Rectal Mucosal Nitric Oxide in Differentiation of Inflammatory Bowel Disease and Irritable Bowel Syndrome
2005; Elsevier BV; Volume: 3; Issue: 8 Linguagem: Inglês
10.1016/s1542-3565(05)00182-5
ISSN1542-7714
AutoresClaudia I. Reinders, Max Herulf, Tryggve Ljung, Jakob Hollenberg, Eddie Weitzberg, Jon O. Lundberg, Per M. Hellström,
Tópico(s)Gastroesophageal reflux and treatments
ResumoBackground & Aims: Differentiating patients with functional bowel disorders from those with inflammatory bowel disease (IBD) can be difficult. Rectal luminal levels of nitric oxide (NO) are greatly increased in IBD. To further evaluate this disease marker, we compared NO in patients with irritable bowel syndrome (IBS) with those found in patients with active IBD and in healthy control subjects. Methods: Rectal NO was measured with chemiluminescence technique by using a tonometric balloon method in 28 healthy volunteers, 39 patients with IBS, 86 with IBD (Crohn's disease and ulcerative colitis), and 12 patients with collagenous colitis. In addition, NO was measured before and after a 4-week treatment period in patients with active ulcerative colitis and repeatedly during 2 weeks in healthy volunteers. Results: NO was low in healthy control subjects (median, 45; 25th–75th percentile, 34–64 parts per billion [ppb]), and variations over time were small. In IBS patients NO was slightly increased (150, 53–200 ppb; P < .001), whereas patients with active IBD or collagenous colitis had greatly increased NO levels (3475, 575–8850 ppb, and 9950, 4475–19,750 ppb, respectively; P < .001). With a cutoff level of 250 ppb, NO had a sensitivity of 95% and a specificity of 91% in discriminating between active bowel inflammation and IBS. Rectal NO correlated with disease activity in IBD and collagenous colitis and decreased markedly in IBD patients responding to anti-inflammatory treatment. Conclusions: Rectal NO is a minimally invasive and rapid tool for discriminating between active bowel inflammation and IBS and a possibly useful add-on for monitoring patients with IBD. Background & Aims: Differentiating patients with functional bowel disorders from those with inflammatory bowel disease (IBD) can be difficult. Rectal luminal levels of nitric oxide (NO) are greatly increased in IBD. To further evaluate this disease marker, we compared NO in patients with irritable bowel syndrome (IBS) with those found in patients with active IBD and in healthy control subjects. Methods: Rectal NO was measured with chemiluminescence technique by using a tonometric balloon method in 28 healthy volunteers, 39 patients with IBS, 86 with IBD (Crohn's disease and ulcerative colitis), and 12 patients with collagenous colitis. In addition, NO was measured before and after a 4-week treatment period in patients with active ulcerative colitis and repeatedly during 2 weeks in healthy volunteers. Results: NO was low in healthy control subjects (median, 45; 25th–75th percentile, 34–64 parts per billion [ppb]), and variations over time were small. In IBS patients NO was slightly increased (150, 53–200 ppb; P < .001), whereas patients with active IBD or collagenous colitis had greatly increased NO levels (3475, 575–8850 ppb, and 9950, 4475–19,750 ppb, respectively; P < .001). With a cutoff level of 250 ppb, NO had a sensitivity of 95% and a specificity of 91% in discriminating between active bowel inflammation and IBS. Rectal NO correlated with disease activity in IBD and collagenous colitis and decreased markedly in IBD patients responding to anti-inflammatory treatment. Conclusions: Rectal NO is a minimally invasive and rapid tool for discriminating between active bowel inflammation and IBS and a possibly useful add-on for monitoring patients with IBD. Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic conditions that can present with similar symptoms, but they have different underlying pathophysiology. IBD is an idiopathic inflammatory condition affecting varying locations of the gastrointestinal (GI) tract. IBS is a chronic disorder of variable symptoms characterized by abdominal pain and changes in bowel habits in the absence of apparent organic disease.1Coffin B. Bouhassira D. Sabate J.M. et al.Alteration of the spinal modulation of nociceptive processing in patients with irritable bowel syndrome.Gut. 2004; 53: 1465-1470Crossref PubMed Scopus (102) Google Scholar It is one of the most frequent causes of chronic diarrhea in adult patients and the most common outpatient diagnosis among gastroenterologists, even though they only see a small fraction of the patients.2Locke G.R. Natural history of irritable bowel syndrome and durability of the diagnosis.Rev Gastroenterol Disord. 2003; 3: S12-S17PubMed Google Scholar The Rome II criteria3Thompson W.G. Longstreth G.F. Drossman D.A. et al.Functional bowel disorders and functional abdominal pain.Gut. 1999; 45: II43-II47Crossref PubMed Scopus (2013) Google Scholar are used in the diagnosis of IBS, but clinical differentiation between IBS and IBD remains problematic because many symptoms overlap. Therefore, many patients are extensively investigated with expensive invasive radiographic and endoscopic imaging to make a diagnosis of exclusion and to rule out malignant disease.4Tibble J.A. Sigthorsson G. Foster R. et al.Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease.Gastroenterology. 2002; 123: 450-460Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar In the clinical setting it would be of value to achieve a feasible method to distinguish a disorder of inflammatory nature (eg, Crohn's disease or ulcerative colitis) from one presumed to be of noninflammatory origin, such as IBS.The gas nitric oxide is a pluripotent biologic messenger involved in numerous physiologic and pathologic events in the GI tract.5Dijkstra G. van Goor H. Jansen P.L. et al.Targeting nitric oxide in the gastrointestinal tract.Curr Opin Investig Drugs. 2004; 5: 529-536PubMed Google Scholar During inflammation the mucosal production of NO is increased. An inducible NO synthase is up-regulated in response to proinflammatory cytokines released in the inflamed area, and this enzyme can generate large quantities of NO during an extended period of time. NO is very short-lived in most biologic systems,6Beckman J.S. Koppenol W.H. Nitric oxide, superoxide, and peroxynitrite the good, the bad, and ugly.Am J Physiol. 1996; 271: C1424-C1437PubMed Google Scholar, 7Marletta M.A. Spiering M.M. Trace elements and nitric oxide function.J Nutr. 2003; 133: 1431S-1433SPubMed Google Scholar and because of this, direct analysis is often difficult. However, in the gaseous phase NO is stable, which has allowed for direct measurements in hollow organs such as the airways8Gustafsson L.E. Leone A.M. Persson M.G. et al.Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans.Biochem Biophys Res Commun. 1991; 181: 852-857Crossref PubMed Scopus (812) Google Scholar, 9Alving K. Weitzberg E. Lundberg J.M. Increased amount of nitric oxide in exhaled air of asthmatics.Eur Respir J. 1993; 6: 1368-1370PubMed Google Scholar and the GI tract.10Lundberg J.O. Hellström P.M. Lundberg J.M. et al.Greatly increased luminal nitric oxide in ulcerative colitis.Lancet. 1994; 344: 1673-1674Abstract PubMed Scopus (231) Google Scholar Patients with inflammatory intestinal disorders including IBD,10Lundberg J.O. Hellström P.M. Lundberg J.M. et al.Greatly increased luminal nitric oxide in ulcerative colitis.Lancet. 1994; 344: 1673-1674Abstract PubMed Scopus (231) Google Scholar, 11Herulf M. Ljung T. Hellström P.M. et al.Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method.Scand J Gastroenterol. 1998; 33: 164-169PubMed Google Scholar gastroenteritis,12Herulf M. Svenungsson B. Lagergren A. et al.Increased nitric oxide in infective gastroenteritis.J Infect Dis. 1999; 180: 542-545Crossref PubMed Scopus (43) Google Scholar and celiac disease13Everts B. Stotzer P. Olsson M. et al.Increased luminal nitric oxide concentrations in the small intestine of patients with coeliac disease.Eur J Clin Invest. 1999; 29: 692-696Crossref PubMed Scopus (16) Google Scholar, 14Herulf M. Blomquist L. Ljung T. et al.Increased rectal nitric oxide in coeliac disease after local challenge with gluten.Scand J Gastroenterol. 2001; 36: 169-173Crossref PubMed Scopus (17) Google Scholar have greatly increased NO levels locally in the gut. Luminal NO can be measured in the rectum with a minimally invasive tonometric balloon technique.11Herulf M. Ljung T. Hellström P.M. et al.Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method.Scand J Gastroenterol. 1998; 33: 164-169PubMed Google Scholar It has been suggested that NO could serve as a sensitive marker of inflammation in the GI tract, which might be useful in screening of patients with suspected IBD and in monitoring patients with an established diagnosis of IBD.15Perner A. Rask-Madsen J. Review article the potential role of nitric oxide in chronic inflammatory bowel disorders.Aliment Pharmacol Ther. 1999; 13: 135-144Crossref PubMed Scopus (76) Google Scholar, 16Lundberg J.O. Lundberg J.M. Alving K. et al.Nitric oxide and inflammation the answer is blowing in the wind.Nat Med. 1997; 3: 30-31Crossref PubMed Scopus (55) Google Scholar In further evaluating such a novel test, it will be essential to establish normal levels of NO in the gut and to study rectal NO levels in other intestinal disorders in which patients might present with symptoms resembling those seen in IBD.The aim of this study was to determine rectal NO levels in patients with IBS and to compare them with those found in patients with active IBD and healthy control subjects. In addition, the variation in rectal NO over time was studied in healthy subjects and in symptomatic ulcerative colitis patients during conventional treatment.Patients and MethodsThis study was done in two parts, the first with a cross-sectional and the second with a longitudinal design in which NO measurements were performed repeatedly in control subjects and before and after medical treatment in patients with active disease. The studies were performed at the Karolinska University Hospital, Stockholm, Sweden between 1999 and 2004. Permission for the study was obtained from the Regional Ethics Committee, and all subjects gave informed consent before entering the study. The patients included were either hospitalized (IBD only) or were visiting an outpatient ward (IBS, IBD, and collagenous colitis patients). The same gastroenterologist (P.M.H.) examined all patients.Cross-sectional StudyTable 1 shows the demographic details of control subjects and patients. The control group consisted of 28 healthy volunteers with no history of GI disease or symptoms.Table 1Demographic Characteristics of Patients and Control Subjects in the Cross-sectional StudyCharacteristicControl subjectsIBSUlcerative colitisCrohn's diseaseCollagenous colitisN2839473912Sex (M/F)16/1211/2824/2321/182/10Age range (y)20–4718–8123–8220–8437–87Disease activity Remission14133 Mild681 Moderate1272 Severe15116Disease location Small bowel4 Ileum3 Ileocecal8 Colon472412 Extensive14 Left-side33Treatment Corticosteroids18201 Sulfasalazine32 5-Aminosalicylic acid2010 Azathioprine22 Open table in a new tab The IBS group comprised 39 patients diagnosed according to the Rome II criteria,3Thompson W.G. Longstreth G.F. Drossman D.A. et al.Functional bowel disorders and functional abdominal pain.Gut. 1999; 45: II43-II47Crossref PubMed Scopus (2013) Google Scholar and all had a typical history and symptoms. The patients were all of the alternating type, and no predominant diarrhea such as chronic diarrhea exceeding 14 days was studied. Patients with chronic constipation were not studied. Each patient had been investigated with a negative outcome of endomysium or transglutaminase antibodies for celiac disease and normal colonoscopy.The IBD group consisted of 47 patients with ulcerative colitis, 39 with Crohn's disease, and 12 patients with collagenous colitis. All had an established diagnosis based on previous endoscopic and microscopic examinations. Duration of disease varied between 1 and 30 years. Patients with ulcerative colitis were classified according to the Truelove-Witts' scoring (0–3) of disease activity17Truelove S.C. Witts L.J. Cortisone in ulcerative colitis final report on a therapeutic trial.Br Med J. 1955; : 1041-1048Crossref PubMed Scopus (2143) Google Scholar: remission (0), mild (1), moderate (2), and severe (3), whereas the Harvey Bradshaw index (HBI) was used for Crohn's disease.18Harvey R.F. Bradshaw J.M. A simple index of Crohn's-disease activity.Lancet. 1980; 1: 514Abstract PubMed Scopus (2086) Google Scholar For some calculations and presentations, disease activity in Crohn's disease was converted to the 4-graded scale used in ulcerative colitis patients: remission (HBI score ≤4), mild (HBI score 5–6), moderate (HBI score 7–9), and severe (HBI score ≥10). Patients in clinical remission had been free of symptoms for at least 6 months. Disease activity in collagenous colitits was also graded on a scale 0–3 on the basis of the number of bowel movements with diarrhea the patients had each day: remission (no diarrhea; score 0), mild (<4/day; score 1), moderate (4–5/day; score 2), and severe (≥6/day; score 3).Longitudinal StudyNO was measured repeatedly in 7 of the healthy volunteers from the cross-sectional study. In these subjects measurements were made once every hour for 6 hours, then once daily for 3 days, and finally once every week for 2 weeks.We also measured rectal NO in 19 patients (9 women and 10 men; age, 18–78 years; other than the patients above) with ulcerative colitis who visited the hospital because of acute onset of active disease. They presented with typical symptoms of flare of ulcerative colitis, ie, frequent bowel movements, urgent defecation, blood in stools, abdominal pain, and affected general well-being, and these symptoms had commenced within less than 24 hours before admission. The majority of the patients were hospitalized because of severe disease (mean hospital stay, 6 days; range, 0–30 days), and all received standard pharmacologic treatment including systemic corticosteroids. NO measurements and disease activity scoring were done on the day of admission and then again 28 days later at a follow-up visit at the hospital. For calculations and presentation of data the patients were divided into 2 groups, those who responded to pharmacologic intervention with complete remission (score 0) during this period and those who were refractory to such treatment (incomplete remission, score ≥1).Nitric Oxide Measurements in PatientsA rapid-response chemiluminescence system (Aerocrine AB, Stockholm, Sweden) was used for NO measurements. The detection limit for NO was 1 part per billion (ppb), and the analyzer was calibrated at known concentrations (100–10,000 ppb) of cylinder gas NO. The chemiluminescence assay is highly specific for NO, and there is no interference from other nitrogen oxides.19Archer S. Measurement of nitric oxide in biological models.Faseb J. 1993; 7: 349-360Crossref PubMed Scopus (851) Google Scholar All silicone balloon-tipped catheters (Argyle; Sherwood Medical, Tullamore, Ireland) were used for tonometric gas sampling.11Herulf M. Ljung T. Hellström P.M. et al.Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method.Scand J Gastroenterol. 1998; 33: 164-169PubMed Google Scholar The catheters were inserted in the rectum by using lubrication gel to a level of 10–15 cm above the anal sphincter. The catheter balloon was inflated with 10 mL of ambient air containing less than 5 ppb NO and left for 10 minutes. During this incubation time the air in the balloon equilibrated with NO gas in the rectum. The gas sample was then withdrawn from the balloon and immediately injected into the chemiluminescence analyzer to measure the NO concentration.In Vitro Testing of the Tonometric CathetersTo determine the rate of recovery for the catheters, we performed experiments in which 6 balloon-tipped catheters were incubated in known concentrations of NO for different periods of time (1, 5, 10, 15, and 20 minutes). Cylinder NO gas (NO in nitrogen; AGA AB, Lidingö, Sweden) at different concentrations was flushed through a canister in which the catheters were inserted and inflated as described elsewhere.11Herulf M. Ljung T. Hellström P.M. et al.Increased luminal nitric oxide in inflammatory bowel disease as shown with a novel minimally invasive method.Scand J Gastroenterol. 1998; 33: 164-169PubMed Google Scholar NO concentrations in the canister were continuously monitored with chemiluminescence technique and kept stable at 100, 1000, or 10,000 ppb. Samples from the catheters were compared with the known concentrations inside the canister, and the recovery (%) was calculated by dividing the concentration in the catheter balloon with the concentration inside the canister.Statistical AnalysisFor statistical analysis and graph plotting, GraphPad Prism version 4 (GraphPad Software, San Diego, CA) was used. According to the Kolmogorov-Smirnov test, all investigated variables were not normally distributed. The cross-sectional and longitudinal variables are expressed as median and 25th–75th percentiles. The in vitro data of the tonometric balloon testing were expressed as mean ± standard error of the mean and the variation of the data as the coefficient of variation. Groups of data were compared by using the Kruskal-Wallis and Mann-Whitney U tests. Correlation was analyzed with the Spearman rank test. A P value of less than .05 was considered significant. Receiveroperating characteristics were assessed by curve analysis as described by Henderson,20Henderson A.R. Assessing test accuracy and its clinical consequences a primer for receiver operating characteristic curve analysis.Ann Clin Biochem. 1993; 30: 521-539Crossref PubMed Scopus (230) Google Scholar and the sensitivity, specificity, positive predictive value, and negative predicted value for distinguishing IBS from IBD were assessed.ResultsCatheter RecoveryThe silicone catheters were found to have an overall recovery rate for NO of 72% ± .6% at 10 minutes, and this increased to 78% ± .6% at 20-minute incubation time. For clinical feasibility the 10-minute incubation time was used for in vivo experiments. Variation of recovery between different concentrations at 10-minute incubation time (n = 18) showed a coefficient of variation of 3.5%.Cross-sectional StudyThe measurement procedure was easily handled and well tolerated by all subjects, and none complained about pain or discomfort. The groups of patients with active ulcerative colitis, Crohn's disease, and collagenous colitis all had greatly increased NO levels compared with control subjects and patients with IBS. Individual NO levels for the healthy control subjects and all patient groups are shown in Figure 1. Healthy control subjects had NO levels of 45 ppb (34–64 ppb), IBS patients 150 ppb (53–200 ppb), patients with active Crohn's disease 1825 ppb (450–6850 ppb), patients with active ulcerative colitis 3550 ppb (575–8275 ppb), and patients with active collagenous colitis had 9950 ppb (4,475–19,750 ppb). IBD patients in clinical remission had a median of 200 ppb (100–400 ppb), and these levels were increased compared with control subjects (P < .001). NO levels did not differ between Crohn's disease and ulcerative colitis but were higher in patients with collagenous colitis (P < .05). Three patients with collagenous colitis were in clinical remission, and NO levels in these patients were less than 50 ppb. IBS patients had significantly higher NO than healthy control subjects (P < .001) but lower than all other patient groups (P < .0001). A correlation was found between rectal NO levels and disease activity in IBD patients (for ulcerative colitis, r = .77 and for Crohn's disease, r = .57; P < .01; Figure 2) and in patients with collagenous colitis (r = .78; P < .0001).Figure 2Rectal NO levels in IBD (Crohn's disease and ulcerative colitis) patients with different disease activity.View Large Image Figure ViewerDownload (PPT)In Crohn's disease, median NO levels were lower in patients with proximal (small bowel/ileocecal) disease location (500 ppb [200–2515 ppb]) compared with those with colon engagement (1975 ppb [450–8850]); however, this difference did not reach significance (P = .07).The ability of rectal NO to distinguish between active IBD and IBS is shown in Figure 3. At a cutoff level of 250 ppb, rectal NO had the highest sensitivity (95%) and specificity (91%) in discriminating between active bowel inflammation (patients with active ulcerative colitis, Crohn's disease, and collagenous colitis, n = 68) and IBS. The positive and negative predicted values were 97% and 86%, respectively. The large overlap in rectal NO between healthy subjects and individuals with IBS made a clear distinction between these 2 entities impossible.Figure 3Receiveroperating characteristics analysis of the ability of rectal NO levels to discriminate between patients with active bowel inflammation (Crohn's disease, ulcerative colitis, and collagenous colitis) and IBS. A cutoff value of 250 ppb for rectal NO levels gives a sensitivity and specificity of 95% and 91%, respectively.View Large Image Figure ViewerDownload (PPT)Longitudinal StudyIn 7 of the healthy subjects NO was measured at 11 occasions, and the average intraindividual variation from the median was 27% (range, 19–34 ppb). Results of repeated measurements of rectal NO over time are presented in Figure 4.Figure 4Individual rectal NO levels in healthy subjects measured repeatedly during a 2-week period.View Large Image Figure ViewerDownload (PPT)Ulcerative colitis patients experiencing an acute flare of disease were studied before and after a period of aggressive medical treatment including systemic glucocorticoids. The levels of rectal NO on the day of hospital admission and 1 month later are shown in Figure 5. In the entire group (n = 19) rectal NO was 13,700 ppb (4,600–22,600) on the day of admission and decreased to 1100 ppb (350–10,000) after 28 days of treatment (P < .01). On admission the mean disease activity score for all 19 patients was 2.3. On day 28, twelve patients were in complete remission (score 0), whereas the remaining 7 patients were in incomplete remission (mean score 1.6). Postanalysis showed that disease activity did not differ significantly between the 2 groups at day 1 (data not shown). In the group with complete remission, NO levels had decreased by almost 95% during the study period (P = .002) but had not changed significantly in patients with incomplete remission (Figure 5).Figure 5Rectal NO levels in patients with active ulcerative colitis measured before and after 4 weeks of medical treatment. NO levels decreased significantly (**P < 0.01) only in patients responding to therapy with complete remission.View Large Image Figure ViewerDownload (PPT)DiscussionThe major finding of this study is that patients with active IBD have greatly elevated rectal NO levels compared with patients with IBS, and this NO can be easily measured with a silicone balloon-tipped catheter. Rectal NO levels seem to correlate with disease activity, and the high luminal levels of NO in active ulcerative colitis decreased markedly after successful medical treatment. In addition, rectal NO was uniformly low in healthy volunteers, and hourly, daily, and weekly variations were small.The distinction between IBS and IBD is often a challenging task, because the 2 disease entities often present with similar symptoms including abdominal pain, bloating, excessive flatus, and altered bowel habits. Although some clinical signs such as the presence of rectal bleeding will support the presence of an inflammatory disease, the differential diagnosis is often not straightforward. In fact, the diagnosis is further hindered by the seemingly growing overlap of pathophysiologic processes between ulcerative colitis and IBS.21Bradesi S. McRoberts J. Anton P. et al.Inflammatory bowel disease and irritable bowel syndrome separate or unified?.Curr Opin Gastroenterol. 2003; 19: 336-342Crossref PubMed Scopus (37) Google Scholar Because of this many patients have to undergo advanced and sometimes invasive diagnostic procedures including radiographic and endoscopic imaging, which have significant implications for health care costs.The present study shows that elevated rectal NO levels are a sensitive and specific biomarker for inflammation in the gut. Individual overlap between active bowel inflammation (IBD and collagenous colitis) and IBS patients was minimal, and when using a cutoff level of 250 ppb, NO had a specificity of 91% and a sensitivity of 95% in discriminating between active bowel inflammation and IBS.Rectal NO is increased in other inflammatory conditions of the bowel including IBD, infective gastroenteritis,12Herulf M. Svenungsson B. Lagergren A. et al.Increased nitric oxide in infective gastroenteritis.J Infect Dis. 1999; 180: 542-545Crossref PubMed Scopus (43) Google Scholar collagenous colitis as shown here and earlier,22Reinders C.I. Hellström P.M. Björk J. et al.Effect of intravenous L-NMMA on nitric oxide production in collagenous colitis.Scand J Gastroenterol. 2004; 39: 32-36Crossref PubMed Scopus (11) Google Scholar and in celiac disease after local gluten challenge in the rectum.14Herulf M. Blomquist L. Ljung T. et al.Increased rectal nitric oxide in coeliac disease after local challenge with gluten.Scand J Gastroenterol. 2001; 36: 169-173Crossref PubMed Scopus (17) Google Scholar Thus, in this sense NO is an unspecific marker of inflammation. Instead, the specificity of NO lies at the tissue level, and the strength of this analyte is that we are measuring a biomarker locally in the affected organ where it is being produced, making it specific for intestinal inflammation. This probably explains why NO and other local markers such as calprotectin in feces4Tibble J.A. Sigthorsson G. Foster R. et al.Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease.Gastroenterology. 2002; 123: 450-460Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 23Tibble J. Teahon K. Thjodleifsson B. et al.A simple method for assessing intestinal inflammation in Crohn's disease.Gut. 2000; 47: 506-513Crossref PubMed Scopus (407) Google Scholar, 24Lundberg J.O. Hellström P.M. Fagerhol M. et al.Calprotectin, lactoferrin and nitric oxide as markers of inflammatory bowel disease.Nat Clin Pract Gastroenterol Hepatol. 2005; 2: 96-102Crossref PubMed Scopus (59) Google Scholar seem to be far superior in terms of sensitivity and specificity compared with unspecific serologic markers of inflammatory activity, eg, C-reactive protein or erythrocyte sedimentation rate. Other attractive features of a rectal NO test are that the procedure is minimally invasive and that analysis and results are at hand instantly. Naturally because of the unspecific increase in rectal NO during inflammation, this test will be of limited value in discriminating between different forms of intestinal inflammation, for example, ulcerative colitis and Crohn's disease. However, once the histopathologic diagnosis of IBD is established, it is possible that NO measurements could aid in monitoring inflammatory disease activity and response to treatment. This is supported by the findings in this study, because rectal NO correlated to disease activity and also decreased markedly in patients responding to anti-inflammatory treatment. Although endoscopy with biopsy remains the gold standard to evaluate disease extent and activity, even this examination has its limitations apart from the high cost and invasiveness of the procedure.25Modigliani R. Mary J.Y. Simon J.F. et al.Clinical, biological, and endoscopic picture of attacks of Crohn's disease Evolution on prednisolone—Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives.Gastroenterology. 1990; 98: 811-818Abstract Full Text PDF PubMed Scopus (707) Google Scholar Patients with IBD and unclear biopsy findings might still have inflammatory activity in other parts of the gut.26Hommes D.W. van Deventer S.J. Endoscopy in inflammatory bowel diseases.Gastroenterology. 2004; 126: 1561-1573Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Such persistent inflammation could likely be revealed by an increase in NO. Indeed, this is supported by the finding that rectal NO was increased in Crohn's disease, even in patients with a proximal disease location. All together, rectal NO measurements might be a useful clinical add-on in the follow-up of patients diagnosed with IBD.The role of NO in GI inflammation has still not been settled because both proinflammatory and anti-inflammatory activity has been described.16Lundberg J.O. Lundberg J.M. Alving K. et al.Nitric oxide and inflammation the answer is blowing in the wind.Nat Med. 1997; 3: 30-31Crossref PubMed Scopus (55) Google Scholar, 27Kubes P. McCafferty D.M. Nitric oxide and intestinal inflammation.Am J Med. 2000; 109: 150-158Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar The fact that patients with collagenous colitis have extremely elevated intestinal NO levels (even higher than in active IBD) supports the notion that NO is not tissue damaging by itself because the inflammation and mucosal lesions in this condition are very discrete. However, NO could still be involved in the pathogenesis of collagenous colitis, for example, in promoting the watery diarrhea typical for this disorder.28Olesen M. Mi
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