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)

At [Na+]o = 118 mM the concentrative transfer of cholic and taurocholic acid from the perfusate into the isolated rat liver displays saturation kinetics (taurocholate: V = 299 nmol-min-1-g-1, Km = 61 muM; Cholate: V=327 nmol-min-1-g-1, Km = 436 muM). Perfusion with an isotonic sodium-free medium did not change the feature of a carrier-mediated transport but did markedly reduce V without affecting Km (taurocholate: V = 65 nmol-min-1-g-1, Km = 78 muM; cholate: V = 104 nmol-min-1-g-1, Km = 354 muM). It was experimentally assured that the observed reduction of bile salt uptake was not a consequence of regurgitation of bile salts or due to an excessive intracellular accumulation during cholestasis in the sodium-free state. The rate of taurocholate efflux is very low when compared with the rapid rate of the uptake. A stimulatory action of extracellular sodium on this pathway was also observed. Inhibition of the (Na+ + K+)-ATPase by 1 mM ouabain resulted in a decrease of bile salt uptake. Activation of the enzyme by potassium readmission to a K+-deprived liver enhanced bile salt uptake. The immediate response to alteration of the enzyme activity suggests a close association of a fraction of bile acid active transport with the sodium pump.
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PMID:Investigations on the sodium dependence of bile acid fluxes in the isolated perfused rat liver. 13 26

Using freeze-fracture techniques, we have examined the changes in the morphology of the tight junctional network around the canalicular lumen of the hepatocytes in rat liver after experimental bile-duct ligation. The more or less regular belt of parallel strands formed by the tight junctions around the canalicular lumen of normal hepatocytes is changed after extrahepatic obstruction. A more irregular network is formed withe a reduced number of strands which also extend more in an abluminal direction with formation of irregular loops. Striking changes are seen at the gap junctions: the small patches normally situated within the tight junctional network become less numerous; at some canaliculi they are even absent; also the larger gap junctional areas normally present in deeer abluminal extensions of the lateral cell membrane become hard to find or are even absent. This altered tight junctional pattern suggests an increased permeability so that the pathway of intercellular escape of biliary constituents towards the blood stream in cholestasis becomes as plausible as transhepatocytic regurgitation. The disappearance of the gap junctions would result in a lack of intercellular communication and uncoupling of liver cells, which may lead to a more individual behaviour of adjecent hepatocytes, explaining the heterogeneity in canalicular changes in cholestasis.
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PMID:Morphologic changes of the junctional complex of the hepatocytes in rat liver after bile duct ligation. 65 22

Earlier studies have identified two main isoenzymes of alkaline phosphatase in the sera of patients with obstructive liver disease. This paper reports on a study of these isoenzymes in specific types of liver disease where the pathology in relation to bile duct obstruction is known. The results have been used to support the theory that in biliary obstruction the increase in serum alkaline phosphatase is in part due to regurgitation of the biliary isoenzymes.
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PMID:An interpretation of the serum alkaline phosphatase isoenzyme patterns in patients with obstructive liver disease. 100 41

The role of the liver lymphatics in the regurgitation of bilirubin during the different stages of cholestasis has been a matter of debate. Earlier studies have shown that 14C-bilirubin injected intravenously one hour after induction of cholestasis was rapidly and completely cleared from the blood and appeared in the thoracic duct lymph in high concentration. During chronic cholestasis the injected 14C-bilirubin was delivered directly back to the blood after conjugation in the liver. The aim of the present study was to investigate the role of the lymphatics in the transport of non-erythroid bilirubin (NEB), a metabolic product of certain tissue haemes, produced mainly in the liver. The study was carried out in dogs. Five dogs were studied in the first hours following bile duct obstruction, and five others after at least one week of cholestasis. 14C-delta-aminolevulinic acid was given as a NEB precursor. In contrast to the results obtained with 14C-bilirubin injection, evidence for a delivery of conjugated labelled NEB directly to the blood during acute cholestasis was found. The concentration curves for NEB and non-NEB radioactivity in the thoracic duct lymph indicated the presence of a secondary biliolymphatic regurgitation. In chronic cholestasis no evidence for such a biliolymphatic regurgitation of NEB was found.
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PMID:The role of the liver lymphatics in the transport of non-erythroid bilirubin during different stages of experimental cholestasis. 117 49

The role of the lymphatics in the regurgitation of bilirubin during acute and chronic extrahepatic cholestasis in the dog was studied after intravenous injection of 14C-bilirubin. In acute cholestasis the injected labelled bilirubin was rapidly removed from plasma and reappeared in thoracic duct lymph as labelled bilirubin conjugates. No labelled conjugates were at any time demonstrated in plasma. This is most easily explained as a result of a bilio-lymphatic regurgitation. In chronic cholestasis the labelled bilirubin conjugates were delivered back into the blood, and no specific transport function of the lymph was found. Our results indicate a change in liver cell secretory direction in long-standing cholestasis.
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PMID:Transport and conjugation of 14C-bilirubin during acute and chronic cholestasis in the cholecystectomized dog. 118 59

To determine whether in complete obstructive cholestasis taurocholate is taken up by hepatocytes and if so whether it is secreted into bile, tritium-labelled taurocholate was localized by histoautoradiography on cryoslices from normal rat livers and from those after bile duct ligation. In non-cholestatic livers the hepatocytes of acinar zones 1 as well as the lumina and the epithelia of bile ductules and ducts became intensely labelled directly after injection of [3H]taurocholate into a mesenterial vein. Four hours and 4 days after bile duct ligation, hepatocytes of all three acinar zones became labelled, but in contrast to the normal state, pericanalicular concentration of silver grains was not observed, not even within 5 min. Fifteen days after bile duct obstruction, cryoslices taken 2 min after injection of [3H]taurocholate exhibited an intense silver grain labelling of all acinar zones, with the highest density at bile canalicular areas of the liver cell plates as well as the proliferated bile ductules and bile ducts. The biliary epithelium of small bile ductules and ducts of non-cholestatic and of bile duct-obstructed livers were also covered with silver grains; the epithelium of larger ducts exhibited significant labelling predominantly at the lateral sites of the cells. The biliary epithelium of the common bile duct was not significantly labelled. The results indicate that in complete obstructive cholestasis (a) taurocholate continues to be taken up from blood by hepatocytes and secreted into bile, but in terms of varying duration of obstruction, (b) all acinar zones are involved in bile salt transport, (c) in the initial phase (4 h and 4 days respectively after bile duct obstruction) hepatocytes fail to concentrate taurocholate at the canalicular site, (d) in a consecutive phase, in which bile ductules and ducts proliferate (demonstrated for a 15-day cholestasis), the taurocholate concentration at the canalicular site of hepatocytes is re-established and biliary secretion seems to be enhanced, (e) the biliary epithelium of bile ductules and ducts may play a significant role in the reabsorption and/or regurgitation of bile salts from bile to blood. Reabsorption/regurgitation of biliary constituents may also be operative in the non-cholestatic state but may become significantly enhanced with bile ductular proliferation.
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PMID:The histoautoradiographic localization of taurocholate in rat liver after bile duct ligation. Evidence for ongoing secretion and reabsorption processes. 271 21

1. Administration of alpha-naphthylisothiocyanate (ANIT) to rats produced dose-dependent increases in plasma bile acid and bilirubin concentrations. Similar increases in plasma bile acid and bilirubin concentrations were evident in bile duct ligated rats, indicating that the severity of cholestasis is almost identical in both models. 2. Plasma alkaline phosphodiesterase I was increased by only 50-80% while alkaline phosphatase was increased more than threefold after ANIT administration. This is in contrast to an earlier study [S. R. Simpson, K. Rahman & D. Billington (1984) Clinical Science 67, 647-652] where, after bile duct ligation, serum alkaline phosphodiesterase I was elevated sixfold before any increase in alkaline phosphatase activity became apparent. Thus, plasma alkaline phosphodiesterase I does not offer as sensitive a marker of intrahepatic cholestasis (induced by ANIT) as it does of extrahepatic cholestasis (induced by bile duct ligation). 3. Hepatic alkaline phosphodiesterase I was unaffected by ANIT pretreatment while hepatic alkaline phosphatase was increased up to seven times. It is suggested that raised plasma alkaline phosphodiesterase I is due to regurgitation of the biliary enzyme rather than overspill of the enzyme from liver into blood. 4. Gel filtration showed that 24 h and 96 h after ANIT administration, rat serum contained a high molecular weight form of alkaline phosphodiesterase I, suggesting a different isoenzyme profile.
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PMID:Plasma alkaline phosphodiesterase I in intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats. 284 2

To study immediate events during extrahepatic cholestasis, we investigated the effect of short-term biliary obstruction on the bioelectrical sinusoidal-canalicular barrier in the rat using molecular weight-matched uncharged and negatively charged inert solute pairs. The bioelectrical barrier averaged -22 +/- 5 and -18 +/- 4 mV (NS) using the pair carboxy-/methoxyinulin and ferrocyanide/sucrose, respectively. After a 20-min biliary obstruction both decreased by 61 and 11%, respectively, but only the large molecular weight pair (the inulins) returned to base line after release of the obstruction. Inert solute clearances were increased after short biliary obstruction depending on molecular size and negative charge (ferrocyanide greater than sucrose greater than carboxyinulin greater than inulin), suggesting that both permeability and bioelectrical barriers were affected by obstruction. The hepatic extraction in vivo of a passively transported drug not excreted into bile (D-propranolol) was not affected by obstruction, whereas that of an actively transported drug (glycocholate) decreased from 66 +/- 8 to 41 +/- 20% during biliary obstruction (P less than 0.01). Unidirectional transfer of glycocholate was not affected by short-term biliary obstruction in the situ perfused rat liver; however, 2 min after [14C]glycocholate administration, increased return was observed in hepatic venous effluent in obstructed animals. Our findings demonstrate a loss of the bioelectrical barrier immediately after short-term biliary obstruction. Decreased hepatic extraction in the view of unaltered sinusoidal uptake demonstrates regurgitation of bile into blood during short-term biliary obstruction.
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PMID:Biliary obstruction dissipates bioelectric sinusoidal-canalicular barrier without altering taurocholate uptake. 291 74

Intrahepatic cholestasis, defined as arrested bile flow, mimics extrahepatic obstruction in its biochemical, clinical and morphological features. It may be due to hepatocyte lesions of which there are three types, termed canalicular, hepatocanalicular and hepatocellular, respectively; or it may be due to ductal lesions at the level of the cholangiole or portal or septal ducts. Defective bile flow due to hepatic lesions reflects abnormal modification of the ductular bile. Defective formation of canalicular bile may involve bile acid-dependent or independent flow. It appears to result most importantly from defective secretion of bile acid-dependent flow secondary to defective uptake from sinusoidal blood, defective transcellular transport and defective secretion; or from regurgitation of secreted bile via leaky tight junctions. An independent defect in bile acid-independent flow is less clear. Defective flow of bile along the canaliculus may reflect increased viscosity and impaired canalicular contractility secondary to injury of the pericanalicular microfibrillar network. Impaired flow beyond the canaliculus may result from ductal injury. Sites of lesions that contribute to cholestasis include the sinusoidal and canalicular plasma membrane, the pericanalicular network and the tight junction and, less certainly, microtubules and microfilaments and Golgi apparatus. A number of drugs that lead to cholestasis have been found to lead to injury at one or more of these sites. Other agents (alpha-naphthylisothiocyanate, methylenedianiline, contaminated rapeseed oil, paraquat) lead to ductal injury resulting in cholestasis. Reports of inspissated casts in ductules (benoxaprofen jaundice) and injury to the major excretory tree (5-fluorouridine after hepatic artery infusion) have led to other forms of ductal cholestasis. Most instances of drug-induced cholestasis present as acute, transient illness, although important chronic forms also occur. The clinical features include the reflection of the cholestasis (pruritus, jaundice), systemic manifestations and extrahepatic organ involvement. While nearly all classes of medicinal agents include some that can lead to cholestasis, there are differences among the various categories. Phenothiazines and related antipsychotic and 'tranquillizer' drugs characteristically lead to cholestatic hepatic injury. The tricyclic antidepressants may lead to cholestatic or hepatocellular injury.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Drug-induced cholestasis. 355 33

Thirty-seven patients were studied on the anatomic routes of bile regurgitation into the blood stream by electron microscopy. The aim was to identify the relationship between the clinical results and pathway of bile regurgitation. These patients were classified into 3 groups; recovered, delayed, and fatal. Transcellular, paracellular, direct communication, necrotic hepatocyte and ruptured ductule pathway were found. In the recovered group, the transcellular pathway was most frequent with an incidence of 54.17%, and a direct communication pathway was found to be 54.55% in the fatal group with a significant difference between that of the recovered and delayed group. Long-duration bile duct obstruction creates bile regurgitation by way of direct communication between the canaliculi and Disse's space, and usually with a poor prognosis, since the serum bilirubin reached the high level of 22.65 mg%. Therefore, it is better to relieve the intrabiliary pressure as early as possible to prevent the jaundice from producing the irreversible change of hepatic canaliculi and Disse's space.
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PMID:Electron microscopic assessment of bile regurgitation of humans in extrahepatic obstructive jaundice. 404 52


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