Cholestasis induced by oestrogen after liver transplantation.
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Adult↗
Biomedical subjects
E A Shaffer
Publications and source records attributed to E A Shaffer.
The use of a gonadotropin-releasing hormone analog and transdermal estrogen to preserve fertility in a woman with severe menorrhagia.
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Administration, Cutaneous↗
Hyperprolactinemia in hepatic encephalopathy may result from impaired central dopaminergic neurotransmission.
Ten patients with liver disease and hepatic encephalopathy (HE) and eight normal controls were studied. Five of the 10 HE patients had hyperprolactinemia. The administration of L-dopa produced a decrease of serum prolactin in all. Prior administration of Carbidopa, a peripheral decarboxylase inhibitor, did not change the prolactin suppression by L-dopa in the normal controls or in the patients with normal baseline prolactin levels. In the hyperprolactinemic group, Carbidopa significantly inhibited the response to L-dopa. Impaired central neurotransmission, at least involving the hypothalamic-pituitary dopaminergic system, may underlie the hyperprolactinemia in HE.
Adult↗
Effect of oral liquids and ranitidine on gastric fluid volume and pH in children undergoing outpatient surgery.
Eighty-eight children (mean age 5.6 yr, range 1-14 yr) about to undergo elective outpatient surgery were randomly assigned to four groups. All children were given phenolsulfonphthalein (PSP) orally 2-3 h before the scheduled time of surgery as a marker dye to assess gastric emptying. Immediately after receiving PSP they were given: group A--liquids, up to 5 ml/kg + placebo (glucose water 0.2 ml/kg); group B--liquids, up to 5 ml/kg + ranitidine 2 mg/kg in glucose water 0.2 ml/kg; group C--placebo only; group D--ranitidine only. Gastric contents were aspirated after induction of anesthesia. Mean volume (range) in ml/kg of aspirated gastric fluid in each group was: group A--0.34 (0-1.0); group B--0.17 (0.07); group C--0.25 (0-1.1); group D--0.16 (0-0.6). The pH mean (range) value was: group A--1.83 (0.9-3.6); group B--4.76 (2.0-7.7); group C--2.10 (1.2-4.1); group D--3.97 (1.3-7.3). PSP could not be detected in the gastric samples from children in whom the ingestion-sampling interval was more than 2.25 h. In comparison with prolonged starvation, administration of oral liquids without ranitidine 2-3 h preoperatively did not produce a significant increase in mean volume of gastric aspirate, and there was no increase in the number of patients with gastric aspirate greater than 0.4 ml/kg. Administration of ranitidine with or without fluids resulted in a decrease in both volume and acidity of gastric contents.
Administration, Oral↗
A novel enteropathy with partial villous atrophy, microscopic colitis, and pemphigoid change.
Microscopic colitis associated with gluten-resistant partial villous atrophy was documented in a 21-year-old woman with chronic nonbloody diarrhea. Electron microscopic examination of the colonic and duodenal biopsies showed focal separations of basal lamina from cryptal epithelial cells forming subepithelial blebs in which were mast cells and fibroblasts. These morphologic features have not been previously described in any inflammatory bowel disease and are reminiscent of bullous pemphigoid of the skin. The findings suggest that not all cases of microscopic colitis lie within the spectrum of collagenous colitis.
Adult↗
Collagenous colitis and microscopic colitis: the watery diarrhea-colitis syndrome.
Nine patients (seven females, two males) with chronic watery diarrhea and nonspecific colonic mucosal inflammation followed for 1-5 yr are presented. Eight were diagnosed as having collagenous colitis on the basis of marked thickening of the subepithelial collagen layer in at least one set of biopsies. The thickness of the collagen table varied with time in all eight cases. When thickening was minimal, morphological features were indistinguishable from microscopic colitis, signifying that, in most cases, collagenous colitis and microscopic colitis are part of the same spectrum of colonic mucosal response. One of the eight patients had documented collagenous colitis and gluten-associated enteropathy for 12 yr. The colitis and duodenal histology improved synchronously when a gluten-free diet and corticosteroids were administered. The ninth patient had microscopic colitis and enteropathy which did not respond to gluten withdrawal. This patient never exhibited thickening of subepithelial collagen in repeated biopsies over 5 yr, suggesting that an entity of microscopic colitis may exist independent of collagenous colitis. Duodenal mucosal biopsies showed normal histology in four other patients with collagenous colitis. The histological variability of collagenization and inflammation during the course of collagenous colitis and microscopic colitis and the clinical feature of watery diarrhea suggest that these two entities be grouped together as the watery diarrhea-colitis syndrome.
Adult↗
Intracellular pH influences the resting membrane potential of isolated rat hepatocytes.
This study in isolated rat hepatocytes sought to determine if the changes in membrane potential associated with intracellular alkalinization or acidification could be attributed to changes in K+ conductance. Intracellular pHi was manipulated using the 'NH4+-pulse' method: inducing intracellular alkalinization with NH4Cl (10 mM), and producing acidification by diluting the NH4+-loaded cells with ammonium ion-free buffer or by adding sodium proprionate. Membrane potential and resistance were measured in freshly isolated rat liver cells using intracellular microelectrodes. The results indicated that intracellular alkalinization was associated with hyperpolarization and decreased membrane resistance, whereas intracellular acidification caused depolarization with increased membrane resistance. As pHi-mediated electrogenic responses have been related to changes in K+ conductance in other epithelial tissues, the influence of K+ transport inhibitors on NH4+-evoked electrical effects was examined. NH4Cl-evoked membrane potential changes were inhibited by the K+ channel blockers, quinine and barium and in potassium depolarized cells (cells bathed in a high K+ medium where [K+]in = [K+]out = 140 mM). Furthermore, Rubidium-86 (86Rb+) efflux from preloaded hepatocytes, a measure of K+ permeability, was enhanced following intracellular alkalinization but inhibited by intracellular acidification. Thus, these results indicate that pHi-evoked electrogenic effects in hepatocytes are mediated through changes in K+ conductance.
Ammonium Chloride↗
Gastric fluid volume, pH, and emptying in elective inpatients. Influences of narcotic-atropine premedication, oral fluid, and ranitidine.
One hundred and twenty healthy, elective surgical inpatients were randomly assigned to one of four groups. Between two and three hours before the scheduled time of surgery all patients ingested a marker dye, phenol red, 50 mg in 10 ml water, with placebo tablet alone (Groups 1 and 2), placebo tablet with 150 ml oral fluid (Group 3), or oral ranitidine 150 mg with oral fluid 150 ml (Group 4). Patients in Group 1 received oral diazepam or no premedication, while those in Groups 2, 3, and 4 received IM narcotic and atropine one hour preoperatively. Following induction of anaesthesia the residual gastric fluid was aspirated through a Salem sump tube and its volume, pH, and phenol red content measured. Mean volumes were Group 1: 24 ml; Group 2: 13 ml; Group 3: 17 ml; Group 4: 14 ml. Mean pH values were Group 1: 2.99; Group 2: 3.03; Group 3: 3.44; Group 4: 5.28. The amount of phenol red in the samples indicated at least 90 per cent gastric emptying had occurred in 90 per cent of patients. We conclude that, in healthy patients, 150 ml oral fluid is almost completely emptied from the stomach within two hours of ingestion, even when followed one hour later by narcotic-atropine premedication.
Adolescent↗
Pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis.
The purpose of this pilot study was to determine whether daily administration of cyclosporin A to symptomatic patients with primary biliary cirrhosis for 1 yr would lead to a significant and sustained improvement in liver enzyme abnormalities. Twelve adult patients (11 female, 1 male; aged 52.6 +/- 8.9 yr, mean +/- SD) with serologic and histologically defined primary biliary cirrhosis were randomized to receive either oral cyclosporin A or vehicle placebo. Cyclosporin A was administered at sufficient dosages to maintain serum radioimmunoassay trough levels between 100 and 200 ng/ml (starting dosage, 2.5 mg/kg.day). After 1 yr of therapy, significant changes from pretreatment values were seen only in recipients of cyclosporin A. These included a 37% decrease in mean serum alkaline phosphatase and a 43% decrease in gamma-glutamyltransferase (controls +3% and -14%, respectively). Mean serum bilirubin and albumin levels and prothrombin times remained unaltered in the two groups, as did the extent of inflammation and fibrosis and the histologic staging of liver biopsy specimens. Although mean serum creatinine levels increased by 51% in recipients of cyclosporin A (+2% in controls), there were no associated changes in diastolic blood pressure or creatinine clearance values. Other side effects including thrombocytopenia, hirsutism, headaches, tremor, and parasthesiae were common in the treated group but not of sufficient severity to warrant adjustment in the dosage or discontinuation of therapy. The observed changes in hepatic, renal, and hematologic tests tended to return to baseline after discontinuation of therapy. Two patients, both placebo recipients, died of liver failure during the study period. The results of this study indicate that in symptomatic primary biliary cirrhosis, cyclosporin A administration is associated with a significant improvement in cholestatic liver enzyme abnormalities that persists for the duration of therapy. A progressive rise in serum creatinine levels and a high incidence of side effects raise concerns regarding the long-term safety of this agent in primary biliary cirrhosis.
Adult↗
Sphincterotomy and passage of glass beads.
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Animals↗
Hepatocellular water and electrolyte secretion.
The study of hepatocellular water and electrolyte secretion has been hampered because of the inaccessibility of the hepatobiliary secretory lumen, the canaliculus. The advent of novel experimental models has allowed the application of electrophysiological techniques to investigate the ionic basis of hepatocellular secretion. The "hepatocyte couplet" isolated from the liver in primary monolayer cultures consists of two hepatocytes which enclose a single canalicular unit. The canaliculus of the couplet appears to behave as it would in vivo, exhibiting both secretory and contractile activity. Intracellular microelectrode recordings from this functional unit have permitted direct electrophysiological assessment of cellular and canalicular potentials and measurement of individual ion conductances across the basolateral membrane surface. Further, the application of patch-clamp electrophysiology to study hepatocellular ion transport pathways has characterized individual channel proteins. Intracellular and (or) patch-clamp electrophysiology has elucidated the ion conductance changes activated by bile salts like taurocholate, neurotransmitters like adrenaline, and hormones such as glucagon. These innovative approaches hold much promise in the future study of the ionic basis of hepatocellular secretion.
Animals↗
Determinants of biliary secretory pressure: the effects of two different bile acids.
Biliary secretory pressure represents the force generated to deliver bile through the biliary system. Bile acid-induced toxicity may decrease canalicular bile formation and (or) induce back diffusion causing cholestasis. To determine if biliary secretory pressure is a sensitive indicator of bile toxicity, taurocholate was compared with a less cytotoxic bile acid, tauroursodeoxycholate. In fasted male Sprague-Dawley rats, the common bile duct was cannulated and the endogenous bile salt pool was removed by enteroclysis. Taurocholate (n = 35) or tauroursodeoxycholate (n = 35) in saline was infused for 1 h. Maximal biliary secretory pressure was then measured by attaching the biliary cannula to a column monometer and recording the maximum height to which bile rose. With taurocholate administration, bile flow and bile salt secretion linearly rose to a maximum infusion of 0.5 mumol/(min.g liver), above which hemolysis and death occurred. In contrast, tauroursodeoxycholate could be infused at higher rates with bile salt secretion plateauing at 1.25 mumol/(min.g liver] Both had similar choleretic potencies. Mean biliary secretory pressure at low (less than 0.15 mumol/(min.g liver] infusions was lower with taurocholate (22.5 cm bile) than tauroursodeoxycholate (25.2 cm). Further, increasing the taurocholate infusion decreased the biliary secretory pressure; yet for taurousodeoxycholate, pressure remained unchanged even at higher infusions. Thus, taurocholate but not tauroursodeoxycholate decreases biliary secretory pressure at high infusion rates, likely a reflection of its toxicity to the hepatobiliary epithelium.
Animals↗
Biliary obstruction after cholecystectomy: diagnosis with quantitative cholescintigraphy.
Fifty patients with recurrent post-cholecystectomy pain underwent hepatobiliary scintigraphy. Time-activity curves were generated from regions of interest over the liver, bile duct, duodenum, and bowel. Patients were divided into obstructed and unobstructed groups with endoscopic retrograde cholangiopancreatography criteria. Measurements from the liver, duodenum, and bowel curves contributed little to the analysis. The washout phase of the bile duct curve showed intermittent emptying in both obstructed and unobstructed groups. Less than one-third of peak activity remained in both groups at 90 minutes. Retention fell more rapidly in the later portion of the sequence in patients with obstruction. Quantification was essential, since differences were subtle and could not be appreciated visually. In the absence of hepatocellular disease, the most reliable criterion was the time at which maximal bile duct activity occurred. A cutoff level of 29 minutes or more was used in the diagnosis of obstruction. A sensitivity of 93% with an adequate specificity of 64% and an overall accuracy of 80% was achieved in the prediction of obstruction.
Adult↗
The effect of protein-calorie malnutrition on the developing liver.
The effects of protein-calorie malnutrition on bile salt metabolism and liver function were studied. Malnutrition was induced in rabbits by combining litters at 7 days of age (13-16 animals) and results compared to control litters (six-eight animals). At age 29-30 days biliary output from the common bile duct was measured directly for three 1-h periods: under basal conditions, and in response to intravenous infusion of exogenous glycodeoxycholic acid at 0.75 and 1.5 mumol/min/kg, respectively. The bile salt pool size was measured by isotope dilution. Final mean body weight and liver weight were significantly decreased in malnourished animals compared to controls. Liver weight/body weight was also less in the malnourished group. Total liver DNA and protein content, as well as the protein to DNA ratio, were less in the malnourished animals compared to controls. Bile flow and bile salt secretion were reduced in the malnourished group when calculated per kg body weight or per mg liver DNA. Bile salt-dependent flow did not differ significantly, but bile salt-independent flow was significantly less in malnourished animals. Bile salt pool size was decreased in the malnourished group. These findings indicate that malnutrition has a greater impact on liver weight than on total body weight in the preweaning period. In addition, malnutrition reduces bile flow, bile salt secretion, and bile salt pool size which, along with the decrease in bile salt-independent flow, may reflect either an impairment of hepatic uptake function or a delay in postnatal development.
Animals↗
Effect of chlorpromazine (CPZ) on cholecystokinin-induced gallbladder contraction: the role of calcium.
Smooth muscle contraction is initiated by a rise in intracellular calcium, which binds to calmodulin resulting in myosin phosphorylation. CPZ impairs smooth muscle contraction by either interfering with calcium influx at low concentrations (less than 1.25 x 10(-5) M) or inactivating calcium-calmodulin at higher levels. This chlorpromazine effect was used to determine if gallbladder agonists act through different intracellular mechanisms. Guinea pig gallbladders were mounted in an organ bath and auxotonic contractions induced by bethanechol, KCl and the octapeptide of cholecystokinin (CCK). Bethanechol and KCl-induced contractions were profoundly inhibited by 1.25 x 10(-5) M CPZ throughout the dose-response curve. In contrast, CPZ did not affect CCK-mediated contractions at CCK concentrations less than 5.7 x 10(-8) M. At maximal CCK doses (3 x 10(-7) M), CPZ had only a modest inhibitory effect of 20%, compared with tension losses of 62 and 80% for bethanechol and KCl, respectively. This inhibition with high-dose CCK was offset by increasing extracellular calcium in the organ bath. The resistance of CCK to CPZ inhibition at low doses within the physiologic range implies that CCK acts independently of extracellular Ca2+ unlike the other agonists. Higher CPZ concentrations, greater than or equal to 1.25 x 10(-4) M, markedly suppressed CCK throughout the dose-response curve. Cholecystokinin may act via myosin phosphorylation, but unlike other agonists any rise in cytoplasmic calcium likely originates from an intracellular site.
Animals↗
Gallbladder function during gallstone dissolution. Effect of bile acid therapy in patients with gallstones.
Impaired gallbladder emptying has been associated with gallstone disease but any effect on or from bile acid therapy for gallstone dissolution is unknown. We evaluated gallbladder filling and emptying with low-dose cholecystokinin infusion (0.02 U/kg.h) by computer-assisted cholescintigraphy in 52 controls versus 31 gallstone patients: 17 treated with 12-15 mg/kg.day of chenodeoxycholic acid and 14 with 8-10 mg/kg.day of ursodeoxycholic acid. Thirteen of 31 patients with complete dissolution had four scans: before, after 3 mo of therapy, after stone dissolution, and after discontinuation of bile acids. The 18 failures had three scans: before and after 3 and 15-18 mo of therapy. Before therapy, the 31 gallstone patients had significantly impaired gallbladder emptying compared with controls, but filling was not decreased. Bile acids significantly decreased emptying in both treatment groups after 3 mo of therapy. In the dissolution group, emptying improved once the stones had dissolved and increased further upon discontinuing the bile acids. In the failures, impaired emptying persisted for up to 15-18 mo. Gallbladder filling in the 31 gallstone patients was also significantly decreased after 3 mo of bile acid therapy, particularly in the failure patients, 5 of whom exhibited zero filling. No differences were detected between ursodeoxycholic acid and chenodeoxycholic acid for either gallbladder function or efficiency of dissolution. Thus, bile acid therapy impairs gallbladder filling and emptying in gallstone patients. Gallstone dissolution improves emptying, which is further enhanced when bile acids are discontinued.
Adult↗
Sodium-dependent taurocholate uptake by isolated rat hepatocytes occurs through an electrogenic mechanism.
The uptake mechanism for the bile salt, taurocholate, by the liver cell is coupled to sodium but the stoichiometry is controversial. A one-to-one coupling ratio would result in electroneutral transport, whereas cotransport of more than one sodium ion with each taurocholate molecule cause an electrogenic response. To better define the uptake of this bile salt, we measured the effect of taurocholate on the membrane potential and resistance of isolated rat hepatocytes using conventional microelectrode electrophysiology. The addition of 20 microM taurocholate caused transient but significant depolarization accompanied by a significant decrease in membrane resistance. The electrical effect induced by taurocholate mimicked that induced by L-alanine (10 mM), the uptake of which is known to occur through an electrogenic, sodium-coupled mechanism. The sodium dependence of taurocholate-induced depolarization was further confirmed by: (1) replacing Na+ with choline +, and (2) preincubating cells with ouabain (2 mM) or with the Na+-ionophore, gramicidin (25 micrograms/ml); both suppressed the electrogenic response. Further, cholic acid, which inhibits sodium-coupled taurocholate uptake in hepatocytes, inhibited taurocholate evoked depolarization. These results support the hypothesis that sodium-coupled taurocholate uptake by isolated hepatocytes occurs through an electrogenic process which transports more than one Na+ with each taurocholate molecule.
Alanine↗
The histopathology of rectosigmoid biopsies from adults with bloody diarrhea due to verotoxin-producing Escherichia coli.
The histopathology of rectosigmoid biopsies from 20 patients with bloody diarrhea resulting from verotoxin-producing Escherichia coli infection is reported. The biopsies displayed a range of appearances, from normal to mild, nonspecific inflammation to acute infectious-type colitis. Surface-adherent or invasive bacteria were not identified. The morphologic features of infectious colitis and the absence of bacteria suggest that verotoxin may be responsible for the pathologic changes.
Bacterial Toxins↗