Inflammatory bowel disease (IBD) is a chronic disease mostly involved with intestine with unknown etiology. Diagnosis, evaluation of severity, and prognosis are still present as challenges for physicians. An ideal biomarker with the characters such as simple, easy to perform, noninvasive or microinvasive, cheap, rapid, and reproducible is helpful for patients and clinicians. Currently biomarkers applied in clinic include CRP, ESR, pANCA, ASCA, and fecal calprotectin. However, they are far from ideal. Lots of studies are focused on seeking for ideal biomarker for IBD. Herein, the paper reviewed recent researches on biomarkers of IBD to get advances of biomarkers in inflammatory bowel disease.
Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC) with unknown etiology. Physicians get the diagnosis of IBD usually based on the combination of clinical features, laboratory tests, radiology, endoscopy, and pathology. Diagnosis, evaluation of severity, and prognosis are still present as challenges for clinicians. Laboratory biomarkers are noninvasive or microinvasive, objective, and rapid and cost less than other techniques, which relieve physiological and financial burden for patients. An ideal biomarker for IBD should be simple, easy to perform, noninvasive or microinvasive, cheap, rapid, and reproducible [
Family history is a risk factor for developing IBD, with a peak incidence in early adult life, although individuals of any age can be affected [
A large number of identified susceptibility loci have been explored in both CD and UC [
The most common mutation occurs in Caucasians other than eastern Asians. Disease predisposing mutations of
GWAS for CD shows the genes regulating autophagy, including autophagy 16-like 1 (
For
Several common variants in the IL-23 receptor gene (
The gene also affects the strategies of treatment. A research in Germany shows that homozygous carriers of IBD risk-increasing
IBD is an immune-related disease, some immune-associated markers are also explored for this disease. The differentiation of UC and CD is also quite difficult for physicians especially when the clinical, endoscopic, and pathologic features are not typical or confused. However, some markers could help to resolve part of them.
Antineutrophil cytoplasmic antibodies (ANCAs) are antibodies for granules of neutrophil cytoplasm; it is first reported in UC patients in 1990 [
ASCAs are antibodies for mannan in cell wall of
Apart from pANCAs and ASCAs, other serological antibodies such as anti-OmpC, ALCAs, ACCAs, AMCAs, anti-L, and anti-C and pancreatic autoantibodies (PAB) also contribute to diagnosis and differential diagnosis of IBD and other diseases [
Various markers have been proposed to objectively evaluate disease activity or inflammation, but sensitivity and specificity have been a concern for each. A combination of biomarkers may be the most useful for prediction or confirmation of clinical disease activity and endoscopically visible inflammation.
C-reactive protein (CRP) is considered as one of the most important protein in acute inflammation; it is consist of 5 components [
Erythrocyte sedimentation rate (ESR) indicates migration speed of red blood cells in plasma; it varies with concentration of plasma and the size of erythrocyte. It is significantly altered when in patients with anemia, globulism, or Mediterranean anemia [
Platelets (PLT) increase in patients with IBD, which contribute to high-coagulated state of IBD, such as the formation of microthrombus [
Mean platelet volume (MPV) indicates average size of platelet; it could reflect the rate of platelet stimulation and production. Kapsoritakis et al. [
Red blood cell distribution (RDW) reflects the size and variability of erythrocytes in peripheral circulation, it is usually detected in blood regular test in hospital [
Fecal calprotectin is a protein in neutrophil granulocytes and macrophages; it consists of S100A8 and S100A9 and is first found and described in 1980 [
More and more studies focus on fecal calprotectin in IBD and confirm its value in diagnosis, disease activity evaluation, effect evaluation, and relapse monitor [
Schoepfer et al. detect fecal calprotectin and IBD-related antibodies; they show that the accuracy of fecal calprotectin is 89% when compared to IBS (sensitivity and specificity were 83% and 100%, resp.); the accuracy is just 91% when combined with ANCAs or ASCAs [
A meta-analysis including 30 prospective studies confirms that the sensitivity and specificity of fecal calprotectin could reach up to 95% and 91%, respectively; the accuracy in children is higher than in adults. Moreover, fecal calprotectin is better than CRP, ESR, ASCA, pANCA, and OmpC [
A systematic review conclude that, for distinguishing between IBD and IBS in adults, these gave pooled sensitivity of 93% and specificity of 94% at fecal calprotectin cutoff level of 50
National Institute for Health and Care Excellence (NICE) guideline for fecal calprotectin diagnostic tests for inflammatory bowel disease gives recommendations for the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults or children, and it is a useful screening test to triage referrals to gastroenterology for investigation of chronic diarrhea, without rectal bleeding, in patients under the age of 60 years [
Lactoferrin is an iron-binding protein; it covers most mucosal surface and interacts with exocrine organs or substances including parotid, tears, vaginal discharge, articular synovia, and latex [
Sugi et al. find that lactoferrin could reflect inflammation of intestine [
Both fecal calprotectin and fecal neopterin concentrations correlated with endoscopic scores in UC (
Scholars consider S100A12 as a novel biomarker which could meet these characters: high sensitivity and specificity, easy to take and detect, cheap, and of good compliance [
The sensitivity and specificity of fecal S100A12 could reach up to 86% and 96% respectively, it is higher than fecal calprotectin [
Foell et al. shows that S100A12 upregulated in serum of UC and CD, and it correlated with disease activity [
A study aims to investigate the role of calprotectin and S100A12 in predicting inflammatory lesions of small bowel in patients undergoing wireless capsule endoscopy (WCE). The result shows that fecal calprotectin is significantly higher in CD patients compared with those with normal WCE or other abnormalities (
MicroRNAs (miRNAs) are small noncoded single-stranded RNAs (approximately 18–24 nucleotides); they are negatively regulatory molecules for genes. The unbalance of miRNAs could emerge in physiopathologic processes of multiple diseases, such as alloplasia, arrhythmia, schizophrenia, cancer, and immune-related diseases [
There is significant increase of adenosine deaminase (ADA) in active CD patients when compared with HC and patients in remission, and ADA correlated with CRP (
A research recruits 214 CD and 110 HC, to detect lipopolysaccharide-binding protein (LBP), CD14, hs-CRP, ASCA IgG/IgA, anti-OMP IgA, and pANCA. Serological LBP increases and soluble CD14 decreases significantly. In addition, LBP and CD14 correlated with hs-CRP; the accuracy of evaluation of active CD equals to hs-CRP [
Serological IgG in IBD has higher affinity for lectin compared with HC. A study takes in 410 IBD (include 290 Japanese and 161 Americans) and HC; abnormal lectin-based IgG glycosylation increases significantly in CD when compared with HC; it correlated with disease activity and has higher specificity than CRP when it combines with ASCA [
Mopterin is a component of piperazine-[2,3-d]-pyrimidine, which is a metabolic product of cyclic guanosine monophosphate [
ST2 is a member of IL-1R superfamily; it is consist of 2 parts (ST2L and sST2) and coded by 2nd chromosome [
A study (30 UC, 30 CD, and 30 HC) demonstrates that there are significantly different concentrations of nitric oxide (NO) between three groups. With a cutoff level of 17.39
Exhaled nitric oxide (NO) could indicate Crohn’s disease involved in lungs; a study shows that exhaled NO increases significantly in CD compared to controls [
Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) notably correlated with endoscopic activity score, which indicates it might be a biomarker to evaluate endoscopic activity [
Serum substance P level sharply increases in 61 UC and 66 CD when compared with HC (
Activated thrombin activatable fibrinolysis inhibitor (TAFIa) is considered to be related with pathogenesis and progress of IBD. Plasma TAFIa increases significantly in CD, and it correlated with WBC, CRP, fibrinogen, and platelet, which indicates it might be a potential IBD biomarker [
Quantitative fecal immunochemical tests (FITs) could detect fecal blood rapidly. A study consists of 152 UC demonstrates that the sensitivity and specificity of FIT could reach up to 92% and 71% when cutoff <100 ng/mL; FIT also correlated with Mayo scores [
Chitinase 3-like-1 (CHI3L1/YKL-40) is a protein excreted by endotheliocytes and macrophages in intestine. The sensitivity and specificity of fecal CHI3L1 could reach up to 84.7% and 88.9% when cutoff was 13.7 ng/g in active-IBD [
Angiogenin increases significantly in IBD when compared with HC. Moreover it shows a sharply decrease of agiogenin when treated IBD patients with aminosalicylic acid (ASA), which indicates that angiogenesis is unbalance in IBD patients [
The activity of mucosal indoleamine 2,3 dioxygenase-1 (IDO1) is quite important in IBD diagnosis [
Higher levels of IL-17A and IFN-
Mucosa-related biomarkers such as mucosal CD11c+ [
Neopterin in urine is used to distinguish active state and nonactive ones [
Others such as soluble intercellular adhesion molecule-1, D-lactate, diamine oxidase,
Drugs for inflammatory bowel disease include aminosalicylic acid, corticosteroids, immunosuppressant, and anti-TNF agents. However, the reaction rate for patients with IBD is not ideal. Some markers are proposed to monitor the effect of the drugs.
As biological agents are widely used in IBD, effect-monitoring of biological agents seems to be quite important. Serological antibodies to infliximab (ATIs) usually affect the treatment of infliximab (IFX). A meta-analysis collecting 13 studies including 1378 IBD patients shows the risk ratio (RR) of patients with ATIs failed treatment was 3.2 (95% CI: 2.0–4.9,
pANCA seems to be valuable for predicting response to anti-TNF, as negative status of pANCA is associated with early response to anti-TNF drugs [
The activity of thiopurine methyltransferase (TPMT) and the concentration of 6-thioguanine nucleotide (6TGN) are considered to be related with the treatment of thioguanine. However, recent study does not find any relationship between them [
A study including 93 patients with UC taking mesalamine maintenance therapy prospectively enrolled from the clinics. Random urine salicylate levels (by colorimetry) were highly correlated with urine 5-ASA metabolite levels (by mass spectrometry;
Some studies also found the association between genetic factors and response to treatment; they affect the strategies of treatment. Multidrug resistant 1 (
Ulcerative colitis is considered to be a precancerous lesion; it could progress to colorectal cancer (CRC) as the disease duration extends. So the surveillance for it before canceration should be emphasized.
M2-pyruvate kinase (M2PK) often exists in undifferentiated or proliferous tissues and could be detected in serum and feces [
Studies found miRNAs up-regulated or down-regulated in mucosa of different sites [
There is no literature on fecal miRNAs and IBD, but fecal miRNA-92a was confirmed to be predictive in CRC and adenomatous polyp; the sensitivities were 71.6% and 56.1%, respectively; specificities were both 73.3% [
Mucosa CHI3L1 is highly expressed in intraepithelial neoplasias mucosa of UC cryptoepithelium and increases when developed to CRC. So it might be a biomarker to monitor malignant degeneration of UC [
Studies on IBD biomarkers were subdivided into 5 parts; however, invasive, expensive, physical, and mental burden for mucosa or tissue restricts its applications. Currently biomarkers applied in clinic include CRP, ESR, pANCA, ASCA, and fecal calprotectin; other biomarkers still need to be confirmed in large clinic research. These biomarkers bring convenience for patients and clinicians, but biomarkers are still far from ideal.
The authors declare that there is no conflict of interests regarding the publication of this paper.