The prognosis of inflammatory bowel disease

The complications of ulcerative colitis generally develop during the first two years of disease. The mortality is higher than expected and the highest likelihood of colectomy also occurs early in the disease. Mortality in Crohn's disease is greater than expected, especially in males. For both conditions, the overall mortality has decreased steadily, and currently is less than 5%. Ulcerative colitis is curable with proctocolectomy and ileostomy. In Crohn's disease, intestinal resection and reanastomosis is followed by recurrence in the majority of patients. The recurrence rate after proctocolectomy and ileostomy for Crohn's disease of the colon also is considerable, ranging from 20% to 35%. In ulcerative colitis, the more colon involved, the more frequent and more serious are the complications. In Crohn's disease, the anatomic pattern of disease tends to predict the type and extent of complications. Both ulcerative colitis and Crohn's disease appear to follow a more severe course in children and adolescents with "inflammatory bowel disease." Patients with either ulcerative colitis or Crohn's disease are at increased risk for the later development of cancer. In ulcerative colitis, the excess risk is limited to colorectal cancer. Patients with Crohn's disease have increased cancer rates for both the small and large bowel. Finally, most patients with these diseases are able to maintain normal occupations and enjoy reasonably stable social and economic situations. The successful adaptation of patients with inflammatory bowel disease is influenced by a hopeful, optimistic personality and by an encouraging, supportive physician.     

Cancer in inflammatory bowel disease

Patients with long-standing inflammatory bowel disease （IBD） have an increased risk of developing colorectal cancer （CRC）. Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeox, ycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn＇s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal- anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.     

Hyperhomocysteinemia as a potential contributor of colorectal cancer development in inflammatory bowel diseases: A review

Homocysteine is an amino acid generated metabolically by the S-adenosylmethionine-dependent transmethylation pathway. In addition to being a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Patients suffering from inflammatory bowel diseases(IBD) including ulcerative colitis and Crohn’s disease are at increased risk of developing colorectal cancer in comparison to healthy individuals. Furthermore, the risk of hyperhomocysteinaemia is significantly higher in IBD patients when compared with controls. In the present article, we review the mechanisms in which hyperhomocysteinemia may contribute to increased risk of colorectal cancer in IBD patients.     

Expression of the carcinoma-associated antigens CA 19-9 and CA-50 in inflammatory bowel disease

The expression of gastrointestinal cancer antigen, CA 19-9, and of carcinoma-associated antigen, CA-50, was studied in formalin-fixed and paraffin-embedded tissue from 18 patients with ulcerative colitis, 29 with Crohn's disease in the colon, four with diverticular disease, and eight with sigmoid volvulus. None of the patients with inflammatory bowel disease showed strong dysplasia or had manifest carcinoma. Both antigens were expressed frequently in patients with inflammatory bowel disease. Of the 18 patients with ulcerative colitis, 17 were positive for both CA 19-9 and CA-50, and of the 29 with Crohn's colitis, 21 were positive for CA 19-9 and 22 for CA-50. No distinct differences in antigenic expression were found between Crohn's disease and ulcerative colitis. CA-50 was expressed in normal colonic mucosa from 10 of 12 patients with sigmoid volvulus or diverticular disease, and such mucosa was positive for CA 19-9 in three of the four patients with diverticular disease and in two of the eight patients with sigmoid volvulus. It is concluded that immunodetection of CA-50 or CA 19-9 is of limited value in the differential diagnosis of inflammatory bowel disease. The usefulness of these antigens as markers for precancerous changes in inflammatory bowel disease is also doubtful, since the expression is also frequent in cases of inflammatory lesions, with no obviously increased risk of malignancy. Supported by grants from the Swedish Cancer Society (project no. 1921-B85-02XA).     

Risk of intestinal cancer in inflammatory bowel disease: a population-based study from olmsted county, Minnesota

BACKGROUND & AIMS: The risk for colorectal cancer in Crohn's disease and ulcerative colitis patients from the United States currently is unknown. We estimated the risk for small-bowel and colorectal cancer in a population-based cohort of 692 inflammatory bowel disease patients from Olmsted County, Minnesota, from 1940 to 2001. METHODS: The Rochester Epidemiology Project was used to identify cohort patients with colorectal and small-bowel cancer. The cumulative probability of cancer and standardized incidence ratios (SIR) were estimated using expected rates from Surveillance, Epidemiology, and End Results, white patients from Iowa, from 1973 to 2000, and Olmsted County, from 1980 to 1999. RESULTS: Colorectal cancer was observed in 6 ulcerative colitis patients vs 5.38 expected (SIR, 1.1; 95% confidence interval [CI], 0.4-2.4), but 4 of these occurred among those with extensive colitis or pancolitis (SIR, 2.4; 95% CI, 0.6-6.0). Six Crohn's disease patients (vs 3.2 expected) developed colorectal cancer (SIR, 1.9; 95% CI, 0.7-4.1). Three Crohn's disease patients developed small-bowel cancer vs 0.07 expected (SIR, 40.6; 95% CI, 8.4-118). CONCLUSIONS: The risk for colorectal cancer was not increased among ulcerative colitis patients overall, but appeared to be increased among those with extensive colitis. The colorectal cancer risk was increased slightly among Crohn's disease patients, who also had a 40-fold excess risk for small-bowel cancer.     

Chemoprevention of Colitis-Associated Dysplasia or Cancer in Inflammatory Bowel Disease

The association between inflammatory bowel disease and colorectal cancer is well known. Although the overall incidence of inflammatory bowel disease has declined recently, patients with this disease still have a 1.7-fold increased risk of colorectal cancer. The risk factors for developing colorectal cancer include extensive colitis, young age at diagnosis, disease duration, primary sclerosing cholangitis, chronic colonic mucosal inflammation, dysplasia lesion, and post-inflammatory polyps. In patients with inflammatory bowel disease, control of chronic inflammation and surveillance colonoscopies are important for the prevention of colorectal cancer. The 2017 guidelines from the European Crohn’s and Colitis Organisation suggest that colonoscopies to screen for colorectal cancer should be performed when inflammatory bowel disease symptoms have lasted for 8 years. Current evidence supports the use of chemoprevention therapy with mesalamine to reduce the risk of colorectal cancer in patients with ulcerative colitis. Other compounds, including thiopurine, folic acid, statin, and tumor necrosis factor-^α inhibitor, are controversial. Large surveillance cohort studies with longer follow-up duration are needed to evaluate the impact of drugs on colorectal cancer risks.     

Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers

BACKGROUND: Ulcerative colitis is associated with an increased risk of colorectal cancer above that of the normal population. The relative risk correlates with the extent and duration of the disease but the genetic basis of ulcerative colitis associated cancer risk is not known. AIMS: To assess the prevalence of microsatellite instability and mismatch repair gene abnormalities in ulcerative colitis associated colorectal cancer. PATIENTS: Forty six patients with colorectal cancer, with a previous histological diagnosis of ulcerative colitis. METHODS: The frequency of microsatellite instability and/or immunohistochemical expression of hMSH2 and hMLH1 was assessed. Thirty three cases were investigated using both approaches. RESULTS: Although 6/41 (14.6%) cases showed microsatellite instability at one or more markers, only one case (2. 4%) exhibited high level instability (at least two markers affected). Of 38 cases which were assessed using antibodies against hMSH2 and hMLH1, only one case (2.6%) showed loss of expression. This case, which showed loss of hMSH2 expression, was the same case which exhibited high level microsatellite instability. The 33 cases which were investigated using both approaches showed that loss of expression of either hMSH2 or hMLH1 was not seen in any case which exhibited microsatellite instability in no more than one marker. CONCLUSIONS: This study suggests that both high level microsatellite instability and loss of expression of hMSH2/hMLH1 are infrequent events in ulcerative colitis associated colorectal cancers. Low level microsatellite instability was not associated with loss of expression of either hMSH2 or hMLH1.     

Crohn's Disease presenting as Isolated Jejunitis Years after Childhood Colitis

We present a case of a patient who had documented ulcerative colitis as a child and later presented with isolated Crohn's jejunitis. Although rare, Crohn's disease must be considered in those patients with segmental inflammation of the small bowel and a prior history of inflammatory bowel disease involving the colon. Patients with colitis that do not show specific criteria for either ulcerative colitis or Crohn's disease should be classified as indeterminant colitis, and a small bowel series is indicated. It may be indicated to obtain a small bowel series in patients with any form of colonic inflammatory bowel disease, periodically, after diagnosis.     

Surveillance colonoscopy for colitic cancer in inflammatory bowel disease

Patients with inflammatory bowel disease are known to be at increased risk for the development of colorectal cancer, especially those with long‐standing extensive ulcerative colitis. Although some recommend prophylactic total proctocolectomy for these high‐risk patients, surveillance colonoscopy to detect ulcerative colitis‐associated colorectal cancer is, instead, generally performed. Dysplasia has been considered to be a useful marker to detect colorectal cancer at surveillance colonoscopy. High‐grade dysplasia is a definite indication for total proctocolectomy, while management of low‐grade dysplasia is still controversial. Patients with Crohn's disease are also considered to be at higher risk for the development of colorectal cancer, although the risk may be lower than in extensive ulcerative colitis. Molecular biology‐based surveillance and chemoprevention for ulcerative colitis‐associated colorectal cancer are also reviewed.     

Carcinogenesis in inflammatory bowel disease

Patients with longstanding ulcerative colitis (UC) and Crohn's disease (CD) have an increased risk of colorectal cancer (CRC). CRC accounts for approximately 15% of all deaths in patients with inflammatory bowel disease (IBD). The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat dysplastic tissue or dysplasia-associated lesions or masses. The risk of CRC for patients with IBD increases by 0.5-1% yearly, 8-10 years after diagnosis. Patients with a young age at disease onset, more extensive colitis, greater inflammatory burden, concomitant primary sclerosing cholangitis, and a family history of CRC are at greatest risk. Most cancers arise in pancolitis and there is little or no increased risk associated with proctitis while left-sided colitis carries an intermediate cancer risk. The CRC risk in patients with colonic CD is similar to that of UC. Colonic dysplasia is a precursor to CRC in IBD. There is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. Newer endoscopic and molecular techniques are being assessed for their effectiveness in augmenting conventional surveillance.     

IBD-related carcinoma and lymphoma

Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Risk factors are extent and severity of colonic inflammation, concurrent primary sclerosing cholangitis, and a positive family history of sporadic CRC. The chromosomal instability, microsatellite instability and hypermethylation pathways form the molecular background of IBD-related carcinogenesis, which is not different from sporadic CRC. The dysplasia-carcinoma sequence of IBD-related colorectal carcinogenesis makes patients suitable for endoscopic surveillance. In the future, new molecular biomarkers and endoscopic techniques may improve early detection of precursor lesions of IBD-related CRC. The potential of aminosalicylates and ursodeoxycholic acid as chemopreventive agents needs to be studied in randomized clinical trials. Patients with IBD who are being treated with thiopurines have a slightly increased risk of developing lymphoproliferative disorders, whereas patients with small bowel Crohn's disease have a high relative risk and a small absolute risk of developing small bowel adenocarcinoma.     

Endoscopic surveillance in Crohn's disease and ulcerative colitis: who needs what and when?

Crohn's disease and ulcerative colitis are chronic inflammatory diseases resulting from an inappropriate innate and adaptive immune response towards commensal microbiota. Patients with Crohn's disease and ulcerative colitis carry an increased risk of developing colon cancer and/or small bowel carcinoma, respectively. The colorectal cancer risks of ulcerative colitis and Crohn's disease with comparable surface area involvement and disease duration are very similar. Early disease onset, disease extent, severity of inflammation, a family history of sporadic colorectal cancer, efficacy and duration of medical therapy, coexisting primary cholangitis and mucosal dysplasia are all risk factors for colorectal cancer. Regular endoscopic surveillance is endorsed by leading professional societies and outlined in guidelines and consensus statements. The yield of endoscopic surveillance, particularly to detect dysplasia, can be improved with chromoendoscopy with methylene blue dye spray-targeted biopsies, autofluorescence plus high-resolution endoscopy, chromoendoscopy-guided confocal laser microscopy and confocal laser microscopy in combination with narrow band imaging and high-resolution endoscopy. Proper bowel preparation, complete, careful inspection of the entire colon, a minimum withdrawal time and adherence to recommended management guidelines ensure a high-quality study and improve surveillance. Dysplasia can be graded by the Vienna or Riddell classification. Colectomy is recommended for patients with flat high-grade dysplasia confirmed by an expert gastrointestinal pathologist.     

Telomerase Activity in Chronic Inflammatory Bowel Disease

Patients with ulcerative colitis have an increased risk of developing colorectal cancer. Telomerase appears to be associated with cellular immortality and might serve as a diagnostic and prognostic marker in carcinogenesis. To test this hypothesis we measured telomerase by a score from 0 (no activity) to 4 (very high activity) in specimens obtained surgically from seven patients with adenocarcinoma of the colon. Intraindividual comparison was made among normal tissue (mean score +/- SD: 0.7 +/- 1.0), tissues adjacent to the tumor (2.7 +/- 0.8), and the tumor center (3.0 +/- 1.0). In addition, from 18 patients with ulcerative colitis, 10 patients with Crohn's disease, and 14 patients without chronic inflammatory bowel disease, biopsies were collected from normal and inflamed areas of the colon. Independent of the duration (0-32 years), grade, and location of the diseases, the telomerase activities were comparable, ranging from 0.4 to 1.0 in ulcerative colitis and from 0.3 to 0.6 in Crohn's disease and averaging 0.4 in controls. Apparently low telomerase activities are present in the mucosa of all patients and the enzyme is not yet upregulated in the potentially premalignant state of active ulcerative colitis, dismissing its prognostic value as an early tumor marker for this disorder.     

Increased group II phospholipase A2 in colonic mucosa of patients with Crohn's disease and ulcerative colitis.

The immunochemical protein content of group II phospholipase A2 (PLA2) and PLA2 enzymatic activity were measured for colonic mucosal biopsy samples obtained from patients with either Crohn's disease of the colon or ulcerative colitis, and control patients without inflammatory bowel disease. Immunoreactive group II PLA2 (IR-PLA2 II) content and PLA2 activity in actively inflamed colonic mucosa of Crohn's disease patients were significantly higher than those in inactively inflamed mucosa of Crohn's disease patients and the colonic mucosa of controls. IR-PLA2 II content and PLA2 activity in severely inflamed mucosa of ulcerative colitis patients were significantly higher than those in the colonic mucosa of the controls. Mucosal PLA2 enzymatic activity was closely correlated with mucosal IR-PLA2 II content in patients with Crohn's disease and ulcerative colitis. These results suggest that an increase in PLA2 enzymatic activity in inflamed colonic mucosa of Crohn's disease and ulcerative colitis was mainly attributed to increased protein content of group II PLA2, and that an increase in mucosal group II PLA2 may be involved in the pathogenesis of intestinal inflammation of Crohn's disease and ulcerative colitis.     

Ectopic colonic mucosa in ulcerative colitis and in Crohn's disease of the colon

Colectomy specimens from 62 patients (22 with ulcerative colitis, 20 with Crohn's disease of the colon, and 20 with invasive adenocarcinoma [without inflammatory bowel disease]) were reviewed for the presence of ectopic colonic mucosa. One or more foci of ectopic colonic mucosa were found in 16 of the 22 specimens (72 per cent) with ulcerative colitis and in 11 of the 20 specimens (55 per cent) with Crohn's disease of the colon. None of the 20 specimens having adenocarcinoma (without chronic inflammatory bowel disease) had ectopic colonic epithelium. The presence of ectopic colonic mucosa was found to be dependent on the age of the patients (more frequent among younger patients) and on the number of sections per specimen. One adenocarcinoma in a case of long-standing ulcerative colitis had apparently originated in ectopic colonic mucosa. This study was supported by grants from the Karolinska Institute.     

Screening for p53 and K-ras mutations in whole-gut lavage in chronic inflammatory bowel disease

OBJECTIVES: Molecular screening for frequently mutated genes may increase the likelihood of identifying cancer risk groups, such as patients with longstanding inflammatory bowel disease. This study investigated the prevalence and time course of p53 and K-ras mutations in colonic lavage fluid of patients with inflammatory bowel disease. METHODS: Colonic lavage fluid from 190 patients with ulcerative colitis (73), Crohn's disease (58) or controls (49 non-tumour, 10 colorectal cancer) was studied by oligomer-specific hybridization for K-ras mutations and single-strand conformation polymorphism (SSCP) for p53 mutations. Follow-up investigations were carried out after 1-3 years. RESULTS: Mutations were most frequent in carcinomas (5/10, 50%) and rare in non-tumour controls (1/49, 2.0%). They were found in Crohn's colitis in 15.4%, in extensive ulcerative colitis in 18.6%, in left-sided ulcerative colitis in 13.3%, and in distal ulcerative colitis in 6.7% (P > 0.05). There was a positive association with disease duration (> or =11 years, P < 0.05). Follow-up investigations detected the same mutation in four patients and revealed new mutations in three patients. CONCLUSIONS: In our large series of patients with inflammatory bowel disease, K-ras and p53 mutations could be detected with reasonable frequency and confirmed at follow-up in at least some patients. Our data encourage the use of molecular screening for the detection of malignant precursor lesions in at-risk patients.     

Peptide YY concentrations in normal ileum and colon and in idiopathic inflammatory bowel disease

Concentrations of the candidate endocrine and paracrine peptide, peptide YY, were measured by specific radioimmunoassay in tissue extracts prepared from normal ileum, normal colon, Crohn's disease, and ulcerative colitis. In both the ascending and descending colon, there were significantly decreased mean concentrations of peptide YY in Crohn's colitis and ulcerative colitis, compared to mean concentrations in normal colon. There was no age-related decrease of concentrations of peptide YY in normal colon. The decrease in concentrations of peptide YY in colon obtained from patients with inflammatory bowel disease did not appear related either to the duration of the clinical symptoms of the disease or to the severity of colonic inflammation. Further studies of the physiological function of peptide YY in man are needed to determine whether these findings might be useful in understanding a component of the pathophysiology of idiopathic inflammatory bowel disease.     

Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease.

Recent studies have suggested that nitric oxide (NO.), the product of nitric oxide synthase in inflammatory cells, may play a part in tissue injury and inflammation through its oxidative metabolism. In this study the colonic generation of oxides of nitrogen (NOx) and nitric oxide synthase activity was determined in ulcerative colitis and Crohn's disease. Colonic biopsy specimens were obtained from inflammatory bowel disease patients and from normal controls. Mucosal explants were cultured in vitro for 24 hours and NOx generation was determined. Nitric oxide synthase activity was monitored by the conversion of [3H]-L-arginine to citrulline. Median NOx generation by inflamed colonic mucosa of patients with active ulcerative colitis and Crohn's colitis was 4.2- and 8.1-fold respectively higher than that by normal human colonic mucosa. In ulcerative colitis and Crohn's colitis nitric oxide synthase activity was 10.0- and 3.8-fold respectively higher than in normal subjects. Colonic NOx generation is significantly decreased by methylprednisolone and ketotifen. The decrease in NOx generation by cultured colonic mucosa induced by methylprednisolone suggests that NO synthase activity is induced during the culture and the steroid effect may contribute to its therapeutic effect. Enhanced colonic NOx generation by stimulated nitric oxide synthase activity in ulcerative colitis and Crohn's disease may contribute to tissue injury.     

Colorectal cancer risk in Crohn＇s disease

There is recognized increased risk for colorectal cancer in patients with inflammatory bowel disease, particularly in long-standing and extensive ulcerative colitis. There also appears to be an increased rate of intestinal cancer in Crohn＇s disease, including both colon and small bowel sites. In Crohn＇s disease, evidence suggests that detection of colorectal cancer may be delayed with a worse prognosis. Some risk factors for cancer in Crohn＇s disease include the extent of inflammatory change within the colon and the presence of bypassed or excluded segments, inclu- ding rectal ＂stump＂ cancer. In addition, the risk for other types of intestinal neoplasms may be increased in Crohn＇s disease, including lymphoma and carcinoid tumors. Earlier detection of colorectal cancer based on colonoscopy screening and surveillance may be achieved but, to date, this has not translated into a positive survival benefit. Moreover, newer staining methods and evolving micro-endoscopic techniques show promise, but have not significantly altered management. Future research should focus on development of molecular or other bio-markers that might predict future dysplasia or cancer development in Crohn＇s disease.