Comprehensive Study of the Biliary Bile Acid Composition of Patients With Cystic Fibrosis and Associated Liver Disease Before and After Udca Administration

Nakagawa, Michiko; Colombo, Carla; Setchell, Kenneth D.R.

doi:10.1002/hep.1840120221

Cited by 73 publications

(31 citation statements)

References 38 publications

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“…36 The relatively low biliary UDCA enrichment that we report following the administration of both bile acids takes into account a spectrum of bile acid metabolites not usually identified by high-performance liquid chromatography. A similarly large amount of unusual bile acids has been previously reported in patients with chronic cholestasis 6,37 but not in patients with necroinflammatory liver disease. 38 Therefore, it can be speculated that cholestasis may initiate alternative metabolic pathways leading to these atypical compounds.…”

Section: Discussionsupporting

confidence: 64%

Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of Its Taurine–Conjugated Species in Patients With Primary Biliary Cirrhosis

et al. 1999

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The clinical effectiveness of ursodeoxycholate in the treatment of liver disease may be limited by its poor absorption and extensive biotransformation. Because in vitro and in vivo studies suggest that the more hydrophilic bile acid tauroursodeoxycholate has greater beneficial effects than ursodeoxycholate, we have compared for the first time the absorption, metabolism, and clinical responses to these bile acids in patients with primary biliary cirrhosis (PBC). Twelve female patients with PBC were sequentially administered tauroursodeoxycholate and ursodeoxycholate (750 mg/d for 2 months) in a randomized, cross-over study. Bile acids were measured in serum, duodenal bile, urine, and feces by gas chromatography-mass spectrometry (GC-MS). Biliary ursodeoxycholate enrichment was higher during tauroursodeoxycholate administration (32.6% vs. 29.2% during ursodeoxycholate; P F .05). Lithocholic acid concentration was consistently higher in all biological fluids during ursodeoxycholate administration. Fecal bile acid excretion was the major route of elimination of both bile acids; ursodeoxycholate accounted for 8% and 23% of the total fecal bile acids during tauroursodeoxycholate and ursodeoxycholate administration, respectively (P F .05). Tauroursodeoxycholate was better absorbed than ursodeoxycholate, and, although it was partially deconjugated and reconjugated with glycine, it underwent reduced biotransformation to more hydrophobic metabolites. This comparative study suggests that tauroursodeoxycholate has significant advantages over ursodeoxycholate that may be of benefit for long-term therapy in PBC. (HEPATOLOGY 1999;29:320-327.)

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Section: Discussionsupporting

confidence: 64%

Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of Its Taurine–Conjugated Species in Patients With Primary Biliary Cirrhosis

et al. 1999

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“…Many of these bile acids have previously been found in other biological fluids of patients with liver disease (15, 24, 25); however, the C,, bile acids homochenodeoxycholic acid and homocholic acid are described for the first time in CAH patients and were recently described in bile from patients with cystic fibrosis (26). Bile acid profiles were similar in the samples analyzed and, interestingly, differed markedly from those found in chronic cholestatic liver diseases, where unusual bile acids generally account for a higher proportion of the total bile acids (26,27). An excellent correlation between the HPLC and GC-MS methods indicates that HPLC can be appropriately used to measure the major bile acids in the bile of patients with chronic active liver disease.…”

Section: Resultsmentioning

confidence: 96%

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

et al. 1991

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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.

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“…It would be of great interest to further assess the role of MCP-1 in hepatocyte-specific knockout models, in parallel with genetic and chemical interventional studies. Intervention aimed at detoxifying TCA, as highlighted by the therapeutic use of ursodeoxycholic acid to displace toxic bile acids from the bile acid pool 37 or neutralizing MCP-1, as suggested by our in vitro experiment, may help prevent progression of the fibrotic liver injury which accompanies these cholestatic diseases in children. Continued investigation of disease mechanisms may not only lead to further development of traditional management approaches, but importantly provide new directions in the prevention and treatment of these diseases.…”

Section: Discussionmentioning

confidence: 96%

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment #

et al. 2009

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Cholestatic liver diseases, such as cystic fibrosis (CF) liver disease and biliary atresia, predominate as causes of childhood cirrhosis. Despite diverse etiologies, the stereotypic final pathway involves fibrogenesis where hepatic stellate cells (HSCs) are recruited, producing excess collagen which initiates biliary fibrosis. A possible molecular determinant of this recruitment, monocyte chemotaxis protein-1 (MCP-1), an HSC-responsive chemokine, was investigated in CF liver disease and biliary atresia. The bile-duct-ligated rat and in vitro coculture models of cholestatic liver injury were used to further explore the role of MCP-1 in HSC recruitment and proposed mechanism of induction via bile acids. In both CF liver disease and biliary atresia, elevated hepatic MCP-1 expression predominated in scar margin hepatocytes, closely associated with activated HSCs, and was also expressed in cholangiocytes. Serum MCP-1 was elevated during early fibrogenesis. Similar observations were made in bile-duct-ligated rat liver and serum. Hepatocytes isolated from cholestatic rats secreted increased MCP-1 which avidly recruited HSCs in coculture. This HSC chemotaxis was markedly inhibited in interventional studies using anti-MCP-1 neutralizing antibody. In CF liver disease, biliary MCP-1 was increased, positively correlating with levels of the hydrophobic bile acid, taurocholate. In cholestatic rats, increased MCP-1 positively correlated with taurocholate in serum and liver, and negatively correlated in bile. In normal human and rat hepatocytes, taurocholate induced MCP-1 expression. Conclusion: These observations support the hypothesis that up-regulation of hepatocyte-derived MCP-1, induced by bile acids, results in HSC recruitment in diverse causes of cholestatic liver injury, and is a key early event in liver fibrogenesis in these conditions. Therapies aimed at neutralizing MCP-1 or bile acids may help reduce fibro-obliterative liver injury in childhood cholestatic diseases.

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Comprehensive Study of the Biliary Bile Acid Composition of Patients With Cystic Fibrosis and Associated Liver Disease Before and After Udca Administration

Cited by 73 publications

References 38 publications

Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of Its Taurine–Conjugated Species in Patients With Primary Biliary Cirrhosis

Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of Its Taurine–Conjugated Species in Patients With Primary Biliary Cirrhosis

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

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment #

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