Katarzyna Neubauer
1, Robert Dudkowiak
2Fecal Markers in Inflammatory Bowel Disease
Markery zapalenia w kale w nieswoistych zapaleniach jelit
1 Department of Gastroenterology and Hepatology, Wroclaw Medical University, Poland
2 Division of Dietetics, Department of Gastroenterology and Hepatology, Wroclaw Medical University, Poland
Abstract
A noninvasive, sensitive, and specific diagnostic tool to support differential diagnosis in patients with suspicion of inflammatory bowel disease (IBD), confirm an IBD, differentiate ulcerative colitis and Crohn’s disease, establish a prognosis of disease course, and evaluate response to therapy is still missing. Fecal markers constitute a promis-ing alternative to currently available tests. The usefulness of fecal calprotectin and lactoferrin in clinical practice has been confirmed. These tests can serve to predict relapse in IBD and rule out IBD in undiagnosed symptomatic patients. Fecal calprotectin can support the differential diagnosis between IBS and IBD and distinguish disease flare from other causes of symptoms. This paper reviews the role of fecal markers associated with inflammation in inflammatory bowel disease (Adv Clin Exp Med 2010, 19, 2, 251–255).
Key words: inflammatory bowel disease, fecal markers, calprotectin, lactoferrin, S100A12.
Streszczenie
Wciąż poszukuje się nieinwazyjnego, czułego i swoistego narzędzia diagnostycznego, które mogłoby być stosowane w diagnostyce różnicowej u pacjentów z podejrzeniem nieswoistych zapaleń jelit (n.z.j.), w potwierdzaniu tego rozpoznania, różnicowaniu wrzodziejącego zapalenia jelita grubego i choroby Leśniowskiego-Crohna oraz pro-gnozowaniu przebiegu choroby i ocenie odpowiedzi na leczenie. Obiecującą alternatywą dla obecnie dostępnych badań wydają się badania w kale substancji związanych z procesem zapalnym. Dotychczas potwierdzono przydat-ność w praktyce klinicznej badania kalprotektyny i laktoferyny w kale. Badanie to może służyć do przewidywania nawrotów choroby, wykluczania n.z.j. lub różnicowania między zaostrzeniem a objawami wywołanymi przez inne przyczyny. Artykuł omawia znaczenie badania stężenia różnych markerów zapalenia w kale w nieswoistych zapa-leniach jelit (Adv Clin Exp Med 2010, 19, 2, 251–255).
Słowa kluczowe: nieswoiste zapalenia jelit, markery w kale, kalprotektyna, laktoferyna, S100A12.
Adv Clin Exp Med 2010, 19, 2, 251–255 ISSN 1230-025X
REvIEWS
© Copyright by Wroclaw Medical University
Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases of unknown origin encompassing Crohn’s disease (CD), ulcer-ative colitis (UC), and indeterminate colitis. The etiopathogenesis of IBD has not been entirely elu-cidated and includes the involvement of genetic, environmental, and immunological factors. The diagnosis of IBD is established with laboratory, endoscopic, radiological, and pathological tests. Currently available biochemical tests have several limitations. It was demonstrated that C-reactive protein (CRP) has advantages over other labora-tory markers such as erythrocyte sedimentation rate (ESR), white blood count, platelet count, and albumin, although correlation with disease
activ-ity is better for Crohn’s disease than for ulcerative colitis [1]. Clinical indices of diseases activity, for example the CDAI (Crohn`s Disease Activity Index), are also not ideal.
evalu-ation of mucosal healing requires invasive endo-scopic tests, a noninvasive marker correlating with mucosal healing is also being sought [3]. A prom-ising alternative to the presently existing tools con-stitute fecal markers.
Fecal Markers
Of all the fecal markers, calprotectin and lac-toferrin are the most often studied. The useful-ness of other stool markers, such as polymorpho-nuclear neutrophil elastase (PMN-e), S100A12, myeloperoxidase, and eosinophilic protein X, has also been assessed in IBD [4] (Table 1). Within the S100 family are three phagocyte-specific calcium-binding proteins which are overexpressed at sites of inflammation: S100A8, S100A9, and S100A12. The usefulness of calcium-binding proteins of the S100 family as inflammation indices was demon-strated in many studies, as reviewed by Foell et al. [5]. S100A8, S100A9, and S100A12 belong to the so-called DAMPs (damage-associated molecu-lar pattern proteins). As reviewed by Foell et al., DAMPs possess excellent diagnostic potential due to the fact that they participate in the initiation of cell stress and inflammation and are released at sites of IBD [6].
The complex S100A8/S100A9 was termed calprotectin. Calprotectin is produced by human neutrophil granulocytes and has a major role in
neutrophil defense. Elevated fecal calprotectin was demonstrated in infectious and inflammatory dis-eases. Fecal calprotectin concentrations were found to be higher during the first year of life compared with adults [7]. Elevated blood levels of S100A12 were found in rheumatoid arthritis, cystic fibro-sis, and IBD. The proinflammatory properties of S100A12 are mediated by binding to the receptor for advanced glycation end products (RAGEs). Agents blocking RAGEs have been shown to sup-press inflammation in an experimental model of chronic colitis [8]. Lactoferrin is a major whey protein present in external secretions (e.g. breast milk) and in polymorphonuclear neutrophils. As reviewed by Hayakawa et al., lactoferrin may play a role in the defense mechanisms of mucous mem-brane. Anti-lactoferrin autoantibodies (anti-Lf) were found in patients with autoimmune diseases (e.g. autoimmune hepatitis, autoimmune pancre-atitis) [9].
Fecal Markers
in Inflammatory
Bowel Disease
Numerous studies have shown elevated fecal calprotectin and lactoferrin in patients with inflam-matory bowel disease. As reviewed by Gisbert et al., only calprotectin and lactoferrin from among the
Table 1. Fecal markers of inflammation [adapted from Foell D, Wittkowski H, Roth J: Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage. Gut 2009, 58, 859–868]
Tabela 1. Markery zapalenia w kale [wg Foell D, Wittkowski H, Roth J: Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage. Gut 2009, 58, 859–868]
Fecal marker
(Marker w kale) Main source (Główne źródło) Correlation with IBD activity (Korelacja z aktywnością n.z.j.) 1. Calprotectin
(Kalprotektyna) neutrophils (cytoplasm), monocytes, epithelium ++ 2. Lactoferrin
(Laktoferyna) brush-border cells, neutrophils, monocytes, macro-phages, lymphocytes +
3. S100A12 neutrophils (cytoplasm) ++
4. PMN-elastase neutrophils (azurophilic granules) ++
5. Tumor necrosis factor α
(Czynnik martwiczy guza) monocytes, macrophages, T cells (+) 6. Myeloperoxidase
(Mieloperoksydaza) neutrophils (azurophilic granules), monocytes, macro-phages, T cells – 7. Eosinophilic protein X
(Proteina X eozynofilii) eosinophils (specific granules) (+)
fecal markers are currently useful in clinical prac-tice. The effectiveness of fecal lactoferrin in evalu-ating response to therapy, predicting recurrence in patients with Crohn’s disease after ileocolonic resection, and distinguishing between organic and functional diseases was confirmed [10]. Moreover, studies revealed that lactoferrin and calprotectin correlate with endoscopic, clinical, and biochemi-cal markers of activity in inflammatory bowel dis-ease [11].
A study by vieira et al. showed that fecal cal-protectin and lactoferrin are sensitive and specific markers of intestinal inflammation. The authors also found that fecal lactoferrin level was related to the degree of inflammation in the intestinal mucosa. Calprotectin and lactoferrin correlated with CRP, CDAI, the Crohn’s Disease Endoscopic Index of Severity (CDEIS), and the Mayo Disease Activity Index (MDAI) [12]. Schoepfer et al. dem-onstrated that fecal calprotectin correlated with the Rachmilewitz Endoscopic Activity Index, DAI, CRP, and WBC. Moreover, the authors showed that fecal calprotectin can serve as a useful tool in monitoring disease course [13]. Results concern-ing the role of fecal calprotectin in Crohn’s disease were similar. Schoepfer et al. demonstrated that fecal calprotectin correlated with endoscopic and clinical indices of disease activity, CRP, and white blood count. Moreover, the authors showed that fecal calprotectin may discriminate inactive from mild, moderate, and highly active disease [14]. Lamb et al. demonstrated that calprotectin and lactoferrin had advantages over CRP, platelet count, and endoscopy in identifying postoperative recurrence in Crohn’s disease [15]. Correlation of fecal calprotectin with the Rachmilewitz Index but not with the CDAI was demonstrated by Kosiara and Paradowski. The authors concluded that this fecal marker can serve as a simple and objective test for evaluating IBD activity [16]. Wagner et al. showed that fecal calprotectin may be a use-ful marker of successuse-ful treatment outcome [17]. Sipponen et al. studied the behavior of fecal cal-protectin and lactoferrin during Crohn’s disease therapy. They confirmed that these stool markers are a reliable sign of mucosal improvement [18].
The utility of PMN-e, calprotectin, and lac-toferrin to monitor disease activity in ulcerative colitis was corroborated by a study by Langhorst et al. [19]. The authors also showed the usefulness of these neutrophil-derived proteins for diagnos-tic and differential diagnosdiagnos-tic purposes (differen-tiating active from non-active IBD and IBD from IBS). Moreover, all the studied stool markers had advantages over CRP in their diagnostic accuracy. The authors concluded that the diagnostic accu-racy in ulcerative colitis can be increased when
a combination of CRP, clinical indices, and stool markers is applied [20]. The value of fecal lactofer-rin as an effective tool in the differential diagnosis of inflammatory and noninflammatory bowel dis-orders was also demonstrated by Duai et al. [21].
Elevated levels of lactoferrin, PMN-E, MPO, and Lys in patients with active IBD compared with inactive IBD were shown. The authors concluded that lactoferrin has an advantage over other stud-ied proteins as a neutrophil-derived fecal marker of inflammation for clinical application [22]. The efficacy of fecal lactoferrin as a marker of disease activity was additionally confirmed in a popula-tion of children and young adults [23].
Based on a systematic review of literature, Konikoff et al. summarized the most important findings regarding fecal calprotectin as a biomark-er of neutrophilic intestinal inflammation. Fecal calprotectin:
– correlates well with histological inflammation; – can predict relapse in IBD;
– can detect pouchitis;
– has an excellent negative predictive value in ruling out IBD in undiagnosed symptomatic patients; fecal calprotectin can support the dif-ferential diagnosis between IBS and IBD. Both positive and negative predictive values seem to be better in children than in adults;
– in patients with an established diagnosis of IBD it can serve as a test to distinguish disease flare from other causes of symptoms;
– in IBD patients it can evaluate response to the applied treatment [24].
S100A12 is studied as another noninvasive marker in IBD. High specificity and sensitivity of fecal S100A12 in differentiating of Crohn’s dis-ease in children has also been demonstrated [25]. The findings of Sidler et al. also showed that it is a promising initial screening test for children with symptoms suggesting IBD [26]. Kaiser et al. demonstrated high specificity and sensitivity of S100A12 in differentiating IBD from IBS or healthy individuals. Additionally, in patients with IBD, S100A12 correlated with inflammatory activ-ity. Moreover, S100A12 had an advantage over fecal calprotectin [27].
Fecal Markers
in the European Crohn’s
and Colitis Organization
(ECCO) Consensus
calprotectin. S100A12 is additionally mentioned as a test which can improve diagnostic accuracy [28]. Neither of these tests was mentioned in the earlier ECCO Consensus [29].
Conclusions
At the present time, DAMPs and lactoferrin seem to be the most suitable fecal markers applied in patients with suspicion or diagnosis of inflam-matory bowel disease. DAMPs are related to the underlying molecular mechanism of intestinal inflammation. Fecal markers are valuable and helpful diagnostic tools in gastroenterological practice.
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Address for correspondence:
Katarzyna Neubauer
Department of Gastroenterology and Hepatology Wroclaw Medical University
Borowska 213 50-556 Wrocław Poland
Tel. + 48 71 733 21 20
E-mail: [email protected]
