Enzymes in feces: useful markers of chronic inflammatory bowel disease

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.     

Role of biochemical markers in sarcoidosis

Sarcoidosis is a systemic granulomatous disease that affects various organs. However, its pathogenesis has not yet been fully understood. Biochemical markers in sarcoidosis appears to be closely related to the immunological events and the activity of inflammatory effector cells at sites of granuloma. These markers, therefore, have been expected to reflect the disease activity and/or to predict prognosis. Although some markers are helpful tools as diagnostic aids and disease activity markers, no single marker allows definitive diagnosis of sarcoidosis or may accurately predict the disease prognosis. Among numerous biochemical markers reported previously, only angiotensin converting enzyme (ACE) serum level has gained a proven value in the clinical field. Further studies are required to identify more useful biochemical markers, which allow definitive diagnosis or predict the disease activity and prognosis in sarcoidosis.     

Serum lysozyme, serum proteins, and immunoglobulin determinations in nonspecific inflammatory bowel disease

The serum levels of lysozyme, serum electrophoresis, and serum immunoglobulins were determined prospectively in 101 patients with ulcerative colitis, ulcerative proctitis, Crohn's disease, or nonclassifiable nonspecific inflammatory bowel disease. Although the mean serum lysozyme concentration of patients with Crohn's disease (10.5 +/- 6.8 microgram/ml) and ulcerative colitis (9.6 +/- 4.1 microgram/ml) performed by a standardized lysoplate method was significantly greater than normal controls (6.0 +/- 1.5 microgram/ml), the results did not correlate with the diagnosis nor with the degree of disease activity. Individually separated protein fractions and serum immunoglobulins also did not correlate with the serum lysozyme levels. This study indicates that measurement of the level of serum lysozyme in individual patients is not helpful in determining the cause or degree of activity of nonspecific inflammatory bowel disease.     

Extracolonic manifestations of inflammatory bowel disease

Patients with inflammatory bowel disease may develop various extracolonic manifestations. Oral and eye complaints are common. Recognition is important because these may be clues to subclinical chronic ulcerative colitis or Crohn's disease. Treatment of the bowel inflammation may improve the extracolonic manifestations, such as peripheral arthritis or erythema nodosum.     

Ultrasonographic findings correspond to clinical, endoscopic, and histologic findings in inflammatory bowel disease and other enterocolitides.

OBJECTIVE: To compare results obtained by abdominal ultrasonography with clinical findings, including endoscopic and histologic findings, to evaluate the location and activity of inflammatory bowel disease, including disease controls in children. METHODS: Ninety-two ultrasonographic scans and 41 colonoscopic examinations with biopsies were performed in 78 patients (1 month to 17.8 years of age) with Crohn's disease (n = 26), ulcerative colitis (n = 21), inflammatory bowel disease of indeterminate type (n = 2), and disease controls (other intestinal disorders, including infectious and ischemic lesions; n = 29). Laboratory parameters for inflammatory bowel disease were determined, and disease activity was assessed by a combination of clinical and laboratory data. Bowel wall thickness and echo texture were recorded in a standardized way by ultrasonography and compared with endoscopic and histologic findings in a segment-by-segment comparison. RESULTS: Sensitivity and specificity of ultrasonography in detecting patients with severe macroscopic lesions depicted on endoscopy were 77% and 83%, respectively. Sensitivity and specificity of ultrasonography in detecting patients with severe histologic inflammation were 75% and 82%. There was a statistically significant correlation between maximal bowel wall thickness and disease activity score (P < .01). CONCLUSIONS: Abdominal ultrasonography may be helpful in evaluating the location, severity, and inflammatory activity of inflammatory bowel disease in children and young adults.     

Infusion services in the gastroenterology practice

Gastroenterology practices looking to diversify their services may want to consider infusion therapies as an opportunity to provide a valuable service to patients and create an additional revenue stream. Although patients with gastrointestinal diseases may benefit from such infusions as crystalloid fluids for rehydration or iron for the treatment of inflammatory bowel disease is currently the only infusion therapy likely to be of economic benefit to the practice. The focus of this article is on the infusion of biologic agents, and it is assumed that such therapies will continue to play an important role in the management of inflammatory bowel disease for many years.     

Anti-tissue transglutaminase antibodies in inflammatory bowel disease: new evidence.

Anti-tissue transglutaminase, previously held to be identical to anti-endomysial antibodies in celiac sprue, has been reported in inflammatory bowel disease patients. To investigate these data further, we evaluated serum and intestinal anti-tissue transglutaminase in inflammatory bowel disease patients, with respect to the Crohn's disease activity index and the integrated disease activity index. Study population comprised: 49 patients with Crohn's disease and 29 patients with ulcerative colitis; 45 patients with celiac sprue and 85 autoimmune patients as disease controls; and 58 volunteers as healthy controls. Immunoglobulin A (IgA) anti-recombinant human tissue transglutaminase and anti-endomysial antibody detection in sera and fecal supernatants were performed. Adsorption of positive sera with recombinant human tissue transglutaminase were also performed. Marked increased anti-tissue transglutaminase concentrations were found in celiac sprue, while low-positive values were also found in Crohn's disease and ulcerative colitis. Anti-endomysial antibodies were detectable only in celiac sprue. Antigen adsorption resulted in a significant reduction of the anti-tissue transglutaminase either in celiac sprue or inflammatory bowel disease sera. A significant correlation between anti-tissue transglutaminase and Crohn's disease activity index or integrated disease activity index scores was found. Anti-tissue transglutaminase was also detectable in fecal supernatants from inflammatory bowel disease patients. Data highlight that both circulating and intestinal anti-tissue transglutaminases are detectable in inflammatory bowel disease, and that they are related to disease activity. These features underline that, in addition to anti-tissue transglutaminase, an anti-endomysial antibody test is necessary in the diagnostic work-up of celiac sprue, especially in patients with known inflammatory bowel disease.     

Small bowel magnetic resonance imaging for inflammatory bowel disease

The presented concept of hydro-magnetic resonance imaging (MRI) using a 2.5% mannitol solution as an orally applicable intraluminal contrast agent is a meaningful, reproducible, and reliable imaging method for the depiction of the small bowel. Especially in patients with Crohn's disease, hydro-MRI is the imaging method of first choice because hydro-MRI offers the advantage of a superior depiction of the inflamed bowel wall and the extramural complications of this disease without radiation exposure. In addition, hydro-MRI allows for a reliable assessment of the inflammatory activity, especially for the differentiation between an active and an inactive (scarred) stenosis. In particular, the mural enhancement, the length as well as the wall thickness of inflamed bowel segments, are considered to be significant MR parameters for the determination of the activity of Crohn's disease. Hydro-MRI of the colon is suitable for the depiction of pathologic changes in ulcerative colitis, but in contrast to Crohn's disease, the assessment of disease activity by hydro-MRI is unreliable in ulcerative colitis, probably because of the low spatial resolution (mucositis in ulcerative colitis vs. transmural inflammation in Crohn's disease). Hydro-MRI does not allow a reliable classification of inflammatory bowel diseases, but in ambiguous cases, hydro-MRI may provide helpful information for the differentiation of Crohn's disease and ulcerative colitis. There are no data of larger patient groups published regarding MR findings in inflammatory bowel diseases besides Crohn's disease and ulcerative colitis, but hydro-MRI is a promising imaging tool for these entities, which should be assessed in additional studies.     

Imaging diagnosis of inflammatory bowel disease

The term "chronic inflammatory bowel disease" represents a spectrum of diseases out of which ulcerous colitis and Crohn's disease are the far most common. Large bowel enemas have lost their relevance compared to colonoscopy over the past years and small bowel enteroclysis has also been widely replaced by CT- and especially MR-enteroclysis meanwhile. The diagnostic value of computed tomography and MR-tomography in chronic inflammatory bowel disease is based on the excellent visualization and documentation of extent and severity of bowel wall inflammation, estimation of inflammatory activity of the disease and of detection of potential extraintestinal complications and/or additional diagnoses by these two methods. Nevertheless, conventional radiological techniques as well as sonography may still be valuable under certain conditions. Furthermore, nowadays imaging of chronic inflammatory bowel diseases includes also White Blood Cell scintigraphy as well as Positrone Emission Tomography which provide informations about extent and especially activity of the disease. The presented article provides an overview of the possibilities and limitations of the available imaging modalities in inflammatory bowel diseases and helps the reader to decide under what conditions which one of the available examinations should be regarded as the most appropriate and promising one.     

Platelet factor 4 and beta-thromboglobulin in inflammatory bowel disease and giant cell arteritis

BACKGROUND: As platelet factors are important in the inflammatory response, we examined the course of platelet factor 4 and beta-thromboglobulin in relation to disease activity in inflammatory bowel disease and in giant cell arteritis. PATIENTS AND METHODS: In a prospective study, the platelet count, platelet factor 4 and beta-thromboglobulin were measured in 20 patients with Crohn's disease, 18 with ulcerative colitis and 19 with giant cell arteritis, during active and inactive disease, as well as in 51 controls without inflammation. RESULTS: Platelet counts were significantly higher in active vs. inactive Crohn's disease, ulcerative colitis and giant cell arteritis. Levels of platelet factor 4 and beta-thromboglobulin were significantly higher in active inflammatory bowel disease and giant cell arteritis, as well as in inactive inflammatory bowel disease and giant cell arteritis, than in the non-inflammatory controls. A positive correlation was found between the Crohn's disease activity index and the platelet count, platelet factor 4 and beta-thromboglobulin. Also, a positive correlation was found between the ulcerative colitis activity index and beta-thromboglobulin. However, even after 12 months of follow-up, in Crohn's disease and ulcerative colitis the mean levels of platelet factor 4 and beta-thromboglobulin were significantly higher than the levels of the controls. CONCLUSION: Platelet factors were correlated with inflammatory bowel disease activity. Levels of platelet factor 4 and beta-thromboglobulin, however, were markedly raised for a long time in clinically inactive inflammatory bowel disease, which might point to a pre-thrombotic state of disease.     

Cytapheresis for pyoderma gangrenosum associated with inflammatory bowel disease: A review of current status

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis clinically characterized by the presence of painful skin ulcerations with erythematous. As it is frequently associated with inflammatory bowel diseases, including ulcerative colitis, gastroenterologists should be familiar with the disease including therapeutic options. Therefore, we have conducted a review focusing on the cytapheresis for PG in cases of inflammatory bowel diseases. A literature search was conducted to extract studies published in the last 20 years, with information on demographics, clinical symptoms, treatment, and the clinical course from a total of 22 cases reported and our recent case. In most patients, cytapheresis was associated with improvement or resolution of PG after failure of conventional therapeutic options such as corticosteroids, antibiotics, immunosuppressive agents and immunoglobulin. Based on the information summarized, cytapheresis is helpful in the majority of patients with PG refractory to medical treatment associated with inflammatory bowel diseases and could be further studied in a multicenter, randomized trial.     

Low S-adenosylmethionine concentrations found in patients with severe inflammatory bowel disease.

BACKGROUND: S-adenosylmethionine is a methyl donor in many cellular reactions including detoxification of constantly produced hydrogen sulphide in the colon. A reduced capacity to detoxify hydrogen sulphide may be implicated in the pathogenesis of inflammatory bowel disease. S-adenosylmethionine could be low if this assumption is correct. We compared S-adenosylmethionine concentrations in whole blood in patients with severe and moderate inflammatory bowel disease with healthy reference persons. METHODS: S-adenosylmethionine concentrations in whole blood were measured using high-pressure liquid chromatography. Patients with Crohn's disease (n=21), ulcerative colitis (n=7) and healthy age-matched reference persons (or controls) (n=17) were studied. RESULTS: S-adenosylmethionine concentrations were significantly decreased in patients with severe inflammatory bowel disease (mean 1.10 mg/l) as compared to patients with moderate Crohn's disease and ulcerative colitis (mean 1.83 mg/l) and reference persons (mean 1.84 mg/l). Statistically significant inverse correlations were found between S-adenosylmethionine concentration and activity index (p<0.01 and R2=0.86) as well as Crohn's disease activity index (p<0.01 and R2=0.50) scores. CONCLUSIONS: Low concentrations of S-adenosylmethionine were found in patients with severe inflammatory bowel disease. Future studies will show whether S-adenosylmethionine is a marker for disease activity and a possible tool for investigation of sulphur toxicity as a causative mechanism in inflammatory bowel disease.     

Inflammatory bowel disease and the X chromosome

A review of documented cases demonstrates a significant association of Turner's syndrome with Crohn's disease and ulcerative colitis; this association relates particularly to genetic constitutions comprising an abnormal rather than an absent X chromosome. The karyotype 46XiXq, in pure or mosaic form, appears to be a significant susceptibility factor for inflammatory bowel disease. This karyotype often gives rise to relatively weak phenotypic characteristics of Turner's syndrome, which may be overlooked in short females with inflammatory bowel disease. The association of inflammatory bowel disease with Turner's syndrome may reflect the presence on the X chromosome of genes involved in disease pathogenesis. Linkage analysis studies, involving microsatellite markers on the X chromosome, are being performed.      

Advances in the assessment of disease activity in inflammatory bowel disease

Knowledge of the severity and extent of the inflammation in inflammatory bowel diseases provides a means of determining rational therapeutic strategies in affected patients. During the past 3 decades, several clinical, laboratory, and combined indices have been proposed for the assessment of inflammatory bowel disease; refinements in radiologic methods and the availability of endoscopy and biopsy have facilitated the accurate assessment of the extent and severity of the disease. In relapsing conditions such as inflammatory bowel disease, however, the use of such procedures is limited by the radiation exposure or the relatively invasive nature of the technique. In this article, we review the proposed methods and recent advances in assessment of patients with inflammatory bowel disease; we also discuss possible strategies at the time of diagnosis, during recurrence, and in evaluation of the efficacy of drug or dietic therapy.     

Role of computed tomography enterography/magnetic resonance enterography: is it in prime time?

Today, cross-sectional imaging modalities, such as computed tomography enterography (CTE) and magnetic resonance enterography (MRE), are particularly suited to evaluate small bowel diseases, especially Crohn's disease (CD). It is well known that CTE/MRE can provide excellent assessment of disease activity as well as the macroscopic features, extramural abnormalities, and complications of the small intestine in patients with CD. In general, CTE is considered as the first-line modality for the evaluation of suspected inflammatory bowel disease and for long-term assessment or follow-up of these patients. Because of the advantage of lack of radiation, MRE is being used more frequently, especially in children or young patients with CD.     

New biomarkers of Crohn's disease: serum biomarkers and development of diagnostic tools

Crohn's disease (CD) is a complex and heterogeneous inflammatory disorder that is part of inflammatory bowel diseases. Its diagnosis is performed on clinical presentation and results of radiography, endoscopy and histological findings. New noninvasive diagnostic biomarkers are needed to allow rapid and accurate CD discrimination. Blood-derived biomarkers correlating with disease activity, supported by genetic evidences and valid for all CD patients subtypes are still missing. Hence, no biomarkers and no related diagnostic tests are recommended or used alone for CD diagnosis in clinical practice. This review describes diagnosis tests based on the detection/quantification of specific acute-phase reactant proteins, enzymes and derived antibody response developed by inflammatory bowel disease patients for pathogens or symbiotic flora determinant, as well as autoantibodies. Their power as diagnostic tools is discussed, as well as new high-throughput techniques, such as microarrays and proteomics, for the discovery of new CD clinical biomarkers and for the development of specific CD diagnostic tests. Some rapidly evolving nanotechnologies, mathematical analysis and bioinformatics methods are also mentioned to highlight their importance for further accurate CD diagnosis.     

Erythema nodosum.

Erythema nodosum represents an inflammatory process in the septa between the subcutaneous fat lobules. The hallmark lesions are exquisitely tender, erythematous nodules that are distributed symmetrically on the extensor surfaces of the lower extremities. Erythema nodosum is considered an immunologic response, and a wide variety of clinically important antigens have been implicated. It may serve as a cutaneous marker for systemic diseases, such as tuberculosis, sarcoidosis, inflammatory bowel disease and lymphoma. The disease is diagnosed by deep elliptical biopsy and pathologic evaluation. The natural history is resolution with treatment of the underlying disorder or spontaneous regression of idiopathic disease.     

The correlation between NF-κB inhibition and disease activity by coadministration of silibinin and ursodeoxycholic acid in experimental colitis

NF‐κB is one of the most important nuclear factors responsible for overexpression of proinflammatory cytokines. This is demonstrated by increased NF‐κB activity and other dependent immune factors in inflammatory bowel disease (IBD). Anti‐inflammatory effects of silibinin and ursodeoxycholic acid (UDCA) along with their NF‐κB inhibitory property are thought to be beneficial in colitis. Trinitrobenzene sulfonic acid was used to induce colitis rat models. After instillation, 48 rats were treated with oral silibinin, UDCA alone or a combination of both. Intraperitoneal dexamethasone was used in the control group. After 12 days of treatment, colonic samples were tested for the severity of mucosal damage macroscopically and microscopically. The levels of activated NF‐κB, IL‐1β, TNF‐α, myeloperoxidase, thiobarbituric acid reactive substances (TBARS), protein carbonyl, and the antioxidant power of the bowel homogenates were determined. The results indicated a significant reduction in NF‐κB activity as well as the levels of IL‐1β, TNF‐α, TBARS, protein carbonyl, myeloperoxidase activity, and an improvement in antioxidant power of colitis in treated rats. Combination therapy resulted in a more prominent improvement in bowel antioxidant power and myeloperoxidase activity. In conclusion, combination of silibinin and UDCA by inhibition of NF‐κB and other relevant inflammatory factors of colitis is a good candidate for management of Crohn’s disease.     

Cytokines in giant-cell arteritis

Cytokines are small proteins that serve as chemical messengers between cells, regulating cell growth and differentiation, tissue repair and remodeling, and many aspects of the immune response. Cytokines are instrumental in determining the nature, magnitude, and duration of inflammatory reactions and, as such, represent ideal targets for interfering with pathogenic processes. In OCA and PMR, cytokines are encountered in two locations, the inflammatory infiltrates accumulating in the arterial wall and in the circulation. IL-6, a cytokine involved in stimulating acute-phase responses, is located upstream of many of the laboratory abnormalities considered helpful in diagnosing and managing GCA/PMR, including elevated ESR and CRP. IL-6 has the potential to be helpful in predicting disease severity and may allow for a tailoring of immunosuppressive therapy. There is evidence suggesting that IL-6 outperforms other chemical markers in detecting disease activity and could, therefore, have a role in monitoring treatment. Interesting pathogenic clues have been derived from studies of cytokines produced in the vascular lesions. IFN-gamma has emerged as a key regulator in determining the nature and direction of the inflammatory response. IFN-gamma appears to be critically involved in modulating the process of intimal hyperplasia, the most destructive consequence of vasculitis, and, as such, emerges as a prime target for novel therapeutic approaches.     

Titres of anti-neutrophil cytoplasmic antibodies in inflammatory bowel disease are not related to disease activity.

In the systemic vasculitides, serial measurement of titres of anti-neutrophil cytoplasmic autoantibodies (ANCA) is useful for follow-up of disease activity and prediction of relapses. ANCA have been detected in patients with inflammatory bowel disease, but their relation to disease activity in these diseases is unclear. We analysed the relation between disease activity and ANCA titres as determined by indirect immunofluorescence in paired samples obtained during active disease and at remission from individual patients with ulcerative colitis (n=60) and Crohn's disease (n=101). In addition, patients were followed prospectively, to study the fluctuations of ANCA with time in relation to disease activity. We did not detect a correlation between disease activity and ANCA titres, either in paired samples from active disease and remission, or in serial samples, either in ulcerative colitis or in Crohn's disease. In contrast to the ANCA-associated systemic vasculitides, serial measurement of ANCA titres is not useful in the monitoring of disease activity in patients with inflammatory bowel disease.