Fernando Azpiroz

The origin of symptoms on the brain-gut axis in functional dyspepsia

It was hypothesized that symptoms in functional dyspepsia are originated by an altered mechanism at the brain-gut axis (one or several) in the process of gastric accommodation to a meal. To test the key mechanisms potentially involved in symptomatic gastric accommodation, the sensorial responses (on a 0-10 perception score) and the gastric tone responses (by electronic barostat) to either gastric accommodation (n = 10) or to cold stress (n = 10) were measured in 20 patients with functional dyspepsia and 20 healthy controls. The mechanical accommodation of the stomach to gastric distention (compliance) was similar in patients (52 +/- 8 mL/mm Hg) and controls (57 +/- 6 mL/mm Hg). However, isobaric gastric distention elicited more upper abdominal discomfort in dyspeptics than in controls (perception scores, 4.7 +/- 0.9 vs. 1.1 +/- 0.5, respectively; mean +/- SE; P less than 0.005). Cold stress induced a similar gastric relaxatory response in dyspeptics and controls (delta vol, 145 mL +/- 40 mL vs. 141 mL +/- 42 mL, respectively); hand perception (scores, 8.3 +/- 0.4 vs. 7.9 +/- 0.4, respectively) and autonomic responses were also similar. It is concluded that an abnormal afferent sensorial pathway (altered gastric perception) may be a major mechanism of symptom production in functional dyspepsia.

Mechanisms of hypersensitivity in IBS and functional disorders

General introduction  The concept of visceral hypersensitivity is accepted as being germane to several functional gastrointestinal disorders (FGIDs). The causes or risk factors associated with this hypersensitivity are unclear. This article addresses the proposed mechanisms leading to hypersensitivity: from genetic to inflammatory disorders, from central to peripheral alterations of function. However, in order to place visceral hypersensitivity in a more global perspective as an aetiological factor for FGIDs, it also provides a review of recent evidence regarding the role of other peripheral mechanisms (the intraluminal milieu), as also genetic factors in the pathophysiology of these disorders. The article has been divided into five independent sections. The first three sections summarize the evidence of visceral hypersensitivity as a biological marker of functional gut disorders, the peripheral and central mechanisms involved, and the role of inflammation on hypersensitivity. In opposition to visceral hypersensitivity as an isolated phenomenon in functional gut disorders, the last two sections focus on the importance of peripheral mechanisms, like motor disturbances, specifically those resulting on altered transport of intestinal gas, and alterations of the intraluminal milieu and genetics.

Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome

BACKGROUND/AIMS Experimental studies have shown gut hypersensitivity in irritable bowel syndrome. The aim of this study was to determine whether heightened perception of gut distention in irritable bowel syndrome is related to either decreased gut compliance, altered mechanosensitive afferents, or nonspecific sensory dysfunction. METHODS In 17 patients with irritable bowel syndrome and 15 healthy controls, stimulus-related perception of (1) intestinal balloon distentions, (2) transmucosal electrical nerve stimulation (15 Hz, 100 microseconds), and (3) somatic transcutaneous electrical nerve stimulation (100 Hz, 100 microseconds) was measured. Individual stimuli of 1-minute duration were randomly applied at 5-minute intervals. RESULTS Patients tolerated smaller intestinal volumes than controls (33 +/- 3 mL vs. 43 +/- 4 mL, respectively; mean +/- SE; P < 0.05), whereas both intestinal compliance and perception of transmucosal electrical nerve stimulation were normal (patients tolerated 58 +/- 5 mA and healthy subjects tolerated 69 +/- 5 mA). Interestingly, patients perceived both stimuli more diffusely than controls; 48% +/- 9% distentions and 52% +/- 9% electrical stimuli were perceived over more than one abdominal region vs. 21% +/- 9% and 18% +/- 6%, respectively, in controls (P < 0.05 for both). In contrast to gut distentions, patients showed higher tolerance of somatic stimuli than controls (68 +/- 7 mA vs. 42 +/- 6 mA, respectively; P < 0.05). CONCLUSIONS Patients with irritable bowel syndrome show selective hypersensitivity of intestinal mechanosensitive pathways associated with a nonspecific, probably central dysfunction of viscerosomatic referral.

Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia

BACKGROUND/AIMS We have previously shown that patients with functional dyspepsia are hypersensitive to gastric distention. The aim of this study was to establish whether this sensory disturbance was confined to the stomach and whether it was associated with gut reflex dysfunction. METHODS In 10 selected patients with dyspepsia and 12 healthy controls, perception and gut reflex responses to gastric distention, duodenal distention, and somatic stimulation were measured. Standardized distentions at fixed pressures were performed by gastric and duodenal barostats. Perception was scored by a detailed symptom questionnaire; gut reflex responses were measured as isobaric volume changes by each barostat. Somatic transcutaneous electrical nerve stimulation was produced on the hand. Individual stimuli (2-minute duration) were randomly applied at 10-minute intervals in stepwise increments in search of the respective threshold for discomfort. RESULTS Patients with dyspepsia had gastric hypersensitivity to distention (discomfort threshold at 6.4 +/- 0.4 mm Hg vs. 8.3 +/- 0.6 mm Hg in controls; mean +/- SE; P < 0.05), whereas duodenal and somatic sensitivity was normal. Furthermore, patients with dyspepsia explicitly recognized their clinical symptoms in all gastric but only in 58% +/- 12% of the duodenal distention trials. In addition, patients with dyspepsia showed defective gastric relaxatory responses to duodenal distention (68 +/- 30 mL gastric expansion vs. 239 +/- 12 mL in controls; P < 0.05). CONCLUSIONS Patients with dyspepsia are selectively hypersensitive to gastric distention; this sensory dysfunction is associated with impaired reflex reactivity of the stomach.

Gastric wall tension determines perception of gastric distention

BACKGROUND & AIMS The primary mechanism that originates symptoms in response to gastric distention remains undefined. The aim of this study was to determine which factor, whether intragastric volume, pressure, or wall tension, determines perception of gastric distention. METHODS Healthy subjects underwent increasing gastric distentions (2-minute duration at 5-minute intervals) either at fixed pressure levels using a conventional barostat (n = 10) or at fixed tension levels using a newly developed computerized tensostat (n = 12); perception was scored by a 0-6 scale. Distentions were performed during basal conditions (intravenous saline) and during gastric relaxation by glucagon administration (4.8 microgram/kg intravenous bolus plus 9.6 microgram. kg-1. h-1 infusion). RESULTS Isobaric distentions with the conventional barostat produced more intense perception during glucagon (95% +/- 40% higher; P < 0.05). However, the factor that determined higher perception could not be ascertained, because at the same pressure levels both intragastric volume and wall tension were greater during glucagon administration (174% +/- 56% and 34% +/- 8% greater, respectively; P < 0.05 vs. saline for both). The tensostat evidenced that perception was selectively related to tension, not to elongation; during glucagon administration, intragastric volumes were significantly larger (80% +/- 28% larger increase; P < 0.05), but perception of isotonic distentions remained the same (27% +/- 22%; nonsignificant change). CONCLUSIONS Gastric wall tension, but not intragastric volume, determines perception of gastric distention, at least below nociception.

Gastric tone determines the sensitivity of the stomach to distention

BACKGROUND/AIMS Whether meal-related symptoms such as postcibal epigastric fullness and discomfort are caused by hypotonic gastric expansion or gastric hypertension is unknown. This study investigated whether symptoms in healthy individuals in response to gastric distention are produced by gastric expansion or by an increase in intragastric pressure. METHODS Increasing gastric distentions (for 5 minutes at 5-minute intervals) at fixed pressure levels (in 2-mm Hg increments) and at fixed volume levels (in 200-mL increments) were performed in 10 healthy subjects per group; perception was measured on a 0-6 scale. Distentions were performed during intravenous infusion of saline (basal) and during gastric relaxation by intravenous administration of glucagon (4.8-micrograms/kg bolus plus 9.6 micrograms.kg-1.h-1 infusion). RESULTS The same distending pressure tested produced 30% +/- 9% larger intragastric volumes and 80% +/- 44% higher perception scores when the stomach was relaxed by glucagon (P < 0.05 vs. basal for both). In contrast, the same distending volumes tested produced 25% +/- 7% lower intragastric pressures and 21% +/- 12% lower perception scores when the stomach was relaxed (P < 0.05 vs. basal for both). CONCLUSIONS Epigastric symptoms in response to gastric distention are influenced by both the intragastric pressure and the intragastric volume.

Anorectal functional testing: review of collective experience.

Anorectal manometry includes a number of specific tests that are helpful in the diagnostic assessment of patients with fecal incontinence and constipation; their purpose is to delineate the pathophysiological mechanism for these symptoms. Some of these tests may also provide helpful information in the assessment of patients with rectal pain or diarrhea, but their sensitivity and specificity are less well established for these symptoms. Tests for which there is consensus regarding their clinical utility include 1) resting anal canal pressure, 2) anal canal squeeze pressure (peak pressure and duration), 3) the rectoanal inhibitory reflex elicited by balloon distension of the rectum, 4) anal canal pressure in response to a cough, 5) anal canal pressure in response to defecatory maneuvers, 6) simulated defecation by means of balloon or radiopaque contrast, 7) compliance of the rectum in response to balloon distension, and 8) sensory thresholds in response to balloon distension. Anal endosonography and pelvic floor electromyography from intra-anal plate electrodes are nonmanometric tests that are also specifically useful in the evaluation of constipation and fecal incontinence. The clinical utility of all anorectal manometric tests is limited by the relative absence of 1) standardization of test protocols and 2) normative data from a large number of healthy individuals. The interpretation of these diagnostic tests is also complicated by the fact that patients are able to compensate for deficits in specific physiological mechanisms maintaining continence and defecation by utilizing other biological and behavioral mechanisms.

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier

Objective Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. Design A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117+ cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. Results Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. Conclusion The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.

Intestinal gas dynamics and tolerance in humans

BACKGROUND & AIMS Abdominal symptoms are often attributed to intestinal gas. In humans, gas production and composition have been previously investigated, but intestinal gas dynamics and tolerance remain virtually unknown. The aim of this study was to establish the relationship between intestinal gas loads, evacuation, perception of symptoms, and objective abdominal distention in healthy humans. METHODS A dose-response study was performed in 46 healthy subjects; intestinal gas was infused for 3 hours (0, 1, 4, 12, and 30 mL/min), and anal gas evacuation, symptom perception, and abdominal distention were measured. A mixture of gases was infused in venous proportions to minimize diffusion. Anal gas recovery and calculations of gas retention were validated using sulfur hexafluoride as a nonabsorbable gaseous marker. RESULTS At all of the infusion rates, gas evacuation rapidly equilibrated and paralleled gas infusion without significant differences in perception. Only 6 subjects retained >400 mL gas, and 5 of them developed abdominal distention and symptoms. By contrast, all but 4 of the 41 subjects without retention tolerated the gas loads without discomfort. CONCLUSIONS Intestinal gas tolerance is normally high, because expeditious gas transit and evacuation prevent gas pooling and symptoms. When this protective mechanism is insufficient, gas retention occurs, and it causes abdominal symptoms and distention.

Antro-fundic dysfunctions in functional dyspepsia

BACKGROUND & AIMS Symptoms in functional dyspepsia have been related to impaired accommodation and hypersensitivity of the proximal stomach. We hypothesized that identification of putative antral dysfunctions provides a more comprehensive pathophysiological interpretation. METHODS In 30 patients with functional dyspepsia and 22 healthy subjects, 2 consecutive studies were performed. In study I, with the subjects in the upright position, the proximal and distal stomach were selectively distended by bags containing air and water, respectively, while perception and fundic relaxation in response to antral distention were measured. In study II, by using air-filled bags connected to a tensostat, the proximal and the distal stomach were selectively distended by positioning the subjects on the right and left lateral decubitus, respectively, while perception, compliance, and the responses to intestinal nutrient infusion were measured. RESULTS Patients with dyspepsia showed hypersensitivity of both the proximal stomach (discomfort at 30 +/- 3 g vs. 62 +/- 2 g in controls; P < 0.05) and the antrum (discomfort at 31 +/- 2 g vs. 53 +/- 4 g in controls; P < 0.05). Fundic and antral fasting tone was normal, but reflex fundic relaxation induced either by antral distention (3 +/- 16 mL at 80 mL of distention vs. 38 +/- 10 mL in controls; P < 0.05) or by intestinal nutrients (35 +/- 7 mL vs. 107 +/- 8 mL in controls; P < 0.05) was markedly impaired. CONCLUSIONS Antral and fundic dysfunctions interact to produce the symptoms of functional dyspepsia, and impaired control of fundic accommodation may lead to overload of a hypersensitive antrum.