Advertisement

Medical Molecular Morphology

, Volume 51, Issue 3, pp 176–185 | Cite as

Serum levels of a cell death biomarker predict the development of cirrhosis-related conditions in primary biliary cholangitis

  • Manabu Hayashi
  • Kazumichi Abe
  • Masashi Fujita
  • Ken Okai
  • Atsushi Takahashi
  • Yoshihiro Nozawa
  • Hiromasa Ohira
Original Paper

Abstract

Non-invasive predictors for the development of cirrhosis-related conditions are needed for patients with primary biliary cholangitis (PBC). We investigated the association between cytokeratin-18 fragments (M30 and M65) and liver histology, treatment response and the development of cirrhosis-related conditions in patients with PBC. We retrospectively reviewed the clinical data of 111 individuals with biopsy-proven PBC. Serum M30 and M65 levels were measured using stored sera. M30 were significantly decreased after treatment, but there was no significant change in the M65 levels. M65 was significantly higher in non-responders according to the Paris-I and Paris-II definitions. In the multivariate analysis, high levels of M65 were significantly associated with advanced Scheuer stage (odds ratio 5.86; 95% confidence interval 0.55–22.2; P = 0.009) and with the development of cirrhosis-related conditions (hazard ratio 3.94; 95% confidence interval: 1.06–14.5, P = 0.039). Among PBC patients without cirrhosis, those with high serum M65 levels at baseline were at higher risk of developing cirrhosis-related conditions (log-rank test; P = 0.001). High levels of serum M65 may be a non-invasive and early predictor of the development of cirrhosis-related conditions in PBC patients. Our findings may help initiate therapies earlier for those at risk for cirrhosis.

Keywords

Primary biliary cholangitis Cytokeratin-18 Biochemical response Nakanuma staging system Scheuer staging system 

Notes

Acknowledgements

We thank C. Sato and R. Hikichi for their excellent technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis. N Engl J Med 353:1261–1273CrossRefPubMedGoogle Scholar
  2. 2.
    Selmi C, Bowlus CL, Gershwin ME, Coppel RL (2011) Primary biliary cirrhosis. Lancet 377:1600–1609CrossRefPubMedGoogle Scholar
  3. 3.
    Poupon R, Chretien Y, Chazouilleres O, Poupon RE (2005) Pregnancy in women with ursodeoxycholic acid-treated primary biliary cirrhosis. J Hepatol 42:418–419CrossRefPubMedGoogle Scholar
  4. 4.
    European Association for the Study of the Liver (2017) EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 67:145–172CrossRefGoogle Scholar
  5. 5.
    Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ (1997) Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 113:884–890CrossRefPubMedGoogle Scholar
  6. 6.
    Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R (2000) The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 32:1196–1199CrossRefPubMedGoogle Scholar
  7. 7.
    Kuiper EM, Hansen BE, Metselaar HJ, de Man RA, Haagsma EB, van Hoek B, van Buuren HR (2010) Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988–2008. BMC Gastroenterol 10:144CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Silveira MG, Brunt EM, Heathcote J, Gores GJ, Lindor KD, Mayo MJ (2010) American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology 52:349–359CrossRefPubMedGoogle Scholar
  9. 9.
    Corpechot C, Chazouilleres O, Poupon R (2011) Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 55:1361–1367CrossRefPubMedGoogle Scholar
  10. 10.
    Kakuda Y, Harada K, Sawada-Kitamura S, Ikeda H, Sato Y, Sasaki M, Okafuji H, Mizukoshi E, Terasaki S, Ohta H, Kasashima S, Kawashima A, Kaizaki Y, Kaneko S, Nakanuma Y (2013) Evaluation of a new histologic staging and grading system for primary biliary cirrhosis in comparison with classical systems. Hum Pathol 44:1107–1117CrossRefPubMedGoogle Scholar
  11. 11.
    Azemoto N, Abe M, Murata Y, Hiasa Y, Hamada M, Matsuura B, Onji M (2009) Early biochemical response to ursodeoxycholic acid predicts symptom development in patients with asymptomatic primary biliary cirrhosis. J Gastroenterol 44:630–634CrossRefPubMedGoogle Scholar
  12. 12.
    Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C, Heathcote EJ, Hirschfield GM (2010) Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 105:2186–2194CrossRefPubMedGoogle Scholar
  13. 13.
    Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD, American Association for the Study of Liver Diseases (2009) Liver biopsy. Hepatology 49:1017–1044CrossRefPubMedGoogle Scholar
  14. 14.
    Van Eyken P, Desmet VJ (1993) Cytokeratins and the liver. Liver 13:113–122CrossRefPubMedGoogle Scholar
  15. 15.
    Caulin C, Salvesen GS, Oshima RG (1997) Caspase cleavage of keratin 18 and reorganization of intermediate filaments during epithelial cell apoptosis. J Cell Biol 138:1379–1394CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ku NO, Liao J, Omary MB (1997) Apoptosis generates stable fragments of human type I keratins. J Biol Chem 272:33197–33203CrossRefPubMedGoogle Scholar
  17. 17.
    Bantel H, Ruck P, Gregor M, Schulze-Osthoff K (2001) Detection of elevated caspase activation and early apoptosis in liver diseases. Eur J Cell Biol 80:230–239CrossRefPubMedGoogle Scholar
  18. 18.
    Denk G, Omary AJ, Reiter FP, Hohenester S, Wimmer R, Holdenrieder S, Rust C (2014) Soluble intracellular adhesion molecule, M30 and M65 as serum markers of disease activity and prognosis in cholestatic liver diseases. Hepatol Res 44:1286–1298CrossRefPubMedGoogle Scholar
  19. 19.
    Sekiguchi T, Umemura T, Fujimori N, Shibata S, Ichikawa Y, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M (2015) Serum cell death biomarkers for prediction of liver fibrosis and poor prognosis in primary biliary cirrhosis. PLoS One 10:e0131658CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, American Association for Study of Liver Diseases (2009) Primary biliary cirrhosis. Hepatology 50:291–308CrossRefPubMedGoogle Scholar
  21. 21.
    Scheuer P (1967) Primary biliary cirrhosis. Proc R Soc Med 60:1257–1260PubMedPubMedCentralGoogle Scholar
  22. 22.
    Nakanuma Y, Zen Y, Harada K, Sasaki M, Nonomura A, Uehara T, Sano K, Kondo F, Fukusato T, Tsuneyama K, Ito M, Wakasa K, Nomoto M, Minato H, Haga H, Kage M, Yano H, Haratake J, Aishima S, Masuda T, Aoyama H, Miyakawa-Hayashino A, Matsumoto T, Sanefuji H, Ojima H, Chen TC, Yu E, Kim JH, Park YN, Tsui W (2010) Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement. Pathol Int 60:167–174CrossRefPubMedGoogle Scholar
  23. 23.
    Bantel H, Lugering A, Heidemann J, Volkmann X, Poremba C, Strassburg CP, Manns MP, Schulze-Osthoff K (2004) Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. Hepatology 40:1078–1087CrossRefPubMedGoogle Scholar
  24. 24.
    Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, Chazouilleres O, Poupon R (2008) Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 48:871–877CrossRefPubMedGoogle Scholar
  25. 25.
    Pares A, Caballeria L, Rodes J (2006) Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 130:715–720CrossRefPubMedGoogle Scholar
  26. 26.
    Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, Houben MH, Witteman BJ, van Erpecum KJ, van Buuren HR, Dutch P. B. C. Study Group (2009) Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 136:1281–1287CrossRefPubMedGoogle Scholar
  27. 27.
    Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, Floreani A, Ponsioen CY, Mayo MJ, Invernizzi P, Battezzati PM, Pares A, Burroughs AK, Mason AL, Kowdley KV, Kumagi T, Harms MH, Trivedi PJ, Poupon R, Cheung A, Lleo A, Caballeria L, Hansen BE, van Buuren HR, Global PBC Study Group (2015) Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 149:1804–1812 (e1804)CrossRefPubMedGoogle Scholar
  28. 28.
    Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, Griffiths L, Lim R, Trembling P, Williamson K, Wareham NJ, Aldersley M, Bathgate A, Burroughs AK, Heneghan MA, Neuberger JM, Thorburn D, Hirschfield GM, Cordell HJ, Alexander GJ, Jones DE, Sandford RN, Mells GF, UK-PBC Consortium (2016) The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 63:930–950CrossRefPubMedGoogle Scholar
  29. 29.
    Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48:452–458CrossRefPubMedGoogle Scholar
  30. 30.
    Namisaki T, Moriya K, Kitade M, Kawaratani H, Takeda K, Okura Y, Takaya H, Nishimura N, Seki K, Kaji K, Sato S, Sawada Y, Yamao J, Mitoro A, Uejima M, Mashitani T, Shimozato N, Nakanishi K, Furukawa M, Saikawa S, Kubo T, Yoshiji H (2017) Clinical significance of the Scheuer histological staging system for primary biliary cholangitis in Japanese patients. Eur J Gastroenterol Hepatol 29:23–30CrossRefPubMedGoogle Scholar
  31. 31.
    Koga H, Sakisaka S, Ohishi M, Sata M, Tanikawa K (1997) Nuclear DNA fragmentation and expression of Bcl-2 in primary biliary cirrhosis. Hepatology 25:1077–1084CrossRefPubMedGoogle Scholar
  32. 32.
    Fox CK, Furtwaengler A, Nepomuceno RR, Martinez OM, Krams SM (2001) Apoptotic pathways in primary biliary cirrhosis and autoimmune hepatitis. Liver 21:272–279CrossRefPubMedGoogle Scholar
  33. 33.
    Fickert P, Wagner M (2017) Biliary bile acids in hepatobiliary injury—what is the link? J Hepatol 67:619–631CrossRefPubMedGoogle Scholar
  34. 34.
    Medina JF, Martinez A, Vazquez JJ, Prieto J (1997) Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology 25:12–17CrossRefPubMedGoogle Scholar
  35. 35.
    Prieto J, Garcia N, Marti-Climent JM, Penuelas I, Richter JA, Medina JF (1999) Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology 117:167–172CrossRefPubMedGoogle Scholar
  36. 36.
    Beuers U (2006) Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318–328CrossRefPubMedGoogle Scholar
  37. 37.
    Sola S, Amaral JD, Castro RE, Ramalho RM, Borralho PM, Kren BT, Tanaka H, Steer CJ, Rodrigues CM (2005) Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-beta1-induced apoptosis in rat hepatocytes. Hepatology 42:925–934CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society for Clinical Molecular Morphology 2018

Authors and Affiliations

  1. 1.Department of GastroenterologyFukushima Medical University School of MedicineFukushimaJapan
  2. 2.Department of PathologyShirakawa Kousei General HospitalShirakawaJapan

Personalised recommendations