Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals.

BACKGROUND: Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS: During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99­1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. FUNDING: British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.

Prevalence, management, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding in the United Kingdom.

BACKGROUND: Coagulopathy after major hemorrhage has been found to be an independent risk factor for mortality after traumatic bleeding. It is unclear whether similar associations are present in other causes of major hemorrhage. We describe the prevalence, use of plasma, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding (NVUGIB). STUDY DESIGN AND METHODS: This study was a multicenter UK national audit. Data were collected prospectively on consecutive admissions with upper gastrointestinal bleeding over a 2-month period to 212 UK hospitals. Coagulopathy was defined as an international normalized ratio (INR) of at least 1.5. Logistic regression was used to examine the relationship between coagulopathy and patient-related outcome measures of mortality, rebleeding, and need for surgery and/or radiologic intervention. RESULTS: A total of 4478 patients were included in the study. Coagulopathy was present in 16.4% (444/2709) of patients in whom an INR was recorded. Patients with coagulopathy were more likely to present with hemodynamic shock (45% vs. 36%), have a higher clinical Rockall score (4 vs. 2), receive red blood cell transfusion (79% vs. 48%) and have high-risk stigmata of hemorrhage at endoscopy (34% vs. 25%). After adjustment for confounders the presence of a coagulopathy was associated with a fivefold increased in the odds of mortality (odds ratio, 5.63; 95% confidence interval, 3.09-10.27; p < 0.001). Only 35% of patients with coagulopathy received fresh-frozen plasma transfusion. CONCLUSIONS: Coagulopathy was prevalent in 16% of patients after NVUGIB and independently associated with more than a fivefold increase in the odds of in-hospital mortality. Wide variation in plasma use exists indicates clinical uncertainty regarding optimal practice.

Outcomes of the Bowel Cancer Screening Programme (BCSP) in England after the first 1 million tests.

INTRODUCTION: The Bowel Cancer Screening Programme in England began operating in 2006 with the aim of full roll out across England by December 2009. Subjects aged 60-69 are being invited to complete three guaiac faecal occult blood tests (6 windows) every 2 years. The programme aims to reduce mortality from colorectal cancer by 16% in those invited for screening. METHODS: All subjects eligible for screening in the National Health Service in England are included on one database, which is populated from National Health Service registration data covering about 98% of the population of England. This analysis is only of subjects invited to participate in the first (prevalent) round of screening. RESULTS: By October 2008 almost 2.1 million had been invited to participate, with tests being returned by 49.6% of men and 54.4% of women invited. Uptake ranged between 55-60% across the four provincial hubs which administer the programme but was lower in the London hub (40%). Of the 1.08 million returning tests 2.5% of men and 1.5% of women had an abnormal test. 17,518 (10,608 M, 6910 F) underwent investigation, with 98% having a colonoscopy as their first investigation. Cancer (n=1772) and higher risk adenomas (n=6543) were found in 11.6% and 43% of men and 7.8% and 29% of women investigated, respectively. 71% of cancers were 'early' (10% polyp cancer, 32% Dukes A, 30% Dukes B) and 77% were left-sided (29% rectal, 45% sigmoid) with only 14% being right-sided compared with expected figures of 67% and 24% for left and right side from UK cancer registration. CONCLUSION: In this first round of screening in England uptake and fecal occult blood test positivity was in line with that from the pilot and the original European trials. Although there was the expected improvement in cancer stage at diagnosis, the proportion with left-sided cancers was higher than expected.

Why do mortality rates for nonvariceal upper gastrointestinal bleeding differ around the world? A systematic review of cohort studies.

BACKGROUND: Discrepancies exist in reported mortality rates of nonvariceal upper gastrointestinal bleeding (NVUGIB). OBJECTIVE: To perform a systematic review assessing possible reasons for these disparate findings and to more reliably compare them. METHODS: The MEDLINE, EMBASE and ISI Web of Knowledge databases were searched for studies reporting mortality rates in NVUGIB involving adults and published in English. To ensure robust and contemporary estimates, studies spanning 1996 to January 2011 that included more than 1000 patients were selected. RESULTS: Eighteen of 3077 studies were selected. Ten studies used administrative databases and the remaining eight used registries. The mortality rates reported in these studies ranged from 1.1% in Japan to 11% in Denmark. There were variations in reported mortality rates among countries and also within countries. Reasons for these disparities included a spectrum of quality in reporting as well as heterogeneous definitions of case ascertainment, differing patient populations with regard to severity of presentation and associated comorbidities, varying durations of follow-up and different health care system-related practices. CONCLUSIONS: Wide differences in reported NVUGIB mortality rates are attributable to differences in adopted methodologies and populations studied. More uniform standards in reporting are needed; only then can true observed variations enable a better understanding of causes of death and pave the way to improved patient outcomes.

Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit.

OBJECTIVE: To describe the patient characteristics, diagnoses and clinical outcomes of patients presenting with acute upper gastrointestinal bleeding (AUGIB) in the 2007 UK Audit. DESIGN: Multi-centre survey. SETTING: All UK hospitals admitting patients with AUGIB. PARTICIPANTS: All adults (>16 years) presenting in or to UK hospitals with AUGIB between 1 May and 30 June 2007. RESULTS: Data on 6750 patients (median age 68 years) was collected from 208 participating hospitals. New admissions (n=5550) were younger (median age 65 years) than inpatients (n=1107, median age 71 years), with less co-morbidity (any co-morbidity 46% vs 71%, respectively). At presentation 9% (599/6750) had known cirrhosis, 26% a history of alcohol excess, 11% were taking non-steroidal anti-inflammatory drugs and 28% aspirin. Peptic ulcer disease accounted for 36% of AUGIB and bleeding varices 11%. In 13% there was evidence of further bleeding after the first endoscopy. 1.9% underwent surgery and 1.2% interventional radiology for AUGIB. Median length of stay was 5 days. Overall mortality in hospital was 10% (675/6750, 95% CI 9.3 to 10.7), 7% in new admissions and 26% among inpatients. Mortality was highest in those with variceal bleeding (15%) and with malignancy (17%). CONCLUSIONS: AUGIB continues to result in substantial mortality although it appears to be lower than in 1993. Mortality is particularly high among inpatients and those bleeding from varices or upper gastrointestinal malignancy. Surgical or radiological interventions are little used currently.

Red blood cell transfusion practice in patients presenting with acute upper gastrointestinal bleeding: a survey of 815 UK clinicians.

BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) accounts for 14% of all red blood cell (RBC) transfusions in the United Kingdom, despite little evidence to guide optimal blood transfusion strategies and few data on the variation in practice. We aimed to survey UK clinicians about their RBC transfusion practice in AUGIB. STUDY DESIGN AND METHODS: A survey describing six clinical vignettes of AUGIB was sent to practicing gastroenterologists, acute care physicians, and upper gastrointestinal surgeons. Respondents were asked to select a hemoglobin (Hb) trigger at which they would ordinarily transfuse RBCs. RESULTS: The response rate was 48% (815/1709). Transfusion triggers differed significantly between all six cases (p < 0.001). There was significant variation in the selected Hb trigger between different clinical specialties for five of the six scenarios. Surgeons were more likely to select a lower Hb transfusion trigger than physicians across all six scenarios (p < 0.005), as were clinicians who had graduated more recently (p < 0.05 for Scenarios 1-3). The responses suggested the belief that restrictive use of RBCs is appropriate, which is in part discordant with actual observed practice. Only 70% of respondents reported familiarity with national guidelines for AUGIB. CONCLUSIONS: There is significant variation in the reported approach to transfusion practice among clinicians caring for patients with AUGIB, with both patient- and clinician-related factors accounting for these differences. Further studies are needed to evaluate the safety and efficacy of differing blood transfusion strategies in patients presenting with AUGIB.

Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit.

OBJECTIVES: To examine the use of endoscopy in the UK for acute upper gastrointestinal bleeding (AUGIB) and compare with published standards. To assess the organisation of endoscopy services for AUGIB in the UK. To examine the relationship between outcomes and out of hours (OOH) service provision. DESIGN: Multi-centre cross sectional clinical audit. SETTING: All UK hospitals accepting admissions with AUGIB. PATIENTS: All adults (>or=16 yrs) presenting with AUGIB between 1st May and 30th June 2007. DATA: Collection A custom designed web-based reporting tool was used to collect data on patient characteristics, comorbidity and haemodynamic status at presentation to calculate the Rockall score, use and timing of endoscopy, treatment including endoscopic, rebleeding and in-hospital mortality. A mailed questionnaire was used to collect data on facilities and service organisation. RESULTS: Data on 6750 patients (median age 68 years) were analysed from 208 hospitals. 74% underwent inpatient endoscopy; of these 50% took place within 24 h of presentation, 82% during normal working hours and 3% between midnight and 8 am. Of patients deemed high-risk (pre-endoscopy Rockall score >or=5) only 55% were endoscoped within 24 h and 14% waited >or=72 h for endoscopy. Lesions with a high risk of rebleeding were present in 28% of patients of whom 74% received endoscopic therapy. Further bleeding was evident in 13% and mortality in those endoscoped was 7.4% (95% CI 6.7% to 8.1%). In 52% of hospitals a consultant led out of hours (OOH) endoscopy rota existed; in these hospitals 20% of first endoscopies were performed OOH compared with 13% in those with no OOH rota and endoscopic therapy was more likely to be administered (25% vs 21% in hospitals with no OOH rota). The risk adjusted mortality ratio was higher (1.21, p=0.10, (95%CI 0.96 to 1.51)) in hospitals without such rotas. CONCLUSIONS: This audit has found continuing delays in performing endoscopy after AUGIB and underutilisation of standard endoscopic therapy particularly for variceal bleeding. In hospitals with a formal OOH endoscopy rota patients received earlier endoscopy, were more likely to receive endoscopic therapy and may have a lower mortality.

Aspirin and folic acid for the prevention of recurrent colorectal adenomas.

BACKGROUND & AIMS: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from randomized trials using aspirin have been inconsistent. Dietary folate intake also has been found to be associated with a reduced risk of colorectal neoplasms in observational studies. METHODS: A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence was performed using a 2 x 2 factorial design. All patients had an adenoma (>/=0.5 cm) removed in the 6 months before recruitment and were followed-up at 4-month intervals with a second colonoscopy after approximately 3 years. The primary outcome measure was a colorectal adenoma diagnosed after baseline. RESULTS: A total of 945 patients were recruited into the study, of whom 853 (90.3%) underwent a second colonoscopy. In total, 99 (22.8%) of 434 patients receiving aspirin had a recurrent adenoma compared with 121 (28.9%) of 419 patients receiving placebo (relative risk, 0.79; 95% confidence interval [CI], 0.63-0.99). A total of 104 patients developed an advanced colorectal adenoma; 41 (9.4%) of these were in the aspirin group and 63 (15.0%) were in the placebo group (relative risk, 0.63; 95% CI, 0.43-0.91). Folate supplementation was found to have no effect on adenoma recurrence (relative risk, 1.07; 95% CI, 0.85-1.34). CONCLUSIONS: Aspirin (300 mg/day) but not folate (0.5 mg/day) use was found to reduce the risk of colorectal adenoma recurrence, with evidence that aspirin could have a significant role in preventing the development of advanced lesions.

Cholesterol profile in people with newly diagnosed coeliac disease: a comparison with the general population and changes following treatment.

Recent studies have suggested that untreated coeliac disease is associated with lower total cholesterol than in the general population while the effect of treatment with a gluten-free diet on the cholesterol profile of clinically apparent coeliac disease is not known. We measured the cholesterol profile at diagnosis, and compared this with Health Survey for England figures, and again following 12 months treatment with a gluten-free diet in 100 consecutive adults with coeliac disease attending the Royal Hallamshire Hospital, Sheffield, UK. The mean total cholesterol was 4.84 (SD 1.2) mmol/l in adults (mean age 51 (SD 16) years) newly diagnosed with coeliac disease. At diagnosis of coeliac disease, men had 21% lower and women had 9% lower mean total cholesterol in comparison to the general population (difference in age-adjusted mean total cholesterol -1.09 mmol/l (95% CI -0.97, - 1.21); -0.46 mmol/l (95% CI -0.24, -0.68), respectively). There was no change in mean total cholesterol following treatment. However, there was a small but statistically significant increase of 0.12 mmol/l (95% CI 0.05, 0.18) in the mean HDL-cholesterol. Total cholesterol was lower at diagnosis in coeliac patients than in the general population and did not increase with 1 year of a gluten-free diet while HDL-cholesterol increased following treatment. Any increase in risk of IHD or stroke in people with coeliac disease is unlikely due to an adverse cholesterol profile either before diagnosis or after treatment with a gluten-free diet.

Ornithine decarboxylase G316A genotype is prognostic for colorectal adenoma recurrence and predicts efficacy of aspirin chemoprevention.

PURPOSE: The chemopreventive activity of aspirin in colorectal neoplasia may be explained in part by its effect on polyamine metabolism. The ornithine decarboxylase (ODC) G316A polymorphism affects polyamine metabolism through altered expression of ODC. We investigated the influence of ODC G316A on the chemopreventive activity of aspirin in colorectal adenoma (CRA) recurrence. EXPERIMENTAL DESIGN: We genotyped ODC G316A in 546 individuals in the United Kingdom Colorectal Adenoma Prevention trial of aspirin for CRA recurrence prevention and pooled our findings with data from two other randomized intervention trials. RESULTS: The United Kingdom Colorectal Adenoma Prevention participants with homozygous ODC 316AA genotype were at reduced CRA recurrence risk [relative risk (RR), 0.43; 95% confidence interval (95% CI), 0.16-1.15], particularly if also exposed to aspirin (RR, 0.24; 95% CI, 0.03-1.71). In the pooled analysis of 2,207 individuals, those with homozygous ODC 316AA genotype were at significantly reduced CRA recurrence risk (RR, 0.68; 95% CI, 0.47-0.99). Following stratification by genotype and aspirin exposure, individuals with homozygous wild-type or heterozygous genotypes derived modest benefit from aspirin (RR, 0.85; 95% CI, 0.72-1.01), whereas in those with both ODC 316AA genotype and aspirin exposure recurrence risk was halved (RR, 0.52; 95% CI, 0.29-0.91). CONCLUSION: The ODC G316A genotype is prognostic for CRA recurrence and predictive of an enhanced response to aspirin in preventing recurrence. This variant has the potential to be a clinically useful genetic marker to identify individuals likely to derive the greatest benefit from aspirin chemoprevention.

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence.

Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence.

The iceberg of celiac disease: what is below the waterline?

BACKGROUND & AIMS: We explored the relationships between anti-tissue transglutaminase antibody and indirect measures of malabsorption and disease activity in people with undetected celiac disease. METHODS: From the Cambridge General Practice Health Study, 7550 participants' serum samples were tested for antiendomysial antibody (EMA). The 87 samples positive for EMA were tested for human anti-tissue transglutaminase antibody (TGA). Multivariate linear regression was used to explore the relationship between TGA concentrations and various physiologic and anthropometric measures. RESULTS: Among the 87 EMA-positive people, there were consistent relationships between increasing TGA levels and various physiologic and anthropometric measures. A 50% increase in the mean TGA level was associated with a 0.02 g/cm2 (95% confidence interval [CI], -0.03 to -0.009) lower mean hip bone mineral density, a 0.1 g/dL (95% CI, -0.17 to -0.01) lower mean hemoglobin, a 0.22 kg/m2 (95% CI, -0.46 to 0.03) lower mean body mass index, a 0.09 mmol/L (95% CI, -0.16 to -0.02) lower serum cholesterol, and a 0.1 mmol/L (95% CI, 0.04 to 0.16) higher random blood glucose concentration, independent of age, sex, and smoking habit. CONCLUSIONS: The relationships we found between concentrations of TGA and various physiologic and anthropometric variables suggest that in reality, celiac disease is a continuum with a variable degree of severity. Although clinically overt disease is defined by symptoms, signs, and small bowel histology, the severity of previously undetected disease variously labeled in the past as silent, potential, or latent could, instead, be estimated by the concentration of a detectable serum antibody.

Genetic variants of UGT1A6 influence risk of colorectal adenoma recurrence.

PURPOSE: The UDP glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9) enzymes participate in the metabolism of nonsteroidal anti-inflammatory drugs, endogenous substances, and carcinogens. Functional polymorphisms of UGT1A6 (T181A and R184S) and CYP2C9 (R144C and I359L) have been reported to modify the protective effect of aspirin on colorectal adenoma risk. We aimed to further investigate the effect of these genetic variants on the development of colorectal neoplasia. EXPERIMENTAL DESIGN: We examined the relationship between UGT1A6 and CYP2C9 genotype and colorectal adenoma recurrence in 546 patients participating in a randomized placebo-controlled aspirin intervention trial. RESULTS: Although colorectal adenoma recurrence was not significantly influenced by CYP2C9 genotype, carriers of variant UGT1A6 alleles were at significantly reduced risk of colorectal neoplasia recurrence [relative risk (RR), 0.68; 95% confidence interval (95% CI), 0.52-0.89]. This risk reduction was also evident when the analysis was confined to advanced neoplasia recurrence (RR, 0.71; 95% CI, 0.47-1.09). When patients were stratified by genotype and aspirin intervention, those with variant UGT1A6 alleles were at reduced recurrence risk irrespective of whether they received aspirin or placebo (RR, 0.62; 95% CI, 0.42-0.92 and RR, 0.63; 95% CI, 0.44-0.91, respectively). CONCLUSIONS: These findings confirm that UGT1A6 variants influence colorectal carcinogenesis independent of aspirin intake and suggest that they may have clinical value in secondary prevention programs for patients diagnosed with colorectal adenoma.

Restrictive versus liberal blood transfusion for gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Acute upper gastrointestinal bleeding is a leading indication for red blood cell (RBC) transfusion worldwide, although optimal thresholds for transfusion are debated. METHODS: We searched MEDLINE, Embase, CENTRAL, CINAHL, and the Transfusion Evidence Library from inception to Oct 20, 2016, for randomised controlled trials comparing restrictive and liberal RBC transfusion strategies for acute upper gastrointestinal bleeding. Main outcomes were mortality, rebleeding, ischaemic events, and mean RBC transfusion. We computed pooled estimates for each outcome by random effects meta-analysis, and individual participant data for a cluster randomised trial were re-analysed to facilitate meta-analysis. We compared treatment effects between patient subgroups, including patients with liver cirrhosis, patients with non-variceal upper gastrointestinal bleeding, and patients with ischaemic heart disease at baseline. FINDINGS: We included four published and one unpublished randomised controlled trial, totalling 1965 participants. The number of RBC units transfused was lower in the restrictive transfusion group than in the liberal transfusion group (mean difference -1·73 units, 95% CI -2·36 to -1·11, p<0·0001). Restrictive transfusion was associated with lower risk of all-cause mortality (relative risk [RR] 0·65, 95% CI 0·44-0·97, p=0·03) and rebleeding overall (0·58, 0·40-0·84, p=0·004). We detected no difference in risk of ischaemic events. There were no statistically significant differences in the subgroups. INTERPRETATION: These results support more widespread implementation of restrictive transfusion policies for adults with acute upper gastrointestinal bleeding. FUNDING: None.

Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence.

Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas.

Toxicity of mycophenolate mofetil in patients with inflammatory bowel disease.

Trials of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) suggest that it may be useful in patients intolerant of azathioprine. We examined the safety and efficacy of MMF in IBD patients intolerant of or unresponsive to azathioprine. Twelve patients [seven with Crohn's disease (CD); seven women; mean age 40 years, range 14-76 years] were treated with MMF 500 mg b.i.d. for a mean of 12.5 weeks. Intolerance was defined as the development of side effects that resolved on discontinuing MMF. Improvement was described as symptomatic improvement, decreased steroid use, or disease entering endoscopic remission. Four patients responded with symptomatic improvement and reduced steroids or mesalazine requirement. Three patients developed headache, nausea, or arthralgia. Three patients developed profuse bloody diarrhea, and in two cases with previously quiescent ulcerative colitis (UC), the source was shown to be ulcers in a drug-induced colitis with histologic features similar to those previously reported in four renal transplant patients on MMF. There is no clear evidence of efficacy of MMF in the treatment of IBD, and its use in this condition should be confined to a randomized controlled trial. Moreover, as patients with UC may be unduly prone to colonic injury, MMF may not be a suitable drug for its treatment.

How often is a positive faecal occult blood test the result of coeliac disease?

BACKGROUND AND AIMS: It has been reported that occult gastrointestinal bleeding as detected by faecal occult blood (FOB) testing can occur in coeliac disease. This study examines whether a positive FOB is a feature of coeliac disease and whether FOB-positive subjects need investigation for coeliac disease. METHODS: First, the records of patients on the Nottingham Register for Coeliac Disease were reviewed for positive FOB testing. Second, the Nottingham colorectal cancer screening trial database was also reviewed to examine how many coeliac patients on the Register had participated and to examine their FOB results. Finally, sera from 309 screening trial participants who were FOB-positive but had no colonic abnormality were screened for immunoglobulin A (IgA) gliadin and IgA endomysial and human tissue transglutaminase (tTG) IgA antibodies. RESULTS: Five of 590 patients on the Register had had FOB tests at the time of diagnosis; four had positive tests during investigation of diarrhoea and/or anaemia. Of 21 patients on the Register who had participated in the colorectal cancer screening trial, one had a positive FOB test and was found to have a rectal tubulo-villous adenoma. Of the 309 FOB-positive patients, 7% (22 subjects) were positive for IgA gliadin antibodies, but none had IgA endomysial antibodies detected and two subjects had positive human tTG antibody assays for coeliac disease. CONCLUSIONS: Occult gastrointestinal bleeding occurs in a small number of symptomatic coeliac disease patients before diagnosis, but is no more frequent in treated and undetected coeliac disease patients than in the general population. Unless there are other indications, coeliac disease does not need to be considered in the investigation of a positive FOB test.