| BackgroundInflammatory bowel diseases (IBD), mainly consisting of Crohn’s disease (CD) and ulcerative colitis (UC), are chronic nonspecific intestinal inflammatory diseases, which the etiology and pathogenesis are not very clear. Patients with IBD are mainly manifested as recurrent abdominal pain, diarrhea, mucopurulent bloody stool, serious diseases can lead to some complications, such as intestinal hemorrhage, perforation, intestinal obstruction, malnutrition, or even develop into the colorectal cancer. IBD is a common disease in European countries, but in recent years, the incidence rate of IBD in our country increased significantly, which has been become a common disease of digestive system in our country. The peak incidence of IBD is mainly in the young age, and current researches have found that the IBD is a kind of lifelong intestinal noninflammatory disease, which is characterized by periodical symptomatic relapse and remission, it can seriously affect the patient’s physical and mental health and lower the quality of life. The treatment goal of IBD is to achieve the intestinal mucosal healing. The gold standard of assessment for intestinal mucosal healing in patients with IBD is endoscopy and histopathological examination. However, endoscopy is an examination with an invasive, time consuming, needing bowel preparation and may have some potential risks, so that it may not be accepted by patients at some times. Therefore, it is impossible to monitor the disease status in the daily management of IBD patients by repeated endoscopy examinations. In clinical practice, if there is one or more simple, reliable and non-invasive biomarkers to assessment the intestinal mucosal disease activity in patients with IBD, it can be easy to be accepted by patients, so as to improve the compliance of patients in the process of diagnosis and treatment, that will also be helpful for physicians to monitor the disease activity of IBD patients in daily routine, so as to achieve the treatment goal of intestinal mucosal healing. At present, clinical disease activity index, such as Crohn’s disease activity index (CDAI) and Mayo scores, are commonly used to evaluate clinical disease activity in patients with IBD. These clinical indexes are simple and easy to be accepted by patients, but they are subjective and heavily reliance on the patient’s symptoms and doctor’s judgement, lacking of objectivity, and sometimes they could not be effective to reflect the truly disease activity of IBD patients. Biochemical markers such as Serum C-reactive protein (CRP) is an important marker for evaluating disease activity in patients with IBD in clinical practice, and it has been proved that serum CRP have a certain correlation with the clinical and endoscopic disease activity of IBD patients. In clinical practice, serum CRP levels can be used to evaluate the status of disease activity in patients with IBD. However, it was also found that their sensitivity is limited, particularly in the assessment of UC patients. It was reported that at least 50% of active patients with UC have normal serum CRP levels. In addition, the lower specificity of CRP also limits its effect in IBD patients and the CRP levels can also found to be significant increased in the peripheral blood of patients with infectious diseases, rheumatoid arthritis and some immune system diseases. In patients with active IBD, their intestinal mucosa truly have a large number of inflammatory cells infiltration, especially by neutrophils. With the process of intestinal peristalsis, feces can take up or carry out a number of biological moleculars which can reflect the disease activity or severity. When compared with the serum biomarkers, the fecal biomarkers can be more accurate and more relatively specific in the evaluation of the disease activity in patients with IBD.Calprotectin is a multifunctional calcium and zinc binding protein. Its molecular weight is 36 KD, which is mainly constituted by two heavy chain with molecular weight of 14 KD and a light chain with molecular weight of 8 KD. It is a calcium binding protein heterotrimeric body composition which is connected by covalent bond, and each chain can be combined with the two Ca2+, thus making it with characteristics of resistance heat and hydrolysis. Calprotectin is mainly derived from neutrophils and monocytes, it accounts for 60% of the cytoplasmic protein of neutrophils, and accounts for 5% of the total cell protein. It was found that calprotectin can be easy detected in the plasma, urine, cerebrospinal fluid, articular cavity fluid, feces and colonic mucosal tissues and calprotectin content in the feces is the highest among these samples. It was also found that the calprotectin levels in feces is 6 times higher than that in serum, and there is also no significant difference in gender. The calprotectin has the functions of anti-microbial activity and anti-protease activity, which make it can be preserved stable for 1 weeks at room temperature. Rugiveit et al did a research and found that there were a large number of neutrophils and mononuclear cells in the mucosa and submucosal layers of the colon in the patients with IBD, and the levels of these inflammatory cells were significantly higher than those in the noninflamed colon mucosa. In other infectious and inflammatory diseases, calprotectin can also be expressed specifically in inflammatory cells such as neutrophils and macrophages, so that the levels of calprotectin in blood, feces, secretion and specific tissues can used to evaluate the presence of inflammation, and to a certain extent, it can reflect the severity of the inflammatory diseases.It was found that fecal calprotectin (FCP) can truly reflect the infiltration of inflammatory cells in the intestinal mucosa in patients with IBD, and a great deal number of studies also found that FCP levels have a good correlation with the clinical disease activity index and endoscopic disease activity scores of IBD patients. FCP can be quickly detected by a method of enzyme-linked immunosorbent assay (ELISA), it has already been widely used in the daily management of IBD patients.Neopterin (NP) is one of the most important pteridine substances in human body which is mainly present in human blood, urine and other body fluids. It is an intermediate metabolites of guanosine triphosphate, and a low molecular pyrimidine compounds of tetrahydrobiopterin biosynthesis process. Neopterin is mainly produced and released by activated phagocytic cells, in particular by the activation of T lymphocyte secretion of interferon-y (IFN-y) which may stimulate the monocyte macrophage production. The level of neopterin in body fluid is an early sensitive indicator which can reflect the cellular immune activation. Studies also found that the neopterin in blood, urine and other body fluids will be significantly increased in some immune system diseases, such as graft-versus-host disease, rheumatoid arthritis, systemic lupus erythematosus, sepsis and other diseases. Studies have found that the neopterin concentrations in serum and urine were significantly increased in patients with IBD, and neopterin concentrations were significantly higher in patients with active IBD than that patients in remission, and also confirmed that neopterin concentrations have a good correlation with the clinical disease activity scores of IBD patients, so as to be a reliable biomarker in evaluation of clinical disease activity in patients with IBD. In recent years, foreign studies have also reported the value of fecal neopterin (FNP) in the evaluation of the endoscopic disease activity of IBD patients.They concluded that the FNP is a reliable and non-invasive biological markers in the evaluation of IBD clinical disease activity, and the accuracy of FNP in the evaluation of the endoscopic disease activity of IBD patients was consistent with FCP. However, there are few clinical studies on the application of FNP in IBD patients, and there is no relevant report in our country.ObjectiveTo investigate the clinical diagnostic value of fecal neopterin and calprotectin on disease activity in patients with inflammatory bowel disease, and compared fecal biomarkers with Serum C-reactive protein which is widely used in clinical practice of IBD patients.MethodsA total of 151 patients with IBD (84 Crohn’s disease, and 67 ulcerative colitis) undergoing a colonoscopy were included between May 2014 and February 2015 in the Department of Gastroenterology, Nanjing General Hospital of Nanjing Military Region Nanjing General Hospital of Nanjing military command. All patients were given written informed consent for participation to the study. The inclusion criteria were IBD patients who were diagnosed by endoscopy and histopathology, and the healthy control group with the same gender and age. The exclusion criteria:(1) when colonoscopy was incomplete (upper limit of the lesions not reached for patients with UC and terminal ileum not reached for patients with CD); (2) when they used nonsteroidal anti-inflammatory drugs within 1 month before the endoscopy or statins (that has been previously shown to decrease CRP); (3) when they had medical history of erosive/ulcerative upper gastrointestinal disease and history of infectious enterocolitis within 1 month before the endoscopy; (4) when combined with other immune system diseases, such as tuberculosis, rheumatoid arthritis, graft versus host disease; (5) urinary incontinence (risk of contamination of fecal samples); (6) pregnancy. IBD was diagnosed by the consensus of diagnosis and treatment of inflammatory bowel disease which was made by experts of IBD in Guangzhou China in 2012.Clinical type of CD is according to Montreal classifiction, disease activity is evaluated by the Best CDAI (when CDAI<150 points divided into remission, CDAI≥150 points divided into active, 150-220 points for mild,221-450 points for moderate and CDAI>450 points for severe):The disease location of UC was used by the Montreal classification, disease activity evaluation was used by modified Mayo score (Mayo scores≤2 points and no single score>1 point for clinical remission.3-5 points for mild activity,6-10 points as a moderate activity,11～12 points for severe activity).The study also included in 50 healthy pepole as a control group, who should only provide 2g fresh fecal samples for the measurement of FNP and FCP concentrations. All IBD patients provided 2g fresh fecal samples for the measurement of FNP and FCP concentrations and 2ml fresh blood samples for the serum C-reactive protein measurement in the day before colonoscopy. Enzyme-linked immunosorbent assay (ELISA) method was used for detection with FNP and FCP concentrations of IBD patients,and the serum CRP concentrations in IBD patients were also detected. Comparing the levels of these markers between IBD patients and healthy people, the correlation between each biomarkers and IBD clinical disease activity scores, and the operator’s curve receiver curve of each biomarkers were also drew to determine the area under the curve, sensitivity and specificity.All datas were statistically analyzed by SPSS 20 software. If the measurement datas meet the normal distribution and homogeneity of variance then using the single factor analysis of variance analysis, and the results of numerical datas are presented as mean and SD. Otherwise, the nonparametric Mann Whitney U test was used as appropriate. Spearman correlation analysis method was used for correlation analysis. A P value< 0.05 was considered statistically significant.ResultsThe levels of FNP、FCP and serum CRP in patients with IBD were significantly higher than those in healthy control group (P<0.05), FNP and FCP concentrations in active IBD patients were also significantly higher than those in remission patients with IBD (P<0.001).In patients with CD, the correlation coefficients between FNP and FCP with clinical activity Index (CDAI) were 0.55 and 0.59 respectively (P<0.001), and in UC patients, the correlation coefficients between FNP and FCP with modified Mayo scores were 0.74 and 0.77 respectively (P<0.001). The correlation coefficients of Serum CRP and clinical disease activity scores in patients with CD and UC were 0.49 and 0.60 respectively (P<0.001), were lower than FNP and FCP. The area under the curve of FNP and FCP in diagnosis of clinical disease activity of CD patients were respective 0.75 and 0.80 (P<0.001), The area under the curve of FNP and FCP in diagnosis of clinical disease activity of UC patients were 0.85 and 0.90 respectively (P<0.001),The area under the curve of serum CRP in diagnosis of clinical disease activity of CD and UC patients were 0.65 and 0.74 respectively (P<0.001),both were lower than FCP and FNP. When combined the FNP and FCP, the area under the curve in diagnosis of clinical disease activity of patients with CD and UC were respective 0.85 and 0.92 (P<0.001).ConclusionThe FNP is a novel reliable and non-invasive biomarker in evaluation the clinical disease activity in patients with IBD,and is as accurate as FCP. It is advisable to combine the marker of FNP and FCP to evaluate the disease activity in patients with IBD in daily management. |
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