Invited critical review
Enzymes in feces: Useful markers of chronic inflammatory bowel disease

https://doi.org/10.1016/j.cca.2007.02.025Get rights and content

Abstract

Background

Ulcerative colitis and Crohn's disease are characterized by a chronic intestinal inflammation. Since the precise etiology is still unknown, current therapies are aimed at reducing or eliminating inflammation.

Methods

Endoscopy and histology on biopsy specimens remain the gold standard methods for detecting and quantifying bowel inflammation. These technique are expensive, invasive and not well tolerated by patients since the need of repeated examinations affects their quality of life. Although disease activity scores and laboratory inflammatory markers are widely used they showed unreliable relations with endoscopy and histology. Fecal markers have been investigated in inflammatory bowel disease (IBD) by many authors for diagnostic purposes, to assess disease activity and of risk of complications, to predict relapse or recurrence, and to monitor the effect of therapy. Many inflammatory mediators have been detected in the feces such as leukocytes, cytokines and proteins from neutrophil activation. Some of these, particularly lactoferrin and calprotectin, have been demonstrated to be useful in detecting active inflammatory bowel disease, in predicting recurrence of disease after surgery or monitoring the effects of medical therapy. Calprotectin and lactoferrin are remarkably stable and easily detect in stool using ELISA so they appear to be equally recommendable as inflammation markers in the lower gastrointestinal tract especially in IBD patients.

Conclusion

Fecal markers are non-invasive, simple, cheap, sensitive and specific parameters and are useful to detect strointestinal inflammation.

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

References (60)

  • M.G. Russel

    Changes in the incidence of inflammatory bowel disease: what does it mean?

    Eur J Intern Med

    (2000)
  • B. Xia et al.

    Inflammatory bowel disease in Hubei province of China

    China Natl J New Gastroenterol

    (1997)
  • S. Shivananda et al.

    Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD)

    Gut

    (1996)
  • L. Lakatos et al.

    Is the incidence and prevalence of inflammatory bowel diseases increasing in Eastern Europe?

    Postgrad Med J

    (2006)
  • Q. Ouyang et al.

    The emergence of inflammatory bowel disease in the Asian Pacific region

    Curr Opin Gastroenterol

    (2005)
  • F. Molinie et al.

    Opposite evolution in incidence of Crohn's disease and ulcerative colitis in Northern France (1988–1999)

    Gut

    (2004)
  • S. Vermeire et al.

    Laboratory markers in IBD: useful, magic, or unnecessary toys?

    Gut

    (2006)
  • C. Niederau et al.

    Inflammatory mediators and acute phase proteins in patients with Crohn's disease and ulcerative colitis

    Hepatogastroenterology

    (1997)
  • M.Z. Mazlam et al.

    Peripheral blood monocyte cytokine production and acute phase response in inflammatory bowel disease

    Gut

    (1992)
  • M.B. Pepys et al.

    Immunological studies in inflammatory bowel disease

  • J. Tibble et al.

    A simple method for assessing intestinal inflammation in Crohn's disease

    Gut

    (2000)
  • S.H. Saverymuttu et al.

    Indium111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease. A comparison with colonoscopy, histology, and fecal indium111-granulocyte excretion

    Gastroenterology

    (1986)
  • D.J. Leddin et al.

    Indium-111-labelled autologous leukocyte imaging and faecal excretion. Comparison of conventional methods of assessment of inflammatory bowel disease

    Dig Dis Sci

    (1987)
  • D'incà R, Dal Pont E, Di Leo V, et al. Calprotectin and lactoferrin in the assessment of intestinal inflammation and...
  • Sv. Kane et al.

    Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation

    AJG

    (2003)
  • M.R. Konokoff et al.

    Role of fecal calprotectin as a biomarker of intestinal inflammation in inflammatory bowel disease

    Inflamm Bowel Dis

    (2006)
  • A. Poullis et al.

    Review article: faecal markers in the assessment of activity in inflammatory bowel disease

    Aliment Pharmacol Ther

    (2002)
  • S.H. Saverymuttu et al.

    111 Indium autologous granulocytes in the detection of inflammatory bowel disease

    Gut

    (1985)
  • S. Nordgren et al.

    Fecal excretion of radiolabeled (51CrCl3) proteins in patients with Crohn's disease

    Scand J Gastroenterol

    (1990)
  • A. Ferguson et al.

    Clinical investigation of gut immune responses. Review of non-parenteral vaccines

    Adv Drug Deliv Rev

    (1995)
  • C.P. Choudari et al.

    Gut lavage fluid protein concentrations: objective measures of disease activity in inflammatory bowel disease

    Gastroenterology

    (1993)
  • L.M. Handy et al.

    Investigation of neutrophils in the gut lumen by assay of granulocyte elastase in wholegut lavage fluid

    Scand J Gastroenterol

    (1996)
  • C.M. Wilson et al.

    Determination of fecal alpha 1-antitrypsin concentration by radial immunodiffusion: two systems compared

    Clin Chem

    (1988)
  • U. Karbach et al.

    Alpha 1-antitrypsin, a reliable endogenous marker for intestinal protein loss and its application in patients with Crohn's disease

    Gut

    (1983)
  • K.B. Jenson et al.

    Serumorosomucoid in ulcerative colitis. Its relation to clinical activity, protein loss, and turnover of albumin and IgG

    Scand J Gastroenterol

    (1976)
  • K. Becker et al.

    Individual fecal alpha 1-antitrypsin excretion reflects clinical activity in Crohn's disease but not in ulcerative colitis

    Hepatogastroenterology

    (1999)
  • M.A. Parsi et al.

    Fecal lactoferrin for diagnosis of symptomatic patients with ileal pouch-anal anastomosis

    Gastroenterology

    (2004)
  • A. Van der Sluys Veer et al.

    Faecal parameters in the assessment of activity in inflammatory bowel disease

    Scand J Gastroenterol Suppl

    (1999)
  • K. Becker et al.

    Fecal excretion of alpha 2 macroglobulin: a novel marker for disease activity in patients with inflammatory bowel disease

    Z Gastroenterol

    (1999)
  • H.J. Klass et al.

    Serum and faecal lysozyme in inflammatory bowel disease

    Gut

    (1978)
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