Primary intrahepatic sclerosing cholangitis with inflammatory bowel disease

A case of primary intrahepatic sclerosing cholangitis associated with inflammatory bowel disease, which is rare in Japan, is reported. A 16-year-old Japanese boy was admitted to our hospital because of abdominal pain and fever. He was diagnosed as having primary intrahepatic sclerosing cholangitis by endoscopic retrograde cholangiography and liver biopsy. Inflammatory bowel disease was diagnosed by colonoscopy and biopsy of the colonic mucosa. Human lymphocyte antigen typing showed HLA-A2, A-9, -B52 and -DR2.     

Primary malignant lymphoma of the large intestine complicating chronic inflammatory bowel disease

Ten cases of malignant lymphoma of the colon and rectum complicating chronic inflammatory bowel disease are presented. Seven patients had chronic ulcerative colitis with a history varying from 6 to 20 years. There was extensive colitis in six of these patients and left-sided colitis in one. All seven lymphomas showed the pathological and immunohistological features of primary B-cell tumours of the gastrointestinal tract with a predominance of high-grade tumours. Three patients had Crohn's disease of the large intestine complicated by malignant lymphoma of the sigmoid colon or rectum. The history of Crohn's disease varied from 30 months to 20 years and in each case there was fissuring and fistulae. There was extensive anal involvement in two cases. Histologically the three lymphomas were heterogeneous: one was of 'granulomatous' T-cell type and the other two were markedly polymorphic and of equivocal phenotype. They were also characterized by numerous multinucleate tumour giant cells. Primary colorectal malignant lymphoma should be regarded as a rare, but significant, complication of ulcerative colitis. Immunosuppression may be an additional factor in the genesis of intestinal lymphoma in Crohn's disease. The prognosis appears to be dependent on factors already known to be of prognostic significance in primary gut lymphomas: a predominance of high-grade tumours suggests that the outlook is generally worse than that for idiopathic primary large intestinal lymphoma.     

Therapeutic effects of Ligularia stenocephala against inflammatory bowel disease by regulating antioxidant and inflammatory mediators

In this report, we studied the effect of leaf extracts of Ligularia stenocephala (LS) on inflammatory bowel disease (IBD) by regulating antioxidant and inflammatory mediators. The water extracts (LSW) exhibited more antioxidant activity than that of ethanol extracts (LSE). The extracts suppress the formation of nitric oxide by down-regulating the inducible nitric oxide synthase and pro-inflammatory cytokines (eg tumor necrosis factor alpha, interleukin (IL)-6, IL-10 and IL-1β expression) through the suppression of nuclear factor-?β activation and mitogen-activated protein kinases phosphorylation in lipopolysaccharide-stimulated macrophage cells. Our in vivo study reveals that the extracts could suppress tissue damage significantly in mice colon. The expression regarding immune-related cytokines was also down-regulated by the extracts of LS leaf. Thus, it is concluded that the extracts could be used as a functional food, which could reduce the formation of oxidants, inflammation and IBD effectively.     

Mannose-binding lectin (MBL) in adult patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) refers to disorders associated with progressive inflammatory processes in the gastrointestinal system. IBD consists of two major forms, Crohn’s disease (CD), and ulcerative colitis (UC). IBD became a global disease in the 21^st century. Its pathogenesis is still not fully understood. Mannose-binding lectin (MBL) is a pattern-recognising molecule, involved in anti-microbial and anti-cancer immunity. It is able to opsonize microorganisms and abnormal host cells, and to initiate complement activation. The aim of this study was to investigate possible involvement of MBL in inflammatory bowel disease in adults. Forty persons diagnosed with CD and 28 with ulcerative colitis were recruited. The control group consisted of 136 healthy persons. Single nucleotide polymorphisms of the MBL2 gene (localised to both promoter and exon 1) were determined as were serum MBL concentrations. The exon 1 variant alleles and MBL deficiency-associated genotypes were more frequent among patients compared with controls, although this difference was not statistically significant. No differences of MBL levels were found between the major groups. However in MBL2 A/A homozygous IBD patients, the median was significantly higher than in corresponding healthy subjects. That was particularly evident in the case of active Crohn’s disease (1493 ng/ml vs. 800 ng/ml, p = 0.021). It may suggest that MBL and MBL-dependent complement activation contributes to excessive inflammation and its adverse effects in the course of CD. It cannot also be excluded that high MBL activity constitutes in some cases part of a multifactorial network conducing to development of CD.     

Neuroinflammation in inflammatory bowel disease

Inflammatory bowel disease is a chronic intestinal inflammatory condition, the pathology of which is incompletely understood. Gut inflammation causes significant changes in neurally controlled gut functions including cramping, abdominal pain, fecal urgency, and explosive diarrhea. These symptoms are caused, at least in part, by prolonged hyperexcitability of enteric neurons that can occur following the resolution of colitis. Mast, enterochromaffin and other immune cells are increased in the colonic mucosa in inflammatory bowel disease and signal the presence of inflammation to the enteric nervous system. Inflammatory mediators include 5-hydroxytryptamine and cytokines, as well as reactive oxygen species and the production of oxidative stress. This review will discuss the effects of inflammation on enteric neural activity and potential therapeutic strategies that target neuroinflammation in the enteric nervous system.     

Probiotics and inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterised by a chronic dysregulation of the inflammatory response in the gastrointestinal tract. While the pathogenesis is unclear, studies have demonstrated that the gastrointestinal tracts of patients with IBD are populated with increased levels of adherent and pathogenic bacteria. This evidence, combined with growing data accumulated from genetic studies as well as animal models of IBD, indicates that an aberrant response to altered enteric flora plays a significant role in the disease process. Current therapies for IBD have been directed towards the development of anti-inflammatory agents and immunomodulators to attenuate the inflammatory response in the gastrointestinal tract. Antibiotics are also partially effective in the treatment of IBD, presumably by altering the bowel flora. However, it is clear from clinical trials that immunomodulators and antibiotics are not effective in a large proportion of patients with IBD and other therapeutic alternatives need to be pursued. Probiotics are microbial supplements capable of recolonising the bowel with non-pathogenic strains of bacteria or yeast. Probiotics have long been shown to be beneficial in both infectious and non-infectious digestive disorders. Growing evidence indicates that probiotics may be effective in the treatment of specific clinical IBD conditions. This article addresses the current evidence for the role of enteric flora in the pathogenesis of IBD and the clinical evidence supporting the use of probiotics in specific clinical IBD conditions.     

Dysplasia in inflammatory bowel disease

The risk of neoplasia in ulcerative colitis and Crohns colitis increases with both the duration and the extent of disease. In patients with extensive or pancolitis, the cancer risk increases dramatically 8 to 10 years after the first onset of disease. Childhood onset of colitis and primary sclerosing cholangitis further increase the risk of developing colorectal carcinoma. The performance of surveillance endoscopy to identify dysplastic precursor lesions via endoscopic biopsy specimens has become the main management strategy to combat this risk. Biopsies should be classified as negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia according to standard criteria. A prophylactic colectomy is the procedure of choice when high-grade dysplasia or low-grade dysplasia associated with a lesion or mass is present. Some centers also recommend a colectomy for the presence of low-grade dysplasia in flat mucosa. Given these management recommendations, care should be taken not to overcall reactive epithelial changes in the face of active colitis. All diagnoses of dysplasia should be confirmed, preferably by a pathologist experienced in interpreting gastrointestinal biopsies.     

Histologic mimics of inflammatory bowel disease

This review summarizes a variety of clinical and histologic mimics of idiopathic inflammatory bowel disease. All the entities that are included demonstrate one or more histologic features typical of idiopathic inflammatory bowel disease that may lead to potential diagnostic confusion and misinterpretation by the pathologist. The elements of the clinical history, laboratory test results, and endoscopic findings that are helpful to the surgical pathologist in considering a diagnosis other than idiopathic inflammatory bowel disease are emphasized. On occasion, a poor response to standard treatment for idiopathic inflammatory bowel disease is the clue that prompts reconsideration of the initial diagnosis. Subtle histologic features, special stains, or other diagnostic methodologies that can aid in proper diagnosis are also discussed.     

Immunopathology of human inflammatory bowel disease

Conclusions Mucosal pIgA, and thereby secretory immunity, are disfavored in IBD as revealed by decreased J-chain expression and strikingly increased IgG production by the mucosal immunocytes in both UC and CD. Moreover, a significant shift from IgA2 to the less-resistant IgA1 subclass takes place. Preferential overproduction of IgG1 is seen in UC; and apical deposits of this isotype on the surface epithelium, together with activated complement, is suggestive of a cytotoxic attack related to a brushborder antigen. Comparison of identical twins, discordant with regard to clinical expression of UC, further suggests that this IgG1 response is genetically determined. The IBD lesions furthermore contain many recently recruited and activated T cells as well as monocyte-like macrophages (L1⁺CD14⁺) with elevated capacity for production of proinflammatory cytokines (IL-1 and TNF-) and ROM. Together all these changes reflect less restricted extravasation of precursor cells because of altered expression of adhesion molecules on the microvasculature. Isolated and cultured intestinal endothelial cells subjected to proinflammatory cytokines show enhanced ICAM-1 expression as well as induction of functional E-selectin and MHC class II molecules with antigen-presenting properties.The immunopathology of IBD thus involves severely altered mucosal homeostasis, apparently reflecting break of tolerance to the indigenous microbial flora, and in addition it appears to include an autoimmune component in UC. The origin of abrogated immunological tolerance at the mucosal level may be alterations both in leukocyte extravasation and in antigen-presenting mechanisms induced by aberrant expression of endothelial and epithelial MHC class II molecules, as well as changed profiles of co-stimulatory molecules on macrophages. A shift from B7.2 on mucosal resident APC to B7.1 on the recently recruited macrophages, may particularly disfavor Th2 immune responses and their associated down-regulatory cytokines. In conclusion, perturbation of a tightly controlled cytokine network with abnormal crosstalk between several mucosal cell types, is probably the first step of a progressive immunopathological development in IBD, but the initiation of this series of events remains undefined.     

Clinical aspects of inflammatory bowel disease

Inflammatory bowel disease (IBD) accompanies its patients throughout life. Current treatment options do not lead to a cure and are accompanied by significant toxicities. Numerous animal models contributed to the understanding of the pathogenesis of the disease and led to the development of novel treatment strategies. Genome‐wide association analysis added a novel dimension. Here, we discuss how characterization of mutated genes in animal models supports the identification of future therapeutic targets.     

Familial occurrence of inflammatory bowel disease

BACKGROUND AND METHODS. We assessed the familial occurrence of inflammatory bowel disease in Copenhagen County, where there has been a long-term interest in the epidemiology of such disorders. In 1987 we interviewed 662 patients in whom inflammatory bowel disease had been diagnosed before 1979, asking whether their first- and second-degree relatives had this disorder. Ninety-six percent of the patients (504 with ulcerative colitis and 133 with Crohn's disease) provided adequate information. RESULTS. As compared with the general population, the first-degree relatives of the 637 patients with ulcerative colitis or Crohn's disease had a 10-fold increase in the risk of having the same disease as the patients, after standardization for age and sex. The risk of having the other of the two diseases was also increased, but less so, and the increase in the risk of having Crohn's disease was not significant in the relatives of patients with ulcerative colitis. The risk of ulcerative colitis in first-degree relatives of patients with ulcerative colitis appeared to be virtually independent of the generation to which the first-degree relative belonged and of the sex of the patient and the relative. The risk of ulcerative colitis in first-degree relatives tended to be higher if the disease had been diagnosed in the patient before the age of 50, but the risk seemed to be independent of the current age of the relatives. The prevalence of the same disease as that of the patient (either ulcerative colitis or Crohn's disease) among second-degree relatives was increased; the prevalence of the other disease was not increased. CONCLUSIONS. The 10-fold increase in the familial risk of ulcerative colitis and Crohn's disease strongly suggests that these disorders have a genetic cause.     

Experimental models of inflammatory bowel disease

The etiology and pathogenesis of inflammatory bowel disease (IBD) remains unsolved, but improved experimental models of enterocolitis have led to progress. Intestinal inflammation and experimental IBD can be induced by chemical or dietary factors or by microbial products. Many animal models of IBD can be used to evaluate new anti-inflammatory drugs. These models, however, usually demonstrate acute, self-limiting colitis. The spontaneous colitis models developed in the cotton-top tamarin monkey and the C3H/HeJBir mouse mimic more features of human IBD. Inflammation is chronic and is under genetic control. The differential genetic susceptibility of inbred rat strains to chronic inflammation have been exploited. Lewis rats injected with bacterial products, peptidoglycan polysaccharide or indomethicin develop chronic relapsing enterocolitis, whereas closely related Buffalo or Fisher rat strains develop only transient inflammation. These models are also useful to test the specific inhibition of inflammatory mediators and target molecules. Over-expression (transgenic) or deletion (knockout) of specific genes have led to the development of rodent models of spontaneous colitis. Inflammation arises from a number of mutations of immunomodulatory molecules, supporting the concept of genetic heterogeneity for IBD. The results obtained from experimental models have generated new hypotheses, expanded human studies, and suggested novel forms of therapy for IBD patients.