Clinical studies on dissolution of gallstones using ursodeoxycholic acid

Ursodeoxycholic acid (UDCA), 7beta hydroxy epimer of chenodeoxycholic acid (CDCA), has been used as a choleretica for 20 years in Japan. Recent report showing increased excretion of UDCA in bile after CDCA administration may suggest the possibility that UDCA has similar effects to CDCA on bile cholesterol unsaturation and on gallstone dissolution. The present paper describes the clinical usefulness of UDCA for gallstone patients during the past two years. Seventy-four gallstone patients with functioning gall-bladders, 19 men and 55 women with a mean age of 48 years, have been treated for 6 months or more. UDCA, supplied in tablets (Ursosan), was given 450 mg per day. The disappearance or the reduction of stone size or number, or both (dissolution effect) was recognized in 32 out of 74 patients (43%). In case of radiolucent stones, the overall effective rate was estimated for 24 of 46 patients (52%). There may be no significant difference in dissolution effect between CDCA and UDCA treatment, however, the merit of UDCA treatment seems to have its few side effects.     

Optimum bile acid treatment for rapid gall stone dissolution.

To determine the optimum bile acid regimen for rapid gall stone dissolution, 48 gall stone patients were divided into four groups of 12 according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime chenodeoxycholic acid (CDCA, 12 mg/kg/day) and bedtime or mealtime ursodeoxycholic acid (UDCA, 12 mg/kg/day). An additional 10 patients treated with a combination of CDCA plus UDCA (each 6 mg/kg/day) at bedtime were matched with the 10 patients on bedtime CDCA and the 10 on bedtime UDCA. The gall stone dissolution rates at six and 12 months were determined by standardised oral cholecystography and expressed as the percentage reduction in the gall stone volume after treatment. The gall stone dissolution rate at six months was higher for UDCA than CDCA treatment (median 78% v 48%, p less than 0.01), and for bedtime than mealtime administration (69% v 39%, p less than 0.02). Both differences were greater for stones less than 8 mm diameter. The dissolution rate was faster for combination therapy than for CDCA alone at both six (82% v 36%, p less than 0.05) and 12 months (100% v 54%, p less than 0.05), but was not different from UDCA alone. We conclude that bile acid treatment should be confined to patients with small gall stones and that bedtime administration of combined UDCA and CDCA is likely to provide the most effective and safe combination.     

Efficacy of Magnesium Trihydrate of Ursodeoxycholic Acid and Chenodeoxycholic Acid for Gallstone Dissolution: A Prospective Multicenter Trial

Background/Aims

Cholecystectomy is necessary for the treatment of symptomatic or complicated gallbladder (GB) stones, but oral litholysis with bile acids is an attractive alternative therapeutic option for asymptomatic or mildly symptomatic patients. This study was conducted to evaluate the efficacy of magnesium trihydrate of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on gallstone dissolution and to investigate improvements in gallstone-related symptoms.

Methods

A prospective, multicenter, phase 4 clinical study to determine the efficacy of orally administered magnesium trihydrate of UDCA and CDCA was performed from January 2011 to June 2013. The inclusion criteria were GB stone diameter ≤15 mm, GB ejection fraction ≥50%, radiolucency on plain X-ray, and asymptomatic/mildly symptomatic patients. The patients were prescribed one capsule of magnesium trihydrate of UDCA and CDCA at breakfast and two capsules at bedtime for 6 months. The dissolution rate, response rate, and change in symptom score were evaluated.

Results

A total of 237 subjects were enrolled, and 195 subjects completed the treatment. The dissolution rate was 45.1% and the response rate was 47.2% (92/195) after 6 months of administration of magnesium trihydrate of UDCA and CDCA. Only the stone diameter was significantly associated with the response rate. Both the symptom score and the number of patients with symptoms significantly decreased regardless of stone dissolution. Adverse events necessitating discontinuation of the drug, surgery, or endoscopic management occurred in 2.5% (6/237) of patients.

Conclusions

Magnesium trihydrate of UDCA and CDCA is a well-tolerated bile acid that showed similar efficacy for gallstone dissolution and improvement of gallstone-related symptoms as that shown in previous studies.     

Retrospective comparison of 'Cheno' and 'Urso' in the medical treatment of gallstones.

In two groups of gallstone patients ideally suited for medical treatment, the effect of six to 18 months' therapy was compared retrospectively in 52 given chenodeoxycholic acid (CDCA) and 46 given ursodeoxycholic acid (UDCA). The minimum dose (mg kg-1 day-1) required to desaturate bile consistently was 10.1 for UDCA and 14.3 for CDCA. In patients completing six months' treatment, 23 of 35 (66%) taking a mean of 7.7 (+/- SEM 0.5) mg UDCA and 34 of 42 (81%) taking 14.7 +/- 0.2 mg CDCA showed partial or complete dissolution of gallstones. The mean dose in the UDCA-treated patients, however, was artefactually lowered by previous dose-response studies: in those who had not taken multiple doses, the mean UDCA intake in the 'responders' at six months was 9.1 +/- 0.3 mg kg-1 day-1. At six months, more UDCA (five of 35 or 14.3%) than CDCA (four of 42 or 9.5%)-treated patients showed complete dissolution of gallstones, but, by one year, the situation was reversed, 20 of 41 (49%) CDCA-treated and eight of 30 (27%) UDCA-treated patients showing complete dissolution of gallstones. Cumulative efficacy at one year had risen to 76% for UDCA and 89% for CDCA. Both treatments reduced the frequency of dyspepsia and biliary colic; 37% of CDCA and 2.6% of UDCA-treated patients showed hypertransaminasaemia; diarrhoea developed in 60% of the CDCA group but in none of the UDCA group.     

Prospective,multicenter study on value of computerized tomography (CT) in gallstone disease in predicting response to bile acid therapy

The aim of the study was to assess the value of quantitative attenuation values (Hounsfield units) and of gallstone pattern by computerized tomography in predicting response to bile acid therapy. We carried out a prospective study in a multicenter setting on 90 consecutive outpatients with radiolucent gallstones. All received bile acid therapy (UDCA 10 mg/kg/day or UDCA+CDCA 5 mg/kg/day of each) up to two years. Hounsfield units for gallstones were recorded using standardized criteria and six categories of patterns were defined: hypodense, isodense, homogenously dense, laminated, rimmed and speckled. We assessed gallstone dissolution rate (percent reduction in volume), response to therapy (>25% reduction in volume), and final outcome of therapy. Eighty-one percent of patients with hypodense/isodense and all four patients with speckled stone pattern responded to therapy, whereas none of the 10 patients with laminated/rimmed and only 45% of patients with homogenously dense stone pattern did. Complete dissolution was achieved by 68%, 50%, 35%, 0% of the hypodense/isodense, speckled, homeogenously dense, rimmed/laminated gallstones, respectively. The use of Hounsfield units did not show an advantage over gallstone pattern for predicting either response or final outcome to bile acid therapy. We conclude that computerized tomography analysis of gallstones is of value in predicting response to bile acid therapy and that gallstone pattern alone predicts response in most cases without the need for quantitative assessment.This study was carried out under the auspices of the British-Italian Gallstone Study Group, which was supported by a grant from Schwarz Pharma Italia.Preliminary results from this work have been presented at the 93rd Annual Meeting of the American Gastroenterological Association in 1992 and published in abstract form (Gastroenterology 102:A329, 1992).     

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.     

Prolonged administration of bile salts for gallstone dissolution and its effect on rectal epithelial cell proliferation

Bile acids and cholesterol metabolites may play a role in large bowel carcinogenesis. Currently, the bile acids chenodeoxycholic (CDCA) and ursodeoxycholic acid (UDCA) are being used for dissolution of cholesterol gallstones in surgical high-risk patients. The effect of prolonged exogenous bile acid intake on rectal epithelial cell proliferation, as a marker for preneoplasia, was evaluated in 19 patients selected for treatment. They were divided into two groups: nine patients received CDCA, 15 mg/kg/day for a mean duration of 11.0 months, while 11 patients received UDCA, 10 mg/kg/day for a mean duration of 9.2 months. Rectal biopsies taken before treatment and at one, three, six, and 12 months of treatment were analyzed and evaluated by three proliferative parameters including labeling index (LI), distribution of labeled cells, and total cells per crypt column. No significant alterations in epithelial cell proliferation were observed among patients treated with UDCA or CDCA with the exception of the number of cells per crypt column which, in the latter instance, deviated only slightly from the predicted values. The lack of major persistent alterations in the proliferative behavior of rectal epithelial cells does not justify any change in the selection of patients for gallstone therapy, but cannot exclude the potentially deleterious long-term effects of bile acid treatment.     

Combination therapy with oral ursodeoxycholic and chenodeoxycholic acids: pretreatment computed tomography of the gall bladder improves gall stone dissolution efficacy.

In a five year study, 55 patients with radiolucent gall stones were treated with the combination of 7.5 mg chenodeoxycholic acid (CDCA) and 5.0 mg ursodeoxycholic acid (UDCA)/kg/day--that is, half the monotherapeutic doses. Side effects were few but four patients could not tolerate the prescribed bile acids because of diarrhoea or nausea. Analysis of fasting duodenal bile confirmed that CDCA+UDCA converted supersaturated into unsaturated bile but the saturation indices did not predict the dissolution response. By actuarial analysis, the confirmed (by ultrasound x2) complete gall stone dissolution rates in all 55 patients were mean (SEM) 29 (7)% at 12 and 44 (8)% at 24 months. The advent of routine computed tomography before treatment enabled comparison of dissolution efficacy in those screened by computed tomography (n = 24), whose maximum gall stone attenuation was less than 100 Hounsfield units, with that in those not screened (n = 29). Although stone size and number were comparable, patients screened by computed tomography had significantly better dissolution rates (p less than 0.025) than those not screened in this way. At 12 months, partial or complete gall stone dissolution rates were 93 (7)% in the screened and 55 (11)% in the non-screened patients. At 18 months, complete dissolution rates were 64 (12%) and 20 (9)% respectively. Computed tomography before treatment is cost effective in selecting those patients likely to achieve gall stone dissolution on treatment with UDCA+CDCA.     

Nucleation time of gall bladder bile in gall stone patients: influence of bile acid treatment.

The time required for precipitation of cholesterol crystals (nucleation time, NT) was determined and related to the cholesterol saturation in gall bladder bile of gall stone free subjects (n = 11), patients with pigment stones (n = 3), and patients with cholesterol gall stones (n = 30) undergoing cholecystectomy. Seven of the gall stone patients had been treated with chenodeoxycholic acid (CDCA) and nine with ursodeoxycholic acid (UDCA), 15 mg/kg/day for three weeks before operation. NT was longer in gall stone free subjects (mean, 20 days), patients with pigment stones (14 days) and patients treated with CDCA (24 days) and UDCA (17 days) compared with untreated patients with cholesterol gall stones (1.5 days). In spite of low cholesterol saturation and prolonged NT, and in contrast to those treated with CDCA, four of the nine patients treated with UDCA had cholesterol crystals in their bile. These observations give further support to the concept that the mechanism for inducing gall stone dissolution may be different for CDCA and UDCA.     

Effect of chenodeoxycholate and ursodeoxycholate on nucleation time in human gallbladder bile.

The effects of treatment with chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) on nucleation time, biliary lipid concentration, and vesicular lipid composition were studied. Gallbladder bile was collected at the time of surgery from 33 cholesterol gallstone patients who were divided into three groups: 16 untreated, 9 pretreated with CDCA (400 mg/day), and 8 pretreated with UDCA (600 mg/day) for 1-3 weeks before surgery. Control bile samples were also collected from nine patients without cholelithiasis. Nucleation time was prolonged significantly in both CDCA- and UDCA-treated groups [12.6 +/- 8.5 (SD) and 21.0 +/- 0 days, respectively] compared with the untreated gallstone group (3.3 +/- 3.2 days). Both treatments significantly decreased the proportion and concentration of both cholesterol and phospholipids present in the vesicular phase. Treatment with UDCA decreased the cholesterol saturation index more than did CDCA at the dose used in this study. In the CDCA-treated group, patients without much change in cholesterol saturation index (greater than 1.0) showed a prolongation of the nucleation time with a significant decrease in vesicular cholesterol concentration, indicating a shift of cholesterol from vesicles to micelles. UDCA-treated patients and CDCA-treated patients with decreased cholesterol saturation index (less than 1.0) showed a greater effect. The authors conclude that UDCA prolongs the nucleation time mainly by decreasing the cholesterol saturation index, whereas CDCA does so by the dual effect of lowering the cholesterol saturation index and shifting cholesterol from vesicles to micelles.     

Hepatoprotection in ethinylestradiol-treated rats is provided by tauroursodeoxycholic acid,but not by ursodeoxycholic acid*

Abstract Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been suggested as potential treatments for drug-induced cholestasis. It was therefore decided to study the effects of administration of UDCA or TUDCA on individual serum bile acid concentrations, conventional liver tests and associated hepatic ultrastructural changes in ethinylestradiol-treated (EE) rats (5 mg/kg per day). Control rats were treated s.c. with propylene glycol. EE-treated rats were randomly assigned to receive daily i.p. injections of placebo, TUDCA or UDCA. Four rats in each group were treated for 4 consecutive days, and a second four for 14 days. After 4 days of treatment, the serum levels of cholic acid and taurocholic acid were significantly increased in EE-treated rats. None of the conventional liver tests were significantly different among the four groups. After 14 days of treatment the serum levels of cholic acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, bilirubin, alkaline phosphatase and gamma glutamyltransferase were significantly raised in EE and EE plus UDCA treated rats. EE plus TUDCA treated rats, however, had no significant changes in these individual serum bile acids or conventional liver tests. The ultrastructure of livers from EE plus TUDCA treated rats was similar to those of controls. On the other hand, EE and EE plus UDCA rats both showed a significant reduction in sinusoidal microvilli. These results show that treatment of rats for 4 days with EE induces significant rises in the serum concentrations of two individual bile acids and that TUDCA protects against this. On treatment over 14 days TUDCA provides protection against changes in several biochemical liver tests as well as ultrastructural hepatoprotection. Treatment with UDCA, however, afforded no such protection.     

Intestinal absorption of ursodeoxycholic acid in patients with extrahepatic biliary obstruction and bile drainage.

Ursodeoxycholic acid (UDCA) dissolves cholesterol gallstones and improves liver function test results in patients with cholestatic liver diseases. Its absorption was studied in patients who had complete extrahepatic biliary obstruction caused by pancreatic carcinoma but no intestinal or liver disease. Six patients received 500 mg chenodeoxycholic acid (CDCA) or 250-2000 mg UDCA in capsules in single oral doses in random order, with an interval of 2 days between the different treatment regimens. In the control period the patients excreted into bile 382.3 +/- 108.0 mumol CDCA (mean +/- SD) and 1866.7 +/- 172.6 mumol cholic acid per 24 hours. After administration of 1273.6 mumol (500 mg) CDCA, biliary excretion of this bile acid increased to 1370.9 +/- 185.7 mumol/24 h, indicating an intestinal absorption rate of 77.6% +/- 9.8%. After oral administration of 636.8 mumol (250 mg), 1273.6 mumol (500 mg), 2547.2 mumol (1000 mg), and 5094.4 mumol (2000 mg) of UDCA, the respective absorption rates were 60.3% +/- 7.4%, 47.7% +/- 9.0%, 30.7% +/- 7.5%, and 20.8% +/- 3.9%, and whereas in the control period no UDCA was detected in the bile, the UDCA percentages measured were 14.6% +/- 8.2%, 19.6% +/- 9.1%, 23.1% +/- 11.3%, and 27.4% +/- 12.1%. The coadministration of CDCA did not enhance the absorption of UDCA. The data indicate that absorption of orally administered CDCA is almost complete, whereas UDCA absorption is incomplete. With increasing doses UDCA absorption decreases. To achieve absorption of adequate amounts of UDCA, high and/or multiple doses are needed.     

Management of recurrent gallstones

The risk of gallstone recurrence following non-surgical treatment has been overestimated in the past for two reasons: (1) diagnosis of primary gallstone dissolution was based on oral cholecystography; and (2) gallstone recurrence was expressed as a cumulative recurrence rate. Results based on better methodologies for diagnosis of gallstones (ultrasonography) and for calculation of results (life-table analysis) have indicated that gallstones recur in about 50% of patients, and that the risk of recurrence is confined mainly to the first 5 years after dissolution.Pretreatment gallstone characteristics, but not patient characteristics, are important risk factors for gallstone recurrence. Multiple stones are more likely to recur than solitary stones, a phenomenon attributable to the presence of a potent pronucleating factor in the bile of patients with multiple stones. This observation, and the finding that NSAID administration may reduce gallstone recurrence via inhibition of mucin secretion, suggests that the nucleation defect might be a key factor in the pathogenesis of recurrent gallstones.Prophylaxis with low-dose CDCA or UDCA has proven ineffective for preventing gallstone recurrence, although it may reduce it. Since the majority of recurrent gallstones are small when first seen because of regular ultrasonographic follow-up, multiple, radiolucent and in functioning gallbladders, they are amenable to bile acid retreatment, and intermittent bile acid therapy is probably a viable strategy for long-term management of cholesterol cholelithiasis.     

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.     

Mucin in gall bladder bile of gall stone patients: influence of treatment with chenodeoxycholic acid and ursodeoxycholic acid.

The concentration of hexosamine, a marker for mucin, was determined and related to the degree of cholesterol saturation and to the occurrence of cholesterol crystals in gall bladder bile of gall stone patients (n = 40) and gall stone free subjects (n = 25). Ten of the gall stone patients had been treated with chenodeoxycholic acid (CDCA) and eight with ursodeoxycholic acid (UDCA) three to four weeks before cholecystectomy. The hexosamine content was significantly higher in gall stone patients (137 (19) ng/ml, mean (SE) than in gall stone free subjects (83 (9) ng/ml, p less than 0.02). Treatment with CDCA or UDCA decreased cholesterol saturation, but did not significantly affect the hexosamine concentration. There was no difference in hexosamine concentration between gall stone patients with and without cholesterol crystals. The results do not support the hypothesis that the degree of cholesterol saturation is important for the mucin content of gall bladder bile in man. Neither do the data indicate that the formation and occurrence of cholesterol crystals in gall bladder bile from gall stone patients is caused by an increased concentration of mucin. As the studies were conducted on patients who had already had gall stones for several years, however, an effect of mucin in the very early stage of gall stone formation cannot be completely excluded.     

Modulation of rat hepatocyte proliferation by bile salts: In vitro and In vivo studies

In this study, the stimulatory effect of bile salts (BS) was evaluated both In vitro, using hepatocyte primary cultures, and In vivo, in normal and 40% partially hepatectomized rats previously fed on BS- enriched diets for 4 weeks. In vitro results show that conjugated cholate (CA) and chenodeoxycholate (CDCA) augmented proliferative activity in rat hepatocytes cultured in absence of mitogens, whereas conjugated deoxycholate (DCA), and ursodeoxycholate (UDCA) did not have any significant effect. None of these BSs increased significantly the replicative response induced by submaximal concentrations of epidermal growth factor (EGF). In vivo, at the end of dietary treatment all animals fed on CA or DCA but not those fed on either CDCA, or UDCA, or tauroursodeoxycholate (TUDCA) developed cholestatic hepatitis and a burst of damage-induced hepatocyte proliferation. After 40% partial hepatectomy (PH), CA- and DCA-treated groups underwent a deterioration of cholestatic hepatitis. On the other hand, in CDCA-, and UDCA-, and TUDCA-treated groups liver histology, serum glutamic pyruvic transaminase (SGPT) and cholestasis indices did not change significantly compared with controls. As far as the proliferative activity, a significant increase was observed not only in CA and DCA but also in UDCA- and TUDCA-fed groups compared with controls, whereas a slight decrease was observed in CDCA-treated animals. In conclusion, our data indicate that conjugated BSs had only a modest stimulatory effect on hepatocyte proliferation In vitro. However, In vivo, in PH rats, UDCA or TUDCA treatment determined a further increase of hepatocellular proliferation not attributable to hepatotoxic effects. Our result suggest that modifications of bile acid pool could modulate hepatocellular proliferation. (Hepatology 1996 May;23(5):1159-66)     

Comparison of effects of chenodeoxycholic and ursodeoxycholic acid and their combination on biliary lipids in obese patients with gallstones.

To study the effects of different bile acids on biliary lipids in obese patients with radiolucent gallstones, 12 subjects were given chenodeoxycholic acid (CDCA) at a dose of 15 mg/kg/day, ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg/day, and an equimolar combination of the two (7.5 + 7.5 mg/kg/day) in accordance with a double-blind crossover design. Mean molar percentage of cholesterol and cholesterol saturation index corrected for urso-rich bile (CSI) decreased significantly with all three treatments, but the combination was more effective in decreasing the CSI than either of the two bile acids given alone (p less than 0.05). Bile became desaturated in 10 of 12 patients receiving the combination, in 4 of 12 receiving CDCA, and 3 of 12 receiving UDCA alone. Combination treatment was well tolerated since mild diarrhea and slight increase in transaminases were observed only in a few patients. We conclude that the combined administration of CDCA and UDCA in equimolar doses is the treatment of choice for dissolution of gallstones in obese patients.     

Lack of response to chenodeoxycholic acid in obese and non-obese patients. Role of cholesterol synthesis and possible response to ursodeoxycholic acid.

This paper describes seven patients with radiolucent gallstones in functioning gallbladders who did not respond to chenodeoxycholic acid (CDCA). Despite large doses (greater than or equal to 19 mg CDCA/kg/day), CDCA-rich bile (CDCA conjugates 70-97% of total biliary bile acids) and greater than or equal to one year's treatment, their fasting duodenal bile remained supersaturated with cholesterol and their gallstones did not dissolve. Five patients came to cholecystectomy, gallstone analysis and liver biopsy for measurement of hepatic cholesterogenesis (HMGCoAR activity). In three who stopped CDCA before surgery, the mean HMGCoAR (pmol/mg microsomal protein/min) of 50.2 was higher than in our untreated gallstone controls (32.2 +/- SEM 2.0; P less than 0.05). Two patients who took CDCA until surgery had a mean HMGCoAR of 33.5--more than twice that in CDCA-treated gallstone controls. These findings suggest that non-response to CDCA may be related to high or unsuppressed hepatic cholesterogenesis. In one patient who did not respond to CDCA, treatment with 19 mg ursodeoxycholic acid/kg/day did desaturate his bile.     

Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters

AIM To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d.UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment.RESULTS At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ± 35.5 U/L, respectively, P ＜ 0.01) in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.     

Hepatoprotective bile acid 'ursodeoxycholic acid (UDCA)' Property and difference as bile acids.

Ursodeoxycholic acid (UDCA) is a bile acid, which is present in human bile at a low concentration of only 3% of total bile acids. It is a 7beta-hydroxy epimer of the primary bile acid chenodeoxycholic acid (CDCA). UDCA is isolated from the Chinese drug 'Yutan' a powder preparation derived from the dried bile of adult bears. For centuries, Yutan has been used in the treatment of hepatobiliary disorders. In Japan, it has also been in widespread use as a folk medicine from the mid-Edo period. In Japan, not only basic studies such as isolation, crystallization, definition of the chemical structure and establishment of the synthesis of UDCA have been conducted but clinical studies have been conducted. First reports on the effects of UDCA in patients with liver diseases came from Japan as early as 1961. In the 1970s, the first prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution was reported. In late 1980s, a number of controlled trials on the use of UDCA in primary biliary cirrhosis (PBC) were reported. Since then, a variety of clinical studies have shown the beneficial effect of UDCA in liver disease worldwide. To date, UDCA is utilized for the treatment of PBC for which it is the only drug approved by the U.S. Food and Drug Administration (FDA). In recent years, with the advent of molecular tools, the mechanisms of action of bile acids and UDCA have been investigated, and various bioactivities and pharmacological effects have been revealed. Based on the results of these studies, the bioactive substances in bile acids that are involved in digestive absorption may play important roles in signal transduction pathways. Furthermore, the mechanisms of action of UDCA is evidently involved. We reveal the physicochemical properties of UDCA as bile acid and overview the established pharmacological effects of UDCA from its metabolism. Furthermore, we overview the current investigations into the mechanism of action of UDCA in liver disease.