Effect of high altitude on human postprandial 13 C-octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception.

OBJECTIVE: At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by 13 C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate. METHODS: A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. STATISTICAL ANALYSIS: variance analyses, bivariate correlation, and multilinear regression analysis. RESULTS: After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). 13 CO2 exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated 13 CO2 -generation under these conditions. CONCLUSION: Quantification of 13 C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. 13 C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.

Evaluation of Acute Mountain Sickness by Unsedated Transnasal Esophagogastroduodenoscopy at High Altitude.

BACKGROUND & AIMS: It is not clear how rapid ascent to a high altitude causes the gastrointestinal symptoms of acute mountain sickness (AMS). We assessed the incidence of endoscopic lesions in the upper gastrointestinal tract in healthy mountaineers after a rapid ascent to high altitude, their association with symptoms, and their pathogenic mechanisms. METHODS: In a prospective study, 25 mountaineers (10 women; mean age, 43.8 ± 9.5 y) underwent unsedated, transnasal esophagogastroduodenoscopy in Zurich (490 m) and then on 2 test days (days 2 and 4) at a high altitude laboratory in the Alps (Capanna Regina Margherita, 4559 m). Symptoms were assessed using validated instruments for AMS (the acute mountain sickness score and the Lake Louise scoring system) and visual analogue scales (scale, 0-100). Levels of messenger RNAs (mRNAs) in duodenal biopsy specimens were measured by quantitative polymerase chain rection. RESULTS: The follow-up endoscopy at high altitude was performed in 19 of 25 patients on day 2 and in 23 of 25 patients on day 4. The frequency of endoscopic lesions increased from 12% at baseline to 26.3% on day 2 and to 60.9% on day 4 (P < .001). The incidence of ulcer disease increased from 0 at baseline to 10.5% on day 2 and to 21.7% on day 4 (P = .014). Mucosal lesions were associated with lower hunger scores (37.3 vs 67.4 in patients without lesions; P = .012). Subjects with peptic lesions had higher levels of HIF2A mRNA, which encodes a hypoxia-induced transcription factor, and ICAM1 mRNA, which encodes an adhesion molecule, compared with subjects without lesions (fold changes, 1.38 vs 0.63; P = .001; and 1.37 vs 0.66; P = .011, respectively). CONCLUSIONS: In a prospective study of 25 mountaineers, fast ascent to a high altitude resulted in rapid onset of clinically meaningful mucosal lesions and ulcer disease. Duodenal biopsy specimens from these subjects had increased levels of HIF2A mRNA and ICAM1 mRNA, which might contribute to the formation of hypoxia-induced peptic lesions. Further studies are needed of the mechanisms of this process.

Assessment of Obstructive Defecation by High-Resolution Anorectal Manometry Compared With Magnetic Resonance Defecography.

BACKGROUND & AIMS: Patients with obstructive defecation have abnormalities of anorectal function and/or structure. Conventional anorectal manometry (ARM) can identify abnormal function and behavior (dyssynergia); however, agreement between manometry and defecography is only fair. High-resolution (HR)-ARM may improve diagnostic agreement by differentiating pressure effects caused by dyssynergia and obstruction. We compared HR-ARM findings with magnetic resonance (MR) defecography in the clinical assessment of patients with symptoms of obstructive defecation defined by Rome III criteria. METHODS: HR-ARM (Manoscan AR 360; Given Imaging, Yoqeam, Israel) assessed anal sphincter function and pressure during simulated defecation. Abnormal manometric findings were classified according to the Rao system and compared with MR defecography as the reference standard. RESULTS: A total of 188 consecutive patients (155 women; age, 19-93 y) with obstructive defecation underwent a full investigation. Compared with patients with dyssynergia on MR imaging (n = 66), patients with structural pathology (n = 87) had lower resting (P < .003) and squeeze pressures (P < .011), but a higher rectoanal pressure gradient (P < .0001) on HR-ARM. High intrarectal pressure with a steep, positive pressure gradient consistent with outlet obstruction on HR-ARM was present in 24 patients with intra-anal intussusception on MR imaging. This pattern was not observed in other patients. Interobserver agreement was substantial for HR-ARM diagnoses (κ = 0.67; 95% confidence interval, 0.559-0.779). Diagnostic accuracy for dyssynergia was 82% compared with MR imaging (sensitivity, 77% [51 of 66]; specificity, 85% [104 of 122]). CONCLUSIONS: The diagnostic agreement between anorectal HR-ARM and MR defecography is high and pressure measurements accurately identify recto-anal dyssynergia and intra-anal outlet obstruction by structural pathology as causes of obstructive defecation.

Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers.

UNLABELLED: Human iron homeostasis is regulated by intestinal iron transport, hepatic hepcidin release, and signals from pathways that consume or supply iron. The aim of this study was to characterize the adaptation of iron homeostasis under hypoxia in mountaineers at the levels of (1) hepatic hepcidin release, (2) intestinal iron transport, and (3) systemic inflammatory and erythropoietic responses. Twenty-five healthy mountaineers were studied. Blood samples and duodenal biopsies were taken at baseline of 446 m as well as on day 2 (MG2) and 4 (MG4) after rapid ascent to 4559 m. Divalent metal-ion transporter 1 (DMT-1), ferroportin 1 (FP-1) messenger RNA (mRNA), and protein expression were analyzed in biopsy specimens by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Serum hepcidin levels were analyzed by mass spectrometry. Serum iron, ferritin, transferrin, interleukin (IL)-6, and C-reactive protein (CRP) were quantified by standard techniques. Serum erythropoietin and growth differentiation factor 15 (GDF15) levels were measured by enzyme-linked immunosorbent assay (ELISA). Under hypoxia, erythropoietin peaked at MG2 (P < 0.001) paralleled by increased GDF15 on MG2 (P < 0.001). Serum iron and ferritin levels declined rapidly on MG2 and MG4 (P < 0.001). Duodenal DMT-1 and FP-1 mRNA expression increased up to 10-fold from baseline on MG2 and MG4 (P < 0.001). Plasma CRP increased on MG2 and MG4, while IL-6 only increased on MG2 (P < 0.001). Serum hepcidin levels decreased at high altitude on MG2 and MG4 (P < 0.001). CONCLUSION: This study in healthy volunteers showed that under hypoxemic conditions hepcidin is repressed and duodenal iron transport is rapidly up-regulated. These changes may increase dietary iron uptake and allow release of stored iron to ensure a sufficient iron supply for hypoxia-induced compensatory erythropoiesis.

Effect on gastric function and symptoms of drinking wine, black tea, or schnapps with a Swiss cheese fondue: randomised controlled crossover trial.

OBJECTIVE: To compare the effects of drinking white wine or black tea with Swiss cheese fondue followed by a shot of cherry schnapps on gastric emptying, appetite, and abdominal symptoms. DESIGN: Randomised controlled crossover study. PARTICIPANTS: 20 healthy adults (14 men) aged 23-58. INTERVENTIONS: Cheese fondue (3260 kJ, 32% fat) labelled with 150 mg sodium (13)Carbon-octanoate was consumed with 300 ml of white wine (13%, 40 g alcohol) or black tea in randomised order, followed by 20 ml schnapps (40%, 8 g alcohol) or water in randomised order. MAIN OUTCOME MEASURES: Cumulative percentage dose of (13)C substrate recovered over four hours (higher values indicate faster gastric emptying) and appetite and dyspeptic symptoms (visual analogue scales). RESULTS: Gastric emptying was significantly faster when fondue was consumed with tea or water than with wine or schnapps (cumulative percentage dose of (13)C recovered 18.1%, 95% confidence interval 15.2% to 20.9% v 7.4%, 4.6% to 10.3%; P<0.001). An inverse dose-response relation between alcohol intake and gastric emptying was evident. Appetite was similar with consumption of wine or tea (difference 0.11, -0.12 to 0.34; P=0.35), but reduced if both wine and schnapps were consumed (difference -0.40, -0.01 to -0.79; P<0.046). No difference in dyspeptic symptoms was present. CONCLUSIONS: Gastric emptying after a Swiss cheese fondue is noticeably slower and appetite suppressed if consumed with higher doses of alcohol. This effect was not associated with dyspeptic symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT00943696.

Effect of meal volume and calorie load on postprandial gastric function and emptying: studies under physiological conditions by combined fiber-optic pressure measurement and MRI.

This study assessed the effects of meal volume (MV) and calorie load (CL) on gastric function. MRI and a minimally invasive fiber-optic recording system (FORS) provided simultaneous measurement of gastric volume and pressure changes during gastric filling and emptying of a liquid nutrient meal in physiological conditions. The gastric response to 12 iso-osmolar MV-CL combinations of a multinutrient drink (MV: 200, 400, 600, 800 ml; CL: 200, 300, 400 kcal) was tested in 16 healthy subjects according to a factorial design. Total gastric volume (TGV) and gastric content volume (GCV = MV + secretion) were measured by MRI during nasogastric meal infusion and gastric emptying over 60 min. Intragastric pressure was assessed at 1 Hz by FORS. The dynamic change in postprandial gastric volumes was described by a validated three-component linear exponential model. The stomach expanded with MV, but the ratio of GCV:MV at t(0) diminished with increasing MV (P < 0.01). Postprandial changes in TGV followed those of GCV. Intragastric pressure increased with MV, and this effect was augmented further by CL (P = 0.02); however, the absolute pressure rise was <4 mmHg. A further postprandial increase of gastric volumes was observed early on before any subsequent volume decrease. This "early" increase in GCV was greater for smaller than larger MV (P < 0.01), indicating faster initial gastric emptying of larger MV. In contrast, volume change during filling and in the early postprandial period were unaffected by CL. In the later postprandial period, gastric emptying rate continued to be more rapid with high MVs (P < 0.001); however, at any given volume, gastric emptying was slowed by higher CL (P < 0.001). GCV half-emptying time decreased with CL at 18 +/- 6 min for each additional 100-kcal load (P < 0.001). These findings indicate that gastric wall stress (passive strain and active tone) provides the driving force for gastric emptying, but distal resistance to gastric outflow regulates further passage of nutrients. The distinct early phase of gastric emptying with relatively rapid, uncontrolled passage of nutrients into the small bowel, modulated by meal volume but not nutrient composition, ensures that the delivery of nutrients in the later postprandial period is related to the overall calorie load of the meal.

Effect of a prebiotic mixture on intestinal comfort and general wellbeing in health.

Specific carbohydrates, i.e. prebiotics such as fructo-oligosaccharide (FOS), are not digested in the small intestine but fermented in the colon. Besides beneficial health effects of an enhanced bifidobacteria population, intestinal gas production resulting from fermentation can induce abdominal symptoms. Partial replacement with slowly fermented acacia gum may attenuate side effects. The aim was to compare the effects of FOS with those of a prebiotic mixture (50 % FOS and 50 % acacia gum; BLEND) and a rapidly absorbed carbohydrate (maltodextrin) on general intestinal wellbeing, abdominal comfort and anorectal sensory function. Twenty volunteers (eight male and twelve female; age 20-37 years) completed this double-blind, randomised study with two cycles of a 2-week run-in phase (10 g maltodextrin) followed by 5 weeks of 10 g FOS or BLEND once daily, separated by a 4-week wash-out interval. Abdominal symptoms and general wellbeing were documented by telephone interview or Internet twice weekly. Rectal sensations were assessed by a visual analogue scale during a rectal barostat test after FOS and BLEND treatment. Both FOS and BLEND induced more side effects than maltodextrin. Belching was more pronounced under FOS compared with BLEND (P = 0.09 for females; P = 0.01 for males), and for self-reported general wellbeing strong sex differences were reported (P = 0.002). Urgency scores during rectal barostat were higher with FOS than BLEND (P = 0.01). Faced with a growing range of supplemented food products, consumers may benefit from prebiotic mixtures which cause fewer abdominal side effects. Sex differences must be taken in consideration when food supplements are used.

Limited diagnostic value of laryngopharyngeal lesions in patients with gastroesophageal reflux during routine upper gastrointestinal endoscopy.

BACKGROUND AND AIMS: There is growing evidence that gastroesophageal reflux disease (GERD) may cause typical laryngeal/pharyngeal lesions secondary to tissue irritation. The prevalence of those lesions in GERD patients is not well established. The aim of this study was to evaluate the prevalence of GERD signs in the laryngopharyngeal area during routine upper gastrointestinal endoscopy. METHODS: Between July 2000 and July 2001, 1,209 patients underwent 1,311 upper gastrointestinal endoscopies and were enrolled in this study. The structured examination of the laryngopharyngeal area during upper gastrointestinal endoscopy was videotaped for review by three gastroenterologists and one otorhinolaryngologist, blinded to the endoscopic esophageal findings. From the 1,209 patients enrolled in this prospective study, all patients (group I, N = 132) with typical endoscopical esophageal findings of GERD (Savary-Miller I-IV) were selected. The sex- and age-matched control group II (N = 132) underwent upper gastrointestinal endoscopy for different reasons, had no reflux symptoms, and had normal esophagoscopy. RESULTS: In the two groups of patients, we found no difference in the prevalence of abnormal interarytenoid bar findings (32%vs 32%), arytenoid medial wall erythema (47%vs 43%), posterior commissure changes (36%vs 34%), or posterior cricoid wall edema (1%vs 3%). The only difference was noted in the posterior pharyngeal wall cobblestoning (66%vs 50%, P= 0.004). CONCLUSION: The results of this large systematic investigation challenge the diagnostic specificity of laryngopharyngeal findings attributed to gastroesophageal reflux.

Efficacy and safety of botulinum toxin a injection compared with topical nitroglycerin ointment for the treatment of chronic anal fissure: a prospective randomized study.

OBJECTIVES: To evaluate the efficacy and safety of botulinum toxin A injection compared with topical nitroglycerin ointment for the treatment of chronic anal fissure (CAF). METHODS: Fifty outpatients with CAF were randomized to receive either a single botulinum toxin injection (30 IU Botox) or topical nitroglycerin ointment 0.2% b.i.d. for 2 wk. If the initial therapy failed, patients were assigned to the other treatment group for a further 2 wk. If CAF still showed no healing at wk 4, patients received combination therapy of botulinum toxin and nitroglycerin for 4 additional wk. Persisting CAF at wk 8 was treated according to the investigator's decision. Healing rates, symptoms, and side effects of the therapy were recorded at wk 2, 4, 8, 12, and 24 after randomization. RESULTS: The group initially treated with nitroglycerin showed a higher healing rate of CAF (13 of 25, 52%) as compared with the botulinum toxin group (6 of 25, 24%) after the first 2 wk of therapy (p < 0.05). At the end of wk 4, CAF healed in three additional patients, all receiving nitroglycerin after initial botulinum toxin injection. Mild side effects occurred in 13 of 50 (26%) patients, all except one were on nitroglycerin. CONCLUSIONS: Nitroglycerin ointment was superior to the more expensive and invasive botulinum toxin injection for initial healing of CAF, but was associated with more but mild side effects.