摘要:

AbstractHepatic encephalopathy is ameliorated by drugs acting on the central GABAA‐benzodiazepine receptor complex. To investigate whether these effects are specific for hepatic encephalopathy or just reflect a nonspecific arousal reaction, various benzodiazepine antagonists like flumazenil or with inverse agonistic properties (Ro 15‐4513, Ro 15‐3505) were studied in uremic encephalopathy in rats after bilateral ureteral ligation (n = 20) and compared with hepatic encephalopathy caused by thioacetamide‐induced acute liver failure (n = 33). As soon as the animals developed clear signs of metabolic encephalopathy, their motor activity was recorded in an animal activity meter for 10 min. Furthermore, a composite score was calculated by grading various behavioral signs from 0 = absent to 3 = apparently normal. Rats were then injected with coded preparations of Ro 15‐4513 (0.5, 2.5 and 5 mg/kg body wt intraperitoneally), flumazenil (2.5, 10, 25 and 40 mg/kg), Ro 15‐3505 (10 mg/kg) or vehicle, and the measurements were repeated. The code was broken after the completion of the study. Pretreatment motor activity was decreased both in hepatic and uremic encephalopathy (20.7 ± 6.4 [S.E.M.] and 41.3 ± 37.1 movements/10 min). In hepatic encephalopathy motor activity and the composite score were improved both by 5 mg/kg Ro 15‐4513 (by 293%, p0.01), whereas vehicle and flumazenil had no effects. In uremic encephalopathy neither drug was effective in improving the neurobehavioral status. These results indicate that the amelioration of neurobehavioral symptoms both by Ro 15‐4513 and Ro 15‐3505 seems to be specific for hepatic encephalopathy and is consistent with the hypothesis that hepatic encephalopathy is associated with an increased GABA‐ergic tone. (HEP

ISSN:0270-9139    

DOI:10.1002/hep.1840140602

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractWe have evaluated the clinical and histopathological outcomes of patients who contracted chronic non A, non B hepatitis as a result of transfusions administered during heart surgery at the National Institutes of Health. Posttransfusion hepatitis developed in 65 of 1,070 (6.1%) patients and became chronic in 45 (69%) of those cases. Antibody to hepatitis C virus was detectable in 53 patients (82%) with posttransfusion non A, non B hepatitis. Thirty‐three patients with chronic non A, non B hepatitis agreed to liver biopsy (group 1). In addition, six other patients with chronic posttransfusion non A, non B hepatitis were evaluated (group 2). These 39 patients were followed between 1 and 24 yr (mean = 9.7 yr). Cirrhosis developed in 8 patients (20%) between 1.5 and 16 yr after blood transfusion. Of the 33 patients in group 1, 11 (33%) died during follow‐up. In two cases (6%), this was related to liver failure. At this writing, two additional patients (6%) have decompensated cirrhosis and one (3%) has debilitating fatigue. Twenty of 33 patients (61%) with histological evidence of chronic active hepatitis or cirrhosis are asymptomatic and have no clinical evidence of liver disease.Thus chronic non A, non B posttransfusion hepatitis appeared to be due to hepatitis C virus infection in most cases. It was associated with the development of cirrhosis in approximately 20% of cases and end‐stage liver disease in 12% of patients followed prospectively. Most patients with histological evidence of cirrhosis or chronic active hepatitis, however, had minimal clinical evidence of liver disease within the time frame of this study. (HEPATOLOGY1991;14:969

ISSN:0270-9139    

DOI:10.1002/hep.1840140603

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractInterferon‐α has been shown recently to selectively enhance hepatocyte expression of HBsAg/pre‐S2in chronic hepatitis B virus infection in a way that may enhance immune recognition. To determine the effect of interferon‐γ on hepatitis B virus antigen expression, hepatocytes isolated from patients with chronic hepatitis B virus infection were incubated in the absence or presence of interferon‐γ and viral antigen expression was assessed by both radioimmunoassay and immunocytochemistry using appropriate monoclonal antibodies.Interferon‐γ inhibited the expression of all hepatitis B virus antigens tested. Intracellular HBsAg measured by radioimmunoassay of sonicated hepatocytes fell by 29% with 1 U/ml (p<0.01) and 36% with 10 U/ml of interferon‐γ (p<0.001) compared with control treatment. Secreted HBsAg was reduced by 19% with 10 U/ml of interferon‐γ (p<0.01). Intracellular HBeAg was also decreased by 29% with 1 U/ml (p<0.05) and 42% with 10 U/ml of interferon‐γ (p<0.05), but no significant change was found in the amount of secreted HBeAg. The proportion of hepatocytes containing various hepatitis B virus antigens and the intracellular viral antigen staining densities also fell significantly with interferon‐γ incubation. Interestingly, the addition of interferon‐γ abolished the augmenting effect of interferon‐α on intracellular HBsAg.These data indicate that interferon‐γ, in contrast to interferon‐α, has an inhibitory effect on hepatocyte expression of all hepatitis B virus antigens including HBsAg/pre‐S2, suggesting that this may be one factor that accounts for their difference in clinical activity in patients with chronic hepatitis B virus

ISSN:0270-9139    

DOI:10.1002/hep.1840140604

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractSera from 31 patients with chronic hepatitis delta virus infection and 18 patients with acute hepatitis delta virus infection were examined for IgA class antibodies to this virus using a newly developed enzyme immunoassay. IgA antibody to hepatitis D virus was detected in 21 (67.7%) of 31 patients with chronic delta viral hepatitis, but in only 1 (5.6%) of the 18 patients with acute infection (p0.2), in the patients with chronic delta hepatitis. The finding that IgA antibody to hepatitis D virus was almost exclusively associated with chronic hepatitis delta virus infection and correlated independently with moderate‐to‐severe histological activity (with a specificity of 90.5% and a sensitivity of 82.6%) suggests that this antibody might be a useful serological marker of underlying liver damage in chronic delta hepatitis. (HEPATOLOGY1991;

ISSN:0270-9139    

DOI:10.1002/hep.1840140605

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractThe relationship between alcoholic liver disease and hepatitis C virus was studied in 80 patients by searching for hepatitis C virus RNA with the polymerase chain reaction and by measuring hepatitis C virus antibodies. By C‐100 enzyme‐linked immunosorbent assay, hepatitis C virus antibodies were found in 2 of 10 patients with fibrosteatosis, 8 of 20 patients with alcoholic hepatitis, 14 of 19 patients with chronic hepatitis and 19 of 31 patients with cirrhosis. Percentages of patients with antibodies found by C‐100 radioimmunoassay and by enzyme‐linked immunosorbent assay based on sequence peptide 42 were lower; of the 16 patients with a low titer by C‐100 enzyme‐linked immunosorbent assay, 10 were negative by radioimmunoassay and 6 were negative by sequence peptide 42. By a second‐generation recombinant immunoblot assay, hepatitis C virus antibodies were found in 1 of 10 patients with fibrosteatosis, 2 of 20 patients with alcoholic hepatitis, 15 of 19 patients with chronic hepatitis and 18 of 31 patients with cirrhosis. Hepatitis C virus RNA was found in 1 of 10 patients with fibrosteatosis, 3 of 20 patients with alcoholic hepatitis, 13 of 19 patients with chronic hepatitis and 20 of 31 patients with cirrhosis. Of the 37 patients with hepatitis C virus RNA, 31 had antibodies by C‐100 enzyme‐linked immunosorbent assay (25 patients at a high titer [cut‐off index>6]), and 31 had antibodies by second‐generation recombinant immunoblot assay. Patients with cirrhosis and hepatitis C virus RNA had higher ALT activity than such patients without hepatitis C virus RNA (p<0.05). Of the 80 patients, 25 patients stopped drinking, 11 of these patients had hepatitis C virus RNA. The ALT of the 11 patients tended to decrease during hospitalization but increased in 7 of 11 after discharge. Of the 14 patients without hepatitis C virus RNA who stopped drinking, ALT decreased significantly (p<0.01) during hospitalization and increased only in 3 of the 14 after discharge. The histological activity index of Knodell for patients with fibrosis, chronic hepatitis or cirrhosis with hepatitis C virus RNA was 11.8 ± 4.2, but without hepatitis C virus RNA it was 8.4 ± 4.3 (p<0.01). Patients with hepatitis C virus RNA had worse periportal and bridging necrosis, intralobular degeneration, focal necrosis and portal inflammation than patients without hepatitis C virus RNA. (HEP

ISSN:0270-9139    

DOI:10.1002/hep.1840140606

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractWe followed up a group of patients with primary biliary cirrhosis who participated in a 4‐yr prospective, double‐blind controlled trial of colchicine therapy for 4 additional years. All were placed on open label colchicine (0.6 mg twice daily) after the trial was concluded. Of the original group of 28 patients treated with colchicine, 8 died and 5 recieved transplants (3 of the 5 died). Of the original placebo control group eight patients died and six received transplants (1 of the 6 died). Surviving patients on long‐term colchicine therapy (mean period = 8.1 yr, range = 5.3 to 9.1) showed reduction of mean serum alkaline phosphatase from 5.1 times the upper limit of normal values to 1.9 times (p<0.01). Mean ALT fell from 1.8 to 1.2 times the upper limit of normal (p = 0.05), and mean serum total bilirubin remained stable (1.6 mg/dl vs. 1.5 mg/dl). Major complications of cirrhosis developed in four patients in the colchicine group and five patients in the original control group. The only side effect of colchicine was diarrhea, which was noted in three patients. The diarrhea resolved with reduction in the dose of colchicine. Colchicine is a safe and inexpensive drug for the long‐term treatment of primary biliary cirrhosis. The biochemical parameters of disease activity (alkaline phosphatase and ALT) remain improved after long‐term follow‐up, and bilirubin values remain stable. However, complications of cirrhosis, deaths and transplantations were not prevented. The clinical usefulness of colchicine in the treatment of primary biliary cirrhosis seems to be limited. (HEPATOLOGY1991;

ISSN:0270-9139    

DOI:10.1002/hep.1840140607

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractAutoantibodies in primary biliary cirrhosis recognize mitochondrial 2‐oxacid dehydrogenase complexes, particularly the E2 subunits. Reactivity with the E3 subunit, common to each of the enzyme complexes, was sought by immunoblotting, with sera screened at 1:100 instead of the conventional 1:1,000 dilution. This was found in 11 of 29 sera from patients with primary biliary cirrhosis but also in 10 of 40 sera from normal subjects. Two‐dimensional immunoblotting and immunoblotting on purified enzymes established that the reactivity was actually with E3 rather than with another component of the 2‐oxoacid enzymes of similar molecular weight. Purified antibodies to E3 eluted from an affinity column did not cross‐react with other components of the 2‐oxoacid enzyme complexes. The antibodies to E3 did not react with theEscherichia colior yeast E3 subunits, suggesting that they are not stimulated by immune responses against microorganisms. Thus the proposal that reactivity to the shared E3 subunit of the 2‐oxoacid enzyme complexes could initiate primary biliary cirrhosis is not reflected at the antibody level. (HEPATOLOGY1991;

ISSN:0270-9139    

DOI:10.1002/hep.1840140608

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractWe describe a detailed study of the effects of ursodeoxycholic acid administration on bile acid composition of the serum and bile of patients with primary biliary cirrhosis. Gas chromatography‐mass spectrometry was used to analyze bile acids from 10 patients with primary biliary cirrhosis before and during ursodeoxycholic acid administration (500 mg/day, corresponding to approximately 8 mg/kg body wt), after group separation of the unconjugated and conjugated fractions by lipophilic anion exchange chromatography. These studies were directed at assessing whether the beneficial role of ursodeoxycholic acid in primary biliary cirrhosis was the consequence of a shift in the hydrophobic/hydrophilic balance of the bile acid pool and whether the hypercholeresis might result from the cholehepatic circulation of unconjugated ursodeoxycholic acid in bile.In basal conditions, the unconjugated bile acids accounted for only 5.5% and 2.5%, respectively, of the total bile acids of serum and bile; cholic acid was the major component of the conjugated fraction of serum and bile (56.0% ± 4.0%, mean ± S.E.M.), and ursodeoxycholic acid was present in only trace amounts. The conjugated fraction contained many unusual bile acids (representing 16.5% ± 1.3% of total) including C25bile acids, iso‐chenodeoxycholic acid and several oxo‐bile acids.After ursodeoxycholic acid administration biochemical indices of liver function all improved, but the proportions of the unconjugated bile acids in serum and bile did not significantly change. Ursodeoxycholic acid became the predominant biliary bile acid of conjugated bile acid fraction (33.4% ± 1.4%) and significant decreases occurred (p<0.05) in biliary levels of cholic acid (28.3% ± 2.3%) and the unusual bile acids (9.2% ± 0.8%), but no changes occurred in the proportions of chenodeoxycholic acid (from 19.4% ± 2.7% to 19.4% ± 1.3%) and deoxycholic acid (from 5.4% ± 1.4% to 6.8% ± 1.3%). The proportions of biliary lithocholic acid increased significantly after ursodeoxycholic acid administration (from 0.7% ± 0.1% to 2.9% ± 0.9%; p<0.05). In serum, ursodeoxycholic acid concentrations attained levels of 64 μmol/L. Serum lithocholic acid concentrations increased, whereas cholic and chenodeoxycholic acids decreased. Relative percentages of individual biliary bile acids in the unconjugated fraction were similar to the conjugated fraction before and after ursodeoxycholic acid treatment. The proportions of biliary unconjugated ursodeoxycholic acid did not change significantly after its administration (from 0.6% to 0.9% of the total).These data provide little support for a significant shift in the hydrophilicity of the circulating bile acid pool after ursodeoxycholic acid administration. However, because the detergency and hepatotoxicity of a bile salt appears to correlate well with the retention index determined by reverse‐phase liquid chromatography, the qualitative changes observed in the biliary pool (i.e., a displacement of cholic acid by ursodeoxycholic acid), suggests that a relative lowering of the hepatotoxicity index of the bile acid pool occurs after ursodeoxycholic acid therapy. Furthermore, our findings indirectly suggest that a hypercholeresis related to the biliary secretion of unconjugated ursodeoxycholic acid does not play a role in the beneficial effects of ursodeoxycholic acid therapy in primary biliary cirrhosis. (HEPATOLO

ISSN:0270-9139    

DOI:10.1002/hep.1840140609

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractThe plasma metallothionein concentration was evaluated in healthy subjects and in patients with several types of liver disorders. Plasma metallothionein concentrations in controls varied between 2.4 and 4.8 ng/ml. Patients with disorders associated with increased liver copper concentrations (i.e., primary biliary cirrhosis and primary sclerosing cholangitis) had significantly (both p<0.002) elevated plasma metallothionein concentrations (range = 1.8 to 52.2 ng/ml), and a considerable number of these were above the maximum control level (21 of 41 patients). In contrast, patients with liver disorders not associated with increased liver copper concentrations (alcoholic and cryptogenic cirrhosis, and acute viral and chronic active hepatitis) generally had normal plasma metallothionein concentrations and only a few were above the maximum control level (11 of 64 patients, maximum = 8.8 ng/ml). The metallothionein concentrations in plasma samples from patients in stage I or II primary biliary cirrhosis were within or slightly above the control range, whereas most patients in stage III had elevated levels (p<0.002), and almost all patients in stage IV had clearly elevated (p<0.0001) concentrations. In primary biliary cirrhosis the plasma metallothionein concentration tended to increase during the evolution of the disorder, and the concentration correlated significantly with the serum total bilirubin concentration.In conclusion, the plasma metallothionein concentration is significantly elevated in patients with primary biliary cirrhosis and in patients with primary sclerosing cholangitis. Although related to the histological stage of primary biliary cirrhosis, the measurement of plasma metallothionein concentrations contributes little to the diagnosis or the evaluation of the severity of these disorders. In patients with liver disorders not associated with increased liver copper concentrations the plasma metallothionein concentration is generally normal. (HEPATOLOGY1991;14:1008–1012

ISSN:0270-9139    

DOI:10.1002/hep.1840140610

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY

摘要:

AbstractColchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 ± 1.82 ml/mm · kg, whereas cirrhotic patients had a mean clearance of 4.22 ± 0.45 ml/mm · kg (p0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child‐Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination. HEPATOLOGY1991;14

ISSN:0270-9139    

DOI:10.1002/hep.1840140611

出版商:W.B. Saunders    

年代:1991

数据来源: WILEY