Fecal biomarkers in the diagnosis and management of inflammatory bowel disease

Dr. Greg Rosenfeld (biography, no disclosures)

What I did before

The gold standard in the diagnosis and management of inflammatory bowel disease (IBD) (which includes Crohns disease and ulcerative colitis) has been and remains to be endoscopy (colonoscopy and on occasion gastroscopy) and biopsy. However, due to the patient discomfort, risks, costs and lack of resources in a single payer system such as in Canada, endoscopy has its limitations. As a result, clinical indices of disease activity have traditionally been used as surrogate markers of disease activity. Unfortunately, such indices are subjective, reliant on patient symptoms and are not specific to IBD, nor do they distinguish functional bowel disease from mucosal inflammation. Biochemical markers such as C-reactive protein (CRP), while useful in clinical practice, lack the sensitivity and specificity to replace endoscopy. Furthermore, the goal for treatment of IBD has shifted toward mucosal healing and away from simply controlling or relieving symptoms. Achieving mucosal healing leads to a change in the natural history of IBD (such as a reduced risk of surgery) whereas concluding that a patient’s IBD is controlled based on a lack of symptoms does not correlate in an improvement in their disease’s expected outcomes. Mucosal healing cannot be determined with clinical parameters.

What changed my practice

Calprotectin is a neutrophil-derived cytosolic protein released from macrophages of inflamed bowel mucosa and shed into the stool. Numerous studies have been published on the role of Fecal Calprotectin (FC) as a sensitive and specific marker of mucosal inflammation. Fecal Calprotectin is a simple laboratory investigation performed on a first-morning stool sample which is widely available in BC at a cost of approximately $115 (Lifelabs). Currently, this test is not covered by the provincial medical services plan, even for patients with IBD. Quantitative assays range between 0 – 1800 ug/g of stool and typically only 5 g of stool is required. Values > 250 ug/g of stool have been shown to correlate very highly with inflammation in the colon and distal small bowel, while values < 100 ug/g correlate with an absence of inflammation. The level of calprotectin correlates with the degree of inflammatory activity in the bowel mucosa.

What I do now

The four most common uses of FC in clinical practice include:

1) Distinguishing IBD from functional disorders.

FC has been shown to be highly sensitive and specific in both the adult (93%, 96%) and the pediatric (92%, 76%) populations. For patients with abdominal symptoms but normal biochemical markers and an absence of physical signs to suggest IBD, a negative FC may alleviate the need to perform a colonoscopy and can be reassuring to both the patient and the physician that a diagnosis of IBD is not being missed. The test has not been shown to be effective in colon cancer screening and should not be used for this purpose.

2) Monitoring disease activity in those known to have IBD.

This may include monitoring for recurrent Crohns disease in a patient who has required surgery to treat their disease, or to predict relapse in those who have remained in clinical remission. Typically, these patients are asymptomatic and a rise in FC level is an early warning of a possible relapse or recurrence. Patients with an FC level < 250 ug/g will usually be continued on their current therapy, while those with a rising level or a level > 250 ug/g will be recommended to undergo colonoscopy or have therapy altered in an effort to achieve better control of their IBD. Several studies are currently looking at the role of calprotectin for monitoring asymptomatic patients to predict flares, however, there are no recommendations regarding the frequency with which calprotectin levels should be obtained in this situation.

3) Monitoring response to therapy for IBD.

When initiating therapy, particularly in a patient who is more likely to require surgery, we would like to be sure that mucosal inflammation resolves with the ultimate goal of therapy being mucosal healing. FC has replaced some of the need for endoscopy to assess the inflammatory burden in such high risk patients. FC has the advantage of being more readily available than colonoscopy and can be performed serially allowing closer monitoring of response to therapy. The FC levels should normalize if treatment of IBD is optimized and a failure to do so is indicative of ongoing inflammation in the bowel. For example, three to six months after starting a patient on an anti TNF agent, we will measure the FC level to ensure it has decreased below 250 ug/g and where the FC remains elevated, a colonoscopy may be warranted.

4) Distinguishing symptoms of irritable bowel syndrome (IBS) from symptoms of IBD in those patients known to have IBD.

Many patients with IBD also have IBS and thus, treating symptoms may result in under or over treatment of their IBD exposing patients to potential unnecessary risks of treatment. FC levels have been shown to reliably distinguish IBS symptoms from IBD and therefore, FC levels can be very helpful in directing therapy for patients with concomitant IBS and IBD.

Overall, fecal calprotectin has proven to be an extremely useful tool in the diagnosis and management of inflammatory bowel disease.

References:

1. Kolypov U, Rosenfeld G, Bressler B, Seidman E. Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease. Inflamm Bowel Dis. 2014;20: 742–756. (View with CPSBC or UBC)
2. Lahiff C, Safaie P, Awais A, et al. The Crohn’s disease activity index (CDAI) is similarly elevated in patients with Crohn’s disease and in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2013;37: 786–794. (View with CPSBC or UBC)
3. Mao R, Xiao Y, Xiang G, et al. Fecal Calprotectin in Predicting Relapse of Inflammatory Bowel Diseases: A Meta-Analysis of Protective Studies. Inflamm Bowel Dis. 2012;18:1894-1899. (View with CPSBC or UBC)
4. Yang Z, Clark N, Park KT. Effectiveness and Cost Effectiveness of Measuring Fecal Calprotectin in Diagnosis of Inflammatory Bowel Disease in Adults and Children. Clin. Gastro and Hep. 2014;12:253-262. (View with CPSBC or UBC)

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Fecal biomarkers in the diagnosis and management of inflammatory bowel disease

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