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)

Partial diversion of bile flow to an external stoma was performed in 6 patients with chronic intrahepatic cholestasis with severe pruritus that had been refractory to medical measures. Four patients with progressive intrahepatic cholestasis and 2 with arteriohepatic dysplasia were treated. Follow-up has been 3-8 yr. Patients with progressive intrahepatic cholestasis have been free of itching since surgery. Serum bile salt concentrations fell from 218-275 microM (normal less than 10) before to less than 10 microM after surgery. Biochemical tests of liver function and histology returned to normal or near normal. Patients with arteriohepatic dysplasia had persistent mild pruritus after surgery. Serum bile salt concentrations fell from 153-317 to 25-37 microM. There was little or no improvement in biochemical tests or histology. Bile volume and bile salt diverted were higher in patients with progressive intrahepatic cholestasis (7.3-13.0 ml/kg.day and 83-137 mumol/kg.day, respectively) than those with arteriohepatic dysplasia (3.2-4.5 ml/kg.day and 21-36 mumol/kg.day). The quality of life since surgery has been excellent in patients with progressive intrahepatic cholestasis, but not as optimal in those with arteriohepatic dysplasia. These findings suggest that partial external biliary diversion can provide effective relief from pruritus and perhaps reversal of liver disease in patients with progressive intrahepatic cholestasis. It should be used in patients with arteriohepatic dysplasia only in those with disabling pruritus.
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PMID:Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. 337 8

Endotoxemia has been incriminated as a major cause of morbidity and mortality in patients with obstructive jaundice. It has been postulated that absence of gastrointestinal bile salt flow in cholestasis enhances portal absorption of bacterial endotoxin from the intestine, thereby predisposing the host to endotoxemia and its complications. This study re-evaluates this pathologic mechanism, using new quantitative chromogenic and conventional qualitative limulus techniques for the detection of bacterial endotoxin. Female Sprague-Dawley rats underwent either ligation of bile duct or sham operation. Serum total bilirubin, serum bile acid and intestinal bile acid concentrations were determined seven, 14 and 21 days after operation. Chromogenic and conventional qualitative limulus lysate endotoxin determinations were simultaneously performed on post-operative days two, seven, 14 and 21. Serum total bilirubin and bile acid concentrations were elevated and intestinal bile acid levels depressed at days seven, 14 and 21 (p less than 0.05). Results of quantitative and qualitative limulus studies failed to demonstrated the coexisting development of portal or systemic endotoxemia in rats with the bile duct ligated after diminution of flow of gastrointestinal bile salt. These data refute the hypothesis that flow of gastrointestinal bile salt enhances portal absorption of intestinally derived endotoxin and suggest alternative mechanisms are involved in the pathogenesis of endotoxemia in obstructive jaundice.
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PMID:Endotoxemia and cholestasis. 341 50

We previously showed that alterations of the bile canalicular membrane are likely to occur following a cholestatic regimen composed sequentially of manganese and bilirubin. The present study was designed primarily to investigate the biliary excretion of organic bile constituents following administration of the manganese-bilirubin combination. Experiments in hyperbilirubinemic Gunn rats were also performed to determine whether the unconjugated or the conjugated form of bilirubin is involved in this cholestatic interaction. Male Sprague-Dawley rats and male homozygous Gunn rats were given the following (i.v.): (a) manganese (4.5 mg per kg); (b) unconjugated bilirubin (25 mg per kg); (c) bilirubin ditaurate (38 mg per kg); (d) manganese-unconjugated bilirubin, or (e) manganese-bilirubin ditaurate. Bile flow was measured and bile was analyzed for manganese, total bilirubin, bile salts, cholesterol and phospholipid content. The results show that: (i) manganese-unconjugated bilirubin treatment caused about a 50% reduction in bile flow in Sprague-Dawley rats, whereas in Gunn rats the manganese-bilirubin ditaurate treatment resulted in about a 75% reduction, and (ii) in both strains, bile salt excretion was not appreciably modified during the cholestatic phase, as biliary bile salt concentration increased. The results suggest that although important differences regarding the form of bilirubin apparently exist, unconjugated bilirubin could be implicated in the cholestatic interaction in both strains of rats. Manganese-bilirubin-induced cholestasis is not related to a defect in bile salt excretion. The latter supports our contention that diminished canalicular membrane permeability to water is likely to be a key factor in this form of experimental cholestasis.
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PMID:Biliary excretion in Sprague-Dawley and Gunn rats during manganese-bilirubin-induced cholestasis. 341 27

The effect of sulfation of common bile acids on the formation of bile was investigated in male rats by infusing them with the sulfate esters of cholic, chenodeoxycholic, deoxycholic, lithocholic or dehydrocholic acid in four step-wise, increasing doses. Each dose was infused for 30 min and bile collected every 10 min. Control studies were performed by using either albumin solution (the bile acid carrier) or corresponding nonsulfated bile acids at concentrations similar to those of the sulfated products. The secretion of sulfated bile acids was slower and less than that of nonsulfated bile acids, demonstrating transport maximum kinetics rather than the secretory rate maximum characteristic of nonsulfated bile acids. Sulfation significantly increased bile salt-independent bile flow and the choleretic potency of the bile acids tested. With the exception of deoxycholic acid, which had a slight stimulatory effect, bile acid sulfation generally prevented a rise in bile acid-dependent phospholipid and cholesterol secretion. In fact, it reduced biliary phospholipid and cholesterol secretion associated with the secretion of endogenous bile acids. These data are in agreement with the physicochemical properties of sulfated bile acids. They indicate that sulfation prevents the cholestatic action of nonsulfated bile acids, perhaps by increasing bile flow via a high choleretic potential and/or by stimulating bile acid-independent bile flow. The effect of sulfated bile acids on the secretion of biliary phospholipids may protect the canalicular membrane from the detergent properties of bile acids and may thus block the cholestasis which results from high, nonsulfated bile acid concentrations.
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PMID:Effect of complete sulfation of bile acids on bile formation in rats. 357 Jan 65

Cyclosporin A (CyA) causes cholestasis in a significant proportion of transplant patients. Doses of 5, 10, and 15 mg CyA/kg body wt or the Miglyol 812 vehicle were administered intraperitoneally for 1, 2, and 3 wk to separate groups of rats to investigate the mechanism of this cholestasis. At 1 wk a dose-response relationship between serum CyA levels and increasing CyA doses was noted. A maximum CyA blood level was achieved by 2 wk with the 10- and 15-mg/kg doses. Subsequent studies were performed using the smaller (10 mg/kg) dose administered for 3 wk. This dose resulted in a marked increase in serum bile acid levels compared with vehicle-treated controls (24.6 +/- 4.0 vs. 4.3 +/- 1.2 mumol/L, p less than 0.001) without inducing significant changes in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, bilirubin, alkaline phosphatase, and albumin levels or hepatic architectural alterations. With CyA treatment, baseline bile flow decreased by 35% and bile salt secretion decreased by 25% compared with vehicle-treated animals. Cyclosporin A and vehicle-treated rats were infused intravenously with taurocholate (4 mumol/min X kg) for 2 h and then depleted of bile salts over the next 24 h. Bile samples collected over this period were graphed as bile salt secretion versus bile flow. The mean slope of the linear regression for the CyA-treated rats was 62% of the control, demonstrating a decrease in bile salt-dependent flow. Extrapolation of the linear regression to the ordinate demonstrated a 22% decrease in bile-independent flow with CyA treatment. Therefore, in our experimental model of CyA-induced cholestasis, the decrease in flow observed was the result of a decrease in both bile salt-dependent and bile salt-independent flows and occurred in the absence of significant biochemical or histologically evident hepatotoxicity.
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PMID:Cyclosporin A-induced cholestasis. The mechanism in a rat model. 359 72

The aim of this paper is to evaluate the relationships among the increase of serum bile acids (SBA) and other common liver function tests in subjects with liver cirrhosis. Our results show that SBA levels are well-correlated with the seriousness of the disease (classified according to Child's criteria), and with the presence of ascites, of oesophageal varices, of hepatic encephalopathy and with the gamma-globulin level. SBA also appear to be well-correlated with total bilirubinemia, and, at a lower extent, with cholesterolemia and albuminemia; no significant linear correlation was found among SBA and cholestasis (alkaline phosphatase, gamma-glutamyl-transpeptidase) or cytolysis (transaminases) indexes. In conclusion, the SBA increase in liver cirrhosis without evidence of cholestasis (as in our patients) seems to be related to liver cell reuptake disturbances and to the presence of porto-systemic shunts, with consequent alterations in entero-hepatic bile salt recirculation.
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PMID:[Serum bile acids in cirrhosis: correlation with liver function parameters and with the severity of the disease]. 367 66

Several different methods have been applied to measure the extent of bile salt deconjugation (deamidation), if any, outside the gastro-intestinal tract of the rat. A breath test has been applied to the rat using peroral or intravenous administration of cholyl-glycine-1-14C. Results for normal rats have been compared with rats with a continuous recirculation of bile to a tail vein. Bile salts labelled with 2,4-3H in the sterol moiety and conjugated with glycine-1-14C have been infused in rats and recirculated via a bile duct tail-vein shunt. The 3H:14C ratio in the bile has been used as an indication of deconjugation. In these experiments the radioactivity pattern of the bile salts has been determined after thin-layer chromatography. Different labelled bile salts have also been infused intraperitoneally and the composition of bile secreted through bile fistulae studied. In none of these experiments, in which the gastro-intestinal content was bypassed and a return of bile salts to the liver in the physiological range ensured, was any deconjugation of glycine-conjugated bile salts observed. When the liver, however, was stressed by anaesthesia and the intraportal infusion of deoxycholyl-2,4-3H-glycine in unphysiological levels, deconjugation occurred as indicated by the appearance in bile of labelled taurine conjugates. In these rats the dose of deoxycholylglycine was clearly toxic as evidenced by partial or complete cholestasis and eventually death of the animal.
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PMID:Deconjugation of bile salts: does it occur outside the contents of the intestinal tract in the rat? 367 27

The cholestasis of benign recurrent intrahepatic cholestasis (BRIC) may be secondary to factors present in the circulation or to an intrinsic abnormality in hepatocyte bile salt secretion. In the present study, we documented the effect of BRIC sera on hepatic bile flow in rats and in vitro [14C]taurocholate bile salt uptake and efflux from isolated rat hepatocytes. Sera from patients with cholestatic disease (2 patients with primary biliary cirrhosis) and healthy volunteers served as controls. Rat hepatic bile flow increased significantly (p less than 0.05) during intravenous infusions of BRIC sera but remained unaltered during infusions with disease and healthy control sera. [14C]Taurocholate uptake by isolated rat hepatocytes was decreased to a similar extent by BRIC and disease control sera. [14C]Taurocholate efflux from hepatocytes was unaltered by BRIC, disease, or healthy control sera. Quantitative technetium-diisopropyliminodiacetic acid cholescintigraphy in the BRIC patient revealed prompt uptake of the radiolabeled organic anion but no biliary excretion after 21 h. Disease control patients also demonstrated prompt hepatic uptake of radiotracer, but some biliary excretion was evident. These results suggest that BRIC cholestasis is not mediated by a circulating cholestatic agent but rather is secondary to an intrinsic abnormality in hepatocyte bile salt secretion.
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PMID:Benign recurrent intrahepatic cholestasis. Evidence for an intrinsic abnormality in hepatocyte secretion. 367 36

Bacterial endotoxins are known to be an important cause of cholestasis, yet not all organisms that cause cholestasis produce endotoxins. In order to determine whether bacterial products other than endotoxins may be involved in the cholestasis process, 14C-taurocholate (TC) uptake by isolated rat hepatocytes was measured in the presence of mid-log, stationary and mid-death phase bacterial broth supernatants from eight common bacterial pathogens. The results were then correlated with a quantitative assessment of endotoxin production by each organism. Supernatants from Haemophilus influenzae, Pseudomonas aeruginosa and Klebsiella pneumonia demonstrated a striking inhibitory effect on bile salt uptake (77.2 +/- 6.7, 46.9 +/- 6.5 and 32.9 +/- 7.1% maximum inhibition of 14C-TC uptake, respectively) when compared to sterile broth controls. Streptococcus faecalis (Enterococcus), Escherichia coli, Staphylococcus aureus and Bacteroides fragilis products, on the other hand, had relatively minor effects (12.3 +/- 5.2, 12.0 +/- 7.5, 8.4 +/- 6.7 and less than 5.0% inhibition respectively), while those from Proteus mirabilis had an intermediate effect (18.5 +/- 8.3% inhibition). Bile salt efflux rates (16.0 +/- 2.7 and 25.1 +/- 4.2 nmol/min/10(6) hepatocytes, mean +/- SEM) were similar in bacteria demonstrating marked uptake inhibition (Haemophilus influenzae, Pseudomonas aeruginosa) when compared to those with only minor inhibitory effects (Staphylococcus aureus, Bacteroides fragilis) (14.3 +/- 1.1 and 18.4 +/- 2.6 nmol/min/10(6) hepatocytes, respectively, p greater than 0.05). 14C-TC uptake inhibition did not correlate with the amount of endotoxin produced by each organism (r = 0.251). The results of this study indicate that bacteria produce a factor other than endotoxin that significantly inhibits bile salt uptake by isolated rat hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sepsis and cholestasis: the in vitro effects of bacterial products on 14C-taurocholate uptake by isolated rat hepatocytes. 377 49

To elucidate the role of calcium in regulation of canalicular bile flow, we studied biliary sucrose permeability and the transport kinetics of taurocholate in the in situ perfused rat liver. Calcium deprivation did not adversely affect viability or ultrastructural appearances of the liver. Removal of calcium led to initial choleresis followed by cholestasis dependent on external ionized calcium concentration. Biliary recovery of [14C]sucrose relative to that of tritiated water was determined by a biliary multiple-indicator dilution technique. Analysis in terms of irreversible thermodynamics suggested that biliary permeability to sucrose increased due to a change in the sieving coefficient from 0.135 to 0.435. Biliary recovery of taurocholate was significantly (P less than 0.001) reduced in low-calcium medium (from 79.6 +/- 6.5 to 17.6 +/- 11.8%). This was not due to a defect in hepatocellular uptake of taurocholate as determined in the perfused rat liver by a multiple-indicator dilution technique and in isolated hepatocytes. We conclude that calcium deprivation-induced cholestasis is characterized by an increased biliary permeability, a defect in cellular translocation and/or canalicular secretion of bile salts, and a defect in bile salt-independent bile flow.
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PMID:Characterization of calcium deprivation-induced cholestasis in the perfused rat liver. 389 57


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