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

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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 (R ² = 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.

Electronic supplementary material

The online version of this article (doi:10.1186/s12876-017-0614-9) contains supplementary material, which is available to authorized users.

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Most cited references 28

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Reverse cholesterol transport and cholesterol efflux in atherosclerosis.

Wan X. Yao, X. Wang, R Ohashi … (2005)

Reverse cholesterol transport (RCT) is a pathway by which accumulated cholesterol is transported from the vessel wall to the liver for excretion, thus preventing atherosclerosis. Major constituents of RCT include acceptors such as high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I), and enzymes such as lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), hepatic lipase (HL) and cholesterol ester transfer protein (CETP). A critical part of RCT is cholesterol efflux, in which accumulated cholesterol is removed from macrophages in the subintima of the vessel wall by ATP-binding membrane cassette transporter A1 (ABCA1) or by other mechanisms, including passive diffusion, scavenger receptor B1 (SR-B1), caveolins and sterol 27-hydroxylase, and collected by HDL and apoA-I. Esterified cholesterol in the HDL is then delivered to the liver for excretion. In patients with mutated ABCA1 genes, RCT and cholesterol efflux are impaired and atherosclerosis is increased. In studies with transgenic mice, disruption of ABCA1 genes can induce atherosclerosis. Levels of HDL are inversely correlated with incidences of cardiovascular disease. Supplementation with HDL or apoA-I can reverse atherosclerosis by accelerating RCT and cholesterol efflux. On the other hand, pro-inflammatory factors such as interferon-gamma (IFN-gamma), endotoxin, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), can be atherogenic by impairing RCT and cholesterol efflux, according to in vitro studies. RCT and cholesterol efflux play a major role in anti-atherogenesis, and modification of these processes may provide new therapeutic approaches to cardiovascular disease. Further research on new modifying factors for RCT and cholesterol efflux is warranted.

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Lecithin cholesterol acyltransferase.

Elizabeth Jonas (2000)

Cholesterol transport in circulation and its removal from tissues depends on the activity of lecithin cholesterol acyltransferase (LCAT). LCAT is a soluble enzyme that converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lyso-phosphatidylcholines on the surface of high-density lipoproteins. This review presents key background information and recent research advances on the structure of human LCAT, its reactions and substrates, and the expression of the LCAT gene. While the three-dimensional structure of LCAT is not yet known, a partial model now exists that facilitates the study of structure-function relationships of the native enzyme, and of natural and engineered mutants. The LCAT reaction on lipoproteins consists of several steps, starting with enzyme binding to the lipoprotein/lipid surface, followed by activation of LCAT by apolipoproteins, binding of lipid substrates and the catalytic steps giving rise to the lipid products. Quantitative data are presented on the kinetic and equilibrium constants of some of the LCAT reaction steps. Finally, overexpression of the human LCAT gene in mice and rabbits has been used to examine the physiologic role of LCAT in vivo and its protective effect against diet induced atherosclerosis.

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The MELD score in patients awaiting liver transplant: strengths and weaknesses.

S. Gitto, Maurizio Biselli, Mauro Bernardi (2011)

Adoption of the Model for End-stage Liver Disease (MELD) to select and prioritize patients for liver transplantation represented a turning point in organ allocation. Prioritization of transplant recipients switched from time accrued on the waiting list to the principle of "sickest first". The MELD score incorporates three simple laboratory parameters (serum creatinine and bilirubin, and INR for prothrombin time) and stratifies patients according to their disease severity in an objective and continuous ranking scale. Concordance statistics have demonstrated its high accuracy in stratifying patients according to their risk of dying in the short-term (three months). Further validations of MELD as a predictor of survival at various temporal end-points have been obtained in independent patient cohorts with a broad spectrum of chronic liver disease. The MELD-based liver graft allocation policy has led to a reduction in waitlist new registrations and mortality, shorter waiting times, and an increase in transplants, without altering overall graft and patient survival rates after transplantation. MELD limitations are related either to the inter-laboratory variability of the parameters included in the score, or to the inability of the formula to predict mortality accurately in specific settings. For some conditions, such as hepatocellular carcinoma, widely accepted MELD corrections have been devised. For others, such as persistent ascites and hyponatremia, attempts to improve MELD's predicting power are currently underway, but await definite validation. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Thorsten Kaiser: +49 341 9722200 , Thorsten.Kaiser@medizin.uni-leipzig.de

Benedict Kinny-Köster: Benedict.Kinny-Koester@medizin.uni-leipzig.de

Michael Bartels: michael.bartels@helios-kliniken.de

Thomas Berg: Thomas.Berg@medizin.uni-leipzig.de

Markus Scholz: markus.scholz@imise.uni-leipzig.de

Cornelius Engelmann: Cornelius.Engelmann@medizin.uni-leipzig.de

Daniel Seehofer: Daniel.Seehofer@medizin.uni-leipzig.de

Susen Becker: Susen.Becker@medizin.uni-leipzig.de

Uta Ceglarek: Uta.Ceglarek@medizin.uni-leipzig.de

Joachim Thiery: Joachim.Thiery@medizin.uni-leipzig.de

Journal

Journal ID (nlm-ta): BMC Gastroenterol

Journal ID (iso-abbrev): BMC Gastroenterol

Title: BMC Gastroenterology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-230X

Publication date (Electronic): 20 April 2017

Publication date PMC-release: 20 April 2017

Publication date Collection: 2017

Volume: 17

Electronic Location Identifier: 57

Affiliations

[1 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, , University Hospital Leipzig, ; Paul-List-Str. 13-15, 04103 Leipzig, Germany

[2 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, Department of Visceral, Vascular, Thoracic and Transplant Surgery, , University Hospital Leipzig, ; Leipzig, Germany

[3 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, Section of Hepatology, Department of Gastroenterology and Rheumatology, , University Hospital Leipzig, ; Leipzig, Germany

[4 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, Institute for Medical Informatics, Statistics and Epidemiology (IMISE), , University Hospital Leipzig, ; Leipzig, Germany

[5 ]ISNI 0000 0000 8517 9062, GRID grid.411339.d, LIFE – Leipzig Research Center for Civilization Diseases, , University Hospital Leipzig, ; Leipzig, Germany

Article

Publisher ID: 614

DOI: 10.1186/s12876-017-0614-9

PMC ID: 5397767

PubMed ID: 28427335

SO-VID: 2e18247f-76ca-405b-977c-f88c0d47ae64

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 October 2016

Date accepted : 13 April 2017

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cholesterol esterification,mortality,model for end-stage liver disease (meld) score,international normalized ratio (inr),orthotopic liver transplantation

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cholesterol esterification, mortality, model for end-stage liver disease (meld) score, international normalized ratio (inr), orthotopic liver transplantation

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

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Gastroenterology

Most cited references 28

Reverse cholesterol transport and cholesterol efflux in atherosclerosis.

Lecithin cholesterol acyltransferase.

The MELD score in patients awaiting liver transplant: strengths and weaknesses.

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