Dissertation committee:
Γαζούλη Μαρία, Καθηγήτρια, Ιατρική σχολή, ΕΚΠΑ
Καραμανώλης Γεώργιος, Αναπληρωτής Καθηγητής, Ιατρική σχολή, ΕΚΠΑ
Παπακωνσταντίνου Ιωάννης, Αναπληρωτής Καθηγητής, Ιατρική σχολή, ΕΚΠΑ
Βλαχογιαννάκος Ιωάννης, Αναπληρωτής Καθηγητής, Ιατρική σχολή, ΕΚΠΑ
Βεζάκης Αντώνιος, Αναπληρωτής Καθηγητής, Ιατρική σχολή, ΕΚΠΑ
Ρουμπελάκη Μαρία, Αναπληρώτρια Καθηγήτρια, Ιατρική σχολή, ΕΚΠΑ
Λάζαρης Ανδρέας, Καθηγητής, Ιατρική σχολή, ΕΚΠΑ
Summary:
Background:The progression in UC management in the recent years has shifted the goals of therapy to endoscopic and even histological healing. Despite the progression, colonoscopy remains the only objective and precise method to assess the disease above goals. However, as a procedure it may not only be inconvenient but also hazardous for patients. The inadequacy of existing serum biomarkers to adequately depict disease endoscopic and histological activity dictates the discovery of new potential serum biomarkers that would also avoid the possible drawbacks of repeated endoscopies. Towards that direction, the present study was designed to evaluate the role of Leucine-rich Alpha-2 Glycoprotein 1 (LRG1), High Mobility Group Box 1 protein (HMGB1), Matrix Metalloproteinase 3 (MMP3) and Annexin A1 (ANXA1) – that have already been correlated with IBD and other autoimmune diseases – as new, novel serum biomarkers of UC activity.Methods:This cross-sectional study selectively included patients with UC treated with 5-ASA, undergoing colonoscopy. Individuals undergoing preventive colonoscopy with no abnormal endoscopic features, were also included as healthy control group (HC). Blood and biopsy samples were obtained from each member of both groups and endoscopic Mayo sub-score (Ms) was recorded for the UC patients. Intramucosal calprotectin (iMC) was evaluated in all biopsy samples taken from controls (normal mucosa) and patients’ inflamed and normal mucosa (if no abnormalities detected). Finally, common biomarkers’ and serum LRG1, HMGB1, MMP3 and ANXA1 levels were measured in the blood samples. Statistical analysis was then performed to analyze the data collected including Pearson and Spearman indices for associations, T-test for mean differences and ROC analysis where statistically significant differences were found.Results:Forty-two UC patients (57% male) and fourteen healthy controls (43% male) were included in our study with a mean age of 49,1 (SD=16.56) and 53,5 (SD=10,98) respectively. Initially the UC patients were classified to groups according to their Ms as follows: 43% as Ms=0, 36% as Ms=1, 14% as Ms=2 and 7% as Ms=3. No correlation was detected between the endoscopic groups - including the aforementioned Ms groups and HC group - as far as their population characteristics are concerned. The common laboratory indices consisted of Hct, Hgb, PLTs, WBC count and ESR were not correlated with the endoscopic UC activity in contrast to CRP which was weakly consistent (r=0,4, p=0,007). Serum levels of LRG1 and HMGB1 were found indifferent between HCs and UC patients while those of MMP3 and ANXA1 were significantly different. The HCs’ mean value of ANXA1 was 1,635μg/ml (SD=0,390) compared to that of the UC group which was 2,228μg/ml (SD=0,305), (p=0,00, AUC=0,881) and the MMP3 mean value of HCs was 3.453ng/ml (SD=0.763) compared to that of UC which was 6.187ng/ml (SD=2.221) (p=0,00, AUC=0.835). Furthermore, the HCs’ ANXA1 levels and those of Μs=0, Ms=1 and Ms=2 groups were also significantly different with the only exception being the Ms=3 group. As for the MMP3 levels, a statistically significant difference was found between HCs and Ms=1, Ms=2 and Ms=3 respectively which was not spotted between HCs and Ms=0. Subsequently, while LRG1, HMGB1, and ANXA1 levels were found to be uncorrelated to endoscopic Ms groups, MMP3 was found significantly correlated with UC endoscopic activity (r=0,54, p=0,000). Finally, the UC patients were divided to groups according to their iMC levels as No, Low, Moderate and High calprotectin groups. When LRG, HMGB1, MMP3 and ANXA1 serum levels were compared according to the iMC groups no correlations were found for LRG, HMGB1, and ANXA1 while MMP3 values were significantly correlated (Pearson r= 0,52, p=0,00).Conclusion:Serum ANXA1 is a potential diagnostic biomarker of UC and serum MMP3 is a potential biomarker of UC endoscopic and histological activity.
Keywords:
Biomarkers, Blood serum, Ulcerative colitis, LRG, HMGB1, Mucosal healing, Endoscopic mucosal activity, Calprotectin
