Cholesterol esterification in plasma as a biomarker for liver function and prediction of mortality

Thorsten Kaiser, Benedict Kinny-Köster, Michael Bartels, Thomas Berg, Markus Scholz, Cornelius Engelmann, Daniel Seehofer, Susen Becker, Uta Ceglarek, Joachim Thiery, Thorsten Kaiser, Benedict Kinny-Köster, Michael Bartels, Thomas Berg, Markus Scholz, Cornelius Engelmann, Daniel Seehofer, Susen Becker, Uta Ceglarek, Joachim Thiery

Abstract

Background: Advanced stages of liver cirrhosis lead to a dramatically increased mortality. For valid identification of these patients suitable biomarkers are essential. The most important biomarkers for liver function are bilirubin and prothrombin time expressed as International Normalized Ratio (INR). However, the influence of several anticoagulants on the prothrombin time limits its diagnostic value. Aim of this study was the evaluation of cholesterol esterification (CE) fraction (esterified cholesterol vs. total cholesterol) as an alternative biomarker for liver synthesis and mortality prediction. Under physiological conditions the CE fraction in blood is closely regulated by lecithin-cholesterol acyltransferase (LCAT) which is produced in the liver.

Methods: One hundred forty-two patients with liver disease clinically considered for orthotopic liver transplant for different indications were enrolled in the study. One patient was excluded because of the intake of a direct oral factor Xa inhibitor which has a strong impact on prothrombin time.

Results: Results of CE fraction were in good agreement with INR (R2 = 0.73; p < 0.001). In patients who died or survived within three months mean CE fraction was 56% vs. 74% (p < 0.001) and mean INR was 2.0 vs. 1.3 (p < 0.001), respectively. The predictive value of CE fraction for three-month mortality risk was higher compared to INR (p = 0.04). Results for one-year mortality were comparable.

Conclusions: The cholesterol esterification fraction is a valid biomarker for liver synthesis and allows reliable prediction of mortality. In contrast to INR, it is independent of anticoagulation and other analytical limitations of coagulation tests.

Keywords: Cholesterol esterification; International Normalized Ratio (INR); Model for end-stage liver disease (MELD) score; Mortality; Orthotopic liver transplantation.

Figures

Fig. 1
Fig. 1
Kaplan-Meier survival analysis for tertiles according to cholesterol esterification and INR: Patients were divided in tertiles according to their a cholesterol esterification fraction and b INR. While for CE all risk groups differ significantly (Table 2), the contrast of the highest INR groups is not significant (logrank test). Censoring is indicated with vertical bars within the curves
Fig. 2
Fig. 2
ROC analysis of single biomarkers for predicting three-month (a) and one-year (b) mortality during follow up (n.s. = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001)

References

    1. Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J, et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 2014;12:145. doi: 10.1186/s12916-014-0145-y.
    1. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33:464–470. doi: 10.1053/jhep.2001.22172.
    1. Kamath PS, Kim WR. The model for end-stage liver disease (MELD) Hepatology. 2007;45:797–805. doi: 10.1002/hep.21563.
    1. Cholongitas E, Germani G, Burroughs AK. Prioritization for liver transplantation. Nat Rev Gastroenterol Hepatol. 2010;7:659–668. doi: 10.1038/nrgastro.2010.169.
    1. Bernardi M, Gitto S, Biselli M. The MELD score in patients awaiting liver transplant: strengths and weaknesses. J Hepatol. 2011;54:1297–1306. doi: 10.1016/j.jhep.2010.11.008.
    1. Trotter JF, Brimhall B, Arjal R, Phillips C. Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl. 2004;10:995–1000. doi: 10.1002/lt.20195.
    1. Kaiser T, Zeuzem S, Lichtinghagen R, Welker MW, Geilenkeuser WJ, Kruse R, et al. Multi-center proficiency tests for Lab-MELD score diagnostics to improve the quality and safety for patients awaiting liver transplantation. Clin Chem Lab Med. 2014;52:e287–289. doi: 10.1515/cclm-2014-0088.
    1. Tripodi A, Caldwell SH, Hoffman M, Trotter JF, Sanyal AJ. Review article: the prothrombin time test as a measure of bleeding risk and prognosis in liver disease. Aliment Pharmacol Ther. 2007;26:141–148. doi: 10.1111/j.1365-2036.2007.03369.x.
    1. Tsakiris DA. Direct oral anticoagulants--interference with laboratory tests and mechanism of action. Semin Hematol. 2014;51:98–101. doi: 10.1053/j.seminhematol.2014.03.007.
    1. McCully SP, Fabricant LJ, Kunio NR, Groat TL, Watson KM, Differding JA, et al. The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients. J Trauma Acute Care Surg. 2013;75:947–953. doi: 10.1097/TA.0b013e3182a9676c.
    1. Kovacs M. International normalised ratio and liver impairment. Lancet. 2002;359:1695. doi: 10.1016/S0140-6736(02)08568-9.
    1. Wei Y, Li J, Zhang L, Zheng D, Shi B, Cong Y. Assessment of validity of INR system for patients with liver disease associated with viral hepatitis. J Thromb Thrombolysis. 2010;30:84–89. doi: 10.1007/s11239-009-0423-2.
    1. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147–56. doi: 10.1056/NEJMra1011170.
    1. Gatt A, Chen D, Pruthi RK, Kamath PS, Leise MD, Ashrani AA, et al. From vitamin K antagonists to liver international normalized ratio: a historical journey and critical perspective. Semin Thromb Hemost. 2014;40:845–851. doi: 10.1055/s-0034-1395160.
    1. Jones DP, Sosa FR, Shartsis J, Shah PT, Skromak E, Beher WT. Serum cholesterol esterifying and cholesteryl ester hydrolyzing activities in liver diseases: relationships to cholesterol, bilirubin, and bile salt concentrations. J Clin Invest. 1971;50:259–265. doi: 10.1172/JCI106490.
    1. Simon JB, Kepkay DL, Poon R. Serum cholesterol esterification in human liver disease: role of lecithin-cholesterol acyltransferase and cholesterol ester hydrolase. Gastroenterology. 1974;66:539–547.
    1. Becker S, Rohnike S, Empting S, Haas D, Mohnike K, Beblo S, et al. LC-MS/MS-based quantification of cholesterol and related metabolites in dried blood for the screening of inborn errors of sterol metabolism. Anal Bioanal Chem. 2015;407(17):5227–5233. doi: 10.1007/s00216-015-8731-1.
    1. United Network for Organ Sharing (UNOS). MELD Calculator. (Accessed 30 Mar 2015).
    1. Jonas A. Lecithin cholesterol acyltransferase. Biochim Biophys Acta. 2000;1529:245–256. doi: 10.1016/S1388-1981(00)00153-0.
    1. Kunnen S, van Eck M. Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis? J Lipid Res. 2012;53:1783–1799. doi: 10.1194/jlr.R024513.
    1. Sperry WM. Cholesterol esterase in blood. J Biol Chem. 1935;111:467–478.
    1. Ohashi R, Mu H, Wang X, Yao Q, Chen C. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM. 2005;98(12):845–856. doi: 10.1093/qjmed/hci136.
    1. Subbaiah PV, Jiang X, Belikova NA, Aizezi B, Huang ZH, Reardon CA. Regulation of plasma cholesterol esterification by sphingomyelin: effect of physiological variations of plasma sphingomyelin on lecithin-cholesterol acyltransferase activity. Biochim Biophys Acta. 1821;2012:908–913.
    1. Seidel D, Alaupovic P, Furman RH. A lipoprotein characterizing obstructive jaundice. I. Method for quantitative separation and identification of lipoproteins in jaundiced subjects. J Clin Invest. 1969;48:1211–1223. doi: 10.1172/JCI106085.
    1. Seidel D. A new immunochemical technique for a rapid, semi-quantitative determination of the abnormal lipoprotein (LP-X) characterizing cholestasis. Clin Chim Acta. 1971;31:225–229. doi: 10.1016/0009-8981(71)90381-0.
    1. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20(4):470–475.
    1. Mucino-Bermejo J, Carrillo-Esper R, Uribe M, Mendez-Sanchez N. Coagulation abnormalities in the cirrhotic patient. Ann Hepatol. 2013;12:713–724.
    1. Tripodi A, Chantarangkul V, Primignani M, Fabris F, Dell’Era A, Sei C, et al. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology. 2007;46:520–527. doi: 10.1002/hep.21732.
    1. Tripodi A. The validity of the INR system for patients with liver disease. J Thromb Thrombolysis. 2011;31:209–210. doi: 10.1007/s11239-010-0508-y.
    1. Bellest L, Eschwege V, Poupon R, Chazouilleres O, Robert A. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology. 2007;46:528–534. doi: 10.1002/hep.21680.
    1. Sermon AM, Smith JM, Maclean R, Kitchen S. An International Sensitivity Index (ISI) derived from patients with abnormal liver function improves agreement between INRs determined with different reagents. Thromb Haemost. 2010;103:757–765. doi: 10.1160/TH09-08-0535.
    1. Tripodi A, Baglin T, Robert A, Kitchen S, Lisman T, Trotter JF. Reporting prothrombin time results as international normalized ratios for patients with chronic liver disease. J Thromb Haemost. 2010;8:1410–1412. doi: 10.1111/j.1538-7836.2010.03877.x.
    1. Porte RJ, Lisman T, Tripodi A, Caldwell SH, Trotter JF. The International Normalized Ratio (INR) in the MELD score: problems and solutions. Am J Transplant. 2010;10:1349–1353. doi: 10.1111/j.1600-6143.2010.03064.x.
    1. Schouten JN, Francque S, van Vlierberghe H, Colle I, Nevens F, Delwaide J, et al. The influence of laboratory-induced MELD score differences on liver allocation: more reality than myth. Clin Transplant. 2012;26(1):70. doi: 10.1111/j.1399-0012.2011.01538.x.
    1. Beutner F, Teupser D, Gielen S, Holdt LM, Scholz M, Boudriot E, et al. Rationale and design of the Leipzig (LIFE) Heart Study: phenotyping and cardiovascular characteristics of patients with coronary artery disease. PLoS One. 2011;6(12):e29070. doi: 10.1371/journal.pone.0029070.

Source: PubMed

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