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Radiology in the current assessment of ulcerative colitis.

Plain abdominal radiography in acute ulcerative colitis is essential to detect acute colonic complications, such as acute dilatation and free perforation. Sealed perforations may not be detected. Useful information can be gained as to the extent and severity of the mucosal lesions, but can be unreliable so that a contrast examination is required. The double contrast barium enema is more accurate than the single contrast study in revealing the early mucosal lesions of colitis. It is the examination of choice to show the extent and severity of disease, and is of considerable value in the differential diagnosis of colitis. In active colitis, the unprepared double contrast barium enema is recommended. The success of the examination relies on the absence of fecal residue adjacent to an active mucosa. The technique, uses, and limitations of this type of examination are described. In the long-term management of colitis, the role of radiology is to show the presence of extensive disease, which indicates an increased risk of malignancy. Lesions such as strictures or polyps may be found and are more likely to be benign than malignant, but confirmation often requires endoscopic biopsy. In the search for malignancy regular barium enema examination is not recommended, as this can only reveal an overt tumor, whereas premalignancy can be detected histologically from an endoscopic biopsy.

Colitis, Ulcerative↗

Proctocolectomy for ulcerative colitis.

The majority of patients with ulcerative colitis can be managed satisfactorily throughout their lives by medical treatment, but a minority require colectomy. In severe attacks, emergency surgery is often required to save the patient's life. In chronic disease not responding well to medical treatment, elective colectomy will restore the patient to good health. Colectomy is also necessary for certain local complications, such as cancer, severe fistulas, and strictures. Prophylactic colectomy is indicated in patients with long-standing disease in whom there are factors associated with a high risk of developing cancer of the large bowel. For all these indications, it is our opinion that single-stage proctocolectomy is the operation of choice in the great majority of patients. Finally, we consider that the best results are obtained when the physician and the surgeon work together in the closest possible cooperation.

Acute Disease↗

[Malignant transformation in ulcerative colitis and surgical implications].

Patients with ulcerative colitis (UC) are at higher risk for cancer. Risk factors are duration of disease, extent of colitis, associated primary sclerosing cholangitis and possibly early onset of UC in childhood. Epithelial dysplasias are considered as precursors of colorectal cancer within the concept of an inflammation-dysplasia-carcinoma sequence. Dysplasia originates multifocally and is difficult to identify by colonoscopy. Histomorphological diagnosis can also be problematical. Surveillance programs utilize colonoscopy with random biopsies to diagnose dysplasia in patients with risk factors. The efficiency of these programs can be markedly increased when certain rules are applied. The ultimate aim must be to perform a proctocolectomy in patients at higher risk before invasive cancer develops. With only a few exceptions, colorectal cancer in UC can be treated by restorative proctocolectomy. Partial resection of the colon should be avoided because of the high frequency of occult carcinomas and multifocal carcinogenesis. There are first results that indicate a higher risk for malignant deterioration in the terminal ileum. After an ileoanal pouch procedure patients with chronic pouchitis seem to have a higher risk for dysplasia. At the moment the risk for malignancy cannot be calculated because of the relatively short follow-up time after ileoanal pouch procedures. However, it is recommended that after restorative proctocolectomy patients be followed by endoscopy and random biopsies for the rest of their lives.

Cell Transformation, Neoplastic↗

Perinuclear antineutrophil cytoplasmic antibody myeloperoxidase-positive vasculitis in association with ulcerative colitis.

We describe a patient with ulcerative colitis (UC) who developed small vessel vasculitis. Perinuclear antineutrophil cytoplasmic antibody myeloperoxidase (p-ANCA-MPO) positivity was detected along with a highly elevated titer of anticardiolipin antibodies. A total proctocolectomy was undertaken and the patient, more than 5 years later, remains in very good condition. The possible causative association between the UC, the p-ANCA-MPO-positive small vessel vasculitis, and the anticardiolipin antibodies is discussed.

Antibodies, Anticardiolipin↗

Neoplastic transformation of the pelvic pouch mucosa in patients with ulcerative colitis.

BACKGROUND & AIMS: Some patients with ulcerative colitis (UC) receiving an ileal pelvic pouch with ileoanal anastomosis (IPAA) develop persistent severe villous atrophy in the pouch mucosa. To investigate if mucosal atrophy indicates a risk for subsequent neoplastic transformation of the ileal pouch mucosa, a follow-up study was undertaken. METHODS: Seven patients with UC and an IPAA in whom persistent severe atrophy (type C) developed and 14 control patients with no or only slight atrophy (type A) were prospectively surveyed by flexible videoendoscopy with multiple biopsies for assessment of possible neoplastic changes. RESULTS: The median time of the pouch in function was 9 years for both groups. Dysplasia was found in 5 of 7 patients in the type C group (71%) compared with none in the type A group (P < 0.001). Four patients had low-grade dysplasia, and 1 patient had sequential multifocal development into high-grade dysplasia. Multifocal DNA aneuploidy was found in 2 patients, 1 with low-grade and 1 with high-grade dysplasia. CONCLUSIONS: Patients with UC and a long-standing IPAA who develop persistent severe mucosal atrophy are at risk also of neoplastic transformation of the pouch mucosa.

Adolescent↗

Prognosis in ulcerative colitis.

In unselected patient populations with ulcerative colitis the overall prognosis is good and has improved over the years. There is still an appreciable excess mortality, however, particularly during the first years after diagnosis and it tends to increase with duration of disease. Patients with severe attacks, total colitis, and high age at diagnosis are particularly at risk. The disease runs an inactive or intermittent course in the majority of patients, although up to one fifth of the patients have a progress of the original extent of the colitis. Worldwide, there has been a time trend of decreased mortality possibly affecting younger patients in particular. Complications of the acute attack with or without surgery, liver disease, and colon cancer account for the major part of the colitis-related deaths whereas the mortality pattern in other respects does not differ significantly from that of the general population. The colon cancer incidence seems lower than previously reported but still accounts for approximately one tenth of all deaths. If this figure can be improved with cancer surveillance and prophylactic colectomy seems probable but remains to be shown. Pregnancy, if planned, should be encouraged when the patient is in remission although the disease or its standard treatment does not seem to dangerously affect the patient, fetus, or the newborn infant. Surgical and medical treatment probably accounts for most of the improvement in prognosis seen over the years. The postoperative mortality has been reduced, especially in series where new surgical procedures have been used. A high frequency of major postoperative complications still remains a challenge for improvement. The medical intensive treatment of the acute attack has contributed to the improved prognosis. If compliance is good, the sulfasalazine prophylaxis may be one of the explanations to the change into a milder disease pattern that has been observed recently. Finally, and most important, a majority of patients sustain a normal life with full working capacity. Those who have surgery adapt well, particularly when a continence-saving procedure is used. The sexual function follows the improvement although the patient's need for support and counseling should not be underestimated.

Adaptation, Psychological↗

Distinction between dysplasia-associated lesion or mass (DALM) and adenoma in patients with ulcerative colitis.

Polyps with epithelial dysplasia in ulcerative colitis (UC) represent either dysplasia-associated lesions or masses (DALMs) or sporadic adenomas. DALMs are frequently associated with associated carcinoma and are an indication for colectomy. Removal of the polyp is treatment of choice for sporadic adenomas. Differentiating between these 2 lesions is not always easy. The goal of this study was to distinguish DALMs from adenomas in patients with UC on a genetic basis. We evaluated genetic alterations in DALMs and compared them with a previously published set of dysplastic polyps in patients with UC that were considered adenomas for the following reasons: (1) polyps were located outside of current active disease; (2) polyps had histological features of sporadic adenomas; and (3) patients displayed a uneventful follow-up after polypectomy (UC-adenomas). In addition, adenomas not associated with UC were studied. Genetic alterations on chromosome 3p were assessed for the markers D3S1766, D3S2409, and D3S2387. LOH with or without microsatellite instability was found in 70%, 37%, and 57% of cases of DALM, respectively. In contrast, UC-adenomas lesions exhibited genetic alterations in 8.3%, 11.7%, and 15.3% for the respective markers. Spontaneous adenomas exhibited genetic alterations in 10.5%, 7.1%, and 0% of cases, which were not significantly different from the UC-adenoma results. These results indicate that UC-adenomas are genetically and biologically similar to sporadic adenomas and that UC-adenomas may biologically represent sporadic adenomas, supporting on a genetic basis the criteria chosen to diagnose adenomas in UC. Genetic markers on chromosome 3p may be useful in the differential diagnosis between DALM and UC-adenomas.

Adenoma↗

Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas.

Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.

Adenoma↗

Clinical outcome of the first ten years of ulcerative colitis and proctitis.

269 patients with ulcerative colitis and a history of less than 6 months when first seen at St. Mark's Hospital in the decade 1966--75 have been followed for up to 11 years. The outcome has been correlated with the maximum extent of the disease observed within 3 months of presentation. 75 patients required hospital admission, 56 within a year of presentation. Extensive colitis developed in 60 patients. The cumulative probability of the disease being extensive was 21% +/- 3% at 5 years and 29% +/- 4% at 10 years. 25 patients required surgical treatment. The cumulative probability of operation was 8% +/- 2% at 5 years and 15% +/- 4% at 10 years. 19 patients are known to have died. The expected number of deaths was 19.2.

Adolescent↗

The natural history of ulcerative colitis.

The majority of patients with ulcerative colitis (UC) will run a typical chronic, relapsing course. The proportion with chronic, continuous symptoms diminishes with time. The greatest impact of the disease is in the first few years after diagnosis, especially in patients with extensive or severe colitis. After this time, the likelihood of requiring surgery declines rapidly, and survival is no different from that of the general population. The long-term course can be best predicted by the course in the preceding period. Most patients are able to lead an essentially normal lifestyle, at work and at home, with either medical or surgical treatment. Awareness of how the patient feels the disease affects his or her life is important. Educating the patient about their illness will also help in management.

Anti-Inflammatory Agents, Non-Steroidal↗

Review article: maintenance of remission in ulcerative colitis.

Seventy percent of patients with ulcerative colitis can expect to experience a relapse over a 12 month period. Sulfasalazine was the first drug demonstrated to reduce this relapse rate to 21 percent. Subsequent studies have demonstrated that 5-aminosalicylic acid (5-ASA) is the main active component, and preparations containing only 5-ASA have similar efficacy to sulfasalazine. 5-ASA is readily absorbed from the small intestine; to achieve high a colonic lumenal concentration therefore requires special release formulation. A variety of 5-ASA preparations is available, differing in their release mechanism, efficacy and side effect profile. Most patients can be maintained in remission using oral 5-ASA medication. For patients with distal or left sided disease the use of rectal 5-ASA is also of proven benefit in maintaining remission. Some patients with frequent or severe relapses require stronger immunosuppression, and in these patients azathioprine or 6-mercaptopurine (6-MP) are of proven benefit. Azathioprine is also invaluable for maintaining remission in patients who have been treated with cyclosporin for a fulminant acute episode of colitis. The exciting spectre of natural bacterial therapies (probiotics) deserves further exploration.

Administration, Oral↗

Acute myelogenous leukemia in patients with ulcerative colitis.

Of approximately 400 patients with ulcerative colitis admitted to the Mount Sinai Hospital in New York City during 1970-1978, five developed acute myelogenous leukemia in the course of their illness. This association may be more than fortuitous.

Adolescent↗

High-dose methylprednisolone in the treatment of active ulcerative colitis.

Twenty patients with severe active ulcerative colitis were entered into a pilot study to test the efficacy of pulsed high-dose methylprednisolone in inducing remission. Of 20 patients, 12 improved, but 8 of 20 patients (40%) who did not went for urgent colectomy. The group proceeding to surgery tended to have more extensive disease. These results contrast unfavorably with historical control data from this unit.

Acute Disease↗

Interleukin-2 production in pediatric inflammatory bowel disease: evidence for dissimilar mononuclear cell function in Crohn's disease and ulcerative colitis.

Crohn's disease (CD) and ulcerative colitis (UC) represent clinically distinct chronic inflammatory bowel diseases (IBD) of unknown etiology. Although the mucosal immune system is implicated in their pathogenesis, immunological differences between the two disorders are not well defined. The aim of this study was to compare in vitro mucosal T-lymphocyte function in CD and UC. Peripheral blood mononuclear cell interleukin-2 (IL-2) production was similar in pediatric IBD and control patients under unstimulated conditions, but was significantly increased in response to phytohemagglutinin (PHA) stimulation for the UC group. Lamina propria mononuclear cells (LPMNC) isolated from colonic resections in IBD patients had significantly lower spontaneous proliferation and IL-2 production in vitro than did LPMNC of control patients. In contrast, significantly greater IL-2 production was detected when the LPMNC of CD patients were cultured with PHA, in comparison with those of UC or control patients. When indomethacin, a prostaglandin synthetase inhibitor, was added to the cultures, significantly increased IL-2 secretion was observed for CD LPMNC, but not for UC cultures, under both stimulated and unstimulated conditions. These findings demonstrate abnormal LPMNC IL-2 production in IBD. Furthermore, our data suggest that inhibition of the prostaglandin synthetase pathway upregulates IL-2 production by LPMNC in CD. These results support the hypothesis that immunoregulatory mechanisms controlling IL-2 production differ between CD and UC.

Adolescent↗

Ca2+ response in neutrophils after exposure to bacterial N-formyl-methionyl-leucyl-phenylalanine: delayed response in ulcerative colitis.

OBJECTIVE: In acute stages of ulcerative colitis (UC), neutrophils migrate from the circulation into inflamed colonic tissue, initiated by yet unknown stimuli. The bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a component of the surface membrane of colonic bacteria such as Escherichia coli and stimulates Ca2+ influx into neutrophils, reflecting the fact that ionized calcium is an important secondary messenger for several neutrophil functions, including locomotion, phagocytosis and free oxygen radical production. Recent studies have revealed that Ca2+ dependent ICAM-1/beta 2-integrin mediated neutrophil migration is impaired in UC patients. The aim of the present work was to study the influx of Ca2+ into peripheral blood neutrophils of UC patients after exposure to FMLP and after binding of either beta 2-integrins or intercellular adhesion molecule-1 (ICAM-1). METHODS: The relative intracellular Ca2+ levels ([Ca2+]i ) were measured spectrofluorometrically in neutrophils isolated from eight UC patients and eight controls. The cells were exposed to 1 nm FMLP, 5 pm free ICAM-1, or antibodies binding ICAM-1 or the beta 2-integrins CD11a, CD11b, CD11c and CD18. RESULTS: A pronounced increase in [Ca2+]i was observed by exposure of cells to FMLP, and neutrophils from UC patients showed a consistent and significant delayed response as compared to cells from control subjects (P < 0.01). Antibody mediated cross-linking of CD18 triggered a small but detectable increase in [Ca2+]i, which did not differ between patients and controls. CONCLUSION: A delayed response to bacterial peptides appears to be a phenotypic trait for neutrophils of UC patients. A connection between FMLP stimulated Ca2+ influx and CD11/CD18 upregulation is discussed.

Adult↗

Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis.

OBJECTIVE: The gross extent of ulcerative colitis (UC) is a recognized risk factor for the development of colitis-related dysplasia and colorectal cancer (CRC). The risk of neoplasia associated with the microscopic extent of colitis is unknown. The aim of this study was to describe the gross and microscopic extent of colitis in patients with UC-related dysplasia/CRC. METHODS: All patients who underwent colectomy at our institution between 1992-2001 with colitis-related dysplasia/CRC were identified. Histological sections from each colectomy specimen were reviewed for the microscopic extent of colitis and the location of all lesions with dysplasia/CRC. RESULTS: Thirty-six patients with colitis-related dysplasia/CRC were identified of whom 30 had slides available for review. Gross pancolitis was identified in 19 patients, though microscopic pancolitis was evident in all 30 patients. Among the 11 patients with only distal gross colitis, 4/15 neoplastic lesions were proximal to the area of gross involvement. CONCLUSIONS: UC-related neoplasia can occur in areas of the colon not grossly involved with colitis, though it did not occur in any patients without microscopic pancolitis. To devise rational cancer surveillance guidelines, further studies are needed to determine the risk of colitis-related neoplasia in patients with microscopic pancolitis but limited gross disease.

Adolescent↗

Clinical status of ulcerative colitis in patients who smoke.

OBJECTIVES: Ulcerative colitis (UC) is largely a disease of nonsmokers. There are few patients who are current smokers, but we have identified a group and reviewed their clinical status, disease activity, and nicotine exposure to examine whether they remain well controlled while smoking. METHODS: Fifty-one patients from three centers with verified UC were reviewed. RESULTS: Thirty of the group were men; mean age 50 yr, with a mean age of onset of 37 yr. Twenty-two patients had proctosigmoid disease, 12 involvement of left colon, and 17 total colitis. All were current smokers; 41 were cigarette smokers averaging 17 daily. At the onset of colitis 30 were nonsmokers, 25 of them were ex-smokers and 19 developed colitis within 2 yr of stopping smoking. Twenty-eight believed smoking improved disease activity and none felt smoking had a detrimental effect on their UC. Eleven were receiving no medication for UC, 40 were receiving 5-ASA (5-aminosalicylic acid) preparations, and only two took oral steroids. All were in clinical remission, with the exception of one patient; mean St. Marks score was 1.5, out of a possible total of 22. Sigmoidoscopic grades were inactive in all patients except three. Histological assessment showed significant activity in only five. Median serum nicotine was 8 ng/ml (range, 0.4-24.4), median serum cotinine 180 ng/ml (range, 20-453), with corresponding salivary cotinine of 255 ng/ml (range, 34-683). Median rise in nicotine 2 min after a cigarette in 35 patients was 12.1 ng/ml (range, 0.4-44). CONCLUSIONS: Because most current smokers with UC have inactive disease, smoking may contribute to the clinical remission in these patients.

Adult↗

A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis.

OBJECTIVES: Medical therapy of refractory ulcerative colitis (UC) is associated with long-term side effects of cyclosporine and steroids. Because cyclosporine acts by inhibiting interleukin-2 (IL-2) production, we studied the efficacy and safety of humanized anti-IL2 receptor (CD25) antibodies daclizumab for refractory UC in an open label pilot study. METHODS: Ten patients with chronically active UC received daclizumab, 1 mg/kg i.v. twice with a 4-wk interval. Clinical, endoscopic, and histological evaluation was scored at regular intervals. CD25 immunohistochemistry was followed in mucosal biopsies. The primary study endpoint was clinical improvement at wk 8. RESULTS: Nine of 10 patients completed the study. The median clinical activity score decreased from a median of 8 (95% CI = 7.2-9.2) at baseline to 3.5 (95% CI = 1.4-4.9) at wk 8 (p < 0.005). Endoscopic scores were significantly decreased at wk 8 (wk 0: 8, 95% CI = 6.3-8.5; wk 8: 5.0, 95% CI = 2.6-6.3; p < 0.01). Mucosal biopsies showed a significant decrease in CD25+ cells, and there was a trend toward lower histology scores at wk 8. Quality of life as assessed by the Inflammatory Bowel Disease Questionnaire increased after therapy (baseline: 131, 95% CI = 119-178; wk 8: 169; 95% CI = 124-216, p < 0.05). Nausea was most frequently reported as an adverse event, but always in patients that were concomitantly started on azathioprine. CONCLUSIONS: The anti-IL-2R antibody daclizumab was safe and well tolerated in acute UC. Patients experienced clinical benefit along with signs of endoscopic improvement, but further controlled trials are needed to determine the therapeutic benefit of this compound.

Antibodies, Monoclonal↗