摘要:

AbstractAlcohol abuse is the most common cause of end‐stage liver disease in the United States, but many transplant centers are unwilling to accept alcoholic patients because of their supposed potential for recidivism, poor compliance with the required immunosuppression regimen and resulting failure of the allograft. There is also concern that alcohol‐induced injury in other organs will preclude a good result. From July 1, 11982, to April 30, 1988, 73 patients received orthotopic liver transplants at the University of Pittsburgh for end‐stage alcoholic liver disease. Fifty‐two (71%) of these were alive at 25 ± 9 mo (mean ± S. D.) after transplantation, when a phone survey of these patients, their wives/husbands, and their physicians was performed to evaluate their subsequent use of alcohol, current medical condition and employment. Data obtained were compared with those for nonalcoholic patients selected as transplant controls. The recidivism rate has been 11.5%, with most patients drinking only socially. Fifty‐four percent of the survivors are employed, 21% classify themselves as homemakers and only 11 (21%) are unable to work. Twenty‐one patients died after transplantation; the most frequent cause of death was sepsis (43%), and intraoperative death was the next most common cause (28.6%). These data demonstrate that alcoholic patients can be transplanted successfully and achieve good health not significantly different from that of individuals transplanted for other causes. Thus orthotopic liver transplantation is a therapeutic option that should be considered for individuals with end‐stage alcoholic liver disease who desi

ISSN:0270-9139    

DOI:10.1002/hep.1840110202

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractChronic ethanol consumption by baboons (50% of energy from a liquid diet) for 18 to 36 mo resulted in significant depletion of hepaticS‐adenosyl‐L‐methionine concentration: 74.6 ± 2.4 nmol/gm vs. 108.9 ± 8.2 nmol/gm liver in controls (p<0.005). The depletion was corrected withS‐adenosyl‐L‐methionine (0.4 mg/kcal) administration (102.1 ± 15.4 nmol/gm afterS‐adenosyl‐L‐methionine–ethanol, with 121.4 ± 11.9 nmol/gm in controls). Ethanol also induced a depletion of glutathione (2.63 ± 0.13 μmol/gm after ethanol vs. 4.87 ± 0.36 μmol/gm in controls) that was attenuated byS‐adenosyl‐L‐methionine (3.89 ± 0.51 μmol/gm inS‐adenosyl‐L‐methionine‐methanol vs. 5.22 ± 0.53 μmol/gm inS‐adenosyl‐L‐methionine controls). There was a significant correlation between hepaticS‐adenosyl‐L‐methionine and glutathione level (r = 0.497; p<0.01). After the baboons received ethanol, we observed the expected increase in circulating levels of the mitochondrial enzyme glutamic dehydrogenase: 95.1 ± 21.4 IU/L vs. 13.4 ± 1.8 IU/L; p<0.001, whereas in a corresponding group of animals givenS‐adenosyl‐L‐methionine with ethanol, the values were only 30.3 ± 7.1 IU/L (vs. 9.6 ± 0.7 IU/L in theS‐adenosyl‐L‐methionine controls). This attenuation byS‐adenosyl‐L‐methionine of the ethanol‐induced increase in plasma glutamic dehydrogenase (p<0.005) was associated with a decrease in the number of giant mitochondria (assessed in percutaneous liver biopsy specimens), with a corresponding change in the activity of succinate dehydrogenase, a mitochondrial marker enzyme. Succinate dehydrogenase activity was increased in liver homogenates of animals fed ethanol (81.4 ± 4.0 mU/mg protein vs. 55.4 ± 2.1 mU/mg in controls; p<0.001), probably reflecting the increased mitochondrial mass.S‐adenosyl‐L‐methionine decreased succinate dehydrogenase levels (66.7 ± 3.6 mU/mg protein inS‐adenosyl‐L‐methionine‐ethanol group vs. 45.5 ± 2.2 mU/mg inS‐adenosyl‐L‐methionine controls; p<0.001).S‐adenosyl‐L‐methionine supplementation also significantly lessened the ethanol‐induced increase of plasma AST. Thus long‐term ethanol intake is associated with hepaticS‐adenosyl‐L‐methionine depletion, which can be corrected at

ISSN:0270-9139    

DOI:10.1002/hep.1840110203

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractA high‐fat diet has previously been shown to be a key factor for induction of alcoholic liver fibrosis in a rat model of intragastric ethanol infusion. To explore a possible mechanism by which the high‐fat diet facilitated such an effect, the present study examined how the high‐fat diet with or without ethanol affected proliferation and collagen formation of hepatic lipocytes, perisinusoidal cells that have been suggested to be involved in liver fibrogenesis. We also evaluated effects of the high‐fat diet on the sensitivity of lipocytes to stimulatory effects of Kupffer cell‐derived factors. Intragastric infusion of ethanol and the high‐fat diet for 9 to 10 wk resulted in induction of a varying degree of perivenular fibrosis in 75% of animals. Lipocytes isolated from these animals (A) had significantly higher basal rates of proliferation (three to four times) and collagen formation (1.5 times) than those isolated from control animals, which were isocalorically infused with the high‐fat diet (H) or the low‐fat diet (L), or those that were fed chowad libitum(C). Lipocytes from the H group exhibited significantly higher relative production of collagen than those from the L group, but their net collagen production was not enhanced. The dialyzed Kupffer cell‐conditioned medium from the A group markedly stimulated proliferation and collagen formation of lipocytes from the groups given the high‐fat diet (A and H) but had minimal effects on those from the L and C groups, establishing the order of decreasing lipocyte sensitivity from the A, H, L to C group. Similarly, lipocytes from the H and A groups exhibited a more profound responsiveness to the stimulatory effect of transforming growth factor β 1 on collagen formation. These results demonstrate (a) that lipocytes isolated from the rats given the high‐fat diet and ethanol are markedly proliferative and produce more collagen; and (b) that the Kupffer cells derived from these animals release factors that stimulate proliferation and collagen formation of lipocytes and (c) that the high‐fat diet sensitizes lipocytes for stimulatory effects of the Kupffer cell‐derived factors and tra

ISSN:0270-9139    

DOI:10.1002/hep.1840110204

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractAlthough administration of 100 mg galactosamine caused severe hepatic injury in C3H/HeN mice, splenectomy reduced the grade of this hepatotoxicity. However, this hepatic injury was scarcely detected in the endotoxin‐resistant C3H/HeJ mice. In addition, in contrast to high lethality in C3H/HeN mice with a combined administration of galactosamine and endotoxin, splenectomy rendered C3H/HeN mice slightly resistant to this treatment. Further resistance was demonstrated in C3H/HeJ mice. In an attempt to clarify the role of endotoxin‐responsive spleen cells in the pathogenesis of hepatic injury, we investigated glactosamine‐induced hepatic injury by transfer of lipopolysaccharide‐treated C3H/HeN or C3H/HeJ spleen cells. Both oxygen‐derived free radical production and the proportion of macrophages in spleen cells were markedly enhanced in C3H/HeN mice after an intraperitoneal injection of lipopolysaccharide. Further increase in oxidative free radical production was found in the dish‐adherent cells (macrophages). These enhancements were not demonstrated in lipopolysaccharide‐treated C3H/HeJ spleen cells. Athough hepatic injury was not demonstrated in both C3H/HeN and C3H/HeJ mice treated with 35 mg galactosamine alone, severe hepatotoxicity was found in these galactosamine‐treated mice when they received lipopolysaccharide‐activated C3H/HeN spleen cells, especially macrophages. Simultaneous administration of superoxide dismutase with the activated spleen cells reduced the grade of hepatic injury. On the other hand, hepatic injury was not demonstrated in the galactosamine‐treated C3H/HeN or C3H/HeJ mice when they received lipopolysaccharide‐treated C3H/HeJ spleen cells, although3H‐galactosamine incorporation into hepatocytes was nearly identical in both C3H/HeN and C3H/HeJ mice. These results suggest that oxidative free radicals of lipopolysaccharide responsive macrophages could contribute to the pathogenesis of galactosamine

ISSN:0270-9139    

DOI:10.1002/hep.1840110205

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractThe effect of ischemia and reperfusion on purine nucleoside phosphorylase was studied in an isolated perfused rat liver model. This enzyme is localized primarily in the cytoplasm of the endothelial and Kupffer cells; some activity is associated with the parenchymal cells. Levels of this enzyme accurately predicted the extent of ischemia and reperfusion damage to the microvascular endothelial cell of the liver. Livers from Lewis rats were subjected to 30, 45 and 60 min of warm (37° C) no flow ischemia that was followed by a standard reperfusion period lasting 45 min. Purine nucleoside phosphorylase was measured at the end of the no flow ischemia and reperfusion periods as was superoxide generation (O2‐). Bile production was monitored throughout the no flow ischemia and reperfusion periods. Control perfusions were carried out for 120 min. A significant rise in purine nucleoside phosphorylase levels as compared with controls was observed at the end of ischemia in all the three groups. The highest level, 203.5 ± 29.2 mU/ml, was observed after 60 min of ischemia. After the reperfusion period, levels of purine nucleoside phosphorylase decreased in the 30‐ and 45‐min groups 58.17 ± 9.66 mU/ml and 67.5 ± 17.1 mU/ml, respectively. These levels were equal to control perfusions. In contrast, after 60 min of ischemia, levels of purine nucleoside phosphorylase decreased early in the reperfusion period and then rose to 127.8 ± 14.8 mU/ml by the end of reperfusion (p<0.0001). Superoxide generation at the beginning of reperfusion was higher than in controls with similar values observed at the end of 30, 45 and 60 min of ischemia. During reperfusion, production of superoxide continued. Bile production was significantly lower at the end of 30 min (0.044 ± 0.026 μl/min/gm), 45 min (0.029 ± 0.0022 μ/min/gm) and 60 min of ischemia (0.022 ± 0.008 μ/min/gm) when compared with bile production by control livers during the corresponding time (0.680 ± 0.195, 0.562 ± 0.133 and 0.480 ± 0.100 μ/min/gm respectively; p<0.001). During reperfusion, rates of bile production were normal after 30 and 45 min of ischemia. In contrast, significantly lower rates of bile production, 0.046 ± 0.36 μ/min/gm (p<0.001) occurred during reperfusion after 60 min of ischemia. Control livers during the same period produced 0.330 ± 0.056 μl/min/gm of bile. The results indicate that purine nucleoside phosphorylase levels may be a good index of oxidative injury to the liver in ischemia reperfusion and reliably predict the functional state of the

ISSN:0270-9139    

DOI:10.1002/hep.1840110206

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractThe activity ofN‐acetylglucosamine‐6‐phosphate deacetylase, a key enzyme in the pathway ofN‐acetylglucosamine catabolism, was measured in hepatocytes, Kupffer cells and sinusoidal endothelial cells from rat liver and cultured human skin fibroblasts. Kupffer cells and endothelial cells had similar high levels of deacetylase activity that were more than twice the level observed in fibroblasts. In contrast, hepatocytes had extremely low activity (several hundredfold less than Kupffer cells and endothelial cells). A major implication of deacetylase deficiency in hepatocytes is thatN‐acetylglucosamine generated as a result of the catabolism of complex carbohydrates in these cells cannot enter glycolysis and must be largely reused for the synthesis of plasma glycoproteins and otherN‐acetylglucosamine‐containing m

ISSN:0270-9139    

DOI:10.1002/hep.1840110207

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractLymphocyte and monocyte function was investigated in eight patients with primary biliary cirrhosis and in age‐matched and sex‐matched controls. In three of the eight cirrhotic patients, two were in the late stage of the disease (stage III) and concanavalin A‐induced suppressor cell function was markedly decreased; it returned to normal levels after 1 mo of treatment consisting of 5 mg per week of orally administered colchicine. The relative percentage of T cell subsets (CD3, CD4 and CD8) and the mean percentage of the helper and the suppressor phenotype were similar in cirrhotic patients and in controls. Basal production of interleukin‐1 activity by a monocyte‐enriched fraction of peripheral blood mononuclear cells of cirrhotic patients was three‐fold above control values: after stimulation with endotoxin, interleukin‐1 values increased tenfold above basal levels in monocyte‐enriched fraction of peripheral blood mononuclear cells of both normal and cirrhotic patients. Colchicine normalized the basal production of interleukin‐1 and inhibited its stimulation by endotoxin by 50%. Culture supernatants of endotoxin‐stimulated monocyte‐enriched fraction of peripheral blood mononuclear cells increased the proliferation of cultured human skin fibroblasts by 50%. In contrast, supernatants from stimulated monocyte‐enriched fraction of peripheral blood mononuclear cells obtained from colchicine‐treated patients significantly inhibited fibroblast proliferation. These findings suggest that stimulated chronic inflammatory cells may play an important role in liver fibrosis. Some of the actions of colchicine could be related to its effects on lymphoc

ISSN:0270-9139    

DOI:10.1002/hep.1840110208

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractRecent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P‐450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham‐operated controls), α‐naphthylisothiocyanate‐induced intrahepatic cholestasis and galactosamine‐induced diffuse hepatocelluar necrosis.The control group had a colchicine clearance of 77.33 ml/min. kg ± 8.27 ml/min kg, a half‐life of 16.68 min ± 0.97 min and a volume of distribution of 1.84 L/kg ± 0.15 L/kg.Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p<0.05) and half‐life to increase by 38% (p<0.05). Volume of distribution did not change.At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p<0.05), terminal half‐life increased to 513.7 min ± 106.6 min (p<0.05) and volume of distribution increased by 175% (p<0.05). Colchicine pharmacokinetics in sham‐operated rats were not statistically different from the above mentioned controls.After α‐naphthylisothiocyanate administration, colchicine clearance decreased by 55% (p<0.05), the halflife increased by 56% (p<0.05) and the volume of distribution decreased by 30% (p<0.05).After administration of galactosamine, 1,000 mg/kg, colchicine clearance decreased by 62% (p<0.05), half‐life increased to 144.72 min ± 35.30 min (p<0.05) and volume of distribution increased by 124% (p<0.05).These data show that experimental hepatic injury in the rat significantly impairs colchicine pharmacokinetics. They also support the hypothesis that the liver is a major rou

ISSN:0270-9139    

DOI:10.1002/hep.1840110209

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractCatalytically active human and rat liverS‐adenosylmethionine synthetase exists mainly in tetramer and dimer form. In liver biopsy samples from cirrhotic patients a marked reduction in totalS‐adenosylmethionine synthetase activity and a specific loss of the tetrameric form of the enzyme exist. We have investigated the possible role of sulfhydryl groups in maintaining the structure and activity ofS‐adenosylmethionine synthetase. Both forms ofS‐adenosylmethionine synthetase are rapidly inactivated byN‐ethylmaleimide, and the loss of enzyme activity correlates with the incorporation of approximately 2 molesN‐ethylmaleimide per mole of subunit. In addition, reaction withN‐ethylmaleimide resulted in displacement of the tetramer‐dimer equilibrium of the enzyme toward the dimer, but no monomer was detected under these conditions. A catalytically active monomericS‐adenosylmethionine synthetase was detected in the cytosolic extract from a liver biopsy sample from a cirrhotic patient, supporting our model for the structure ofS‐adenosylmethionine synthetase. Because treatment ofS‐adenosylmethionine synthetase withN‐ethylmaleimide resembles the situation of this enzyme in cirrhotic patients, it is proposed that impaired protection of the enzyme from oxidizing agents caused by a decreased synthesis of glutathione can explain the diminished synthesis ofS‐adenosylmeth

ISSN:0270-9139    

DOI:10.1002/hep.1840110210

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY

摘要:

AbstractControversy exists concerning the localization of the enzyme Na+, K+‐ATPase to canalicular membranes in hepatocytes. Most studies find enzyme activity only at the basolateral plasma membrane domain of the hepatocyte. However, Na+, K+‐ATPase activity has been detected recently in a canalicular membrane fraction prepared by Mg++ precipitation, suggesting that differences in membrane domain fluidity account for these discrepancies. To reinvestigate this question, we used free‐flow electrophoresis to further purify canalicular liver plasma membranes originally separated by sucrose density centrifugation. With this technique, canalicular membranes devoid of Na+, K+‐ATPase activity by routine assay were separated into six subfractions. More than 80% of the activities of canalicular marker enzymes was recovered in two subfractions closest to the anode, which were totally devoid of Na+, K+‐ATPase activity. However, Na+, K+‐ATPase activity could now be detected in the four other fractions that contained only small amounts of canalicular marker enzymes. The basolateral marker enzyme, glucagonstimulated adenyl cyclase, comigrated with this cryptic Na+, K+‐ATPase activity. Furthermore, addition of 6 μmol/L [12‐(2‐methoxyethoxy)‐ethyl‐8‐(cis‐2‐noctylcyclopropyl)‐octanoate], a membrane‐fluidizing agent, to the original canalicular membrane preparation and to all subfractions did not stimulate or unmask latent Na+, K+‐ATPase activity. Finally, when canalicular membranes isolated by Mg++ precipitation were subjected to free‐flow electrophoresis, they could not be separated from the more positively charged Na+, K+‐ATPase‐containing fractions, probably because of alterations in surface charge. Together these findings suggest that Na+, K+‐ATPase is a basolateral enzyme, that represents a small contaminant when present in canalicular liver plasma membranes and that methodological differen

ISSN:0270-9139    

DOI:10.1002/hep.1840110211

出版商:W.B. Saunders    

年代:1990

数据来源: WILEY