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Biomedical subjects

S Erlinger

Publications and source records attributed to S Erlinger.

At least 181 records · Page 10Linked to original sources
PubMed1988

Drug-induced cholestasis.

Acute, drug-induced hepatocellular cholestasis (either pure or cholestatic hepatitis) is a common manifestation of drug-induced hepatic injury. The drugs most frequently responsible are hormonal steroids and psychopharmacological agents (in particular phenothiazines and some antidepressants). Cholestasis usually subsides without sequelae in less than six months. Acute, drug-induced ductular cholestasis is uncommon and can resemble biliary tract obstruction. Complete recovery occurs promptly after the withdrawal of the causative drug in most cases. The pathogenetic mechanism may be immunoallergic. Prolonged ductular or ductal cholestasis can follow drug-induced acute hepatitis despite prompt withdrawal of the offending drug. This syndrome, observed mainly with chlorpromazine and uncommonly with twenty other drugs, is characterized by the progressive disappearance of small bile ducts and by manifestations mimicking primary biliary cirrhosis. However, its prognosis appears to be better than that of primary biliary cirrhosis, the condition being reversible in the majority of cases or even subsiding completely. The mechanism is still unknown, but several features suggest some form of autoimmunity. Extrahepatic cholestasis related to sclerosing cholangitis is a frequent and long-term complication of intra-arterial infusion of floxuridine in patients treated for hepatic metastases from colorectal carcinoma. Although it may be reversible, floxuridine-induced sclerosing cholangitis has a poor prognosis and can lead to death in a few patients. The mechanism is probably related to the vascular supply of the common hepatic duct and its relationship to the perfusion territory of floxuridine.

Bile↗
PubMed1988

Cholestatic effect of cyclosporine in the rat. An inhibition of bile acid secretion.

Cyclosporine administration in patients with organ transplants may cause cholestasis. In the rat, intraperitoneal administration of cyclosporine, 10 mg/kg, for three weeks did not cause liver function test abnormalities or hepatic histological lesions. However a significant reduction of bile flow and bile acid secretion rates was observed. The fact that reduction of bile flow was related to a decrease of the bile acid-independent flow suggests that cyclosporine-induced cholestasis results from an inhibition of bile acid secretion. Whether this inhibition is caused by the parental molecule or by cyclosporine metabolites needs to be clarified.

Animals↗
PubMed1988

Immunoperoxidase localization of bile salts in rat liver cells. Evidence for a role of the Golgi apparatus in bile salt transport.

The mechanisms of intracellular transport of bile acids from the sinusoidal pole to the canalicular pole of the hepatocyte are poorly understood. There is physiological and autoradiographic evidence for a vesicular pathway. The purpose of this study was to determine the localization of natural bile acids in the liver using antibodies against cholic acid conjugates and ursodeoxycholic acid. An indirect immunoperoxidase technique was used on rat liver sections fixed either with paraformaldehyde (PF) and saponin, a membrane-permeabilizing agent that allows penetration of antibodies into the cell, or with PF alone. Retention of taurocholate in the liver after tissue processing was 26 +/- SD 15% of the bile acid initially present. When sections fixed with PF and saponin were incubated with the antibody against cholic acid conjugates, a granular cytoplasmic staining was observed by light microscopy in all hepatocytes. By electron microscopy, strong electron-dense deposits were observed mostly on vesicles of the Golgi apparatus (GA) and, sometimes, in the smooth endoplasmic reticulum (SER). After taurocholate infusion, the intensity of the reaction increased. When the liver was fixed with PF alone, almost no reaction was visible on light microscopy, but on electron microscopy the label was localized on the hepatocyte plasma membrane, mainly on the bile canalicular domain and to a lesser extent on the sinusoidal domain. With the antibody against ursodeoxycholic acid, no staining was observed in three of four livers, and a slight staining was observed in one. However, after infusion of ursodeoxycholic acid, staining of GA and SER vesicles was observed when the liver was fixed with PF and saponin. With PF alone, the reaction was intense on the canalicular membrane. These results support the view that, within the limits of the method, vesicles from the GA and possibly vesicles of the SER are involved in the intracellular transport of bile acids before canalicular secretion.

Animals↗
PubMed1988

[Hepatobiliary changes during exclusive parenteral feeding in infants with severe diarrhea].

In order to specify the factors responsible for the hepatic changes occurring during total parenteral nutrition (TPN) and to propose a preventive treatment, 30 infants treated for severe protracted diarrhea were prospectively distributed into 4 groups: I (n = 10): controls; II (n = 7): oral administration of human milk since the 15th day of TPN; III (n = 5): oral metronidazole since the 15th day; IV (n = 8): parenteral antibiotic therapy for septicemia since the 1st day. Contrary to group IV, the first 3 groups were randomly constituted on the 15th day. Liver function tests, bile and serum biliary acids, duodenal flora, hepato-biliary ultrasonography and, in 12 cases, liver histology were sequentially studied. Liver function changes were observed on the 15th day in all groups. An improvement occurred 15 days later in the infants treated, when the control group worsened (p less than 0.02). A significant increase of bile chenodeoxycholic acid levels was observed in the control group only (p less than 0.01), without change in lithocholic acid levels. These results lead the authors to recommend the preventive use of metronidazole or human milk during prolonged TPN in infants.

Bile Acids and Salts↗
PubMed1986

Prolonged cholestasis after ajmaline-induced acute hepatitis.

We report the cases of 3 patients in whom ajmaline-induced acute hepatitis was followed by anicteric cholestasis persisting for more than 1 year after cessation of administration of the drug. Ajmaline was given for 8-16 days before the onset of acute hepatitis. Jaundice was preceded by fever, chills and abdominal pain, and was associated with hypereosinophilia. The initial lesions included centrilobular cholestasis and portal inflammatory infiltration. Jaundice lasted for 3 weeks to 11 months. In these 3 patients liver tests were still abnormal 17-26 months after ajmaline withdrawal; histological examination, performed 9-26 months after the onset of jaundice, showed a decreased number of interlobular bile ducts, ductular proliferation, and mild portal fibrosis; circulating immune complexes were demonstrated. These observations demonstrate that prolonged cholestasis can follow ajmaline-induced acute hepatitis. Persistence of cholestasis long after the withdrawal of ajmaline suggests some form of autoimmunity.

Acute Disease↗
PubMed1986

[Hepatitis D].

The hepatitis D virus (or delta agent) is a defective virus whose replication has an absolute requirement for the hepatitis B virus. Type D hepatitis occurs exclusively in patients simultaneously or previously infected by the hepatitis B virus, often intravenous drug abusers or male homosexuals. Infection by the hepatitis D virus is often responsible for an increase in the severity of the hepatic lesions due to the hepatitis B virus. It can result in fulminant hepatitis. The best prevention is vaccination against hepatitis B.

Hepatitis D↗
PubMed1985

What is cholestasis in 1985?

Bile secretion involves a number of specific transport systems in the hepatocytes. These are located at the baso-lateral membrane (bile acid/sodium co-transport, sodium/proton exchange), intracellularly or at the canalicular membrane (bile acid secretory carrier, bicarbonate transport system). In addition, the paracellular (tight junction) pathway allows passage of inorganic ions and waters. Cholestasis may result from an alteration of these transport systems (hepatocellular cholestasis), from obstruction of intrahepatic bile ducts or obstruction of extrahepatic bile ducts. The main proposed mechanisms of hepatocellular cholestasis are reviewed.

Bile↗
PubMed1985

Bicarbonate-stimulated ATPase activity of bovine liver alkaline phosphatase.

A commercial preparation of bovine hepatic alkaline phosphatase was found to have a Mg2+-stimulated ATPase activity. The pH optimum was 8.5, the Km for ATP was 4.2 X 10(-5) M and the Vmax was 88.3 mumol Pi . h-1 . mg-1. HCO3- had a stimulatory effect on Mg2+ -ATPase activity. Other anions had no effect or an inhibitory effect while Na+, K+ and ouabain had no effect. Purification of the commercial preparation by gel filtration and affinity chromatography yielded a fraction with alkaline phosphatase and (Mg2+ + HCO3-)ATPase activities that had been enriched respectively 27-fold and 23-fold; both activities were inhibited by levamisole (93.1% and 93.8%, respectively) and the purified fraction was found to be a single protein on sodium dodecyl sulfate polyacrylamide gel electrophoresis. These results suggest that alkaline phosphatase and (Mg2+ + HCO3-)ATPase may be properties of the same liver protein that might be involved in biliary HCO3- transport and bile secretion.

Alkaline Phosphatase↗
PubMed1985

Pefloxacin kinetics in cirrhosis.

Pefloxacin pharmacokinetics were evaluated in 16 patients with histologically proved cirrhosis of the liver and compared with those in 12 healthy subjects. In the patients with cirrhosis, the mean (+/- SD) t1/2, although highly variable, was significantly longer (35.10 +/- 19.00 hours) than in the normal subjects (11.00 +/- 2.64 hours; P less than 0.001). In the patients, the volume of distribution was decreased by 18% (P less than 0.02) and total plasma clearance was markedly decreased (2.66 +/- 1.85 vs. 8.19 +/- 2.80 L/hr X 1.73 m2; P less than 0.001). The t1/2 was longer in patients with ascites or jaundice than in patients without these complications. The urinary excretion of unchanged pefloxacin was higher in the patients than in the subjects, while the excretion of N-desmethyl pefloxacin (a major metabolite of the drug) was lower. It is proposed that the decreased plasma clearance of pefloxacin in patients with cirrhosis is a result of decreased hepatic metabolism of the drug, and that the dosage should probably be modified in these patients.

Adult↗
PubMed1985

Dome formation in the human colon carcinoma cell line Caco-2 in culture. Influence of ouabain and permeable supports.

We studied formation of domes in cell monolayers of the human colon carcinoma cell line Caco-2 which has been shown to exhibit signs of enterocytic differentiation and transport properties. After a 24 hr incubation with 4 X 10(-8) M ouabain, the number of domes seen on Caco-2 cell monolayers grown on plastic dishes was not significantly altered. After a 90 min preincubation with ouabain, 86rubidium uptake by Caco-2 cells was inhibited by ouabain, indicating that the cells have an ouabain-sensitive Na+, K+-ATPase, while dome formation was unaffected by ouabain. Domes were observed in Caco-2 cell monolayers grown on Nuclepore filters when the pore size was 0.015 micron but not when it was 0.030 micron. Our results suggest that dome formation in the Caco-2 cell line could be independent of Na+, K+-ATPase activity and might be due to accumulation of molecules having an effective hydrodynamic radius comprised between 0.015 and 0.030 micron.

Biological Transport, Active↗
PubMed1985

Effect of acid-base balance and acetazolamide on ursodeoxycholate-induced biliary bicarbonate secretion.

Biliary bicarbonate secretion may play an important role in canalicular bile flow. The aim of this study was to examine the effect of disturbances in acid-base balance on ursodeoxycholate (UDCA)-induced choleresis and bicarbonate secretion. Isolated rat livers were perfused with an erythrocyte-free solution in a recirculating system. In the absence of bile acid infusion, bicarbonate concentration in bile varied in parallel with that in the perfusate (15.6-35.1 mM), irrespective of the perfusate pH (7.26-7.55). Bicarbonate concentration in bile was not significantly different from that in the perfusate. Under UDCA infusion (2 mumol/min), bicarbonate concentration in bile and perfusate was correlated (P less than 0.001). Bicarbonate concentration in bile was always higher than that in the perfusate. Perfusate pH changes (7.25-7.56) induced by changes in perfusate carbon dioxide tension had no significant effect on bicarbonate secretion or bile flow. A significant correlation was found between bile flow and bicarbonate secretion both with and without UDCA. Acetazolamide (1 mM) significantly decreased both UDCA-stimulated bile flow (-27.7%) and bicarbonate concentration (-51.8%). These results suggest that canalicular bicarbonate secretion includes an equilibrative component that is possibly linked to diffusion of plasmatic CO2 or HCO3- and a concentrative transport that is stimulated by UDCA, is independent of plasma pH, and involves carbonic anhydrase.

Acetazolamide↗
PubMed1985

Role of H+ transport in ursodeoxycholate-induced biliary HCO-3 secretion in the rat.

Biliary bicarbonate secretion may occur by transport of bicarbonate itself or of H+ (or OH-). To distinguish between these two mechanisms, we have studied the effects of bicarbonate deprivation or substitution by weak acids in the perfusate of isolated rat livers on ursodeoxycholate-induced bicarbonate secretion. Livers were perfused with an erythrocyte-free solution containing either the impermeant buffer Tricine (25 mM) or 25 mM Tricine and 13 mM bicarbonate, acetate, or 5,5-dimethyloxazolidine-2,4-dione (DMO), and ursodeoxycholate was infused. Tauroursodeoxycholate, which does not stimulate bicarbonate secretion, served as a control. During ursodeoxycholate infusion 1) the increase in bile flow, in microliter X min-1 X g liver-1 (+/- SE), was significantly higher in livers perfused with Tricine and bicarbonate (1.29 +/- 0.06), Tricine and acetate (1.46 +/- 0.07), and Tricine and DMO (1.30 +/- 0.04) than in livers perfused with Tricine alone (0.99 +/- 0.04); and 2) biliary bicarbonate, acetate, or DMO concentrations and bile pH were significantly higher than the corresponding perfusate values. In contrast, during tauroursodeoxycholate infusion bile flow was the same whatever the perfusate, and bile pH was lower than pH of the perfusate. Therefore, ursodeoxycholate-induced choleresis and bile alkalinization do not depend on bicarbonate as such (which can be replaced by acetate or DMO). This suggests that ursodeoxycholate-induced biliary bicarbonate secretion is the result of H+ (or OH-) transport rather than transport of bicarbonate itself.

Animals↗
PubMed1985

Mechanism of uptake of dihydroergotamine by isolated rat hepatocytes: effect of troleandomycin.

The mechanism of uptake of dihydroergotamine (DHE) was studied in isolated rat hepatocytes and the effect of troleandomycin on DHE uptake was examined. The uptake was linear for 75 sec and reached an equilibrium at 5 min with an intracellular/extracellular concentration ratio of approximately 65. The initial velocity of uptake was linearly related to the concentration of DHE in the extracellular medium with a diffusion constant of 127 pmol X min-1 X mg of protein-1 X microM-1. Metabolic inhibitors (KCN, carbonylcyanide-M-chlorophenylhydrazone and antimycin A) had no effect on DHE uptake. Replacement of sodium by choline chloride in the extracellular medium decreased slightly but significantly (P less than .02) the uptake of DHE. The addition of troleandomycin (300 microM) in the incubation medium decreased the initial velocity of uptake of DHE (control, velocity of uptake = 88 pmol X min-1 X mg of protein-1 X microM-1; troleandomycin, velocity of uptake = 55 pmol X min-1 X mg of protein-1 X microM-1; P less than .05). These results suggest that DHE enters into the hepatocytes by passive diffusion. The high intracellular/extracellular concentration ratio suggests that intracellular binding occurs and results in an accumulation of DHE in the cells.

Animals↗
PubMed1984

The importance of conjugation in biliary secretion of ursodeoxycholate and 7-ketolithocholate in the rat.

The biliary maximum secretory rate (SRmax.) of glycoursodeoxycholate in the bile fistula anaesthetized rat was about five times that of unconjugated ursodeoxycholate. Likewise, the biliary SRmax. of tauro-7-ketolithocholate was more than three times that of unconjugated 7-ketolithocholate. The SRmax. of 7-ketolithocholate infused with taurine (to avoid depletion of the taurine pool) was still significantly lower than that of exogenous tauro-7-ketolithocholate. These data support the hypothesis that, for bile acids that are poorly water soluble, the maximal biliary secretion rate is dependent on conjugating capacity, which is the limiting step in the overall transport from plasma into bile.

Animals↗
PubMed1982

Furosemide-sensitive salt transport in the Madin-Darby canine kidney cell line. Evidence for the cotransport of Na+, K+, and Cl-.

Confluent monolayer cultures of the Madin-Darby canine kidney (MDCK) cell line have been shown to possess a furosemide and bumetanide-sensitive (Na+,K+)-cotransport system. We have studied the effect of anion substitutions on (Na+,K+)-cotransport. In Na+-depleted cells, bumetanide-sensitive uptake of 22Na+ or 86Rb+ exhibited an absolute requirement for extracellular Cl-. Chloride could be replaced in the buffers by Br-, but not by F-, I-, acetate, nitrate, thiocyanate, sulfate, or gluconate. The effect of Cl- was saturating, and Na+-stimulated 86RB+ uptake as well as K+-stimulated 22Na+ uptake was shown to be dependent on the square of the Cl- concentration. The concentration of Cl- which gave half-maximal stimulation of cation cotransport varied between 58 and 70 mM. There was a small degree of cooperativity between the binding affinities for Cl- and K+ at constant Na+ concentrations. Bumetanide-sensitive 36Cl- uptake could be demonstrated when extracellular Na+ and K+ were present simultaneously. Uptake through this system was unaffected by changes in the membrane potential or by the imposition of pH gradients. Together these data strongly suggest that the bumetanide-sensitive transport system in Madin-Darby canine kidney cells co-transports Na+, K+, and Cl- in a ratio of 1:1:2.

Animals↗