Alternative diagnoses and demographics associated with a raised quantitative faecal immunochemical test in symptomatic patients.

BACKGROUND: The faecal immunochemical test (FIT) has proven utility for colorectal cancer detection in symptomatic patients. However, most patients with a raised faecal haemoglobin (f-Hb) do not have colorectal cancer. We investigated alternative diagnoses and demographics associated with a raised f-Hb in symptomatic patients. METHODS: A retrospective, observational study was performed of patients with FIT submitted between August 2018 to January 2019 in NHS Greater Glasgow and Clyde followed by colonoscopy. Colonoscopy/pathology reports were searched for alternative diagnoses. Covariables were compared using the χ2 test. Multivariate binary logistic regression identified independent predictors of a raised f-Hb. RESULTS: 1272 patients were included. In addition to colorectal cancer (odds ratio (OR), 9.27 (95% confidence interval (CI): 3.61-23.83; p < 0.001)), older age (OR, 1.52 (95% CI: 1.00-2.32; p = 0.05)), deprivation (OR, 1.54 (95% CI: 1.21-1.94; p < 0.001)), oral anticoagulants (OR, 1.78 (95% CI: 1.01-3.15; p = 0.046)), rectal bleeding (OR, 1.47 (95% CI: 1.15-1.88; p = 0.002)), advanced adenoma (OR, 7.52 (95% CI: 3.90-14.49; p < 0.001)), non-advanced polyps (OR, 1.78 (95% CI: 1.33-2.38; p < 0.001)) and inflammatory bowel disease (IBD) (OR, 4.19 (95% CI: 2.17-8.07; p < 0.001)) independently predicted raised f-Hb. Deprivation (Scottish Index of Multiple Deprivation (SIMD) 1-2: OR, 2.13 (95% CI: 1.38-3.29; p = 0.001)) independently predicted a raised f-Hb in patients with no pathology found at colonoscopy. CONCLUSIONS: An elevated f-Hb is independently associated with older age, deprivation, anticoagulants, rectal bleeding, advanced adenoma, non-advanced polyps and IBD in symptomatic patients. Deprivation is associated with a raised f-Hb in the absence of pathology. This must be considered when utilising FIT in symptomatic patients.

Combining the quantitative faecal immunochemical test and full blood count reliably rules out colorectal cancer in a symptomatic patient referral pathway.

PURPOSE: Faecal Immunochemical Test (FIT) has proven utility for Colorectal Cancer (CRC) detection in symptomatic patients. Most studies have examined FIT in symptomatic patients subsequently referred from primary care. We investigated associations between CRC and FIT in both referred and non-referred symptomatic patients. METHODS: A retrospective, observational study of all patients with a FIT submitted Aug 2018 to Jan 2019 in NHS GG&C was performed. Referral to colorectal/gastroenterology and decision to perform colonoscopy were recorded. FIT results were grouped as f-Hb < 10/10-149/150-399/ ≥ 400 µg/g. The MCN cancer registry identified new cases of CRC. Covariables were compared using the χ2 test. Multivariate binary logistic regression identified independent predictors of CRC. RESULTS: A total of 4968 patients were included. Raised FIT correlated with decision to refer (p < 0.001) and scope (p < 0.001). With 23-month median follow-up, 61 patients were diagnosed with CRC. These patients were older (median 69 vs 59 years, cancer and no cancer respectively, p = 0.001), more likely to be male (55.7% vs 42.1%, p = 0.033), and to report rectal bleeding (51.7% vs 36.1%, p = 0.013). FIT (< 10 µg/g 8.2% vs 76.7% and ≥ 400 µg/g 55.7% vs 3.8%, p < 0.001) and anaemia (45.9% vs 19.7%, p < 0.001) were associated with CRC. On multivariate analysis, age (p = 0.023), male sex (p = 0.04), FIT (≥ 400 OR 54.256 (95% CI:20.683-142.325; p < 0.001)), and anaemia (OR 1.956 (1.071-3.574; p = 0.029)) independently predicted CRC. One patient (0.04%) with a negative FIT and normal haemoglobin had CRC. CONCLUSION: GP referral and secondary care investigation patterns were influenced by FIT. The combination of normal Hb and f-Hb excluded CRC in 99.96% of cases, providing excellent reassurance to those prioritising access to endoscopy services.

Yield of colorectal cancer at colonoscopy according to faecal haemoglobin concentration in symptomatic patients referred from primary care.

AIM: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). The aim of this study was to examine the diagnostic yield of colonoscopy by faecal haemoglobin (f-Hb) concentration in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). METHOD: In three Scottish NHS Boards, FIT kits (HM-JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by general practitioners to guide referrals for patients with lower GI symptoms (laboratory data studied for 12 months from December 2015 onwards in Tayside, 18 months from June 2018 onwards in Fife and 5 months from September 2018 onwards in Greater Glasgow and Clyde). Cases of CRC diagnosed at colonoscopy were ascertained from colonoscopy and pathology records. RESULTS: Four thousand eight hundred and forty one symptomatic patients who underwent colonoscopy after FIT submission were included. Of the 2166 patients (44.7%) with f-Hb <10 µg Hb/g faeces (µg/g), 14 (0.6%) were diagnosed with CRC, with a number needed to scope (NNS) of 155. Of the 2675 patients (55.3%) with f-Hb ≥10 µg/g, 252 were diagnosed with CRC (9.4%) with a NNS of 11. Of the 705 patients with f-Hb ≥400 µg/g, 158 (22.4%) were diagnosed with CRC with a NNS of 5. Over half of those diagnosed with CRC with f-Hb <10 µg/g had coexisting anaemia. CONCLUSION: Symptomatic patients with f-Hb ≥10 µg/g should undergo further investigation for CRC, while higher f-Hb concentrations could be used to triage for urgency during the COVID-19 recovery phase. Patients with f-Hb <10 µg/g and without anaemia are very unlikely to be diagnosed with CRC and the majority need no further investigation.

Randomized controlled trial: Flexible sigmoidoscopy as an adjunct to faecal occult blood testing in population screening.

OBJECTIVES: Flexible sigmoidoscopy screening at around age 60 can reduce colorectal cancer incidence. Insufficient evidence exists on flexible sigmoidoscopy at age 60 in a population being offered biennial faecal occult blood test screening from age 50. This randomized controlled trial assessed if flexible sigmoidoscopy would be an effective adjunct to faecal occult blood test. METHODS: In the Scottish Bowel Screening Programme between June 2014 and December 2015, 51,769 individuals were randomized to be offered flexible sigmoidoscopy instead of faecal occult blood test at age 60 or to continue faecal occult blood test. Those not accepting flexible sigmoidoscopy and those with normal flexible sigmoidoscopy were offered faecal occult blood test. All with flexible sigmoidoscopy-detected neoplasia or a positive faecal occult blood test result were offered colonoscopy. RESULTS: Overall flexible sigmoidoscopy uptake was 17.8%, higher in men than women, and decreased with increasing deprivation (25.7% in the least to 9.2% in the most deprived quintile). In those who underwent flexible sigmoidoscopy, detection rate for colorectal cancer was 0.13%, for adenoma 7.27%, and for total neoplasia 7.40%. In those who underwent colonoscopy after a positive flexible sigmoidoscopy, detection rate for colorectal cancer was 0.28%, adenoma 8.66%, and total neoplasia 8.83%. On an intention to screen basis, there was no difference in colorectal cancer detection rate between the study and control groups. Adenoma and total neoplasia detection rate were significantly higher in the study group, with odds ratios of 5.95 (95%CI: 4.69-7.56) and 5.10 (95%CI: 4.09-6.35), respectively. CONCLUSIONS: In a single screening round at age 60, there was low uptake and neoplasia detection rate. Flexible sigmoidoscopy detected significantly more neoplasia than faecal occult blood test alone.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.

A prospective evaluation of the predictive value of faecal calprotectin in quiescent Crohn's disease.

BACKGROUND: Faecal calprotectin (FC) is a non-invasive marker of gastrointestinal inflammation. AIM: To determine whether higher FC levels in individuals with quiescent Crohn's disease are associated with clinical relapse over the ensuing 12 months. METHODS: A single centre prospective study was undertaken in Crohn's disease patients in clinical remission. The receiver operating characteristic (ROC) curve for the primary endpoint of clinical relapse by 12 months, based on FC at baseline, was calculated. Kaplan-Meier curves of time to relapse were based on the resulting optimal FC cutoff for predicting relapse. RESULTS: Of 97 patients recruited, 92 were either followed up for 12 months without relapsing, or reached the primary endpoint within that period. Of these, 10 (11%) relapsed by 12 months. Median FC was lower for non-relapsers, 96 µg/g (IQR 39-237), than for relapsers, 414 µg/g (IQR 259-590), (p=0.005). The area under the ROC curve to predict relapse using FC was 77.4%. An optimal cutoff FC value of 240 µg/g to predict relapse had sensitivity of 80.0% and specificity of 74.4%. Negative predictive value was 96.8% and positive predictive value was 27.6%, FC ≥240 µg/g was associated with likelihood of relapse by 12-months 12.18 (95% CI 2.55-58.2) times higher than lower values (p=0.002). CONCLUSIONS: In this prospective dataset, FC is a useful tool to help identify quiescent Crohn's disease patients at a low risk of relapse over the ensuing 12 months. FC of 240 µg/g was the optimal cutoff in this cohort.

The nonerosive reflux disease-gastroesophageal reflux disease controversy.

PURPOSE OF REVIEW: To analyse the concept of nonerosive reflux disease (NERD), examining its evolving definition and its relationship to reflux disease and functional gastrointestinal disorders. RECENT FINDINGS: The advent of the Montreal definition of gastroesophageal reflux disease (GERD) and the Rome III definition of functional upper gastrointestinal disorders has refined the concept of NERD. The high prevalence of GERD symptoms and the strong overlap between GERD and irritable bowel syndrome is due to the influence of NERD. Subtle differences exist between patterns of acid exposure in NERD and erosive disease on pH testing. Symptom generation in NERD may be influenced by altered mucosal permeability. Improvements in endoscopic technology demonstrate esophageal mucosal changes in NERD which are not seen in controls. There is a general acknowledgement that the inferior symptomatic response to acid suppression reported in NERD is attributable, at least in part, to contamination of study populations by patients with functional heartburn. SUMMARY: NERD is common and its definition continues to evolve. For the present, however, this should be considered to be heartburn with and without regurgitation due to gastroesophageal reflux in the absence of esophageal mucosal erosions. Future studies examining treatment response of GERD subgroups must exclude functional heartburn if NERD is to be properly understood.

N-nitrosamine generation from ingested nitrate via nitric oxide in subjects with and without gastroesophageal reflux.

BACKGROUND & AIMS: Nitrate ingestion leads to high luminal concentrations of nitric oxide being generated where saliva meets gastric acid. Nitric oxide generates N-nitrosative stress on reacting with oxygen at neutral pH. We aimed to ascertain if luminal nitric oxide exerts nitrosative stress in the human upper gastrointestinal tract, and to assess the influence of acid reflux on this phenomenon. METHODS: A silicone tube, segmented every 15 mm and containing phosphate buffer pH 7.4 and the secondary amine morpholine, was inserted into the upper gastrointestinal tract of 16 healthy volunteers and 16 Barrett's esophagus patients. The tube wall has the same permeability properties as an epithelial lipid membrane, allowing passage of gases such as nitric oxide, but not hydrogen ions. After 2 hours, the tube was removed and the concentrations of nitrite and N-nitrosomorpholine in each segment were measured. Healthy volunteers were studied with and without ingestion of (15)N-enriched nitrate and Barrett's esophagus patients were studied with and without stimulation of acid reflux. RESULTS: In healthy volunteers, N-nitrosomorpholine was generated in the tube sections exposed to gastric acid and increased 2-fold after nitrate. The N-nitrosomorpholine was 77% enriched with (15)N, confirming its source was the ingested nitrate. In the Barrett's patients, generation of N-nitrosomorpholine was shifted proximally with 80% of nitrosative stress occurring within the esophagus during periods of acid reflux. CONCLUSIONS: This study demonstrates the in situ formation of N-nitrosamine from dietary nitrate via nitric oxide. During acid reflux, nitrosative stress occurs almost entirely within the esophagus and may contribute toward carcinogenesis at this site.