H. W. Verspaget

Crohn's disease in the elderly : A comparison with young adults

We compare the clinicopathological features of 98 Crohns disease (CD) patients with initial symptoms at 40 years of age or older (elderly; male n = 56, female n = 42) with those of 347 CD patients with onset of symptoms between the age of 16 and 40 years (young adults; male n = 166, female n = 181). The frequency of presenting symptoms, such as diarrhea, rectal blood loss, and weight loss were comparable in both groups, except for abdominal pain/cramps, which occurred somewhat less frequently in the elderly (59% vs. 71%, p < 0.05). The mean lag time between onset of symptoms and first visit to a general practitioner (GP) was considerably shorter in the elderly than in the young adults (0.2 years vs. 0.6 years, p < 0.001), as was the lag time between GP and referral to a specialist (0.6 years vs. 1.0 years, p < 0.07). Overall, this resulted in a significantly (p < 0.01) shorter time to establish the diagnosis in the elderly (1.8 years vs. 2.7 years). Crohns disease as correct initial diagnosis was in the elderly less frequently observed than in the young adults (49% vs. 61%, p < 0.05), in contrast to diverticulitis (7.1% vs. 0%) and malignancy (6.1% vs. 0.9%), which were more frequently encountered as incorrect preliminary diagnosis in the elderly (both p < 0.005). The percentage of patients who underwent an abdominal operation was similar in both groups (83% vs. 77%), but the diagnosis CD was in the elderly more frequently established at first operation than in young adults (25% and 12%, p < 0.005). The elderly were found to undergo a bowel operation or resection earlier after onset of symptoms. The development of recurrence after bowel resection, although occurring in a lower percentage of patients, was significantly shorter than in the young adults (3.7 years vs. 5.8 years, p < 0.02). Arthritic extraintestinal manifestations were equally frequent in both groups, but elderly patients had significantly less relatives in the first or second degree affected by CD (3.1% vs. 12%, p < 0.02). We conclude that the diagnosis Crohns disease is more readily established in elderly patients. Moreover, these patients less frequently have abdominal pain/cramps as a presenting symptom, a shorter time interval between onset of symptoms and first resection, and subsequent recurrence of the disease. In addition, elderly CD patients have less relatives affected by the same disease. Thus, CD in the elderly appears to be characterized by a more rapid development.

Crohn's disease of the upper gastrointestinal tract

Although Crohns disease (CD) is generally found in the ileum and/or colon, since the 1960s it has become evident that this chronic inflammatory disorder of unknown aetiology can affect the whole gastrointestinal tract from mouth to anus. In 0.5-13% of patients with ileocolonic CD the disease occurs in the upper gastrointestinal tract as well (i.e., from mouth through jejunum). With the radiological double-contrast technique, however, early signs of upper gastrointestinal CD may be detected in 20-40% of patients with ileocolitis. On the other hand, histologically evaluated biopsies from the lower oesophagus, body of the stomach, gastric antrum and the duodenal bulb of patients with Crohns disease from whom the upper gastrointestinal tract is normal, according to X-ray or endoscopy may reveal lesions, which are considered to be pathologically diagnostic. Jejunal involvement occurs in 4-10% of patients with ileitis, ileocolitis or colitis. In early studies biopsies of apparently normal buccal mucosa from patients with Crohns disease showed a significant correlation between the activity of the disease, as defined by the Crohns Disease Activity Index, and the number of plasma cells containing IgM, suggesting a generalized activated humoral defence system during relapse. A diagnosis of Crohns disease of the upper gastrointestinal tract can be achieved by combining recognition of clinical, roentgenographic, and endoscopic features. Provided that other causes of granulomatous involvement of the gastrointestinal tract can be excluded, non-caseating granulomas are generally accepted as the histological proof of Crohns disease. When Crohns disease does involve the upper gastrointestinal tract, there is nearly always concomitant disease in the small bowel or colon. Compared to patients with an ileocolonic localization, patients with Crohns disease in the upper gastrointestinal tract more frequently have colic-like abdominal pain and/or cramps, nausea and anorexia as presenting symptoms and are younger at onset of the disease. Medical therapeutic principles are the same as for Crohns disease elsewhere in the gastrointestinal tract. Absolute indications for surgical treatment are massive bleeding, progressive stenosis, and extensive fistula formation.

Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell ‘stemness’ via the bone morphogenetic protein pathway

Background Promoter hypermethylation is an important and potentially reversible mechanism of tumour suppressor gene silencing in cancer. Compounds that demethylate tumour suppressor genes and induce differentiation of cancer cells, but do not have toxic side effects, would represent an exciting option in cancer therapy. Statins are cholesterol-lowering drugs with an excellent safety profile and associated with a reduced incidence of various cancers including colorectal cancer (CRC). The authors have previously shown that statins act by activating tumour suppressive bone morphogenetic protein (BMP) signalling in CRC, increasing expression of BMP2. BMP2 is silenced by hypermethylation in gastric cancer. Aim To investigate whether BMP2 is methylated in CRC, whether statins can reverse this, and what implications this has for the use of statins in CRC. Methods Methylation-specific PCR, bisulphite sequencing, immunoblotting, reverse transcription PCR, quantitative PCR, fluorescence-activated cell sorting analysis, an in vitro DNA methyltransferase (DNMT) assay, and cell viability studies were performed on CRC cells. The effect of statins was confirmed in a xenograft mouse model. Results BMP2 is silenced by promoter hypermethylation in cell lines with the hypermethylator phenotype and in primary tumours. Treatment with lovastatin downregulates DNMT activity, leading to BMP2 promoter demethylation and to upregulation of expression of BMP2 as well as other genes methylated in CRC. Statins alter gene expression, indicating a shift from a stem-like state to a more differentiated state, thereby sensitising cells to the effects of 5-fluorouracil. In a xenograft mouse model, simvastatin treatment induces BMP2 expression, leading to differentiation and reduced proliferation of CRC cells. Conclusions Statins act as DNMT inhibitors, demethylating the BMP2 promoter, activating BMP signalling, inducing differentiation of CRC cells, and reducing ‘stemness’. This study indicates that statins may be able to be used as differentiating agents in combined or adjuvant therapy in CRC with the CpG island methylator phenotype.

MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients.

Background:Upregulation of the matrix metalloproteinases MMP-2 and MMP-9 in various cancers has been associated with worse survival of the patients.Methods:We assessed MMP-2 and MMP-9 levels in normal colorectal mucosa from colorectal cancer patients in relation to the course of the disease.Results:A high protein expression of MMP-2 as well as MMP-9 in normal mucosa was found to be correlated with worse 5-year survival. The combination of both parameters was an even stronger prognostic factor. These protein levels were found not to be related to the corresponding single nucleotide polymorphisms of MMP-2 (−1306C>T) and MMP-9 (−1562C>T). Multivariate analyses indicated that the MMP-2 and MMP-9 levels in normal mucosa are prognostic for survival, independent of TNM classification.Conclusion:MMP-2 and MMP-9 levels in normal mucosa are indicative of the course of disease in colorectal cancer patients.

Crohn's Disease of the Upper Gastrointestinal Tract: the Value of Endoscopic Examination

The involvement of the upper gastrointestinal (GI) tract has been considered to be a rare manifestation of Crohns disease (CD). Retrospective studies have reported prevalence figures of 0.5-13%. The diagnosis of CD of the upper GI tract is based on clinical, radiological, endoscopic and histologic features. In contrast to the retrospective studies, prospective studies, in which patients with CD underwent routine endoscopic evaluation with biopsies, revealed a much higher frequency of endoscopic and histologic abnormalities. Since Helicobacter pylori is the most frequent cause of gastritis and the most important etiologic factor in peptic ulcer disease, it is important to assess the contribution of H. pylori in the interpretation of the abnormalities observed in the upper GI tract in patients with CD. Therapy for CD of the upper GI tract consists of drug therapy and endoscopic or surgical interventions and is in fact similar to that for distal CD. Corticosteroids are still the most important drugs in the treatment of CD of the upper GI tract. Sometimes adjunctive therapy, e.g. gastric antisecretory drugs and mucosa protective agents, is beneficial. Endoscopic evaluation of the upper GI tract with biopsies should be part of the work-up of CD patients.

Treatment of Helicobacter pylori infection favourably affects gastric mucosal superoxide dismutases.

BACKGROUND AND AIMS: Excessive production of reactive oxygen metabolites (ROMs) by phagocytic cells is thought to contribute to the mucosal pathology of Helicobacter pylori infection. Previously, H pylori infection was shown to have a differential effect on some gastric mucosal scavenger enzymes of ROMs-namely, mitochondrial and cytoplasmic superoxide dismutases-reflected by a large increase in the cytokine inducible manganese superoxide dismutase and a marginal decrease in the constitutive copper/zinc superoxide dismutase. The present study was performed to evaluate whether these altered mucosal superoxide dismutase concentrations and activities in H pylori associated gastritis are reversed to normal by successful treatment of the infection. PATIENTS AND METHODS: In two different treatment groups-namely, omeprazole or ranitidine, in combination with clarithromycin and metronidazole (OME/AB (n = 33) and RAN/AB (n = 30))-manganese superoxide dismutase and copper/zinc superoxide dismutase concentrations were evaluated by enzyme linked immunosorbent assays in homogenates of gastric antrum and corpus biopsy specimens obtained before and eight weeks after successful treatment of H pylori infection. Superoxide dismutase activities in these homogenates were determined spectrophotometrically in eight patients of both groups before and after successful treatment. The concentrations of gastric mucosal superoxide dismutases were also determined in 12 patients with a persistent H pylori infection, with (n = 4) or without (n = 8) eradication therapy. Infection and eradication of H pylori were confirmed by a combination of culture and histology. RESULTS: Concentrations of manganese superoxide dismutase were significantly lower after than before therapy in antral (p < 0.001 in both treatment groups) and corpus (p < 0.001 in both treatment groups) mucosa. By contrast, copper/zinc superoxide dismutase concentrations were significantly higher (p < 0.001) only in antral mucosa of the OME/AB treated group. Manganese superoxide dismutase activity was significantly lower after than before treatment in antral (OME/AB p < 0.01, RAN/AB p < 0.001), but not in corpus mucosa. Copper/zinc superoxide dismutase activity was not significantly altered by therapy. In the 12 patients with a persistent H pylori infection no major changes in the gastric mucosal superoxide dismutase concentrations were found. CONCLUSIONS: The raised manganese superoxide dismutase and reduced copper/ zinc superoxide dismutase concentrations and activities in H pylori associated gastritis were reversed towards normal by successful treatment of the infection.

Selective immunomodulation in patients with inflammatory bowel disease : future therapy or reality ?

Knowledge of the aetiology and pathogenesis of the inflammation in ulcerative colitis and Crohns disease is still insufficient. It is thought that some antigen is the trigger which induces a chain of immune reactions but the origin of this antigen has not so far been elucidated. In theory, an antigen-presenting cell forms a complex with endotoxin-derived peptides as antigen. T-helper lymphocytes recognize this complex, are activated and start to produce cytokines. For inflammatory bowel diseases (IBD) the most important cytokines identified are interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), gamma-interferon (G-IFN), and tumor necrosis factor-alpha (TNF-alpha). Inhibition of these cytokines can be achieved by administration of cyclosporine, which inhibits the function of T-helper lymphocytes. Orally, intravenously, and locally administered cyclosporine is able to improve the disease activity in ulcerative colitis and Crohns disease, but its use is limited because of side-effects. The novel immunosuppressant FK506 has comparable actions to cyclosporine in regulating cytokine production and may even be more effective than cyclosporine. The receptor antagonist of IL-1 (IL-1ra) competitively binds to the IL-1 receptor located on several lymphocytes. Treatment of animals with IL-1ra has been successful and clinical trials using recombinant IL-1ra are underway in IBD. Antibodies against alphaIL-2r have also been used successfully in animal studies. No experience with this substance has been obtained in man. The use of alpha-interferon seems to be effective in some patients with Crohns disease. CD4 and CD8 molecules on lymphocytes are needed to form the interaction between antigen, antigen-presenting cell, and lymphocytes. Specific monoclonal antibodies against CD4 are successfully used in patients with active ulcerative colitis and Crohns disease. TNF-alpha shares many of the proinflammatory activities of IL-1. In preliminary studies, especially in patients with Crohns disease, the effects of the administration of antibodies to TNA-alpha were excellent.

Suppression of intestinal mucosal natural killer cells by corticosteroids

Background: Corticosteroid therapy of patients with inflammatory bowel disease can give rise to systemic side‐effects. Budesonide is a topically acting corticosteroid with low systemic bioavailability and is efficacious in the treatment of inflammatory bowel disease. Natural killer cells were previously found to be altered, both systemically and locally, in patients with inflammatory bowel disease. Modulatory effects of budesonide, prednisolone, dexamethasone, and cortisol on peripheral blood NK cells have already been described, but have never been assessed on mucosal NK cells from the intestine.

A Thirty-Year Follow-Up Surveillance Study for Neoplasia of a Dutch Ulcerative Colitis Cohort

Background. Patients with ulcerative colitis have an increased risk of developing colorectal cancer (CRC). The aim of this study is to assess the yield of surveillance colonoscopies in a tertiary referral cohort of ulcerative colitis patients and to identify different risk groups for dysplasia. Methods. A cohort of 293 patients (148 males, mean age 33.8 years at diagnosis) was built up at our center and started the surveillance program 8–12 years after start of symptoms. They underwent colonoscopies every one to three years. Endpoints were dysplasia or a (sub)total colectomy. Results. After a follow-up period of 10 years, the cumulative incidence of any dysplasia was 23.5%, and of CRC 4.0%. After 15 years these percentages were 33.3% and 6.8%. Patients with pancolitis (n = 178) had a significantly higher cumulative risk of dysplasia than patients with distal disease, HR 1.9 (95%CI 1.1–3.3). Patients who started surveillance at an older age are at increased risk for any dysplasia, HR 1.03 (95%CI 1.01–1.05). Conclusions. This prospective surveillance study shows a high yield of dysplasia in ulcerative colitis patients. We recommend developing separate surveillance programs for different risk groups. In our opinion patients with distal colitis can follow the general population surveillance program.