Bloating, like some other descriptors for abdominal SPECIAL REPORTS AND REVIEWS. Abdominal Bloating

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1 GASTROENTEROLOGY 2005;129: SPECIAL REPORTS AND REVIEWS Abdominal Bloating FERNANDO AZPIROZ and JUAN R. MALAGELADA Digestive System Research Unit, Hospital General Vall d Hebron, Autonomous University of Barcelona, Barcelona, Spain Abdominal bloating is a common and significant clinical problem that remains to be scientifically addressed. Bloating is one of the most bothersome complaints in patients with various functional gut disorders. However, in the current standard classification, abdominal bloating is merely regarded as a secondary descriptor, which masks its real clinical effect. Four factors are involved in the pathophysiology of bloating: a subjective sensation of abdominal bloating, objective abdominal distention, volume of intra-abdominal contents, and muscular activity of the abdominal wall. The primer to elicit subjective bloating may be any of the other 3 factors, or the sensation may be related to distorted perception. All of these mechanisms may play an independent role or may be interrelated. Gas transit studies have evidenced that patients with bloating have impaired reflex control of gut handling of contents. Segmental pooling, either of gas or of solid/liquid components, may induce a bloating sensation, particularly in patients with altered gut perception. Furthermore, altered viscerosomatic reflexes may contribute to abdominal wall protrusion and objective distention, even without major intra-abdominal volume increment. Bloating probably is a heterogeneous condition produced by a combination of pathophysiological mechanisms that differ among individual patients and that in most cases are subtle and undetectable by conventional methods. Further advances in the pathophysiology and clinical forms of bloating are warranted to develop mechanistic strategies rather than the current empiric treatment strategies for comprehensive and effective management of this problem. Bloating, like some other descriptors for abdominal sensations, is an ambiguous term that alludes both to the subjective sensation and to the objective abdominal distention. The ambiguity of the English term is shared by other languages. Furthermore, bloating means different things to different patients (and to their doctors). Some use the term bloating to refer to the sensation of a swollen/distended abdomen, and others use it to refer to the sensation of a full belly, the feeling of abdominal pressure or wall tension, or the sensation of excess gas. Yet others use it for various apparently unrelated sensations, such as needing to burp; nausea; crampy, gurgling, or rumbling stomach; or needing to go to the bathroom. Many patients with bloating, approximately 24%, report no visible abdominal distention. 1 As clinicians, when inquiring about bloating, do we really know what we are specifically asking the patient? In this review, we primarily focus on bloating, meaning the subjective sensation of abdominal distention, and, among other aspects, we will also address whether the subjective sensation of the patient corresponds with objective distention of the abdomen. In the current gold standard classification of functional gut disorders, abdominal bloating and distention are merely regarded as secondary descriptors. 2,3 Thus, patients with bloating as their predominant complaint are dispersed among different categories, such as functional dyspepsia and irritable bowel syndrome (IBS), and lumped together with nonbloating patients. 2,3 Only patients who do not meet the criteria that define these categories, ie, by exclusion, are categorized as having functional bloating. 3 In the past few years, various clinical studies have raised the significance of abdominal bloating as an important, troublesome, and poorly understood clinical problem. It is also highly prevalent. The sensation of abdominal bloating may affect 10% 30% of the population in community-based studies. 3 In a survey of US householders, 15.9% of the adult population reported abdominal bloating or distention within the month before the interview, and in more than 75% of them, the symptom was moderate or severe. 4 Bloating is one of the most common and bothersome complaints in a large proportion of patients with various functional gut disorders, such as functional dyspepsia 5,6 and IBS, 7 9 and it is frequently associated with constipation 10,11 and diarrhea. 1 The importance of bloating is placed in perspective by considering the enormous economic burden imposed by this type of functional gut disorder. 12 Abbreviation used in this paper: IBS, irritable bowel syndrome by the American Gastroenterological Association /05/$30.00 doi: /j.gastro

2 September 2005 ABDOMINAL BLOATING 1061 Despite its clinical, social, and economic importance, bloating remains substantially ignored, without a proper clinical classification, a known pathophysiology, or an effective treatment. 13 It is not even clear to what extent individual patients complaints of bloating correlate with objective evidence of abdominal distention, and the uncertainty regarding the subjective or the objective origin of the complaints further adds to the confusion. In summary, bloating is a common and highly significant clinical problem that remains to be scientifically addressed. Aims and Methods Our aim was to clarify the concept, clinical importance, and pathophysiology of abdominal bloating and, thereby, to pave the way for the comprehensive management of this problem. Specifically, we performed a critical analysis of the following topics: the pathophysiological mechanisms involved in bloating, the various forms of presentation of bloating in clinical practice, and the current treatment options for this heterogeneous condition. To this aim, a literature review was performed based on a PUBMED search over January 1989 to September 2004 on the following terms: abdominal bloating, IBS and intestinal gas, and IBS and flatulence. A total of 473 articles were identified. These articles, as well as chapters on intestinal gas in standard textbooks, served as literature sources for articles published before However, only articles relevant to the areas of controversy have been quoted. The experimental evidence available on this subject is scarce; hence, this review is necessarily, to some extent, based on theoretical analysis and the authors interpretation of existing data. References indicate the original source of information, but the referenced article may not necessarily support the concepts expressed. Pathophysiology of Bloating: Putative Factors and Mechanisms Four factors are included in the pathophysiology of bloating: subjective sensation, objective girth changes, volume of intra-abdominal contents, and muscular activity of the abdominal walls (Figure 1). The primer to elicit subjective bloating may be any of the other 3 factors, or the sensation may be related to distorted perception. These mechanisms, ie, abnormal perception, objective distention, intra-abdominal volume increment, and abdominal wall dystony, may play an independent role or may be interrelated. Indeed, objective abdominal distention, whether accompanied or not by a subjective Figure 1. Factors involved in bloating. Subjective bloating may be related to objective abdominal distention or to distorted perception. Objective abdominal distention may be due to increased abdominal contents or to intra-abdominal content redistribution. Intra-abdominal content may increase at the expense of either intraluminal or extraluminal volume. Changes in abdominal wall activity may induce a subjective sensation of bloating and/or objective abdominal distention due to content redistribution, even without a net increment in intraabdominal volume. sensation of bloating, may be due to changes in abdominal wall activity produced either by a real volume increment of abdominal contents or just by intra-abdominal content redistribution. Intra-abdominal content may increase at the expense of either intraluminal volume (ie, gas or liquid/solid gut content) or extraluminal volume (ie, tissue water increment due to edema or vascular congestion). Changes in abdominal wall activity, which are potentially related to viscerosomatic reflexes, may increase the tension of abdominal muscles, which may be subjectively interpreted as a bloating sensation but may also produce objective abdominal distention due to redistribution of intra-abdominal contents even in the absence of net changes in intra-abdominal volume. The experimental evidence, in terms of the amount of data, supporting each one of these possible mechanisms is frankly uneven and will be analyzed below. Most of the information available relates to the role of intestinal gas in bloating, because this has been the primary focus of experimental studies on this topic. Bloating, like many other abdominal symptoms, is probably a heterogeneous condition produced by a combination of pathophysiological mechanisms that differ among individual patients. The pathophysiology of bloating will be reviewed below by analyzing the relation of bloating to objective

3 1062 AZPIROZ AND MALAGELADA GASTROENTEROLOGY Vol. 129, No. 3 Table 1. Do Patients With a Bloating Sensation Have Objective Abdominal Distention? Study Method Result Poynard 20 Tape measure No Maxton 21 Tape measure Yes Maxton 21 Computed tomographic scan Yes Sullivan 22 Tape measure Yes Lea 25 Plethysmography Yes Lea 26 Plethysmography Variable a a Constipation-predominant yes; diarrhea-predominate no. distention, abdominal wall dystony, abnormal perception, and intra-abdominal contents. The latter issue is by far the best documented, including aspects on the role of intestinal gas, impaired handling of gut contents, the responsible area of the gut, and the intra-abdominal component that gives rise to bloating. Does the Subjective Sensation of Bloating Really Correspond With Objective Distention? This is a deceptively simple and key question, yet it is not easy to answer. Most patients indicate that their abdomen is or becomes episodically distended, and their claim is often corroborated by a proxy. However, the examining doctor may be mystified or uncertain and, in any case, unable to either prove or disprove the assertion. There are indeed patients whose abdomens appear to be truly distended. However, to show even the seemingly obvious may be difficult, because there are no practical office or bedside devices to reliably measure abdominal volume. Tape measures of abdominal girth have been shown to reproducibly detect even small changes in abdominal circumference induced experimentally by intestinal gas infusion However, tape measurement requires an immobilized patient fitted with a belt-type measuring device that remains in place during the entire experiment, and each individual serves as his or her own control. Measurements performed in the context of clinical research studies have not yielded uniform results (Table 1). A multicenter study evaluating patients with functional gut disorders (IBS and functional dyspepsia) failed to detect differences in abdominal circumference between those who reported visible abdominal distention and those who did not. 20 Using a tape measure, Maxton et al 21 showed that in women with IBS, girth significantly increased during the day. Furthermore, the anteroposterior diameter of the abdomen measured by computed tomography was also shown to increase during the day. 21 Another study reported that in patients with bloating, girth, but not weight, increased during episodes of visible abdominal distention. However, in this study, measurements were performed by the patients themselves, and the variability of the changes reported ( cm in girth and kg in weight; mean SD) was quite large. 22 More recently, automated methods have been developed to measure girth changes. 23,24 Preliminary results with an ambulatory technique using inductance plethysmography indicate that clinical variations in girth are significantly greater in IBS patients complaining of bloating than in healthy subjects. 25 However, the relationship of distention to subjective bloating is variable, showing a good correlation in constipation-predominant IBS patients, but not in diarrhea-predominant IBS. 26 Hence, it seems that subjective claims of distention represent true perceptions of a real event in a significant proportion of patients, but this may not be the case in many others. For one thing, some patients complain of bloating but readily acknowledge no physical evidence of abdominal distention. Others point toward a distended abdomen that the examining physician appreciates as normal. Finally, other patients, usually with persistent bloating, show a prominent, fatty abdomen associated with IBS-like symptoms that they interpret as secondary to gut distention. A prospective study reported that patients with bloating were more likely to have experienced recent weight gain than healthy controls, despite similar age, sex, and body mass index between groups. 22 Thus, fat accumulation in the abdomen may favor the development or awareness of bloating as a symptom. Abdominal wall activity. The shape of the abdomen is determined by the disposition of the walls of the abdominal cavity, specifically, the vertebral column, which determines the configuration of the posterior abdominal wall, the diaphragm, and the anterolateral musculature. The influence of the pelvic floor, with its limited mobility, is probably insignificant. Even without increments in intra-abdominal volume, a change in the relative position of the walls may produce visible, objective distention. Furthermore, signals arising from the abdominal wall for instance, because of a muscular dystony may induce a subjective sensation of abdominal bloating, even in the absence of true abdominal distention, and this could explain some cases of apparently imaginary bloating. Is a classic article, Alvarez 27 described in great detail a series of patients in whom pronounced abdominal distention was, in his view, related to the muscular activity of the abdominal wall. This hypothesis is substantiated by the fact that in some patients, visible abdominal distention has a very rapid onset 27,28 and resolves instantaneously by gentle abdominal palpation while asking the patient to relax, by anesthesia, 27 or by hypnotic

4 September 2005 ABDOMINAL BLOATING 1063 induction (Whorwell, personal communication, November 1995). Furthermore, distention may affect only part of the abdomen, and rapid resolution is not associated with gas evacuation. 27 However, experimental evidence of these abdominal wall hypotheses has been difficult to obtain. Computed tomography has failed to identify differences in lumbar lordosis and diaphragmatic position in patients with bloating. 21 It has also been reported that patients with bloating have weak abdominal muscles as compared with healthy controls. 22 In contrast, McManis et al 29 studied a group of patients with IBS and abdominal distention by means of surface electromyography and found that patients and healthy subjects alike increased electromyographic activity in the lower abdomen while standing compared with lying supine, but there were no differences between groups. Using a more elaborate technique and simultaneously recording the muscular activity at 8 different sites, we recently reproduced these results. 30 However, we were also able to show a dystonic response of the abdominal wall to intra-abdominal volume increments in patients with bloating. Intestinal gas retention modeled by rectal gas infusion during anal blockade increased the muscular tone of the abdominal muscles in healthy subjects in the upright position. Similar volumes of gas retention produced significantly greater objective abdominal distention and subjective symptoms in patients with bloating than in healthy subjects. Exaggerated abdominal distention in patients was associated with failed contraction of the abdominal musculature and even paradoxical relaxation of the internal oblique. 30 Animal studies have shown the relevance of viscerosomatic reflexes. For instance, chemical irritation of the colon in rats induces abdominal wall contractions that are inhibited by colonic distention. 31 Abnormal viscerosomatic reflex activity may also participate in the mechanism of abdominal distention and muscular wall dystony in patients with bloating. Abnormal perception. Abnormal perception related to cognitive interpretation, abdominal wall sensations, or visceral sensitivity is probably a key contributing factor to the sensation of abdominal bloating. Some patients with a normal or simply fatty abdomen, but with a distorted interpretation of reality, may believe, sometimes to the point of the obsession, that their abdomen is distended. Suarez et al 32 elegantly showed that people who regarded themselves as severely lactose intolerant and complained of bloating after consumption of even small amounts of dairy products, when specifically tested in a double-blind fashion, recorded negligible symptoms when consuming 250 ml of milk, whether it was lactose hydrolyzed or not. Hence, despite their conviction, the experimental evidence proved that customary milk-related symptoms in these patients had an imaginary origin. However, in other cases, altered perception seems to be due to genuine hypersensitivity with impaired modulation of sensory signals. 33 Hence, the bloating sensation could plausibly arise from a hypersensitive abdominal wall (for instance, in case of abdominal wall trauma, injuries, or scars) and may give the patient the sensation of increased abdominal wall tension, which is interpreted as bloating. This mechanism may contribute to postoperative bloating after laparotomy. Alternatively, the sensation may arise from abdominal viscera. Indeed, visceral hyperalgesia has been well characterized in patients with functional gut disorders, such as functional dyspepsia and IBS. 33 In these patients, physiological stimuli in the gut, normally unperceived, may induce abdominal symptoms specifically, bloating. Furthermore, probing stimuli in the laboratory, such as gut distention, tend to reproduce the customary symptoms, depending on the area on the gut stimulated, and in some patients they induce the sensation of bloating. 33 The area of the gut affected by the sensory dysfunction depends on the clinical syndrome. 34 It has been shown that patients with IBS have increased sensitivity in the large and the small bowel. 3,35 By contrast, in patients with functional dyspepsia, the stomach seems predominantly affected. Specifically, in a group of patients with postprandial bloating, gastric, but not duodenal, distentions induced an exaggerated perception and reproduced the customary bloating symptom. 36 It has been recently shown that in dyspeptic patients with postprandial symptoms (most of them with dysmotility-like dyspepsia and bloatingrelated symptoms), fundic distention reproduced the customary symptoms better than antral distention, whereas in dyspeptic patients with ulcer-like pain during fasting, antral distention replicated their usual symptoms more closely. 37 In other studies, using different selection criteria, intestinal hypersensitivity has been also shown in dyspeptic patients. 2 In patients with functional gut disorders, altered sensitivity combines with impaired control of gut motility, and both dysfunctions may interact to produce their symptoms. 33 This also applies to bloating. Basically, intraluminal trapping of contents causing focal distention in a hypersensitive area would have a synergistic effect in inducing the symptoms. Indeed, minor motility disturbances that do not compromise function may become clinically relevant and produce symptoms only in the presence of altered gut perception. Intra-abdominal contents. Abdominal distention and bloating may be due to a pooling of intraluminal

5 1064 AZPIROZ AND MALAGELADA GASTROENTEROLOGY Vol. 129, No. 3 Figure 2. Intestinal gas metabolism. Gas input results from swallowing, chemical reactions, diffusion from blood, and bacterial fermentation. Gas output is achieved by eructation, absorption, bacterial consumption, and anal evacuation. Gas transit determines the time of exposure for diffusion of gases across the gut blood barrier, as well as for bacterial consumption and, hence, may influence intestinal gas volume, composition, and tolerance. contents, tissue water increment in viscera, or even free intraperitoneal content, such as ascites. Of all elements within the abdominal cavity, intraluminal gas seems to be the most versatile. Given the characteristic rapid fluctuations of nonorganic bloating, intestinal gas has been, and is still considered, the most likely candidate to explain bloating, whereas other putative causes have received much less attention. The gas hypothesis. Little is known about intestinal gas homeostasis, but it seems to be a finely regulated process. Many studies on different populations using different methods have shown that despite the very large capacity of the entire gastrointestinal tract, the total volume of intraluminal gas amounts only to ml. 18,38 40 This fairly constant and relatively low volume is astonishing if one considers the diverse and complicated processes of gas input and gas output. 14 Physiological background. Gas input results from swallowing, chemical reactions, diffusion from blood, and bacterial fermentation. Gas output is achieved by eructation, absorption, bacterial consumption, and anal evacuation (Figure 2). Swallowing introduces a small amount of air into the stomach that is obviously much greater with gaseous beverages. Air in excess is eliminated from the stomach by belching, absorption, or emptying into the intestine. Chemical reactions specifically, neutralization of acids and alkalis in the upper gut produce enormous quantities of carbon dioxide, 41 which is absorbed in the small bowel. In the colon, intraluminal bacteria play a major role in gas metabolism by both producing and consuming large amounts of intraluminal gases, and their activity constitutes the determinant of anal gas output. The net effect of colonic flora on gas metabolism depends on the balance between gas-producing and gas-consuming microorganisms, which varies considerably among individuals. 14 The composition of the colonic microflora seems to be determined by early environmental conditions, but there may also be an adaptive component to alimentary habits later in life. 42,43 In approximately 90% of the general Western population, the colon harbors hydrogen-producing bacteria that ferment undigested substrates, particularly carbohydrates, and release hydrogen and carbon dioxide Part of the colonic flora consumes intraluminal gases, and this may account for a considerable proportion of intraluminal gas disposal Both hydrogen and carbon dioxide are consumed in large quantities, and oxygen that reaches the colon is partly consumed by aerobic bacteria, thereby reducing the intraluminal content of oxygen. Most individuals have a pool of sulfate-reducing bacteria that may be present throughout the colon. 46 These bacteria consume hydrogen and release very small amounts of sulfurcontaining gases (hydrogen sulfide and methanethiol) that are highly odoriferous. Approximately 30% of the population also has a pool of methanogenic bacteria in the left colon that consume large quantities of hydrogen and release methane. 46,47,49 51 Because of the competition for hydrogen of both bacterial pools, in these subjects sulfate-reducing bacteria are circumscribed to the right colon. 46 Intraluminal gases tend to equilibrate with the gases in venous blood, depending on 3 factors: the partial pressure of each gas at both sides of the gut-blood barrier, its diffusibility, and the time of exposure of the gas to the diffusible surface, that is, the speed of gas transit. 14,52,53 Hence, highly diffusible gases present in large quantities within the gut, such as carbon dioxide in the small bowel, are readily absorbed. Oxygen, coming from swallowed air, is also absorbed from the small intestine to equilibrate with its partial pressure in blood. The diffusibility of nitrogen is much lower, but still, a

6 September 2005 ABDOMINAL BLOATING 1065 Figure 3. The gas challenge test. To evaluate gut propulsion, gas is infused at a constant rate in the jejunum while anal gas outflow is measured. Objective abdominal distention and subjective sensations are simultaneously measured. large proportion of nitrogen in flatus may derive from blood. Part of the gases produced by colonic bacteria diffuse into the blood and are excreted by breath, where they can be detected by gas chromatography. 14 Indeed, approximately half of the hydrogen evacuated follows this pathway. 54,55 This is the basis for the hydrogen and methane breath tests. The remaining gases are eliminated by the anus. The composition of intraluminal gas varies greatly along the gut, and the composition of the anal outflow reflects the net balance of multiple processes within the gut lumen. 46 During basal conditions, nitrogen accounts for most of the volume in flatus, but after consumption of meals rich in fermentable carbohydrates, hydrogen, carbon dioxide, and methane (in producers) markedly rise and predominate. The amount of oxygen, the other major component in flatus, is fairly low (approximately 10%). Various other gases are also present in trace quantities. 14 It is important to remember that gas transit determines the time of exposure for diffusion of intraluminal gases across the gut blood barrier, as well as for bacterial consumption, and, hence, may influence not only the volume of gas in the gut, but also the final composition of gas in flatus. 56 Intestinal gas transit and tolerance have been measured by using a gas challenge test. The test consists of an infusion of a mixture of gases, in various proportions to minimize absorption, into the jejunum while anal gas output is quantified (Figure 3). A dose response study showed that most healthy subjects propel and evacuate as much gas as is infused, up to 30 ml/min, without discomfort. 17 Hence, gas transit is finely adapted to a very broad range of intestinal gas loads, but the type of motor activity that determines gas transit is not known. Gas infusion does not induce detectable changes in small-bowel intestinal motility recorded by manometry. 57 In contrast, preliminary experiments with the barostat suggest that gas infusion induces tonic changes: a contraction orad to the infusion site and a relaxation distal to the collection site. 58 Conceivably, movement and displacement of large masses of low-resistance gas are produced by changes in tonic activity and capacitance of the gut. 59 Gas boluses infused into the left colon have been shown to elicit forceful peristaltic contractions preceding small gas expulsion, 60 but this type of phasic event has not been recorded during continuous gas infusion with a barostat located inside the rectum. 58 Hence, these phasic events could be a response to focal distention produced by abrupt intraluminal gas delivery. Do Patients With Bloating Produce More Intestinal Gas? As described previously, gas production is determined by 2 main factors: the amount of fermentable foodstuffs that escape small-bowel absorption and enter the colon and the composition of the colonic flora. Thus, bloating may be a clinical feature of malabsorption disorders in which excessive amounts of unabsorbed substrates are fermented in the colon. Under special circumstances, such as bacterial overgrowth, abnormal fermentation of foodstuffs may take place within the small bowel. In both of these situations, intestinal malabsorption and bacterial overgrowth, bloating, and other gas symptoms usually constitute a minor part of the clinical presentation and, hence, are of limited clinical relevance. The real challenge in clinical practice is individuals who complain of gas symptoms without detectable abnormalities by conventional testing, that is, patients with functional gastrointestinal disorders or, more precisely, with disorders of gastrointestinal function. 3 Whether some degree of nutrient malabsorption plays a role in patients with functional bloating remains doubtful. Some studies suggest that the absorption capacity of certain substrates in the small bowel is reduced in IBS patients However, other studies did not replicate these results. 64,65 Furthermore, it has been shown that people with proven lactose malabsorption tolerate 250 ml of milk without symptoms because the colon is able to deal with a certain amount of unabsorbed substrates via fermentation and absorption of short-chain fatty acids and absorption/consumption of gases. 32 Because the definition of malabsorption is somewhat ambiguous, some investigators have explored the effect of exclusion diets on bloating. Again, the results have been inconclusive. 66 Furthermore, potential beneficial effects

7 1066 AZPIROZ AND MALAGELADA GASTROENTEROLOGY Vol. 129, No. 3 Table 2. Do Patients With Bloating Produce More Intestinal Gas? Study Method Result Lasser 67,68 Washout No Haderstorfer 69 Breath test No King 54 Calorimetry Yes a Pimentel 70 Breath test Yes a Hydrogen production was larger, but total gas (hydrogen plus methane) production was not different from that in controls. of excluding offending foodstuffs may not necessarily imply excess fermentation, because other possible pathophysiological mechanisms, such as allergic or atopic reactions, may be involved. In a brilliant series of studies in the 1970s, Levitt 38 measured intestinal gas production by using a washout technique. In these studies, gas was measured by infusing argon into the intestine at a relatively high flow rate (40 ml/min) and recovering rectal gas. During fasting, with no nutrients arriving into the colon, gas production was similar in healthy subjects and IBS patients 67 (Table 2). A single study, published only in abstract form, reported on postprandial gas production and showed no differences between patients with bloating and healthy controls. 68 Evaluation of intestinal gas production by breath tests has yielded conflicting results (Table 2). In one study, intestinal hydrogen production was measured during waking hours for 7 days in IBS patients with bloating and in a group of healthy controls. Breath hydrogen concentration was found to be similar in both groups, despite significantly higher rates of bloating in patients during the test period. 69 Furthermore, breath hydrogen concentrations did not correlate with symptoms of bloating. In contrast, another study measuring total excretion (breath plus anal) by indirect calorimetry showed that on a standard diet, IBS patients excreted more hydrogen than healthy subjects. This suggests that patients might have a hyperactive gas-producing colonic flora. 54 However, some subjects produced methane as well as hydrogen, and when the total volume excreted (hydrogen plus methane) was measured, no difference was found between both groups. A third research line showed that the proportion of abnormal lactulose breath tests in IBS patients was higher than that in healthy controls; this was attributed to small-bowel bacterial overgrowth because oral neomycin normalized the breath test and reduced IBS symptoms more than did placebo. 70 This interpretation has been questioned: it has been argued that the reliability of the lactulose breath test to diagnose small-bowel bacterial overgrowth is uncertain, that the reported symptom response to antibiotic therapy was relatively poor, and that the placebo response was unusually low compared with other studies. 71 In any event, it is important to point out that increased intestinal gas production (or reduced consumption), be it due to malabsorption, hyperactive colonic flora, or bacterial overgrowth, would likely result in flatulence, but not necessarily bloating, because most healthy subjects are able to propel and evacuate very large gas loads without perception of abdominal distention. 17,32 Hence, other factors should be also operating to produce bloating. Intraluminal gas volume. In their early studies with the washout technique, Lasser et al 67,68 showed that the amount and composition of intestinal gas in IBS patients was similar to that of healthy subjects (Table 3). Using a similar technique, we did not find significant differences in intestinal gas volume among patients complaining of abdominal bloating and healthy controls. 18,39 Two separate studies using plain abdominal radiographs 72,73 concluded that intra-abdominal gas content was larger in IBS patients than in healthy subjects (by 54% and 118%, respectively), but no significant correlation between gas content and symptoms was found. The method was shown to be technically reproducible, but changes in body position from upright to supine increased the estimated gas content by 67%. 72 A multicenter study using abdominal plain x-ray films taken 1 to 2 hours after breakfast or lunch found a larger (approximately 28%) total gas area in patients with IBS complaining of visible abdominal distention as opposed to patients who did not. 20 However, the correlation between the abdominal gas content and the usual intensity of distention was poor. It is interesting to note that no difference was found between patients with and without abdominal distention when their symptoms were more typical of functional dyspepsia than of bloating. Because the total intraluminal gas volume in IBS, measured by independent studies, is only ml, 18,39,67,68 the percentage differences reported by these 3 studies would account for a relatively small difference in absolute volume. In fact, a computed tomography study of intestinal gas could not detect significant differences between con- Table 3. Do Patients With Bloating Have More Gas Volume Within the Gut? Study Method Result Lasser 67,68 Washout No Serra 39 Washout No Caldarella 18 Washout No Chami 72 X-ray film Yes Koide 73 X-ray film Yes Poynard 20 X-ray film Yes Maxton 21 Computed tomographic scan No

8 September 2005 ABDOMINAL BLOATING 1067 Figure 4. Severity of symptoms induced by infusion of gas into the jejunum of healthy subjects and patients complaining of excessive gas, abdominal pain, and bloating (reprinted with permission 67 ). trols and patients with significant daytime girth increments and bloating. 21 These data suggest that clinical bloating may not be simply the result of too much intestinal gas, but rather that other factors, ie, abnormal gas handling and distribution within the gut, may be involved. Impaired gut handling. Conventional studies on gut motility and transit of chyme have failed to detect consistent abnormalities that could explain bloating. However, studies on intestinal gas transit and tolerance suggest that patients with bloating have impaired intestinal handling of gas loads. 18,19,39,67 These gas transit studies may be of particular relevance by disclosing gut propulsive abnormalities that, in conjunction with sensory abnormalities, probably constitute the pathophysiological basis of bloating. Only a very small proportion of healthy individuals (approximately 15%) show impaired handling and increased perception of intestinal gas. 17 If this fraction of the otherwise healthy population were to be challenged with a gas overload, they would experience abdominal symptoms. 17 Likewise, increased colonic gas formation, experimentally induced by direct infusion of starch into the colon, produces abdominal symptoms only in a small fraction of healthy subjects. 74 A similar effect can be observed in the case of experimental malabsorption induced by amylase inhibitors. 75 These findings suggest that some people are prone to bloating, but this symptom may develop only under special circumstances. In their seminal work with the washout technique, Lasser et al 67 noted that a proportion of patients with bloating and related symptoms did not tolerate the procedure (Figure 4), and in some of them the infused gas refluxed into the stomach. This was interpreted as an indication of some kind of gut motor dysfunction. Using a gas challenge test, we later showed that bloating patients who met Rome II criteria for either IBS or functional bloating diagnoses had impaired transit and tolerance of intestinal gas. 18,19,39 These patients retained gas and/or experienced abdominal discomfort in response to intestinal gas loads that are well tolerated by most healthy individuals (Figure 5). Furthermore, the gas challenge reproduced their customary symptoms. In these experiments, patients also developed objective abdominal distention that correlated with the volume of gas retained in their guts. Mechanisms of impaired gas handling. The mechanism of gas retention in such patients remains unknown. However, in healthy subjects, 2 mechanisms have been experimentally shown to be involved in intestinal gas retention: increased resistance to gas flow, modeled by self-restraint anal gas evacuation; and impaired intestinal propulsion, produced by glucagon-induced motor inhibition 76 (Figure 6). By using the gas challenge test, it was shown that gas retention produced by impaired propulsion induced objective abdominal distention, which was well tolerated. However, when gas retention and objective distention were produced by increased resistance to flow, subjective abdominal complaints were much higher than when gas retention was induced by pharmacological inhibition of propulsion. Hence, abdominal distention depends largely on the volume of gas retained, but abdominal discomfort likely relates more directly to uncoordinated intestinal motility rather than to weak propulsion. Conceivably, small gas Figure 5. Individual responses (perception and gas retention) to a gas challenge test (12 ml/min jejunal gas plus 0.5 kcal/min duodenal lipids for 120 minutes). Healthy subjects tolerated the challenge test with low perception and retention. In contrast, patients who complained of bloating had impaired gut handling and fell outside the normal ranges. Reprinted with permission. 18

9 1068 AZPIROZ AND MALAGELADA GASTROENTEROLOGY Vol. 129, No. 3 Figure 6. Mechanisms of gut retention and intraluminal pooling. Retention can be due to a high-resistance barrier obstructing flow or to impaired propulsion. Symptom perception depends on the mechanism of retention: at the same volumes, flow obstruction produces more symptoms than impaired propulsion, but objective abdominal distention is similar. bubbles pushed against high-resistance barriers may increase intestinal wall tension and produce symptoms. Furthermore, if several bubbles are trapped at different levels, perception would increase by spatial summation phenomena. 77 In healthy subjects, voluntary anal contraction has been shown to effectively retain gas. 76 In most bloated patients, gas retention and symptoms during the gas challenge test were similar whether gas was collected by an external cannula or by an intrarectal cannula that bypassed the anal gate. 39 Nevertheless, in clinical practice, there are patients in whom the anus probably contributes to gas retention, either because of poor anal relaxation (functional outlet obstruction; see below) or voluntary inhibition of anal flatus as a result of social or psychological interferences. Reflex control. Further data suggest that impaired gas transit in patients with unexplained bloating is the result of abnormal reflex control. Gas transit is regulated by viscerovisceral reflexes that operate along the gastrointestinal tract. 58,78 Intraluminal lipids dosedependently delay gas transit and induce retention of exogenous gas loads. 19 Lipids seem more effective when infused into the ileum than into the duodenum, in consonance with the activation of the ileal brake mechanism that regulates the transit of solid/liquid chyme. 79 By contrast, other reflexes speed gas transit. For instance, gastric distention produces an immediate evacuation of the endogenous gas present in the gut and accelerates the transit of exogenous gas loads, thus suggesting the release of gastrocolic reflexes. 78 However, the gastrocolic reflex seems to be part of a more generalized reflex phenomenon, because distention performed at various levels of the gut, such as the duodenum or the rectum, produces the same stimulatory effect. 58,78 Furthermore, focal gut distention antagonizes the inhibitory effect of lipids. 58,78 It has been shown that intestinal gas clearance is enhanced in the erect position 80 and during mild physical activity 81 ; this suggests that somatovisceral reflexes may also participate in the regulation of intestinal gas transit. Conceivably, under physiological conditions, different types of reflexes interact to produce a net final effect. It has been shown that the slowing effect of lipids is up-regulated in patients with bloating, 19 whereas the accelerating effect of distention is markedly impaired. 82 Indeed, the gas challenge test, in conjunction with intraluminal lipid infusion, provides a clear-cut distinction between IBS/bloated patients and healthy subjects: patients retain large volumes of gas and or report symptoms, thus indicating that gas propulsion may be ineffective or symptomatic. 19 Which Area of the Gut Gives Rise to Bloating? In healthy subjects, gas tolerance depends on the site of retention. In a model of gas retention modeled by infusion during blocked anal gas outflow, it was shown that similar volumes of gas retention produced significantly more abdominal symptoms with jejunal than with rectal gas infusion, whereas abdominal distention was similar. 83 Scintigraphic imaging using xenon 133 to label gas showed that gas infused into the jejunum predominantly accumulated in the small bowel and proximal colon, whereas gas infused per rectum largely accumulated in the distal colon. 83 These data indicate that gas-related symptoms are determined by intestinal gas distribution, whereas abdominal distention depends on the total volume of gas retained in the gut. Xenon-133 scintigraphy has been also used to investigate segmental gas transit. In healthy individuals, total gut transit of gas was expeditious, and, interestingly, small-intestinal transit time was similar to colonic transit time. Hence, in contrast to solids and liquids, the speed of intestinal gas clearance is equally determined by the passage time through the small-intestinal and colonic compartments. Using the gas challenge technique, we have shown that in patients with bloating, intestinal gas clearance is delayed because of impaired small-intestinal propulsion, whereas colonic transit is normal. 84 These data were confirmed by measuring the responses to gas directly infused at different levels of the gut via an intraluminal catheter. These responses showed that patients retained gas infused into the jejunum, but not infused into the ileum or cecum. 84 Hence, the ileocolonic junction does not seem to be responsible for gas retention, and, altogether, these data point toward the prox-

10 September 2005 ABDOMINAL BLOATING 1069 imal small bowel, rather than the colon, as the source of symptoms in patients complaining of abdominal bloating. Indeed, large amounts of carbon dioxide are physiologically produced from neutralization of acids in the proximal small bowel. 14,41 Carbon dioxide is rapidly absorbed into the bloodstream, but the luminal fraction may still overflow an incompetent intestine and produce symptoms. At the same time, it would seem reasonable to contemplate other possibilities. For instance, patients with increased gas production who are unwilling or unable to expel excess gas may accumulate gas in the colon. Conceivably, the area of the gut in which bloating originates also depends on the clinical features. Indeed, postprandial bloating in dyspeptic patients may originate in the stomach. 36,37 Normally, a meal largely accommodates in the proximal stomach, partly because antral filling induces a fundic relaxatory reflex. Additionally, when gastric emptying starts, intestinal nutrients induce enterofundic relaxatory reflexes that control the accommodation process over the postprandial period. Dyspeptic patients show impaired enterofundic and antrofundic relaxatory reflexes, and this may result in defective fundic accommodation, with distal displacement of intragastric contents and antral overload. 37 Furthermore, these patients show increased gastric perception, which also affects the antrum. 37 The mixed sensory motor dysfunction, leading to overdistention of a hypersensitive antrum, may explain the genesis of dyspeptic bloating independently of gas transit in the bowel. Gas or No Gas: Which Is the Key Offending Element? Gas transit studies in patients with unexplained bloating have evidenced a failure of gut propulsive motility associated with increased perception, which, in some way, seems to play a pathophysiological role in their abdominal symptoms. However, the triggering factor of bloating may not be invariably gas, but other element(s) of gut content. Bloating may be a prominent feature in the absence of increased gas production. Levitt et al 85 nicely showed the disparities between bloating and flatulence by observing the responses of healthy subjects to oral loads of either lactulose or 2 types of fiber (psyllium and methylcellulose). Lactulose, which is not absorbed in the small intestine and is fermented in the colon, releasing hydrogen, induced flatulence, a sensation of rectal gas, and bloating. It is interesting to note that neither fermentable (psyllium) nor nonfermentable (methylcellulose) fiber produced hydrogen release detectable by the breath test and did not induce flatulence or rectal gas sensation but still induced the sensation of abdominal bloating. The authors concluded that bloating associated with experimental fiber overload presumably reflects an increased intraluminal mass. Increased intestinal fluid content may also be an important cause of bloating under some circumstances, for instance, in acute diarrheal conditions and perhaps in some instances of postprandial bloating. However, data on the transit of chyme in the small bowel in relation to bloating are inconsistent and show both accelerated 86 and delayed 87 transit. It has been hypothesized that the terminal ileum and the ileocolonic junction play a special role in the regulation of chyme transit. However, specific studies on ileocecal transit have also yielded contradictory results, 88,89 although chyme arrival to the cecum seems temporarily related to symptoms. 87 In some patients, intestinal infusion of nutrients reproduces customary postprandial bloating and visible abdominal distention. They may constitute a specific subset of patients, different from typical dyspepsia and IBS, but data available on this condition are too scanty to allow even speculative conclusions. Abdominal bloating and distention may also derive from an expansion in extraluminal water content in the abdominal cavity. Vascular ingurgitation and visceral edema, conceivably under neurohormonal influences, could be involved in some forms (for instance, menstrual bloating), but this possibility has not been explored and stands only on a theoretical basis. An Integrative Overview Bloating may be produced by different mechanisms. The pathophysiology of bloating may be evident, for instance, in case of intra-abdominal volume increment, but in most patients, the dysfunction that leads to bloating is more subtle and difficult to detect by conventional methods. Gas transit studies have evidenced that patients with bloating have impaired reflex control of gut handling of contents (Figure 7). Segmental pooling, either of gas or of solid/liquid components, may induce a bloating sensation, particularly in patients with altered gut perception. Gut stimuli induce viscerosomatic reflexes to adapt the abdominal wall to its content, and some data indicate that patients with bloating also have affected viscerosomatic reflexes that lead to abdominal wall dystony and abnormal protrusion (Figure 7). Clinical Presentation General Clinical Features Abdominal bloating presents some characteristic and well-recognized features, but given the scarcity of

11 1070 AZPIROZ AND MALAGELADA GASTROENTEROLOGY Vol. 129, No. 3 Figure 7. Pathophysiology of bloating. Bloating may be produced by intra-abdominal volume increment, but in most cases the dysfunction is more subtle and multifactorial. Impaired reflex control of gut handling of contents may result in segmental pooling and bloating sensations, particularly in patients with altered gut perception. Impaired viscerosomatic reflexes may lead to abdominal wall dystony and distention, even without major increments in intra-abdominal volume. systematic investigations, data are mostly based on physicians impressions. Recently, Whitehead s group (personal communication, December 2003) has initiated a large-scale study to characterize the diverse clinical presentations of bloating; this study may yield useful information. Bloating, as with most functional gastrointestinal symptoms, is much more frequent in women than in men. 1,4 The severity of bloating may vary from very mild to severe and uncomfortable. 4 An important aspect of the anamnesis is to discriminate whether bloating is uncomfortable/painful or whether the patient has associated but separate abdominal discomfort or pain. 7,8 It is also important to record the patient s own impression about the presence and severity of objective abdominal distention. 1 Bloating may be localized in the upper abdomen (sometimes associated with dyspeptic symptoms) or in the lower abdomen, as part of IBS or related syndromes. Of course, a large overlap exists, and many patients describe bloating of the entire abdomen. 1,28 Bloating may be related to food intake. A substantial number of patients with bloating, up to 82%, describe that it develops or worsens in the early postprandial period. 28 Some patients complain of even being unable to complete a full meal because of bloating. This effect is more pronounced when eating large and specially fatty meals. Postprandial bloating is a characteristic feature in specific subgroups of patients, such as those with dyspepsia and binge eaters (see below). Some patients claim specific food intolerances in connection with bloating, 1 but the putative mechanism of the intolerance, or even whether this is real or imaginary, remains unclear. Highfiber foods or fiber supplements are frequently reported to worsen bloating, in consonance with the experimental findings of Levitt et al 86 described previously. Dairy products are frequently reported as deleterious, but only an undetermined fraction of these cases are due to genuine lactose intolerance, particularly when intolerance occurs in response to low quantities of dietary lactose. 32 Fatty foods and carbonated drinks are also frequently reported as offending. Both of these possibilities are supported by some experimental evidence, as described previously, but in some patients the relation may actually be based on imaginary assumptions. Food intolerances may be related to atopic phenomena, but most likely this is an uncommon occurrence. Circadian variations are a common feature of bloating. 1,21,28 In most patients, bloating progressively develops during daily activity and tends to diminish or disappear after night rest. This probably has a physiological basis, because continuous measurement of girth in healthy subjects has shown that girth progressively increases during the day and returns to basal at night. 24,25 Meals are another factor that has been shown to increase girth in healthy subjects. 24 Girth is also larger in the upright position than in the supine position, 24 and likewise, bloating tends to be alleviated by lying down, 28 which may point to a contribution from the abdominal musculature. Stress is reported by some patients (approximately one third in one study) to worsen bloating, 28 and patients tend to feel better when relaxed. 1 In some patients, bloating is associated with tiredness and difficulties sleeping, and these symptoms altogether impair quality of life. No clear mechanism has been elucidated. Some patients characteristically describe a rapid onset of bloating after a precipitating event: 60 seconds in 35% and 10 minutes in another 26%. 28 Such abrupt development would fit with either a vascular or muscular mechanism of bloating, but this remains purely speculative. Abdominal rumbling is a frequent associated feature, but passing flatus or stool does not necessarily alleviate bloating. 1,28 In up to 40% of women, bloating gets worse before and during the menstrual period. 1,90 Furthermore, bloating is one of the most frequent menstrual symptoms. 91