This Month in Gastroenterology

Abstract

Persons with ulcerative colitis (UC) are at an increased risk for developing colorectal cancer. Surveillance colonoscopy with biopsies for histopathological evaluation is the current practice to reduce colorectal cancer (CRC) morbidity and mortality. The efficacy of this practice is still debated. Rutter et al report prospectively collected data from St. Mark’s Hospital colonoscopic surveillance program over a 30-year period. Six hundred patients with a diagnosis of UC and at least 8 years of colitis symptoms, who had begun a screening program, were included in the study. Surveillance colonoscopies were performed every 1–2 years. The primary endpoint was defined as death, colectomy, withdrawal from the surveillance program, or census date (January 1, 2001). A total of 2627 colonoscopies were performed during 5932 patient-years follow-up. There were 74 patients (12.3%) who were diagnosed with neoplasia. CRC was diagnosed in 30 patients (5%). Sixteen of these cancers were interval cancers (cancers presenting after a negative colonoscopy or an advanced cancer diagnosed at surveillance). The median duration of UC at the time of CRC diagnosis was 23.5 (range, 11–48). The cumulative incidence of CRC calculated according to the duration of colitis was 2.5% at 20 years, 7.6% at 30 years, and 10.8% at 40 years (Figure 1). This study demonstrated a benefit from surveillance in 69% of patients with cancer or surgically confirmed dysplasia. These findings suggest that the surveillance program at St. Mark’s Hospital is effective in reducing morbidity and mortality related to CRC in the UC patient population. Nonetheless, our current means of surveillance are far from perfect, and improved screening methods are needed. See page 1030 The true overall risk of colorectal cancer in ulcerative colitis (UC) and Crohn’s disease (CD) is not certain. Several studies have addressed this issue and have resulted in different estimates of risk. These various estimates are likely a result of different study designs and study populations. Studies conducted in referral centers typically generate higher risk estimates than those calculated from population-based studies. Jess et al report the first study in over 20 years to address the incidence of intestinal cancer in a population-based IBD cohort. The study by Jess et al was performed in Olmsted County, Minnesota, and followed 692 patients with IBD (378 UC, 314 CD) who were diagnosed with IBD between the years 1940 and 2001. Person-years were calculated from the year of diagnosis to the year of intestinal cancer diagnosis, death, or December 31, 2002. Standardized incidence ratios (SIR, observed number of cancers/expected number of cancers) and cumulative probability of cancer were estimated. Expected rates of cancer were obtained from the Surveillance, Epidemiology, and End Results, Iowa whites, 1973–2000, and Olmsted County, 1980–1999. The data were also stratified according to disease extent or location and according to disease duration for both UC and for CD (Figures 2 and 3).Figure 3Cumulative incidence of colorectal cancer in patients with Crohn’s disease (n = 314) compared with expected incidence of cancer (SEER data, Iowa whites, 1973–2000) (P = .66, log-rank). A population-based cohort study from Olmsted County, Minnesota, 1940–2001.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Six CRCs were observed in the UC cohort compared with 5.38 expected cases (SIR 1.1; 95% CI, 0.4–2.4). When the data were stratified according to disease extent, the CRC risk was greatest in extensive colitis (SIR 2.4; 95% CI, 0.6–6.0). There was no relationship between CRC risk in UC and disease duration. Six CRCs were observed in the CD cohort compared with 3.2 expected cases (SIR 1.9; 95% CI, 0.7–4.1). Surprisingly, CRC risk was greater in subjects with only small bowel involvement (SIR 3.0; 95% CI, 0.6–8.7) and was not increased in CD patients with only colonic involvement (SIR 0.8; 95% CI, 0.02–4.7). There was no relationship between CRC risk in CD and disease duration. Three patients with CD developed small bowel cancer compared with 0.07 expected cases (SIR 41.1; 95% CI, 8.5–120). This population-based study did not find an increased risk of CRC in UC patients, although the risk was elevated in patients with extensive colitis. There was a slight increase in CRC risk and a 40-fold increase in small bowel cancer in patients with CD. See page 1039 Corticosteroids are often used to treat active Crohn’s disease. While corticosteroids are an effective therapy for the treatment of active Crohn’s disease, 20%–40% of patients treated with corticosteroids become steroid-dependent. Furthermore, corticosteroids are associated with many systemic adverse effects limiting their usefulness in inflammatory bowel disease. While azathioprine (AZA) and 6-mercaptopurine (6-MP) are effective steroid sparing agents in the treatment of Crohn’s disease, their onset of action is typically 3 months. Lemann et al set out to evaluate the utility of infliximab (given at 0, 2, and 6 weeks) in addition to AZA or 6-MP compared with AZA/6-MP alone in achieving clinical remission off steroids in steroid-dependent Crohn’s disease patients. One hundred thirteen patients were enrolled in the trial and randomized to receive AZA (2–3 mg/kg per day) or 6-MP (1–1.5 mg/kg per day) and either infliximab or placebo. Patients were stratified according to whether they had been receiving AZA/6-MP for more than 6 months (failure stratum) at inclusion or were naïve to immunomodulatory therapy (naïve stratum). The primary endpoint was remission off steroids at week 24. The percentage of patients achieving the primary endpoint was significantly higher in patients receiving infliximab compared with placebo (57% vs 29%; OR 3.3; 95% CI: 1.5–7.4; P = .003). In both the naïve and failure stratum, the success rate was significantly higher in the infliximab group compared with the placebo group at weeks 12 and 24 (Figure 4). At 52 weeks, the success rate in the infliximab group was significantly better than placebo among patients in the naïve stratum, but was not significantly better in the failure stratum. Only 27% of patients treated with infliximab in the failure stratum were in clinical remission at 52 weeks compared with 52% of patients treated with infliximab in the naïve stratum. In all patients, steroid resistance was significantly lower in patients treated with infliximab (5% vs 23%, OR 5.1; 95% CI: 1.3–19.2; P = .001), and the median cumulative dose of prednisone was significantly lower in the infliximab group compared with the placebo group. Factors associated with clinical remission at 24 weeks identified in multivariate logistic regression analysis included low CDAI at baseline, young age, absence of small bowel disease, and long duration of steroids before entry into the trial. The results of this study suggest that the combination of infliximab given for 3 doses with AZA or 6-MP in steroid-dependent patients increases the rate of clinical remission off steroids at 24 weeks compared with AZA/6-MP given alone. In steroid-dependent patients naïve to AZA or 6-MP, infliximab may be useful as a bridge to AZA/6-MP therapy. See page 1054 FATP5, a member of the fatty acid transport protein family, is involved in the uptake of fatty acids in the liver. It has also been suggested that FATP5 plays an active role in bile acid metabolism by acting as a bile acid-CoA ligase. Hubbard et al used their recently developed FATP5 knockout mouse to examine the role of FATP5 in bile acid conjugation, de novo synthesis, and body weight homeostasis in vivo. The total bile acid concentrations in the gallbladder bile, feces, liver, serum, and urine were similar in the FATP5 and wild-type mice. Interestingly, while 95% of the bile acids in the gallbladder bile were conjugated in the wild-type mice, only 17% of the bile acids were conjugated in the FATP5 knockout mice. Eighty-three percent of bile acids were unconjugated in the FATP5 knockout mice compared with only 5% in the wild-type mice. These findings suggest FATP5 is crucial in the conjugation of bile acids. These authors also measured the concentrations of taurochenodeoxycholate, a conjugated bile acid produced through de novo synthesis in the liver. This conjugated bile acid was found in similar concentrations in the FATP5 knockout mice and wild-type mice supporting the concept that the deletion of FATP5 does not interfere with de novo synthesis of bile acids (Figure 5). Furthermore, FATP5 knockout mice had similar body weights and lengths compared with the wild-type mice, and minimal fat malabsorption even in the presence of a high-fat diet. Nonetheless, the FATP5 deletion mice showed decreased food intake and increased energy expenditure on a high-fat diet resulting in a resistance to diet-induced obesity. The FATP5 knockout mice demonstrated improved glucose tolerance profiles and a trend toward decreased plasma insulin on the high-fat diet. These authors conclude that FATP5 is the major bile acid-CoA ligase in vivo. Furthermore, decreased bile acid conjugation in these knockout mice did not result in significant fat malabsorption or cholestasis, but the deletion of this protein is important for body weight homeostasis in the presence of a high-fat diet. See page 1259 Thirty-Year Analysis of a Colonoscopic Surveillance Program for Neoplasia in Ulcerative ColitisGastroenterologyVol. 130Issue 4PreviewBackground & Aims: The value of colonoscopic surveillance for neoplasia in long-standing extensive ulcerative colitis remains controversial. This study reports on prospectively collected data from a surveillance program over a 30-year period. Methods: Data were obtained from the prospective surveillance database, medical records, colonoscopy, and histology reports. The primary end point was defined as death, colectomy, withdrawal from surveillance, or census date (January 1, 2001). Follow-up information was obtained for patients who left the program. Full-Text PDF Risk of Intestinal Cancer in Inflammatory Bowel Disease: A Population-Based Study From Olmsted County, MinnesotaGastroenterologyVol. 130Issue 4PreviewThe 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. Full-Text PDF Infliximab Plus Azathioprine for Steroid-Dependent Crohn’s Disease Patients: A Randomized Placebo-Controlled TrialGastroenterologyVol. 130Issue 4PreviewBackground & Aims: The aim of this study was to evaluate the usefulness of short-term infliximab combined with azathioprine (AZA) or 6-mercaptopurine (6-MP) in steroid-dependent Crohn’s disease patients. Methods: Patients with active disease despite prednisone given for more than 6 months were eligible and were stratified as follows: the failure stratum consisted of patients receiving AZA/6-MP at a stable dose for more than 6 months, and the naive stratum consisted of patients not treated previously with AZA/6-MP. Full-Text PDF Mice Deleted for Fatty Acid Transport Protein 5 Have Defective Bile Acid Conjugation and Are Protected From ObesityGastroenterologyVol. 130Issue 4PreviewBackground & Aims: Fatty Acid Transport Protein 5 (FATP5) is a liver-specific member of the FATP/Slc27 family, which has been shown to exhibit both fatty acid transport and bile acid-CoA ligase activity in vitro. Here, we investigate its role in bile acid metabolism and body weight homeostasis in vivo by using a novel FATP5 knockout mouse model. Methods: Bile acid composition was analyzed by mass spectroscopy. Body weight, food intake, energy expenditure, and fat absorption were determined in animals fed either a low- or a high-fat diet. Full-Text PDF