Yonsei Med J.  2006 Dec;47(6):817-825. 10.3349/ymj.2006.47.6.817.

Bile Acid Analysis in Biliary Tract Canacer

• Park JY
• Park BK
• Ko JS
• Bang S
• Song SY
• Chung JB

• KMID: 1777171
• DOI: http://doi.org/10.3349/ymj.2006.47.6.817

Abstract

The etiology of biliary tract cancer is obscure, but there are evidences that bile acid plays a role in carcinogenesis. To find the association between biliary tract cancer and bile acid, this study compared the bile acid concentration and composition among patients with biliary cancer, biliary tract stones, and no biliary disease. Bile was compared among patients with biliary tract cancer (n = 26), biliary tract stones (n = 29), and disease free controls (n = 9). Samples were obtained by percutaneous transhepatic biliary drainage, endoscopic nasobiliary drainage, or gallbladder puncture, and analyzed for cholic, deoxycholic, chenodeoxycholic, lithocholic, and ursodeoxycholic acid composition. Total bile acid concentration was lower in the cancer group than the biliary stone and control groups; the proportions of deoxycholic (2.2% vs. 10.2% and 23.6%, p < 0.001 and p < 0.001, respectively) and lithocholic acid (0.3% vs. 0.6% and 1.0%, p = 0.065 and p < 0.001, respectively) were also lower. This result was similar when disease site was limited to bile duct or gallbladder. Analysis of cases with bilirubin < or = 2.0 mg/dL also showed lower total bile acid concentration and deoxycholic acid composition in the cancer group compared to controls (5.7% vs. 23.6%, p = 0.003). Although the presence of bile duct obstruction explains some of the difference in total concentration and composition of bile acid, there are other contributing mechanisms. We suspect the alteration of bile acid transport might decrease bile acid excretion and cause the accumulation of carcinogenic bile acid in bile duct epithelium.

Keyword

Bile; bile acid; biliary tract cancer

MeSH Terms

Tumor Markers, Biological/analysis
Middle Aged
Male
Humans
Gallbladder Neoplasms/metabolism
Female
Cholic Acids/*analysis/metabolism
Cholelithiasis/metabolism
Biliary Tract Neoplasms/*chemistry/metabolism
Aged, 80 and over
Aged
Adult
Adolescent

Reference

1. Javitt NB. Bile acid synthesis from cholesterol: regulatory and auxiliary pathways. FASEB J. 1994. 8:1308–1311.

2. Cameron RG, Imaida K, Tsuda H, Ito N. Promotive effect of steroids and bile acids on hepatocarcinogenesis initiated by diethylnitrosamine. Cancer Res. 1982. 42:2426–2428.

3. Makino T, Obara T, Ura H, Kinugasa T, Kobayashi H, Takahashi S, et al. Effects of phenobarbital and secondary bile acids on liver, gallbladder, and pancreas carcinogenesis initiated by N-nitrosobis (2-hydroxypropyl) amine in hamsters. J Natl Cancer Inst. 1986. 76:967–975.

4. Thompson MB. Bile acids in assessment of hepatocellular function. Toxicol Pathol. 1996. 24:62–71.

5. Einarsson K. Effect of ursodeoxycholic acid on hepatic cholesterol metabolism. Scand J Gastroenterol Suppl. 1994. 204:19–23.

6. Oyama K, Shiota G, Ito H, Murawaki Y, Kawasaki H. Reduction of hepatocarcinogenesis by ursodeoxycholic acid in rats. Carcinogenesis. 2002. 23:885–892.

7. Kinami Y, Ashida Y, Seto K, Takashima S, Kita I. Influence of incomplete bile duct obstruction on the occurrence of cholangiocarcinoma induced by diisopropanolnitrosamine in hamsters. Oncology. 1990. 47:170–176.

8. Kinami Y, Ashida Y, Gotoda H, Seto K, Kojima Y, Takashima S. Promoting effects of bile acid load on the occurrence of cholangiocarcinoma induced by diisopropanolnitrosamine in hamsters. Oncology. 1993. 50:46–51.

9. Funabiki T, Sugiue K, Matsubara T, Amano H, Ochiai M. Bile acids and biliary carcinoma in pancreaticobiliary maljunction. Keio J Med. 1991. 40:118–122.

10. Strom BL, Soloway RD, Rios-Dalenz J, Rodriguez-Martinez HA, West SL, Kinman JL, et al. Biochemical epidemiology of gallbladder cancer. Hepatology. 1996. 23:1402–1411.

11. Lee JH, Park YH, Seo JH, Chung JB, Lee SJ, Chung JP, et al. Biliary bile acid analysis in the patients with bile duct cancer. Korean J Gastroenterol. 2000. 35:103–110.

12. Castleden WM, Detchon P, Misso NL. Biliary bile acids in cholelithiasis and colon cancer. Gut. 1989. 30:860–865.

13. Kinugasa T, Uchida K, Kadowaki M, Takase H, Nomura Y, Saito Y. Effect of bile duct ligation on bile acid metabolism in rats. J Lipid Res. 1981. 22:201–207.

14. Hong SK, Kim KH, Kim WJ. Effect of bile acids on biliary excretion of cholesterol in rabbits. Yonsei Med J. 1973. 14:109–115.

15. Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol. 2005. 39(4):Suppl 2. S111–S124.

16. Trauner M, Arrese M, Soroka CJ, Ananthanarayanan M, Koeppel TA, Schlosser SF, et al. The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology. 1997. 113:255–264.

17. Lee JM, Trauner M, Soroka CJ, Stieger B, Meier PJ, Boyer JL. Expression of the bile salt export pump is maintained after chronic cholestasis in the rat. Gastroenterology. 2000. 118:163–172.

18. Paulusma CC, Kothe MJ, Bakker CT, Bosma PJ, van Bokhoven I, van Marle J, et al. Zonal down-regulation and redistribution of the multidrug resistance protein 2 during bile duct ligation in rat liver. Hepatology. 2000. 31:684–693.

19. Bolder U, Ton-Nu HT, Schteingart CD, Frick E, Hofmann AF. Hepatocyte transport of bile acids and organic anions in endotoxemic rats: impaired uptake and secretion. Gastroenterology. 1997. 112:214–225.

20. Shoda J, Kano M, Oda K, Kamiya J, Nimura Y, Suzuki H, et al. The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliary secretory function. Am J Gastroenterol. 2001. 96:3368–3378.

21. Ikematsu Y, Tomioka T, Kitajima T, Inoue K, Tajima Y, Kanematsu T. Tauroursodeoxycholate and cholestyramine enhance biliary carcinogenesis in hamsters. World J Surg. 2000. 24:22–26.

22. Holzinger F, Z'graggen K, Buchler MW. Mechanisms of biliary carcinogenesis: a pathogenic multi-stage cascade towards cholangiocarcinoma. Ann Oncol. 1999. 10:Suppl 4. 122–126.

23. Tocchi A, Basso L, Costa G, Lepre L, Liotta G, Mazzoni G, et al. Is there a causal connection between bile acids and colorectal cancer? Surg Today. 1996. 26:101–104.

24. Nagengast FM, van den Ban G, Ploemen JP, Leenen R, Zock PL, Katan MB, et al. The effect of a natural high-fibre diet on faecal and biliary bile acids, faecal pH and whole-gut transit time in man. A controlled study. Eur J Clin Nutr. 1993. 47:631–639.

25. Barone M, Maiorano E, Ladisa R, Pece A, Berloco P, Strazzabosco M, et al. Ursodeoxycholate further increases bile-duct cell proliferative response induced by partial bile-duct ligation in rats. Virchows Arch. 2004. 444:554–560.

26. Antsaklis G, Lewin MR, Sutor DJ, Cowie AG, Clark CG. Gallbladder function, cholesterol stones, and bile composition. Gut. 1975. 16:937–942.

27. Cohn MS, Schwartz SI, Faloon WW, Adams JT. Effect of sphincteroplasty on gallbladder function and bile composition. Ann Surg. 1979. 189:317–321.