ISSN:0270-9139    

DOI:10.1002/hep.1840090502

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractIsaxonine and several other drugs transformed by cytochrome P‐450 into reactive metabolites apparently lead to immunoallergic hepatitis in man. Protein epitopes modified by the covalent binding of the metabolites have been proposed as possible targets for the immune response. The purpose of this work was to determine whether covalently bound metabolites are indeed present on hepatocyte plasma membrane proteins. In a first series of experiments, rats were killed 15 or 60 min after administration of [2‐14C]isaxonine (0.2 mmole · kg−1i.p.), and various fractions were prepared from isolated hepatocytes; microsomal contamination of the plasma membrane fraction was 1.2% or less. At 60 min, the amount of isaxonine metabolite covalently bound per mg of protein was similar in plasma membranes (0.42 nmole metabolite · mg protein−1) and in microsomes (0.38); both values were decreased by about 70% in rats pretreated with piperonyl butoxide, an inhibitor of cytochrome P‐450. At 15 min, however, covalent binding to plasma membrane proteins (0.06 nmole metabolite · mg protein−1) was only half of that to microsomal proteins (0.12). In a second series of experiments, [2‐14C] isaxonine (0.1 mM) was incubated with NADPH, hepatic microsomes and plasma membranes. The reactive isaxonine metabolite became bound extensively to microsomal proteins, but not to plasma membrane proteins. These results show that administration of isaxonine leads to the presence of isaxonine adducts on the proteins of the hepatocyte plasma membrane. They are consistent with thein situbinding of a highly unstable metabolite in the endoplasmic reticulum, or its immediate vicinity, some of these proteins then migrating toward the plasma

ISSN:0270-9139    

DOI:10.1002/hep.1840090503

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractThe prevalence of apparent amiodarone‐related hepatic injury in 104 patients followed prospectively is compared to that reported in the literature. Asymptomatic elevation of serum aminotransferase levels was detected in approximately one‐fourth of the patients, a figure similar to the average of reported cases. The frequency of extrahepatic organ toxicity was increased in patients with elevated levels. Symptomatic “hepatitis” developed in 3% of this series and in less than 1% of cases in the litérature. Evidence of hepatic phospholipidosis and the development of pseudoalcoholic liver injury is most likely due to the biochemical effects of the drug and to possible metabolic idiosyncrasy, respectively. Serial blood enzyme measurements, as recommended by the manufacturer, may offer some protection against the development of more serious liver injury. However, levels of amiodarone may persist in various tissues for weeks to months following withdrawal, and stopping the drug does not guarantee the prompt reversal of any organ toxicity. Accordingly, the risks posed and benefits offered by amiodarone should be carefully weighed prior to discontinuing the drug, as the risk of sudden cardiac death may outweigh the hazards of ongoing hepatic, pulmonary or other

ISSN:0270-9139    

DOI:10.1002/hep.1840090504

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractBoth human porphyria cutanea tarda and experimental hexachlorobenzene‐induced porphyria are associated with hepatic injury and are potentiated by excess hepatic iron. The mechanisms whereby cellular injury occurs and the synergistic role of iron overload are unknown. In the present experiments, we studied hepatic mitochondrial function and lipid peroxidation in rats with hexachlorobenzene‐induced porphyria in which iron loading was achieved by dietary carbonyl iron supplementation. Female rats were treated for 8 weeks, receiving a chow diet supplemented with hexachlorobenzene (0.2%, w/w), carbonyl iron (1.0%, w/w) or hexachlorobenzene + iron. Hepatic total porphyrins were increased 100‐fold in rats receiving hexachlorobenzene (hexachlorobenzene alone and hexachlorobenzene + Fe), and total hepatic iron was increased approximately 10‐fold in rats receiving iron supplementation (Fe alone and hexachlorobenzene + Fe). There was a significant increase in mitochondrial lipid peroxidation in rats treated with hexachlorobenzene alone and hexachlorobenzene + Fe. A significant reduction in mitochondrial respiratory control ratios and in oxidative phosphorylation (ADP/O ratios) using glutamate and succinate as substrates was demonstrated when rats were treated with hexachlorobenzene + iron. The reductions in respiratory control ratios were due to a combination of an inhibitory defect in electron transport as evidenced by an irreversible decrease in State 3 respiration and an uncoupling effect as evidenced by an increase in State 4 respiration. These findings suggest that lipid peroxidation and mitochondrial dysfunction may contribute to the hepatotoxicity seen in hexachlorobenzene‐induced

ISSN:0270-9139    

DOI:10.1002/hep.1840090505

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractThe diagnosis of alcoholic hepatitis is difficult to establish by conventional clinical and laboratory methods, and a firm diagnosis relies on liver histology. Since there are severe limitations in following patients with repeated liver biopsies, noninvasive procedures are needed to assess the presence of alcoholic hepatitis in chronic alcohol abusers. It has been suggested that serum Type III procollagen peptide levels correlates with the degree of inflammation in chronic liver disease. Since inflammation is a major histological finding in alcoholic hepatitis, we therefore studied the usefulness of measuring serum Type III procollagen peptide and laminin values in 45 consecutive chronic alcohol abusers, with or without cirrhosis, in detecting those with alcoholic hepatitis. The results showed that both Type III procollagen peptide and laminin values were elevated in all of the patients with established liver damage. However, the values were highest in those with liver cirrhosis plus alcoholic hepatitis (Type III procollagen peptide 50.4 ± 36.4 ng per ml vs. 8.1 ± 2.6 in controls, p<0.01; laminin 4.50 ± 1.49 units per liter vs. 1.24 ± 0.26 units per liter in controls, p<0.01), followed by subjects with alcoholic hepatitis alone (Type III procollagen peptide 23.5 ± 17.6 ng per ml, p<0.01; laminin 2.60 ± 1.09 units per liter, p<0.01). Whereas Type III procollagen peptide values did not discriminate among patients with cirrhosis (21.5 ± 10.1 ng per ml) and those with steatofibrosis (14.3 ± 3.2 ng per ml), nor among those with alcoholic hepatitis and those with steatofibrosis, laminin values did (respectively, 2.12 ± 0.60 units per liter and 1.42 ± 0.41 units per liter, p<0.01). We thus suggest that independently of whether Type III procollagen peptide or laminin serum values reflect increased deposition or breakdown of extracellular matrix components, they are useful in recognizing alcoholic hepatitis

ISSN:0270-9139    

DOI:10.1002/hep.1840090506

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractSexual behavior in women with liver disease was examined in 150 women to determine whether liver disease influenced sexual desire, frequency or performance. The average age of women studied was 53 years (range: 26 to 76 years), and a wide variety of liver diseases were represented. Sexual desire was reduced in 33%. Difficulty in becoming sexually aroused was noted by 18%. Orgasm during intercourse was not experienced by 25%. The frequency of sexual intercourse decreased since onset of disease in 27%. Dyspareunia was a complaint by 21%, most often attributed to decreased vaginal lubrication. Liver disease was considered a significant factor interfering with sexual function in 17%. No statistical difference was found between sexual desire or function in our study and in large studies of sexual behavior in women. Each category was subdivided by presence or absence of cirrhosis, pre‐ or postmenopausal state, laboratory values and duration of disease. Except for a greater number of postmenopausal women with complaints of painful intercourse, no statistical differences or trends were found. Nonalcoholic liver disease does not affect sexual desire, function or performance. Variables other than liver disease influence sexuality. Women with liver disease can thus be reassured that they can maintain normal sexual relation

ISSN:0270-9139    

DOI:10.1002/hep.1840090507

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractHepatic aldehyde dehydrogenase isozyme activity was measured in 51 patients with various types of liver diseases, including 24 patients with alcoholic liver disease, to elucidate the relationship between hepatic aldehyde dehydrogenase activity and liver disease, especially alcoholic liver disease. The levels of low‐Kmand total aldehyde dehydrogenase activity in the liver decreased both in alcoholic and nonalcoholic liver disease patients, who showed an isoelectric focusing pattern of the usual type. There was no significant difference in the aldehyde dehydrogenase activity between alcoholic and nonalcoholic liver disease. In alcoholic liver disease, the decrease in the activity was significantly correlated with the progression of liver histology. The activity in liver cirrhosis was significantly lower than that in the other types of alcoholic liver disease. In nonalcoholic liver disease patients, the unusual type of hepatic aldehyde dehydrogenase activity observed was not different from the unusual type observed in nonhepatobiliary disease patients. These results indicate that the reduction of hepatic low‐Kmaldehyde dehydrogenase activity is a change that occurs subsequent to liver damage. Genetic abnormality in aldehyde dehydrogenase may not be important in the pathogenesis of alcoholic liver inj

ISSN:0270-9139    

DOI:10.1002/hep.1840090508

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractSix intraoperative blood samples were obtained at intervals from each of 100 individuals undergoing their first liver transplants. The patients fell into the following diagnostic categories: postnecrotic cirrhosis 28, primary biliary cirrhosis 20, sclerosing cholangitis 19, miscellaneous diseases 14, carcinoma/neoplasia 12 and fulminant hepatitis 7. Coagulation factor values in the initial (baseline) blood samples varied by patient diagnosis. In general, all factor levels were reduced except factor VIII:C, which was increased to almost twice normal. The slight intraoperative changes in factors II, VII, IX, X, XI and XII suggested that a steady‐state relationship existed between depletion (consumption/bleeding) and repletion (transfusion, transit from extra‐ to intravascular space), even in the anhepatic state. In contrast, there were rapid and very significant falls in factor VIII and fibrinogen and a less pronounced decrease in factor V, all reaching their nadirs in early to mid‐Stage III. The cause of these coagulation changes appears to be activation of the fibrinolytic s

ISSN:0270-9139    

DOI:10.1002/hep.1840090509

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractWe measured 2′,5′‐oligoadenylate synthetase activity in peripheral blood mononuclear cells and serum of 14 HBsAg‐ and HBeAg‐positive patients with chronic hepatitis B with or without acute exacerbation. Elevated levels of 2′,5′‐oligoadenylate synthetase in peripheral blood mononuclear cells and serum were found in seven chronic hepatitis B patients with acute exacerbation, whereas in the remaining seven chronic hepatitis B patients without acute exacerbation, both levels were similar to those of normal subjects despite active hepatitis B virus multiplication. 2′,5′‐Oligoadenylate synthetase levels in peripheral blood mononuclear cells and serum, which were not statistically different from those of normal subjects prior to acute exacerbation, increased during acute exacerbation from 3‐to 23‐fold over initial levels following elevations in ALT activity. 2′,5′‐Oligoadenylate synthetase levels fluctuated over a normal range while ALT levels were elevated, and they returned to a baseline with ALT normalization. This suggests that thein vivointerferon system may be activated during acute exacerbation, and that this activation may not be a result of hepatitis B virus multiplication alone, but also of a host‐immune response to hepatitis B virus multiplication.Three patients were treated with interferon during acute exacerbation. All three had elevated levels of 2′,5′‐Oligoadenylate synthetase in peripheral blood mononuclear cells and serum just before treatment. 2′,5′‐Oligoadenylate synthetase levels increased only 1.1 ‐to 2.2‐fold over initial levels during treatment, with none of the patients clearing HBeAg during and after treatment. This suggests that interferon treatment may not be effective during acute exacerbation, since the invivointerferon system has already been activated. Measurement of 2′,5′‐oligoadenylate synthetase levels may be useful in evaluating thein vivostate of the interferon system and in

ISSN:0270-9139    

DOI:10.1002/hep.1840090510

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractMonocytes play an important role in the initiation and regulation of the antiviral immune response. These cells have a dense framework of intermediate filaments composed of vimentin monomers. In 35 patients with chronic hepatitis B, 26 healthy controls, seven patients with acute liver damage and eight patients with inactive HBsAg‐negative cirrhosis, we investigated the expression of vimentin filaments, C3b and IgGFc receptors, HLA‐DR molecules and the phagocytic activity in monocytes purified from venous blood. In the same subjects, we also studied the display of CD2, CD3 and CD5 on lymphocytes.In patients with chronic hepatitis B manifesting viral replication (n = 21; Group 1), the expression of vimentin filaments and the other functional monocyte parameters were decreased, whereas in patients in the nonreplicative phase of the disease (n = 14; Group 2) and in control cases with various forms of acute liver damage or inactive HBsAg‐negative cirrhosis, they were similar to those found in healthy subjects. In Group 1, there was also a selective defect in the display of CD3 on lymphocytes. The expression of this molecule correlated with the functional state of monocytes. In three patients with chronic hepatitis B that changed from the replicative to the nonreplicative phase of the disease, the expression of vimentin filaments in monocytes and of CD3 on lymphocytes increased to normal levels. On the other hand, the incubation of patients' monocytes with γ‐interferon corrected the diminished expression of vimentin filaments and the other decreased functional parameters.These findings show that in the replicative phase of chronic hepatitis B, there are alterations in the initial steps of activation of antiviral immune response and that γ‐IFN is able to correct the monocyte dysfunction present in these patients. Furthermore, it is suggested that the expression of immunoreactive vimentin filaments may be a dynamic indicator of the functional state o

ISSN:0270-9139    

DOI:10.1002/hep.1840090511

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY