Invited critical reviewEnzymes in feces: Useful markers of chronic inflammatory bowel disease
Introduction
Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are chronic illnesses that affect the gastrointestinal tract. The incidence rate of UC varies between 0.5 and 24.5/105 inhabitants/y, while that of CD varies between 0.1 and 16/105 inhabitants/year, with prevalence rates of IBD reaching up to 396/105 inhabitants. Recent data from South Europe [1], [2], [3], East Europe [4] and Asia [5] in the mid-1990s report a rise of the incidence of IBD and in some areas it is already comparable to rates reported in Northern Europe or North America [6]. The anatomic location and degree of inflammation determine the predominant symptoms that include rectal bleeding, diarrhea and abdominal pain. In the absence of rectal bleeding it can be difficult to differentiate between functional disorders of the lower GI tract and therefore, the diagnosis needs invasive and expensive testing such as endoscopy with biopsy for histological examination, small bowel series or barium enema. One of the major problems of clinical management of UC and CD is the lack of univocal diagnostic tool.
Several laboratory markers are used in the diagnosis of IBD and to monitor of IBD disease activity. These include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), acute phase protein (albumin), and platelets; however, none of these markers is specific for inflammation of the gastrointestinal tract [7].
The pathogenesis of inflammatory bowel diseases implies the loss of the barrier function and the loss of the tolerance against luminal and self antigens and both these phenomenon cause the recruitment of leukocytes in the intestinal wall [8], [9]. Activated leucocytes infiltrate the mucosa and can be detected in feces due to shedding in the intestinal lumen [10], [11]. The most important leukocyte population in the intestinal wall in IBD are the polymorphonuclear cells. In fact, high fecal neutrophil levels were detected in inflammatory bowel disease patients and may be used as surrogate markers of active disease [12], [13]. Nevertheless neutrophil determination in the stools is rather inefficient because of their brief lifetime that implies that the sample should be examined within a few hours of its collection. On the contrary calprotectin, lactoferrin and other proteins are produced in significant amounts by inflammatory cells and both lactoferrin and calprotectin fecal levels have been demonstrated to correlate with colorectal and intestinal inflammation in several studies [14], [15], [16]. We evaluate the clinical applicability of inflammatory enzymes in the feces for diagnosis of IBD, to assess disease activity, to monitor the response to treatment and for diagnosis of recurrent disease after surgery.
Section snippets
Fecal markers in chronic inflammatory bowel disease
Fecal markers include a heterogeneous group of substances that either leak from or are generated by the inflamed intestinal mucosa. The inflamed hyper-permeable mucosa of patients with inflammatory bowel disease is associated with increased protein cytokines and markers of neutrophil activation in fecal samples [17].
The fecal excretion of Indium 111-labeled leukocytes is considered the gold standard fecal marker of inflammation since strict correlations with intestinal inflammation were
Neutrophil-derived proteins in the feces in IBD
Lysozyme is a polymorphonuclear neutrophil-derived enzyme which catalyses the hydrolysis of Gram-positive bacterial cell walls. Fecal lysozyme was found significantly elevated in patients with active and inactive CD, active UC and non-inflammatory bowel gastrointestinal diseases with diarrhea, compared to healthy controls [30]. Fecal lysozyme correlates with excretion of Indium 111-labeled granulocytes in patients with colonic disease but not in those with small bowel disease [31], therefore it
Fecal enzymes in the clinical management of inflammatory bowel disease
Apart from screening and assessing response to treatment, the fecal calprotectin and lactoferrin have a further major advantage over the leukocytes labeling technique in predicting relapse of IBD. It has been shown that, in patients with clinically quiescent IBD, fecal calprotectin values > 50 mg/l may be used to predict clinical relapse of disease within a few months with over 80% sensitivity [16]. Symptoms of IBD are the direct consequence of the inflammatory process itself and vary depending
Conclusions
Lactoferrin and calprotectin appear to be the most used and useful fecal markers of intestinal inflammation. Many studies have confirmed the accuracy of these markers in the diagnosis and surveillance of patients with IBD. They are inexpensive and easily measured and, therefore, suitable for extensive use. Both tests appear to be useful in detecting bowel inflammation in symptomatic patients, achieving a similar diagnostic accuracy. Different cut-off values are suggested for different patient
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