Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, elevated bile acids, and, specifically, elevated disulphated progesterone metabolites. We aimed to study changes in these parameters during treatment with dexamethasone or ursodeoxycholic acid (UDCA) in 40 out of 130 women included in the Swedish ICP intervention trial (26 randomized to placebo or UDCA, 14 randomized to dexamethasone). Serum bile acid profiles and urinary steroid hormone metabolites were analyzed using isotope-dilution gas chromatography-mass spectrometry and electrospray-mass spectrometry. We found that all patients displayed ICP-typical serum bile acid profiles with >50% cholic acid at baseline but almost 80% UDCA upon treatment with this bile acid. In UDCA-treated patients, relative amounts of disulphated progesterone metabolites in urine decreased by 34%, 48% (P < 0.05), and 55% (P < 0.05) after 1, 2, and 3 weeks of treatment, respectively, which was significantly correlated to improvements of pruritus scores but not to serum bile acid levels. In contrast, in patients randomized to dexamethasone or placebo, no changes in steroid metabolites or pruritus scores were observed. Conclusion: UDCA treatment in ICP decreased urinary excretion of disulphated progesterone metabolites, suggesting that amelioration of pruritus is connected to stimulation of hepatobiliary excretion of progesterone disulphates.     

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

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

Stimulation of bile acid 6α-hydroxylation by rifampin

Background: Rifampin was shown to relieve pruritus in cholestatic liver diseases. There has been much speculation about the origin of pruritus, but it has not yet been comprehensively explained. The role of bile acids in producing pruritus is obscure and still under debate. Since rifampin both inhibits the uptake of bile acids into the hepatocyte and strongly induces mixed-function oxidases in the liver, the beneficial effects of this drug might be a consequence of altered bile acid metabolism.Methods: We investigated the influence of rifampin on urinary bile acid excretion with special respect to glucuronide and sulphate conjugates in 14 healthy volunteers before and after administration of rifampin, 600 mg×7 days, using each subject as his or her own control.Results: Bile acid glucuronide excretion increased from 0.55 to 1.19 μmol/24 h. This was in particular due to a significant increase of the urinary excretion of the 6α-hydroxylated hyocholic and hyodeoxycholic acids, the relative amounts of which accounted for about two thirds of the urinary bile acid excretion. Excretion of sulphates, however, decreased from 1.40 to 0.86 μmol/24 h due to a significantly reduced excretion of lithocholic acid sulphate. No changes in the excretion rates of other primary and secondary bile acids and no changes in their conjugation patterns were observed.Conclusions: The results provide evidence that rifampin induces 6α-hydroxylation of bile acids. The products are subsequently glucuronidated at the 6α-hydroxy groups, thus stimulating renal excretion of potentially toxic bile acids.     

Profiles of bile acids and their glucuronide and sulphate conjugates in the serum, urine and bile from patients undergoing bile drainage.

Bile acid profiles in serum, urine, and bile from patients undergoing bile drainage and the changes of serum bile acids after bile drainage were studied. Bile acids were separated into non-glucuronidate-non-sulphate, glucuronidated, and sulphated fractions and were measured by mass fragmentography using conjugates of deuterium labelled bile acids as internal standards. Glucuronidated and sulphated bile acids contribute 14-32% and 16-44% of serum bile acids, 4-11% and 61-82% of urine bile acids and 0.2-1% and 0.3-2% of biliary bile acids respectively. After bile drainage the concentration of serum non-glucuronidated-non-sulphated bile acids decreased more rapidly than glucuronidated and sulphated bile acids. There was little biliary excretion of the glucuronidated and sulphated bile acids. Such conjugation appears to have a role in facilitating bile acid excretion by the urinary route.     

Effect of ursodeoxycholic acid on bile acid metabolism in primary biliary cirrhosis

We have compared the effect of ursodeoxycholic acid with placebo on the clinical state, blood liver chemistries and serum and urinary bile acids in four patients with primary biliary cirrhosis. All parameters were evaluated monthly, and bile acid composition was measured by capillary gas-liquid chromatography. At the time of admission, all patients showed intense pruritus, and their serum alkaline phosphatase, AST and ALT levels were elevated 4.3, 2.7 and 2.3 times over control values. Serum bile acids were elevated almost 38-fold with 2.5 times more cholic acid than chenodeoxycholic acid. Urinary bile acid output was elevated 28 times the control values, and 36% were 1 beta-hydroxycholic acid, 1 beta-hydroxydeoxycholic acid and hyocholic acid (3 alpha,6 alpha, 7 alpha-trihydroxy-5 beta-cholanoic acid). Three months of placebo administration did not significantly affect the clinical or biochemical presentations, and the serum and urinary bile acid composition did not change. In contrast, ursodeoxycholic acid feeding (12 to 15 mg per kg per day) for 6 months abolished pruritus in two and lessened itching in two subjects and reduced serum alkaline phosphatase, AST and ALT levels by 21, 35 and 47%, respectively. The mean values for the total serum bile acid concentrations in these patients declined 26% from the pretreatment value, but the proportion of ursodeoxycholic acid increased from 3 to 40% of the total bile acids; thus, total fasting serum endogenous bile acid levels decreased almost 50%. Similar changes were noted in the urinary bile acids, in which ursodeoxycholic acid became the major bile acid, and approximately 18% were hydroxylated at C-1, C-6 and C-21.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary excretion of bile acids in bile duct-ligated rats

Background. In patients with complete bile duct obstruction, the only pathway of bile acid elimination is through the urine. However, the urinary excretion of various bile acid conjugates in the presence of bile duct obstruction has not been clarified. Given this factor, the urinary excretion of various bile acids was compared in rats that were bile duct-ligated for 3 days. Methods. After urinary bladder cannulation, radiolabeled bile acids were intravenously injected, and urine samples were collected every 2 h for 6 h, and radioactivity was counted. Results. Urinary excretion (cumulative percent dose during 6 h) of taurocholate and cholate was similar (19.3% and 16.8%). Urinary excretion of tauroursodeoxycholate, lithocholate, and taurolithocholate-sulfate was less effective (12.7%, 9.8% and 2.1%, respectively). Cholate was mostly conjugated with taurine, and lithocholate was mostly conjugated with taurine and further hydroxylated. Conclusions. These results indicate that unconjugated bile acids were taken up by the liver and excreted into the blood after further biotransformation even under conditions of complete bile duct obstruction. Although bile acid sulfates are the major bile acids in the urine of patients with obstructive jaundice, monohydroxylated bile acids are considered not to be so effectively excreted into the urine, even with conjugation with taurine and sulfate, in rats. Received: October 4, 2002 / Accepted: November 8, 2002 RID="*" ID="*" Reprint requests to: H. Takikawa Acknowledgments. This work was partly supported by a Grant-in-Aid by the Japan Society for the Promotion of Science (C2-14570510).     

Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis.

Samples of serum, bile, and urine were collected simultaneously from patients with cholestasis of varying aetiology and from patients with cirrhosis; their bile acid composition was determined by gas/liquid chromatography and mass spectrometry. In cholestasis, the patterns in all three body fluids differed consistently and strikingly. In serum, cholic acid was the major bile acid and most bile acids (greater than 93%) were unsulphated, whereas, in urine, chenodeoxycholic was the major bile acid, and the majority of bile acids (greater than 60%) were sulphated. Secondary bile acids were virtually absent in bile, serum, and urine. The total amount of bile acids excreted for 24 hours correlated highly with the concentration of serum bile acids; in patients with complete obstruction, urinary excretion averaged 71-6 mg/24 h. In cirrhotic patients, serum bile acids were less raised, and chenodeoxycholic acid was the predominant acid. In healthy controls, serum bile acids were consistently richer in chenodeoxycholic acid than biliary bile acids, and no bile acids were present in urine. No unusual monohydroxy bile acids were present in patients with primary biliary cirrhosis, but, in several patients, there was a considerable amount of hyocholic acid present in the urinary bile acids. The analyses of individual bile acids in serum and urine did not appear to provide helpful information in the differential diagnosis of cholestasis. Thus, in cholestasis, conjugation of chenodeoxycholic acid with sulphate becomes a major biochemical pathway, urine becomes a major route of bile acid excretion, and abnormal bile acids are formed.     

Effect of ursodeoxycholic acid on the kinetics of the major hydrophobic bile acids in health and in chronic cholestatic liver disease.

Beneficial effects of ursodeoxycholic acid in chronic cholestatic liver diseases have been attributed to displacement of hydrophobic bile acids from the endogenous bile acid pool. To test this hypothesis, we determined pool sizes, fractional turnover rates, synthesis/input rates and serum levels of deoxycholic acid and chenodeoxycholic acid before and 1 mo after the start of treatment with ursodeoxycholic acid (13 to 15 mg/kg body wt/day) in four healthy volunteers and five patients with chronic cholestatic liver diseases (three with primary biliary cirrhosis and two with primary sclerosing cholangitis). Bile acid kinetics were determined by combined capillary gas chromatography-isotope ratio mass spectrometry in serum samples after administration of [2H4] deoxycholic acid and [13C]chenodeoxycholic acid. In healthy volunteers, deoxycholic acid pool sizes decreased during administration of ursodeoxycholic acid by 72%. In patients with cholestatic liver diseases, deoxycholic acid pool sizes before ursodeoxycholic acid treatment were only 13% of those in healthy volunteers and were unaffected by ursodeoxycholic acid treatment. Chenodeoxycholic acid pool sizes were not different in healthy volunteers and in patients with cholestatic liver disease, and were not altered by ursodeoxycholic acid treatment. In both healthy volunteers and patients with cholestatic liver disease, synthesis/input rates and serum levels of deoxycholic acid and chenodeoxycholic acid were not altered by ursodeoxycholic acid treatment. Because in our patients improvement of serum liver tests during short-term ursodeoxycholic acid treatment was noted without a decrease of the pool sizes of the major hydrophobic bile acids, we conclude that displacement of hydrophobic endogenous bile acids is not the mechanism of action of ursodeoxycholic acid in chronic cholestatic liver disease.     

Ursodeoxycholic acid ingestion after ileal resection

The effect of ursodeoxycholic acid ingestion on biliary bile acids and biliary lipids was studied in six patients after ileal resection. All patients had bile acid malabsorption, as documented by increased breath and fecal excretion of¹⁴C after oral administration of [1-¹⁴C] cholylglycine. Fasting duodenal bile was collected by intubation before and seven days after ursodeoxycholic acid administration (4 g/day), and biliary bile acid and lipid composition were determined. Ursodeoxycholic acid ingestion increased the percentage of ursodeoxycholic acid in bile tenfold (3.6±2.6% vs 38.6±12.0%) and decreased chenodeoxycholic acid in bile by approximately 40%. Before ursodeoxycholic acid ingestion, bile was supersaturated in all patients. After ursodeoxycholic acid ingestion, cholesterol saturation decreased in all six patients by an average of 43%, and bile became unsaturated in five. Ursodeoxycholic acid ingestion had no effect on stool frequency. We conclude that, as in subjects with an intact enterohepatic circulation, ursodeoxycholic acid therapy has litholytic potential in patients after ileal resection.This work was supported by NIH Grants AM 15887 and RR 585 and by the Mayo Foundation. Part of this work was reported at the 1979 meeting of the American Gastroenterological Association and published in abstract form.At the time this work was done, Dr. LaRusso was a Teaching and Research Scholar of the American College of Physicians.     

Relationship between serum and biliary bile acids as an indicator of chenodeoxycholic and ursodeoxycholic acid-induced hepatotoxicity in the rhesus monkey

The relationship between serum and biliary concentrations of bile acids was studied in 20 rhesus monkeys which developed hepatotoxicity after six months of treatment with 40 and 120 mg/kg/day doses of chenodeoxycholic (cheno) and ursodeoxycholic (urso) acids, respectively. During the treatment, lithocholate—all of which was unsulfated—increased several-fold both in serum and in bile. There was a significant correlation between serum and biliary concentrations of lithocholate. Similarly close correlations existed between the serum and biliary concentrations of the conjugates of cheno and urso which increased during treatment with the respective bile acids. The serum levels of cholate and deoxycholate remained normal, although their concentrations in bile decreased considerably during treatment with cheno and urso, respectively. Further studies have to establish whether serum determinations of lithocholate can also be used in man to study the role of this bile acid in the liver function abnormalities which develop in some patients treated with cheno or urso and/or whether measurement of serum cheno and urso could be useful for the monitoring of patient compliance with the respective bile acid treatment.The study was supported in part by grant AM-19689 from the National Institutes of Health. Dr. Fromm is recipient of Research Career Development Award AM-00290 from the National Bazzoli is a Research Fellow in Gastroenterology sponsored by the National Council of Research, Rome, Italy, and by NATO.The skillful technical assistance of Prafulla Amin and Susan Ceryak is gratefully acknowledged.A preliminary report of this work was published in abstract form inGastroenterology (78:1301, 1980).     

Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis

Ursodeoxycholic acid has been proposed for the treatment of primary biliary cirrhosis. The aim of this study was to evaluate the effect of ursodeoxycholic acid administration on bile acid metabolism in patients with early-stage primary biliary cirrhosis. Biliary bile acid composition, primary bile acid pool sizes, synthesis, and fractional turnover rate were measured before and after four weeks of ursodeoxycholic acid administration (600 mg/day) in nine patients with biopsy-proven primary biliary cirrhosis (stages I-III). Molar percentages of chenodeoxycholic, cholic, and deoxycholic acids in bile were significantly decreased by ursodeoxycholic acid administration, while its biliary concentration increased to 34.2% at the end of the same four-week period. The cholic and chenodeoxycholic acid pools decreased, although not significantly, while the deoxycholic acid pool was reduced by 60% (from 0.7±0.12 to 0.29±0.07 mmol,P<0.002). Primary bile acid synthesis was slightly increased, and fractional turnover rate was significantly increased. The conversion rate of cholic to deoxycholic acid was measured and found to be significantly increased (P<0.05) after ursodeoxycholic acid administration; however, serum levels of both free and conjugated deoxycholic acid were significantly decreased (from 23.2±9.7 to 3.8±1.9 μmol/liter,P<0.001). We conclude that in patients with primary biliary cirrhosis, ursodeoxycholic acid administration replaces endogenous bile acids in the enterophepatic circulation by increasing bile acid fractional turnover rate without significant increments of their hepatic synthesis.     

Acute effects of ursodeoxycholic and chenodeoxycholic acid on the small intestinal absorption of bile acids

The effects of ursodeoxycholic acid and chenodeoxycholic acid on the small-intestinal absorption of endogenous bile acids were studied in patients with ileostomies who served as a model to investigate small-intestinal absorption in humans. In the control period, the eight patients excreted 327 +/- 91 (mean +/- standard error of the mean) mumol/8 h cholic acid and 214 +/- 38 mumol/8 h chenodeoxycholic acid by their ileal fluid. Following ursodeoxycholic acid administration (500 mg), ileal excretion of cholic acid increased to 517 +/- 96 mumol/8 h, and that of chenodeoxycholic acid increased to 337 +/- 42 mumol/8 h, indicating decreased absorption of these bile acids. Following chenodeoxycholic acid administration (500 mg), no significant increase of cholic acid excretion was observed, whereas chenodeoxycholic acid excretion increased as expected. It is concluded that following ursodeoxycholic acid administration the absorption of common bile acids from the small intestine decreases markedly. This effect of ursodeoxycholic acid on intestinal absorption of common bile acids probably is responsible for the decrease of their plasma concentrations, the reduction of their pool sizes, the increase of their fractional turnover rates, and most likely also contributes to the increased hepatic synthesis of cholic acid.     

Differing effects of ursodeoxycholic or chenodeoxycholic acid on biliary cholesterol saturation and bile acid metabolism in man

A dose-response study comparing ursodeoxycholic and chenodeoxycholic acid was carried out in six men with asymptomatic radiolucent gallstones present in well-visualizing gallbladders. The study tested the effects of a low (averaging 6 mg/kg/day) or medium dose (averaging 11 mg/kg/day) of each bile acid on the cholesterol saturation of bile as well as on bile acid metabolism, as inferred from biliary and fecal bile acid composition. Ursodeoxycholic acid, at low or medium doses, induced bile desaturation in most patients, whereas chenodeoxycholic acid did not. Despite the greater desaturation efficacy of ursodeoxycholic acid, biliary bile acids became less enriched with the administered bile acid during ursodeoxycholic acid treatment than during chenodeoxycholic acid treatment. Both bile acids were nearly completely 7-dehydroxylated to lithocholic acid by colonic bacteria, but biliary lithocholic increased only slightly (and similarly) with each bile acid. Fecal bile acid composition suggested that administered ursodeoxycholic acid suppressed endogenous bile acid synthesis much less than chenodeoxycholic acid. The results indicate that ursodeoxycholic acid and chenodeoxycholic acid have similar but not identical effects on bile acid metabolism, but that for a given dose, ursodeoxycholic acid is a more potent desaturating agent than chenodeoxycholic acid. The results suggest that cholesterol gallstone dissolution with ursodeoxycholic acid should occur with a dose of 8–10 mg/kg in most nonobese patients.Supported in part by NIH grants AM 15887, 16770, and 21506.     

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

Objective: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease.
Methods: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo.
Results: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group ( n = 61 ) compared with 8% in the placebo group ( n = 57 ) ( p < 0.0001 ). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair ( r = 0.75 , p ≤ 0.00002 ) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker.
Conclusion: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.     

Changes in bile acid composition in patients with primary biliary cirrhosis induced by ursodeoxycholic acid administration

We describe a detailed study of the effects of ursodeoxycholic acid administration on bile acid composition of the serum and bile of patients with primary biliary cirrhosis. Gas chromatography-mass spectrometry was used to analyze bile acids from 10 patients with primary biliary cirrhosis before and during ursodeoxycholic acid administration (500 mg/day, corresponding to approximately 8 mg/kg body wt), after group separation of the unconjugated and conjugated fractions by lipophilic anion exchange chromatography. These studies were directed at assessing whether the beneficial role of ursodeoxycholic acid in primary biliary cirrhosis was the consequence of a shift in the hydrophobic/hydrophilic balance of the bile acid pool and whether the hypercholeresis might result from the cholehepatic circulation of unconjugated ursodeoxycholic acid in bile. In basal conditions, the unconjugated bile acids accounted for only 5.5% and 2.5%, respectively, of the total bile acids of serum and bile; cholic acid was the major component of the conjugated fraction of serum and bile (56.0% +/- 4.0%, mean +/- S.E.M.), and ursodeoxycholic acid was present in only trace amounts. The conjugated fraction contained many unusual bile acids (representing 16.5% +/- 1.3% of total) including C25 bile acids, iso-chenodeoxycholic acid and several oxo-bile acids. After ursodeoxycholic acid administration biochemical indices of liver function all improved, but the proportions of the unconjugated bile acids in serum and bile did not significantly change.(ABSTRACT TRUNCATED AT 250 WORDS)     

24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice

BACKGROUND & AIMS: Current therapy for primary sclerosing cholangitis is of limited efficacy. Multidrug resistance gene 2 knockout mice (Mdr2(-/-)) represent a well-characterized model for sclerosing cholangitis. Experiments were performed to test in such mice the therapeutic effects of 24-norUrsodeoxycholic acid, a C(23) homologue of ursodeoxycholic acid with 1 fewer methylene group in its side chain. METHODS:Mdr2(-/-) mice were fed a diet containing 24-norUrsodeoxycholic acid (0.5% wt/wt) or ursodeoxycholic acid (0.5% wt/wt) as a clinical comparator for 4 weeks; controls received standard chow. Effects on serum liver tests, liver histology, markers of inflammation and fibrosis, and bile acid transport and metabolism were compared. 24-norUrsodeoxycholic acid metabolism was studied in serum, liver, bile, and urine. RESULTS: 24-norUrsodeoxycholic acid markedly improved liver tests and liver histology and significantly reduced hydroxyproline content and the number of infiltrating neutrophils and proliferating hepatocytes and cholangiocytes. 24-norUrsodeoxycholic acid underwent extensive phase I/II metabolism (hydroxylation, sulfation, and glucuronidation), thereby increasing the hydrophilicity of biliary bile acid secretion. There was a coordinated induction of bile acid detoxifying enzymes (Cyp2b10, Cyp3a11, and Sult2a1) and efflux pumps (Mrp3 and Mrp4). Ursodeoxycholic acid, in contrast, increased alanine transaminase and alkaline phosphatase levels, had no significant effects on hydroxyproline content, and induced biliary transporters and detoxification enzymes to a much smaller extent than 24-norUrsodeoxycholic acid. CONCLUSIONS: 24-norUrsodeoxycholic acid ameliorates sclerosing cholangitis in Mdr2(-/-) mice. Its therapeutic mechanisms involve (1) increasing the hydrophilicity of biliary bile acids, (2) stimulating bile flow with flushing of injured bile ducts, and (3) inducing detoxification and elimination routes for bile acids.     

Ursodeoxycholic acid therapy in cystic fibrosis-associated liver disease: a dose-response study.

Previous studies from our groups have demonstrated improvements in biochemical markers of liver function when cystic fibrosis patients with associated liver disease were administered oral ursodeoxycholic acid. The magnitude of the response was somewhat less than that found when comparable doses (10 to 15 mg/kg body wt/day) of ursodeoxycholic acid are given to other liver disease patients; this may be explained by the bile acid malabsorption that is characteristic of the disease. For this reason a dose-response study was carried out in nine cystic fibrosis patients with liver disease to establish whether improved efficacy could be obtained with higher doses. Ursodeoxycholic acid in doses of 5, 10 and 15 mg/kg body wt/day was given orally for consecutive 2-mo periods in a replicated Latin-square design. After this, all patients received 20 mg/kg body wt/day. Liver function, individual serum bile acids and biliary bile acid composition were determined at entry and at the end of each treatment period. Our data demonstrate that the magnitude of the biochemical improvement in serum liver enzymes was significantly greater with higher doses of ursodeoxycholic acid; at 20 mg/kg body wt/day it was similar to that reported for patients with other liver diseases administered lower doses. Biliary ursodeoxycholic acid enrichment increased with increasing doses, attaining 42% +/- 6% of the total biliary bile acids with the highest dose. Fasting serum ursodeoxycholic acid concentrations increased during ursodeoxycholic acid administration but were variable and correlated poorly with the dose of ursodeoxycholic acid administered, whereas no correlation was found between serum ursodeoxycholic acid concentration and the proportion of ursodeoxycholic acid in bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol 7α-hydroxylase activities in the rat, guinea pig, and rabbit: Effects of cholesterol and bile acids

The regulation of the classic and alternative bile acid synthetic pathways by key hepatic enzyme activities (microsomal cholesterol 7α-hydroxylase and mitochondrial sterol 27-hydroxylase, respectively) was examined in bile acid depletion and replacement and cholesterol-feeding experiments with rats, guinea pigs, and rabbits. The bile acid pool was depleted by creating a bile fistula (BF) and collecting bile for 2 to 5 days, and it was replaced by intraduodenal infusion of the major biliary bile acids (taurocholic acid [TCA], glycochenodeoxycholic acid [GCDCA], and glycocholic acid [GCA] in the rat, guinea pig, and rabbit, respectively) at rates equivalent to the measured hepatic flux of the bile acids. To study the effects of cholesterol, the animals were fed for 7 days on a basal diet with and without 2% cholesterol. Cholesterol 7α-hydroxylase and sterol 27-hydroxylase activities, measured by isotope incorporation assays, were related to bile acid output and composition and hepatic cholesterol concentrations. Intraduodenal infusion of bile acids increased the output of the tested bile acids, but did not significantly change hepatic cholesterol concentrations and had no effect on sterol 27-hydroxylase activity. Neither bile acid depletion nor replacement affected sterol 27-hydroxylase activity when three different substrates (cholesterol, 5β-cholestane-3α,7α-diol, and 5β-cholestane-3α,7α,12α-triol) were tested. In contrast, feeding 2% cholesterol increased hepatic cholesterol concentrations in rats, guinea pigs, and rabbits threefold, twofold, and eightfold, respectively, and increased hepatic mitochondrial sterol 27-hydroxylase activity (conversion of cholesterol to 27-hydroxycholesterol) in all three animal models. The stimulation and feedback inhibition of cholesterol 7α-hydroxylase activity by bile acid depletion and replacement were observed in all three animal models, whereas the effect of cholesterol feeding was species-dependent (cholesterol 7α-hydroxylase activity increased in the rat, did not change in the guinea pig, and was inhibited in the rabbit). Thus, in contrast to sterol 27-hydroxylase, which was upregulated by cholesterol but not affected by bile acid depletion and replacement in all three animal models, cholesterol 7α-hydroxylase activity was controlled consistently and inversely by the hepatic flux of bile acids, but was species-dependent in its response to a 1-week feeding with 2% cholesterol.     

Ileal absorption of bile acids in patients with chronic cholestasis

The effect of cholestasis on ileal bile acid absorption is controversial in animal models (up-or down-regulation) and unknown in humans. We therefore studied values of the selena homotaurocholic acid (SeHCAT) test before and after long-term administration (>3 months, 13–15 mg/kg/day) of ursodeoxycholic acid (UDCA) in 27 patients with chronic cholestatic liver diseases (24 women, 3 men; mean age, 50 years; 24 primary biliary cirrhosis, 2 secondary biliary cirrhosis, 2 others). The control group consisted of 14 healthy volunteers. Seven-day SeHCAT percentage retention was identical in the 12 untreated cholestatic patients (serum bilirubin, 75 ± 42 µmol/L, alkaline phosphatase, 4.2 ± 1.0N; mean ± SEM) and in the control group (43.6 ± 2.9 and 43.8 ± 4.2%, respectively). In the 22 patients treated by UDCA for 38 ± 8 months, SeHCAT percentage retention was 20.3 ± 3.0%. In the seven patients with the SeHCAT test done before and after UDCA treatment (16 ± 5 months), SeHCAT percentage retention decreased significantly under UDCA therapy (42.0 ± 4.4 vs 19.4 ± 4.1%; P < 0.02). We conclude that, in patients with chronic cholestasis (1) SeHCAT percentage retention is not altered—taken together with the known defect of biliary excretion, this lack of increase in SeHCAT percentage retention argues against up-regulation of bile acid ileal transport; and (2) UDCA treatment induces a decrease in the SeHCAT percentage retention—this effect may be related primarily to a decreased bile acid ileal absorption.