucosa, especially in relation to hepatic cholesterol metabolism, gallstone disease and treatment with bile acids. Gallbladder mucosa and liver tissue samples were collected in 44 patients undergoing cholecystectomy; 30 had cholesterol gallstones and the rest were stone free. Ten of the gallstone patients were treated with chenodeoxycholic acid and eight received ursodeoxycholic acid, with a daily dose of 15 mg/kg body wt, for 3 wk before surgery.

The 3–hydroxy–3–methylglutaryl coenzyme A reductase activity, governing cholesterol synthesis, was considerably lower in the gallbladder mucosa than in liver tissue (28 ± 6 and 120 ± 40 pmol/min/mg protein). The acyl coenzyme A:acyltransferase activity in the gallbladder mucosa catalyzing the esterification of cholesterol was, on the other hand, several times higher than corresponding activity in the liver (92 ± 23 and 11 ± 2 pmol/min/mg protein). In the presence of exogenous cholesterol, the acyl coenzyme A:acyltransferase activity increased about twofold in the gallbladder mucosa.

The acyl coenzyme A:acyltransferase activity of the gallbladder mucosa from untreated gallstone patients was not stimulated further by the addition of exogenous cholesterol. Otherwise, there were no significant differences in acyl coenzyme A:acyltransferase and 3–hydroxy–3–methylglutaryl coenzyme A reductase activities in the gallbladder mucosa of gallstone patients compared with gallstone–free controls.

Treatment with chenodeoxycholic and ursodeoxycholic acids did not affect the 3–hydroxy–3–methylglutaryl coenzyme A reductase activity of the gallbladder mucosa but reduced the acyl coenzyme A:acyltransferase activity by 60% to 65%. A positive correlation was obtained between the cholesterol concentration in bile and the acyl coenzyme A:acyltransferase activity in the gallbladder mucosa in the whole series of patients (Spearman's rank–order correlation coefficient [rS] = 0.42, p < 0.05).

We conclude that human gallbladder mucosa has a lower 3–hydroxy–3–methylglutaryl coenzyme A reductase activity but acyl coenzyme A:acyltransferase activity several times higher than that in liver tissue. Disturbance of cholesterol metabolism in the gallbladder mucosa, which might contribute to the high cholesterol content of gallbladder bile in patients with cholesterol gallstones, was not found. (Hepatology 1992;16:320-326.)
Immunomodulatory Effects of Ursodeoxycholic Acid on Immune Responses
Authors: Yoshikawa Masahide , Tsujii Tadasu , Matsumura Keisuke , Yamao Junnichi , Matsumura Yoshinobu , Kubo Ryouichi , Fukui Hiroshi , Ishizaka Shigeaki
Published: March 2007

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Experimental evidence supporting the usefulness of ursodeoxycholic acid as a potentially beneficial therapeutic agent for primary biliary cirrhosis has been reported from the biochemical and physiological aspects.

In this study, we investigated the direct effects of ursodeoxycholic acid on immunoglobulin and cytokine production in vitro using plaque–forming cell assay and enzyme–linked immunosorbent assay. It was demonstrated that ursodeoxycholic acid suppressed the production of IgM, IgG and IgA induced by Staphylococcus aureus Cowan I in peripheral blood mononuclear cells derived from healthy subjects and patients with primary biliary cirrhosis and also in human B lymphoma cell lines. Furthermore, ursodeoxycholic acid suppressed interleukin–2 and interleukin–4 production induced by concanavalin A and interferon–γ production induced by polyinosinic–polycytidylic acid, but it did not affect interleukin–1 and interleukin–6 production induced by lipopolysaccharide in peripheral blood mononuclear cells. In addition, ursodeoxycholic acid suppressed the concanavalin A–induced thymocyte proliferation mediated by interleukin–1. Cytotoxicity against lymphocytes was not observed at the concentrations of ursodeoxycholic acid used. These results suggest that the beneficial effect of ursodeoxycholic acid in primary biliary cirrhosis is mediated in part by immunosuppression. (Hepatology 1992;16:358-364.)
Purification of 3α–Hydroxysteroid and 3β–Hydroxysteroid Dehydrogenases From Human Liver Cytosol
Authors: Takikawa Hajime , Fujiyoshi Makoto , Nishikawa Kou , Yamanaka Masami
Published: March 2007

We previously reported that the human Y′ bile acid binder, which has higher bile acid binding affinities than rat Y′ binders (3α–hydroxysteroid dehydrogenases), has dihydrodiol dehydrogenase activity and is different from 3α–hydroxysteroid dehydrogenases. In this study, 3α–hydroxysteroid dehydrogenases and 3β–hydroxysteroid dehydrogenase were purified from human liver, and bile acid binding affinities and enzyme kinetics of the 3α–hydroxysteroid dehydrogenases were studied. On chromatofocusing of pooled Affigel blue fraction of the Y′ fraction, three 3α–hydroxysteroid dehydrogenase peaks eluted at pH 6.0, 5.7 and 5.4. These peaks did not bind bile acids, and further purification by hydroxyapatite–high–performance liquid chromatography gave pure 3α–hydroxysteroid dehydrogenases with identical Mr (36,000) having dihydrodiol dehydrogenase activity. 3β–Hydroxysteroid dehydrogenase was eluted together with Y′ bile acid binder at pH 7.2 on chromatofocusing and was separated from Y′ bile acid binder on hydroxyapatite–high.–performance liquid chromatography as a pure protein with Mr 32,000. The apparent Kms of 3α–hydroxysteroid dehydrogenases were similar to those of rat enzymes. In conclusion, we purified human hepatic 3α–hydroxysteroid dehydrogenases, which have similar characteristics to rat enzymes, but do not bind bile acids or reduce bile acid precursors. These data further support the importance of human bile acid binder in intracellular bile acid transport in the human liver. (Hepatology 1992;16:365-371.)
Increased Tissue–Type Plasminogen Activator Activity in Orthotopic But Not Heterotopic Liver Transplantation: the Role of the Anhepatic Period
Authors: Bakker Minke C. , Metselaar Herold J. , Groenland Theo N. , Gomes Maria J. , Knot Eduard A.R. , Hesselink Eric J. , Schalm Solco W. , Stibbe Jeanne , Terpstra Onno T.
Published: March 2007

The major cause of the increased tissue–type plasminogen activator activity during orthotopic liver transplantation is still unclear. Both the lack of hepatic clearance of tissue–type plasminogen activator in the anhepatic period and increased endothelial release from the graft on reperfusion have been proposed as the major causes. Heterotopic liver transplantation avoids the resection of the host liver and is a useful model to help differentiate between these two possibilities. In this study the fibrinolytic system was evaluated in 10 orthotopic liver transplantations, 18 heterotopic liver transplantations and a control group of 10 partial hepatic resections.

A marked increment in tissue–type plasminogen activator activity, from 0.2 to 5.2 IU/ml (p <0.02), was observed during the anhepatic period of orthotopic liver transplantation, which rapidly normalized after reperfusion. In contrast, tissue–type plasminogen activator activity levels remained normal in heterotopic liver transplantation and partial hepatic resections. In orthotopic liver transplantation and in heterotopic liver transplantation no increase occurred in tissue–type plasminogen activator activity after reperfusion. The first venous hepatic outflow after reperfusion did not contain elevated tissue–type plasminogen activator activity levels. Plasma degradation products of fibrin and fibrinogen increased during the anhepatic period of orthotopic liver transplantation (from 2.60 to 8.80 μg/ml [p <0.008] and from 0.40 to 1.60 μg/ml [p <0.04], respectively) and remained elevated thereafter. In heterotopic liver transplantation and partial hepatic resections these levels remained low.

In conclusion, the lack of hepatic clearance during the anhepatic period is probably the most important factor in the evolution of increased tissue–type plasminogen activator activity during orthotopic liver transplantation. (Hepatology 1992;16:404-408.)
Ischemic Injury in Liver Transplantation: Difference in Injury Sites Between Warm and Cold Ischemia in Rats
Authors: Ikeda Tetsuo , Yanaga Katsuhiko , Kishikawa Keiji , Kakizoe Saburo , Shimada Mitsuo , Sugimachi Keizo
Published: March 2007

Using liver allografts with warm or cold ischemia, we evaluated functional and morphological alterations in hepatocytes, sinusoidal endothelial cells and Kupffer cells in a rat transplantation model. All recipients of allografts with either 4 hr of cold or 30 min of warm ischemia lived more than 22 days and were judged viable. On the other hand, all recipients of grafts with 6 hr of cold or 60 min of warm ischemia died within 2 days and were therefore judged to be nonviable. With these viable and nonviable allograft models, hepatocyte function was evaluated by the bile output and serum glutamic–oxaloacetic transaminase, serum glutamic–pyruvic transaminase and serum lactate dehydrogenase levels; endothelial cell function was judged by the serum hyaluronic acid level, and Kupffer cell function was measured by an intravenous colloidal carbon clearance test.

Hepatocyte injury was the prominent feature in warm ischemic grafts, especially in the nonviable ones. On the other hand, serum hyaluronic acid values were significantly higher in the nonviable cold ischemic group, compared with the viable counterpart, suggesting that the functional depression of endothelial cells was predominant in cold, nonviable livers. Histological examinations coincided with the above findings. The phagocytic activity of Kupffer cells was depressed by warm or cold ischemia, whereas the number of Kupffer cells was reduced in the warm ischemia group. We conclude that in liver allografts the main site of injury in warm ischemia is the hepatocytes and suggest that cold ischemia is associated with endothelial cell damage. (Hepatology 1992;16:454-461.)
Inhibition of Hepatic Metastasis of Colon Carcinoma by Asialo Gm1-Positive Cells in the Liver
Authors: Shiratori Yasushi , Nakata Ryo , Okano Ken'ichi , Komatsu Yutaka , Shiina Shuichiro , Kawase Tateo , Sugimoto Tsuneaki , Omata Masao , Tanaka Mitsugu
Published: March 2007

This study investigates the role of hepatic asialo GM1-positive cells in inhibiting hepatic metastasis of colon carcinoma (colon adenocarcinoma 38) in mice after administration of a biological response modifier, streptococcal derivative (OK432). Administration of OK432 increased the number of asialo GM1-positive cells in the liver, enhanced natural killer activity of hepatic mononuclear cells and reduced the number of hepatic metastases of colon carcinoma inoculated into the superior mesenteric vein. Administration of antiserum against asialo GM1 reduced the number of hepatic asialo GM1-positive cells, abolished natural killer activity of hepatic mononuclear cells and increased the number of hepatic metastases. In addition, administration of antiserum against asialo GM1 even after OK432 treatment also decreased the number of asialo GM1-positive cells, reduced natural killer activity of hepatic mononuclear cells and increased the number of hepatic metastases of colon carcinoma. However, administration of gadolinium chloride, which suppresses phagocytic function of Kupffer cells, did not influence the natural killer activity of hepatic mononuclear cells or the number of hepatic metastases. In vivo tumor–neutralization assay revealed that tumor growth was inhibited by the hepatic mononuclear asialo GM1-positive cells, but not by T lymphocytes or Kupffer cells after OK432 administration. These results suggest that an increased number of hepatic asialo GM1-positive cells after administration of OK432 plays an important role in protecting against metastasis of colon carcinoma in the liver. (Hepatology 1992;16:469-478.)
Tumor Necrosis Factor and Endotoxin in the Pathogenesis of Liver and Pulmonary Injuries After Orthotopic Liver Transplantation in the Rat
Authors: Goto Moritaka , Takei Yoshiyuki , Kawano Sunao , Tsuji Shingo , Fukui Hiroyuki , Fushimi Hiroaki , Nishimura Yoshiya , Kashiwagi Toru , Fusamoto Hideyuki , Kamada Takenobu
Published: March 2007

This study examines whether tumor necrosis factor and endotoxin are involved in the pathogenesis of primary nonfunction of graft and pulmonary complication after orthotopic liver transplantation. Livers from Lewis rats were stored for either 1 or 4 hr in ice–cold Euro–Collins solution (1–hr storage and 4–hr storage group, respectively). Subsequently, donor livers were implanted orthotopically. In some experiments, anti-tumor necrosis factor antibody was administered intravenously before and immediately after the surgery into animals that received livers stored for 4 hr. Blood samples for the measurement of tumor necrosis factor and endotoxin were collected by way of an indwelling catheter placed in the suprahepatic vena cava. Serum tumor necrosis factor was elevated at all time points studied postoperatively in rats of the 4–hr storage group; however, tumor necrosis factor was not detected in the serum in the 1–hr storage group. Endotoxin was also elevated significantly in the serum of the former group compared with levels in the serum of the latter group. The peak value of endotoxin occurred 1 hr earlier than that of tumor necrosis factor, suggesting that the rise in endotoxin stimulated release of tumor necrosis factor. The histological study of livers stored for 4 hr showed substantial hepatocellular degeneration 24 hr after surgery, whereas hepatocellular damage was minimal in the 1–hr storage group. Serum ALT levels 24 hr after the operation in the 1–hr and 4–hr storage groups were 169 ± 46 IU/L and 374 ± 41 IU/L (mean ± S.E.M., p < 0.05), respectively. Histological studies of the lung revealed substantial alveolar edema, leukocyte infiltration and alveolar hemorrhage in the 4–hr storage group; however, these findings were minimal in the lungs in the 1–hr storage group. Anti-tumor necrosis factor antibody treatment effectively attenuated both the liver and pulmonary injuries and the serum ALT activities (163 ± 9 IU/L, p < 0.05) compared with nontreated animals. Thus this study demonstrates that endotoxemia occurred in the early postoperative stage, followed by elevation of levels of tumor necrosis factor in blood. These events may contribute to the pathogenesis of primary nonfunction of the graft and pulmonary complications after orthotopic liver transplantation. (Hepatology 1992;16:487-493.)
The Immune Response in Chronic Hepatitis B Virus Infection: the “Core” of the Problem?
Authors: Baker James R.
Published: March 2007

Individuals with chronic hepatitis B virus (HBV) infection are generally divided into asymptomatic healthy carriers and patients with chronic liver disease. Several studies have suggested that the hepatitis B core antigen could be an immunological target of cytotoxic T lymphocytes (CTL). To investigate the possible pressure site from CTL, the entire core region of HBV DNA was sequenced in 30 subjects (10 asymptomatic healthy carriers and 20 patients with chronic liver disease). No significant changes in the nucleotide sequence and deduced amino acid residue were noted in the 10 healthy carriers. In contrast, a cluster of changes in a small segment of 18 amino acids (codons 84-101 from the start of the core gene) was found in 15 of the 20 chronic liver disease patients. All these 15 patients had advanced liver diseases (chronic active hepatitis and cirrhosis), whereas only mild liver disease (chronic persistent hepatitis) was found in the five patients without mutations. These data suggest that the region with mutation clustering is the major target of CTL, and that the mutations evolve under the pressure of immune selection.
An “Ironic” Case of Mistaken Identity?
Authors: Kowdley Kris V. , Tavill Anthony S.
Published: March 2007

An iron loaded liver from a 40 year old man with occult haemochromatosis was transplanted into a 19 year old woman with acute liver failure secondary to a paracetamol overdose. Increased parenchymal hepatic iron was found in a liver specimen at biopsy under–taken because of mild rejection 30 days after transplantation. After transplantation the patient had two episodes of liver rejection confirmed by biopsy. The hepatic iron concentration fell from 161 μmol/g on day 30 after transplant to 26.5 μmol/g (normal < 40) on day 210. Iron absorption, measured 45 days after transplant, was in the normal range at 12.4%. The rapid fall in hepatic iron and the normal iron absorption study result suggest that the genetic defect of haemochromatosis is not exclusively an intrahepatic defect.
The Degree of Variability in the Amino Terminal Region of the E2/Ns1 Protein of Hepatitis C Virus Correlates With Responsiveness to Interferon Therapy in Viremic Patients
Authors: Okada Shun-Ichi , Akahane Yoshihirc , Suzuki Hiroshi , Okamoto Hiroaki , Mishiro Shunji
Published: March 2007

We investigated amino acid heterogeneity in the variable regions of the E2/NS1 viral protein in interferon–responsive and interferon–nonresponsive patients with chronic hepatitis C virus infection. The study assessed whether any particular heterogeneity pattern(s) could be useful in predicting responsiveness to interferon treatment. The nucleic acid sequences of the hepatitis C virus genome were analyzed from six patients with chronic hepatitis treated with an interferon–β, three of whom did not respond to the therapy and another three who showed remarkable improvement in the serum levels of liver enzymes and hepatitis C virus RNA after 6 mo. The complementary DNA clones propagated from each of the nonresponders showed significant diversity of both nucleotide and amino acid sequence, especially at the hypervariable region 1 within the putative E2/NS1 gene of the virus, suggesting that these patients were infected with a large heterogeneous pool of hepatitis C virus variants. In contrast, the responders showed little or no diversity in the sequence of the complementary DNA clones, suggesting that they were infected with one or a small population of viral genotypes containing significantly less variability in the E2/NS1 hypervariable region 1. These results suggested that a large variable population of hepatitis C virus genotypes is implicated in patients who are nonresponders to interferon treatment. In addition, a significant change in the hepatitis C virus genotype population was observed in nonresponders after interferon treatment. This may reflect a differential viral sensitivity to interferon, selective immune pressure by the host or both. (Hepatology 1992;16:619-624.)
Hepatitis B and C Viral Infections in Patients With Hepatocellular Carcinoma
Authors: Ruiz Juan , Sangro Bruno , Cuende José I. , Beloqui Oscar , Riezu-Boj JosBé I. , Herrero JOSé I. , Prieto Jesús
Published: March 2007

The prevalence of hepatitis B and C virus infections was studied in 70 patients diagnosed as having hepatocellular carcinoma. In addition to viral serological markers, serum hepatitis B virus DNA and hepatitis C virus RNA were determined with a nested polymerase chain reaction assay. Twelve patients (17%) were HBsAg positive, 26 (37%) had antibodies to HBs, HBc or both and 32 (46%) were negative for all hepatitis B virus serological markers. Prevalence of the antibody to hepatitis C virus was 63% (44 patients). Hepatitis B virus DNA was detected in 24 of the 66 tested patients (36%). Twelve of these hepatitis B virus DNA–positive patients were HBsAg negative (seven were positive for antibody to HBs, antibody to HBc or both and five were negative for all hepatitis B virus serological markers). Hepatitis C virus RNA was found in 42 of 68 patients (62%): A high correlation (95%) existed between hepatitis C virus RNA and hepatitis C virus antibodies. Nevertheless, two patients without antibody to hepatitis C virus had serum hepatitis C virus RNA sequences. Coinfection by the two viruses was detected in nine subjects (14%), but no clinical differences were found between these and the rest of the patients. We conclude that nearly 90% (62 of the 70 patients studied) of cases of hepatocellular carcinoma in our geographical area are related to hepatitis virus infections (detected by serological or molecular studies). Hepatitis C is more prevalent than hepatitis B virus in patients with hepatocellular carcinoma, and the infection is still active when the tumor is diagnosed. This fact is probably important in the contribution of hepatitis C virus to the development of hepatocellular carcinoma. (Hepatology 1992;16:637-641.)
In Situ Hybridization Studies in Hepatitis A Infection
Authors: Taylor Michael G. , Goldin Robert D. , Karayiannis Peter , Thomas Howard C.
Published: March 2007

Anin situhybridization method using radiolabeled oligonucleotide probes was developed to study primary sites of hepatitis A virus replication in an experimental animal model of infection. Hepatitis A genomic sequences were demonstrated in hepatocytes of four marmosets with acute hepatitis A by use of antisense probes. In two of these animals, staining was also found when a sense probe was used, which is consistent with active replication in the hepatocytes. The specificity of the hybridization signal was confirmed by neutralization with “cold” (i.e., unlabeled) probes and by absence of hybridization with non–A hepatitis and reverse antisense probes. The hepatocyte appeared to be the only cell type showing staining. No hybridization was found in other organs, including the intestine (n = 4) and, in one animal, the kidney and spleen. (Hepatology 1992;16:642-648.)
A Pilot Study of Ribavirin Therapy for Chronic Hepatitis C
Authors: di Bisceglie Adrian M. , Shindo Michiko , Fong Tse-Ling , Fried Michael W. , Swain Mark G. , Bergasa Nora V. , Axiotis Constantine A. , Waggoner Jeanne G. , Park Yoon , Hoofnagle Jay H.
Published: March 2007

Interferon–α therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and may be associated with intolerable side effects. Ribavirin is a nucleoside analog with a broad spectrum of antiviral action. We conducted an uncontrolled pilot study of ribavirin therapy in 13 patients with chronic hepatitis C. Ribavirin was given for 6 mo, in a dose that was increased, at 2–mo intervals, from 600 mg to 1,000 mg to 1,200 mg/day. Serum ALT levels gradually decreased in all 13 treated patients; the mean percentage of decrease was 67% (from 210 U/L [range = 109 to 593] to 63 U/L [range = 22 to 108 U/L]; p = 0.0006) after 6 mo of treatment. Serum aminotransferase levels fell to the normal range in four patients (31%). In the 3 to 6 mo after cessation of ribavirin therapy, serum aminotransferase activities gradually rose to near pretreatment levels in all but one patient. Therapy was associated with a significant decrease in the geometric mean titer of hepatitis C virus RNA in serum (1:1,981 vs. 1:199; p < 0.02) although no patients lost hepatitis C virus RNA from serum during therapy. No significant improvement was seen in liver histological appearance. Ribavirin therapy resulted in mild, reversible hemolysis; no patient exhibited symptomatic anemia. These findings suggest that ribavirin has a beneficial effect in patients with chronic hepatitis C, although further studies are needed to determine how ribavirin is best used. (Hepatology 1992;16:649-654.)
A Clinicopathological Study of Human Liver Allograft Recipients Harboring Preformed Igg Lymphocytotoxic Antibodies
Authors: Demetris Anthony J. , Nakamura Kenjiro , Yagihashi Atsuhito , Iwaki Yuichi , Takaya Shunichi , Hartman Grace G. , Murase Noriko , Bronsther Oscar , Manez Rafael , Fung John J. , Iwatsuki Shunzaburo , Starzl Thomas E.
Published: March 2007

Twenty–six adult patients with preformed IgG donor lymphocytotoxic antibodies received primary liver allografts under FK 506 immunosuppression. The effect of the crossmatch–positive state on early graft function and on the immunopathological and histopathological findings was compared with that of 52 crossmatch–negative control recipients. The presensitized (crossmatch–positive) patients had prolongation of early graft dysfunction, underwent more clinically indicated biopsies and had a higher incidence of cellular rejection, both overall (p < 0.05) and within 10 days of transplantation (p < 0.01). They also had a higher incidence of graft failure in the first 180 days (p < 0.01). Hyperacute rejection with necrotizing or neutrophilic arteritis was not seen in the crossmatchpositive grafts. However, histological findings associated with presensitization included platelet margination in central veins and sinusoids in biopsy specimens 60 to 90 min after graft revascularization. Later biopsy specimens had neutrophilic portal venulitis followed by cholangiolar proliferation, acute cholangiolitis and centrilobular hepatocyte swelling that mimicked preservation injury, endothelial activation of arteries with medial changes and relapsing episodes of acute cellular rejection. These clinicopathological observations suggest that lymphocytotoxic antibodies can have a deleterious effect on liver allograft function and survival, even if they do not precipitate immediate or hyperacute rejection. (Hepatology 1992;16:671-681.)
Localization of Cytochrome P–450 Gene Expression in Normal and Diseased Human Liver By In Situ Hybridization of Wax–Embedded Archival Material
Authors: Palmer Colin N.A. , Coates Philip J. , Davies Susan E. , Shephard Elizabeth A. , Phillips Ian R.
Published: March 2007

The localization of the expression of several cytochrome P–450 genes in normal and diseased human liver was investigated by in situ hybridization of formalin–fixed, paraffin wax-embedded archival tissue samples with 35S–labeled antisense RNA probes. The results demonstrated that genes coding for members of the cytochrome P–450 3A subfamily (CYP3A) were preferentially expressed in hepatocytes in acinar zone 3 (the centrilobular region), whereas genes coding for CYP1A2, CYP2A, 2B and 2C were expressed uniformly throughout the liver acinus. In cirrhotic livers, CYP2A and 2B genes (and to a lesser extent, CYP3A genes) were highly expressed in isolated hepatocytes located at the junction of parenchyma with fibrous septa. The cause and significance of the position–dependent expression of specific cytochrome P–450 genes in normal and diseased human liver are discussed. (Hepatology 1992;16:682-687.)
Limitations of Current Preoperative Liver Imaging Techniques for Intrahepatic Metastatic Nodules of Hepatocellular Carcinoma
Authors: Utsunomiya Tohru , Matsumata Takashi , Adachi Eisuke , Honda Hiroshi , Sugimachi Keizo
Published: March 2007

To determine the limitations of the latest techniques in preoperative liver imaging for hepatocellular carcinoma, 20 patients with histologically proven intrahepatic metastatic tumors were studied. In 32 masses, we were able to assess the relationship between these intrahepatic metastatic tumors and the findings of preoperative imaging individually. Six intrahepatic metastatic tumors not exceeding 5 mm in diameter were missed in all the imaging examinations. The detection rate was 60% in 13 intrahepatic metastatic tumors of 5 to 10 mm, 77% in 10 intrahepatic metastatic tumors of 10 to 20 mm and 100% in 3 intrahepatic metastatic tumors exceeding 20 mm. In total, computed tomographic imaging during arterial portography demonstrated the highest rate of detection (40%) of all the studies performed. Magnetic resonance imaging, which was recently introduced, was rather disappointing (31%) in this series. In two patients, intrahepatic metastatic tumors were only histologically confirmed. Our study suggests a low rate of detection of intrahepatic metastatic tumors with current preoperative imaging modalities. For improvement of prognosis after hepatectomy for hepatocellular carcinoma adjuvant therapy and extended hepatectomy seem necessary if the functional capacity of the remaining liver permits. (Hepatology 1992;16:694-701.)