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Abrahamsson A, Gåfvels M, Reihnér E, Björkhem I, Einarsson C, Eggertsen G. Polymorphism in the coding part of the sterol 12α‐hydroxylase gene does not explain the marked differences in the ratio of cholic acid and chenodeoxycholic acid in human bile. Scand J Clin Lab Invest 2009; 65:595-600. [PMID: 16271991 DOI: 10.1080/00365510500333684] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
OBJECTIVE In humans, two primary bile acids are synthesized: cholic acid (CA) and chenodeoxycholic acid (CDCA), the first and rate-limiting enzyme being cholesterol 7alpha-hydroxylase (CYP7A1). CA has one more hydroxyl group at position 12alpha. This hydroxylation is carried out by the sterol 12alpha-hydroxylase (CYP8B1). Earlier, we and others have noticed a marked variation in the ratio between CA and CDCA in human bile. The aim of this study was to investigate whether this marked difference could be due to a genetic polymorphism in the gene of the CYP8B1. MATERIAL AND METHODS Screening for genetic polymorphisms was carried out in a 2.4-kb-long area including the exon and part of the promoter region in subjects who had undergone cholecystectomy earlier, and where bile acid analysis had been performed. Among these subjects those with very high or low CA/CDCA ratios (ranging from 0.9 to 6.8) were investigated. The subjects were all female, normolipidaemic, having normal weight and a normal thyroid function. RESULTS No polymorphisms were found in the investigated sequence. However, a statistically significant correlation was found between the activity of the CYP7A1 and the ratio between CA and CDCA. The difference in ratio could, at least in part, be explained by the difference in rate of bile acid synthesis. CONCLUSION The difference in ratio between CA and CDCA cannot be explained by a polymorphism in the coding area of the CYP8B1.
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Affiliation(s)
- A Abrahamsson
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institute, Stockholm.
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2
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Kolovou GD, Kostakou PM, Anagnostopoulou KK, Cokkinos DV. Therapeutic effects of fibrates in postprandial lipemia. Am J Cardiovasc Drugs 2009; 8:243-55. [PMID: 18690758 DOI: 10.2165/00129784-200808040-00004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Hypertriglyceridemia is observed in many metabolic diseases such as the metabolic syndrome, diabetes mellitus, or mixed dyslipidemia frequently leading to premature coronary heart disease (CHD). Additionally, several studies have shown that postprandial hypertriglyceridemia is pronounced in patients with CHD, metabolic syndrome, hypertension, and other pathologic conditions. The triglyceride-rich lipoprotein remnants accumulating in the postprandial state seem to be involved in atherogenesis and in events leading to thrombosis. Since abnormal postprandial lipemia is associated with pathologic conditions, its treatment is of clinical importance.Fibrates are of significant help in managing hypertriglyceridemia. This review summarizes the effect of fibric acid derivatives on postprandial lipemia. Fibrates decrease the production of and enhance the catabolism of triglyceride-rich lipoproteins through the activation of peroxisome proliferator-activated receptor-alpha. Results of clinical studies with fibrates have confirmed their action in decreasing postprandial triglyceride levels by increasing lipoprotein lipase activity, decreasing apolipoprotein CIII production, and by increasing fatty acid oxidation in the liver.It is concluded that fibrates are effective agents in lowering the postprandial increase in remnant lipoprotein particles and retinyl palmitate. Furthermore, fibrates can also affect the postprandial lipid profile by increasing hepatic lipase levels and in some cases, by reducing cholesterol ester transfer protein activity. The main target of fibrate therapy is to improve fasting hypertriglyceridemia, which is an essential component associated with improving postprandial lipemia. Fibrates are well tolerated by patients and adverse effects have been reported rarely after their administration.
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Affiliation(s)
- Genovefa D Kolovou
- 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece.
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3
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Abstract
Gallstone disease is one of the most prevalent gastrointestinal diseases with a substantial burden to health care systems that is supposed to increase in ageing populations at risk. Aetiology and pathogenesis of cholesterol gallstones still are not well defined, and strategies for prevention and efficient nonsurgical therapies are missing. This review summarizes current concepts on the pathogenesis of cholesterol gallstones with focus on the uptake and secretion of biliary lipids and special emphasis on recent studies into the genetic background.
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Affiliation(s)
- H-U Marschall
- Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
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4
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Abstract
AIM: To further elucidate the pathogenesis and mechanisms of the high risk of gallstone formation in Crohn’s disease.
METHODS: Gallbladder bile was obtained from patients with Crohn’s disease who were admitted for elective surgery (17 with ileal/ileocolonic disease and 7 with Crohn’s colitis). Fourteen gallstone patients served as controls. Duodenal bile was obtained from ten healthy subjects before and after the treatment with ursodeoxycholic acid. Bile was analyzed for biliary lipids, bile acids, bilirubin, crystals, and crystal detection time (CDT). Cholesterol saturation index was calculated.
RESULTS: The biliary concentration of bilirubin was about 50% higher in patients with Crohn’s disease than in patients with cholesterol gallstones. Ten of the patients with Crohn’s disease involving ileum and three of those with Crohn’s colitis had cholesterol saturated bile. Four patients with ileal disease and one of those with colonic disease displayed cholesterol crystals in their bile. About 1/3 of the patients with Crohn’s disease had a short CDT. Treatment of healthy subjects with ursodeoxycholic acid did not increase the concentration of bilirubin in duodenal bile. Several patients with Crohn’s disease, with or without ileal resection/disease had gallbladder bile supersaturated with cholesterol and short CDT and contained cholesterol crystals. The biliary concentration of bilirubin was also increased in patients with Crohn’s colitis probably not due to bile acid malabsorption.
CONCLUSION: Several factors may be of importance for the high risk of developing gallstones of both cholesterol and pigment types in patients with Crohn’s disease.
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Affiliation(s)
- Annika Lapidus
- Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden
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Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, Peters JM. The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR). Toxicol Sci 2005; 90:269-95. [PMID: 16322072 DOI: 10.1093/toxsci/kfj062] [Citation(s) in RCA: 205] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors that modulate target gene expression in response to endogenous and exogenous ligands. Ligands for the PPARs have been widely developed for the treatment of various diseases including dyslipidemias and diabetes. While targeting selective receptor activation is an established therapeutic approach for the treatment of various diseases, a variety of toxicities are known to occur in response to ligand administration. Whether PPAR ligands produce toxicity via a receptor-dependent and/or off-target-mediated mechanism(s) is not always known. Extrapolation of data derived from animal models and/or in vitro models, to humans, is also questionable. The different toxicities and mechanisms associated with administration of ligands for the three PPARs will be discussed, and important data gaps that could increase our current understanding of how PPAR ligands lead to toxicity will be highlighted.
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Affiliation(s)
- Marjorie A Peraza
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
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6
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Nowak G, Norén UG, Wernerson A, Marschall HU, Möller L, Ericzon BG. Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats. Transpl Int 2005; 17:804-9. [PMID: 15815896 DOI: 10.1007/s00147-004-0703-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2003] [Revised: 09/30/2003] [Accepted: 10/20/2003] [Indexed: 10/25/2022]
Abstract
Liver donor pre-treatment with ursodeoxycholic acid (UDCA) may protect against injury during transplantation. In the present study we evaluated whether enteral administration of UDCA has an effect on bile flow and protects the liver from injury related to transplantation. Wistar rats were used in liver perfusion (LP) and transplantation (LTx) models. Rats were enterally administered UDCA (800 mg/kg) 3 h before cold perfusion. In LP, bile flow and bile acid composition were analysed. In LTx, serum ALT and liver histology were analysed. LP showed biliary UDCA enrichment up to 36+/-13% in pre-treated rats, causing higher bile flow (P = 0.026) compared with control rats. LTx showed lower ALT and TUNEL positive hepatocytes in the UDCA group (P < 0.02 and P < 0.05). In conclusion, augmented bile salt-dependent bile flow is preserved in the liver after cold storage. Enteral donor pre-treatment with UDCA protects the liver against ischaemia-reperfusion injury.
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Affiliation(s)
- Grzegorz Nowak
- Department of Transplantation Surgery, Karolinska Institute, Huddinge University Hospital B56, 141 86 Stockholm, Sweden.
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7
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Nowak G, Noren UG, Wernerson A, Marschall HU, Moller L, Ericzon BG. Enteral donor pre-treatment with ursodeoxycholic acid protects the liver against ischaemia-reperfusion injury in rats. Transpl Int 2004. [DOI: 10.1111/j.1432-2277.2004.tb00514.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Du L, Xu Y, Musson DG. Simultaneous determination of clofibrate and its active metabolite clofibric acid in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet absorbance detection. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 794:343-51. [PMID: 12954386 DOI: 10.1016/s1570-0232(03)00500-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A reversed-phase high-performance liquid chromatographic (HPLC) using ultraviolet (UV) absorbance detection method for simultaneous determination of clofibrate (I) and its major metabolite clofibric acid (II) in human plasma has been developed to support a clinical study. I, II and internal standard (I.S., III) are isolated from human plasma by 96-well solid-phase extraction (SPE) C(18)z.ccirf;AR plate and quantified by direct injection of the SPE eluent onto the HPLC with UV detection wavelength at 230 nm. Two chromatographic methods, isocratic and step gradient, have been validated from 1.0 to 100.0 microg/ml and successfully applied to plasma sample analysis for a clinical study. The lower limit of quantitation (LLOQ) is 1.0 microg/ml for both I and II when 500 microl plasma sample is processed. Sample collection and preparation is conducted at 5 degrees C to minimize the hydrolysis of I to II in human plasma.
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Affiliation(s)
- Lihong Du
- Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486, USA.
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9
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Gustafsson U, Sahlin S, Einarsson C. High level of deoxycholic acid in human bile does not promote cholesterol gallstone formation. World J Gastroenterol 2003; 9:1576-9. [PMID: 12854167 PMCID: PMC4615508 DOI: 10.3748/wjg.v9.i7.1576] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study whether patients with excess deoxycholic acid (DCA) differ from those with normal percentage of DCA with respect to biliary lipid composition and cholesterol saturation of gallbladder bile.
METHODS: Bile was collected during operation through puncturing into the gallbladder from 122 cholesterol gallstone patients and 46 gallstone-free subjects undergoing cholecystectomy. Clinical data, biliary lipids, bile acid composition, presence of crystals and nucleation time were analyzed.
RESULTS: A subgroup of gallstone patients displayed a higher proportion of DCA in bile than gallstone free subjects. By choosing a cut-off level of the 90th percentile, a group of 13 gallstone patients with high DCA levels (mean 50 percent of total bile acids) and a large group of 109 patients with normal DCA levels (mean 21 percent of total bile acids) were obtained. The mean age of the patients with high DCA levels was higher than that of the group with normal levels (mean age: 62 years vs 45 years) and so was the mean BMI (28.3 vs 24.7). Plasma levels of cholesterol and triglycerides were slightly higher in the DCA excess groups compared with those in the normal DCA group. There was no difference in biliary lipid composition, cholesterol saturation, nucleation time or occurrence of cholesterol crystals in bile between patients with high and normal levels of DCA.
CONCLUSION: Gallstone patients with excess DCA were of older age and had higher BMI than patients with normal DCA. The two groups of patients did not differ with respect to biliary lipid composition, cholesterol saturation, nucleation time or occurrence of cholesterol crystals. It is concluded that DCA in bile does not seem to contribute to gallstone formation in cholesterol gallstone patients.
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Affiliation(s)
- Ulf Gustafsson
- Department of Surgery, Danderyd Hospital, Stockholm, Sweden
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Hillebrant CG, Nyberg B, Gustafsson U, Sahlin S, Björkhem I, Rudling M, Einarsson C. Effects of combined treatment with pravastatin and ursodeoxycholic acid on hepatic cholesterol metabolism. Eur J Clin Invest 2002; 32:528-34. [PMID: 12153554 DOI: 10.1046/j.1365-2362.2002.01015.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Treatment with ursodeoxycholic acid and also, to some degree, statins reduces cholesterol saturation of bile. The present study aimed [1] to study the effects of combined treatment with ursodeoxycholic acid and pravastatin on hepatic cholesterol metabolism and [2] to evaluate if the addition of pravastatin to ursodeoxycholic acid treatment has beneficial effects on the lipid composition of gallbladder bile in gallstone patients. MATERIALS AND METHODS Nineteen patients with cholesterol gallstones were subjected to combined treatment with ursodeoxycholic acid (500 mg bid) and pravastatin (20 mg bid) for three weeks before cholecystectomy. Eleven patients received ursodeoxycholic acid only and 20 untreated gallstone patients served as controls. Gallbladder bile was collected, and for both the patients receiving combined treatment and the controls a liver biopsy was also obtained peroperatively. RESULTS The cholesterol saturation of bile averaged 59% in the patients on combined treatment, 60% in the ursodeoxycholic acid-treated patients, and 130% in the untreated controls. In the patients receiving ursodeoxycholic acid, this bile salt constituted approximately 60% of all bile salts. The patients receiving combined treatment had reduced cholesterol synthesis, as reflected by a 45% reduction in serum lathosterol. The activity and the mRNA levels of cholesterol 7 alpha-hydroxylase and the mRNA levels for the low density lipoprotein-receptor were not significantly affected. CONCLUSIONS Pravastatin does not further reduce the cholesterol saturation of bile in gallstone patients treated with ursodeoxycholic acid, although hepatic cholesterol synthesis is inhibited. The study supports the important concept that de novo synthesized cholesterol is not particularly important for biliary cholesterol secretion in humans.
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Affiliation(s)
- C-G Hillebrant
- Karoliniska Institutet, Huddinge University Hospital, Stockholm, Sweden
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Gustafsson U, Sahlin S, Einarsson C. Biliary lipid composition in patients with cholesterol and pigment gallstones and gallstone-free subjects: deoxycholic acid does not contribute to formation of cholesterol gallstones. Eur J Clin Invest 2000; 30:1099-106. [PMID: 11122325 DOI: 10.1046/j.1365-2362.2000.00740.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Four main disturbances have been attributed to cholesterol gallstone disease: hypersecretion of cholesterol from the liver with cholesterol supersaturation in bile; disturbed motility with defective absorption and secretion by the gallbladder; increased crystallisation of cholesterol in the gallbladder bile; and slow intestinal transit with increased amount of deoxycholic acid in the bile acid pool. We aimed to evaluate the biliary lipid composition in a large series of gallstone patients, with emphasis on the amount of deoxycholic acid and with respect to number of stones, compared to gallstone free subjects. MATERIALS AND METHODS Bile was sampled during operations through puncture of the gallbladder from 145 cholesterol gallstone patients, 23 patients with pigment stones and 87 gallstone free patients undergoing cholecystectomy. Biliary lipid composition, cholesterol saturation, bile acid composition, nucleation time and cholesterol crystals were analysed. RESULTS The patients with cholesterol gallstones showed higher molar percentage of cholesterol, lower total biliary lipid concentration, higher cholesterol saturation, shorter nucleation time and higher proportion of crystals in bile than the other groups. The nucleation time was significantly shorter in multiple cholesterol gallstone patients, but this was not due to higher cholesterol saturation. Male cholesterol gallstone patients showed higher cholesterol levels, lower total biliary lipid concentration, and higher cholesterol saturation in bile than female patients. There was no difference in biliary content of deoxycholic acid, but significantly lower content of cholic acid in gallstone patients compared to gallstone free patients. CONCLUSIONS We conclude that deoxycholic acid does not contribute to gallstone formation in cholesterol gallstone patients. The short nucleation time in patients with multiple cholesterol stones is not due to higher cholesterol saturation.
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12
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Howard WR, Pospisil JA, Njolito E, Noonan DJ. Catabolites of cholesterol synthesis pathways and forskolin as activators of the farnesoid X-activated nuclear receptor. Toxicol Appl Pharmacol 2000; 163:195-202. [PMID: 10698678 DOI: 10.1006/taap.1999.8869] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The nuclear receptors are a family of transcriptional mediators that, upon activation, bind DNA and regulate gene transcription. Among these receptors, the farnesoid X-activated receptor (FXR) has recently been identified as one activated by bile acids and farnesol. To investigate the potential of other sterols to activate FXR, as well as to examine relevant relationships among identified activators of FXR, the current study used a mammalian cell transcription assay to quantify and compare activation potential. In addition to the classical bile acids deoxycholate (DCA) and chenodeoxycholate (CDCA), FXR was shown to be transcriptionally active in the presence of the androgen catabolites 5alpha-androstan-3alpha-ol-17-one (androsterone) and 5beta-androstan-3alpha-ol-17-one (etiocholanolone), as well as the sterol bronchodilatory drug forskolin. Conversely, cholesterol and several other key precursors to the androgens and bile acids were either not active or only slightly active. Furthermore, it was observed that the bile acid ursodeoxycholate (UDCA) could inhibit DCA and CDCA activation of FXR in a manner parallel to its ability to antagonize DCA and CDCA induction of apoptosis. By far, the most efficacious activator of FXR was forskolin. Interestingly, although it is classically viewed as an initiator of the adenylate cyclase/protein kinase A (PKA) pathway, PKA inhibition did not inhibit forskolin's activation of FXR nor was cyclic AMP (cAMP) able to stimulate FXR-mediated transcription. These data would suggest that forskolin acts as a ligand for FXR rather than as a secondary activator of FXR and could have important implications with respect to its potential toxicity and pharmacological use.
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Affiliation(s)
- W R Howard
- Department of Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0084, USA
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13
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Hillebrant C, Nyberg B, Angelin B, Axelson M, Björkhem I, Rudling M, Einarsson C. Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity. J Intern Med 1999; 246:399-407. [PMID: 10583711 DOI: 10.1046/j.1365-2796.1999.00572.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
UNLABELLED Hillebrant C-G, Nyberg B, Angelin B, Axelson M, Björkhem I, Rudling M, Einarsson C (Huddinge University Hospital and Karolinska Hospital, Karolinska Institute, Stockholm, Sweden). Deoxycholic acid treatment in patients with cholesterol gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase activity. J Intern Med 1999; 246: 399-407. OBJECTIVES Based on animal studies, hydrophobic bile acids have been postulated to be particularly strong inhibitors of bile acid synthesis. The present study was undertaken to characterize in humans the effects of one of the most hydrophobic of the common bile acids, deoxycholic acid (DCA), on the transcriptional regulation and activity of the cholesterol 7alpha-hydroxylase, on hepatic cholesterol metabolism and on biliary lipid metabolism and plasma lipids. DESIGN, SUBJECTS AND SETTINGS: Thirteen patients with cholesterol gallstone disease were treated with DCA (750 mg day-1) for 3 weeks prior to cholecystectomy. Blood samples were collected before and during treatment. At operation, a liver biopsy and gallbladder bile were obtained. Twenty-eight untreated gallstone patients undergoing cholecystectomy served as controls. The study was carried out at a university hospital. RESULTS Deoxycholic acid comprised 72 +/- 6% (mean +/- SEM) of total biliary bile acids in DCA-treated patients (n = 8), and 21 +/- 2% in the controls (n = 16; P < 0.001). Cholesterol saturation of gallbladder bile averaged 102% in both treated (n = 7) and untreated (n = 16) patients. Cholesterol 7alpha-hydroxylase and HMG CoA reductase activities and mRNA levels were not different between DCA-treated and untreated gallstone patients. The LDL receptor mRNA levels were similar in both groups of patients. Plasma levels of total cholesterol were lowered by 10% upon DCA treatment (P < 0.05). CONCLUSIONS Treatment with DCA did not significantly affect mRNA levels and activity of hepatic cholesterol 7alpha-hydroxylase or HMG CoA reductase in patients with cholesterol gallstones. There was no effect on the saturation of gallbladder bile, Thus, the present study could not verify that the hydrophobicity of the bile acid pool is a major factor regulating human hepatic cholesterol 7alpha-hydroxylase activity.
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Affiliation(s)
- C Hillebrant
- Department of Gastroenterology, Huddinge University Hospital, Sweden
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14
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Abstract
Patients with Crohn's disease (CD) have an increased risk of developing gallstones, but the mechanisms are unknown. In a previous study, we found a subnormal cholesterol saturation in the bile of patients with short ileal resections due to CD. The aim of this study was to test the hypothesis that (a) CD patients with a long ileal resection have an altered biliary composition and (b) that CD patients with short or long ileal resection have an increased content of bilirubin in their bile. Biliary lipid composition, cholesterol saturation, bile acid pattern, and bilirubin concentration were determined in fasting duodenal bile of 10 CD patients with long ileal resections and in 4 patients with short resections. Ten healthy subjects served as controls. Cholesterol saturation was significantly lower in those CD patients who had a long or short resection compared with the healthy subjects. Bile acid composition in the CD patients was characterized by a significant decrease in the deoxycholic acid fraction and a prominent increase in the ursodeoxycholic acid fraction. The bilirubin concentrations, expressed as micromoles of bilirubin per millimole bile acid, were 45-50% higher in patients who had a long or a short ileal resection compared with healthy controls. Based on these results, CD patients who had had an ileal resection seem not to be at an increased risk of cholesterol gallstone formation but rather at risk of developing pigment stones.
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Affiliation(s)
- A Lapidus
- Department of Gastroenterology and Hepatology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden
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15
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Tazuma S, Yamashita G, Ochi H, Miura H, Kajihara T, Hattori Y, Miyake H, Nishioka T, Hyogo H, Sunami Y, Yasumiba S, Kajiyama G. Effects of cerivastatin sodium, a new HMG-CoA reductase inhibitor, on biliary lipid metabolism in patients with hypercholesterolemia. Clin Ther 1998; 20:477-85. [PMID: 9663363 DOI: 10.1016/s0149-2918(98)80057-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has become common in the treatment of hypercholesterolemia. The present uncontrolled study was undertaken to determine the effect of cerivastatin sodium (BAY w 6228), a new HMG-CoA reductase inhibitor, on biliary lipid levels in patients with hypercholesterolemia. Twenty-one hypercholesterolemic patients (World Health Organization type IIa = 16 patients; type IIb = 5 patients) received placebo during a 4- to 6-week observation period, after which they received cerivastatin sodium 0.2 mg/d for 12 weeks. Fasting blood samples were drawn for the measurement of serum lipid levels early in the morning before the start of treatment and once a month for each of the 12 weeks of cerivastatin sodium treatment. Gallbladder bile samples were aspirated with a duodenal tube by cerulein stimulation to assess bile lithogenicity. Serum total cholesterol levels decreased markedly after 12 weeks. However, no significant difference was found in the molar percentage composition of biliary lipids (e.g., cholesterol, phospholipids, and total bile acids) or in individual biliary bile acids. Consequently, no significant change in bile cholesterol saturation index was found. The index values before and after 12 weeks of treatment were 0.81 +/- 0.38 and 0.80 +/- 0.47, respectively, whereas when patients were grouped by type of hypercholesterolemia, there was a tendency toward decreased lithogenicity in patients with type IIb but not type IIa hypercholesterolemia. We concluded that cerivastatin sodium was an effective cholesterol-lowering drug that did not appear to worsen biliary lipid metabolism and that may decrease lithogenicity in patients with type IIb hypercholesterolemia.
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Affiliation(s)
- S Tazuma
- First Department of Internal Medicine, Hiroshima University School of Medicine, Japan
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16
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Ericzon BG, Eusufzai S, Söderdahl G, Duraj F, Einarsson K, Angelin B. Secretion and composition of bile after human liver transplantation: studies on the effects of cyclosporine and tacrolimus. Transplantation 1997; 63:74-80. [PMID: 9000664 DOI: 10.1097/00007890-199701150-00014] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cyclosporine (CsA) and tacrolimus (FK506) have recently been reported to inhibit canalicular transport of bile acids in vitro and thereby possibly induce cholestasis. A relative reduction of chenodeoxycholic acid (CDCA) has been observed after liver transplantation when CsA is used as immunosuppressant. We tested the hypothesis that CsA induces cholestasis and reduces CDCA secretion as compared with treatment with monoclonal antibodies (OKT3), and that CsA differs from FK506 with regard to its effects on biliary lipid secretion. Bile flow, biliary lipid secretion rates, and biliary bile acid composition were determined during the first 10 days after transplantation in 29 liver transplant recipients. Two prospective randomized studies were performed that compared CsA and OKT3 and compared CsA- and FK506-based regimens. In study 1, bile acid output averaged 0.75+/-0.15 micromol/min in the CsA I group and 0.54+/-0.11 micromol/min in the OKT3 group on postoperative day 1. Bile flow and bile acid output then increased, and there was no significant difference between the two groups. The relative proportion of CDCA decreased to the same extent in both groups. In study 2, mean bile acid outputs on postoperative day 1 were 0.57+/-0.26 micromol/min and 0.55+/-0.15 micromol/min in the CsA 2 and FK506 groups, respectively. The following increase in bile acid secretion was significantly larger in the FK506 group. After transplantation, the relative proportion of CDCA decreased with time in both groups, but the reduction was more rapid in the FK506 group. In conclusion, CsA did not inhibit bile secretion during short-term treatment after liver transplantation. Compared with patients given CsA-based treatment, patients with FK506-based treatment recovered bile secretion more rapidly.
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Affiliation(s)
- B G Ericzon
- Department of Transplantation Surgery, Huddinge University Hospital, Sweden
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Abstract
AIMS/METHODS Bile acid kinetics and biliary lipid composition were studied in seven patients, aged 17-70 years with cystic fibrosis. All patients were of normal height and weight, and were in good clinical condition. Ultrasonography indicated a small gallbladder in one and non-visualized gallbladder in two patients. Serum concentrations of cholesterol and transaminases were essentially normal. Substitution with pancreatic enzymes was discontinued at least 1 week before the investigation. Bile acid kinetics were determined by the isotope dilution technique using [24-14C] cholic and [24-14C] chenodeoxycholic acids. RESULTS The mean pool size of cholic acid was 3.3 (range 0.8-6.9) mmol, and that of chenodeoxycholic acid 2.3 (1.2-2.7) mmol, corresponding to 49 +/- 16 and 36 +/- 4 mumol/kg, respectively. The mean synthesis of cholic acid was 1.3 (0.5-3.6) mmol/day and of chenodeoxycholic acid 0.8 (0.2-1.7) mmol/ day and related to body weight 20 +/- 6 and 12 +/- 3 mumol.kg.day-1, respectively. Fractional turnover rates averaged 0.48 (0.24-0.67) and 0.36 (0.10-0.65) day-1, respectively. The kinetic values were not significantly different from controls, aged 21 to 68 years. The biliary lipid composition of fasting gallbladder bile showed a low-normal molar percentage of cholesterol, and in no case was bile supersaturated. The duodenal bile acid concentration was similar in patients and controls, but the bile acid distribution was significantly different; cholic acid constituted a higher percentage (p < 0.001) and chenodeoxycholic and deoxycholic acid lower percentages (p < 0.05 and p < 0.01, respectively) in cystic fibrosis patients than in controls. CONCLUSIONS The findings of normal concentrations of bile acids in duodenal bile and normal to large pool sizes of bile acids in all patients, despite a marked fat malabsorption, are in contrast to some previous reports. The data indicate that biliary lipid metabolism is normal in well-nourished and well-controlled adult patients with cystic fibrosis.
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Affiliation(s)
- B Strandvik
- Department of Pediatrics, Faculty of Medicine, Göteborg University, Sweden
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18
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Rodrigues CM, Kren BT, Steer CJ, Setchell KD. Formation of delta 22-bile acids in rats is not gender specific and occurs in the peroxisome. J Lipid Res 1996. [DOI: 10.1016/s0022-2275(20)37597-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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19
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Ståhlberg D, Reihnér E, Rudling M, Berglund L, Einarsson K, Angelin B. Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: reduced activity of cholesterol 7 alpha-hydroxylase. Hepatology 1995; 21:1025-30. [PMID: 7705775 DOI: 10.1002/hep.1840210421] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Bezafibrate is a hypolipidemic fibric acid derivative known to induce cholesterol supersaturation of bile. To characterize its effects on hepatic cholesterol metabolism, 31 normolipidemic, normal-weight patients with gallstones undergoing cholecystectomy were studied. Eleven patients (5 men) were randomized to treatment with bezafibrate, 200 mg three times daily for 4 weeks before operation; the remaining 20 patients (5 men) served as nontreatment controls. At operation, a liver biopsy specimen was obtained under standardized conditions and several important parameters of cholesterol metabolism were assayed. Bezafibrate treatment lowered total plasma cholesterol and triglycerides 30% and 37%, respectively. The hepatic cholesterol 7 alpha-hydroxylase activity was reduced by approximately 60% in the bezafibrate treated patients compared with the controls, whereas the acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity was similar in the two groups. The total 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity was increased twofold in the treated patients, whereas the active enzyme remained about the same as in the controls. The low-density lipoprotein (LDL) receptor binding activity was unaffected by the treatment. Bezafibrate treatment significantly reduces cholesterol 7 alpha-hydroxylase activity, and it is suggested that this may play an important role for the development of supersaturated bile during such therapy.
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Affiliation(s)
- D Ståhlberg
- Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Sweden
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20
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Akerlund JE, Björkhem I, Angelin B, Liljeqvist L, Einarsson K. Apparent selective bile acid malabsorption as a consequence of ileal exclusion: effects on bile acid, cholesterol, and lipoprotein metabolism. Gut 1994; 35:1116-20. [PMID: 7926917 PMCID: PMC1375066 DOI: 10.1136/gut.35.8.1116] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
A new model has been developed to characterise the effect of a standardised ileal exclusion on bile acid, cholesterol, and lipoprotein metabolism in humans. Twelve patients treated by colectomy and ileostomy for ulcerative colitis were studied on two occasions: firstly with a conventional ileostomy and then three months afterwards with an ileal pouch operation with an ileoanal anastomosis and a protective loop ileostomy, excluding on average 95 cm of the distal ileum. The ileostomy contents were collected during 96 hours and the excretion of bile acids and cholesterol was determined using gas chromatography-mass spectrometry. Fasting blood and duodenal bile samples were collected on two consecutive days. After the exclusion of the distal ileum, both cholic and chenodeoxycholic acid excretion in the ileostomy effluent increased four to five times without any change in cholesterol excretion. Serum concentrations of lathosterol (a marker of cholesterol biosynthesis) and 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) were increased several fold. Plasma concentrations of total VLDL triglycerides were also increased whereas the concentrations of total and LDL cholesterol, and apolipoprotein B were decreased. There were no changes in biliary lipid composition or cholesterol saturation of bile. The results show that the exclusion of about 95 cm of distal ileum causes malabsorption of bile acids but apparently not of cholesterol. The bile acid malabsorption leads to increased synthesis of both bile acids and cholesterol in the liver. It is suggested that bile acids can regulate cholesterol synthesis by a mechanism independent of the effect of bile acids on cholesterol absorption. The enhanced demand for cholesterol also leads to a decrease in plasma LDL cholesterol and apolipoprotein B concentrations. The malabsorption of bile acids did not affect biliary lipid composition or cholesterol saturations of VLDL triglycerides.
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Affiliation(s)
- J E Akerlund
- Department of Surgery, Karolinska Institute at Huddinge University Hospital, Sweden
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21
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22
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Holland RE, Rahman K, Morris AI, Coleman R, Billington D. Effects of niacin on biliary lipid output in the rat. Biochem Pharmacol 1993; 45:43-9. [PMID: 8424822 DOI: 10.1016/0006-2952(93)90375-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The mechanisms for the hypocholesterolaemic action of niacin (nicotinic acid) were examined in rats administered niacin at a dose of 400 mg/kg body wt/day for either 2 or 4 weeks. Another group of rats were administered diosgenin, an inhibitor of acyl-CoA:cholesterol acyltransferase, as a 1% (w/w) supplement in the diet for 7 days. Both agents produced small increases in bile flow rates (up to 40%) and mild hepatotoxicity evidenced by small increases in serum transaminase activities. Niacin treatment for 2 or 4 weeks lowered serum cholesterol concentrations by 13% or 29%, respectively, with the greatest decrease occurring in the low density lipoprotein fraction. This was accompanied by relatively large increases in biliary cholesterol output (114% and 130% after 2 and 4 weeks treatment, respectively) with smaller increases in the biliary output of phospholipid (18% and 45%) and bile acid (26% and 14%). Diosgenin treatment increased serum cholesterol by 29% and increased the biliary output of cholesterol, phospholipid and bile acid by 800%, 10% and 45%, respectively. Thus, both agents increased the cholesterol saturation of bile (100% by niacin, 500% by diosgenin). Cholesterol and phospholipid in fistula bile from control rats were present in lamellar and micellar forms. Niacin treatment did not alter the physical form of biliary lipids whilst diosgenin caused the appearance of vesicular lipid in fistula bile. Thus, increased biliary secretion of cholesterol explains, at least in part, the hypocholesterolaemic action of niacin. In addition, since aggregation of biliary vesicles is involved in cholesterol gallstone formation in humans, the non-appearance of vesicular material in fistula bile from niacin-treated rats may be of some importance.
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Affiliation(s)
- R E Holland
- School of Biomolecular Sciences, Liverpool John Moores University, U.K
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23
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Angelin B, Olivecrona H, Reihnér E, Rudling M, Ståhlberg D, Eriksson M, Ewerth S, Henriksson P, Einarsson K. Hepatic cholesterol metabolism in estrogen-treated men. Gastroenterology 1992; 103:1657-63. [PMID: 1426886 DOI: 10.1016/0016-5085(92)91192-7] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase], bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men.
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Affiliation(s)
- B Angelin
- Department of Medicine, Karolinska Institute, Huddinge University Hospital, Sweden
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24
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Sirtori CR, Calabresi L, Werba JP, Franceschini G. Tolerability of fibric acids. Comparative data and biochemical bases. Pharmacol Res 1992; 26:243-60. [PMID: 1437989 DOI: 10.1016/1043-6618(92)90212-t] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Fibric acids are an established class of drugs for the treatment of hyperlipoproteinaemias. Although they have been in use for 30 years or longer, some doubts remain as to their relative tolerability, both as a class and as single agents. Some side effects, e.g. lithogenicity, may be related to their mode of action, while others, e.g. the acute muscular syndrome, may be linked to the spatial conformation of the molecule. These disadvantages should, however, be weighed against the additional, potentially therapeutic properties shown by these compounds. In particular, effects on maturity onset diabetes and hyperuricaemia, as well as a very interesting fibrinolytic potential, have been described for some of them. A painstaking comparative analysis of the major literature data pertaining to the clinical toxicological profile of these agents allow to conclude that, while belonging to a chemical class, fibric acids show dramatic differences from one another, in terms of side effects and of additional pharmacodynamic activities. Moreover, in the case of lithogenicity for example, considerable differences exist between normo- and hyperlipidaemic subjects. Overall, newer molecules of more sophisticated design have a significantly improved tolerability profile vs the old clofibrate.
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Affiliation(s)
- C R Sirtori
- Center E. Grossi Paoletti, University of Milano, Italy
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25
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Sahlin S, Ahlberg J, Reihnér E, Ståhlberg D, Einarsson K. Cholesterol metabolism in human gallbladder mucosa: relationship to cholesterol gallstone disease and effects of chenodeoxycholic acid and ursodeoxycholic acid treatment. Hepatology 1992; 16:320-6. [PMID: 1639340 DOI: 10.1002/hep.1840160207] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The objective of this study was to investigate cholesterol metabolism in human gallbladder mucosa, especially in relation to hepatic cholesterol metabolism, gallstone disease and treatment with bile acids. Gallbladder mucosa and liver tissue samples were collected in 44 patients undergoing cholecystectomy; 30 had cholesterol gallstones and the rest were stone free. Ten of the gallstone patients were treated with chenodeoxycholic acid and eight received ursodeoxycholic acid, with a daily dose of 15 mg/kg body wt, for 3 wk before surgery. The 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, governing cholesterol synthesis, was considerably lower in the gallbladder mucosa than in liver tissue (28 +/- 6 and 120 +/- 40 pmol/min/mg protein). The acyl coenzyme A:acyltransferase activity in the gallbladder mucosa catalyzing the esterification of cholesterol was, on the other hand, several times higher than corresponding activity in the liver (92 +/- 23 and 11 +/- 2 pmol/min/mg protein). In the presence of exogenous cholesterol, the acyl coenzyme A:acyltransferase activity increased about twofold in the gallbladder mucosa. The acyl coenzyme A:acyltransferase activity of the gallbladder mucosa from untreated gallstone patients was not stimulated further by the addition of exogenous cholesterol. Otherwise, there were no significant differences in acyl coenzyme A:acyltransferase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities in the gallbladder mucosa of gallstone patients compared with gallstone-free controls. Treatment with chenodeoxycholic and ursodeoxycholic acids did not affect the 3-hydroxy-3-methylglutaryl coenzyme A reductase activity of the gallbladder mucosa but reduced the acyl coenzyme A:acyltransferase activity by 60% to 65%.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S Sahlin
- Department of Surgery, Danderyd Hospital, Sweden
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26
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Lapidus A, Einarsson K. Effects of ileal resection on biliary lipids and bile acid composition in patients with Crohn's disease. Gut 1991; 32:1488-91. [PMID: 1773954 PMCID: PMC1379248 DOI: 10.1136/gut.32.12.1488] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biliary lipid composition, cholesterol saturation, and bile acid pattern were determined in fasting duodenal bile of 10 patients (four men and six women, mean age 41 years) with Crohn's disease and a history of ileal resection (mean 64 cm). The data were compared with corresponding values in a group of healthy subjects. None of the patients with Crohn's disease had supersaturated bile. Cholesterol saturation was significantly lower in the patients with Crohn's disease than in the healthy subjects. The molar percentage of cholesterol was also lower among the patients but there was no significant difference. The molar percentages of phospholipids and bile acids were normal. Bile acid composition in the patients with ileal resection was characterised by a significant decrease in the deoxycholic acid fraction and a pronounced increase in the ursodeoxycholic acid fraction compared with the healthy subjects. The surprisingly high percentage of ursodeoxycholic acid may contribute to the low degree of cholesterol saturation in bile. Based on these results patients with Crohn's disease should not have an increased risk of cholesterol gall stone formation.
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Affiliation(s)
- A Lapidus
- Department of Medicine, Karolinska Instituet at Huddinge University Hospital, Sweden
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27
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Sahlin S, Ahlberg J, Angelin B, Reihnér E, Einarsson K. Nucleation time of gall bladder bile in gall stone patients: influence of bile acid treatment. Gut 1991; 32:1554-7. [PMID: 1773966 PMCID: PMC1379262 DOI: 10.1136/gut.32.12.1554] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The time required for precipitation of cholesterol crystals (nucleation time, NT) was determined and related to the cholesterol saturation in gall bladder bile of gall stone free subjects (n = 11), patients with pigment stones (n = 3), and patients with cholesterol gall stones (n = 30) undergoing cholecystectomy. Seven of the gall stone patients had been treated with chenodeoxycholic acid (CDCA) and nine with ursodeoxycholic acid (UDCA), 15 mg/kg/day for three weeks before operation. NT was longer in gall stone free subjects (mean, 20 days), patients with pigment stones (14 days) and patients treated with CDCA (24 days) and UDCA (17 days) compared with untreated patients with cholesterol gall stones (1.5 days). In spite of low cholesterol saturation and prolonged NT, and in contrast to those treated with CDCA, four of the nine patients treated with UDCA had cholesterol crystals in their bile. These observations give further support to the concept that the mechanism for inducing gall stone dissolution may be different for CDCA and UDCA.
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Affiliation(s)
- S Sahlin
- Department of Surgery, Karolinska Institute, Danderyd Hospital, Sweden
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28
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Odman B, Ericsson S, Lindmark M, Berglund L, Angelin B. Gemfibrozil in familial combined hyperlipidaemia: effect of added low-dose cholestyramine on plasma and biliary lipids. Eur J Clin Invest 1991; 21:344-9. [PMID: 1909637 DOI: 10.1111/j.1365-2362.1991.tb01380.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Gemfibrozil is frequently used for lipid-lowering in familial combined hyperlipidaemia (FCHL) and in other forms of combined hyperlipidaemia. This therapy increases biliary cholesterol saturation, enhancing the risk for gallstone formation. Furthermore, in hypertriglyceridaemia, LDL cholesterol levels often tend to rise. We have explored the possibility that addition of a low dose of cholestyramine to gemfibrozil therapy obliterates these phenomena. Eighteen gallstone-free patients with definite (n = 5) or probable (n = 10) FCHL, or combined hyperlipoproteinaemia (n = 3) were randomized to a 6 week treatment with gemfibrozil, 600 mg b.i.d., or gemfibrozil 600 mg b.i.d. plus 4 g cholestyramine o.d. After 6 weeks the patients were crossed over to the alternative treatment. Plasma lipoproteins and biliary lipids were determined at baseline and at the end of each period. Institution of gemfibrozil treatment resulted in a decrease in plasma cholesterol by 15% (P less than 0.05) and in plasma triglycerides by 47% (P less than 0.05); HDL cholesterol increased by 18% (P less than 0.05). Addition of cholestyramine further decreased plasma and LDL total cholesterol by 9% (P less than 0.05). Total triglycerides and HDL cholesterol did not change. Gemfibrozil treatment was associated with a rise in the relative biliary concentration of cholesterol from 5.6 +/- 0.4 to 6.9 +/- 0.5 molar percent (P less than 0.01), and a parallel decrease in the relative concentration of bile acids, resulting in an increased cholesterol saturation of the bile, from 77 +/- 5 to 90 +/- 6% (P less than 0.05). This change was not observed during the combined therapy (mean cholesterol saturation, 82 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- B Odman
- Department of Medicine, Karolinska Institute, Huddinge University Hospital, Sweden
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Horiuchi I, Ohya T, Tazuma S, Mizuno T, Takizawa I, Kajiyama G. Effects of pravastatin (CS-514) on biliary lipid metabolism in patients with hyperlipidemia. Metabolism 1991; 40:226-30. [PMID: 1900342 DOI: 10.1016/0026-0495(91)90101-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Pravastatin was administered to 20 patients with hyperlipidemia type IIa and IIb, for a period of 8 to 16 weeks at a daily dose of 10 to 20 mg, to investigate the effects on serum and biliary lipids. At the end of the treatment with pravastatin, the serum cholesterol level was significantly reduced, by 20%, compared with the control level. On the other hand, no significant differences were observed in serum high-density lipoprotein (HDL) cholesterol and triglyceride levels. Additionally, the administration of pravastatin did not change mode % compositions of biliary lipids, such as cholesterol, phospholipids, and total bile acids, as well as individual biliary bile acids. Consequently, there was not any significant change of the cholesterol saturation index. Based on the above results, our findings suggest that, for the treatment of hyperlipidemia, pravastatin is a highly effective cholesterol-lowering drug that does not affect biliary lipid metabolism.
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Affiliation(s)
- I Horiuchi
- First Department of Internal Medicine, Hiroshima University School of Medicine, Japan
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30
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Carrella M, Ericsson S, Del Piano C, Angelin B, Einarsson K. Effect of cholestyramine treatment on biliary lipid secretion rates in normolipidaemic men. J Intern Med 1991; 229:241-6. [PMID: 2007842 DOI: 10.1111/j.1365-2796.1991.tb00338.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
This study was designed to clarify the effect of bile acid sequestrant treatment on the total biliary output rates of cholesterol, phospholipids and bile acids in man, and to correlate these changes with the alterations in plasma lipoprotein levels. For this purpose nine healthy, normolipidaemic men were treated with 16 g of cholestyramine daily over a period of 4 weeks, and the biliary secretion rates were measured by a duodenal perfusion technique. Resin therapy, which profoundly increases de novo synthesis of bile acids, resulted in a lowering of total plasma cholesterol levels, mainly due to a 35% reduction in low density lipoprotein (LDL) cholesterol, and in a 33% increase in plasma triglyceride levels, reflecting enhanced very low density lipoprotein (VLDL) triglyceride concentrations; high density lipoprotein (HDL) levels did not change. However, these lipoprotein changes did not correlate with any alterations in biliary lipid output. Total hepatic secretion rates of the biliary lipids remained generally unchanged during treatment, with a tendency towards lower cholesterol output, resulting in a lower molar percentage of cholesterol in hepatic bile, 3.4 +/- 0.4 vs. 2.9 +/- 0.2 mol %. This is probably due to an increased rate of conversion of cholesterol to bile acids in the hepatocyte. It is concluded that, in man, the liver may adapt well to changes in the enterohepatic circulation of bile acids, thereby maintaining output rates of biliary lipids at a relatively constant level.
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Affiliation(s)
- M Carrella
- Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Sweden
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31
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Zimetbaum P, Frishman WH, Kahn S. Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins. J Clin Pharmacol 1991; 31:25-37. [PMID: 2045526 DOI: 10.1002/j.1552-4604.1991.tb01883.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low-density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high-density lipoprotein (HDL) cholesterol levels. Their effects on low-density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid, Parke-Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG-CoA reductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.
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Affiliation(s)
- P Zimetbaum
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
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32
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Reihnér E, Angelin B, Rudling M, Ewerth S, Björkhem I, Einarsson K. Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients. J Lipid Res 1990. [DOI: 10.1016/s0022-2275(20)42109-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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33
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Ericzon BG, Eusufzai S, Kubota K, Einarsson K, Angelin B. Characteristics of biliary lipid metabolism after liver transplantation. Hepatology 1990; 12:1222-8. [PMID: 2227822 DOI: 10.1002/hep.1840120524] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Biliary lipid metabolism was studied after 10 liver transplantations with continuous drainage of bile. Within 3 wk after transplantation, the new liver produced bile with concentrations of biliary lipids in agreement with those reported for T-tube bile in cholecystectolized nontransplanted subjects. Although changes in biliary lipid composition occurred swiftly in response to various forms of disturbed liver function, they did not provide substantially more information than did standard serum tests or simple measurements of bile flow in most patients. Secretion rates of phospholipids and cholesterol were found to be completely bile acid dependent. For each micromole of bile acids, 0.22 and 0.08 mumol of phospholipids and cholesterol were secreted, respectively. When bile flow was related to bile acid output, a linear relationship was found (r = 0.89), with a positive intercept indicating a bile acid-independent bile flow of approximately 44 microliters/min. Analysis of individual bile acids showed almost exclusively primary bile acids. The relative proportion of chenodeoxycholic acid was more prominent during the first days after transplantation. Different explanations for this are discussed.
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Affiliation(s)
- B G Ericzon
- Department of Transplantation Surgery, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
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34
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Reihnér E, Rudling M, Ståhlberg D, Berglund L, Ewerth S, Björkhem I, Einarsson K, Angelin B. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med 1990; 323:224-8. [PMID: 2114543 DOI: 10.1056/nejm199007263230403] [Citation(s) in RCA: 219] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. METHODS Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. RESULTS Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (P less than 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (P less than 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; P less than 0.001). The expression of LDL receptors was increased by 180 percent (P less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. CONCLUSIONS Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.
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Affiliation(s)
- E Reihnér
- Department of Surgery, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
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35
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Abstract
Biliary lipid composition and plasma lipoprotein levels were determined in nine gallstone-free male patients with familial combined hyperlipidaemia (FCHL). In the basal situation, stimulated fasting duodenal bile from the patients contained a higher relative concentration of cholesterol than bile obtained from age- and sex-matched normal controls (n = 22), 6.5 +/- 0.3 (SEM) vs. 4.7 +/- 0.2 mol % (P less than 0.01). This resulted in a higher cholesterol saturation of bile from FCHL patients, 85 +/- 6 vs. 70 +/- 2% (P less than 0.05). After 6 weeks of treatment with acipimox, 750 mg day-1, total plasma triglycerides were lowered from 7.5 +/- 1.5 to 4.6 +/- 0.7 mmol l-1 (P less than 0.05) and plasma cholesterol decreased from 8.0 +/- 0.1 to 7.1 +/- 0.3 mmol l-1 (P less than 0.05) in the FCHL patients. These changes were mainly due to a decrease in very low density lipoprotein concentrations while low density lipoprotein levels remained unaltered. The relative proportion of cholesterol in stimulated fasting duodenal bile was reduced from 6.5 +/- 0.3 to 4.3 +/- 0.5 mol % (P less than 0.01), resulting in 'normalization' of biliary cholesterol saturation, from 85 +/- 6 to 58 +/- 6% (P less than 0.005). No correlations between the changes in biliary lipid composition and those in plasma lipoprotein levels were observed. The results indicate that treatment with acipimox in patients with FCHL, a disorder commonly associated with supersaturated bile, does not increase biliary cholesterol, and presumably not the risk for gallstone formation.
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Affiliation(s)
- S Ericsson
- Department of Medicine, Karolinska Institute, Huddinge University Hospital, Sweden
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36
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Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity. Gastroenterology 1989; 97:1498-505. [PMID: 2583415 DOI: 10.1016/0016-5085(89)90395-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The present work tested the hypothesis that portal venous bile acids regulate the activity of the cholesterol 7 alpha-hydroxylase and studied the influence of hepatic microsomal free cholesterol concentration on the enzyme activity. Operative liver biopsies and samples of portal venous blood were obtained from a total of 61 patients with gallstones who were undergoing cholecystectomy. Fifteen of the patients were treated with cholestyramine (16 g/day) for 2-3 wk before operation and 23 patients with chenodeoxycholic acid (15 mg/kg.day) or ursodeoxycholic acid (15 mg/kg.day) for 3-4 wk before operation. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity, the concentration of free cholesterol in the microsomes, and the levels of individual bile acids in portal venous blood. Cholestyramine treatment increased the cholesterol 7 alpha-hydroxylase activity about sixfold, from 7.6 +/- 1.1 (mean +/- SEM) to 45.7 +/- 6.7 pmol/min.mg protein. Administration of chenodeoxycholic acid reduced the enzyme activity considerably to 1.0 +/- 0.3 pmol/min.mg protein, whereas ursodeoxycholic acid did not significantly affect the enzyme activity (7.9 +/- 2.2 pmol/min.mg protein). The concentration of microsomal free cholesterol remained essentially unchanged in spite of a 45-fold variation in enzyme activity. There was a negative correlation between the absolute as well as the relative concentration of chenodeoxycholic acid in portal blood and the activity of the cholesterol 7 alpha-hydroxylase, whereas there was no correlation between the total concentration of bile acids and the enzyme activity. It is concluded that the composition of individual bile acids may be more important than the total concentration of bile acids in the portal vein for the regulation of the cholesterol 7 alpha-hydroxylase activity in humans. It is further concluded that chenodeoxycholic acid is a considerably stronger suppressor of bile acid synthesis than ursodeoxycholic acid.
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37
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Henriksson P, Einarsson K, Eriksson A, Kelter U, Angelin B. Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma. J Clin Invest 1989; 84:811-6. [PMID: 2760214 PMCID: PMC329723 DOI: 10.1172/jci114240] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
To assess if and by which mechanisms pharmacological estrogen treatment induces gallstone disease, we examined patients with recently diagnosed prostatic cancer randomly allocated to estrogen therapy (n = 37) or orchidectomy (n = 35). According to gallbladder ultrasonography, after 1 yr new gallstones had developed in 5 of 28 estrogen-treated patients, compared with 0 of 26 orchidectomized patients (P = 0.03). Estrogen therapy for 3 mo increased the relative concentration of cholesterol and cholesterol saturation of bile by approximately 30% (n = 10). Serum LDL cholesterol was reduced by approximately 40%, and its relative change related inversely to that of bile cholesterol (Rs = -0.77). There were no changes in biliary or serum lipids after orchidectomy (n = 9). Secretion rates of biliary lipids were measured with a duodenal perfusion technique. Patients on chronic estrogen therapy (n = 5) had approximately 40% higher biliary excretion rates of cholesterol than age-matched controls (n = 7). Phospholipid secretion was also higher, but no difference in bile acid secretion was found. We conclude that an increased hepatic secretion of cholesterol results in increased cholesterol saturation of bile and an enhanced rate of gallstone formation during estrogen treatment. The changes in bile cholesterol seem to be related to the induced changes in serum lipoprotein metabolism.
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Affiliation(s)
- P Henriksson
- Department of Medicine, Karolinska Institute, Huddinge, Sweden
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38
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Angelin B. Effect of thiazide treatment on biliary lipid composition in healthy volunteers. Eur J Clin Pharmacol 1989; 37:95-6. [PMID: 2591472 DOI: 10.1007/bf00609433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
An increased incidence of cholecystitis has been observed in thiazide-treated patients. In order to test the possibility that the therapy might have caused an increase in the cholesterol saturation of gallbladder bile, biliary lipid composition was determined in fasting duodenal bile obtained from 10 healthy individuals after cholecystokinin injection, before and after 3 weeks of treatment with hydrochlorthiazide. The mean relative concentration of cholesterol was increased in 6 subjects, from 4.7 to 5.6 mol%, and the cholesterol saturation of bile was increased in 7, from 69 to 81%. These preliminary results indicate that thiazide treatment may to some extent increase biliary cholesterol saturation, and this may, at least in part, explain the higher prevalence of symptomatic gallbladder disease during such therapy.
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Affiliation(s)
- B Angelin
- Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden
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39
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Abstract
Fenofibrate, a potent analogue of clofibrate, causes changes in biliary lipid composition similar to those seen with clofibrate and other derivatives of fibric acid, although there is a suggestion that the increase in cholesterol content may be accompanied by an increase in phospholipid content as well as a decrease in bile acid content. This may favor liquid crystal formation, and fenofibrate may have less propensity to cause gallstones than would other derivatives. Many other factors are also important in determining whether supersaturated bile will result in gallstone formation, and the use of this compound should be monitored in the future to determine the clinical importance of these findings.
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Affiliation(s)
- R H Palmer
- Columbia University College of Physicians and Surgeons, New York, New York
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40
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Eriksson M, Angelin B. Bezafibrate therapy and biliary lipids: effects of short-term and long-term treatment in patients with various forms of hyperlipoproteinaemia. Eur J Clin Invest 1987; 17:396-401. [PMID: 3121342 DOI: 10.1111/j.1365-2362.1987.tb01133.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Several hypolipidaemic drugs increase biliary cholesterol saturation and induce the formation of cholesterol gallstones. In order to determine the influence of bezafibrate, a clofibrate analogue with hypolipidaemic properties, on bile lipid composition, we studied twelve patients with various forms of hyperlipoproteinaemia (six type IIA, three type IIB and three type IV hyperlipoproteinaemia; six had a genetic diagnosis of familial hypercholesterolaemia and five familial combined hyperlipidaemia). After 4 weeks of therapy, when serum lipids were significantly reduced, the relative proportion of cholesterol in stimulated fasting duodenal bile was increased by 28% (P less than 0.001). Phospholipids were concomitantly increased and bile acids decreased, resulting in an increase in biliary cholesterol saturation from 89 +/- 4% to 105 +/- 8% (SEM, P less than 0.02). The changes induced were similar in patients with familial hypercholesterolaemia and familial combined hyperlipidaemia. After 1 year of continued treatment, serum lipid responses were unaltered. The changes in biliary lipids were also persistent as the relative cholesterol concentration remained increased by 33% (P less than 0.01) and cholesterol saturation averaged 106 +/- 8% (P less than 0.02). Although the effect on bile cholesterol appeared to be transient in some patients, the results of the present study suggest that the risk of cholesterol gallstone formation may be increased during bezafibrate therapy.
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Affiliation(s)
- M Eriksson
- Department of Medicine, Karolinska Instituet, Huddinge University Hospital, Stockholm, Sweden
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41
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Imai Y, Kawata S, Inada M, Miyoshi S, Minami Y, Matsuzawa Y, Uchida K, Tarui S. Effect of cholestyramine on bile acid metabolism in conventional rats. Lipids 1987; 22:513-6. [PMID: 3626777 DOI: 10.1007/bf02540367] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Effects of cholestyramine on biliary secretion of cholesterol, phospholipids and bile acids and fecal excretion of sterols and bile acids were examined in Wistar male rats. Six rats were fed a basal diet, and the other six were fed a basal diet supplemented with 5% cholestyramine for eight days. Bile flow and biliary secretion of bile acids and phospholipids (per hour per rat) decreased with cholestyramine treatment, while biliary cholesterol secretion (per hour per rat) remained unchanged. In the biliary bile acid composition, a marked increase of chenodeoxycholic acid with a concomitant decrease of beta-muricholic acid was observed in cholestyramine-treated rats. Fecal excretion of total sterols and bile acids increased about three- and four-fold, respectively, after cholestyramine treatment. The increase of fecal bile acids derived from cholic acid was more predominant than that derived from chenodeoxycholic acid, resulting in an increase of the cholic acid group/chenodeoxycholic acid group ratio.
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42
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Angelin B, Eriksson M, Einarsson K. Combined treatment with cholestyramine and nicotinic acid in heterozygous familial hypercholesterolaemia: effects on biliary lipid composition. Eur J Clin Invest 1986; 16:391-6. [PMID: 3100307 DOI: 10.1111/j.1365-2362.1986.tb01014.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
In ten patients with heterozygous familial hypercholesterolaemia, combination therapy with cholestyramine and nicotinic acid was instituted for a minimum of 2 months. During therapy, plasma low-density lipoprotein levels were reduced by 32%, and low-density lipoprotein to high-density lipoprotein ratios by 40%. The cholesterol saturation of fasting gall-bladder bile was reduced by 33% during treatment. We conclude that long-term combination therapy with cholestyramine and nicotinic acid is practically feasible in heterozygous familial hypercholesterolaemia, normalizes plasma cholesterol and low-density lipoprotein levels in many patients, and does not result in unwanted side-effects on biliary lipids. It should therefore be considered as the therapy of choice in this condition.
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43
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Okolicsanyi L, Lirussi F, Strazzabosco M, Jemmolo RM, Orlando R, Nassuato G, Muraca M, Crepaldi G. The effect of drugs on bile flow and composition. An overview. Drugs 1986; 31:430-48. [PMID: 2872047 DOI: 10.2165/00003495-198631050-00003] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Many drugs are eliminated via the hepatobiliary route, after biotransformation in the liver. Some of them may affect bile flow and/or the hepatic secretion of biliary lipids such as bile acids, cholesterol and phospholipids. Bile acids are the most potent agents which increase bile flow, especially unconjugated bile acids. Other drugs which increase bile flow include phenobarbitone (phenobarbital), theophylline, glucagon and insulin. In contrast, ethacrynic acid, amiloride, ouabain, oestrogens and chlorpromazine are among those agents which decrease bile flow. Biliary bile acid secretion is altered by a variety of drugs, including cheno- and ursodeoxycholic acids (CDCA and UCDA), the bile acid sequestrants cholestyramine and colestipol, and ethinyloestradiol. The composition of bile can also be altered by drug therapy. Thus, clofibrate increases biliary cholesterol secretion, and reduces bile acid concentrations, without altering biliary phospholipid concentrations. However, other clofibrate derivatives may produce changes of a different pattern, suggesting that the risk of developing gallstones may differ for each derivative. Nicotinic acid and d-thyroxine also increase biliary cholesterol saturation, while CDCA and UDCA reduce biliary cholesterol concentration. The potential consequences of drug-induced changes in bile flow and composition extend to the liver, the gallbladder and the intestine. If adverse effects are to be avoided, further study in this often overlooked area is required.
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44
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Abstract
In humans, clofibrate increases the degree of bile cholesterol saturation and predisposes patients to cholesterol gallstone formation. To determine if this activity extends to the related hypolipidemic agent fenofibrate, duodenal bile lipid composition was studied in 15 subjects before they participated in a double-blind study of that drug. Eight subjects were studied again on fenofibrate and six on placebo; five placebo patients were also studied later on open-label fenofibrate. The results were similar in the double-blind and open-label studies, and changes in bile lipid composition were comparable to those seen in studies of clofibrate. Fenofibrate caused a significant decrease in the molar percentage of bile acids and increases in the molar percentage of phospholipids and cholesterol. The changes in bile acids and phospholipids had opposing effects on the cholesterol-holding capacity of bile. A statistically significant increase in the cholesterol saturation index was only apparent when all fenofibrate bile analyses were compared with all untreated bile analyses. The results demonstrated that fenofibrate has clear effects on bile lipid composition that may be associated with an increased propensity for gallstone formation, and when fenofibrate is used, patients should be monitored for this possibility.
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45
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Jung W, Kohlmeier M, Nikolaus T, Schlierf G. Effects of Acipimox on plasma lipids and biliary lipids in healthy subjects. RESEARCH IN EXPERIMENTAL MEDICINE. ZEITSCHRIFT FUR DIE GESAMTE EXPERIMENTELLE MEDIZIN EINSCHLIESSLICH EXPERIMENTELLER CHIRURGIE 1985; 185:457-68. [PMID: 4089312 DOI: 10.1007/bf01851852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The effects of Acipimox (5-methylpyracine-2-carboxylic acid-4-oxide, 3 X 250 mg/day) on plasma lipids, lipoproteins, and biliary lipids were studied in 14 healthy male volunteers using a double blind cross-over design. There was a significant (P less than 0.05) rise of HDL-cholesterol by 9.8%, while effects on other lipids and lipoproteins were small and insignificant (total cholesterol minus 6.5%, LDL-cholesterol minus 11.8%, free cholesterol minus 4.2%, total triglycerides plus 13.5% and phospholipids plus 3.9%). There was a significant rise of the HDL-cholesterol/LDL-cholesterol ratio by 23.6% (P less than 0.02) and of the HDL-cholesterol/total cholesterol ratio by 16% (P less than 0.05). Apolipoproteins AI, AII, and B were not significantly affected. The ratio of HDL-cholesterol/Apo AI increased significantly (P less than 0.05), and the ratio of HDL-cholesterol/Apo AII rose from 1.22 to 1.32 (P less than 0.05), while the ratio LDL-cholesterol/Apo B fell from 1.96 to 1.73. The composition of HDL and LDL, therefore, must have been altered by Acipimox. The relative cholesterol concentration in bile was significantly (P less than 0.05) increased by treatment with Acipimox, while bile acids and phospholipids were not significantly affected. The lithogenic index rose significantly by 15.1% (P less than 0.02) as calculated according to Admirand and Small, while calculations according to Hegard and Dam yielded a slight insignificant rise (P less than 0.1). The findings suggest that treatment with Acipimox might be associated with an increased risk of cholelithiasis. However, only long-term epidemiologic studies can ultimately demonstrate whether or not Acipimox increases the risk of gallstone formation.
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46
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Podda M, Zuin M. Effects of fenofibrate on biliary lipids and bile acid pool size in patients with type IV hyperlipoproteinemia. Atherosclerosis 1985; 55:135-42. [PMID: 4004987 DOI: 10.1016/0021-9150(85)90092-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Lipid-lowering drugs, notably clofibrate, may induce a supersaturation of bile with cholesterol, thus favouring the development of cholelithiasis. In order to see whether or not fenofibrate, a clofibrate analogue, has any influence on biliary cholesterol saturation, we determined the lipid composition of gallbladder bile and the bile acid pool size in 15 patients with type IV hyperlipoproteinemia before and after 6-8 weeks of treatment with a daily dose of 300 mg of the drug. At the end of treatment plasma triglycerides were markedly decreased, whereas no detectable influence on liver cell integrity or bile excretory function could be demonstrated in any patient by comparing the pre- and post-treatment serum levels of liver enzymes, bilirubin and bile acids. The mean bile cholesterol saturation index did not significantly change and cholic acid was the only bile acid to increase significantly. In the 3 patients with an initial saturation index of less than 1, bile became supersaturated with cholesterol. However, in no case were the limits of the metastable phase for cholesterol solubility in bile exceeded. Though only long-term prospective studies may give a definitive answer about the lithogenic potential of fenofibrate, our data on gallbladder bile composition in patients with type IV hyperlipoproteinemia indicate that it is not very likely that fenofibrate administration will increase the risk of gallstone formation in severely hyperlipidemic patients.
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47
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Leiss O, von Bergmann K, Gnasso A, Augustin J. Effect of gemfibrozil on biliary lipid metabolism in normolipemic subjects. Metabolism 1985; 34:74-82. [PMID: 3855325 DOI: 10.1016/0026-0495(85)90064-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The mechanisms of the lipid-lowering agent gemfibrozil on biliary lipid metabolism were studied in eight normolipemic male volunteers. These measurements were performed before and after 3 months of administration. During administration of gemfibrozil, plasma cholesterol decreased by 19% (P less than 0.01) and triglycerides by 46% (P less than 0.01), and HDL cholesterol increased by 10% (P less than 0.01). The lithogenic index in gallbladder bile increased from 0.73 to 1.37 (P less than 0.05) and in hepatic bile from 0.86 to 1.42 (P less than 0.01). The increase in lithogenicity of gallbladder bile and hepatic bile was due to an increased biliary output of cholesterol from 47 to 70 mg/h (P less than 0.01) and a decreased output of bile acids from 943 to 694 mg/hr (P less than 0.01), whereas phospholipid output was not altered. The reduction in bile acid output was a result of a significant decrease in chenodeoxycholic acid secretion (r = 0.852; P less than 0.01). Cholic acid output was not affected by gemfibrozil. These results suggest that administration of gemfibrozil enhances the possible risk of gallstone formation like clofibrate.
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48
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von Bergmann K, Leiss O. Effect of short-term treatment with bezafibrate and fenofibrate on biliary lipid metabolism in patients with hyperlipoproteinaemia. Eur J Clin Invest 1984; 14:150-4. [PMID: 6428905 DOI: 10.1111/j.1365-2362.1984.tb02105.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Sixteen patients with different types of hyperlipoproteinaemia were treated with the clofibrate analogues, bezafibrate or fenofibrate. Serum lipids and lipid composition of gallbladder bile were measured before and after 3-4 weeks of treatment. Both bezafibrate and fenofibrate reduced serum lipids effectively but increased the lithogenic index of bile from 1.11 to 1.47 and 1.25 to 1.80 (P less than 0.01), respectively, by increasing molar percent of cholesterol and decreasing molar percent of bile acids. Measurements of biliary lipid secretion in three patients before and after bezafibrate administration revealed a marked and significant increase in cholesterol secretion (from 119 to 166, from 58 to 128, and from 149 to 172 mumol h-1, respectively; P less than 0.05) without altering bile acid and phospholipid output. These results indicate that bezafibrate and fenofibrate exhibit the same effect on biliary lipid metabolism as clofibrate and might therefore induce cholesterol gallstone disease.
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49
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Angelin B, Einarsson K, Leijd B. Effect of ciprofibrate treatment on biliary lipids in patients with hyperlipoproteinaemia. Eur J Clin Invest 1984; 14:73-8. [PMID: 6421601 DOI: 10.1111/j.1365-2362.1984.tb00707.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Treatment with hypolipidaemic drugs such as clofibrate increases secretion of biliary cholesterol and induces supersaturation of bile, leading to an increased risk of gallstone formation. Ciprofibrate is a phenoxyisobutyrate derivative with lipid-lowering effects in hyperlipoproteinaemia. We analysed serum lipid levels and biliary lipid composition and cholesterol saturation of gallbladder bile in nineteen hyperlipoproteinaemic patients before and after 6 weeks treatment with ciprofibrate, 100 mg daily. In addition, hepatic secretion rates of biliary lipids were determined in eight of the patients. Ten of the patients were also studied after 1 year of treatment. Short-term treatment reduced the serum cholesterol levels by about 20% (P less than 0.001) and the serum triglycerides by about 40% (P less than 0.001). The relative cholesterol concentration and cholesterol saturation of bile were not significantly increased for the group as a whole, nor in patients with familial hypercholesterolaemia (n = 9), or with other types of hyperlipidaemia (n = 10). During treatment, however, fourteen patients had saturated bile compared with nine before treatment. An increase in cholesterol saturation was the consequence of an increased hepatic secretion of cholesterol whereas the secretion rates of bile acids and phospholipids were unaffected. After 1 year of treatment the serum lipid concentrations were reduced to about the same level as after 6 weeks, whereas biliary lipid composition and cholesterol saturation had returned to pre-treatment values. In contrast to clofibrate ciprofibrate exerts hypolipidaemic effects without consistently increasing the relative cholesterol concentration in bile. In some patients it leads to a transient rise in cholesterol saturation of gallbladder bile.(ABSTRACT TRUNCATED AT 250 WORDS)
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50
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Kesäniemi YA, Grundy SM. Clofibrate, caloric restriction, supersaturation of bile, and cholesterol crystals. Scand J Gastroenterol 1983; 18:897-902. [PMID: 6676922 DOI: 10.3109/00365528309182112] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Lipid composition, cholesterol saturation, and cholesterol crystal formation of gallbladder bile were studied in seven type-IV hyperlipoproteinemic subjects who did not have gallstones. Thereafter, biliary cholesterol solubilization was overloaded, first by clofibrate and then by caloric restriction treatment. Initially increased cholesterol saturation was still increased by both clofibrate and caloric restriction treatment, but none of the subjects developed cholesterol crystals in bile, indicating that they had a mechanism to maintain cholesterol in solution in the bile despite remarkable supersaturation. This suggests that the patients who are at risk of developing gallstones can be better selected by cholesterol crystal analysis of bile samples than by analysis of lipid composition of bile.
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