Effects of treatment with deoxycholic acid and chenodeoxycholic acid on the hepatic synthesis of cholesterol and bile acids in healthy subjects

The degradation of cholesterol to bile acids is regulated by a negative-feedback mechanism by the bile acids, especially the hydrophobic bile acids, returning to the liver via the portal vein. Chenodeoxycholic acid (CDCA) is a potent suppressor of the cholesterol 7alpha-hydroxylase, the rate-determining enzyme in bile acid formation. CDCA may also suppress hepatic 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Conflicting reports have appeared regarding the suppression on bile acid synthesis by the most hydrophobic bile acid of human bile, deoxycholic acid (DCA). To study the suppressive effects of CDCA and DCA on hepatic cholesterol and bile acid synthesis in humans, 10 healthy subjects were treated with CDCA or DCA for 3 weeks in a randomized cross-over study with a washout period of 4 weeks in between. Serum levels of 7alpha-hydroxy-4-cholesten-3-one, reflecting cholesterol 7alpha-hydroxylase activity, and 7-dehydrocholesterol, reflecting HMG CoA reductase activity, and bile acids were repeatedly measured during the study periods. After 3 weeks of treatment with CDCA or DCA, CDCA constituted 70% and DCA 74% of the total serum bile acids, respectively. CDCA and DCA decreased the serum levels of 7alpha-hydroxy-4-cholesten-3-one by 80% and 75%, respectively. Negative correlations between the percentages of CDCA and DCA and the serum concentration of 7alpha-hydroxy-4-cholesten-3-one were obtained. CDCA reduced the serum level of 7-dehydrocholesterol by 29%, whereas treatment with DCA tended to increase the level of 7-dehydrocholesterol. Treatment of healthy subjects with CDCA and DCA reduces bile acid synthesis. CDCA also inhibits cholesterol synthesis, whereas DCA does not.     

Effects of pravastatin and ursodeoxycholic acid on cholesterol and bile acid metabolism in patients with cholesterol gallstones

To investigate the effects of pravastatin and ursodeoxycholic acid (UDCA) on cholesterol and bile acid metabolism in humans, 41 patients with cholesterol gallstone disease were allocated to four groups and treated with pravastatin (20 mg/day), UDCA (600 mg/day), both pravastatin and UDCA, or neither drug (control) for 1–2 weeks prior to elective cholecystectomy. Cholesterol 7α-hydroxylase activity and serum levels of total 7α-hydroxycholesterol were significantly increased by pravastatin and unaffected by UDCA. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was markedly increased by pravastatin and decreased by UDCA. UDCA significantly decreased biliary cholesterol concentration and the cholesterol saturation index and prolonged the nucleation time; however, pravastatin alone had little effect on biliary lithogenicity. Serum total and low-density lipoprotein (LDL)-cholesterol levels were reduced most by the combined administration of pravastatin and UDCA. In conclusion, at a dose of 20 mg/day, pravastatin increased bile acid synthesis but did not decrease biliary lithogenicity. UDCA had no significant effect on bile acid synthesis, but markedly decreased biliary lithogenicity.     

Effect of ursodeoxycholic acid and chenodeoxycholic acid on cholesterol and bile acid metabolism

Orally administered UDCA dramatically reduces the secretion of cholesterol into the bile. During UDCA therapy cholesterol balance is maintained by a reduction in both the relative and absolute absorption of cholesterol and, perhaps, by a combined moderate enhancement of bile acid synthesis and a suppression of cholesterol production. The percentage of UDCA in the bile is limited by the inability of UDCA to suppress bile acid synthesis from cholesterol and by the conversion of UDCA to CDCA by the intestinal bacteria.     

Effects of ursodeoxycholic acid and taurine on serum liver enzymes and bile acids in chronic hepatitis

Hydrophobic bile acids have been shown to be hepatotoxic, whereas treatment with ursodeoxycholic acid, a hydrophilic bile acid, has improved liver function indices in patients with chronic liver disease. Taurine administration has also been suggested to be useful for chronic hepatitis, taurine-conjugated bile acids being more hydrophilic than glycine-conjugated bile acids. To determine if taurine and ursodeoxycholic acid are beneficial and if their effects are additive, a double-blind, randomized trial was designed comparing the effects of ursodeoxycholic acid, taurine, and a combination of the two on indices of liver injury in 24 patients with chronic hepatitis. They were assigned at random to two of the four following treatments: ursodeoxycholic acid (600 mg/day), taurine (1.5 g/day), ursodeoxycholic acid plus taurine (600 mg + 1.5 g/day) or placebo, given in two successive cycles of 2 mo each, according to a balanced incomplete-block design. Ursodeoxycholic acid became the predominant biliary bile acid when administered alone or in combination with taurine, and taurine conjugate levels increased during taurine administration. Ursodeoxycholic acid reduced aspartate aminotransferase (35%), alanine aminotransferase (33%), and gamma-glutamyl transpeptidase (41%), whereas taurine alone did not. The addition of taurine to ursodeoxycholic acid produced only minor changes in the effects of ursodeoxycholic acid alone. Results were confirmed by the administration of ursodeoxycholic acid, in a successive open phase of the study, to the entire patient population, which was large enough for different subsets of patients to be compared. Serum bile acids were measured at entry and during the open phase: primary bile acids did not change, whereas ursodeoxycholic acid levels increased from trace amounts to very high levels, especially in patients with more severe histological disease. It is concluded that ursodeoxycholic acid, but not taurine, improves enzymatic indices of liver injury in chronic hepatitis.     

Effects of ethinyl estradiol and phenobarbital on bile acid synthesis and biliary bile acid and cholesterol excretion.

Bile acid synthesis calculated from respiratory (14)CO2 derived from the catabolism of [26 or 27-(14)C]cholesterol to bile acids in rats with intact enterohepatic circulations decreased 50% after 5 days of ethinyl estradiol treatment (5 mg per kg per day). Maximal derepressed bile acid synthesis, measured as biliary bile acid excretion after bile acid pool depletion, was also reduced 50% by ethinyl estradiol treatment. Because ethinyl estradiol did not alter biliary cholesterol excretion, bile contained less bile acid relative to cholesterol. Hepatic bile acid concentration was not increased by ethinyl estradiol treatment. Because the inhibitory effect of ethinyl estradiol on bile acid synthesis required 5 days of treatment it is concluded that bile acid synthesis probably was not reduced by negative feedback repression of 7alpha-hydroxylase, the rate-limiting enzyme in bile acid synthesis, which has a half-life of 2 to 3 hr. During the first 14 hr after bile duct cannulation, before bile acid pool depletion, ethinyl estradiol-treated rats excreted less than one-half as much bile acid and the same amount of cholesterol as controls. The bile acid to cholesterol ratio was therefore decreased. Rats treated simultaneously with phenobarbital and ethinyl estradiol excreted significantly more bile acid than rats treated with ethinyl estradiol alone, but biliary cholesterol excretion was not increased. The proportion of biliary bile acid relative to cholesterol was thereby restored to the control value. In contrast, after 14 hr of bile drainage and depletion of the bile acid pool, rats treated with ethinyl estradiol and those treated with phenobarbital-ethinyl estradiol excreted the same amount of bile acid. Thus, when phenobarbital is administered with ethinyl estradiol, it increases the bile acid pool size and biliary bile acid excretion, but it does not increase bile acid synthesis. The increase in pool size and biliary bile acid excretion might be due to the phenobarbital-induced increase in ileal absorption of bile acids.     

Low-dose ursodeoxycholic acid prolongs cholesterol nucleation time in gallbladder bile of patients with cholesterol gallstones

The high rate of stone recurrence represents a drawback of non-surgical therapy of cholesterol gallstone disease. Although most studies report that long-term bile acid treatment does not have protective effects, preliminary results suggest that low-dose ursodeoxycholic acid decreases the rate of gallstone recurrence in a subgroup of younger patients. To clarify the underlying mechanism we investigated whether low-dose ursodeoxycholic acid treatment influences biliary cholesterol saturation and/or nucleation time of cholesterol. Ten patients with cholesterol gallstones and functioning gallbladder received 250 mg ursodeoxycholic acid/day at bedtime 6-10 days prior to cholecystectomy. Eleven patients with cholesterol gallstones without treatment served as controls. Cholesterol crystals were present in the gallbladder bile of 7 out of the 10 patients receiving ursodeoxycholic acid and in all control biles. Ursodeoxycholic acid treatment significantly (P less than 0.02) decreased the cholesterol saturation index (mean +/- S.E.: 0.94 +/- 0.05 vs. 1.43 +/- 0.18) and led to an approximately 5-fold prolongation (P less than 0.005) of the cholesterol nucleation time (mean +/- S.E.: 12.0 +/- 2.4 vs. 2.3 +/- 0.7 days). We conclude that low-dose ursodeoxycholic acid might be effective in the prevention of post-dissolution gallstone recurrence by both decreasing cholesterol saturation and prolonging cholesterol nucleation time.     

LDL cholesterol lowering by bile acid malabsorption during inhibited synthesis and absorption of cholesterol in hypercholesterolemic coronary subjects

BACKGROUND AND AIMS: Recent large-scale trials have consistently documented the fact that a 25-35% reduction in low-density lipoprotein cholesterol (LDL-C) can delay the progression of atherosclerosis. This raises the question as to how much it is possible to reduce serum cholesterol using feasible therapies. The aim of this study was to investigate the cholesterol-lowering efficacy of a triple therapy combining bile acid malabsorption with the inhibition of cholesterol synthesis and absorption. METHODS AND RESULTS: Eleven consecutive hypercholesterolemic coronary patients from Lipid Clinics on a low-fat, low-cholesterol baseline diet added simvastatin (20 mg/day) for three months, and then dietary plant stanol ester margarine (2.25 g of stanols/day) for eight weeks; finally, cholestyramine 8 g/day was added for another eight weeks. This was a before-after trial, in which the results of each period were compared with baseline and those of the previous period. Serum lipids were quantitated using commercial kits, and serum sterols by means of gas-liquid chromatography. Simvastatin lowered LDL-C by 39% (p < 0.001), and additional stanol ester margarine by a further 13% (p < 0.05). The triple treatment led to 67% reduction from baseline (p < 0.001), with all LDL-C values being < 2.6 mmol/L, and increased high-density lipoprotein cholesterol (HDL-C) by 15% (p < 0.01). It also increased the serum lathosterol/cholesterol ratio (p < 0.01), thus indicating an upregulation of cholesterol synthesis, and increased the serum sitosterol ratio (p < 0.01) despite the simultaneous consumption of plant stanols. CONCLUSIONS: The massive reduction in LDL and increase in HDL-C obtained using our triple therapy suggests that the combination of stanol ester with only moderate doses of statin and resin makes it possible to control LDL-C levels effectively in hypercholesterolemic subjects.     

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.     

Effect of ursodeoxycholic acid administration on biliary lipid composition and bile acid kinetics in cholesterol gallstone patients

The effect of ursodeoxycholic acid (UDCA) on bile lipid composition and bile acid kinetics was evaluated in seven cholesterol gallstone patients following one month of UDCA administration (12 mg/kg/day). UDCA administration induces a significant reduction in the cholesterol saturation index (SI). After UDCA treatment, UDCA becomes the predominant biliary bile acid while chenodeoxycholic, cholic, and deoxycholic acid are significantly reduced. UDCA pool significantly increases, and chenodeoxycholic, cholic, and total bile acid pools significantly decrease. The reduction in bile lithogenicity during UDCA administration suggests that UDCA may be useful for cholesterol gallstone treatment in man.     

Hepatic cholesterol and bile acid synthesis in Japanese patients with cholesterol gallstones

In Japan the composition of gallstones is changing rapidly from the once-predominant brownpigment stones to cholesterol ones. The present work was undertaken to clarify the mechanism of cholesterol supersaturated bile production in Japanese patients with cholesterol gallstones. In 26 non-obese and normolipidemic patients (11 with cholesterol gallstones, 8 with black- or brown-pigment gallstones, 7 without gallstones) a liver biopsy and hepatic bile were surgically obtained under standardized conditions. The cholesterol saturation of hepatic bile was significantly higher in cholesterol gallstone patients than in gallstone-free controls (195 ±10 vs. 146 ±8%, respectively; P < 0.01). The microsomal activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis, cholesterol 7 α-hydroxylase, the rate-limiting enzyme for bile acid synthesis, and 7 α-hydroxy-4-cholesten-3-one 12 α-hydroxylase (12 α-hydroxylase), the rate-limiting enzyme for cholic acid synthesis, were assayed simultaneously in the same subjects. There were positive correlations between HMG-CoA reductase and cholesterol 7 α-hydroxylase activities (Rs = 0.62, P < 0.005), and between cholesterol 7 α-hydroxylase and 12 α-hydroxylase activities (Rs = 0.44, P < 0.05) in all subjects, irrespective of the existence of gallstones. The activities of the three rate-limiting enzymes did not differ significantly among the three groups (cholesterol stone, pigment stone and stone-free). In conclusion, the cholesterol supersaturation of hepatic bile in nonobese and normolipidemic Japanese patients with cholesterol gallstones does not result from an increased hepatic cholesterol synthesis or a decreased bile acid synthesis. This study was supported in part by a Grant-in-Aid for Scientific Research (No. 02454226) from the Ministry of Education, Science and Culture of Japan, and a grant from University of Tsukuba Project Research.     

Regulation of bile acid synthesis. II. Effect of bile acid feeding on enzymes regulating hepatic cholesterol and bile acid synthesis in the rat

Bile acid synthesis is believed to be regulated by bile salts returning to the liver via the portal vein and suppressing cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the bile acid biosynthesis pathway. In order to characterize the relative effectiveness of bile salts in regulating bile acid synthesis, seven different bile acids were administered (1% w/w in chow) to rats over a 14-day period. Biliary bile salt composition was determined from bile samples obtained prior to killing; in all cases, the fed bile acid became the predominant bile salt in bile. The specific activities of microsomal cholesterol 7 alpha-hydroxylase, HMG-CoA reductase and acylconenzyme A:cholesterol acyltransferase were determined after killing. Hydrophilic bile salts (ursocholic, hyocholic, ursodeoxycholic and hyodeoxycholic) did not inhibit HMG-CoA reductase or cholesterol 7 alpha-hydroxylase activities. By contrast, more hydrophobic bile salts (cholic, chenodeoxycholic and deoxycholic) inhibited the activities of these two enzymes in order of increasing hydrophobicity. Neither hydrophobic nor hydrophilic bile salts inhibited acylcoenzyme A:cholesterol acyltransferase activity. No consistent effect of bile acid feeding on total microsomal cholesterol was observed. Based on the results of these studies, we propose that the hydrophilic-hydrophobic balance of the bile acid pool may play an important role in the regulation of bile acid synthesis. We postulate that the activities of cholesterol 7 alpha-hydroxylase and HMG-CoA reductase may be regulated by hydrophobic bile acid-induced changes in the lipid composition and physicochemical properties (fluidity) of the microsomal membranes to which both of these rate-limiting enzymes are attached.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of ursodeoxycholic acid on biliary lipid coupling and on cholesterol absorption during fasting and eating in subjects with cholesterol gallstones

The aim of this study was to determine the effect of chronic ursodeoxycholic acid administration on coupling of bile acids with cholesterol and phospholipid in hepatic bile, and on cholesterol absorption in the duodenum. A range of bile acid secretion rates was obtained during an evening meal and an overnight fast. Duodenal perfusion of polyethylene glycol as a nonabsorbable recovery marker and of [3H]cholesterol and [14C]lecithin as absorbable recovery markers was combined with continuous intravenous infusion of indocyanine green as a hepatic bile marker. Six subjects with gallstones were studied before and during chronic administration of ursodeoxycholic acid (675 mg/day). Duplicate pretreatment studies revealed good reproducibility for biliary lipid coupling and cholesterol absorption. During ursodeoxycholic acid administration there was a significant alteration not only in bile acid/cholesterol coupling (p less than 0.001), but also in bile acid/phospholipid coupling (p less than 0.001). Mean cholesterol absorption decreased from 25% to 15% (p less than 0.001) during ursodeoxycholic acid administration. These effects of chronic ursodeoxycholic acid administration on biliary lipid coupling are similar to those reported for acute administration, and are thus consistent with an effect caused by bile acid lipid-solubilizing capacity.     

Biliary bile acids in primary biliary cirrhosis: effect of ursodeoxycholic acid.

Bile acid composition in fasting duodenal bile was assessed at entry and at 2 years in patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) (10-12 mg/kg/d) taken as a single bedtime dose. Specimens were analyzed by a high-pressure liquid chromatography method that had been validated against gas chromatography. Percent composition in bile (mean +/- SD) for 98 patients at entry for cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), lithocholic (LCA), and ursodeoxycholic (UDCA) acids, respectively, were 57.4 +/- 18.6, 31.5 +/- 15.5, 8.0 +/- 9.3, 0.3 +/- 1.0, and 0.6 +/- 0.9. Values for CA were increased, whereas those for CDCA, DCA, LCA, and UDCA were decreased when compared with values in normal persons. Bile acid composition of the major bile acids did not change after 2 years on placebo medication. By contrast, in patients receiving UDCA for 2 years, bile became enriched with UDCA on average to 40.1%, and significant decreases were noted for CA (to 32.2%) and CDCA (to 19.5%). No change in percent composition was observed for DCA and LCA. Percent composition at entry and changes in composition after 2 years on UDCA were similar in patients with varying severity of PBC. In patients whose bile was not enriched in UDCA (entry and placebo-treated specimens), CA, CDCA, DCA, and the small amount of UDCA found in some of these specimens were conjugated to a greater extent with glycine (52%-64%) than with taurine (36%-48%). Treatment with UDCA caused the proportion of all endogenous bile acids conjugated with glycine to increase to 69% to 78%, while the proportion conjugated with taurine (22%-31%) fell (P <.05). Administered UDCA was also conjugated predominantly with glycine (87%).     

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.     

Hepatocellular bile acid transport and ursodeoxycholic acid hypercholeresis

This review focuses on mechanisms of bile acid transport across the basolateral and canalicular hepatocyte plasma membranes and on ursodeoxycholic acid (UDCA) hypercholeresis and biotransformation. Conjugated trihydroxy bile acids enter hepatocytes via a sodium-coupled mechanism localized to the basolateral membrane, which is saturable, concentrative, inhibited by other bile acids as well as by furosemide and bumetanide, and exhibits developmental changes in rats and probably also in humans. The stoichiometry of sodium-coupled bile acid uptake has been controversial. Hydrophobic, unconjugated dihydroxy and monohydroxy bile acids, including UDCA, enter hepatocytes more rapidly than does taurocholate, and their uptake is largely nonsaturable and sodium independent. A hydroxyl-exchange mechanism that mediates the uptake of cholic acid has also been reported, but its existence is controversial. Current evidence suggests that a 49-kDa protein mediates Na⁺-dependent taurocholate uptake and that a 54-kDa protein is involved in Na⁺-independent bile acid uptake. Studies with canalicular membrane vesicles have demonstrated saturable, sodium-independent taurocholate transport, which is sensitive to electrical potential, exhibits trans-stimulation, and appears to be mediated by a 100-kDa canalicular membrane glycoprotein. Studies in mutant rats with conjugated hyperbilirubinemia suggest the presence of a separate canalicular transport mechanism utilized by sulfated bile acids and organic anions such as bilirubin and sulfobromophthalein. UDCA produces in some species a dramatic hypercholeresis that is greater than expected based on the osmotic effect of the secreted bile acid. The hypercholeresis appears attributable to stimulation of biliary bicarbonate output and is decreased or abolished in the perfused rat liver by amiloride or perfusate Na⁺ substitution. These same maneuvers dramatically alter UDCA biotransformation (unconjugated UDCA disappears from bile, and UDCA glucuronide becomes a major metabolite) and lower hepatocyte intracellular pH. These and other findings indicate that UDCA hypercholeresis is tightly linked to biliary excretion of the unconjugated species and suggest that UDCA biotransformation may be influenced by intracellular pH.     

Effect of ursodeoxycholic acid on biliary bile acid and bile lipid composition in gallstone patients

In five patients with radiolucent gallstones, the effect of ursodeoxycholic acid (Urso) in doses of 250, 500, 750, 1,000, and 1,250 mg per day on biliary lipid and bile acid composition was studied. Biliary cholesterol decreased from 8.8 +/- 0.8 mole% to 4.4 +/- 0.2 mole% at 500 mg Urso per day (7.1 mg per kg) and to 4.2 +/- 0.3 mole% at 750 mg Urso per day (10.7 mg per kg). Administration of 1,000 or 1,250 mg Urso per day produced no further decrease of biliary cholesterol. The biliary content of phospholipids and total bile acids remained unchanged. During Urso treatment, the relative amounts of glyco-Urso and tauro-Urso in bile increased. Glyco-Urso reached a plateau at 49.1 +/- 2.1% of total bile acids during treatment with 1,000 mg Urso per day, and tauro-Urso increased up to 4.3 +/- 1.5% of total bile acids at 250 mg Urso per day. Simultaneously cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid decreased. The data indicate that Urso treatment reduces biliary cholesterol efficiently already at a dose of 500 mg per day; biliary bile acid composition changes up to 1,000 mg Urso per day. Doses greater than 1,000 mg per day produced no additional alterations in bile composition.     

Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy

Background/Aims and Methods: The mechanism(s) behind the effects of ursodeoxycholic acid on serum steroid sulphate profiles in patients with intrahepatic cholestasis of pregnancy is not clear. Conjugated progestone metabolites and bile acids have therefore been analyzed in serum and urine of patients with intrahepatic cholestasis of pregnancy before and during treatment with ursodeoxycholic acid using chromatographic and mass spectrometric methods.Results: The concentration of glycine-/taurine-conjugated bile acids decreased from 8.9±3μmol/l (mean± SEM) before treatment to 1.8±0.6 sml/l during treatment with ursodeoxycholic acid. The total bile acid excretion in urine decreased from 56±14 to 32±5.6 μmol/g creatinine. The proportion of cholic acid in serum and urine, and of 1β-, 2β- and 6α-hydroxylated cholic acids in urine decreased markedly during ursodeoxycholic acid while the percentages of 3α, 12α-dihydroxy-3-oxo-4-cholenoic acid and chenodeoxycholic acid were unchanged. The levels in serum and excretion in urine of sulphated steroids decreased during ursodoexycholic acid, by 45–49% for disuphates and 33–35% for monosulphates. The ratios of 3α- to 3β-hydroxysteroid disulphates were lowered by ursodeoxycholic acid from 1.1 (mean) to 0.68 in serum, and from 1.2 to 0.70 in urine. The corresponding ratios for monosulphates before the during ursodeoxycholic acid were 6.9 and 4.5, respectively, in serum, and 21 and 5.2 respectively, in urine. The major monosulphates in urine, dominated by 5α-pregnane-3α, 20α-diol, were also conjugated with N-acetylglucosamine. The excretion of these double conjugates decreased from 27±8.4 to 15±5.3 μmol/g creatinine during ursodoexycholic acid. In contrast to suplhated steroids, the concentrations of glucruronides were unchanged in serum and their excretion in urine tended to increase during ursodeoxycholic acid. The metabolism of ursodeoxycholic acid was similar to that described in nonpregnant subjects. In addition to metabolites hydroxylated in the 1β-, 5β-, 6αβ and 22-positions, a 4-hydroxy-ursodeoxycholic acid was tentatively identified. This occurred predominantly as a double conjugate with glucine/taurine and glucuronic acid, as did other 4-hydroxylated bile acids of probable foetal origin.Conclusions: The results are compatible with the contention that ursodeoxycholic acid stimulates the biliary excretion of sulphated progesterone metabolites, particularly those with a 3α-hydroxy-5α(H) configuration and disulphates. The effects(s) appears to be independent of the stimulation of bile acid secretion. An effect of ursodeoxycholic acid on the reductive metabolism of progesterone cannot be excluded.     

Serum bile acids and oral ursodeoxycholic acid tolerance test in the diagnosis of esophageal varices

The purpose of this study was to compare the endoscopic findings based on the general rules for recording endoscopic findings on esophageal varices by the Japanese Research Society for Portal Hypertension with liver function tests including serum bile acids and bile acid clearance tests in 64 patients with liver cirrhosis. Cases of esophageal varices showed significantly higher serum bile acid levels and greater ICG retention than those without esophageal varices. The oral ursodeoxycholic acid tolerance test was significantly impaired in the group with esophageal varices (p less than 0.05). In cases with esophageal varices, there was no significant difference in serum bile acid levels between white and blue varix patients, while serum bile acid levels in the red-color sign-positive group were significantly higher than those in the negative group (p less than 0.01). Serum bile acid levels increased in parallel with the form of varices as reflected by the shape and size of varices and with the location of varices which reflects the longitudinal-extent of varices. These results indicate that the impaired clearance of serum bile acids in liver cirrhosis is closely related with the red-color sign on the variceal surface and with the form and location of esophageal varices, which may reflect the grade of portal-systemic shunting.