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Biomedical subjects

K D Setchell

Publications and source records attributed to K D Setchell.

At least 91 records · Page 5Linked to original sources
PubMed1991

Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism.

Ursodeoxycholic acid was administered to a patient with benign recurrent intrahepatic cholestasis to prevent cholestatic episodes. A detailed study of bile acid metabolism in this patient was carried out in the anicteric and icteric phases before and after ursodeoxycholic acid (750 mg/day) administration. Urinary, biliary and serum bile acids were measured by gas chromatography-mass spectrometry and by high-performance liquid chromatography techniques. During the anicteric phase the daily urinary excretion and serum concentrations of bile acids were within normal ranges, indicating normal hepatic uptake and secretion of bile acids during the cholestasis-free period. Only slight qualitative differences from normal individuals were observed; the relative proportions of deoxycholic acid in the bile and serum were higher, and 12-oxo-lithocholic acid was the predominant urinary bile acid. During the icteric phase a marked increase in the urinary excretion of primary bile acids and C-1, C-2, C-4 and C-6 hydroxylated metabolites was found. Serum bile acid concentrations increased before the rise in bilirubin, suggesting an acute disturbance in bile acid transport at the onset of the cholestatic attack. After ursodeoxycholic acid administration in the anicteric phase, bile became enriched with the exogenous bile acid, but little qualitative change was found in the other metabolites present in the urine, serum or bile during the anicteric or icteric phases. Prolonged administration of ursodeoxycholic acid failed to prevent recurrence of a cholestatic episode, suggesting that in benign recurrent intrahepatic cholestasis, oral ursodeoxycholic acid may be of little benefit in the treatment or prevention of cholestasis despite marked enrichment of the bile acid pool with this hydrophilic bile acid.

Adult↗
PubMed1990

Comprehensive study of the biliary bile acid composition of patients with cystic fibrosis and associated liver disease before and after UDCA administration.

The biliary bile acid composition was determined for patients with cystic fibrosis and associated liver disease before and after the administration of ursodeoxycholic acid (10 to 15 mg/kg body wt/day). Bile acids were analyzed by fast atom bombardment ionization-mass spectrometry, high performance liquid chromatography and gas chromatography-mass spectrometry after individual bile acids were separated according to their mode of conjugation using the lipophilic anion exchanger, diethylaminohydroxypropyl Sephadex LH-20. More than 50 individual bile acids were identified in the bile of cystic fibrosis patients and these acids were predominantly secreted as glycine and taurine conjugates. Small proportions (less than 8% of the total) of unconjugated and sulfate conjugates were present. Of interest was the identification of two side-chain-elongated (C25) bile acids, homocholic and homochenodeoxycholic acids. After ursodeoxycholic acid was administered, duodenal bile became enriched with the conjugated species of ursodeoxycholic acid (accounting for 11.9% to 32.5% of the total biliary bile acids), but to a lesser extent than reported previously for patients with other liver diseases or gallstones who received comparable doses of ursodeoxycholic acid, and this presumably occurs because of bile acid malabsorption that is a feature of cystic fibrosis. The mean glycine/taurine ratio increased from 2.4 before ursodeoxycholic acid administration to 5 after ursodeoxycholic acid administration even though these patients also received taurine. Despite the relatively low enrichment of the bile by ursodeoxycholic acid, biochemical indices of liver function all improved in these patients after ursodeoxycholic acid administration.

Adolescent↗
PubMed1990

Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis.

The hydrophilic bile acid ursodeoxycholic acid (UDCA) has recently been shown to improve indexes of liver function in adult patients with various liver diseases. The clinical and biochemical responses to UDCA administration (10 to 15 mg/kg body weight per day) were therefore investigated in nine patients with cystic fibrosis and evidence of liver disease. All patients were receiving pancreatic enzymes and taurine supplementation. Liver function tests were done and serum bile acid concentrations and biliary bile acid composition were determined before and during UDCA therapy; fat balance studies and fecal bile acid excretion were carried out before and 6 months after UDCA treatment. After 2 months of bile acid therapy, biliary bile acid composition was enriched in UDCA from approximately 5% before treatment to 25%, at the expense of cholic and chenodeoxycholic acids, thus making the pool more hydrophilic. This enrichment is lower than that reported for adults with chronic liver diseases. Serum concentrations of UDCA increased significantly but variably. UDCA became the predominant fecal bile acid excreted (12% to 67%), indicating a variable absorption of the administered bile acid. Liver function improved in all patients after 2 to 6 months of therapy, although the degree of improvement (aspartate aminotransferase, -34%; alanine aminotransferase, -41%; gamma-glutamyltranspeptidase, -41% alkaline phosphatase, -19%) was lower than that observed in adults with chronic liver diseases. Mean coefficient of fat absorption and growth rate were, on average, unaffected by UDCA therapy, although an improvement was noted for three patients with greater severity of steatorrhea. The study indicates that UDCA can be used safely in this patient population but that higher doses of UDCA may be of greater benefit in the treatment of the liver disease associated with cystic fibrosis.

Adolescent↗
PubMed1990

Bile acid metabolism in early life: studies of amniotic fluid.

Bile acid metabolism of the human fetus was examined in early gestation (weeks 13-19) and compared with the full-term fetus from the analysis of amniotic fluid collected from healthy pregnant women. Total individual bile acids were determined by gas-liquid chromatography-mass spectrometry after solvolysis and hydrolysis of bile acid conjugates. Additionally, bile acids were separated according to their mode of conjugation by lipophilic anion exchange chromatography. Qualitatively the bile acid profiles of amniotic fluid in early gestation were similar and markedly different from those of full-term fetuses. Chenodeoxycholic acid was the major bile acid identified in early gestation and concentrations exceeded those of cholic acid, but by full term this relationship was reversed. Over 50 bile acids were identified in the amniotic fluids, these included C-1, C-4, and C-6 hydroxylated species and reflected primary hepatic synthesis by the fetus. At full term, 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acid was one of the major bile acids identified in amniotic fluid. The monohydroxy bile acids lithocholic and 3 beta-hydroxy-5-cholenoic acids were present in significant proportions during early gestation, but by full term these accounted for only a few percent of the total bile acids. Quantitatively the total bile acid concentration of amniotic fluid was less than 4 mumol/l. The majority of bile acids were found to be glyco-, tauro-, and sulfate-conjugates. The more hydrophobic bile acids tended to be preferentially sulfated. These data indicate that significant and major changes in bile acid metabolism take place between early and late gestation in the human fetus.

Amniotic Fluid↗
PubMed1989

The use of thermospray liquid chromatography/tandem mass spectrometry for the class identification and structural verification of phytoestrogens in soy protein preparations.

The thermospray mass spectra of the phytoestrogens have intense protonated molecular ions but contain few or no ions indicative of structure. Tandem mass spectrometry (MS/MS) was used to obtain daughter ion spectra containing ions unique to the different structural characteristics of each phytoestrogen subclass and was used both to confirm identification and propose structures for unknowns. In addition to unique daughter ion spectra, MS/MS was used as a class identifier to detect phytoestrogens through the neutral loss of 56 (due to consecutive losses of CO) that is common to all members of this family. Several sources of soy protein were investigated to confirm the presence or absence of phytoestrogens. In one preparation investigated, daidzein and genistein were detected as well as an unknown phytoestrogen of the Biochanin A subclass. This unknown has been tentatively identified as 6,7-dihydroxy-4'-methoxyisoflavone using its daughter ion spectrum.

Animal Feed↗
PubMed1989

Thermospray ionization liquid chromatography-mass spectrometry: a new and highly specific technique for the analysis of bile acids.

A rapid, highly specific and sensitive combined high performance liquid chromatography-mass spectrometric (LC-MS) method is described for the analysis of bile acids in biological fluids. Ionization of polar bile acid conjugates is achieved in the thermospray interface that is used to directly couple the LC column to the mass spectrometer, thereby allowing continuous monitoring of the LC effluent. Maximum sensitivity (4-10 pmol) is achieved by recording the negative ions generated in the ionization process and mass spectra obtained for the principal bile acid conjugates are characterized by intense [M-H]-pseudo-molecular ions and fragment ions due to consecutive losses of water corresponding to a number of hydroxyl groups in the molecule. The mass spectrometer thus provides molecular weight and useful structural information for each compound separated by HPLC. Applications of the LC-MS technique to the analysis of bile acids in bile and serum samples after an initial solid-phase extraction step highlight the potential of the thermospray interface for enhancing the specificity and sensitivity of the HPLC technique for bile acid analysis.

Animals↗
PubMed1989

Identification of 3 alpha,4 beta,7 alpha-trihydroxy-5 beta-cholanoic acid in human bile: reflection of a new pathway in bile acid metabolism in humans.

The chemical synthesis, nuclear magnetic resonance, and mass spectrometric characteristics of the first C-4 hydroxylated bile acid analogues are described. The data definitively confirm, for the first time, the identity of 3 alpha,4 beta,7 alpha-trihydroxy-5 beta-cholanoic acid in human fetal gallbladder bile. In addition, 3 alpha,4 beta,7 alpha-12 alpha-tetrahydroxy-5 beta-cholanoic was identified in the feces from healthy newborn infants many days after birth, indicating a hepatic origin for C-4 hydroxylation of bile acids. To our knowledge bile acids hydroxylated at the C-4 position of the steroid nucleus have never been previously recognized in any mammalian species. The finding of this novel bile acid which accounts for 5-15% of the total biliary bile acids in early gestation indicates that C-4 hydroxylation is a unique and important metabolic pathway in early human development.

Bile↗
PubMed1988

Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile.

A detailed study of the qualitative and quantitative composition of bile acids in human fetal gallbladder bile is described. Bile was collected during early gestation (weeks 16-19) and analyzed by gas chromatography and mass spectrometry, fast atom bombardment ionization mass spectrometry, and high performance liquid chromatography. Bile acids were separated into different conjugate groups by chromatography on the lipophilic anion exchange gel, diethylaminohydroxypropyl Sephadex LH-20. Quantitatively more than 80% of the bile acids were secreted into bile conjugated to taurine. Unconjugated bile acids and glycine conjugates accounted for 5-10% of the total biliary bile acids. Bile acid sulfates were present only in trace amounts indicating that quantitatively sulfation is not an important pathway in bile acid metabolism during development. Total biliary bile acid concentrations were low (0.1-0.4 mM) when compared to reported values for adult bile (greater than 10 mM). Chenodeoxycholic acid was the major biliary bile acid and exceeded cholic acid concentrations by 1.43-fold indicating either a relative immaturity in 12 alpha-hydroxylase activity during early life or a dominance of alternative pathways for chenodeoxycholic acid synthesis. A relatively large proportion of the biliary bile acids comprised metabolites not found in adult bile. The presence of relatively high proportions of hyocholic acid (often greater than cholic acid) and several 1 beta-hydroxycholanoic acid isomers indicates that C-1 and C-6 hydroxylation are important pathways in bile acid synthesis during development. We describe, for the first time, evidence for the existence of a C-4 hydroxylation pathway in the metabolism of bile acids, which may be unique to early human development. Mass spectrometry was used to confirm the identification of 3 alpha,4 beta,7 alpha-trihydroxy-5 beta-cholanoic and 3 alpha,4 beta-dihydroxy-5 beta-cholanoic acids. Quantitatively, these C-4 hydroxylated bile acids accounted for 5-15% of the total biliary bile acids of the fetus, suggesting that C-4 hydroxylation is quantitatively an important pathway in the bile acid metabolism during early life.

Bile↗
PubMed1988

Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis.

A new inborn error in bile acid synthesis, manifest in identical infant twins as severe intrahepatic cholestasis, is described involving the delta 4-3-oxosteroid 5 beta-reductase catalyzed conversion of the key intermediates, 7 alpha-hydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one for chenodeoxycholic and cholic acid synthesis, to the respective 3 alpha-hydroxy-5 beta (H) products. This defect was detected by fast atom bombardment ionization-mass spectrometry from an elevated excretion and predominance of taurine conjugated unsaturated hydroxy-oxo-bile acids. Gas chromatography-mass spectrometry confirmed these to be 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids (75-92% of total). Fasting serum bile acid concentrations were greater than 37 mumol/liter; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5 alpha-H)-bile acids (approximately 30%) were present. Biliary bile acid concentration was less than 2 mumol/liter and consisted of chenodeoxycholic, allo-chenodeoxycholic, and allo-cholic acids. These biochemical findings, which were identical in both infants, indicate a defect in bile acid synthesis involving the conversion of the delta 4-3-oxo-C27 intermediates into the corresponding 3 alpha-hydroxy-5 beta(H)-structures, a reaction that is catalyzed by a delta 4-3-oxosteroid-5 beta reductase enzyme. This defect resulted in markedly reduced primary bile acid synthesis and concomitant accumulation of delta 4-3-oxo-and allo-bile acids. These findings indicate a pathway in bile acid synthesis whereby side chain oxidation can occur despite incomplete alterations to the steroid nucleus, and lend support for an active delta 4-3-oxosteroid 5 alpha-reductase catalyzing the conversion of the delta 4-3-oxosteroid intermediates to the respective 3 alpha-hydroxy-5 alpha(H)-structures.

Bile Acids and Salts↗
PubMed1988

Veno-occlusive disease of the liver in captive cheetah.

Liver tissues from 126 captive cheetah were evaluated by light microscopy and histochemistry; eight animals were evaluated by electron microscopy. The main hepatic lesion, a vascular lesion resembling veno-occlusive disease (VOD) of the liver and characterized by subendothelial fibrosis and proliferation of smooth muscle-like cells in the central veins, was seen in 60% of the sexually mature cheetah. Although this hepatic vascular lesion was seen in cheetah as young as 1 year of age, the most severe lesions, usually associated with liver failure, were found in cheetah between the ages of 6 and 11. There was no sex predisposition, and in approximately 40% of the VOD cases, liver disease was not suspected clinically or at necropsy. VOD was found in other felidae, especially in the snow leopard. High levels of vitamin A in livers, as well as in diets of the cheetah, could be a contributing factor in the development of VOD in some groups of cheetah.

Acinonyx↗
PubMed1987

On the homogeneity of stools with respect to bile acid composition and normal day-to-day variations: a detailed qualitative and quantitative study using capillary column gas chromatography-mass spectrometry.

Fecal bile acid excretion was determined using recently developed techniques in order to investigate: the extent of the homogeneity in composition and concentration of individual bile acids in a single stool sample, the detailed qualitative and quantitative day-to-day variations in total and individual bile acids in the typical healthy adult, information on the relative proportions of conjugated bile acids in healthy stools, and inter-individual variations in fecal bile acid excretion. Bile acids were extracted from feces and separated into groups based upon their mode of conjugation using lipophilic gel chromatography, prior to analysis by capillary column gas chromatography-mass spectrometry. The majority of bile acids were excreted in the unconjugated form, while in all samples, conjugated bile acids accounted for less than 6% of the total fecal bile acids excreted, of which sulphated bile acids represented less than 3% of the total. Quantitative total and individual bile acid excretion, determined from single daily collections exhibited wide variations in values from day-to-day, and in accordance with early findings, indicates the need to use a minimum of 3- to 5-day collections for a more reliable index of bile acid excretion in feces. Examination of frozen and sectioned single stools revealed wide variations in water content and in quantitative bile acid concentration and composition within the stool. These data indicate random stool samples, which are commonly used in clinical studies, and data expressed as concentrations to be unsatisfactory for the accurate determination of fecal bile acid excretion.

Adult↗
PubMed1987

High-performance liquid chromatographic analysis of phytoestrogens in soy protein preparations with ultraviolet, electrochemical and thermospray mass spectrometric detection.

The phytoestrogens daidzein, genistein, coumestrol, formononetin, and Biochanin A are separated on a C18 reversed-phase column (Hypersil ODS) with methanol-0.1 M ammonium acetate buffer, pH 4.6 (60:40, v/v) as eluent. The retention and resolution are affected by buffer concentrations, pH type, and proportion of organic solvent in the mobile phase. Detection in the (low pg range) is achieved with an electrochemical detector, and the compounds are positively identified by high-performance liquid chromatography-thermospray mass spectrometry. Daidzein and genistein were found in high concentrations in all soy protein preparations analyzed.

Chromatography, High Pressure Liquid↗
PubMed1987

Rapid high-performance liquid chromatography assay for salivary and serum caffeine following an oral load. An indicator of liver function.

A rapid isocratic reversed-phase high-performance liquid chromatography (HPLC) system for the quantitative measurement of serum and salivary caffeine is described. The best separation of caffeine from other methylxanthines was achieved by chromatography on an ODS-Hypersil column using a solvent system of 0.1 M ammonium acetate pH 4.6-acetonitrile (85:15, v/v). The effluent was monitored at 280 nm. Caffeine was extracted from diluted serum and saliva samples (10-500 microliter) by adsorption on a small Bond-Elut C18 cartridge and recovered by elution with methanol. Thermospray HPLC-mass spectrometry conditions were optimized to afford a means of directly identifying caffeine in samples. The positive-ion mass spectrum was characterized by an intense protonated molecular ion, MH+, at m/z 195 and negligible fragmentation. When the mass spectrometer was operated in selected ion monitoring mode, caffeine could be detected in less than 1 microliter of serum and saliva at a concentration of 1 microgram/ml. Caffeine (3.5 mg/kg body wt.) was administered orally to healthy adults, children, and newborn infants, and to patients with liver disease. The clearance rate and half-life were determined as a test of liver function. A prolongation in the elimination of caffeine was observed in patients with liver disease and, although there was some overlap in the values obtained for patients with noncirrhotic liver disease and healthy persons, the oral caffeine load test may usefully serve as a dynamic assessment of liver function in the serial follow-up of patients with liver disease.

Adult↗
PubMed1987

Dietary estrogens--a probable cause of infertility and liver disease in captive cheetahs.

The cheetah in the wild is "racing towards extinction" mostly due to habitat destruction. Its survival will probably depend on accelerated captive breeding. At this time, however, reproductive failure and liver disease threaten the future of the captive cheetah population. Histopathological evaluation of more than 100 cheetah livers identified venocclusive disease as the main hepatic lesion responsible for liver disease in this species. Analysis of the commercial feline diet by high-performance liquid chromatography and gas-liquid chromatography-mass spectrometry revealed large amounts of two phytoestrogens identified as daidzein and genistein. These compounds were found to be derived from a soybean product that was a component of the cheetah diet, and their concentrations both ranged from 18 to 35 micrograms/g diet. The adult cheetah consequently consumes approximately 50 mg/day of these weak estrogens. When extracts of the diet were tested for estrogenicity using a bioassay, a dose-related increase in uterine weight was observed. In 4 cheetahs studied, withdrawal of this feline diet by substitution with a chicken diet resulted in an improvement in conventional liver function tests and a normalization in the appearance of hepatic mitochondria. We conclude that the relatively high concentrations of phytoestrogens from soybean protein present in the commercial diet fed to captive cheetahs in North American zoos may be one of the major factors in the decline of fertility and in the etiology of liver disease in this species. The survival of the captive cheetah population could depend upon a simple change of diet by excluding exogenous estrogen.

Acinonyx↗