Submit a Manuscript: http://www.wjgnet.com/esps/ World J Gastroenterol 2017 January 21; 23(3): 437-446 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1007-9327 (print) ISSN 2219-2840 (online) DOI: 10.3748/wjg.v23.i3.437 © 2017 Baishideng Publishing Group Inc. All rights reserved. ORIGINAL ARTICLE Basic Study α2-Heremans-schmid glycoprotein (fetuin A) downregulation and its utility in inflammatory bowel disease Anastassios C Manolakis, Gregory Christodoulidis, Andreas N Kapsoritakis, Panagiotis Georgoulias, Elisavet K Tiaka, Kostas Oikonomou, Varvara J Valotassiou, Spyros P Potamianos Anastassios C Manolakis, Andreas N Kapsoritakis, Elisavet K which permits others to distribute, remix, adapt, build upon this Tiaka, Kostas Oikonomou, Spyros P Potamianos, Department work non-commercially, and license their derivative works on of Gastroenterology, University of Thessaly, School of Medicine, different terms, provided the original work is properly cited 41110 Larissa, Greece and the use is non-commercial. See: http://creativecommons. org/licenses/by-nc/4.0/ Gregory Christodoulidis, Department of Surgery, University of Thessaly, School of Medicine, 41110 Larissa, Greece Manuscript source: Invited manuscript Panagiotis Georgoulias, Varvara J Valotassiou, Laboratory of Correspondence to: Gregory Christodoulidis, MD, PhD, Nuclear Medicine, University of Thessaly, School of Medicine, Department of Surgery, University of Thessaly, School of 41110 Larissa, Greece Medicine, Filellinon, 41110 Mezourlo, Larissa, Greece. [email protected] Author contributions: Manolakis AC, Christodoulidis G, Telephone: +30-241-3502727 Kapsoritakis AN, Georgoulias P and Potamianos SP designed Fax: +30-241-3502727 the research. Manolakis AC, Christodoulidis G, Tiaka EK, Oikonomou K, Valotassiou VJ performed the research; Received: September 22, 2016 Georgoulias P and Valotassiou VJ contributed reagents/analytic Peer-review started: September 23, 2016 tools and carried out assays; Manolakis AC and Tiaka EK First decision: November 9, 2016 analyzed the data; Manolakis AC, Christodoulidis G, Kapsoritakis Revised: November 25, 2016 AN and Potamianos SP wrote the paper. Accepted: December 21, 2016 Article in press: December 21, 2016 Supported by the Hellenic Society of Gastroenterology, No. Published online: January 21, 2017 5496. Institutional review board statement: The study was reviewed and approved by the University of Thessaly Medical School Ethics Committee. Abstract AIM Informed consent statement: Informed consent was obtained To investigate the impact of inflammatory bowel from all study participants, along with a verbal permission for the disease (IBD) on α2-Heremans-Schmid Glycoprotein use of the acquired samples for scientific research. (AHSG/fetuin A) and potential associations with disease and patient characteristics. Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported. METHODS Data sharing statement: No additional data are available. AHSG serum levels were determined in treatment-naïve newly-diagnosed patients, 96 with ulcerative colitis Open-Access: This article is an open-access article which was (UC), 84 with Crohn’s disease (CD), 62 with diarrhea- selected by an in-house editor and fully peer-reviewed by external predominant or mixed irritable bowel syndrome (IBS, reviewers. It is distributed in accordance with the Creative D- and M- types) and 180 healthy controls (HC), by Commons Attribution Non Commercial (CC BY-NC 4.0) license, an enzyme linked immunosorbent assay (ELISA). WJG|www.wjgnet.com 437 January 21, 2017|Volume 23|Issue 3| Manolakis AC et al . Fetuin A in IBD All patients were followed for a minimum period of markers i.e. , C-reactive protein or serological markers 3 years at the Gastroenterology Department of the linked to IBD course i.e. , anti-glycan antibodies. University Hospital of Larissa, Greece. C-reactive protein (CRP), anti-glycan antibodies, anti-Saccharomyces cerevisiae mannan antibodies IgG, anti-mannobioside Manolakis AC, Christodoulidis G, Kapsoritakis AN, Georgoulias carbohydrate antibodies IgG, anti-laminariobioside P, Tiaka EK, Oikonomou K, Valotassiou VJ, Potamianos SP. carbohydrate antibodies IgG and anti-chitobioside α2-Heremans-schmid glycoprotein (fetuin A) downregulation and carbohydrate antibodies IgA were also determined via its utility in inflammatory bowel disease. World J Gastroenterol immunonephelometry and ELISA, respectively. 2017; 23(3): 437-446 Available from: URL: http://www. wjgnet.com/1007-9327/full/v23/i3/437.htm DOI: http://dx.doi. RESULTS org/10.3748/wjg.v23.i3.437 The mean ± SE of serum AHSG, following adjustment for confounders, was 0.32 ± 0.02 g/L in IBD, 0.32 ± 0.03 g/L in CD and 0.34 ± 0.03 g/L in UC patients, significantly lower than in IBS patients (0.7 ± 0.018 g/L) INTRODUCTION and HC (0.71 ± 0.02 g/L) (P < 0.0001, in all cases). Inflammatory bowel disease (IBD) has been long ago AHSG levels were comparable between the CD and UC groups. Based on AHSG levels IBD patients could be recognized as a systemic inflammatory entity and as distinguished from HC with about 90% sensitivity and such, it is anticipated to induce changes exceeding specificity. Further adjusted analysis verified the inverse the boundaries of bowel mucosa, being reflected in [1-7] association between AHSG and penetrating, as well a broader spectrum of tissues, including blood . as stricturing CD (partial correlation coefficient: -0.45 Examples of such changes are the fluctuations in the and -0.33, respectively) (P < 0.05). After adjusting levels of C-reactive protein (CRP), tumour necrosis for confounding factors, inverse correlations between factor alpha (TNF-α), interleukins, S100 proteins, AHSG and CRP and the need for anti-TNFα therapy or metalloproteinases, angiogenins, etc[4-7]. Since a dif- surgery, were found (partial correlation coefficients: ferent task is carried out by each of these biomarkers, -0.31, -0.33, -0.41, respectively, P < 0.05, in all cases). it has been proposed that IBD induces multifarious Finally, IBD individuals who were seropositive, for at responses which in turn, may affect the levels of least one marker, had AHSG levels falling within the different compounds via feedback mechanisms, two lower quartiles (OR = 2.86, 95%CI: 1.5-5.44, consumption or reprioritisation of synthesis[4-8]. These P < 0.001) while those with at least two serological observations along with the inflammatory nature markers positive exhibited AHSG concentrations within of IBD itself seem to encourage the study of novel the lowest quartile (OR = 5.03, 95%CI: 2.07-12.21, P proteins that tend to become affected by the establish- < 0.001), after adjusting for age, sex and smoking. [3,8] ment of systemic inflammation . Such a candidate is CONCLUSION fetuin A or α2-Heremans-Schmid glycoprotein (AHSG), AHSG can be used to distinguish between IBD and a substance synthesized in the liver, bone marrow and fetal organs, exhibiting properties similar to those IBS patients or HC while at the same time “predicting” [9] complicated disease behavior, need for therapy possessed by negative acute-phase proteins . AHSG escalation and surgery. Moreover, AHSG may offer has been shown to carry out various immunologic new insights into the pathogenesis of IBD, since it is tasks, including regulation of macrophage-related involved in key processes. lipopolysaccharide-triggered opsonisation, TNF-α and transforming growth factor beta (TGF-β) levels[10-13]. Key words: Inflammatory bowel disease; Irritable bowel AHSG is also an inhibitor of ectopic tissue calcification syndrome; Fetuin A such as that taking place in coronary arteries and heart valves, while at the same time promoting min- © The Author(s) 2017. Published by Baishideng Publishing eralization within fibrils and subsequently, proper bone Group Inc. All rights reserved. formation[13-15]. Other recently discovered properties of AHSG include a binding ability to insulin receptor, α Core tip: 2-Heremans-Schmid Glycoprotein (AHSG/ modifying its sensitivity, participation in wound healing fetuin A) a multi-task negative acute-phase protein is as well as tumor growth processes, through the induc- downregulated in patients with inflammatory bowel [8,9] tion of a more effective cell migration . Increased disease (IBD). Based on this significant decrease AHSG levels have been recorded in fetal organs a discrimination between IBD patients with either (probably reflecting an additional role for AHSG in Crohn’s disease or ulcerative colitis and those with normal organ development), in adults with either irritable bowel syndrome or healthy controls can be made. A more robust AHSG decrease correlates well metabolic syndrome or increased insulin resistance with and predicts complicated disease behavior, need alone, patients infected with the severe acute respira- for biological therapy and surgery, within three years tory syndrome-coronavirus as well as individuals at from diagnosis. These associations are supported high risk for future cardiovascular events: stroke and [8,9,16] by additional links between AHSG and acute-phase acute myocardial infarction . Low levels of AHSG WJG|www.wjgnet.com 438 January 21, 2017|Volume 23|Issue 3| Manolakis AC et al . Fetuin A in IBD Table 1 Patient/control and disease characteristics UC CD IBS HC No 96 84 62 180 Age, yr (mean ± SD) 50.2 ± 13.4 42.3 ± 15.6 49 ± 19.4 46.7 ± 12.3 Age at onset ≥ 40 yr - 15 - - < 40 yr - 69 - - Sex Male 60 45 36 114 Female 36 39 26 66 Current smoking Yes 24 57 39