Skip to main content
PMC home page
Journal of Clinical and Experimental Hepatology logoLink to Journal of Clinical and Experimental Hepatology
. 2012 Apr 12;2(1):19–26. doi: 10.1016/S0973-6883(12)60078-4

Comparison of Circulating Endothelial Cell/Platelet Count Ratio to Aspartate Transaminase/Platelet Ratio Index for Identifying Patients with Cirrhosis

Saurabh Sethi *, Douglas A Simonetto *, Soha S Abdelmoneim *,**, Michael B Campion †, Irakli Kaloiani *, Amy C Clayton †, Walter K Kremers ‡, Kevin C Halling †, Patrick S Kamath *, Jayant Talwalkar *, Vijay H Shah *,*
PMCID: PMC3940317  PMID: 25755402

Abstract

Background/Objectives

Circulating endothelial cells (CECs) are indicative of vascular injury and correlate with severity of vascular diseases. A pilot study showed that the ratio of CEC to platelet count (CEC/PC) was effective in predicting cirrhosis. Therefore, we evaluated CEC/PC in a larger cohort of patients, correlated it with cirrhosis, and compared its operating characteristics with previously described biomarker for cirrhosis, the AST/platelet ratio index (APRI).

Methods

Fifty-three patients with cirrhosis, 20 matched healthy controls, and 9 patients with noncirrhotic liver disease were recruited. Peripheral blood sample was collected and analyzed to enumerate nucleated CEC CD146+, CD105+, CD45– using a commercial assay.

Results

Median CEC counts were significantly higher in patients with cirrhosis (62 cells/4 mL, interquartile range [IQR]: 43.5–121) as compared with controls (31 cells/4 mL, IQR: 22.2–40). The CEC/PC was also significantly elevated in cirrhotics (0.69, IQR: 0.39–1.48) compared with controls (0.12, IQR: 0.09–0.20) and noncirrhotics (0.21, IQR: 0.08–0.43). Receiver operator characteristic (ROC) analysis revealed that CEC cutoff value of ≥37 cells/4 mL showed sensitivity of 81% and specificity of 75% for differentiating cirrhosis from controls (area under the curve [AUC]: 0.80; 95% confidence interval [CI] 0.67–0.91). The CEC/PC ratio cutoff value of ≥0.23 showed sensitivity of 91% and specificity of 82% (AUC: 0.92; 95% CI 0.83–0.99). The APRI cutoff value of ≥0.4 showed sensitivity of 94% and specificity of 85% for differentiating cirrhosis from control patients (AUC: 0.96; 95% CI 0.90–1.0). A product of CEC and APRI, termed CAPRI (CEC-APRI), effectively distinguished patients with cirrhosis from controls; with cutoff value of ≥12.7, showing higher sensitivity of 98% and specificity of 85% (AUC: 0.98; 95% CI 0.96–1.0).

Conclusion

The CEC/PC ratio is significantly elevated in patients with cirrhosis and demonstrates comparable operating characteristics to previously described APRI. Furthermore, CAPRI, compiled as product of CEC to APRI showed outstanding ability to distinguish patients with cirrhosis from controls, although larger studies are necessary for validation.

Keywords: APRI, CAPRI, circulating endothelial cells, cirrhosis, non-invasive markers, portal hypertension

Abbreviations: APRI, AST/platelet ratio index; AST, aspartate aminotransferase; AUC, area under the curve; CAPRI, CEC with APRI; CEC, circulating endothelial cell; CTP, Child–Turcotte–Pugh; EGD, esophagogastroduodenoscopy; ELF, enhanced liver fibrosis; IQR, interquartile range; MELD, model for end-stage liver disease; PC, platelet count; ROC, receiver operator characteristic

Full Text

The Full Text of this article is available as a PDF (177.2 KB).

References

  • 1.Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371:838–851. doi: 10.1016/S0140-6736(08)60383-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Luxon BA. Noninvasive tests for liver fibrosis. Postgrad Med. 2006;119:8–13. doi: 10.1080/00325481.2006.11446044. [DOI] [PubMed] [Google Scholar]
  • 3.Patel K. Noninvasive tools to assess liver disease. Curr Opin Gastroenterol. 2010;26:227–233. doi: 10.1097/MOG.0b013e3283383c68. [DOI] [PubMed] [Google Scholar]
  • 4.Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069–1075. doi: 10.1016/S0140-6736(00)04258-6. [DOI] [PubMed] [Google Scholar]
  • 5.Woywodt A, Blann AD, Kirsch T. Isolation and enumeration of circulating endothelial cells by immunomagnetic isolation: proposal of a definition and a consensus protocol. J Thromb Haemost. 2006;4:671–677. doi: 10.1111/j.1538-7836.2006.01794.x. [DOI] [PubMed] [Google Scholar]
  • 6.Goon PK, Boos CJ, Lip GY. Circulating endothelial cells: markers of vascular dysfunction. Clin Lab. 2005;51:531–538. [PubMed] [Google Scholar]
  • 7.Widemann A, Sabatier F, Arnaud L. CD146-based immuno-magnetic enrichment followed by multiparameter flow cytometry: a new approach to counting circulating endothelial cells. J Thromb Haemost. 2008;6:869–876. doi: 10.1111/j.1538-7836.2008.02931.x. [DOI] [PubMed] [Google Scholar]
  • 8.Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ. Evidence for the involvement of endothelial cell integrin alphaV-beta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med. 1998;4:408–414. doi: 10.1038/nm0498-408. [DOI] [PubMed] [Google Scholar]
  • 9.Bonello L, Basire A, Sabatier F, Paganelli F, Dignat-George F. Endothelial injury induced by coronary angioplasty triggers mobilization of endothelial progenitor cells in patients with stable coronary artery disease. J Thromb Haemost. 2006;4:979–981. doi: 10.1111/j.1538-7836.2006.01858.x. [DOI] [PubMed] [Google Scholar]
  • 10.Bull TM, Golpon H, Hebbel RP. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost. 2003;90:698–703. doi: 10.1160/TH03-04-0251. [DOI] [PubMed] [Google Scholar]
  • 11.Lee KW, Lip GY, Tayebjee M, Foster W, Blann AD. Circulating endothelial cells, von Willebrand factor, interleukin-6, and prognosis in patients with acute coronary syndromes. Blood. 2005;105:526–532. doi: 10.1182/blood-2004-03-1106. [DOI] [PubMed] [Google Scholar]
  • 12.Woywodt A, Schroeder M, Gwinner W. Elevated numbers of circulating endothelial cells in renal transplant recipients. Transplantation. 2003;76:1–4. doi: 10.1097/01.TP.0000074569.65127.26. [DOI] [PubMed] [Google Scholar]
  • 13.Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol. 2009;50:604–620. doi: 10.1016/j.jhep.2008.12.011. [DOI] [PubMed] [Google Scholar]
  • 14.Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol. 2007;46:927–934. doi: 10.1016/j.jhep.2007.02.006. [DOI] [PubMed] [Google Scholar]
  • 15.Abdelmoneim SS, Talwalkar J, Sethi S. A prospective pilot study of circulating endothelial cells as a potential new biomarker in portal hypertension. Liver Int. 2010;30:191–197. doi: 10.1111/j.1478-3231.2009.02132.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Snyder N, Gajula L, Xiao SY. APRI: an easy and validated predictor of hepatic fibrosis in chronic hepatitis C. J Clin Gastroenterol. 2006;40:535–542. doi: 10.1097/00004836-200607000-00013. [DOI] [PubMed] [Google Scholar]
  • 17.Mancuso P, Burlini A, Pruneri G, Goldhirsch A, Martinelli G, Bertolini F. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood. 2001;97:3658–3661. doi: 10.1182/blood.v97.11.3658. [DOI] [PubMed] [Google Scholar]
  • 18.Janssens D, Michiels C, Guillaume G, Cuisinier B, Louagie Y, Remacle J. Increase in circulating endothelial cells in patients with primary chronic venous insufficiency: protective effect of Ginkor Fort in a randomized double-blind, placebo-controlled clinical trial. J Cardiovasc Pharmacol. 1999;33:7–11. doi: 10.1097/00005344-199901000-00002. [DOI] [PubMed] [Google Scholar]
  • 19.Mutin M, Canavy I, Blann A, Bory M, Sampol J, Dignat-George F. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood. 1999;93:2951–2958. [PubMed] [Google Scholar]
  • 20.Nadar SK, Lip GY, Lee KW, Blann AD. Circulating endothelial cells in acute ischaemic stroke. Thromb Haemost. 2005;94:707–712. doi: 10.1160/TH04-12-0795. [DOI] [PubMed] [Google Scholar]
  • 21.Thabut D, Shah V. Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension? J Hepatol. 2010;53:976–980. doi: 10.1016/j.jhep.2010.07.004. [DOI] [PubMed] [Google Scholar]
  • 22.Remkova A, Remko M. Homocysteine and endothelial markers are increased in patients with chronic liver diseases. Eur J Intern Med. 2009;20:482–486. doi: 10.1016/j.ejim.2009.03.002. [DOI] [PubMed] [Google Scholar]
  • 23.Sebastiani G, Alberti A. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy. World J Gastroenterol. 2006;12:3682–3694. doi: 10.3748/wjg.v12.i23.3682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology. 2008;134:1670–1681. doi: 10.1053/j.gastro.2008.03.001. [DOI] [PubMed] [Google Scholar]
  • 25.Carey E, Carey WD. Noninvasive tests for liver disease, fibrosis, and cirrhosis: Is liver biopsy obsolete? Cleve Clin J Med. 2010;77:519–527. doi: 10.3949/ccjm.77a.09138. [DOI] [PubMed] [Google Scholar]
  • 26.Poynard T, Imbert-Bismut F, Munteanu M. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3:8. doi: 10.1186/1476-5926-3-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Halfon P, Bourliere M, Deydier R. Independent prospective multicenter validation of biochemical markers (fibrotest-actitest) for the prediction of liver fibrosis and activity in patients with chronic hepatitis C: the fibropaca study. Am J Gastroenterol. 2006;101:547–555. doi: 10.1111/j.1572-0241.2006.00411.x. [DOI] [PubMed] [Google Scholar]
  • 28.Rossi E, Adams L, Prins A. Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients. Clin Chem. 2003;49:450–454. doi: 10.1373/49.3.450. [DOI] [PubMed] [Google Scholar]
  • 29.Wai CT, Greenson JK, Fontana RJ. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–526. doi: 10.1053/jhep.2003.50346. [DOI] [PubMed] [Google Scholar]
  • 30.Rosenberg WM, Voelker M, Thiel R. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–1713. doi: 10.1053/j.gastro.2004.08.052. [DOI] [PubMed] [Google Scholar]
  • 31.Nobili V, Parkes J, Bottazzo G. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009;136:160–167. doi: 10.1053/j.gastro.2008.09.013. [DOI] [PubMed] [Google Scholar]
  • 32.Kelleher TB, Mehta SH, Bhaskar R. Prediction of hepatic fibrosis in HIV/HCV co-infected patients using serum fibrosis markers: the SHASTA index. J Hepatol. 2005;43:78–84. doi: 10.1016/j.jhep.2005.02.025. [DOI] [PubMed] [Google Scholar]
  • 33.Lackner C, Struber G, Liegl B. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology. 2005;41:1376–1382. doi: 10.1002/hep.20717. [DOI] [PubMed] [Google Scholar]
  • 34.Lieber CS, Weiss DG, Morgan TR, Paronetto F. Aspartate aminotransferase to platelet ratio index in patients with alcoholic liver fibrosis. Am J Gastroenterol. 2006;101:1500–1508. doi: 10.1111/j.1572-0241.2006.00610.x. [DOI] [PubMed] [Google Scholar]
  • 35.Schiavon LL, Schiavon JL, Filho RJ. Simple blood tests as noninvasive markers of liver fibrosis in hemodialysis patients with chronic hepatitis C virus infection. Hepatology. 2007;46:307–314. doi: 10.1002/hep.21681. [DOI] [PubMed] [Google Scholar]
  • 36.Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology. 2007;46:912–921. doi: 10.1002/hep.21835. [DOI] [PubMed] [Google Scholar]
  • 37.Adams LA, Bulsara M, Rossi E. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem. 2005;51:1867–1873. doi: 10.1373/clinchem.2005.048389. [DOI] [PubMed] [Google Scholar]
  • 38.Becker L, Salameh W, Sferruzza A. Validation of hepascore, compared with simple indices of fibrosis, in patients with chronic hepatitis C virus infection in United States. Clin Gastroenterol Hepatol. 2009;7:696–701. doi: 10.1016/j.cgh.2009.01.010. [DOI] [PubMed] [Google Scholar]
  • 39.Lok AS, Ghany MG, Goodman ZD. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort. Hepatology. 2005;42:282–292. doi: 10.1002/hep.20772. [DOI] [PubMed] [Google Scholar]
  • 40.Thomson SJ, Cowan ML, Johnston I, Musa S, Grounds M, Rahman TM. ‘Liver function tests’ on the intensive care unit: a prospective, observational study. Intensive Care Med [Research Support, Non-US Gov't] 2009;35:1406–1411. doi: 10.1007/s00134-009-1511-7. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical and Experimental Hepatology are provided here courtesy of Elsevier

RESOURCES