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Licensed Unlicensed Requires Authentication Published by De Gruyter April 5, 2019

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

  • Jens-Ulrik Stæhr Jensen EMAIL logo , Lars Peters , Theis S. Itenov , Morten Bestle , Katrin M. Thormar , Thomas T. Mohr , Bettina Lundgren , Jesper Grarup , Jens D Lundgren and for the Procalcitonin And Survival Study (PASS) Group

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.


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.

Acknowledgments

The authors wish to thank: The Procalcitonin And Survival Study Data and Safety Monitoring Board for the primary study: H. Masur (Chair), J. Chastre, H. Schønheyder, C. Pedersen and the Procalcitonin And Survival Study Group (PASS-group): M. Steensen; K. Thornberg; D. Strange; A.Ø. Lauritsen; P. Søe-Jensen; N. Reiter; N.E. Drenck; P. Fjeldborg; Z. Fox; J. Kjær; D. Kristensen; M. B. Rasmussen; C. S.v. Hallas; M. Zacho; C. Østergaard; P.L. Petersen; S. Hougaard; T. Mantoni; L. Nebrich; A. Bendtsen; L.H. Andersen; F. Bærentzen; Andreas Eversbusch; B. Bømler; R. Martusevicius; T. Nielsen; P.M. Bådstøløkken; U. Grevstad; P. Hallas; A. Lindhardt; T. Galle; K. Graeser; E. Hohwu-Christensen; P. Gregersen; L.M. Pedersen; L.C. Hallengreen; I. Rye; J. Cordtz; K.R. Madsen; P.R.C. Kirkegaard; L. Findsen; L.H. Nielsen; D.H. Pedersen; J.H. Andersen; C. Albrechtsen; A. Jacobsen; T. Jansen; A.G. Jensen; H.H. Jørgensen; M. Vazin; L. Lipsius; M. Skielboe; B. Thage; C. Thoft; M. Uldbjerg; E. Anderlo; M. Engsig; F. Hani; R.B. Jacobsen; L. Mulla; U. Skram; T. Waldau; T. Faber; B. Andersen; I. Gillesberg; A. Christensen; C. Hartmann; R. Albret; D.S. Dinesen; K. Gani; M. Ibsen; J.A. Petersen; P. Carl; E. Gade; D. Solevad; C. Heiring; M. Jørgensen; K. Ekelund; A. Afshari; N. Hammer; M. Bitsch; J.S. Hansen; C. Wamberg; T.D. Clausen; R. Winkel; J. Huusom; D.L. Buck; U. Grevstad; K. Lenz; P. Mellado; H. Karacan; J. Hidestål; J. Høgagard; J. Højbjerg; J. Højlund; S. Hestad; M. Østergaard; N. Wesche; S.A. Nielsen; H. Christensen; H. Blom; C.H. Jensen; K. Nielsen; N.G. Holler; C.D. Rossau; M. Glæemose; M.B. Wranér; C.B. Thomsen; B. Rasmussen; C. Lund-Rasmussen; B. Bech; K. Bjerregaard; L. Spliid, L.L.W. Nielsen; K.M. Larsen; M. Goldinger; D. Illum; C. Jessen; A. Christiansen; A. Berg; T. Elkmann; J.A.K. Pedersen; M. Simonsen; H. Joensen (Deceased); H. Alstrøm; C. Svane; A. Engquist.

  1. 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.

  2. 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.

  3. 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.

  4. Employment or leadership: None declared.

  5. Honorarium: None declared.

  6. 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.

References

1. Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015;41:1549–60.10.1007/s00134-015-3822-1Search in Google Scholar

2. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370:1412–21.10.1056/NEJMoa1305727Search in Google Scholar

3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303–10.10.1097/00003246-200107000-00002Search in Google Scholar

4. Bakker J, Grover R, McLuckie A, Holzapfel L, Andersson J, Lodato R, et al. Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized,double-blind, placebo-controlled multicenter study (study no. 144-002). Crit Care Med 2004;32:1–12.10.1097/01.CCM.0000105118.66983.19Search in Google Scholar

5. Casteleijn E, Kuiper J, Van Rooij HC, Kamps JA, Koster JF, Van Berkel TJ. Endotoxin stimulates glycogenolysis in the liver by means of intercellular communication. J Biol Chem 1988;263:6953–5.10.1016/S0021-9258(18)68587-4Search in Google Scholar

6. Wallington J, Ning J, Titheradge MA. The control of hepatic glycogen metabolism in an in vitro model of sepsis. Mol Cell Biochem 2008;308:183–92.10.1007/s11010-007-9627-ySearch in Google Scholar

7. Nesseler N, Launey Y, Aninat C, White J, Corlu A, Pieper K, et al. Liver dysfunction is associated with long-term mortality in septic shock. Am J Respir Crit Care Med 2016;193:335–7.10.1164/rccm.201508-1660LESearch in Google Scholar

8. 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 2009;35:1406–11.10.1007/s00134-009-1511-7Search in Google Scholar

9. Jenniskens M, Langouche L, Vanwijngaerden YM, Mesotten D, Van den Berghe G. Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive Care Med 2016;42:16–27.10.1007/s00134-015-4054-0Search in Google Scholar

10. Sieg A, Stiehl A, Raedsch R, Ullrich D, Messmer B, Kommerell B. Gilbert’s syndrome: diagnosis by typical serum bilirubin pattern. Clin Chim Acta 1986;154:41–7.10.1016/0009-8981(86)90086-0Search in Google Scholar

11. Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397–404.10.1096/fasebj.6.7.1563592Search in Google Scholar

12. Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life 2002;54:195–9.10.1080/15216540214929Search in Google Scholar

13. Weigel PH, Hascall VC, Tammi M. Hyaluronan synthases. J Biol Chem 1997;272:13997–4000.10.1074/jbc.272.22.13997Search in Google Scholar

14. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol 2001;20:499–508.10.1016/S0945-053X(01)00172-XSearch in Google Scholar

15. Henriksen JH, Bentsen KD, Laurent TC. Splanchnic and renal extraction of circulating hyaluronan in patients with alcoholic liver disease. J Hepatol 1988;6:158–66.10.1016/S0168-8278(88)80027-8Search in Google Scholar

16. Lebel L. Turnover of circulating hyaluronan. Studies in man and experimental animal (dissertation). Acta Univ Ups 1989;217:1–54.Search in Google Scholar

17. Berg S, Jansson I, Hesselvik FJ, Laurent TC, Lennquist S, Walther S. Hyaluronan: relationship to hemodynamics and survival in porcine injury and sepsis. Crit Care Med 1992;20:1315–21.10.1097/00003246-199209000-00020Search in Google Scholar

18. Alston-Smith JP, Fraser JR, Laurent TC. Effects of endotoxin in hepatic endocytosis of hyaluronan BOOK: hepatic endocytosis of lipids and proteins. München, Germany: Zuckschwerdt, 1992.Search in Google Scholar

19. Berg S, Brodin B, Hesselvik F, Laurent TC, Maller R. Elevated levels of plasma hyaluronan in septicaemia. Scand J Clin Lab Invest 1988;48:727–32.10.3109/00365518809088752Search in Google Scholar PubMed

20. Itenov TS, Kirkby NS, Bestle MH, Nilsson AC, Erlandsen EJ, Peters L, et al. Hyaluronic acid assays: turbidimetric or enzyme-based immune assay? A method comparison study. J Clin Lab Anal 2016;30:524–8.10.1002/jcla.21897Search in Google Scholar PubMed PubMed Central

21. Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen MH, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med 2011;39:2048–58.10.1097/CCM.0b013e31821e8791Search in Google Scholar PubMed

22. Majeed M, McQueen F, Yeoman S, McLean L. Relationship between serum hyaluronic acid level and disease activity in early rheumatoid arthritis. Ann Rheum Dis 2004;63:1166–8.10.1136/ard.2003.010942Search in Google Scholar PubMed PubMed Central

23. Williams JM, Greenslade JH, Chu K, Brown AF, Lipman J. Severity scores in emergency department patients with presumed infection: a prospective validation study. Crit Care Med 2016;44:539–47.10.1097/CCM.0000000000001427Search in Google Scholar PubMed

24. White LE, Hassoun HT, Bihorac A, Moore LJ, Sailors RM, McKinley BA, et al. Acute kidney injury is surprisingly common and a powerful predictor of mortality in surgical sepsis. J Trauma Acute Care Surg 2013;75:432–8.10.1097/TA.0b013e31829de6cdSearch in Google Scholar PubMed PubMed Central

25. Jensen JS, Itenov TS, Thormar KM, Hein L, Mohr TT, Andersen MH, et al. Prediction of non-recovery from ventilator-demanding acute respiratory failure, ARDS and death using lung damage biomarkers: data from a 1200-patient critical care randomized trial. Ann Intensive Care 2016;6:114.10.1186/s13613-016-0212-ySearch in Google Scholar PubMed PubMed Central

26. Nesseler N, Launey Y, Aninat C, Morel F, Malledant Y, Seguin P. Clinical review: the liver in sepsis. Crit Care 2012;16:235.10.1186/cc11381Search in Google Scholar PubMed PubMed Central

27. Vincent JL, Angus DC, Artigas A, Kalil A, Basson BR, Jamal HH, et al. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003;31:834–40.10.1097/01.CCM.0000051515.56179.E1Search in Google Scholar PubMed

28. Brun-Buisson C, Meshaka P, Pinton P, Vallet B, Group ES. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 2004;30:580–8.10.1007/s00134-003-2121-4Search in Google Scholar PubMed

29. van der Laan LJ, Dopp EA, Haworth R, Pikkarainen T, Kangas M, Elomaa O, et al. Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo. J Immunol 1999;162:939–47.10.4049/jimmunol.162.2.939Search in Google Scholar

30. Guo L, Zheng Z, Ai J, Huang B, Li XA. Hepatic scavenger receptor BI protects against polymicrobial-induced sepsis through promoting LPS clearance in mice. J Biol Chem 2014;289:14666–73.10.1074/jbc.M113.537258Search in Google Scholar PubMed PubMed Central

31. Dwivedi DJ, Grin PM, Khan M, Prat A, Zhou J, Fox-Robichaud AE, et al. Differential expression of PCSK9 modulates infection, inflammation and coagulation in a murine model of sepsis. Shock 2016;46:672–80.10.1097/SHK.0000000000000682Search in Google Scholar PubMed

32. Schouten M, van’t Veer C, Poulussen N, Meijers JC, Levi M, Esmon CT, et al. The cytoprotective effects of endogenous activated protein C reduce activation of coagulation during murine pneumococcal pneumonia and sepsis. Thromb Res 2015;135:537–43.10.1016/j.thromres.2014.12.020Search in Google Scholar PubMed


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2018-1350).


Received: 2018-12-20
Accepted: 2019-03-04
Published Online: 2019-04-05
Published in Print: 2019-08-27

©2019 Walter de Gruyter GmbH, Berlin/Boston

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