|Year : 2018 | Volume
| Issue : 2 | Page : 205-210
The role of serum S100A12 (calgranulin C) as a diagnostic marker in Egyptian patients with irritable bowel syndrome and ulcerative colitis
Yousry Hashem1, Elsayed M Mahmoud1, Diaa Eltiby1, Ahmed Ghazy1, Mohammed Rashed2, Sayed Abd-Alraheem3
1 Department of Tropical Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
3 Department of Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
|Date of Submission||11-Jun-2018|
|Date of Acceptance||12-Sep-2018|
|Date of Web Publication||27-Feb-2019|
Asistant lecturer of Tropical Medicine, Damietta
Source of Support: None, Conflict of Interest: None
Background S100A12, a proinflammatory protein secreted by granulocytes, is known to be elevated in different diseases of inflammatory origin, including inflammatory bowel disease.
Aims To evaluate the role of serum S100A12 as a diagnostic marker in patients with irritable bowel syndrome (IBS) and inflammatory bowel disease.
Patients and methods A cross-sectional study was conducted on 70 persons who fulfilled the designed inclusion criteria and were classified into four groups: group I included 10 healthy persons; group II included 20 patients known to have IBS; group III included 20 patients known to have ulcerative colitis (UC) in remission; and group IV included 20 patients known to have UC in active state. Serum S100A12 level was measured in all patients using a highly sensitive enzyme-linked immunosorbent assay.
Results The mean serum S100A12 level for UC patients in exacerbation was 83.93±30.78 pg/ml, UC patients in remission 64.03±19.87 pg/ml, the mean value of serum S100A12 was 47.73±11.15 pg/ml in the IBS group, and the mean value for the control group was 45.32±8.60 pg/ml. So, there is a significant high level of serum S100A12 in UC groups compared with the IBS group and the control group. Serum S100A12 levels were significantly higher in active UC patients compared with IBS/healthy controls (P<0.01). Serum S100A12 levels were significantly higher in UC in remission compared with the IBS and control groups (P<0.05). Serum S100A12 levels were significantly higher in active UC compared with UC in remission (P<0.05). There is no significant difference between the IBS group and the control group regarding serum S100A12 levels (P>0.05). The performed analysis also focused on the determination of a cutoff for UC prediction that would exhibit the highest possible sensitivity and specificity. This optimal cutoff was estimated at 52.8 pg/ml with a sensitivity and a specificity of 80 and 75%, respectively.
Conclusions Serum S100A12 can be used as a noninvasive marker to distinguish UC from IBS.
Keywords: clinical activity index, inflammatory bowel disease, irritable bowel syndrome, serum S100A12, ulcerative colitis
|How to cite this article:|
Hashem Y, Mahmoud EM, Eltiby D, Ghazy A, Rashed M, Abd-Alraheem S. The role of serum S100A12 (calgranulin C) as a diagnostic marker in Egyptian patients with irritable bowel syndrome and ulcerative colitis. Al-Azhar Assiut Med J 2018;16:205-10
|How to cite this URL:|
Hashem Y, Mahmoud EM, Eltiby D, Ghazy A, Rashed M, Abd-Alraheem S. The role of serum S100A12 (calgranulin C) as a diagnostic marker in Egyptian patients with irritable bowel syndrome and ulcerative colitis. Al-Azhar Assiut Med J [serial online] 2018 [cited 2020 Jul 6];16:205-10. Available from: http://www.azmj.eg.net/text.asp?2018/16/2/205/253090
| Introduction|| |
Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are common conditions that may present with a similar symptom complex of abdominal pain and altered bowel habits. However, the two conditions differ markedly in their pathophysiology, prognosis, and therapeutic approaches . There is a considerable overlap between symptoms in patients with IBS and IBD. IBS-like symptoms are frequently reported in patients before the diagnosis of IBD . Discriminating IBS from IBD, especially with mild disease activity, is a common clinical challenge and the clinical and laboratory tools plays an important role in differentiating these disorders . The etiology of IBD involves complex interactions among the susceptibility genes, the environment, and the immune system. These interactions lead to a cascade of events that involve the activation of neutrophils, production of proinflammatory mediators, and tissue damage . IBD has been long ago recognized as a systemic inflammatory entity and, as such, it is anticipated to induce changes exceeding the boundaries of bowel mucosa, being reflected in a broader spectrum of tissues, including blood . Examples of such changes are the fluctuations in the levels of C-reactive protein (CRP), serum amyloid A, tumor necrotic factor α, interleukins, S100 proteins , metalloproteinases , and angiogenesis . Some of these substances have been introduced as inflammatory markers and have been used in clinical practice in patients with suspected or confirmed IBD for diagnostic purposes. The sufficiency of these markers, however, has been challenged repeatedly due to a moderate performance, making the study of new markers in IBD mandatory . There are numerous studies examining the significance of several fecal, serum, or mucosal markers including members of the S100 protein family such as S100A8/9 and S100A12 . Since the vast majority of available literature is focused on S100A8/9  and to a lesser extent on S100A12 and their role in IBD , our aim in the current case–control study was to investigate the serum S100A12 levels in patients with ulcerative colitis (UC) during exacerbation and remission and comparing with those obtained from patients with IBS, and control persons and to detect its sensitivity and specificity as a noninvasive biomarker in the identification of such patients.
| Patients and methods|| |
Seventy consecutive patients were recruited from the outpatient clinic, as well as from the Inpatient Unit of the Tropical Medicine Department, Al-Azhar University. The study was approved by Al-Azhar Damietta Faculty of Medicine Ethical committee. An informed consent was obtained from each participant. Inclusion criteria included were Egyptian patients above 18 years old; confirmed diagnosis of UC was ascertained using conventional clinical, endoscopic, radiological, and histopathological criteria; and confirmed diagnosis of IBS after full workup according to Rome III criteria. Ten healthy persons were included as a control group. Patients with IBS and IBD were questioned about their general well-being, the frequency of bowel habit, the presence/absence of abdominal pain or blood in the stool, and clinical examination were completed to all the studied patients. All patients were investigated and treated according to the guidelines. Patients with positive stool culture, medical history of major gastrointestinal surgical procedures especially resection anastomosis operation, liver cell failure, chronic renal failure, congestive heart failure, patients receiving NSAIDs, and patients with active inflammatory condition like acute otitis media, glomerulonephritis, cystic fibrosis, rheumatoid, and psoriatic arthritis or Kawasaki disease were excluded from the study. All patients were subjected to full medical history, through clinical examination, laboratory investigations [complete blood count, erythrocyte sedimentation rate (ESR), CRP, stool analysis, stool culture, and sensitivity, liver function tests, kidney function tests, and serum S100A12]. Abdominal ultrasonography, endoscopic examination and biopsy, and histopathological examination of tissue samples were done for selected patients. Serum S100A12 was done using enzyme-linked immunosorbent assay kit for S100 calcium-binding protein A12 (S100A12). Organism: Homo sapiens (human) produced by (USCN Life Science Inc., Wuhan Economic & Technological Development Zone, Hubei, China) the kit is a sandwich enzyme-linked immunoassay for in-vitro quantitative measurement of S100A12 in human serum.
Data were collected, revised, coded, and entered to the statistical package for the social sciences (IBM SPSS, version 23, IBM , Manhattan, New York city, USA). The parametric quantitative data were presented as mean ± SDs, and ranges while non parametric data presented as median and interquartile range. Also qualitative variables were presented as number and percentages. The comparison between groups regarding qualitative data was done by using χ2 test. The comparison between two independent groups with quantitative data and parametric distribution were done by using independent t test while nonparametric data were compared using the Mann–Whitney test. The comparison between more than two independent groups with quantitative data and parametric distribution was done by using one-way analysis of variance test with post-hoc analysis using the least significant difference test, while those with nonparametric data were done by using Kruskal–Wallis test. Spearman’s correlation coefficients were used to assess the correlation between two quantitative parameters in the same group. Also receiver-operating characteristic curve was used to assess the best cutoff point with sensitivity, specificity, positive, and negative predictive value and area under the curve. The confidence interval was set to 95% and the margin of error accepted was set to 5%. So, the P value was considered significant at the level of less than 0.05.
| Results|| |
Seventy individuals were involved in this study and were classified into four groups: group I included 10 healthy persons as the control group; group II included 20 patients known to have IBS with normal colonoscopy and histopathological examination; group III included 20 patients known to have UC, in remission state, and group IV included 20 patients known to have UC, in active state.
[Table 1] and [Table 2] shows highly significant elevation of serum S100A12 levels in UC patients (groups III and IV) in comparison with IBS patients (group II) and control group (group I). But no significance shown between IBS patients (group II) and control group (group I).
|Table 1 Comparison between different studied groups regarding serum S100A12 levels|
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|Table 2 Copmarison between different studied groups regarding serum S100A12|
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[Table 3] shows comparison of serum S100A12 level in patients at different stages of activity and colonoscopy findings shows a significant elevation of serum S100A12 levels in patients with high activity in clinical activity index (CAI) and colonoscopic activity index in comparison with lower stages of disease activity by CAI and lower colonoscopic activity index.
|Table 3 Comparison of serum S100A12 level in patients at different stages of activity and colonoscopy findings|
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[Table 4] shows serum S100A12 levels correlate significantly with other inflammatory parameters in UC patients (ESR and CRP).
|Table 4 Correlation between serum S100A12 levels with other inflammatory markers|
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| Discussion|| |
IBD remains a diagnostic challenge for the clinician who faces a repertoire of diverse and fluctuating symptoms and signs. It is mainly due to a subtle or atypical presentation that in some cases the discrimination of Crohn’s disease (CD) or UC, from other diseases of the alimentary tract, especially from IBS, becomes rather problematic .
Around one-third of patients with IBD experience persistent gastrointestinal tract symptoms similar to IBS in the absence of objective evidence of disease activity . The presenting symptoms of IBS and IBD can be similar, distinguishing them on the basis of clinical signs and symptoms can be difficult until recently colonoscopy was often used to rule out IBD .
Several markers are used for diagnostic purposes. A simple, economic, and reliable test as an alternative to more complex procedures for IBD diagnosis is still under investigation . IBD has been long ago recognized as a systemic inflammatory entity and, as such, it is anticipated to induce changes exceeding the boundaries of bowel mucosa, being reflected in a broader spectrum of tissues, including blood . Intestinal inflammation in UC is characterized by an influx of neutrophils into the intestinal mucosa, thereby altering the intestinal barrier function during IBD . S100A12 is a calcium-binding protein with proinflammatory properties. It is secreted by activated neutrophils and interacts with the multiligand receptor for advanced glycation end products (RAGE) . There are numerous studies examining the significance of several fecal, serum, or mucosal markers including members of the S100 protein family such as S100A8/9 and S100A12 . The vast majority of available literature is focused on S100A8/9  and to a lesser extent on S100A12 and their role in IBD . Our aim in the current case–control study was to investigate serum S100A12 levels in patients with UC during exacerbation and remission and comparing with those obtained from patients with IBS, and control persons and to detect its sensitivity and specificity as a noninvasive biomarker in the identification of such patients. The results of our study have shown that there was a significant high level of serum S100A12 in UC groups compared with the IBS group and the control group as the mean serum S100A12 level for UC patients in exacerbation was 83.93±30.78 pg/ml, UC patients in remission 64.03±19.87 pg/ml, and the mean value of serum S100A12 was 47.73±11.15 pg/ml in the IBS group and the mean value for the control group was 45.32±8.60 pg/ml. The performed analysis also focused on the determination of a cutoff for UC prediction that would exhibit the highest possible sensitivity and specificity. This optimal cutoff was estimated at 52.8 pg/ml. These results support the role of serum S100A12 in differentiating between UC and IBS. Our results are in agreement with those conducted by Manolakis et al. , who found that there was significantly higher serum S100A12 in the IBD group compared with the IBS group. Manolakis et al.  determined the serum S100A12 in a total of 201 patients of whom 64 patients were with UC, 64 with CD, and 73 with IBS patients, who are sex-matched and age-matched with the IBD groups. The study reported that a significant elevation in serum S100A12 levels which correlated well with IBD but not with IBS. The median values of serum S100A12 levels were 68.2 ng/ml (range, 43.4–147.4 ng/ml) in UC, 70 ng/ml (range, 41.4–169.8 ng/ml) in CD, and 43.4 ng/ml (range, 34.4–74.4 ng/ml) in IBS patients. UC and CD patients had significantly higher serum S100A12 levels compared with IBS patients, thus allowing the distinction between the two entities. The optimal cutoff was estimated at 54 ng/ml and was shown to predict both CD and UC with a sensitivity of 66.7% and a specificity of 64.4%. Although, our performance is superior to the one reported by Manolakis et al. , our study was carried out on a small sample size and on UC only and 50% of our patients was selected in exacerbating condition besides the different best cutoff point and laboratory methods. In addition to studies performed by Manolakis et al. , Brinar et al.  evaluated serum S100A12 in 300 adults with IBD (150 CD and 150 UC), 100 non-IBD inflammatory controls (including diverticulitis, infectious enterocolitis, and ischemic colitis) and 143 healthy controls. Significantly elevated serum S100A12 concentrations were seen in both IBD groups (median 242 ng/ml for CD and median 223 ng/ml for UC) and non-IBD inflammatory controls (median, 94.7 ng/ml) compared with healthy individuals (53.5 ng/ml). Also Leach et al.  undertook a cohort study to determine serum S100A12 concentrations in 39 children with IBD 29 with CD (four with UC and six with IBD unclassified) and 33 age-matched non-IBD controls. Serum S100A12 concentrations were greater in the IBD group compared with the non-IBD group [median, 196 (13–810) ng/ml vs. median, 82 (15–4242) ng/ml]. Although serum S100A12 was significantly increased in the children with CD [median, 239 (27–14 810) ng/ml], the median level was higher in those with UC [median, 750 (247–1391) ng/ml] and not elevated in the IBD unclassified group [median, 94 (40–294) ng/ml]. This may reflect the small numbers of patients in the latter two groups. Similarly Foell et al.  demonstrated an elevated serum S100A12 in a study of 74 adult patients with IBD. Forty of these patients were diagnosed with CD and 34 with UC. High levels of S100A12 were seen in active CD (470±125 ng/ml) and active UC (401±20 ng/ml) compared with healthy individuals (75±15 ng/ml). Although these studies generally agreed with our work regarding elevated serum level S100A12 in IBD patients, they were different from our study with respect to the age of IBD patients, some of their patients were children. using different enzyme-linked immunosorbent assay and furthermore they did not discriminate specifically between IBD and IBS regarding the serum level of S100A12 unlike the current study. In contrast to the results of our study, Sidler et al.  demonstrated no significant difference in serum S100A12 level between children with IBD and children with other gastrointestinal disorders. Therefore, serum S100A12 level does not appear to accurately detect children with gastrointestinal inflammation, similar to standard inflammatory markers. The non-IBD group in their study included children with a range of gastrointestinal disorders such as Helicobacter pylori infection and various systemic inflammatory processes. The median value for serum S100A12 in the IBD group was 270 ng/ml and the median value for serum S100A12 in the non-IBD group was 141 ng/ml. They reported that serum S100A12 had lower test utility, with a sensitivity of 21% and a specificity of 81%. Although variations in assay procedures and differences between adults and children must also be taken into account and furthermore they did not discriminate specifically between IBD and IBS regarding the serum level of S100A12. As regards CRP levels in UC patients, in our study we demonstrated a positive CRP in the IBD group compared with the IBS group. Similarly Bakir et al.  study showed a highly significant positive correlation between IBD cases and positive CRP in comparison to IBS cases. In addition to studies performed by Bakir et al. , Schoepfer et al.  found that CRP had 64% sensitivity and 92% specificity in discriminating IBD (n=64) from IBS (n=30). Shine et al.  were the first to show that a CRP increase can be used to differentiate IBD from functional bowel disorders. In 82 patients with chronic abdominal symptoms, 19 were diagnosed with CD, 22 with UC, and 41 with a functional bowel disorder. All of the 19 patients with CD and 59% of the 22 patients with UC showed increases in CRP compared with none of the 41 patients with functional symptoms. In our study, we found positive correlations between S100A12 and a well-known marker of inflammation CRP. Our results are in agreement with those conducted by Manolakis et al. . As regards ESR in UC patients, according to our study there was a positive, statistical correlation between serum S100A12 levels in UC patients and ESR. This can be explained by a study of Desai et al.  who reported that ESR is an indirect measurement of plasma acute-phase protein concentration and is influenced by the morphology of erythrocytes as well as some plasma constituents such as immunoglobulins. As the concentrations of many serum proteins vary in patients with IBD and as some have long lives, the ESR is not rapidly responsive to change in clinical status (the ESR may take several days to decrease even when rapid clinical improvement occurs). Hence, the ESR is a crude assessment of disease activity. In UC, where clinical, endoscopic, and histological activity is used to assess the overall disease, the correlation between ESR and disease activity is good. However, it may be normal in proctitis and proctosigmoiditis. In our study S100A12 serum levels of UC patients with active and inactive disease were both higher than those of IBS individuals. Mean serum S100A12 level for UC patients in exacerbation was 83.93±30.78 pg/ml, UC patients in remission was 64.03±19.87 pg/ml, and the mean value of serum S100A12 was 47.73±11.15 pg/ml in the IBS group and the mean value for the control group was 45.32±8.60 pg/ml. In our study serum S100A12 exhibits a significant positive correlation with CAI as the mean value of serum S100A12 in patients with inactive disease status according to CAI was 64.03±19.87 pg/ml, in patients with mild disease activity it was 51.66±7.06 pg/ml, in patients with moderate activity 70.41±7.26 pg/ml, and in patients with severe disease activity was 115.91±20.06 pg/ml. Also there is a significant positive correlation between serum S100A12 and the histological picture regarding the degree of activity in UC patients as the mean value of serum S100A12 in patients with normal colonoscopic finding was 47.73±11.15 pg/ml, in patients with inactive disease activity in colonoscopy was 64.03±19.87 pg/ml, in patients with mild disease activity in colonoscopy was 51.66±7.06 pg/ml, in patients with moderate disease activity in colonoscopy was 70.41±7.26 pg/ml, and in patients with high disease activity in colonoscopy was 115.91±20.06 pg/ml. Similarly Brinar et al.  reported that S100A12 was higher in endoscopically active UC compared with inactive disease (357 ng/ml vs. 121 ng/ml). The authors concluded that S100A12 could not be used as an accurate biomarker of inflammation but this data was resulted as the study was conducted on IBD patients both UC and CD and patients were chosen regardless of the disease activity, but in our study patients were only UC patients and disease activity was taken in consideration as 50% of patients were in exacerbation and this could be explained by a study of Foell et al. , who reported that serum levels of S100A12 were higher in CD than in UC. The correlation of S100A12 levels with disease activity indices was lower in CD than in UC. Even in patients with inactive CD, they found significantly elevated S100A12 serum levels compared with controls. Foell et al.  explained that by the more systemic nature of immunological disturbances in CD compared with UC and even in inactive disease, a few neutrophils remain in the intestinal tissue which might be responsible for elevated serum levels in these patients. S100A12 may therefore be a very sensitive parameter of residual disease activity . As the neutrophil influx is a very early event during the inflammatory process of IBD, S100A12 may also be a useful marker in determining relapse of IBD. It is also conceivable that Crohn’s disease activity index (CDAI) scores may have been falsely low in their patients who were consequently regarded to be in remission, despite having residual disease activity . Brignola et al.  found altered laboratory parameters in 55% of patients with inactive disease according to CDAI scores. The results of the present study agreed partially with that of Manolakis et al.  who demonstrated that S100A12 serum levels of IBD patients with active and inactive disease were both higher than those of the IBS group, but no significant correlations between its level and CAI and CDAI .
| Conclusion|| |
Serum S100A12 can be used as a noninvasive marker to distinguish IBD from IBS. The increase in serum S100A12 was correlated with the classical marker of inflammation CRP. The levels of serum S100A12 varied significantly with disease severity in patients with UC, so it can be used in monitoring disease activity in such patients without the need for recurrent endoscopic interventions.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4]