Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the rat, plasma IgA is rapidly endocytosed by hepatocytes and translocated to the bile via a receptor-mediated vesicular transport system which appears to remain intact even during cholestasis. During the latter phenomenon, there is an accumulation of secretory IgA (sIgA) in plasma. These data suggest that biliary IgA can be regurgitated into the plasma compartment. The present study was designed to determine the location and mechanism(s) by which this might occur. 125I-labeled human polymeric IgA (pIgA) or sIgA was infused retrograde into the rat common bile duct at a flow rate of 20 microliter per min (5 to 10 micrograms per min pIgA; 7 micrograms per min sIgA) over 1 hr. Blood and liver samples were collected 10, 30 and 60 min, and radioactivity determined. Radioactive label appeared in the blood by 10 min and increased linearly with time. By 30 min, however, the liver had reached saturation. All of the label found in the blood was intact starting material, i.e., pIgA or sIgA. Electron microscopic autoradiography analysis clearly demonstrated the presence of grains in vesicles in hepatocyte pericanalicular cytoplasm, as well as in vesicles near the sinusoidal plasma membrane. No grains were observed associated with bile duct or ductule epithelium at any time period. Further, there was no grain accumulation near the parenchymal cell intercellular spaces indicating that paracellular flow plays little or no role in large protein regurgitation. In addition, by 60 min, there were grains associated with Kupffer cells. These data provide the first evidence that hepatocytes, during times of elevated biliary pressure can readily transport macromolecules from bile to plasma via nonreceptor-mediated membrane-limited vesicles.
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PMID:The fate of polymeric and secretory immunoglobulin A after retrograde infusion into the common bile duct in rats. 650 May 10

The vesicular transport system for biliary secretion of plasma-derived proteins was investigated in rats with chronic bile duct obstruction. Horseradish peroxidase, previously demonstrated to be a suitable tracer for vesicular transport, was employed in these studies. Both the time course of horseradish peroxidase secretion into bile and the morphological events in its uptake, transport, and biliary secretion were found to proceed in a manner essentially identical to that of sham-operated control animals. In addition, fragmentation of hepatocytes leading to sloughing into bile of large pieces of cytoplasm bearing horseradish peroxidase-containing endocytic transport vesicles frequently was observed in the cholestatic animals. These data suggest that the vesicular transport system for the secretion into bile of plasma-derived proteins remains intact and functional during chronic bile duct obstruction and that another mechanism, possibly fragmentation and solubilization of hepatocyte membranes followed by regurgitation of proteins released from endocytic vesicles, may be responsible for the elevation of biliary proteins within plasma seen during cholestasis.
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PMID:Vesicular transport of horseradish peroxidase during chronic bile duct obstruction in the rat. 661 34

Development of intrahepatic cholestasis induced by alpha-naphthylisothiocyanate was studied in rats. At various times after alpha-naphthylisothiocyanate application, livers were isolated from treated rats and perfused hemoglobin-free to assess cholestatic parameters. Unstimulated bile flow was found to only slightly decrease up to 10 h after alpha-naphthylisothiocyanate administration. In contrast, secretion into bile of sulfobromophthalein and taurocholate declined markedly between 4 and 7 h as their concentrations in the perfusate increased, and stimulation of bile flow by taurocholate decreased. The permeability of the bile-to-perfusate barrier to [14C]sucrose and [32P]orthophosphate increased in parallel with the changes in sulfobromophthalein and taurocholate distributions. This correlation of changes in the distribution of cholephilic substances with biliary accessibility for extracellular markers suggests that, in alpha-naphthylisothiocyanate-induced cholestasis, increased leakage of tight junctions may contribute to regurgitation of bile constituents into the vascular system.
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PMID:Development of intrahepatic cholestasis by alpha-naphthylisothiocyanate in rats. 705 45

The rat liver after extrahepatic biliary obstruction was studied by SEM and TEM in correlation with basic histochemical techniques. Cholestasis was verified by serological methods. The biochemical data (increase in serum bilirubin values, a gradual lowering of the albumin fraction), in agreement with the ultrastructural results of a sparse RER, suggested a gradual decrease of the protein synthetic activity of the hepatocyte. SEM and TEM revealed numerous fat-storing cells, closely associated with patches of connective fibrils in the subendothelial spaces. Further ultrastructural observations demonstrated: a) a proliferation of the intrahepatic biliary tree (ductular proliferation, including newly formed ducts with sacculation and diverticuli); b) an increased number of canaliculo-ductular junctions and, c) an increase in the length of the bile canalicular network due to its tortuous course, pocketing and side branching. The occurrence of an intact cytoplasmic barrier separating the bile canalicular lumen from the Disse's space together with the results obtained by retrograde infusion of ferritin into the biliary tree suggested that the regurgitation pathway by ductular reabsorption and by transhepatocytic transport is the best documented and most acceptable, at least in the rat.
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PMID:A scanning and transmission electron microscopic study of experimental extrahepatic cholestasis in the rat. 733 53

Bile duct ligation in rats increased alkaline phosphatase activity in serum and liver. In the serum, the activity reached a peak 24 h after bile duct ligation, earlier than in the liver. This finding indicates that the elevation of serum alkaline phosphatase activity is not due to simple overspill of this enzyme from the liver into the circulation. An electrophoretic study, employing polyacrylamide gel with Triton X-100, and a gel filtration study disclosed that 24 h after bile duct ligation the serum contained a high molecular weight form of alkaline phosphatase in addition to the hepatic and intestinal isoenzymes. The high molecular weight form was also found in bile, indicating that regurgitation of bile contributed to the increase in alkaline phosphatase activity in the serum. The absence of the high molecular weight alkaline phosphatase in the sera of rats with intrahepatic cholestasis induced by alpha-naphthylisothiocyanate suggests that, in this type of cholestasis, regurgitation of bile alkaline phosphatase does not play an important role in the elevation of serum alkaline phosphatase activity. These findings indicate that the high molecular weight alkaline phosphatase in serum is a useful diagnostic marker of biliary obstruction.
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PMID:Mechanism of elevation of serum alkaline phosphatase activity in biliary obstruction: an experimental study. 742 80

Clinical and morphological diagnosis of cholestasis involves a variety of different parameters, but bile fluid formation and composition of bile are usually not accessible in patients. In contrast, a pathophysiological definition of cholestasis can be based on current knowledge on the mechanisms of bile formation. Hence, causes of cholestasis may be localized in each step of the process of bile formation. 1. Inhibition of fluid formation reduces maximal secretory capacity. 2. Inhibition of the transcellular hepatobiliary transport may involve transport carriers, binding proteins, and the systems of biotransformation. 3. Mechanical obstruction or regurgitation of bile constituents due to increased permeability of the bile tract may inhibit the biliary elimination of cholephilic compounds. Consequences of the inhibition of biliary elimination are retention in the liver and the whole organism of potentially toxic compounds. Among these are endogenous compounds such as bile acids and cysteinyl-leukotrienes, but xenobiotics as well may become more toxic in cholestasis. The composition of bile and portal venous blood is altered. In experimental animals, changes in secretory function can already be observed before clinically used indicator enzymes of cholestasis increase. This functional inhibition of biliary elimination can be characterized as "subclinical" cholestasis that may, nevertheless, inhibit the elimination and potentiate the toxicity of cholephilic endo- and xenobiotics.
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PMID:Cholestasis: pathophysiology and pathobiochemistry. 748 88

Bile acid processing in the long-term, bile duct obstructed rat liver was studied ex vivo. Twenty four and 72 h, respectively, after bile duct obstruction the isolated liver was perfused with taurodeoxycholate (16 nmol/min per g liver) the bile duct still being closed. Uptake, metabolism and regurgitation profile were traced by bolus injection of tritium-labeled bile acid; in addition, concurrent histological changes were examined by light- and electron microscopy. Ligation caused dilatation of the intrahepatic ductular branches and increased the serum bile acid concentration to 740 +/- 75 microM (controls: 16 +/- 2.12), reaching its maximum within 24 h. At 16 nmol/min per g liver uptake rate was > 96% in controls and in bile duct obstructed rats. Maximal uptake rates (assessed separately) differed between controls and bile duct obstructed rats (700 nmol/min per g liver vs. 460). Controls excreted more than 80% of labeled bile acid in bile within 10 min after bolus injection. Biliary recovery of label was virtually completed after 30 min. In bile duct obstructed rats excretion of label back to the perfusate effluent (regurgitation) started quantitatively 5 min after bolus application and peaked between 10 and 40 min; after 80 min, effluent recovery was incomplete (about 60% of bolus injected). Biliary bile acids of controls consisted of about 20% taurodeoxycholate-metabolites; bile acids in the perfusate effluent of bile duct obstructed rats of about 55%. The major metabolite in all animal groups was taurocholate; minor metabolites were tauroursocholate, tauro-3 alpha,7 = 0,12 alpha-cholanoic acid and 3-sulfo-taurodeoxycholate. Histologically, inflammation and periportal edema were present after 1 day of bile duct obstruction. After 3 days, marked proliferation of bile ductules was the dominant histological feature. It is concluded that during initial bile duct obstruction, bile acid processing is not altered, although ultrastructural alterations occur early.
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PMID:Pattern of bile acid regurgitation and metabolism during perfusion of the bile duct obstructed rat liver. 779 Jul 9

The preceding pages have described an organism that is far removed from mammals on the taxonomic scale of vertebrates but one that has proven to have a unique and most useful system for studies of liver function and, in particular, bile product transport and excretion. It is also an organism in which iron loading can be studied in the liver and other organs and tissues. Many of the events that occur in this animal during its life cycle with regard to bile pigment metabolism as normal programmed phenomena are unparalleled among the vertebrates. In the larval (ammocoete) period of lampreys, there is an intrahepatic gallbladder and a biliary tree that is well equipped for the storage, transport, and elimination of bile products into the intestine for ultimate excretion with the feces. The importance of the patency of these bile ducts to bile excretion is illustrated in one species of lampreys in which the bile ducts of young ammocoetes become infested with larval nematodes to a degree that bile pigment regurgitation into the blood results in a green serum that is identified as biliverdin. Despite having serum levels of biliverdin that would be toxic to humans, these individuals live a complete larval life. The larvae of all lamprey species undergo a phase of metamorphosis in which they transform into adults. During this phase the larval gallbladder, the bile canaliculi of the hepatocytes, and all the intrahepatic bile ducts completely regress in a developmental process called lamprey biliary atresia. The epithelium of the extrahepatic common bile duct transforms and expands into a caudal portion of the endocrine pancreas of the adult. Many of the events of lamprey biliary atresia resemble events occurring during experimental and pathological conditions of mammalian cholestasis, including disruption to the bile-blood barrier (intercellular junctions), accumulation of bile components in the cytoplasmic inclusions, and alteration of the distribution of membrane enzymes in hepatocytes. Regression of the bile ducts and ductules is accompanied by a periductular fibrosis that seems to be a product of activity by lipocytes (Ito cells). The regurgitation of bile products into the interstitial tissue of the liver during early biliary atresia may be the stimulus for both inflammatory (granulomatous) and autoimmune responses. There are no bile ducts in adults lampreys, yet they seem to show no immediate consequences of the absence of an exocrine mechanism for the elimination of bile products.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biliary atresia in lampreys. 827 15

The effect of hepatocellular trauma due to bile reflux and endotoxaemia on liver glycogen metabolism was studied in guineapigs with common bile duct obstruction. Considerable drops in basal glycogen levels of hepatocytes from bile duct ligated (BDL) animals were recorded in comparison with the sham operated (SHAM) ones. However, the regurgitation of bile did not affect the basal blood glucose concentrations of BDL guineapigs. The circulating glucose was consumed, mainly reflecting the level of energy requirement of the peripheral tissues in the endotoxaemic SHAM pair-fed animals and the BDL group. The hepatic glycogen stores failed to prevent the SHAM group from becoming hypoglycaemic at the end of the eighth hour after endotoxin administration. Enhancement in glucose consumption and diminished liver glycogen indicated the necessity of glucose intake in the early phase of extrahepatic bile duct obstruction. It was concluded that both endogenous and exogenous glucose have limited value in improving energy metabolism in lethal endotoxaemia following bile duct obstruction.
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PMID:The effect of lethal endotoxaemia on the liver glycogen metabolism in guineapigs with common bile duct obstruction. 854 53

Drug-induced cholestasis may be due to impairment of hepatocellular bile secretion (pure cholestasis or cholestatic hepatitis), obstruction of ductules (cholangiolitis) or interlobular ducts (cholangitis), or extrahepatic obstruction (sclerosing cholangitis). Mechanisms of hepatocellular cholestasis are multiple and include inhibition of various transport systems, cytoskeleton poisoning, disturbed intracellular calcium homeostasis and increased permeability with regurgitation of bile constituents into plasma. Pure hepatocellular cholestasis is mostly observed with sex steroid hormones and anabolic steroids. Ductular or ductal cholestasis (drug-induced cholangiopathy) may be acute and self-limited, or prolonged with ductopenia, occasionally leading to biliary cirrhosis. An immune mechanism has been proposed. Sclerosing cholangitis with strictures near the confluent of hepatic ducts is observed after intraarterial administration of floxuridine for chemotherapy of hepatic metastases. Some drugs may induce the formation of cholesterol gallstones, or precipitate in bile and form biliary sludge or stones in the gallbladder or common bile duct.
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PMID:Drug-induced cholestasis. 913 22


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