Clinical Review
Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease

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Abstract

Faecal calprotectin has been proposed as a non-invasive surrogate marker of intestinal inflammation in inflammatory bowel disease. Close correlation between faecal calprotectin concentration and faecal leukocyte excretion quantified with 111indium has been described. This faecal marker can be detected using simple and cheap techniques. Faecal calprotectin has a good diagnostic precision for separating organic and functional intestinal diseases. However, the specificity for the diagnosis of inflammatory bowel disease is lower than desirable, as several diseases other than inflammatory bowel disease – specially colorectal neoplasia and gastrointestinal infection – can also increase faecal calprotectin. High concentration of calprotectin in faeces is a strong argument to carry out a colonoscopy in order to rule out the presence of inflammatory bowel disease or other organic pathologies. Parallelism between faecal calprotectin levels and inflammatory bowel disease activity has been confirmed, although this faecal marker appears to better reflect the disease activity in ulcerative colitis than in Crohn's disease. Faecal calprotectin's capacity to predict inflammatory bowel diseases relapse is promising. It has been suggested that, in inflammatory bowel disease patients receiving treatment, a normalization or decrease in faecal calprotectin concentrations is an accurate indicator of endoscopic healing. Greater faecal calprotectin concentration has been shown in asymptomatic first-degree relatives of patients with inflammatory bowel disease, suggesting that there is a high prevalence of subclinical intestinal inflammation in them.

Introduction

There is no pathognomonic symptom nor sign for inflammatory bowel diseases (IBDs) – Crohn's disease (CD) and ulcerative colitis (UC) – so, a series of suggestive clinical, radiological, endoscopic and histological data is needed for diagnosis while rejecting other diseases that show similar clinical manifestations [1].

Endoscopy (and histology on biopsy specimens) remains the gold standard method for detecting and quantifying bowel inflammation. This technique is expensive, invasive and not well tolerated by patients as the need for repeated examinations affects their quality of life [2]. Thus it is clear that a simple, rapid, sensitive, specific, inexpensive, and non-invasive marker to detect and monitor intestinal inflammation, both in general but especially in IBD, is needed [3].

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 [4]. These markers can be classified into serological, faecal and miscellaneous categories [4]. Biological markers could, theoretically, have diverse uses for IBD, as for any other disease, such as to diagnose the specific process, stratify the disease in different subtypes, estimate activity, evolution and prognosis, and predict response to treatment [5].

Among the various serological and biological markers available, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-neutrophil cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiase antibodies (ASCA) stand out [5]. However, these systemic markers have low sensitivity and specificity for intestinal inflammation and correlate poorly with symptoms and disease activity indexes [5], [6], [7], [8]. On the other hand, faecal markers have the theoretical advantage of having higher specificity for the diagnosis of gastrointestinal diseases such as IBD because their levels are not raised in extra-digestive processes [7], [9], [10], [11], [12]. Another potential benefit of faecal markers is that they may avoid the necessity of endoscopic exploration to estimate diseases’ activity if they correlate closely with lesions in the colonic mucosa [7], [9], [10], [11], [12].

As calprotectin appears to be the most used and useful faecal marker of intestinal inflammation [2], the aim of the present manuscript will be to critically pose a series of questions on the role of faecal calprotectin as a biological marker in IBD and subsequently answer them based on scientific evidence. Questions will be asked from a practical perspective to obtain the most useful conclusions for the clinician who diagnoses and treats IBD patients.

Bibliographical searches were performed in MEDLINE electronic database up to September 2007 looking for the following words (all fields): (“inflammatory bowel disease” OR “Crohn's disease” OR “ulcerative colitis”) AND (calprotectin OR faecal marker).

The mean sensitivity and specificity of the faecal calprotectin determination (e.g., for the discrimination of organic vs. functional disorders, or for the diagnosis of IBD) were calculated and expressed as weighted mean (and corresponding 95% confidence interval; 95% CI) to make due allowance for the number of patients included in each study.

Section snippets

Calprotectin's overview

Diverse digestive diseases, IBD included, show a higher disposal of leukocytes in faeces [13], [14]. In fact, 111indium marked leukocytes in faeces has been used as a reference test to measure IBDs degree of activity, though this technique has fallen into disuse due to the exposition to ionizing radiation and the need to retrieve faeces during a long period of time [13], [14]. These findings led to the idea that an increased translocation of granulocytes into the intestinal mucosa in conditions

What are the main advantages of the faecal calprotectin assay?

The potential strength of faecal calprotectin assessment is that it is a measure of mucosal inflammatory activity that may be detected at a level insufficient to cause an increase in ESR and CRP, and levels in the stool seem to be unaffected by a variety of non-intestinal conditions, which may result in an elevation of the systemic inflammatory markers [20].

Calprotectin has the advantage of showing excellent stability in faeces at room temperature for as long as a week [2], [13], [14], [21].

What are the main disadvantages and limitations of the faecal calprotectin assay?

A main disadvantage of faecal calprotectin is that it increases after the use of non-steroidal anti-inflammatory drugs (aspirin included), probably due to the associated induced enteropathy [22], [23], [24], [25], [26], [27], [28]. Therefore termination of these medications’ treatment should be recommended before taking samples for analysis [28].

It has been suggested that faecal calprotectin changes with age. However, it has been shown that the suggested cut-off level for adults in some studies

What is the utility of calprotectin in the diagnosis of organic intestinal disease?

Clinical manifestations of intestinal or colonic diseases (IBD, colonic cancer, etc.) are relatively unspecific, so the range of diagnostic possibilities of a patient showing, for example, diarrhoea and abdominal pain is considerably wide. This frequent digestive clinical history may be caused by organic or functional diseases. Mainly in the absence of rectal bleeding it can be difficult to distinguish between these two possibilities. To carry out an accurate diagnosis, a colonoscopy is usually

Faecal calprotectin for the diagnosis of IBD

Faecal calprotectin levels are generally increased (compared to asymptomatic controls) in IBD patients, as is summarized in Table 2[16], [17], [20], [21], [24], [28], [33], [34], [35], [36], [38], [40], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57]. The use of the determination of the diverse biological markers (faecal calprotectin included) to distinguish between IBD patients and asymptomatic controls lacks interest in clinical practice. Much more

Which are the type of units for faecal calprotectin measurement and the best cut-off point for its determination?

The original ELISA method for calprotectin determination was first described in 1992 by Roseth et al. [21], and the results were provided in “per liter of faecal homogenate”. In 2000, a new assay for faecal calprotectin became widely available, which was five times as sensitive as the original assay and measured this faecal biomarker in μg/g rather than mg/L [63]. A number of authors have asserted that results obtained from the old assay method may be directly compared with results obtained

Is there a correlation between biological markers and IBDs activity?

The classification systems of IBDs clinical activity are based, mostly, in subjective criteria (both patient and doctor's) therefore they are not totally reliable. Partly due to this, correlation between classic activity indexes and the endoscopic and histological lesions is far from perfect [13]. Thus, any objective analytic variable directly correlating with clinical, endoscopic or anatomopathologic activity would be of great value. Furthermore, analytical markers – in serum or faeces – are

Is faecal calprotectin determination useful to predict the relapse of IBD?

IBD courses naturally with activity relapses and longer or shorter remission periods. Both UC and CDs relapses are mostly unpredictable. Having a marker able to accurately estimate the risk of relapse would allow preventive treatment, maybe more intense, for just the patients’ subgroup that really needs it and avoid general prescription of maintenance therapy. Another benefit of a truthful prediction of relapses is that it would allow early treatment, that will theoretically produce faster and

What role does faecal calprotectin play in the assessment of IBD treatment response?

Estimation of the response to IBD treatment is generally based on the evaluation of symptoms, while endoscopy controls are exceptional. It has been proposed that patients who do not reach intestinal mucosa's cure after treatment have higher chances of suffering clinical relapse. Consequently, endoscopic lesions normalization should be the real therapeutical aim for IBD patients [76], [77]. However, routine confirmation of endoscopic and histological healing is not realistic. Therefore,

Is faecal calprotectin determination of any use in IBD patients with bowel resection surgery?

One of the most common problems in the treatment of CD is the high frequency of recurrence after bowel resection [78]. The clinical manifestations of CD recurrence are fever, diarrhoea, abdominal pain, rectal bleeding, and weight loss. On the other hand, some of these symptoms, such as chronic abdominal pain or obstructing crises, may be caused by postoperative adhesions that do not benefit from immunosuppressive treatment. The differential diagnosis may usually require an evaluation of

Do (asymptomatic) first-degree relatives of patients with IBD have normal faecal calprotectin concentrations?

High faecal levels of calprotectin relate to a greater turnover of leukocytes in the gut wall and to neutrophil migration into the gut lumen. Greater faecal calprotectin concentration has recently been shown in asymptomatic first-degree relatives of patients with CD. Some authors have reported that half of the first-degree relatives of patients with this disease had elevated faecal calprotectin concentrations, suggesting its use as a subclinical biomarker of CD [55]. More recently, it has been

Summary

Several digestive diseases, IBD included, course with higher leukocyte disposal in faeces, and close correlation between faecal calprotectin concentration and faecal leukocyte excretion quantified with 111indium has been described. This faecal marker can be detected using simple and cheap techniques and it has excellent stability in faeces over a long period of time. Since IBDs clinical manifestations are relatively unspecific, a biological marker able to distinguish between patients with

Conflict of interest statement

None declared.

List of abbreviations

    ANCA

    anti-neutrophil cytoplasmic antibodies

    ASCA

    anti-Saccharomyces cerevisiae antibodies

    CD

    Crohn's disease

    CRP

    C-reactive protein

    ESR

    erythrocyte sedimentation rate

    IBD

    inflammatory bowel disease

    UC

    ulcerative colitis

Acknowledgement

CIBEREHD is funded by the Instituto de Salud Carlos III.

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