Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity Eray Yagmur a, 1 , Alexander Koch b, 1 , Michaela Haumann a , Rafael Kramann c , Christian Trautwein b , Frank Tacke b, ⁎ a Medical Care Center, Dr. Stein and colleagues, Wallstraße 10, 41061 Mönchengladbach, Germany b Department of Medicine III, RWTH-University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany c Department of Medicine II, RWTH-University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany abstract article info Article history: Received 24 August 2011 received in revised form 21 October 2011 accepted 25 October 2011 Available online xxxx Keywords: Critical illness Intensive care medicine Liver cirrhosis Sepsis Biomarker Hyaluronan Objectives: The matrix protein hyaluronic acid (HA, hyaluronan) has possibly additional immune-regulatory functions in inflammation. We aimed at evaluating serum HA concentrations in critically ill patients. Design and methods: We analyzed serum HA levels in 164 critically ill patients at a medical ICU and 61 healthy controls, with respect to organ dysfunction, systemic inflammation and mortality. Results: Hyaluronan serum concentrations upon admission to ICU were significantly elevated in critically ill patients compared to healthy controls, with the highest levels in patients with pre-existing liver cirrhosis or sepsis. HA levels were closely correlated with biomarkers of hepatic and renal function, systemic inflammation, demand of treatment measures and clinical scores of disease severity, but could not predict risk of mortality. Conclusions: Measurement of serum HA may supplement the assessment of disease severity in ICU patients. Our data suggest that HA might have implications in the pathogenesis of critical illness and sepsis. © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Introduction Hyaluronic acid (HA), also termed hyaluronan, is a high molecular weight glycosaminoglycan with linear polysaccharide structure and synthesized by many cell types, including fibroblasts or other matrix- producing cells [1]. In healthy individuals, HA is abundantly found in heart valves, skin, skeletal tissues, the vitreous of the eye, and synovial fluid, thus representing a matrix component that exerts lubricant-like functions by binding large amounts of water [2]. More recently, it has been unraveled that HA, besides its properties as a matrix protein, additionally exerts functions in the regulation of inflammatory pro- cesses [3]. Interestingly, inflammatory cytokines like tumor necrosis factor (TNF), lymphotoxin and interferons stimulate HA production, for instance after lung injury [4]. The accumulation of HA in inflamed tissue is subsequently involved in attracting neutrophils and T-cells and by modulating their effector functions [5,6]. HA is normally found at low concentrations in the circulation, be- cause it is rapidly cleared from the bloodstream by the endothelial cells in the liver sinusoids [7]. HA serum concentrations have been evaluated as a biomarker for fibrotic liver diseases. Serum HA levels appear to be closely associated with the degree of fibrosis in patients with chronic liver diseases, due to the increased extracellular matrix deposition in hepatic fibrosis and reduced clearance by sinusoidal en- dothelial cells [8–10]. Moreover, serum HA levels have been de- scribed to be elevated in patients with sepsis, potentially caused by impaired endothelial clearance in the liver sinusoids, but the exact regulation of HA levels remained elusive [11,12]. More recently, ex- perimental animal models suggested that high-molecular weight HA might be a promising new treatment option for sepsis-induced lung injury by ameliorating pulmonary capillary leakage and by limiting inflammatory cascades [13,14]. However, there are no sufficient data at present concerning the mechanisms of HA regulation in critically ill patients from large co- horts. Before testing the possible therapeutic effects of HA in humans, clinical studies on profiles of endogenous HA regulation in the criti- cally ill are needed. Therefore, we conducted the present study on a large cohort of well characterized critically ill patients to provide in- formation about HA serum concentrations in different circumstances of critical disease such as sepsis or decompensated liver cirrhosis, to identify possible pathogenic functions of HA by correlations with a wide number of markers of inflammation, organ dysfunction and me- tabolism, and to examine potential protective effects of HA for the outcome of critically ill patients. Clinical Biochemistry xxx (2011) xxx–xxx ⁎ Corresponding author. Fax: + 49 241 80 82455. E-mail address: frank.tacke@gmx.net (F. Tacke). 1 These authors contributed equally to this work. CLB-07837; No. of pages: 6; 4C: 0009-9120/$ – see front matter © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2011.10.016 Contents lists available at SciVerse ScienceDirect Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem Please cite this article as: Yagmur E, et al, Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity, Clin Biochem (2011), doi:10.1016/j.clinbiochem.2011.10.016