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Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer

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Abstract

Background and aims

Hyperbilirubinemia is a critical complication following hepatectomy for biliary cancer. Hepatic multidrug resistance protein 2 (MRP2), a bilirubin transporter, is shown to be down-regulated by acute biliary obstruction in rats. However, little is known about the effect of chronic obstruction by malignancy on the MRP2 expression in patients or the association of MRP2 expression with posthepatectomy hyperbilirubinemia.

Materials and Methods

The MRP2 expression before hepatectomy was determined by immunostaining and Western blotting in patients with biliary cancer. To directly determine the effect of chronic bile duct obstruction on the MRP2 expression, the expression levels were compared between the cholestatic and noncholestatic lobes in each of seven patients. In another 39 patients, the correlation of the MRP2 expression of the anticipated remnant liver with the posthepatectomy severe hyperbilirubinemia, defined as a serum total bilirubin concentration≥200 μmol/l, was evaluated.

Results

The MRP2 staining in the cholestatic lobes was weak and not restricted to the canalicular membrane, unlike the noncholestatic lobes. The expression levels in the cholestatic lobes were 45% of those in the noncholestatic lobes. Postoperative maximum bilirubin levels were significantly correlated with MRP2 expression of the anticipated remnant liver. The MRP2 expression had been already impaired before hepatectomy in all patients who eventually developed severe hyperbilirubinemia.

Conclusions

Decreased MRP2 expression, caused by biliary obstruction due to cancer, is a possible risk factor for posthepatectomy severe hyperbilirubinemia.

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References

  1. Nimura Y, Hayakawa N, Kamiya J, Kondo S, Shionoya S (1990) Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. World J Surg 14:535–544

    Article  CAS  PubMed  Google Scholar 

  2. Nagino M, Nimura Y, Hayakawa N, Kamiya J, Kondo S, Sasaki R, Hamajima N (1993) Logistic regression and discriminant analyses of hepatic failure after liver resection for carcinoma of the biliary tract. World J Surg 17:250–255

    Article  CAS  PubMed  Google Scholar 

  3. Pichlmayr R, Weimann A, Klempnauer J, Oldhafer KJ, Maschek H, Tusch G, Ringe B (1996) Surgical treatment in proximal bile duct cancer. A single-center experience. Ann Surg 224:628–638

    Google Scholar 

  4. Miyazaki M, Ito H, Nakagawa K, Ambiru S, Shimizu H, Shimizu Y, Kato A, Nakamura S, Omoto H, Nakajima N, Kimura F, Suwa T (1998) Aggressive surgical approaches to hilar cholangiocarcinoma: hepatic or local resection? Surgery 123:131–136

    Article  CAS  PubMed  Google Scholar 

  5. Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, Kling N, Wex C, Lobeck H, Hintze R (1999) Extended resections for hilar cholangiocarcinoma. Ann Surg 230:808–819

    Google Scholar 

  6. Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M (1999) Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 230:663–671

    Google Scholar 

  7. Tsao JI, Nimura Y, Kamiya J, Hayakawa N, Kondo S, Nagino M, Miyachi M, Kanai M, Uesaka K, Oda K, Rossi RL, Braasch JW, Dugan JM (2000) Management of hilar cholangiocarcinoma. Comparison of an American and a Japanese experience. Ann Surg 232:166–174

    Google Scholar 

  8. Nagino M, Kamiya J, Uesaka K, Sano T, Yamamoto H, Hayakawa N, Kanai M, Nimura Y (2001) Complications of hepatectomy for hilar cholangiocarcinoma. World J Surg 25:1277–1283

    Article  CAS  PubMed  Google Scholar 

  9. Arai T, Yoshikai Y, Kamiya J, Nagino M, Uesaka K, Yuasa N, Oda K, Sano T, Nimura Y (2001) Bilirubin impairs bactericidal activity of neutrophils through an antioxidant mechanism in vitro. J Surg Res 96:107–113

    Article  CAS  PubMed  Google Scholar 

  10. Dixon JM, Armstrong CP, Duffy SW, Davies GC (1983) Factors affecting morbidity and mortality after surgery for obstructive jaundice: a review of 373 patients. Gut 24:845–852

    CAS  PubMed  Google Scholar 

  11. Welsh FKS, Ramsden CW, MacLennan K, Sheridan MB, Barclay GR, Guillou PJ, Reynolds JV (1998) Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice. Ann Surg 227:205–212

    Google Scholar 

  12. Trauner M, Meier PJ, Boyer JL (1997) Molecular pathogenesis of cholestasis. N Engl J Med 339:1217–1227

    Article  Google Scholar 

  13. Trauner M, Meier PJ, Boyer JL (1999) Molecular regulation of hepatocellular transport systems in cholestasis. J Hepatol 31:165–178

    Article  CAS  PubMed  Google Scholar 

  14. Trauner M, Arrese M, Soroka CJ, Ananthanarayanan M, Koeppel TA, Schlosser SF, Suchy FJ, Keppler D (1997) The rat canalicular conjugates export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 113:255–264

    CAS  PubMed  Google Scholar 

  15. Vos TA, Hooiveld GJEJ, Konning H, Childs S, Meijer DKF, Moshage H, Jansen PLM, Muller M (1998) Up-regulation of the multidrug resistance genes, mrp1 and mdr1b, and down-regulation of the organic anion transporter, mrp2, and the bile salt transporter, spgp, in endotoxemic rat liver. Hepatology 28:1637–1644

    Article  CAS  PubMed  Google Scholar 

  16. Kubitz R, Wettstein M, Warskulat U, Haussinger D (1999) Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone. Gastroenterology 116:401–410

    CAS  PubMed  Google Scholar 

  17. Paulusma CC, Kothe MJC, Bakker CTM, Bosma PJ, Bokhoven I, Marle J, Bolder U, Tytgat GNJ, Elferink RPJ (2000) Zonal down-regulation and redistribution of the multidrug resistance protein 2 during bile duct ligation in rat liver. Hepatology 31:684–693

    Article  CAS  PubMed  Google Scholar 

  18. Nagino M, Nimura Y, Kamiya J et al (1995) Changes in hepatic lobe volume in biliary tract cancer patients after right portal vein embolization. Hepatology 21:434–439

    CAS  PubMed  Google Scholar 

  19. Uesaka K, Nimura Y, Nagino M (1996) Changes in hepatic lobar function after right portal embolization. An appraisal by biliary indocyanine green excretion. Ann Surg 223:77–83

    Google Scholar 

  20. Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S, Kuwano M (1996) A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res 56:4124–4129

    CAS  PubMed  Google Scholar 

  21. Shoda J, Kano M, Oda K, Kamiya J, Nimura Y, Suzuki H, Sugiyama Y, Miyazaki H, Todoroki T, Stengelin S, Kramer W, Matsuzaki Y, Tanaka N (2001) 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 96:3368–3378

    Article  CAS  PubMed  Google Scholar 

  22. Shoda J, Miura T, Utsunomiya H, Oda K, Yamamoto M, Kano M, Ikegami T, Tanaka N, Akita H, Ito K, Suzuki H, Sugiyama Y (2004) Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver. Hepatology 39:167–178

    Article  CAS  PubMed  Google Scholar 

  23. Shimizu T, Sato O, Tsukada K (1996) Reestimation of the bilirubin decrease rate “b” (b value) in patients with obstructive jaundice. J Hepatobiliary Pancreat Surg 3:12–16

    Article  Google Scholar 

  24. Sano K, Kubota K, Bandai Y, Makuuci M (1999) Rate of bilirubin decrease as a risk predictor in hepato-biliary–pancreatic surgery. Hepatogastroenterology 46:2171–2177

    CAS  PubMed  Google Scholar 

  25. Boerma EJ (1990) Research into the results of resection of hilar bile duct cancer. Surgery 108:572–580

    CAS  PubMed  Google Scholar 

  26. Sugiura Y, Nakamura S, Iida S, Hosoda Y, Ikeuchi S, Mori S, Sugioka A (1994) Extensive resection of the bile ducts combined with liver resection for cancer of the main hepatic duct junction: a cooperative study of the Keio Bile Duct Cancer Study Group. Surgery 115:445–451

    CAS  PubMed  Google Scholar 

  27. Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R (1997) Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 15:947–954

    CAS  PubMed  Google Scholar 

  28. Nagino M, Nimura Y, Kamiya J, Kanai M, Uesaka K, Hayakawa N, Yamamoto H, Kondo S, Nishio H (1998) Segmental liver resections for hilar cholangiocarcinoma. Hepatogastroenterology 45:7–13

    CAS  PubMed  Google Scholar 

  29. Lee JM, Trauner M, Soroka CJ, Stieger B (2000) Expression of the bile salt export pump is maintained after chronic cholestasis in the rat. Gastroenterology 118:163–172

    CAS  PubMed  Google Scholar 

  30. Soroka CJ, Lee JM, Azzaroli F, Boyer JL (2001) Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology 33:783–791

    Article  CAS  PubMed  Google Scholar 

  31. Zollner G, Fickert P, Zenz R, Fuchsbichler A, Stumptner C, Kenner L, Ferenci P, Stauber RE, Krejs GJ, Denk H, Zatloukal K, Trauner M (2001) Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33:633–646

    Article  CAS  PubMed  Google Scholar 

  32. Kawaguchi T, Sakisaka S, Mitsuyama K, Harada M, Koga H, Taniguchi E, Sasatomi K, Kimura R, Ueno T, Sawada N, Mori M, Sata M (2000) Cholestasis with altered structure and function of hepatocyte tight junction and decreased expression of canalicular multispecific organ anion transporter in a rat model of colitis. Hepatology 31:1285–1295

    Article  CAS  PubMed  Google Scholar 

  33. Nagino M, Hayakawa N, Nimura Y, Dohke M, Kitagawa S (1992) Percutaneous transhepatic biliary drainage in patients with malignant biliary obstruction of the hepatic confluence. Hepatogastroenterology 39:296–300

    CAS  PubMed  Google Scholar 

  34. Nimura Y, Kamiya J, Kondo S, Nagino M, Kanai M (1995) Technique of inserting multiple biliary drains and management. Hepatogastroenterology 42:323–331

    CAS  PubMed  Google Scholar 

  35. Kanai M, Nimura Y, Kamiya J, Kondo S, Nagino M, Miyachi M, Goto Y (1996) Preoperative intrahepatic segmental cholangitis in patients with advanced carcinoma involving the hepatic hilus. Surgery 119:498–504

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. N. Iwahashi for assistance with Western blotting.

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Tatsuharu Yamada, Toshiyuki Arai, Masato Nagino, Koji Oda & Yuji Nimura

  2. The Department of Gastroenterology, Institute of Clinical Medicine, Tsukuba University School of Medicine, Tsukuba, Japan

    Junichi Shoda

  3. The Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

    Hiroshi Suzuki & Yuichi Sugiyama

Authors
  1. Tatsuharu Yamada
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  2. Toshiyuki Arai
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  3. Masato Nagino
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  4. Koji Oda
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  6. Hiroshi Suzuki
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  8. Yuji Nimura
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Correspondence to Yuji Nimura.

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Yamada, T., Arai, T., Nagino, M. et al. Impaired expression of hepatic multidrug resistance protein 2 is associated with posthepatectomy hyperbilirubinemia in patients with biliary cancer. Langenbecks Arch Surg 390, 421–429 (2005). https://doi.org/10.1007/s00423-005-0564-5

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  • DOI: https://doi.org/10.1007/s00423-005-0564-5

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