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Evolving concepts on inflammatory bowel disease. Are we happy with the present nosology?

The term inflammatory bowel disease traditionally comprises ulcerative colitis, Crohn's disease and indeterminate colitis, an intermediate variant of the two major forms. The term is commonly used in the literature and in clinical practice even though it has never been revised in a Consensus Conference. The present nosology of inflammatory bowel disease seems not to be entirely satisfactory as it is limited to chronic diseases only and does not include several recently described idiopathic inflammatory bowel disorders. Although the aetiology of inflammatory bowel disease remains unknown, both ulcerative colitis and Crohn's disease are characterized by a similar pathogenesis which consists in a persistent intestinal inflammation resulting from disregulation of the gut mucosal immune system. The pathogenetic mechanisms could, therefore, provide a suitable criterion for the classification of idiopathic inflammatory bowel disease. A revised classification of inflammatory bowel disease is thus proposed. It seems reasonable to subclassify inflammatory bowel disease into acute and chronic forms. Acute forms should include the sudden attacks of ulcerative colitis and Crohn's disease with rapid and complete resolution and the so-called "acute self-limited colitis". The chronic forms should comprise, besides the classical forms of ulcerative colitis, Crohn's disease and indeterminate colitis, also other idiopathic inflammatory bowel conditions such as collagenous colitis, lymphocytic colitis and eosinophilic gastroenteritis.

Diagnosis, Differential↗

Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease?

In inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC), one would expect that TNF or IL-6 stimulates the hypothalamus, which activates the hypothalamus-autonomic nervous system (HANS) axis and the hypothalamic-pituitary-adrenal (HPA) axis in a parallel fashion. The study was initiated in order to investigate the parallelism of the HANS and HPA axes. We measured a typical marker of the HANS axis (neuropeptide Y, NPY) and of the HPA axis (serum cortisol). Plasma NPY was positively correlated with serum cortisol in control subjects (R(Rank)=0.259, p=0.026), which is a sign for the parallel activation of the two axes in healthy subjects. However, serum cortisol was not correlated with plasma NPY in CD or UC patients. In the active CD or UC, inclusion of patients with and without prior prednisolone therapy revealed a negative correlation between the serum cortisol and plasma NPY (CD: R(Rank)=-0.285, p<0.05; UC: R(Rank)=-0.510, p<0.01). This study demonstrates that the two stress axes seem to act in a parallel fashion in control subjects but are uncoupled in IBD patients. Uncoupling of these two axes may be partly due to prior corticosteroid therapy, whereas inverse coupling is a result of simultaneous corticosteroid therapy. It is discussed how the uncoupling of the two anti-inflammatory stress axes can appear.

Adult↗

Cytokine expression in intestinal mucosal biopsies. In situ hybridisation of the mRNA for interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha in inflammatory bowel disease.

Etiology and pathogenesis of inflammatory bowel disease (IBD) remain obscure. There is substantial evidence that proinflammatory cytokines such as Interleukin-1 beta (IL-1 beta), Interleukin-6 (IL-6) and Tumour Necrosis Factor-alpha (TNF-alpha) exhibit a key role in the the inflammatory process. In situ hybridisation can depict individual cells producing cytokine mRNA. We performed hybridisation with antisense probes specific for IL-1 beta, IL-6 and TNF-alpha on sections of paraffine-embedded biopsies. Specimens obtained from three control persons and six cases of Crohn's disease (CD) were investigated. Only few positive cells were found in tissue sections of control persons, clusters of lamina propria cells or epithelial cells containing cytokine mRNA were not observed. Inflammatory bowel disease tissue contained large numbers of cells producing mRNA specific for the three proinflammatory cytokines assayed. IL-1 beta, IL-6 and TNF-alpha mRNA were predominantly detected corresponding to cells of the lamina propria. Single cells containing mRNA specific for IL-6 were also found among the epithelial lining of intestinal crypts. Epithelial cells containing IL-1 beta and IL-6 mRNA were found in specimens derived from one patient with Crohn's disease. Notably, large amounts of cells containing cytokine mRNA were not only found in inflamed, but also in macroscopically normal mucosa. In conclusion, using proinflammatory cytokines as a model, we established in situ hybridisation on sections of mucosal biopsies permitting further insight into immune activation at individual cell level.

Biopsy↗

[Chronic inflammatory bowel diseases in cats].

The aetiology of chronic idiopathic intestinal inflammation is unknown. It is characterized by a diffuse infiltration with inflammatory cells into the intestinal mucosa and sometimes submucosa. Cats with chronic intermittent vomiting and diarrhoea, later on accompanied by anorexia and weight loss, are presented. Definitive diagnosis can be obtained by intestinal biopsy only. An immune pathogenesis is suspected, which is supported by the fact, that chronic inflammatory bowel disease responds to steroid therapy.

Animals↗

Immunological basis of inflammatory bowel disease: role of the microcirculation.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine and/or colon of unknown etiology in which patients suffer from severe diarrhea, rectal bleeding, abdominal pain, fever, and weight loss. Active episodes of IBD are characterized by vasodilation, venocongestion, edema, infiltration of large numbers of inflammatory cells, and erosions and ulcerations of the bowel. It is becoming increasingly apparent that chronic gut inflammation may result from a dysregulated immune response toward components of the normal intestinal flora, resulting in a sustained overproduction of proinflammatory cytokines and mediators. Many of these Th1 and macrophage-derived cytokines and lipid metabolites are known to activate microvascular endothelial cells, thereby promoting leukocyte recruitment into the intestinal interstitium. This review discusses the basic immune mechanisms involved in the regulation of inflammatory responses in the gut and describes how a breakdown in this protective response initiates chronic gut inflammation.

Animals↗

Cerebral thromboembolic disease in pediatric and adult inflammatory bowel disease: case report and review of the literature.

Cerebral and retinal vascular disease are rare complications of inflammatory bowel disease. Most reports are of adult patients, with only seven instances described in children. The eighth case, a 14-year-old boy with ulcerative colitis and cerebral venous thrombosis is reported in whom the diagnosis was confirmed by magnetic resonance imaging. The adult and pediatric literature is also reviewed.

Adolescent↗

Pharmacotherapy of inflammatory bowel disease.

The standard treatments for inflammatory bowel disease have been aminosalicylates and corticosteroids, administered both systemically and topically. They are frequently extremely effective, especially at higher doses. Unfortunately steroid side effects are too frequent and agents with low systemic bioavailability (budesonide, beclamethasone and tixocortol) are being investigated. Azathioprine, although a useful adjunct to steroids, has occasional and unpredictable severe side effects. Cyclosporin is an important new therapy in severe refractory disease. Several new phospholipid mediator inhibitors, mepacrine, zileuton, and ridogrel, may be useful in moderate colitis. Other topical treatments, butyrate, acetarsol and bismuth subsalicylate, can be beneficial in refractory distal disease. Quadruple antimycobacterials, antioxidants and antimicrobials warrant further study, while newer immunosuppressives such as methotrexate, FK 506 and monoclonal antibodies against helper T lymphocytes show some early promise.

Colitis, Ulcerative↗

Genomic structure, chromosome mapping and expression analysis of the human AVIL gene, and its exclusion as a candidate for locus for inflammatory bowel disease at 12q13-14 (IBD2).

Chronic inflammatory bowel disease is a multifactorial disorder with two major clinical forms, Crohn's disease and ulcerative colitis. One of the potential susceptibility loci for inflammatory bowel disease (IBD2) was localized at 12q13-14 in the vicinity of the deoxyribonucleic acid marker D12S83 by linkage analysis. A candidate susceptibility gene for IBD2 in this region is the AVIL gene. AVIL encodes a protein (advillin) which belongs to the gelsolin/villin family of proteins and might therefore be involved in morphogenesis of microvilli. We have determined the genomic organization of the AVIL gene, including the transcription start site and its localization with respect to D12S83. The 2457 bp coding region of AVIL consists of 19 exons and is localized to 12q14 proximal to D12S83. Primer extension analysis suggests two transcription start sites localized at -548 and -664 bp upstream to the ATG translation codon. We have evaluated AVIL as a candidate susceptibility gene for IBD2 in 24 unrelated patients with evidence of linkage to chromosome 12, as well as in 91 individuals from 19 affected IBD families for putative single nucleotide polymorphisms.

Chromosome Mapping↗

Gastrointestinal tract antigenic profile of cotton-top tamarin, Saguinus oedipus, is similar to that of humans with inflammatory bowel disease.

As an animal model for human inflammatory bowel disease and colorectal cancer, the cotton-top tamarin remains controversial. Demonstration of antigenic similarity to the human would enhance its validity. Using colonic extracts and washings, we compared binding of seven monoclonal antibodies reactive with bowel and cancer antigens in both tamarins and humans with inflammatory bowel disease. Additionally, telomerase activity was tested for. Expression of a mucin antigen specific to human cancer was increased in tamarin colonic washings as well as aminoproteoglycans and EGFR in tamarin extracts, as compared to those of humans with inflammatory bowel disease (P < 0.005). An adenoma-associated antigen and k-ras p21 protein were negative in the tamarin. A trend to greater telomerase activity exists in tamarins. The antigenic similarity validates this model for human inflammatory bowel disease and colorectal cancer. A trend to increased telomerase activity in tamarins is consistent with the greater predisposition to cancer in these animals.

Animals↗

Drug therapy of inflammatory bowel disease.

Although the etiology of inflammatory bowel disease is unknown and specific therapy is unavailable, enough information on existing empiric agents is available to allow rational therapy. These agents include sulfasalazine, steroids, immunosuppressive drugs, metronidazole and cholestyramine. Sulfasalazine is a two-part molecule that depends on bacterial cleavage in the colon to deliver locally acting 5-aminosalicylate, whose mechanism of action may relate to inhibition of prostaglandin synthesis. The other half of the molecule, sulfapyridine, is responsible for most of the side effects of the drug. While the efficacy of sulfasalazine in the treatment and prevention of attacks of ulcerative colitis is well established, its use in Crohn's disease appears to be limited to patients with active colitis and ileo-colitis. Sulfasalazine is of major benefit in preventing relapses in patients with ulcerative colitis in remission. New formulations of 5-aminosalicylate may allow delivery of the apparently active moiety to the small bowel and colon without concomitant sulfapyridine toxicity. Corticosteroids are highly effective in acute attacks of ulcerative colitis and Crohn's ileitis and ileo-colitis; the mechanism of antiinflammatory action remains speculative. However, maintenance therapy with steroids is ineffective in preventing relapses or recurrent attacks of either ulcerative colitis or Crohn's disease. Steroid enemas allow topical administration to patients with distal colitis and proctitis with few systemic side effects. In children with growth failure associated with active Crohn's disease, amelioration by steroid therapy may actually restore normal growth. Immunosuppressive agents such as azathioprine and 6-mercaptopurine are of little value in active Crohn's disease when administered alone; however, in combination with other agents they may help diminish steroid dose, close fistulae and prevent relapse. Their mode of action likely depends on long-term cytostatic effects on immune effector cells. Concern for leukopenia and the development of late malignancy has limited their use to patients not responding to other therapies. Metronidazole, an antimicrobial agent that is effective against anaerobes, has recently been shown useful in Crohn's disease involving the colon and perianal area. Its mechanism of action is uncertain, but may be related to its antibacterial actions on anaerobes. Cholestyramine can be successfully used to control bile salt-induced diarrhea in Crohn's patients with terminal ileal resections. Effective drug therapy of inflammatory bowel disease is only part of a total program of management including reassurance, frequent explanation, well-timed use of surgery, and an understanding physician.

Adjuvants, Immunologic↗

The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease.

BACKGROUND AND AIMS: Emerging data indicate that alterations in cytokine synthesis may play a role in inflammatory bowel disease (IBD) pathogenesis. The differential production of cytokines has been linked to single nucleotide polymorphisms in gene promoter regions, signal sequences, and gene introns. The aim of this study was to assess the relationship between polymorphisms involving five cytokine genes (TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma), and IBD susceptibility and disease phenotype. METHODS: Cytokine genotyping was performed utilizing polymerase chain reaction. The specific gene polymorphisms that were probed for included: -1082(G/A), -819(T/C), and -592(A/C) in the IL-10 promoter, -308(G/A) in the TNF-alpha promoter, codon 10 (T/C), and codon 25 (G/C) of the TGF-beta signal sequence, +874(T/A) of intron 1 of IFN-gamma, and -174(C/G) in the IL-6 promoter. RESULTS: A total of 193 IBD patients (138 Crohn's disease (CD) and 55 ulcerative colitis (UC)) and 92 controls were evaluated. No association between IBD, UC, or CD susceptibility and the cytokine gene polymorphisms were found. Patients with ileocolonic CD were more likely to possess the IL-6 -174 GG genotype compared to those with nonileocolonic disease (p= 0.006). Patients with ileal CD were more likely to possess the IL-6 -174 GC genotype compared to those with nonileal disease (p= 0.0004). An increased number of CD patients with isolated colonic disease possessed the IL-6 -174 CC genotype compared to those with nonisolated colonic disease (p= 0.032). CONCLUSION: The cytokine gene polymorphisms studied here do not appear to influence IBD susceptibility. There does, however, appear to be an influence on disease phenotype, particularly on CD site.

Adult↗

Portal vein bile acids in patients with severe inflammatory bowel disease.

The incidence of several forms of liver disease associated with inflammatory bowel disease has been putatively ascribed to a toxic effect on the liver of portal vein bile acids abnormal in type or amount. To examine this possibility, total bile acid concentrations (sulphated and non-sulphated) were measured by gas-liquid chromatography in inferior mesentric vein serum of 19 patients undergoing colectomy for severe inflammatory bowel disease (IBD). Similar determinations were obtained on a control group of eight patients requiring colectomy for other non-inflammatory conditions. Mean values for mesenteric vein serum bile acid concentrations (muM/1) were 19.6+/-1.8 in controls and 16.3+/-2.0 in IBD. The mean sulphated bile acid fraction did not exceed 10% of total, although there was considerable variability (up to 40% of total). Lithocholic acid levels (entirely sulphated in all patients) were low. Although the IBD group showed a more than two-fold increase in mean lithocholate concentration (0.54+/-0.15 muM/1) over controls (0.21 +/- muM/1), this difference was not statistically significant. No significant intra-group difference was noted in the non-sulphated and sulphated fractions for cholic, chenodeoxycholic, and deoxycholic acid species, respectively. No unidentified or unusual bile acids were observed. There was no correlation between bile acid measurements and liver histology. These findings fail to support the hypothesis that liver disease often found in association with severe inflammatory bowel disease represents a form of bile acid toxicity. The invariable finding of total sulphation of the lithocholic acid fraction even in the presence of severe mucosal disease was unexpected.

Adult↗

Epidemiology of inflammatory bowel disease.

The search for the cause of inflammatory bowel disease through epidemiologic investigation is centered on documenting disease variability and determining the reason for such variability. An examination of the person, place, and time variability of inflammatory bowel disease can provide important clues to disease pathogenesis. Although there is a great deal of variability in the epidemiology of inflammatory bowel disease among populations, there is little difference in these populations between Crohn's disease and ulcerative colitis with regard to person, place, or time variability. With notable exceptions, such as cigarette smoking, the epidemiologic variability of ulcerative colitis and Crohn's disease is remarkably similar. Such similarities are unlikely to be coincidences. The possible implications from this observation are that ulcerative colitis and Crohn's disease are actually different expressions of the same disease, expressions determined by such factors as cigarette smoking, or that two separate diseases share a near complete set of risk factors. Whichever theory is correct, environmental risk factors, which are preventable, are certain to be involved in causative mechanisms.

Age Factors↗

Influence of an elemental diet in protein exudation in chronic inflammatory bowel disease.

13 patients with chronic inflammatory bowel disease were treated with an elemental diet (Vivasorb). Intestinal protein exudation was studied during the treatment by means of of 131I-albumin. 131I-albumin studies showed no significant change of albumin degradation and, by inference, of intestinal protein loss in the group as a whole. A high initial albumin degradation rate augured treatment with elemental diet and prednisone to be unsuccessful. It is concluded that measurement of intestinal protein leakage is of no predictive value as regards the effect of treatment of chronic inflammatory bowel disease with elemental diet. Apparently, diminishing protein exudation is a late phenomenon during a course of clinical remission.

Adolescent↗

Surgical complications and skin test reactivity in patients with inflammatory bowel disease.

One hundred patients with inflammatory bowel disease were admitted to the Mount Sinai Hospital, New York, for surgical treatment. These patients were studied to evaluate the association between skin test reactivity and postoperative complications. Skin tests were performed prior to surgery using four recall antigens. Sixty patients were found to be anergic. The postoperative complication rate was significantly higher in the anergic patients when compared with those patients who were able to react to at least one skin test antigen. Twenty-seven anergic patients had 34 complications and almost 60% of these complications were of the septic type. Only 11 patients who responded to the skin tests had postoperative complications. Complications in the anergic patients required longer hospitalization and more frequent operative correction. There were no deaths in this series. Although anergic patients with inflammatory bowel disease are prone to experience septic complications, their prognosis appears to be better than the morbidity and mortality reported in the literature for anergic patients with other conditions.

Adult↗

Immunological disorders in inflammatory bowel disease and immunotherapeutic implications.

Ulcerative colitis and Crohn's disease, also called inflammatory bowel diseases, are characterised by altered mucosal and systemic immune responses. An increase in T helper (h) 1 cytokines, such as interleukin-2 and interferon-gamma, has been found in mucosa from patients affected by Crohn's disease. On the contrary, in patients with ulcerative colitis, mucosal cytokines seem to belong to the Th2 type with an increased release of interleukin-4, and -10. B lymphocytes isolated from lamina propria of patients with ulcerative colitis produce perinuclear anti-neutrophil cytoplasmic antibodies, thus suggesting a status of hyperactivation of these cells in inflammatory bowel diseases, which may lead to autoimmune phenomena. Polymorphonuclear cells and monocytes/macrophages heavily infiltrate the intestinal mucosa and release proinflammatory cytokines, such as interleukin-1, -6, -8 and tumour necrosis factor-alpha. Endotoxins or lipopolysaccharides, major constituents of the gram-negative bacterial cell wall, are present in the circulation of patients with inflammatory bowel diseases and may account for the release of both cytokines and free radicals. Finally, besides immunosuppressive drugs (e.g. cyclosporin A), immunotherapy with neutralising monoclonal antibodies against tumour necrosis factor-alpha has been experimented in Crohn's disease with encouraging results. In addition, novel promising therapeutic approaches in these diseases include the administration of recombinant interleukin-10 or interleukin-11.

Animals↗

Two cases of pericarditis associated with inflammatory bowel disease.

Extraintestinal manifestations are common complications of inflammatory bowel disease (IBD) whereas the association of cardiac disease with IBD is rarely reported. Cardiac manifestations may be diagnosed before, concomitantly or after the diagnosis of the specific type of inflammatory bowel disease. Pericarditis and myocarditis are potentially serious complications. This extraintestinal manifestation developed in one patient concomitantly with onset of intestinal disease. One patient had ulcerative colitis (UC), while other had Crohn's disease (CD). Indomethacin was effective in one and the other patient required prednisone in addition. Chest symptoms in patients with inflammatory bowel disease should be evaluated to exclude myopericardial disease.

Adult↗