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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological markers
  5. Acknowledgements
  6. References

Summary

Background

Traditionally, inflammatory bowel disease activity is assessed by clinical activity indices that measure clinical symptoms and endoscopic indices that measure endoscopic inflammation. Biological markers are a non-invasive way of objectively measuring inflammation and can play an adjunctive or primary role in the assessment of disease activity.

Aim

To review the data on biological markers for assessment of disease activity and prediction of relapse in inflammatory bowel disease.

Methods

To collect relevant articles, a PubMed search was performed from 1980 to 2006 using following search terms in combination: inflammatory bowel disease, biomarkers, inflammation, disease activity, relapse, acute phase reactants cytokines, interleukins, adhesion molecules, integrins, calprotectin and lactoferrin.

Results

Biological activity markers can be classified into serological, faecal and miscellaneous categories. Acute phase reactants levels correlate with disease activity and some can be used to help predict relapse. Cytokines and adhesion molecules are elevated in active disease inconsistently. Faecal markers are useful in assessment of disease activity and relapse.

Conclusions

Acute phase reactants and faecal markers are useful to assess the disease activity in clinical practice. More data are required on cytokines and adhesion molecules. C-reactive protein, erythrocyte sedimentation rate, interleukins and faecal markers may be useful in predicting a relapse.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological markers
  5. Acknowledgements
  6. References

Biological markers of disease activity have been studied in inflammatory bowel disease (IBD) as indicators of disease severity or activity and to predict the risk of relapse in patients in remission. Assessment of disease activity in patients with IBD can be carried out using clinical disease activity indices, endoscopic indices, serum markers, faecal markers and miscellaneous tests. Clinical indices give only indirect measurement of disease activity and may not accurately predict inflammatory activity found by endoscopic and histological examination. Endoscopy is accurate but is invasive and expensive. Hence, there has been a search for biological markers of disease activity, which are simple to use in clinical practice, reliable and inexpensive. This study will focus on the utility of biomarkers in measuring disease activity and predicting relapse in patients with IBD. The biomarkers that will be reviewed are listed in Table 1.

Table 1.   Biomarkers that may be used to determine activity in inflammatory bowel disease
Serological 
 Acute phase reactantsESR, C-reactive protein, α1-acid glycoprotein (orosomucoid), thrombopoietin, platelet count, fibrinogen, lactoferrin, serum amyloid A, α1-antitrypsin
 CytokinesInterleukins (IL-1, IL-2, IL-6, IL-8, IL-10, IL-15), interleukin receptors (IL-1 and IL-2), interleukin receptor antagonists (IL-1RA), TNF-α, TNF-α receptor concentration
 OthersElastase, myeloperoxidase, leucocyte esterase, serum tenascin C, B2-microglobulin, neutrophil elastase, soluble adhesion molecules and angiogenic proteins
FaecalFaecal excretion of 111Indium-labelled white cells and leucocytes products and serum proteins (α1-antitrypsin excretion, lysozyme excretion, calprotectin, lactoferrin)
Other111Indium-labelled white cells scan, intestinal permeability test, whole gut lavage fluid for immunoglobulin and albumin

Serological markers

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological markers
  5. Acknowledgements
  6. References

Acute phase reactants

An extensive list of acute phase reactants is provided in Table 2 but those relevant to IBD are discussed.1 Haemoglobin, platelet count, mean platelet volume, erythrocyte sedimentation rate (ESR), serum thrombopoietin, serum erythropoietin, C-reactive protein and orosomucoid (α1-acid glycoprotein) have been used for assessment of disease activity singly or in combination. ESR and C-reactive proteins are the most commonly used markers.

Table 2.   Acute phase reactants
  1. Reproduced from Ref.1

Protein whose plasma concentrations increase 
 Complement systemC3, C4, C9, factor B, C1 inhibitor, C4b-binding protein, mannose-binding lactin
 Coagulation and fibrinolytic systemFibrinogen, plasminogen, tissue plasminogen activator, urokinase, protein S, vitronectin, plasminogen activator inhibitor 1
 Antiproteasesα1-Protease inhibitor, α1-antichymotrypsin, pancreatic secretory trypsin inhibitors, inter-α-trypsin inhibitors
 Transport proteinsCeruloplasmin, haptoglobulin, hemopexin
 Participants in inflammatory responsesSecreted phospholipase A2, lipopolysaccharide-binding protein, interleukin-1 receptor antagonists, granulocyte colony-stimulating factor
 OthersC-reactive protein, serum amyloid A, α1-acid glycoprotein, fibronectin, ferritin, angiotensinogen
Proteins whose plasma concentrations decreaseAlbumin, transferrin, transthyretin, α2-HS glycoprotein, α-fetoprotein, thyroxine-binding globulin, insulin-like growth factor 1, factor XII

Erythrocyte sedimentation rate

Erythrocyte sedimentation rate is an indirect measurement of plasma acute phase protein concentration and is influenced by erythrocytes morphology as well as plasma constituents such as immunoglobulins.1 As the concentrations of many serum proteins vary in patients with IBD and as some have long half 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 ulcerative colitis (UC), where clinical, endoscopic and histological activity is used to assess the overall disease, the correlation between ESR and disease activity is good.1–5 However, it may be normal in proctitis and proctosigmoiditis. In Crohn's disease (CD), the ESR appears to be a less accurate measure of disease activity. The ESR does appear to increase with increasing disease activity but this correlates more with colonic disease and does not reflect the disease activity of small bowel.2–5

Orosomucoid

Orosomucoid (α1-acid glycoprotein) is an acute phase protein synthesized predominantly in the liver in response to tissue injury, inflammation or infection, and it may have a physiological role such as immunomodulation. The levels of circulating orosomucoid correlate with disease activity of IBD as assessed by standard disease activity indices but a long half life of 5 days limits its usefulness as an indicator of improvement in disease activity.6, 7

C-reactive protein

C-reactive protein is produced as an acute phase reactant predominantly in the liver in response to stimulation by interleukin (IL)-6, TNF-α and IL-1β, which are produced at the site of inflammation.8 CRP functions as an opsonin for bacterial sequences and nuclear material expressed during apoptosis. CRP has been used as a marker to diagnose and to predict the activity of inflammatory disease. CRP synthesis by the liver is the only factor determining plasma CRP concentration. Hence, only the liver failure or therapies affecting acute phase stimulus may decrease CRP.8 The normal value of CRP for systemic inflammation is 0.8 mg/dL (8 mg/L). In the presence of acute phase stimulus, CRP production is rapidly upregulated. Once the acute phase stimulus disappears, CRP concentrations quickly decrease due to short half-life of 19 h. This makes CRP a valuable marker to detect the activity of IBD. In CD, serum levels of CRP correlate with disease activity. For UC, same trend can be observed although CRP is overall lower than in CD. In a recent study, CRP elevation was significantly associated with moderate to severe clinical activity, active disease at ileocolonoscopy and histological severe inflammation (Table 3) but not with abnormal small bowel imaging in patients with CD. In UC patients, CRP elevation was significantly associated with severe clinical activity and active disease at colonoscopy but not with histological inflammation.9 There is a good correlation between CRP and other measures of inflammation such as the CD activity index, radioactive-labelled faecal granulocyte excretion and faecal calprotectin.3, 10, 11 However, some patients have low CRP in the face of active disease. These patients often have exclusive ileal disease and low body mass index.12 The value of CRP as a predictor of relapse is controversial with some studies finding it an accurate predictor and others not.13–15

Table 3.   Clinical disease activity and laboratory parameters of inflammation (CRP, ESR) in 147 IBD patients
 CD tested, N (%)UC tested, N (%)
  1. Modified from Ref.9

Clinically active CD/ UC91/10438/43
CRP elevated47/104 (45)19/43 (44)
ESR elevated16/51 (31)19/43 (44)

Other markers

Leucocytosis is not a useful marker of disease activity in clinical practice as there are many factors besides disease activity (systemic glucocorticosteroids, immunosuppressants, presence of abscess) that affect it. Platelet count correlates with disease activity in IBD but it is not used in clinical practice in IBD as there are other factors such as haemorrhage from other sites and iron deficiency anaemia which can cause elevation of platelet count.16, 17 Neopterin, an intermediate metabolite in the synthetic pathway of biopterin, is synthesized and released from monocytes/macrophages upon non-specific stimulation. The level of neopterin in urine and serum has been shown to correlate with disease activity of UC and CD but this is not IBD specific.18, 19

Cytokines

The expression of proinflammatory cytokines is markedly increased in the intestinal mucosa in patients with active IBD, although not always accompanied by increased concentration of cytokines in the serum (Figure 1). The evaluation of serum concentration of cytokines produced in the intestine has yielded inconsistent results.

image

Figure 1.  The figure shows the response of mucosal immune system on exposure to antigenic stimuli. Initially there is cytokine mediated T-cell response. TNF-α, Interleukins 1, 6, 12 and 18 may play a role. After CD4 cells are activated, effector cytokines, TNF-α, Interleukins 4 and 13 and interferon-γ mediated the intestinal inflammatory response. Levels of these cytokines may in mucosa, serum or stool may be useful as biomarkers. Reproduced with permission from Cominelli F. Cytokine based therapies for Crohn’s disease. New paradigms. New Engl J Med 2004;351:2045–48.

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TNF-α and TNF-α receptor

Tumor necrosis factor-α is produced by activated macrophages and monocytes. Although the serum concentration of TNF-α is often increased in patients with active IBD, serum concentrations of TNF-α have not been consistently elevated and are thus of limited utility as markers of disease activity in these patients.20–22 The same conclusion applies to the measurement of TNF-α concentration in stool.23, 24 Serum levels of soluble TNF-α receptors were increased in two studies in both CD and UC but not in another study.22, 25, 26 From the available studies, TNF-α does not seem to be promising as a marker of activity in IBD. Further studies are needed on the use of TNF receptors.

Interleukins, interleukin receptors and interleukin receptor antagonists

Interleukin-1 is a proinflammatory cytokine. Interleukin receptor antagonists (IL-1RA) levels are increased in patients with active IBD and IL-1RA/IL-1 ratio decreases with increasing IBD activity.27, 28

Interleukin-2 receptor (IL-R) is shed by activated T cells into circulation along with IL-2. IL-2 receptor is more stable than IL-2 and hence more reliable than IL-2 for detection in circulation. It also has advantage over acute phase proteins in that it more accurately reflects the underlying immunopathogenic process. IL-2 receptor has three different subunits, which behave differently with respect to inflammation and UC or CD.29, 30 IL-2 receptor-α correlates positively with increasing disease activity in both UC and CD.30

Interleukin-6 possesses both anti-inflammatory and proinflammatory effects. Elevated serum IL-6 concentrations are found in active CD but not always in UC.31

A recent study found higher concentrations of soluble TNF receptor I, soluble TNF receptor II, soluble IL-1 receptor I, IL-6 and soluble IL-6 receptor in patients with active CD when compared with inactive CD and healthy controls.32 Soluble IL-1 receptor II concentrations were profoundly decreased in patients with active CD compared to patients with inactive CD and healthy controls, and negatively correlated with CRP concentrations. Deficient production of soluble IL-1RII was specific to CD and not observed in UC.

Interleukin-8 is produced by polymorphonuclear cells, macrophages and epithelial cells, it is important for neutrophil chemotaxis. Serum IL-8 is elevated in patients with active UC but many patients have concentration below the detectable level. Serum IL-8 not elevated in patients with active CD. Thus, serum IL-8 level is a poor marker of disease activity in patients with IBD.33

Interleukin-10 and IL-15 are anti-inflammatory cytokines. The concentration of IL-10 is elevated in serum of patients in active UC and CD, suggesting that IL-10 acts as a naturally occurring immunosuppressant in the acute inflammatory process of IBD.34

A study evaluated 78 cytokines, growth factors and receptors using antibody-based protein microarrays amplified by rolling circle amplification and found no differences in circulating concentrations of proinflammatory cytokines but found that paediatric IBD patients in remission compared to those with active disease had higher concentrations of specific circulating cytokines, including the regulatory cytokines IL-12p40 and TGF-β1.35

The cytokines, cytokines receptors and/or cytokine transcripts have also been studied in the intestinal mucosa. IL-1β, IL-2, soluble IL-2 receptor, IL-6, IL-8, IL-23, IL-27, TNF-α and IL-15 (anti-inflammatory cytokine) have been found to be elevated and may correlate with endoscopic and disease activity.36–39

Adhesion molecules

Leucocytes do not readily adhere to vascular endothelium in an unstimulated state. However, inflammatory signals induce the expression of proteins on the endothelial cell surface that promote the adhesion and extravasation of activated immune cells from the circulation into the underlying tissues.40 These proteins are known as cell adhesion molecules and they are expressed by immune cell, endothelial cell and epithelial cells. They can be in soluble form or leucocyte-bound form. Amongst these key molecules are L-, P- and E-selectin and cell adhesion molecules [mucosal adressin-cell adhesion molecule (MAdCAM-1), intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) on the endothelial cells]. Integrins are secondary adhesion molecules and need to be activated before they engage in cell adhesion. The integrins interact with specific ligands, the addressins on the endothelium (α4β1-integrin binds to VCAM-1 and α4β7-integrin binds to MAdCAM-1).41

The serum concentrations as well as their in situ expression have been studied in IBD. sICAM-1 and sE-selectin are elevated in the serum of patients with IBD but CRP and microalbuminuria reflect clinical disease activity more accurately.42 There is significant overlap between UC and CD, between IBD and controls and between inactive and active IBD. Thus, there is no support to the routine use of soluble adhesion molecules as disease activity markers in IBD.

Other markers

Serum tenascin C is a multifunctional matrix protein present in connective tissue and is induced in inflammation and repair. Tenascins modulates cell adhesion. It has been studied as a marker of activity of IBD but it is not disease specific.43 Serum levels of B2-microglobulin was useful in a study to assess the disease activity in CD but not in UC.44 Plasma levels of neutrophil elastases is an independent parameter for assessment of disease activity and may be more useful than other markers such as ESR and CRP in identifying the patients in remission.45

Faecal markers

As serum markers can be elevated in a variety of conditions, it seems likely that faecal marker of inflammation, in absence if enteric infection would be more specific for IBD. Faecal markers can be divided into faecal excretion of leucocytes, serum proteins or leucocyte products. Faecal excretion of leucocyte is discussed later in this review. Faecal excretion of leucocyte products is more promising. Faecal lactoferrin and calprotectin have been studied frequently in recent years.

Faecal calprotectin

Calprotectin was first isolated from granulocytes in 1980 and named L1 protein.46, 47 The name calprotectin come from the fact that it binds to calcium and it has antimicrobial properties. It represents 50–60% of neutrophilic cytosolic protein. It is released from cells during cell activation or death. It is stable in faeces for several days after excretion. It is easily measured in stool by commercially available enzyme-linked immunosorbent assays (ELISA). Faecal calprotectin measurement correlates well with the more difficult and more expensive measurement of 111Indium-labelled leucocyte excretion.48 The median faecal calprotectin level is 2 mg/L in healthy individuals with an upper limit of 10 mg/L. Faecal calprotectin level has been shown to be a sensitive marker of activity in CD and to correlate well with endoscopic and histological activity in UC.49–52 Faecal calprotectin normalizes along with endoscopic healing in CD.49 Tibble et al. found that faecal calprotectin level of 50 μg/g was sensitive and specific marker of relapse in both CD and UC (sensitivity of 90% and specificity of 83%). In this study, patients with faecal calprotectin level of 50 μg/g had 13-folds increased risk of relapse.53 However, a recent study by Costa et al. had different conclusions.54 They found that faecal calprotectin level of 150 μg/g had a sensitivity of 89% for predicting a relapse within the next year in UC and 87% in CD. The specificity was 82% in UC and 43% in CD. After multivariate analysis, patients with CD with faecal calprotectin level of more than 150 μg/g had a non-significant twofold increase in the risk of relapse whereas patient with UC and with faecal calprotectin level of more than 150 μg/g had significant 14-fold increase in the risk of relapse (Figure 2). They concluded that faecal calprotectin was stronger predictor of relapse in UC than in CD.

image

Figure 2.  The likelihood of relapse in Crohn's disease and ulcerative colitis in patients with fecal calprotectin value of more than or less than 150 mg/dl. Reproduced from Costa et al.55 Gut 54, (2005) 364.

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Faecal lactoferrin

Lactoferrin is a glycoprotein found in many body fluids as well as in granules of neutrophil granulocytes. Faecal lactoferrin levels quickly increase after influx of neutrophils into intestinal lumen during inflammation. Faecal lactoferrin is measured by ELISA on a single stool sample. The concentration faecal lactoferrin in healthy individuals is 1.45 ± 0.4 μg/g of faecal weight. In active IBD this value can rise to several hundred.55 Faecal lactoferrin concentration is increased in patients with active IBD when compared to those with inactive IBD with specificity between 85% and 90%. Faecal lactoferrin levels may rise significantly prior to a clinically evident relapse and may be a good marker to predict subsequent IBD flares.56, 57

Recent studies comparing faecal lactoferrin and calprotectin have suggested that both tests are similarly useful in the assessment of the disease activity of IBD. Faecal excretion of calprotectin correlated with finding of colonic inflammation at endoscopy while faecal excretion of lactoferrin correlated with histological inflammation.58, 59

Other faecal markers

Faecal α1-antitrypsin level has been extensively studied in IBD but the data on this protein and its correlation with disease are inconsistent.55 Other markers such as myeloperoxidase, leucocyte esterase and TNF-α have a less promising data.56

Intestinal permeability

Intestinal permeability using differential 5 h urinary excretion ratio (ratio of lactulose and l-rhamnose) and CrEDTA have been used for assessment of disease activity as well as for prediction of relapse in patients with CD.51 This assay has been of limited value in assessing the disease activity but does appear to predict relapse. Less than 20% of patients who have normal intestinal permeability relapse in 6 months.46

White cell scan and 4-day faecal excretion test

Abdominal scanning with 111-Indium white cell technique visualizes segments of inflamed bowel and quantitates the degree of intestinal inflammatory activity. When combined with 4-day faecal excretion of labelled white cells, the inflammatory activity can be quantified accurately and can be used to document the response to treatment. Faecal excretion of 111Indium-labelled white blood cells has a good correlation with colitis but not ileitis and poor correlation with the CD activity index. The disadvantage is that these are expensive and more technically demanding.45

Whole gut lavage

Gut lavage fluid proteins have been studied as marker of disease activity in IBD and gut lavage IgG was been found to be a more specific disease marker than albumin in the lavage fluid.60

Prediction of relapse in inflammatory bowel disease

If relapse can be predicted in IBD, it is likely to change the approach to treatment. Laboratory markers have been studied to predict a relapse, more in CD than UC.

Brignola et al. formulated a prognostic index based on ESR, α2-globulin and α1-glycoprotein (Table 4).61 High value (prognostic index > 0.35) predicted relapse at 18 months. Normal values did not predict remission in all patients.

Table 4.   A laboratory index for predicting relapse in asymptomatic patients with Crohn's disease61
  1. A value more than +0.35 suggests likelihood of relapse. Accuracy 88%, sensitivity 71%, specificity and positive predictive value 100%.

−3.5 + (ESR × 0.03) + (acid α1-glycoprotein × 0.013) +  (α2-globulin × 2)

As mentioned earlier, CRP value has been studied to predict relapse with some studies finding it useful while others have not. In a study of patients with CD, those with clinically inactive disease with elevated CRP had higher chance of relapse in the following 2 years than those with normal CRP.13 A combination of CRP and ESR has also been used to predict relapse in patients with CD.14 Patients with CRP > 20 mg/L and an ESR > 15 mm/first hour had an eightfold increased risk of relapse in the next 6 weeks.

Reinisch et al. found that serum levels of IL-6 were useful to predict relapse in steroid-induced remission in patients with CD.62 Louis et al. found that high serum level of soluble IL-2 receptors in patients with CD was highly predictive of relapse and was complementary to other inflammatory and clinical markers in the prediction of relapse of disease.63

The role of faecal calprotectin and lactoferrin in prediction of relapse of IBD has been discussed earlier. The level of faecal calprotectin in prediction of relapse needs further study.

Bitton et al. followed ESR, CRP, IL-1β, IL-6 and IL-15 values at base line, 6 months and 12 months and found that they were not useful in predicting a relapse in UC.64 Yamomoto et al. studied conventional blood markers, plasma and mucosal levels of cytokines (IL-1β, IL-6, TNF-α and IL-8) to predict relapse in patients with UC.65 Only higher rectal mucosal IL-8 levels were significantly associated with relapse. Thus, faecal markers and rectal mucosal IL-8 are the only promising biomarker for prediction of relapse in patients with UC.

Small intestinal permeability has been recently studied to predict the relapse in patients with small intestinal CD and had sensitivity and specificity of 84% and 61%, respectively, to predict the relapse.46 Thus, some of the biomarkers may be useful in predicting a relapse.

In conclusion, assessment of disease activity in patients with IBD is important both in clinical practice and in clinical trials. Biological disease activity markers have been studied for assessment of disease activity and to predict relapse in patients with IBD. These include serological markers such as acute phase reactants, cytokines and adhesion molecules, faecal markers such as calprotectin and lactoferrin, measurement of intestinal permeability, white cell scan and measurement of gut lavage fluid protein. C-reactive protein was found to be useful in some studies. The data on ILs, IL-Rs and IL-RAs and adhesion molecules are limited or inconsistent. Faecal calprotectin and lactoferrin are promising markers. For predicting relapse, CRP, ESR, IL-2, IL-6, IL-8 and faecal markers may be of value.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Serological markers
  5. Acknowledgements
  6. References

The authors gratefully acknowledge secretarial help of Courtney N. Hoover and Susanne F. Benouna.

References

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  2. Abstract
  3. Introduction
  4. Serological markers
  5. Acknowledgements
  6. References
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