Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition

Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.

Development and validation of a large, modular test meal with liquid and solid components for assessment of gastric motor and sensory function by non-invasive imaging.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study introduces the large 'Nottingham Test Meal' (NTM) for assessment of gastric motor and sensory function by non-invasive imaging. METHODS: NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and 12 solid agar-beads (0 kcal) with known breaking strength. Gastric fullness and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gastric emptying (GE) were measured in 24 healthy volunteers (HVs) by gastric scintigraphy (GS) and magnetic resonance imaging (MRI). The contribution of secretion to gastric volume was assessed. Parameters that describe GE were calculated from validated models. Inter-observer agreement and reproducibility were assessed. KEY RESULTS: NTM produced moderate fullness (VAS ≥30) but no more than mild dyspeptic symptoms (VAS <30) in 24 HVs. Stable binding of meal components to labels in gastric conditions was confirmed. Distinct early and late-phase GE were detected by both modalities. Liquid GE half-time was median 49 (95% CI: 36-62) min and 68 (57-71) min for GS and MRI, respectively. Differences between GS and MRI measurements were explained by the contribution of gastric secretion. Breaking strength for agar-beads was 0.8 N/m(2) such that median 25 (8-50) % intact agar-beads and 65 (47-74) % solid material remained at 120 min on MRI and GS, respectively. Good reproducibility for liquid GE parameters was present and GE was not altered by agar-beads. CONCLUSIONS & INFERENCES: The NTM provided an objective assessment of gastric motor and sensory function. The results were reproducible and liquid emptying was not affected by non-nutrient agar-beads. The method is potentially suitable for clinical practice.

Measurement of gastric meal and secretion volumes using magnetic resonance imaging.

MRI can assess multiple gastric functions without ionizing radiation. However, time consuming image acquisition and analysis of gastric volume data, plus confounding of gastric emptying measurements by gastric secretions mixed with the test meal have limited its use to research centres. This study presents an MRI acquisition protocol and analysis algorithm suitable for the clinical measurement of gastric volume and secretion volume. Reproducibility of gastric volume measurements was assessed using data from 10 healthy volunteers following a liquid test meal with rapid MRI acquisition within one breath-hold and semi-automated analysis. Dilution of the ingested meal with gastric secretion was estimated using a respiratory-triggered T1 mapping protocol. Accuracy of the secretion volume measurements was assessed using data from 24 healthy volunteers following a mixed (liquid/solid) test meal with MRI meal volumes compared to data acquired using gamma scintigraphy (GS) on the same subjects studied on a separate study day. The mean ± SD coefficient of variance between 3 observers for both total gastric contents (including meal, secretions and air) and just the gastric contents (meal and secretion only) was 3 ± 2% at large gastric volumes (>200 ml). Mean ± SD secretion volumes post meal ingestion were 64 ± 51 ml and 110 ± 40 ml at 15 and 75 min, respectively. Comparison with GS meal volumes, showed that MRI meal only volume (after correction for secretion volume) were similar to GS, with a linear regression gradient ± std err of 1.06 ± 0.10 and intercept -11 ± 24 ml. In conclusion, (i) rapid volume acquisition and respiratory triggered T1 mapping removed the requirement to image during prolonged breath-holds (ii) semi-automatic analysis greatly reduced the time required to derive measurements and (iii) correction for secretion volumes provided accurate assessment of gastric meal volumes and emptying. Together these features provide the scientific basis of a protocol which would be suitable in clinical practice.

Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Upper esophageal sphincter and esophageal motility in patients with chronic cough and reflux: assessment by high-resolution manometry.

The pathophysiology of chronic cough and its association with dsymotility and laryngopharyngeal reflux remains unclear. This study applied high-resolution manometry (HRM) to obtain a detailed evaluation of pharyngeal and esophageal motility in chronic cough patients with and without a positive reflux-cough symptom association probability (SAP). Retrospective analysis of 66 consecutive patients referred for investigation of chronic cough was performed. Thirty-four (52%) were eligible for inclusion (age 55 [19-77], 62% female). HRM (ManoScan 360, Given/Sierra Scientific Instruments, Mountain View, CA) with 10 water swallows was performed followed by a 24-hour ambulatory pH monitoring. Of this group, 21 (62%) patients had negative reflux-cough SAP (group A) and 13 (38%) had positive SAP (group B). Results from 23 healthy controls were available for comparison (group C). Detailed analysis revealed considerable heterogeneity. A small number of patients had pathological upper esophageal sphincter (UES) function (n=9) or esophageal dysmotility (n=1). The overall baseline UES pressure was similar, but average UES residual pressure was higher in groups A and B than in control group C (-0.2 and -0.8mmHg vs. -5.4mmHg; P<0.018 and P<0.005). The percentage of primary peristaltic contractions was lower in group B than in groups A and C (56% vs. 79% and 87%; P=0.03 and P<0.002). Additionally, intrabolus pressure at the lower esophageal sphincter was higher in group B than in group C (15.5 vs. 8.9; P=0.024). HRM revealed changes to UES and esophageal motility in patients with chronic cough that are associated with impaired bolus clearance. These changes were most marked in group B patients with a positive reflux-cough symptom association.

Rumination variations: aetiology and classification of abnormal behavioural responses to digestive symptoms based on high-resolution manometry studies.

BACKGROUND: Rumination is the voluntary, albeit subconscious return of gastric contents to the mouth. Currently, rumination syndrome and repetitive belching disorders are considered separate diagnoses, as defined by Rome III criteria and high-resolution oesophageal manometry (HRM). AIM: To test the hypothesis that these conditions represent a common behavioural response to aversive digestive stimuli and that successful treatment can be directed at both the stimulus and the response. METHODS: Case-note review of consecutive patients with a final diagnosis of behavioural digestive disorders between August 2009 and October 2011. RESULTS: Thirty-five of 46 (76%) patients exhibited 'classical' rumination with abdomino-gastric strain (R-waves) driving gastric contents across the lower oesophageal sphincter; 5 (11%) had 'reflux-related' rumination with R-waves seen during gastro-oesophageal common cavity (reflux) events and 6 had (13%) supra-gastric belching. All received at least one biofeedback session at the time of diagnosis with a good response reported by 20/46 (43%) of the patients, which included 3 with supra-gastric belching. Additionally, rumination ceased in cases in which definitive treatment relieved the symptoms that triggered abnormal behaviour (e.g. fundoplication in 'reflux-rumination'). CONCLUSIONS: Rumination and many of its variations, excluding only some cases of supra-gastric belching, are associated with abdomino-gastric strain, a generic abnormal behavioural response to a variety of aversive digestive stimuli. All types of rumination can respond to biofeedback. High-resolution oesophageal manometry identifies subgroups with distinct mechanisms of disease that respond to specific management targeted at the symptoms that trigger the abnormal behaviour.

The gastro-esophageal reflux barrier: biophysical analysis on 3D models of anatomy from magnetic resonance imaging.

BACKGROUND: The function and structure of the gastro-esophageal junction (GEJ) determine its efficacy as a reflux barrier. This study presents a novel methodology for the quantitative assessment of GEJ and proximal gastric morphology from magnetic resonance (MR) imaging. Based on this data we propose a new conceptualization of the hypothesis that a flap valve mechanism contributes to reflux protection. METHODS: 3D models of the GEJ and proximal stomach were reconstructed from MR images in 12 healthy volunteers during respiration and on eating a test meal to maximum satiation. A rotating plane analysis measured the gastro-esophageal insertion angle and span of contact. An ellipsoid fit provided quantitative assessment of gastric shape and orientation relative to a fixed anatomical reference point. Position of the esophageal insertion on the 'gastric ellipse' was noted. An ellipsoid-cylinder model was designed to analyze the relationships among parameters describing the GEJ morphology. KEY RESULTS: The insertion angle became more acute on expiration, but did not change with meal ingestion. In contrast the span of contact did not vary with respiration, but increased with gastric filling. Changes in gastric morphology with distension further augmented the span of gastro-esophageal contact in almost 70% of the studies. CONCLUSIONS & INFERENCES: Novel MR imaging and biophysical analysis of the GEJ and proximal stomach provide a quantitative description of structures contributing to the reflux barrier. Changes in these parameters during respiration and on eating support the hypothesis that structural components of a functional 'flap valve' like mechanism contribute to reflux protection.

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contraction waves and emptying: an MRI study.

Gastric emptying (GE) may be driven by tonic contraction of the stomach ('pressure pump') or antral contraction waves (ACW) ('peristaltic pump'). The mechanism underlying GE was studied by contrasting the effects of clonidine (alpha(2)-adrenergic agonist) and sumatriptan (5-HT(1) agonist) on gastric function. Magnetic resonance imaging provided non-invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min(-1) IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r(2 )=49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r2=15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the 'pressure pump' mechanism.

High-resolution manometry in clinical practice: utilizing pressure topography to classify oesophageal motility abnormalities.

High-resolution manometry capable of pressure monitoring from the pharynx to the stomach together with pressure topography plotting represents an unquestionable evolution in oesophageal manometry. However, with this advanced technology come challenges and one of those is devising the optimal scheme to apply high-resolution oesophageal pressure topography (HROPT) to the clinical evaluation of patients. The first iteration of the Chicago classification was based on a systematic analysis of motility patterns in 75 control subjects and 400 consecutive patients. This review summarizes the analysis process as it has evolved. Individual swallows are analysed in a stepwise fashion for the morphology of the oesophagogastric junction (OGJ), the extent of OGJ relaxation, the propagation velocity of peristalsis, the vigour of the peristaltic contraction, and abnormalities of intrabolus pressure utilizing metrics that have now been customized to HROPT. These results are then synthesized into a comprehensive diagnosis that, although based on conventional manometry criteria, is also customized to HROPT measures. The resultant classification objectifies the identification of three unique subtypes of achalasia. Additionally, it provides enhanced detail in the description of distal oesophageal spasm, nutcracker oesophagus subtypes, and OGJ obstruction. It is our expectation that modification of this classification scheme will continue to occur and this should further clarify the utility of pressure topography plotting in assessing oesophageal motility disorders.

Characterization of gastric volume responses and liquid emptying in functional dyspepsia and health by MRI or barostat and simultaneous C-acetate breath test.

The assessment of gastric accommodation and emptying by different methodologies provides inconsistent results. We aimed to compare magnetic resonance imaging (MRI), barostat and 13C-acetate breath test (BT) for the assessment of gastric volume responses and emptying in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent: (i) continuous BT with simultaneous MRI in the upright position after ingestion of isocaloric, 300 kcal, 200 and 800 mL meals, both labelled with 100 mg of (13)C-acetate; and (ii) BT with gastric barostat after ingestion of the 200 mL meal. MRI measured total gastric volume and gastric content volume (GCV) at baseline, after filling and during emptying. Meal emptying half-times (T(1/2)) for MRI and BT were calculated (mean +/- SD). We found: (i) Initial GCV was lower in FD than in HC (762 +/- 22 vs 810 +/- 52 mL, P < 0.04) after the 800 mL meal but not the 200 mL meal. T(1/2)(MRI) was shorter for the 800 mL than the 200 mL meal (P < 0.001), but similar in HC and FD (200 mL: HC 117 +/- 30 min vs FD 138 +/- 42 min, ns; 800 mL: HC 71 +/- 16 min vs FD 78 +/- 27 min, ns). In contrast, T(1/2)(BT) was similar between meals and groups (200 mL: HC 111 +/- 11 min vs FD 116 +/- 19 min; 800 mL: HC 114 +/- 14 min vs FD: 113 +/- 17 min). (ii) Barostat measurements showed similar postprandial volume increases between groups. We conclude that direct measurements by MRI provide a sensitive, non-invasive assessment of gastric accommodation and emptying after a meal. In contrast to MRI, BT did not detect faster emptying of high-volume compared to low-volume liquid nutrient meals in HC or FD.

Pneumocystis colonisation is common among hospitalised HIV infected patients with non-Pneumocystis pneumonia.

BACKGROUND: When Pneumocystis DNA is recovered from respiratory specimens of patients without Pneumocystis pneumonia (PCP), patients are said to be colonised with Pneumocystis, although the significance of this state is unknown. Understanding risk factors for and outcomes of colonisation may provide insights into the life cycle and transmission dynamics of Pneumocystis jirovecii. METHODS: We performed a cross sectional study of the prevalence and clinical predictors of Pneumocystis colonisation in 172 HIV infected, PCP negative inpatients undergoing diagnostic evaluation of 183 episodes of pneumonia at either the Medical Center of Louisiana at New Orleans between 2003 and 2005 or San Francisco General Hospital between 2000 and 2005. DNA was extracted from sputum and bronchoalveolar lavage specimens and amplified using a nested PCR assay at the mitochondrial large subunit (18S) ribosomal RNA locus. Colonisation was deemed present if Pneumocystis DNA was identified by both gel electrophoresis and direct DNA sequencing. RESULTS: 68% (117/172) of all patients were colonised with Pneumocystis. No strong associations with colonisation were identified for any demographic factors. Among clinical factors, having a CD4+ T cell count

Oesophageal high-resolution manometry: moving from research into clinical practice.

Manometry measures pressure within the oesophageal lumen and sphincters, and provides an assessment of the neuromuscular activity that dictates function in health and disease. It is performed to investigate the cause of functional dysphagia, unexplained "non-cardiac" chest pain, and in the pre-operative work-up of patients referred for anti-reflux surgery. Manometric techniques have improved in a step-wise fashion from a single pressure channel to the development of high-resolution manometry (HRM) with up to 36 pressure sensors. At the same time, advances in computer processing allow pressure data to be presented in real time as a compact, visually intuitive "spatiotemporal plot" of oesophageal pressure activity. HRM recordings reveal the complex functional anatomy of the oesophagus and its sphincters. Spatiotemporal plots provide objective measurements of the forces that move food and fluid from the pharynx to the stomach and determine the risk of reflux events. The introduction of commercially available HRM has been followed by rapid uptake of the technique. This review examines the current evidence that supports the move of HRM from the research setting into clinical practice. It is assessed whether a detailed description of pressure activity identifies clinically relevant oesophageal dysfunction that is missed by conventional investigation, increasing diagnostic yield and accuracy. The need for a new classification system for oesophageal motor activity based on HRM recordings is discussed. Looking ahead the potential of this technology to guide more effective medical and surgical treatment of oesophageal disease is considered because, ultimately, it is this that will define the success of HRM in clinical practice.

Assessment of cadmium, lead and vanadium status of large animals as related to the human food chain.

Cadmium (Cd) and lead (Pb) are of established toxicological significance for humans, and it is important that intakes from foods not cause excessive exposure. Both elements concentrate to high levels in liver and kidneys of large, domestic food animals (cattle, sheep and swine), and Pb also concentrates in bone, which is sometimes used in the form of bone meal as a dietary supplement. Milk is a significant source of Cd and Pb for infants and toddlers. Levels of these elements in domestic food animal tissues and milk are presently within acceptable ranges for human consumption. Vanadium (V) sources to animals may increase and create potential human food problems; however, at the present time meats and milk are safe to consume with respect to this element.

Dietary model for production of experimental zinc deficiency in man.

A semipurified diet based on soy protein was developed to induce mild zinc deficiency in five male volunteers. Each of seven daily menus provided (mean +/- SD) 2248 +/- 128 kcal, 56.6 +/- 5.7 protein, 261 +/- 30 g carbohydrate, 110 +/- 21 g fat, 8.5 +/- 1.4 g fiber, and 4.8 +/- 1.3 mg zinc. The analytical value for phytate:zinc molar ratio was 21 +/- 9. One subject, who received five of the menus for 28 wk, lost approximately 200 mg body zinc and 7% weight; zinc concentration declined 25% in plasma, 30% in lymphocytes, and 55% in neutrophils. This dietary model allowed simple formulation of new menus for subjects in diverse states of health. It caused no ill effects after prolonged consumption, and all deficiency symptoms were reversed by zinc supplementation of 30 mg/d for 20 wk. With simple manipulation, this dietary model may be used safely for gradual induction of zinc and/or other micronutrient deficiencies in humans.

Preparation of inositol phosphates from sodium phytate by enzymatic and nonenzymatic hydrolysis.

Procedures for preparing myo-inositol bis-, tris-, tetrakis-, and pentakisphosphates from sodium phytate were established. Hydrolysis was achieved by autoclaving or enzymatic treatment; the inositol phosphates were separated by anion-exchange chromatography and were identified by fast atom bombardment-mass spectrometry. Enzymatic hydrolysis was more specific than autoclaving for isomer formation, whereas autoclaving was more efficient for producing the bis- and trisphosphates, which did not accumulate in significant amounts under the conditions of enzymatic hydrolysis. Sodium salts of the inositol phosphates were more powdery and less hygroscopic than the potassium salts. The procedures were satisfactory for producing gram quantities of each inositol phosphate, amounts adequate for animal studies of effects on mineral bioavailability.

Purified reference diets for weanling rats: effects of biotin and cellulose.

Standardized purified diets limited to required nutrients are needed for nutritional and toxicological studies. In the present study, we formulated a biotin- and cellulose-free diet of reproducible mineral composition (diet A), based on diet AIN-76, and fed it to weanling Long-Evans rats for 3 wk. Inductively coupled argon plasma atomic emission spectrometry was used to determine Ca, Cu, Fe, K, Mg, Mn, Na, P and Zn in liver, duodenum, kidney, spleen and femur. Results were compared with those obtained with rats fed biotin- and/or cellulose-supplemented variations of diet A, diet AIN-76 and diet NIH-31 (an open-formula stock diet). Weanling rats grew slowly and steadily on purified diet A. Growth rates increased when diet A was supplemented with biotin and cellulose. In general, differences among tissue mineral levels in rats fed diet NIH-31 and those fed diet AIN-76 were more pronounced than those among groups fed our purified diets. Values for hemoglobin and hematocrit were significantly lower in rats fed all purified diets than in those fed diet NIH-31. Diets A + biotin, A + cellulose and A + cellulose + biotin appear satisfactory as reference diets for measuring mineral interactions at near-requirement levels as well as effects of fiber on mineral utilization or for studies on vitamins whose endogenous synthesis may be influenced by dietary fiber.