The effectual level of ursodeoxycholic acid in therapy for non-advanced chronic cholestasis is fifty percent of total serum bile acids

Ursodeoxycholic acid therapy (600 mg/day) was evaluated in twelve patients with nonadvanced chronic cholestasis. Within four months, ursodeoxycholic acid replaced more than 50% of total bile acids in 8 patients and the reduction of serum γ-glutamyltranspeptidase, alkaline phosphatase and transaminases averaged 30% or more. The serum levels of chenodeoxycholic acid depend on those of ursodeoxycholic acid, but are not related to those of biochemical parameters. Drug therapy was continued in three poor responders for 2–3 four-month periods. In one case an increase of the serum proportion of ursodeoxycholic acid was associated with a reduction in biochemical parameters. The other two cases had high serum levels of chenodeoxycholic acid and/or cholic acid throughout the entire course of treatment. While the treatment of chronic cholestasis requires an effectual serum proportion of ursodeoxycholic acid, it is important to distinguish endogenous persistent hyper-bile-acidemia from ursodeoxycholic acid-related acidemia.     

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 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.     

Effect of ursodeoxycholic acid administration on bile duct proliferation and cholestasis in bile duct ligated rat

The origin, mechanism, and significance of the bile duct proliferation (BDP) associated with cholestasis remain unexplained. This study examined the effect of oral administration of ursodeoxycholic acid (UDCA) on both BDP and cholestasis in the rat. After bile duct ligation, male Sprague-Dawley rats were treated for 30 days with either UDCA (5 mg/day) (group A) or saline solution (group B). Animals were sacrificed at day 30. The serum activity of aminotransferase (ALT, AST), alkaline phosphatase, and -glutamyltransferase (GGT) was significantly lower (P<0.01) in the UDCA-treated rats. Total serum bilirubin and total serum bile acids were lower (P<0.001) in group A. Moreover, the control of BA in bile was reduced also (P<0.02). Conversely, serum cholesterol levels were not different between the two groups. Histological examination showed that the number of ductular cells in the portal areas was significantly (P<0.001) reduced in UDCA-treated as compared to saline-treated rats. The replication activity, assessed as the number of bromodeoxyuridine-positive cells, was also significantly lower in treated animals (33±11 vs 64±22 per 1000 cells;P<0.001). Lobular bile ductules were three times larger in group B, and extrahepatic duct measurements confirmed this increase in size of the larger biliary ducts (P<0.001). These findings demonstrate that UDCA reduces BDP in response to BD ligation. Although the mechanism(s) of this effect is still hypothetical, UDCA may reduce the level of irritating bile salts such as chenodeoxycholic acid and lithocolate and increase periductular bile acid recirculation. These data support the beneficial effect of UDCA treatment in chronic cholestatic disease.     

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%).     

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.     

Increase of sulfated ursodeoxycholic acid in the serum and urine of patients with chronic liver disease after ursodeoxycholic acid therapy

The present study was undertaken in order to investigate the influence of ursodeoxycholic acid (UDCA) on the composition of sulfate-conjugated bile acids in the serum and urine of patients with chronic active hepatitis and compensated liver cirrhosis. After a 12 week UDCA treatment (600 mg/day), total serum bile acid concentration increased two-fold in patients with compensated liver cirrhosis and increased slightly in patients with chronic active hepatitis. The percentage of sulfated bile acids significantly increased in patients with both compensated liver cirrhosis and chronic active hepatitis. UDCA made up 63% of the total serum bile acids in compensated liver cirrhosis and 61% in chronic active hepatitis after UDCA treatment. Of the serum bile acids after UDCA treatment, 35.2 and 53.9% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. Urinary excretion of total bile acid and UDCA after UDCA treatment in compensated liver cirrhosis were higher than in chronic active hepatitis. UDCA made up 68% of the total urinary bile acids in compensated liver cirrhosis and 64% in chronic active hepatitis after UDCA treatment. Of the urinary bile acids after UDCA treatment, 51.8 and 54.8% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. UDCA treatment for compensated liver cirrhosis was less effective than for chronic active hepatitis. We found that sulfate conjugation is one of the major metabolic pathways for UDCA after UDCA treatment in chronic liver diseases.     

Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid

Intrahepatic cholestasis of pregnancy (ICP) is a disease characterized by generalized pruritus and biochemical cholestasis that appears typically during the last trimester of gestation. The most predictive and accurate markers for diagnosis and follow-up of ICP are increased total bile acid levels (above 11,0 micromol/L), enhanced cholic acid percentage (above 42%) and decreased glycine/taurine bile acid ratio (below 1.0). Although essentially benign for the mother, evidence associates ICP with fetal poor prognosis resulting from increased transfer of bile acids from mother to fetus, who showed reduced ability to eliminate bile acids across the placenta. Those conditions lead to an accumulation of bile acids in the cord blood serum, meconium and amniotic fluid that may account for a diminished fetal well-being and sudden intra-uterine death by ICP. Ursodeoxycholic acid (UDCA) treatment was shown to reduce the bile acid content in the fetal compartment, while restoring the ability of the placenta to carry out vectorial transfer of these compounds towards the mother, decreasing bile acid levels in maternal serum and its passage to the fetus. In addition, UDCA administered to the mother also lowers the amount of bile acids present in colostrum without either increasing the UDCA concentration or causing major changes in lithocholic acid levels, further supporting the safety of UDCA in late pregnancy. Therefore, it is tempting to indicate UDCA as a first choice therapy for ICP as much as relevant aspects of fetal outcome may also be improved. This review focuses on the altered bile acid profiles in maternal and fetal compartments during ICP and its recovery by UDCA administration. Further elucidation of the precise mechanisms of action of UDCA and its therapeutic potential in improving fetal prognosis could result in the approval of UDCA for ICP treatment.     

Effect of chronic administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids in man

The effect of long-term administration of ursodeoxycholic acid on the ileal absorption of endogenous bile acids was determined using the tauro 23 (75Se) selena-25 homotaurocholic acid test in a controlled double-blind study involving healthy subjects (n = 15). Subjects received placebo or 13 to 15 mg/kg/day ursodeoxycholic acid for 5 wk. In the placebo group (n = 7) there was no change in the composition of serum bile acids or in the mean percentage of retention of tauro 23(75Se) selena-25 homotaurocholic acid (36.1% +/- 6.0% vs. 38.7% +/- 6.7%). In contrast, in the ursodeoxycholic acid group, serum ursodeoxycholic acid conjugates increased and the percentage of retention of tauro 23 (75Se) selena-25 homotaurocholic acid fell from 45.8% +/- 6.8% to 20.5% +/- 5.7% (p less than 0.01). We conclude that ursodeoxycholic acid administration reduces ileal absorption of endogenous bile acids. These findings provide a rational explanation for the changes in the composition of the bile acid pool during ursodeoxycholic acid therapy and could have important therapeutic implications.     

Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: a dose-response study.

The effect of ursodeoxycholic acid administration on liver function tests and on bile acid metabolism was investigated in 18 patients with chronic active hepatitis. Three different doses of ursodeoxycholic acid--250 mg, 500 mg and 750 mg--were administered daily to each patient for consecutive 2-mo periods. The order of doses was randomly assigned according to a replicated Latin-square design. A significant decrease in serum transaminases and gamma-glutamyl transpeptidase occurred with the lowest dose of ursodeoxycholic acid, which corresponded to 4 mg/kg body wt/day, and no further significant decrease with the higher doses was seen. Biliary bile acid composition was determined by high-performance liquid chromatography and gas chromatography-mass spectrometry. At entry the relative proportions of major bile acids were similar to those observed in normal individuals. During treatment the mean percentage of ursodeoxycholic acid in bile (22% with the 250 mg dose, 32% with the 500 mg dose and 34% with the 750 mg dose) was lower than values previously reported for patients with gallstones and normal liver function. The major bile acids were cholic, chenodeoxycholic and deoxycholic acids. A number of unusual bile acids were identified by gas chromatography-mass spectrometry, but these accounted for only 3% to 5% of the total and did not change during ursodeoxycholic acid therapy. No correlation between the improvement in liver function tests and the percentage of ursodeoxycholic acid in bile existed. These data suggest that even a slight enrichment of bile with ursodeoxycholic acid, as is attained with 250 mg/day, is effective in improving biochemical markers of liver function in patients with chronic active hepatitis.     

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 serum liver enzymes and bile acid metabolism in chronic active hepatitis C virus infection

Aim:  Many reports have revealed ursodeoxycholic acid (UDCA) to be effective against chronic hepatitis C virus (HCV). However, some cases resist this therapy and the mechanism of action remains unclear. In this study, UDCA was administered to patients with chronic HCV and the correlation between the bile acids of the biliary bile and serum and the drug efficacy was investigated.
Methods:  Fifteen patients were given 600 mg/day of UDCA for more than 24 weeks. The serum bile acid concentrations and biliary and serum bile acid were collected before and after 24 weeks of UDCA treatment, and composition determined by high-performance liquid chromatography.
Results:  The treatment was effective in nine cases (ALT decreased to less than twice the normal values 80 IU/L) and ineffective in six cases. There was no significant difference in the serum bile acid concentrations before and after UDCA treatment between the values of both cases. After UDCA treatment, the serum percentage of UDCA (effective, 62.5 ± 2.0; ineffective, 53.5 ± 2.5, ( P  = 0.02)) and the percentage of chenodeoxycholic acid (CDCA) showed no remarkable changes. In the biliary bile the percentage of CDCA (effective, 30.9 ± 2.0; ineffective, 20.0 ± 3.0, ( P  = 0.007)) and the percentage of UDCA showed no remarkable changes.
Conclusion:  In the effective cases, the percentage of UDCA in the serum and the percentage of CDCA in biliary bile were significantly higher than in the ineffective cases. This indicates that, when effective, CDCA decreases in hepatocytes and this reduction contributes to hepatoprotection.     

Diagnostic value of serum primary bile acids in detecting bile acid malabsorption.

Serum cholic and chenodeoxycholic acid conjugates were measured in fasting conditions and after meals in 14 patients with bile acid malabsorption due to ileal resection. Mean serum fasting levels of both primary bile acids did not differ from the controls. After meals, serum cholic acid peaks were lower in patients with ileal resection than in control subjects (p less than 0.001), while chenodeoxycholic acid peaks were reduced in colectomised patients (p less than 0.01). In the sera from patients with ileal resection, the glycine/glycine + taurine ratio for cholic and chenodeoxycholic acid increased (p less than 0.001) from morning to evening, and glycine/glycine + taurine ratio for chenodeoxycholic acid was significantly (p less than 0.01) different from the controls in the sera collected in the evening. The results are consistent with the concept of a better intestinal conservation of chenyl, mainly of the glycine conjugated from, than of cholylconjugates, in patients with ileal resection; this is probably because of passive absorption in the intestine. The postprandial peaks of serum cholic acid conjugates may therefore be regarded as a test of ileal dysfunction, while peaks of chenodeoxycholic acid conjugates suggest colonic impairment.     

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.     

Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations

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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.     

Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy.

The efficacy and safety of ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy was investigated in an open pilot study. Five patients received 1 gm/day of ursodeoxycholic acid during 20 days and another three patients received two identical periods of treatment separated by a 14-day interval free of the drug. Pruritus and serum levels of total bile salts and glutamic-pyruvic transaminase improved significantly during treatment with ursodeoxycholic acid. In the three patients who received two periods of treatment with ursodeoxycholic acid, pruritus and the laboratory alterations relapsed in the second week after the drug was discontinued, but they improved again when ursodeoxycholic acid was readministered. No adverse reactions were detected in the mothers or in their babies. All newborns were thriving normally during a follow-up period that lasted 5 mo after delivery. It is concluded that UDCA appears to be safe when administered in late pregnancy; its promising efficacy in the treatment of intrahepatic cholestasis of pregnancy should now be confirmed in controlled clinical trials.     

Effects of ursodeoxycholic acid on synthesis of cholesterol and bile acids in healthy subjects

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA) decreases biliary secretion of cholesterol and is therefore used for the dissolution of cholesterol gallstones. It remains unclear whether these changes in biliary cholesterol excretion are associated with changes in cholesterol synthesis and bile acid synthesis. We therefore studied the activities of rate-limiting enzymes of cholesterol synthesis and bile acid synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol 7alpha-hydroxylase, respectively, in normal subjects during UDCA feeding. METHODS: UDCA was given to 8 healthy volunteers (5 men, 3 women; age 24-44 years) in a single dose of 10-15 mg/kg body weight for 40 days. Before and during (days 3, 5, 10, 20, 30 and 40) UDCA treatment, urinary excretion of mevalonic acid and serum concentrations of 7alpha-hydroxy-4-cholesten-3-one (7alpha-HCO) were determined as markers of cholesterol and bile acid synthesis, respectively. The Wilcoxon signed rank test and Spearman's rank correlation coefficient were used for statistical analysis. RESULTS: Cholesterol synthesis and serum lipid concentrations remained unchanged during UDCA treatment for 40 days. However, synthesis of bile acids increased during long-term treatment with UDCA as reflected by an increase in 7alpha-HCO serum concentrations from 39.7 +/- 21.3 ng/ml (median 32.8 ng/ml) before treatment to 64.0 +/- 30.4 ng/ml (median 77.5 ng/ml) at days 30-40 of UDCA treatment (p < 0.05). CONCLUSIONS: UDCA treatment does not affect cholesterol synthesis in the liver, but does increase bile acid synthesis after prolonged treatment. This may represent a compensatory change following decreased absorption of endogenous bile acids as observed with UDCA therapy.     

Effect of ursodeoxycholic acid (UDCA) therapy for compensatory liver cirrhosis on liver function tests and serum bile acid metabolism]

Effect of ursodeoxycholic acid (600 mg/day 12 weeks) on liver function tests and bile acid metabolism were investigated in 6 patients with compensatory liver cirrhosis (CLC) and 6 with chronic active hepatitis (CAH). Serial determination of serum GOT, GPT and gamma-GTP after the initiation of UDCA revealed significant reduction in mean levels of these enzymes after 4 weeks, and further improvement was observed at the end of the 12-weeks treatment regimen (CLC: 79.3%, 81.1%, 51.5% of initial values, respectively, CAH: 61.2%, 59.3%, 42.8%). On the other hand, after UDCA administration, serum total bile acid increased and UDCA became the predominant bile acid in CLC and CAH patients. Other endogenous bile acids decreased in both groups, but reduction rate of serum chenodeoxycholic acid level in CLC was smaller than that in CAH group (CLC: 86.1% of initial values, respectively, CAH: 54.2%). During UDCA treatment, apparent side effect was not observed. We suggest that UDCA administration might constitute effective treatment for compensatory liver cirrhosis as well as chronic hepatitis.