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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

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Volume 57, Issue 9

Issues

Biomarker-assisted identification of sepsis-related acute liver impairment: a frequent and deadly condition in critically ill patients

Jens-Ulrik Stæhr Jensen
  • Corresponding author
  • CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark
  • Department of Internal Medicine C, Respiratory Medicine Section, Copenhagen University Hospital, Herlev-Gentofte, Denmark
  • Email
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/ Lars Peters
  • CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark
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/ Theis S. Itenov
  • CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark
  • Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hillerød, Denmark
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/ Morten Bestle
  • Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hillerød, Denmark
  • Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Glostrup, Denmark
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/ Katrin M. Thormar
  • Department of Anesthesia and Intensive Care, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  • Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Gentofte, Denmark
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/ Thomas T. Mohr
  • Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Glostrup, Denmark
  • Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Gentofte, Denmark
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/ Bettina Lundgren / Jesper Grarup
  • CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark
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/ Jens D Lundgren
  • CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Copenhagen, Denmark
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/
Published Online: 2019-04-05 | DOI: https://doi.org/10.1515/cclm-2018-1350

Abstract

Background

The prognostic impact of mild/moderate liver impairment among critically ill patients is not known. We aimed to determine whether acute liver impairment, as measured by several biomarkers, (i) is frequent, (ii) influences prognosis and (iii) to determine whether such an effect is specific for infected critically ill patients.

Methods

A biomarker and clinical cohort study based on a randomized controlled trial. All-cause mortality was the primary endpoint. Biomarkers hyaluronic acid (HA), bilirubin, albumin, alkaline phosphatase and the international normalized ratio (INR) were determined. Multivariable statistics were applied to estimate risk increase according to liver biomarker increase at baseline and the model was adjusted for age, APACHE II, severe sepsis/septic shock vs. milder infection, chronic alcohol abuse Charlson’s co-morbidity index, cancer disease, surgical or medical patient, body mass index, sex, estimated glomerular filtration rate, mechanical ventilation and the other biomarkers. Time-to-event graphs were used. The patients were critically ill patients (n = 1096) from nine mixed medical/surgical intensive care units without known hepatobiliary disease.

Results

HA levels differed between infected patients (median 210.8 ng/mL [IQR: 93.2–556.6]) vs. the non-infected (median 56.8 ng/mL [IQR: 31.9–116.8], p < 0.001). Serum HA quartiles 2, 3 and 4 were independent predictors of 90-day all-cause mortality for the entire population (infected and non-infected). However, the signal was driven by the infected patients (positive interaction test, no signal in non-infected patients). Among infected patients, HA quartiles corresponded directly to the 90-day risk of dying: 1st quartile: 57/192 = 29.7%, 2nd quartile: 84/194 = 43.3%, 3rd quartile: 90/193 = 46.6%, 4th quartile: 101/192 = 52.3 %, p for trend: <0.0001. This finding was confirmed in adjusted analyses: hazard ratio vs. 1st quartile: 2nd quartile: 1.3 [0.9–1.8], p = 0.14, 3rd quartile: 1.5 [1.1–2.2], p = 0.02, 4th quartile: 1.9 [1.3–2.6], p < 0.0001). High bilirubin was also an independent predictor of mortality.

Conclusions

Among infected critically ill patients, subtle liver impairment, (elevated HA and bilirubin), was associated with a progressive and highly increased risk of death for the patient; this was robust to adjustment for other predictors of mortality. HA can identify patients at high risk.

This article offers supplementary material which is provided at the end of the article.

Keywords: biomarkers; infection; liver impairment; mortality

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About the article

Corresponding author: Jens-Ulrik Stæhr Jensen, MD, PhD, CHIP & PERSIMUNE, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen and University of Copenhagen, Blegdamsvej 9, Copenhagen, Denmark, Phone: +45 35455757, Fax: +45 35455758

aParticipating investigators are listed in the Acknowledgements.


Received: 2018-12-20

Accepted: 2019-03-04

Published Online: 2019-04-05

Published in Print: 2019-08-27


Data availability: The clinical and biochemical data used to support the findings of this study are restricted by the Ethics Board for the Capital Region of Denmark, KF 01-272-753, KF 11 297 287 and the Danish data protection law, in order to protect patient privacy. Data are available from the corresponding author for researchers who meet the criteria for access to confidential data. External researchers can apply the Ethics Board of the Capital Region of Denmark for access. The authors will guide and help with such an application.

Author contributions: Contributors: JUJ, TSI and JDL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed substantially to conception and design, or acquisition of data, or analysis and interpretation of data. JUJ and JDL drafted the article. Statistical analysis: JUJ, TSI, JDL. Obtained funding: JUJ, JDL, BL. Administrative, technical, or material support: All authors. All other authors revised it critically for important intellectual content. All authors gave final approval of the version to be published.

Research funding: This work was supported by the Danish National Research Foundation [Funder Id: http://dx.doi.org/10.13039/501100001732, Grant Number: DNRF126] (CHIP & PERSIMUNE), The Lundbeck Foundation, and the Idella Foundation.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf and declare: Dr. Jensen reports travelling to medical congress in 2016 with Roche Pharmaceutical and 2017 with Boehringer-Ingelheim. Other than this, Dr. Jensen has no conflicts of interest. Our institution received reagents for HA from Corgenix Inc, CO, USA. No financial funding was received from any company. All authors declare: no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 57, Issue 9, Pages 1422–1431, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2018-1350.

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