Breathomics--exhaled volatile organic compound analysis to detect hepatic encephalopathy: a pilot study.

The current diagnostic challenge with diagnosing hepatic encephalopathy (HE) is identifying those with minimal HE as opposed to the more clinically apparent covert/overt HE. Rifaximin, is an effective therapy but earlier identification and treatment of HE could prevent liver disease progression and hospitalization. Our pilot study aimed to analyse breath samples of patients with different HE grades, and controls, using a portable electronic (e) nose. 42 patients were enrolled; 22 with HE and 20 controls. Bedside breath samples were captured and analysed using an uvFAIMS machine (portable e-nose). West Haven criteria applied and MELD scores calculated. We classify HE patients from controls with a sensitivity and specificity of 0.88 (0.73-0.95) and 0.68 (0.51-0.81) respectively, AUROC 0.84 (0.75-0.93). Minimal HE was distinguishable from covert/overt HE with sensitivity of 0.79 and specificity of 0.5, AUROC 0.71 (0.57-0.84). This pilot study has highlighted the potential of breathomics to identify VOCs signatures in HE patients for diagnostic purposes. Importantly this was performed utilizing a non-invasive, portable bedside device and holds potential for future early HE diagnosis.

Faecal calprotectin for differentiating between irritable bowel syndrome and inflammatory bowel disease: a useful screen in daily gastroenterology practice.

OBJECTIVE: To determine the best faecal calprotectin (FCP) cut-off level for differentiating between irritable bowel syndrome (IBS) and organic disease, particularly inflammatory bowel disease (IBD), in patients presenting with chronic diarrhoea. DESIGN: Retrospective analysis of patients who had colonoscopy, histology and FCP completed within 2 months. SETTING: District general hospital. PATIENTS: Consecutive new patients with chronic diarrhoea lasting longer than 4 weeks. INTERVENTIONS: Patients were seen by a single experienced gastroenterologist and listed for colonoscopy with histology. Laboratory investigations included a single faecal specimen for calprotectin assay (lower limit of detection: 8 µg/g), the results used for information only. MAIN OUTCOME MEASURES: Six FCP cut-off levels (range 8-150 µg/g) were compared against the 'gold standard' of histology: inflammation 'present' or 'absent'. RESULTS: Of 119 patients studied, 98 had normal colonoscopy and histology. The sensitivity of FCP to detect IBD at cut-off levels 8, 25 and 50 µg/g was 100% (with corresponding specificity 51%, 51%, 60%). In contrast, the lowest FCP cut-off, 8 µg/g, had 100% sensitivity to detect colonic inflammation, irrespective of cause (with negative predictive value (NPV) 100%). Importantly, 50/119 patients (42%) with FCP <8 µg/g had normal colonoscopy and histology. CONCLUSIONS: Our results suggest that using FCP to screen patients newly referred for chronic diarrhoea could exclude all without IBD and, at a lower cut-off, all without colonic inflammation, thus avoiding the need for colonoscopy. Such a major reduction has implications for resource allocation.

Development and application of a new electronic nose instrument for the detection of colorectal cancer.

Colorectal cancer is a leading cause of cancer death in the USA and Europe with symptoms that mimick other far more common lower gastrointestinal (GI) disorders. This difficulty in separating colorectal cancer from these other diseases has driven researchers to search for an effective, non-invasive screening technique. Current state-of-the-art method of Faecal Immunochemical Testing achieving sensitivity ~90%, unfortunately the take-up in the western world is low due to the low patient acceptability of stool samples. However, a wide range of cancers have been distinguished from each-other and healthy controls by detecting the gas/volatile content emanating patient biological media. Dysbiosis afforded by certain disease states may be expressed in the volatile content of urine - a reflection of the gut bacteria's metabolic processes. A new electronic nose instrument was developed at the University of Warwick to measure the gas/volatile content of urine headspace, based on an array of 13 commercial electro-chemical and optical sensors. An experimental setup was arranged for a cohort of 92 urine samples from patients of colorectal cancer (CRC), irritable bowel syndrome (IBS) and controls to be run through the machine. Features were extracted from response data and used in Linear Discriminant Analysis (LDA) plots, including a full 3-disease classification and one focussing on distinguishing CRC from IBS. The latter case was tested by the success of re-classification using an (n-1) K-nearest neighbour algorithm, showing 78% sensitivity and 79% specificity to CRC.

The scars of time: the disappearance of peptic ulcer-related pyloric stenosis through the 20th century.

BACKGROUND: The changing pattern of haemorrhage and perforation from peptic ulcer disease is well documented but little is known about pyloric stenosis, the third complication of the disease. METHODS: We reviewed records relating to definitive operations (with intent to cure) for peptic ulcer disease carried out in York, UK from 1929-1997. We categorised the patients as pyloric stenosis and no pyloric stenosis based on findings at operation and examined the change in total number of cases with pyloric stenosis and proportion of cases with pyloric stenosis, by year of operation and by decade of birth. To place our results in perspective, we reviewed world literature to examine rates of pyloric stenosis as a percentage of operative cases reported in other case series in the 20th century. RESULTS: 4178 patients were included in the analysis; 3697 without pyloric stenosis and 481 with pyloric stenosis (11.5%). Analysis by birth cohort showed that the proportion found to have pyloric stenosis at surgery fell from 17% in the first cohort (birth 1880-89) to only 2.9% in the last cohort (birth 1950-59; p<0.001). Mean age at operation fell more steeply for those with pyloric stenosis: 74 to 30 years vs. 65 to 28 years (p <0.001). The trend of final decline started before the introduction of modern medical treatment. Review of similar case series from across the world shows a similar decline in the proportion of peptic ulcer cases showing pyloric stenosis at operation. CONCLUSION: The reduction in pyloric stenosis over the last several decades is disproportionately greater than the change seen in peptic ulcer disease requiring surgery. Our findings suggest that this reduction in pyloric stenosis is largely the result of the changing natural history of the disease rather than due to the introduction of acid-suppressing medication.

Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention.

BACKGROUND: Bile acid diarrhoea is a common, under-diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis. AIM: To measure serum FGF19 and SeHCAT retention prospectively in patients with chronic diarrhoea. METHODS: One hundred and fifty-two consecutive patients were grouped according to (75) Se-homocholic acid taurine (SeHCAT) 7-day retention: normal (>15%) in 72 (47%) diarrhoea controls; ≤15% in 54 (36%) with primary bile acid diarrhoea, and in 26 (17%) with secondary bile acid diarrhoea. Fasting blood was assayed for FGF19, 7α-hydroxy-4-cholesten-3-one (C4) and total bile acids. RESULTS: FGF19 was significantly lower in the primary bile acid diarrhoea group compared with the diarrhoea control group (median 147 vs. 225 pg/mL, P < 0.001), and also in the secondary group (P < 0.006). FGF19 and SeHCAT values were positively correlated (rs = 0.44, P < 0.001); both were inversely related to C4. Other significant relationships included SeHCAT and body mass index (BMI)(P = 0.02), and FGF19 with age (P < 0.01). The negative and positive predictive values of FGF19 ≤ 145 pg/mL for a SeHCAT <10% were 82% and 61%, respectively, and were generally improved in an index including BMI, age and C4. In a subset of 28 primary patients, limited data suggested that FGF19 could predict response to sequestrant therapy. CONCLUSIONS: Reduced fibroblast growth factor 19 is a feature of bile acid diarrhoea. Further studies will fully define its role in predicting the response of these patients to therapy.

Dietary phosphilipids and sterols protective against peptic ulceration.

The prevalence of duodenal ulceration in regions of developing countries with a stable diet is related to the staple food(s) in that diet. A higher prevalence occurs in areas where the diet is principally milled rice, refined wheat or maize, yams, cassava, sweet potato or green bananas, and a lower prevalence in areas where the staple diet is based on unrefined wheat or maize, soya, certain millets or certain pulses. Experiments using animal peptic ulcer models showed that the lipid fraction in foods from the staple diets of low prevalence areas gave protection against both gastric and duodenal ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promoted healing of ulceration. The protective activity was found to lie in the phospholipid, sterol and sterol ester fractions of the lipid. Amongst individual phospholipids present in the phospholipid fraction, phosphatidyl ethanolamine (cephalin) and phosphatidyl choline (Lecithin) predominated. The sterol fraction showing activity contained ß-sitosterol, stigmasterol and an unidentified isomer of ß-sitosterol. The evidence shows that dietary phytosterols and phospholipids, both individually and in combination, have a protective effect on gastroduodenal mucosa. These findings may prove to be important in the prevention and management of duodenal and gastric ulceration including ulceration due to NSAIDs.

Evaluation of gut bacterial populations using an electronic e-nose and field asymmetric ion mobility spectrometry: further insights into 'fermentonomics'.

The fermentation of undigested foods in the large bowel, by its resident bacteria, results in the production of several chemicals including volatile gases. Perturbance in gut bacteria is known to influence colonic and metabolic health, but to determine this requires prolonged culture (often unsuccessful) or expensive genomic sequencing. Clearly this is not practical for daily clinical practice. Previously, we have reported our insights into fermentonomics through the detection of volatile organic compounds (VOCs) in patients with gastrointestinal and metabolic diseases, using the electronic nose. In this paper we report on the changes in the fermentone produced by patients undergoing complete versus partial bowel cleansing. Using urine samples, preliminary results from 23 individuals receiving bowel cleansing indicate the ability of the electronic nose to distinguish between the partial and complete procedures. Moreover in a subset of individuals, we have been able to track evolving bacterial recolonization over time using the e-nose and field asymmetric ion mobility spectrometry (FAIMS). Such an approach has practical application in tracking bacterial dysbiosis following perturbation.

Mortality in Barrett's esophagus: three decades of experience at a single center.

BACKGROUND AND STUDY AIMS: There is a view that the majority of deaths in patients with Barrett's esophagus are from causes other than esophageal adenocarcinoma (EAC). The aim of this analysis was to establish the pattern of mortality for a number of causes in patients with Barrett's esophagus. PATIENTS AND METHODS: This was a single-center prospective cohort study of patients from Rotherham District General Hospital, which is a secondary referral center. The cohort consisted of 1239 patients who were diagnosed with Barrett's esophagus between April 1978 and March 2009.  Follow-up for mortality was undertaken by "flagging" the patients with the NHS Information Center. Causes of death were compared with UK Office of National Statistics age- and sex-specific mortality data for 1999, the median year of diagnosis. Analysis was by a "person - years at risk" calculation from date of diagnosis. RESULTS: The ratio of observed deaths from EAC compared with those expected in this cohort was 25.02 - a very large excess. There was no difference in mortality from colorectal cancer or circulatory disease and there were fewer deaths from cancers other than esophageal adenocarcinoma and colon cancer compared with national statistics. There was a small statistically significant difference in mortality from all causes but this disappeared completely when deaths from esophageal adenocarcinoma were excluded. CONCLUSIONS: Overall, mortality in Barrett's esophagus is increased significantly but only as a result of the large excess of deaths from EAC. This strengthens the case for endoscopic surveillance if successful interventions can be undertaken in patients with Barrett's esophagus to prevent development of esophageal adenocarcinoma.

Insights into 'fermentonomics': evaluation of volatile organic compounds (VOCs) in human disease using an electronic 'e-nose'.

Detection of volatile organic compounds (VOCs) is a common requirement in industry for which numerous methods are available. The electronic nose (e-nose) is an example. Rather than individual chemicals, the e-nose recognizes the 'aroma fingerprint' created by the collection of VOCs in samples, comparable to the human nose. We report on a novel application for gastrointestinal and metabolic medicine, and compare its results to mass spectrometry. Fermentation of undigested foods in the large bowel by its resident bacteria results in the creation of several chemicals including volatile gases that influence colonic and metabolic health. Using urine samples, preliminary results indicate the ability of the e-nose to distinguish between controls and those with inflammatory bowel disease or diabetes (separation rate of ∼97%). This emphasizes the different patterns of fermentation. Our term 'fermentonomics' describes the investigation and analysis of the fermentome by such non-invasive means. Such an approach has potentially wide application in medicine.

A United Kingdom inflammatory bowel disease database: making the effort worthwhile.

BACKGROUND: Inflammatory bowel disease (IBD), a paradigm of chronic illness, requires for its safe clinical management ready access to complete information, not always possible using paper records. AIM: To develop an IBD database (DB) for both individual patient management and collating information across centres. METHODS: Access® based, with a minimum dataset. RESULTS: Prospectively collected data for 11,432 patients from 21 centres. PROFILE DIAGNOSIS: Ulcerative colitis (UC) 56%, Crohn's disease (CD) 40%, indeterminate colitis 4%. M:F ratio: UC 1.08:1, CD 0.72:1. Median age at diagnosis: UC 39, CD 30 years. Operated: UC 16%, CD 47%. Thiopurine use: UC 16%, CD 29%. IBD related mortality: 0.74%. DISCUSSION: A snapshot of this large IBD cohort shows the disease profile across the UK is similar to other large series. Unexpected gaps, sometimes large emerged (e.g. data on smoking and immunosuppression) highlighting the need for clear definition, consistency and completeness of data collection. Clinical management is made easier by the 'at a glance' summary, automated clinic letters, and facility for monitoring and audit, but the time required limited its 'real-time' use. CONCLUSION: Our experience shows it is possible to collect data from centres across the country which truly reflects clinical practice. We have learned as much from the process itself as from the data, principally, information needs to be well defined, validated at entry, and updated at every visit, a time consuming sequence which we had underestimated. Our lessons learned may help inform the development of a national database, and support national IBD standards and audit.

Colonic fermentation--more than meets the nose.

Fermentation of undigested foods in the colon by its resident bacteria affects not only colonic health (protection against inflammation and tumour formation) but also influences metabolic health. Studying fermentation directly is difficult for lack of access. We hypothesise that the anatomical structure of the colon is suited to act as a fermenting chamber with the gaseous molecules (VOCs) emitted having direct effects on the colonocytes as well as gut neural and metabolic effects. We refer to this complex system as the 'fermentome', and further hypothesise that alteration in the 'fermentome' through dietary modification will have a direct impact on colonic as well as metabolic health and disease. The VOCs emitted may play a role in bacterial chemical signalling within the colon but importantly could also function as a 'gas' biomarker. Measurement of such VOCs through non-invasive methods would have important application as a hypothesis-generating tool with subsequent clinical application.

Time, change and peptic ulcer disease in Rotherham, UK.

BACKGROUND AND AIM: We have documented the changing pattern of peptic ulcer disease in our centre in the last quarter of the 20th century and speculate on the reasons thereof. PATIENTS AND METHODS: The profile of peptic ulcer disease patients presenting newly to our centre (population 250,000) from 1977 to 2001 was examined. All patients were prospectively followed and detailed records kept. Results are presented in 5-year periods. RESULTS: Seven thousand five hundred and ninety new peptic ulcer disease patients (5564 duodenal ulcer+2026 gastric ulcer) were seen, peaking in 1982-1986 but declining thereafter, and with a falling male preponderance. Patients with gastric ulcer were older than those with duodenal ulcer; were older than duodenal ulcer, the mean age of both increased over time and the age gap from the general population widened. The numbers presenting with perforation changed little but haemorrhage increased, particularly amongst the elderly. Ulcers refractory to H2 receptor antagonists declined even before proton pump inhibitors were introduced. Elective surgery, already declining before H2 receptor antagonists, had virtually disappeared by 1992-1996. DISCUSSION AND CONCLUSION: Peptic ulcer disease affects an older population, an increasing proportion of whom present with haemorrhage. Refractoriness to H2 receptor antagonists and the need for elective operation was declining even before the emergence of modern treatment. We suggest the changes observed result not only from modern therapy but also substantially from a changing natural history.

Intestinal secretory and absorptive function in Trichinella spiralis mouse model of postinfective gut dysfunction: role of bile acids.

OBJECTIVE: Observations showing that bile acid malabsorption is frequent in irritable bowel syndrome (IBS) suggest that alterations in bile acid-induced secretion and absorption could contribute to IBS-associated diarrhoea. The secretory response to bile acids, fluid transport and bile absorption was examined in intestinal tissues from a Trichinella spiralis mouse model of postinfectious gut dysfunction in vitro. Changes in the protein expression of apical sodium-dependent bile acid transporter (ASBT) were also measured. DESIGN: T. spiralis-infected mice were killed at 18 and 25 days postinfection. Jejunal, ileal, proximal and distal colon segments were exposed to taurodeoxycholic acid (TDCA) or cholic acid. Short circuit current (SCC) increases were determined. Tritiated taurocholic acid (3H-TCA) absorption was determined in everted jejunal and ileal sacs. ASBT protein expression was determined by Western blot analysis and immunohistochemistry. RESULTS: Basal SCC increased in ileum and distal colon at 18 and 25 days postinfection, respectively. Ileal SCC responses to TDCA and cholic acid were enhanced at 18 days postinfection. Distal colon SCC response to TDCA was raised at 18 days postinfection but was significantly reduced by 25 days. Ileal 3H-TCA uptake was significantly reduced at 18 and 25 days postinfection. Surprisingly, increased ASBT expression was observed in infected animals. CONCLUSIONS: In a T. spiralis model of postinfectious gut dysfunction, decreased bile absorption and enhanced secretion in response to bile acids was observed. Decreased absorption was not, however, caused by decreased ASBT as increased expression was observed. If similar events occur postinfection, the combined effects of these disturbances may contribute to some symptoms observed in postinfectious IBS patients.

A clinical trial comparing pantoprazole and esomeprazole to explore the concept of achieving 'complete remission' in gastro-oesophageal reflux disease.

BACKGROUND AND AIM: The outcome of gastro-oesophageal reflux disease treatment is traditionally assessed by measuring endoscopically confirmed healing and symptom relief separately. Both terms together, indicating complete remission, are intuitively a more realistic clinical endpoint but are assessed less often. AIM: To explore this concept, we formally compared the efficacy of the proton pump inhibitors (PPIs) pantoprazole and esomeprazole using rates of complete remission judged against rates of healing and symptom relief separately. METHODS: Five hundred and eighty-two patients with erosive gastro-oesophageal reflux disease were randomized to treatment for 4, 8, or 12 weeks with either pantoprazole or esomeprazole 40 mg daily. Symptom relief was assessed with the validated ReQuesttrade mark-GI subscale. RESULTS: Approximately 75% of patients were free of symptoms or had no oesophageal lesions after 4 weeks' treatment, rising to about 93% and 96%, respectively, at 12 weeks. Complete remission rates were, however, lower at these time points; approximately 60% and about 90%, respectively. Both PPIs had similar efficacy. CONCLUSIONS: Endoscopically confirmed healing and symptom relief assessed separately over-estimated the benefits of both drugs. In contrast, complete remission indicates that patients may be treated inadequately when given the standard 4- to 8-week treatment. We suggest that complete remission is a more reliable and clinically relevant endpoint of treatment.

Mechanisms underlying mechanosensitivity of mesenteric afferent fibers to vascular flow.

Spinal afferent neurons, with endings in the intestinal mesenteries, have been shown to respond to changes in vascular perfusion rates. The mechanisms underlying this sensitivity were investigated in an in vitro preparation of the mesenteric fan devoid of connections with the gut wall. Afferent discharge increased when vascular perfusion was stopped ("flow off"), a response localized to the terminal vessels just prior to where they entered the gut wall. The flow-off response was compared following pharmacological manipulations designed to determine direct mechanical activation from indirect mechanisms via the vascular endothelium or muscle. Under Ca(2+)-free conditions, responses to flow off were significantly augmented. In contrast, the myosin light chain kinase inhibitor wortmannin (1 microM, 20 min) did not affect the flow-off response despite blocking the vasoconstriction evoked by 10 microM l-phenylephrine. This ruled out active tension, generated by vascular smooth muscle, in the response to flow off. Passive changes caused by vessel collapse during flow off were speculated to affect sensory nerve terminals directly. The flow-off response was not affected by the N-, P-, and Q-type Ca(2+) channel blocker omega-conotoxin MVIIC (1 muM intra-arterially) or the P2X receptor/ion channel blocker PPADS (50 microM). However, ruthenium red (50 microM), a blocker of nonselective cation channels, greatly reduced the flow-off response and also abolished the vasodilator response to capsaicin. Our data support the concept that mesenteric afferents sense changes in vascular flow during flow off through direct mechanisms, possibly involving nonselective cation channels. Passive distortion in the fan, caused by changes in blood flow, may represent a natural stimulus for these afferents in vivo.

Systematic review: do we need a new gastro-oesophageal reflux disease questionnaire?

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is highly prevalent in Western countries. Because the majority of patients do not present with endoscopic abnormalities, the assessment of the symptom severity and quality of life, and their response to treatment, has become increasingly important. Self-assessed symptom questionnaires are now key instruments in clinical trials. AIM: To evaluate the validity of available GERD measurement tools. METHODS: An ideal GERD symptom assessment instrument, suitable as a primary end-point for clinical trials, should possess the following characteristics: (i) be sensitive in patients with GERD; (ii) cover the frequency and intensity of typical and atypical GERD symptoms; (iii) be multidimensional (cover all symptom dimensions); (iv) have proven psychometric properties (validity, reliability and responsiveness); (v) be practical and economical; (vi) be self-assessed; (vii) use 'word pictures' which are easy to understand for patients; (viii) respond rapidly to changes (responsiveness over short time intervals); (ix) be used daily to assess changes during and after therapy; and (x) be valid in different languages for international use. RESULTS: A literature review revealed five scales that met some of the above characteristics, but did not fulfil all criteria. CONCLUSION: There is a need for a new evaluative tool for the assessment of GERD symptoms and their response to therapy.

Evaluation of GERD symptoms during therapy. Part I. Development of the new GERD questionnaire ReQuest.

BACKGROUND/AIMS: The changes in gastroesophageal reflux disease (GERD)-related symptoms on treatment are variously described, but currently available questionnaires have shortcomings. We therefore developed a self-assessment reflux questionnaire (ReQuest). This article describes the process of development and testing. MATERIALS AND METHODS: For the first version of ReQuest the symptom spectrum of GERD and the various symptom descriptions were investigated. The 67 identified symptom descriptions were condensed empirically into 6 dimensions, to which a 7th dimension on general well-being was added. The symptom burden of the dimensions was measured by frequency and/or intensity. ReQuest was translated into different languages and then tested in focus groups. The initial validation was based on data from a clinical trial of patients with erosive GERD, treated with pantoprazole 20 or 40 mg daily for 28 days. Factor analyses determined the contribution of each symptom to the different dimensions. Additionally, correlation analyses between the identified factors and the dimensions were performed. RESULTS: On the basis of factor analyses, ReQuest was reduced to a 60-item scale. The factors generated correlated strongly with the dimensions and confirmed the empirical process mathematically. CONCLUSION: ReQuest provides a valuable, self-assessment tool for evaluating the daily treatment response in patients with erosive GERD.

International validation of ReQuest in patients with endoscopy-negative gastro-oesophageal reflux disease.

BACKGROUND: Reflux Questionnaire (ReQuest), a newly developed gastro-oesophageal reflux disease-sensitive scale, can be used to reliably evaluate the effect of treatment on gastro-oesophageal reflux disease symptoms. AIM: International validation of this scale, in patients suffering from endoscopy-negative gastro-oesophageal reflux disease. METHODS: In this open, multicentre and multinational clinical trial 840 endoscopy-negative gastro-oesophageal reflux disease patients received pantoprazole 20 mg daily for 28 days. The long and short versions of ReQuest were completed both in the pre-treatment and treatment phases. For scale development an item reduction analysis was performed. Internal consistency, test-retest reliability and responsiveness were calculated for psychometric analysis. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale and the Psychological General Well-being questionnaire by means of correlation coefficients. RESULTS: Factor analyses confirmed the content validity of both long and short version of ReQuest. Psychometric calculations proved high internal consistency (Cronbach's alpha: 0.9), test-retest reliability [Intraclass Correlation Coefficient: 0.9 (long vs. long) and 0.8 (short vs. short)], and responsiveness (Responsiveness Index 320.3) of the scale, for which also good construct validity was achieved (correlation coefficient: Gastrointestinal Symptom Rating Scale 0.6; Psychological General Well-being -0.4). CONCLUSION: ReQuest proved valid, reliable, and responsive in this multinational clinical trial to evaluate treatment response in endoscopy-negative gastro-oesophageal reflux disease patients.