Search

24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling 'ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on 'Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders., (2015 S. Karger AG, Basel.)

New insights into the molecular mechanisms of bile formation and cholestasis have provided new concepts for pharmacotherapy of cholestatic liver diseases. The major aim in all forms of cholestasis is the reduction of hepatocellular retention of bile acids and other potentially toxic constituents of bile. Reduction of hepatocellular retention may be achieved by drugs that stimulate hepatocellular secretion via the canalicular route into the bile or via the alternative route across the basolateral membrane into the blood, and by drugs that stimulate the hepatocellular metabolism of hydrophobic bile acids to hydrophilic, less toxic metabolites. In cholestatic liver diseases that start with an injury of the biliary epithelium (e.g., primary biliary cirrhosis; PBC), protection of the cholangiocytes against the toxic effects of hydrophobic bile acids is most important. When hepatocellular retention of bile acids has occurred, the inhibition of bile acid-induced apoptosis becomes another target of therapy. Ursodeoxycholic acid protects the biliary epithelium by reducing the toxicity of bile, stimulates hepatobiliary secretion by upregulating transporters and inhibits apoptosis. It is the mainstay of therapy in PBC but of benefit also in a number of other cholestatic liver diseases. New drugs such as 6-ethyl-chenodeoxycholic acid and 24-nor-ursodeoxycholic acid are being evaluated for the treatment of cholestatic liver diseases.

A review is presented of Gustav Paumgartner's five decades of research and practice in hepatology focusing on biliary physiology and disease. It begins with studies of the excretory function of the liver including hepatic uptake of indocyanine green, bilirubin, and bile acids. The implications of these studies for diagnosis and understanding of liver diseases are pointed out. From there, the path of scientific research leads to investigations of hepatobiliary bile acid transport and the major mechanisms of bile formation. The therapeutic effects of the hydrophilic bile acid, ursodeoxycholic acid, have greatly stimulated these studies. Although ursodeoxycholic acid therapy for dissolution of cholesterol gallstones and some other nonsurgical treatments of gallstones were largely superseded by surgical techniques, ursodeoxycholic acid is currently considered the mainstay of therapy of some chronic cholestatic liver diseases, such as primary biliary cirrhosis. The major mechanisms of action of ursodeoxycholic acid therapy in cholestatic liver diseases are discussed. An attempt is made to illustrate how scientific research can lead to advances in medical practice that help patients.

Ursodeoxycholic acid (UDCA) is widely used for the treatment of cholestatic liver diseases. Multiple mechanisms of action of UDCA have been described aiming at one or more of the pathogenetic processes of cholestatic liver diseases: (1) protection of injured cholangiocytes against toxic effects of bile acids, (2) stimulation of impaired biliary secretion, (3) stimulation of detoxification of hydrophobic bile acids, and (4) inhibition of apoptosis of hepatocytes. Through one or more of these mechanisms, UDCA slows the progression of primary biliary cirrhosis and improves a number of other cholestatic disorders.

Background: In animal models ursodeoxycholic acid (UDCA) showed a chemoprotective effect against colon cancer. To explain this, a reduced proliferation of the colorectal mucosal proliferation was suggested. We, therefore, examined the influence of UDCA on the proliferation of normal colorectal mucosa in humans., Methods: Following endoscopic polypectomy, 20 patients with colorectal adenomas were randomized to receive either UDCA (750 mg/day, n = 10, group A) or placebo (n = 10, group B) for 6 months in a double-blinded way. Colorectal biopsies were sampled before and at the end of the medication by total colonoscopy. Colorectal mucosal proliferation was measured by FACScan analysis of propidium iodine labeling. Serum was sampled, and serum bile acids were analyzed by gas chromatography., Results: The proliferation rates at the end of the study were similar in both groups (median 15.4%; range 12.0-20.9 in group A; median 16.0%, 14.0-20.2 in group B, p = 0.41). Serum lithocholic acid levels at the end of the study were significantly higher in group A (1.3 micromol/l, 0.9-1.8) than in group B (0.7 micromol/l, 0-1.7, p < 0.02), whereas serum deoxycholic acid levels were similar in both groups., Conclusions: In this study, UDCA treatment for 6 months does not seem to induce changes in the proliferative behavior of the colorectal mucosa in patients with adenomas. It seems likely that a putative chemopreventive effect of UDCA in humans is not exerted by a reduction of the colorectal proliferation., (Copyright 2003 S. Karger AG, Basel)

Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca(2+)- and protein kinase C-alpha-dependent mechanisms and/or activation of p38(MAPK) and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules (e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid-induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level.

Background: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA., Methods: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months., Results: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids., Conclusions: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

Background: Cholestyramine is the first-line treatment for cholestasis-induced pruritus and is prescribed along with ursodeoxycholic acid (UDCA) in patients with cholestatic liver diseases. Impairment of the intestinal absorption of endogenous hydrophobic bile acids by cholestyramine is well known. It is unclear, however, whether cholestyramine also impairs the absorption of the hydrophilic bile acid, UDCA, in man., Aims: To study serum levels of UDCA and endogenous bile acids as well as endogenous bile acid synthesis during simultaneous or separate administration of UDCA and cholestyramine in vivo; and absorption of UDCA both in the presence and absence of its hydrophobic epimer, chenodeoxycholic acid (CDCA), by cholestyramine in vitro., Patients and Methods: Five healthy subjects received UDCA (12.5 +/- 0.5 mg kg-1 daily) as a single dose for periods of 14 days with or without cholestyramine (4 g daily). Fasting serum levels of bile acids and of 7alpha-hydroxy-4-cholesten-3-one (alpha-HC), a measure of endogenous bile acid synthesis, were determined by gas chromatography and high pressure liquid chromatography, respectively. In vitro, bile acid solutions were incubated for 24 h in the presence or absence of cholestyramine, and bile acid concentrations were determined in the supernatant., Results: Simultaneous administration of UDCA and cholestyramine in man led to a decrease of fasting serum levels of UDCA by 60% when compared to UDCA serum levels during administration of UDCA alone. In contrast, serum levels of endogenous bile acids were not affected and alpha-HC serum levels were found increased 2. 7-fold indicating stimulation of endogenous bile acid synthesis by cholestyramine. Administration of cholestyramine and UDCA at an interval of 5 h tended to diminish the effect of cholestyramine on UDCA serum levels. In vitro, conjugated and unconjugated UDCA were effectively bound by cholestyramine both in the presence and absence of hydrophobic bile acids., Conclusions: The results strongly support the recommendation to administer UDCA and cholestyramine at different times of day.

Background & Aims: The value of adjuvant bile acid dissolution therapy after extracorporeal shockwave lithotripsy (ESWL) of gallbladder stones is under debate. A double-blind, randomized, multicenter trial was conducted to determine the safety and efficacy of repeated ESWL with and without adjuvant bile acid therapy., Methods: At five centers, 153 patients with gallstones and good gallbladder emptying were randomized to undergo up to six high-energy lithotripsy sessions combined with ursodeoxycholic acid (UDCA, 750 mg/day; n = 77) or placebo (n = 76)., Results: Six months after the initial treatment, 77% of patients with small single stones (< or = 20 mm in diameter), 60% with large single stones (> 20 mm in diameter), and 41% with multiple stones were free of stones. Administration of UDCA had no effect on stone disappearance in the whole study group but tended to improve stone disappearance rates in patients with large single stones and tended to decrease biliary adverse effects in patients with multiple stones., Conclusions: Repeated high-energy ESWL without adjuvant bile acid therapy represents a safe and effective treatment in patients with small single stones and good gallbladder emptying. In patients with large single stones and multiple stones, adjuvant bile acid therapy may be beneficial.

Background: Although it has been shown that chronic administration of ursodeoxycholic acid increases gallbladder fasting and residual volume, it is unknown whether ursodeoxycholic acid exerts an acute effect on gallbladder volume. We therefore evaluated the effect of a single oral dose of ursodeoxycholic acid on gallbladder volume in healthy volunteers., Methods: After the volunteers had fasted overnight, gallbladder volume was measured sonographically every 15 min for 5 h. Following a 1-h control period group I (n = 8) received ursodeoxycholic acid (1000 mg) orally with 100 ml of water, whereas group II (n = 8) received 100 ml of water (placebo) only. Gallbladder volumes were calculated, applying the sum-of-cylinders method. Serum levels of ursodeoxycholic acid were determined by gas chromatography at 1-h intervals., Results: Gallbladder fasting volumes before ursodeoxycholic acid were similar in both groups (24.0 +/- 2.3 ml versus 25.4 +/- 3.3 ml; NS). After ingestion of ursodeoxycholic acid (group I) gallbladder volume increased rapidly, reaching 27.6 +/- 3.1 ml (p < 0.04) 1 h and 38.4 +/- 3.4 ml (p < 0.02) 4 h after ingestion of ursodeoxycholic acid. The individual gallbladder volumes after ingestion of ursodeoxycholic acid in group I increased to 146%-211% of pretreatment values. Ursodeoxycholic acid serum levels increased from 0.94 +/- 0.38 mumol/l to 10.51 +/- 1.36 mumol/l (p < 0.001) and correlated closely with gallbladder volumes (r = 0.80; p < 0.05). After ingestion of water only (group II) gallbladder volume decreased transiently from 15 min to 30 min after water intake and then remained at pretreatment values throughout the study period., Conclusion: Administration of a single oral dose of ursodeoxycholic acid causes a rapid increase in gallbladder volume, which reaches 163 +/- 10% of pretreatment volume at 4 h and is closely correlated with ursodeoxycholic acid serum levels.

Inhibitors of the HMG-CoA reductase have been shown to further reduce the biliary cholesterol saturation in patients treated with oral bile acids for cholesterol gallbladder stones. It was the aim of our study to evaluate the efficacy of simvastatin in addition to ursodeoxycholic acid in the dissolution of gallstone fragments after shock wave lithotripsy and adjuvant bile acid dissolution therapy. Eighteen patients with a single radiolucent gallbladder stone and a serum cholesterol of more than 250 mg/dl were randomly assigned to receive either ursodeoxycholic acid alone (750 mg per day, group A, n = 9) or in combination with simvastatin (20 mg per day, group B, n = 9) for the dissolution of the gallstone fragments generated by extracorporeal shock wave lithotripsy. The two groups were well matched regarding their baseline characteristics. At the primary end point of the study 6 months after lithotripsy, there was no difference between the groups in the rate of gallstone disappearance with 4 of 9 patients being stone free in each group. As evaluated by life table analysis, even further follow-up showed no significant difference between the groups (P = 0.8). In group B, serum cholesterol levels decreased by 22% at 3 months (P = 0.01 vs. baseline) and by 24% at six months (P = 0.02) during treatment while no significant change was observed in group A. With both regiments, no adverse effects were observed. While simvastatin added to ursodeoxycholic acid resulted in a decrease of elevated serum cholesterol levels in gallstone patients, it did not enhance stone disappearance after shock wave lithotripsy and adjuvant bile acid dissolution therapy.

During ursodeoxycholic acid therapy for chronic cholestatic liver disease, the serum levels of lithocholic acid increase about twofold. Lithocholic acid has been shown to be hepatotoxic in some animal species. Administration of psyllium hydrophilic mucilloid (PHM), a dietary fiber, has been reported to increase the bile acid mass excreted by the feces. We, therefore, studied the effect of PHM (3 x 3.25 g/day) on serum bile acids including lithocholic acid in 12 patients with primary sclerosing cholangitis (n = 7) and primary biliary cirrhosis (n = 5) receiving ursodeoxycholic acid therapy. After 2 and 6 weeks of treatment with PHM, the serum levels of ursodeoxycholic acid increased by 52.4 +/- 72.8% (p < 0.05) and 40.5 +/- 69.6% (NS), respectively. The absolute serum levels of lithocholic acid were not significantly changed. This led to a decrease of the relative amount of lithocholic acid as referred to total bile acids and to ursodeoxycholic acid in serum by 27.4 +/- 34.5% (p < 0.05) and 25.5 +/- 32.8% (p < 0.05), respectively, after 6 weeks of PHM treatment.

Bile acid dissolution therapy alone or in combination with extracorporeal shock-wave lithotripsy continues to be a safe and effective non-surgical treatment for highly selected patients with cholesterol gallstone disease. Its disadvantages are the duration of drug treatment and potential stone recurrence. Its advantages, however, are non-invasiveness, low rate of morbidity, and lack of mortality. Considering the variety of options in modern gallstone therapy, the careful selection of treatment should be tailored to the individual patient's clinical and personal situation. This will involve the patient in the decision-making process.

Serum bile acid levels and distributions were studied every 6 mo in patients with primary biliary cirrhosis who were randomly assigned to receive ursodeoxycholic acid (13 to 15 mg/kg/day) (n = 73) or a placebo (n = 73) over a 2-yr period. In the ursodeoxycholic acid group, ursodeoxycholic acid was the predominant serum bile acid at 6 mo and throughout the 2-yr treatment period. The total concentration of endogenous bile acids decreased with a reduction in cholic acid (in the ursodeoxycholic acid group and the placebo group, respectively [mean +/- S.E.]: 13.0 +/- 2.2 and 12.6 +/- 2.5 mumol/L at entry vs. 3.5 +/- 0.6 and 9.0 +/- 2.2 mumol/L at 2 yr; p < 0.002), chenodeoxycholic acid (in the ursodeoxycholic acid group and the placebo group, respectively: 12.1 +/- 1.7 and 12.7 +/- 2.3 mumol/L at entry vs. 5.8 +/- 0.8 and 10.7 +/- 2.2 mumol/L at 2 yr; p < 0.02) and 3 beta-hydroxy-delta 5-cholenoic acid. The concentration of deoxycholic acid did not change, whereas that of lithocholic acid increased significantly (in the ursodeoxycholic acid group and the placebo group, respectively: 0.63 +/- 0.06 and 0.81 +/- 0.12 mumol/L at entry vs. 1.26 +/- 0.12 and 0.90 +/- 0.15 mumol/L at 2 yr; p < 0.001). These changes were independent of the histological stage of the disease. Thus during ursodeoxycholic acid administration the liver was exposed to a lower level of endogenous bile acids and to an increased concentration of ursodeoxycholic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate the biotransformation of orally administered ursodeoxycholic acid in man. The distribution of ursodeoxycholic acid and its metabolites in gallbladder bile, in serum and in urine with emphasis on separation of their unconjugated, amidated and sulfated species in particular, was investigated. Seven gallstone patients were given 750 mg of ursodeoxycholic acid daily for 2-3 weeks. Six gallstone patients who did not receive ursodeoxycholic acid served as controls. Ursodeoxycholic acid became the major bile acid in gallbladder bile contributing 43% to total bile acids. 2% of biliary ursodeoxycholic acids were in the unconjugated form, 87% in the amidated form and 11% in the sulfated form. Iso-ursodeoxycholic acid was found in bile in small amounts and was present only as the sulfated species and not as the amidated one. Other metabolites of ursodeoxycholic acid tentatively identified in bile were 1 beta, 12 beta, 6 alpha- and 21,22-hydroxylated derivatives of ursodeoxycholic acid. Lithocholic acid in bile tended to increase under ursodeoxycholic acid treatment and was positively correlated to ursodeoxycholic acid. The concentration of cholic acid in bile decreased significantly whereas the levels of deoxycholic acid and chenodeoxycholic acid did not change. Total bile acid concentration in serum and excretion of bile acids in urine increased from 5.4 +/- 1.1 to 18.4 +/- 9.5 mumol l-1 (mean +/- SD, P < 0.005) and from 5.6 +/- 1.3 to 13.1 +/- 7.9 mumol g-1 creatinine (mean +/- SD, P < 0.05) after ursodeoxycholic acid ingestion mainly due to spillover and excretion of ursodeoxycholic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and safety of ursodeoxycholic acid for the treatment of primary sclerosing cholangitis were evaluated in a prospective, randomized, double-blind, placebo-controlled trial. Fourteen patients with primary sclerosing cholangitis documented by cholestatic serum enzyme pattern, liver histological appearance and endoscopic retrograde cholangiography were included in the trial. Six patients received ursodeoxycholic acid (13 to 15 mg/kg body wt/day), and eight patients received placebo. Two patients had to be withdrawn from the study, one because of UDCA-related diarrhea and the other because of worsening of the disease during placebo treatment. Patients in the ursodeoxycholic acid group improved significantly during 1 yr of treatment with respect to serum levels of bilirubin (median = -50%), alkaline phosphatase (median = -67%), gamma-glutamyltransferase (median = -53%), AST (median = -54%) and ALT (median = -36%) compared with the placebo group, but not with respect to serum levels of hydrophobic bile acids. During ursodeoxycholic acid treatment, histopathological features also improved significantly, as evaluated by multiparametric score. Expression of human leukocyte antigen class I molecules appeared to be markedly reduced on liver cells after ursodeoxycholic acid treatment. We conclude that ursodeoxycholic acid is beneficial in reducing disease activity in patients with primary sclerosing cholangitis.

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.

A prospective, double-blind, randomized, single-center study was conducted to compare ursodeoxycholic acid alone with the combination of ursodeoxycholic acid and chenodeoxycholic acid for dissolution therapy of gallstone fragments after shock wave lithotripsy. Patients with single radiolucent gallstones up to 30 mm in diameter or up to three stones of similar total volume received either 750 mg ursodeoxycholic acid alone (group A, n = 138) or the combination of 500 mg ursodeoxycholic acid and 500 mg chenodeoxycholic acid (group B, n = 144) in a single bedtime dose. The bile acids were administered from 2 wk before electrohydraulic lithotripsy until 3 mo beyond complete disappearance of all fragments. Patient's characteristics, stones (group A, 82% single stones, maximum diameter 19 +/- 5 mm, mean +/- S.D.; group B, 82% single stones, 18 +/- 5 mm), lithotripsy treatment and follow-up period were not different between the two groups. Between the two groups, no statistically significant difference was found in the time required for complete clearance of the fragments (group A, median time = 15 mo; group B, median time = 13 mo; p = 0.7). At 12 mo after lithotripsy, the probability of complete clearance was 46% +/- 5% in group A and 49% +/- 5% in group B. Diarrhea occurred significantly more often in group B than in group A (p less than 0.001) and was the main reason for withdrawal of randomized medication. Severe adverse effects of the bile acids were not observed. It is concluded that monotherapy with ursodeoxycholic acid is as efficient as the combination of ursodeoxycholic acid and chenodeoxycholic acid for fragment dissolution after lithotripsy.(ABSTRACT TRUNCATED AT 250 WORDS)

The appearance of iso-ursodeoxycholic acid (isoUDCA; 3 beta,7 beta-dihydroxy-5 beta-cholan-24-oic acid) in serum of patients with chronic cholestatic liver disease and of healthy subjects during administration of ursodeoxycholic acid (UDCA) is reported. Comparison of the mass spectrum of the newly appearing bile acid with that of authentic 3 beta,7 beta-dihydroxy-5 beta-cholan-24-oic acid revealed its identity as the 3 beta-epimer of UDCA. The appearance of 13C-isoUDCA in serum after ingestion of 13C-UDCA proved its product precursor relationship with UDCA. The putative intermediate in the epimerization of UDCA to isoUDCA, 3-oxo-7 beta-hydroxy-5 beta-cholan-24-oic acid, was identified in serum of patients with cholestatic liver disease during treatment with UDCA. Serum concentrations of isoUDCA after 4 weeks of UDCA treatment were 1.37 +/- 0.79 mumol/l (mean +/- S.D.) in eight patients with primary biliary cirrhosis (PBC), 1.25 +/- 0.91 mumol/l in six patients with primary sclerosing cholangitis (PSC) and 3.87 +/- 0.44 mumol/l in four healthy controls. The intestinal bacterial flora as well as microsomal enzymes of the liver may be involved in the epimerization of UDCA to isoUDCA as indicated by decreased serum levels of isoUDCA under antibiotic treatment with doxycycline (100 mg/day) in healthy subjects and a correlation (r = 0.873, p less than 0.001) between the hepatic microsomal function measured by the 14C-aminopyrine breath test and the fractional conversion of applied UDCA to isoUDCA (isoUDCA/UDCA + isoUDCA) in patients with PBC or PSC. Future studies of bile acid metabolism under UDCA treatment should include measurement of isoUDCA to further elucidate its biological role.

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.

Portal-systemic spill-over of unconjugated ursodeoxycholic acid (UDCA) was assessed in ten healthy subjects, six patients with mild chronic liver disease and eight patients with cirrhosis. Following oral administration of UDCA (1.5 mg/kg body weight), serum concentrations of unconjugated UDCA were measured during 2 h using a capillary gas-liquid chromatographic method. Peak time of UDCA varied from 15 to 30 min, but was not significantly different in the three groups studied. Peak concentration was increased up to two-fold in patients with mild, and up to three-fold in patients with cirrhotic liver disease. Since, in addition, plasma disappearance rate (k) was markedly impaired in cirrhotics (1.7 +/- SD 0.5%/min, compared to 2.8 +/- 0.6 in healthy controls), the calculated area under the curve (AUC) was on the average five-fold that in controls. In two healthy and four cirrhotic subjects, the data obtained after oral administration were compared with those after i.v. loading with the same UDCA dose. The k-values after the two routes of administration were practically identical. Calculated systemic availability was 50% in normals, 78-87% in cirrhotics, 90 and 136% in two patients with surgical porta-caval shunt. It is concluded that the portal-systemic spill-over of UDCA in patients with liver disease is increased primarily due to portal-systemic shunting. Since in the normal liver hepatic extraction of conjugated, endogenous bile acids is greater than 80%, diminished first-pass elimination is expected to augment systemic concentrations even more, particularly when measured after a meal.