British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease worldwide. It can generally be diagnosed by blood testing and remedied by iron replacement therapy (IRT) using the oral or intravenous route. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal (GI) pathologies. Because blood is iron-rich it can result from chronic blood loss, and this is a common mechanism underlying the development of IDA-for example, as a consequence of menstrual or GI blood loss.Approximately a third of men and postmenopausal women presenting with IDA have an underlying pathological abnormality, most commonly in the GI tract. Therefore optimal management of IDA requires IRT in combination with appropriate investigation to establish the underlying cause. Unexplained IDA in all at-risk individuals is an accepted indication for fast-track secondary care referral in the UK because GI malignancies can present in this way, often in the absence of specific symptoms. Bidirectional GI endoscopy is the standard diagnostic approach to examination of the upper and lower GI tract, though radiological scanning is an alternative in some situations for assessing the large bowel. In recurrent or refractory IDA, wireless capsule endoscopy plays an important role in assessment of the small bowel.IDA may present in primary care or across a range of specialties in secondary care, and because of this and the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease- with investigation sometimes being inappropriate, incorrectly timed or incomplete, and the role of IRT for symptom relief neglected. It is therefore important that contemporary guidelines for the management of IDA are available to all clinicians. This document is a revision of previous British Society of Gastroenterology guidelines, updated in the light of subsequent evidence and developments.

The influence of a simple blood transfusion policy on overtransfusion in acute upper gastrointestinal haemorrhage.

Blood transfusion is widely used in the management of acute upper gastrointestinal haemorrhage (AUGIH). Trial data suggests that excessive transfusion may be detrimental, yet overtransfusion remains commonplace. This study reports the impact of introducing a simple cross-match policy in a district general hospital, which resulted in a substantial fall in the prevalence of overtransfusion (odds ratio 0.43; 95% confidence interval 0.19-0.98), with potential patient benefits in terms of rebleeding, and a reduction in the total blood transfused from 162 to 121 units per 100 patients with AUGIH. For the cost of blood alone, this corresponds to projected savings across the NHS in England in excess of £2 million per annum.

Role of prescribed medication in the development of iron deficiency anaemia in adults-a case-control study.

OBJECTIVE: To estimate the strength of association between exposure to selected classes of prescribed medications and the risk of developing iron deficiency anaemia (IDA), specifically considering oral anticoagulants (OACs), antidepressants, antiplatelet agents, proton pump inhibitors (PPIs) and non-steroidal anti-inflammatories. DESIGN: A case-control study involving the analysis of community repeat prescriptions among subjects referred with IDA, and unmatched controls referred as gastroenterology fast-tracks for other indications. Multivariable logistic regression modelling was used to calculate ORs for the association between IDA presentation and each medication class, adjusted for age, sex and coprescribing. For those classes showing significance, it was also used to calculate risk differences between those in the IDA group with or without haemorrhagic lesions on investigation. RESULTS: A total of 1210 cases were analysed-409 in the IDA group, and 801 in the control group. Significant associations were identified between presentation with IDA and long-term exposure to PPIs (OR 3.29, 95% CI: 2.47 to 4.41, p<0.001) and to OACs (OR 2.04, 95% CI: 1.29 to 3.24, p=0.002). IDA was not associated with long-term exposure to any of the other three drug classes. In contrast to the relationship with PPIs, the association with OACs was primarily in the IDA sub-group with haemorrhagic lesions. CONCLUSION: Long-term exposure to PPIs and OACs are independently associated with the risk of developing IDA. There are grounds for considering that these associations may be causal, though the underlying mechanisms probably differ.

Colorectal cancer and the blood loss paradox.

Background: Faecal occult blood (FOB) positivity and iron deficiency anaemia (IDA) are common manifestations of colorectal cancer (CRC) and both potentially facilitate diagnosis at an earlier, more treatable stage. It has been assumed that both are the consequence of low-grade blood loss from the tumour bed. Method: A retrospective analysis of 1121 cases of CRC diagnosed at a single centre between 2010 and 2016, comparing cases presenting via FOB-based Bowel Cancer Screening Programme (BCSP) and IDA pathways for a series of variables including age, sex, tumour location and prevalence of anaemia. Results: The BCSP and IDA pathways each accounted for about 15% of the total case load. There were significant differences between the BCSP and IDA sub-groups in median age (68 vs 78 years: p<0.001), median haemoglobin (138 vs 89 g/L: p<0.001) and proportion of lesions in right colon (31.1% vs 82.5%: p<0.001). The major disparity in the prevalence of anaemia (overall 20.0% vs 98.2%: p<0.001) persisted when controlled for tumour location. Conclusion: Paradoxically, CRC screening through the detection of FOB positivity and IDA identifies distinctly different sub-populations of cases. The theoretical implication is that an additional mechanism may be required to explain the development of IDA in CRC. The practical implication is that detection of IDA may have a complementary role to the BCSP in population screening for CRC.

The dedicated iron deficiency anaemia clinic: a 15-year experience.

OBJECTIVE: To report our cumulative experience from a dedicated iron deficiency anaemia (IDA) clinic over the last 15 years-with particular emphasis on referral rate, uptake of investigation, impact on endoscopy services, diagnostic yield of gastrointestinal (GI) investigation and the issue of recurrent IDA. METHOD: A series of analyses of a register of 2808 referrals to the Poole IDA clinic between 2004 and 2018. RESULTS: The study population of 2808 had a sex ratio of 1.9 (female/male ratio) and a median age of 72 years (IQR: 60-79). A rising referral rate over the study period appears to be plateauing at around 2 cases per 1000 population per annum. On the basis of a snapshot audit, investigation of IDA may now account for over 20% of all diagnostic endoscopies.Overall, 86% of cases underwent examination of the upper and lower GI tract. Significant GI pathology was identified in 27% of the investigated cohort. Adenocarcinoma of the upper or lower GI tract was found in 8.3%, the majority in the right colon. The prevalence of recurrent IDA was estimated at 12.4%, and the results of investigation of this subgroup are reported. CONCLUSION: Unexplained IDA is common, particularly in those over 60 years, and may be the first indication of underlying GI malignancy in over 8% of cases. Unresolved challenges include accommodating the resulting endoscopy workload, establishing a risk/benefit ratio for investigating those with major comorbidities and the management of recurrent IDA.

Evidence for improved prognosis of colorectal cancer diagnosed following the detection of iron deficiency anaemia.

Iron deficiency anaemia (IDA) is common in colorectal cancer (CRC), especially, in right-sided CRC which is known to have an overall worse prognosis. The associations between diagnostic pathway (Bowel Cancer Screening Programme (BCSP), IDA, symptomatic) and tumour side/stage was assessed using logistic regression models in 1138 CRC cases presenting during 2010-2016 at a single secondary-care centre in the UK. In the IDA sub-group, the relationship between CRC stage and the event of having a blood count prior to CRC diagnosis was examined using Bayesian parametric survival model. IDA was found as the only significant predictor of right-sided CRC (OR 10.61, 95% CI 7.02-16.52). Early-stage CRC was associated with both the IDA (OR 1.65, 95% CI 1.18-2.29) and BCSP pathway (OR 2.42, 95% CI 1.75-3.37). At any age, the risk of detecting CRC at late-stage was higher in those without a previous blood count check (hazard ratio 1.53, 95% credibility interval 1.08-2.14). The findings of this retrospective observational study suggest a benefit from diagnosing CRC through the detection of IDA, and warrant further research into the prognosis benefit of systematic approach to blood count monitoring of the at-risk population.

Broad external validation of a multivariable risk prediction model for gastrointestinal malignancy in iron deficiency anaemia.

BACKGROUND: Using two large datasets from Dorset, we previously reported an internally validated multivariable risk model for predicting the risk of GI malignancy in IDA-the IDIOM score. The aim of this retrospective observational study was to validate the IDIOM model using two independent external datasets. METHODS: The external validation datasets were collected, in a secondary care setting, by different investigators from cohorts in Oxford and Sheffield derived under different circumstances, comprising 1117 and 474 patients with confirmed IDA respectively. The data were anonymised prior to analysis. The predictive performance of the original model was evaluated by estimating measures of calibration, discrimination and clinical utility using the validation datasets. RESULTS: The discrimination of the original model using the external validation data was 70% (95% CI 65, 75) for the Oxford dataset and 70% (95% CI 61, 79) for the Sheffield dataset. The analysis of mean, weak, flexible and across the risk groups' calibration showed no tendency for under or over-estimated risks in the combined validation data. Decision curve analysis demonstrated the clinical value of the IDIOM model with a net benefit that is higher than 'investigate all' and 'investigate no-one' strategies up to a threshold of 18% in the combined validation data, using a risk cut-off of around 1.2% to categorise patients into the very low risk group showed that none of the patients stratified in this risk group proved to have GI cancer on investigation in the validation datasets. CONCLUSION: This external validation exercise has shown promising results for the IDIOM model in predicting the risk of underlying GI malignancy in independent IDA datasets collected in different clinical settings.

Refinement and validation of the IDIOM score for predicting the risk of gastrointestinal cancer in iron deficiency anaemia.

OBJECTIVE: To refine and validate a model for predicting the risk of gastrointestinal (GI) cancer in iron deficiency anaemia (IDA) and to develop an app to facilitate use in clinical practice. DESIGN: Three elements: (1) analysis of a dataset of 2390 cases of IDA to validate the predictive value of age, sex, blood haemoglobin concentration (Hb), mean cell volume (MCV) and iron studies on the probability of underlying GI cancer; (2) a pilot study of the benefit of adding faecal immunochemical testing (FIT) into the model; and (3) development of an app based on the model. RESULTS: Age, sex and Hb were all strong, independent predictors of the risk of GI cancer, with ORs (95% CI) of 1.05 per year (1.03 to 1.07, p<0.00001), 2.86 for men (2.03 to 4.06, p<0.00001) and 1.03 for each g/L reduction in Hb (1.01 to 1.04, p<0.0001) respectively. An association with MCV was also revealed, with an OR of 1.03 for each fl reduction (1.01 to 1.05, p<0.02). The model was confirmed to be robust by an internal validation exercise. In the pilot study of high-risk cases, FIT was also predictive of GI cancer (OR 6.6, 95% CI 1.6 to 51.8), but the sensitivity was low at 23.5% (95% CI 6.8% to 49.9%). An app based on the model was developed. CONCLUSION: This predictive model may help rationalise the use of investigational resources in IDA, by fast-tracking high-risk cases and, with appropriate safeguards, avoiding invasive investigation altogether in those at ultra-low predicted risk.

Evolving patterns in the presentation of coeliac disease over the last 25 years.

OBJECTIVE: To document changes in the clinical features of coeliac disease (CD) at presentation over the last 25 years. DESIGN: Observational study. PATIENTS: 802 subjects diagnosed between 1993 and 2017 at a single general hospital. OUTCOME MEASURES: Date of diagnosis, age, sex, postcode, symptoms, haematinic deficiency, smoking status, serology, family history and autoimmune phenomena. RESULTS: The incidence of diagnosed CD rose threefold during the course of the study, with a rising prevalence of positive coeliac serology and positive family history of CD, and a falling prevalence of symptoms and haematinic deficiencies. There was little change in the female predominance, age at diagnosis or high prevalence of other autoimmune conditions over the 25 years, and a paucity throughout of cigarette smokers, particularly heavy smokers. A cohort of patients with seronegative CD was identified who shared many of the characteristics of seropositive CD, but with a significantly older age at diagnosis and a higher prevalence of cigarette smokers. CONCLUSION: There have been major changes in the epidemiology of CD over the last 25 years, of relevance to both our understanding of the aetiopathogenesis of CD and the requirement for service provision. The implications are discussed.

Determinants of endomysial antibody status in untreated coeliac disease.

BACKGROUND: Serum endomysial antibody (EMA) is a highly specific marker of untreated coeliac disease (CD). The published estimates of sensitivity however vary widely and the explanation for this remains unclear. OBJECTIVE: To determine the relative prevalence of EMA-negative CD and to identify clinical and histological characteristics which relate to EMA status. METHOD: Retrospective analysis of prospectively collected data on incident cases of CD in a single hospital over a 10-year period with determination of EMA status before gluten withdrawal. RESULTS: From a total of 241 participants, 37 [15% (95% confidence interval: 11, 20%)] were EMA negative, of whom only four were IgA deficient. EMA-positive and EMA-negative patients shared a number of characteristics including female predominance and a high prevalence of HLA DQ2. EMA status was associated with age-test sensitivity and exceeded 98% below the age of 35 years, falling to around 80% in older age groups overall, and lower still in current cigarette smokers. EMA status was not influenced by sex, family history of CD, other autoimmune disease, or by potential clinical or histological markers of disease severity. CONCLUSION: A substantial proportion of patients with true CD are EMA negative. This has implications for the pathogenesis of the disease. It also limits the value of EMA as a screening test, particularly in older adults and cigarette smokers.

Is the risk of adult coeliac disease causally related to cigarette exposure?

OBJECTIVE: Previous studies have shown an association between cigarette smoking and coeliac disease, but it has yet to be established whether this relationship is causal. The aim of this study was to assess causality using the Bradford Hill criteria. METHODS: A matched case-control study using a questionnaire to establish a detailed smoking history for 138 incident cases of adult coeliac disease and 276 age-matched and sex-matched controls. Subjects were categorized according to their active cigarette exposure prior to diagnosis of the matched case, and odds ratios and tests for linear trends were calculated. RESULTS: At the time of diagnosis, 10% of cases and 30% of controls were current smokers (odds ratio, 0.21 and 95% confidence interval, 0.11-0.40 for coeliac disease in current smokers versus never smokers). A biological gradient was demonstrated for total, recent and current cigarette exposure. The greatest risk reduction related to current exposure (odds ratio, 0.15, and 95% confidence interval, 0.06-0.37 for coeliac disease in current heavy smokers versus never smokers). CONCLUSIONS: This study strengthens the case for a causal relationship between smoking and coeliac disease by demonstrating a strong, temporally appropriate and dose-dependent effect, thus meeting the Bradford Hill criteria. This suggests that cigarette smoking truly protects against the development of adult coeliac disease.

A case-control study of childhood environmental risk factors for the development of inflammatory bowel disease.

OBJECTIVE: To clarify the relationship between childhood environment and the risk of subsequent development of Crohn's disease or ulcerative colitis. DESIGN AND OUTCOME MEASURES: A case-control study, assessing the risk of inflammatory bowel disease in relation to a series of historical and serological markers of childhood circumstance, analysed using the maximum likelihood form of conditional logistic regression. SETTING: District general hospital (secondary care institution). PARTICIPANTS: Subjects with Crohn's disease (n = 139) or ulcerative colitis (n = 137) aged between 16 and 45 years, each matched for sex and age with an outpatient control. RESULTS: Helicobacter seroprevalence was substantially reduced in Crohn's disease (OR 0.18; 95% CI, 0.06-0.52) but not in ulcerative colitis (OR 0.91; 95% CI, 0.38-2.16). In ulcerative colitis, a strong negative association with childhood appendectomy was confirmed (OR 0.05; 95% CI, 0.01-0.51). Crohn's disease was associated with childhood eczema (OR 2.81; 95% CI, 1.23-6.42) and the frequent use of a swimming pool (OR 2.90; 95% CI 1.21-6.91). There was no association between hepatitis A seroprevalence and either disease. CONCLUSION: The findings are consistent with the hypothesis that improved childhood living conditions are associated with increased risk of Crohn's disease. The study confirms that the negative association between appendectomy and ulcerative colitis relates primarily to events in childhood. Overall, the findings strongly support the assertion that childhood environment is an important determinant of the risk of inflammatory bowel disease in later life, with quite distinct risk factors for ulcerative colitis and Crohn's disease.

The development of a nurse-led iron deficiency anaemia service in a district general hospital.

OBJECTIVE: To improve the quality of care provided to patients with iron deficiency anaemia (IDA). DESIGN: Service development. SETTING: District General Hospital. PATIENTS: Adults with IDA. MAIN OUTCOME MEASURES: Descriptive report of the practicalities and benefits of establishing an IDA clinic. CONCLUSIONS: The IDA clinic is a novel service development which enhances the management of patients with this common condition, by facilitating prompt confirmation of the diagnosis, replacement therapy and investigation for serious underlying pathology, in particular gastrointestinal malignancy.

Clinical risk factors for underlying gastrointestinal malignancy in iron deficiency anaemia: the IDIOM study.

OBJECTIVE: Ten percent of adults presenting with iron deficiency anaemia (IDA) have underlying cancer. This analysis - the Iron Deficiency as an Indicator Of Malignancy (IDIOM) study - was undertaken to assess whether five simple clinical parameters can usefully predict the likelihood of gastrointestinal (GI) malignancy on subsequent investigation of patients with IDA. DESIGN: Retrospective observational study, with multivariable analysis of the predictive value of sex, age, haemoglobin concentration (Hb), mean red cell volume (MCV) and iron studies for the risk of underlying GI malignancy. SETTING: District General Hospital IDA clinic. PATIENTS: 720 adults with confirmed IDA. RESULTS: Sex, age and Hb were strongly associated with the risk of GI malignancy-the parsimonious model including only these variables yielded ORs of 4.0 (95% CI 2.3 to 7.0) for males compared with females; 3.3 (95% CI 1.7 to 6.4) for age >70 years compared with ≤70 years; and 5.3 (95% CI 2.4 to 11.7) for a Hb of ≤91.4 g/L compared with ≥111.5 g/L. Combining these risk factors identified a subgroup (12% of the study population) at particularly low risk (<2% likelihood), and a second subgroup (16% of the study population) at especially high risk (>20% likelihood) of underlying GI malignancy. CONCLUSIONS: Three simple and objective clinical parameters can be combined to provide a clinically useful cancer risk stratification model for subjects with IDA. This may assist with patient counselling and the prioritisation of investigational resources.

Aggressive Helicobacter pylori-negative peptic ulceration as the initial manifestation of Crohn's disease.

Peptic ulceration is a recognised feature of Crohn's disease, but the characteristics of this manifestation are rather poorly described. Furthermore, most reports in the literature relate to ulcer disease in cases of established Crohn's disease. The authors report a series of four cases in which the diagnosis of Crohn's disease was preceded by peptic ulceration. Potential confounding factors were as far as possible excluded, implying a true association. Characteristics of the ulcer disease included (1) a multifocal distribution, (2) Helicobacter pylori negativity and (3) an unusually aggressive clinical course despite proton pump inhibitor therapy, necessitating endoscopic or surgical intervention in three cases. Crohn's-related peptic ulceration is a relatively common manifestation which may precede the diagnosis of Crohn's disease itself. Recognition of the underlying diagnosis may be hampered by non-specific histology, but is important in view of the aggressive course of the ulceration, which may respond to medical therapy for Crohn's disease.